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2021 guidelines have made important revisions to the diagnostic criteria for CIDP.
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CIDP is classified as typical or variant (distal, multifocal/focal, motor or sensory).
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Each type of CIDP has specific clinical and electrodiagnostic criteria.
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May upgrade diagnosis of possible CIDP to CIDP if ≥2 supportive criteria are present.
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Guideline use is likely to aid in the differential diagnosis of CIDP and its variants.
Abstract
The 2021 guideline of the European Academy of Neurology/Peripheral Nerve Society on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) includes important revisions to the previous 2010 guideline. This article highlights the new criteria and recommendations for the differential diagnosis of CIDP. In the revised guideline, the CIDP spectrum has been modified to include typical CIDP and four well-characterized CIDP variants, namely distal, multifocal/focal, motor and sensory CIDP, replacing the term ‘atypical’ CIDP. To improve the diagnosis of CIDP, the revised guideline attempts to improve the specificity of the diagnostic criteria for typical CIDP and the four CIDP variants. Specific clinical and electrodiagnostic (including both motor and sensory conduction) criteria are provided for typical CIDP and each of the CIDP variants. The levels of diagnostic certainty have been changed to CIDP and possible CIDP, with the removal of probable CIDP (due to the lack of difference in the accuracy of the electrodiagnostic criteria for probable CIDP) and definite CIDP (due to the lack of a gold standard for diagnosis). If the clinical and electrodiagnostic criteria allow only for a diagnosis of possible CIDP, cerebrospinal fluid analysis, nerve ultrasound, nerve magnetic resonance imaging, objective treatment response, and nerve biopsy can be used as supportive criteria to upgrade the diagnosis to CIDP. Although the revised guideline needs to be validated and its strengths and weaknesses assessed, using the guideline will likely improve the accuracy of diagnosis of CIDP and variants of CIDP, and aid in distinguishing CIDP from conditions with similar features.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a term for a syndrome or group of disorders although it does not include all immune demyelinating neuropathies. In the late 1970s, the term CIDP was coined to distinguish it from, but also relate it to, acute inflammatory demyelinating polyneuropathy, the most common form of Guillain-Barré syndrome (GBS).
A joint taskforce of the European Federation of Neurological Societies (EFNS) and the Peripheral Nerve Society (PNS) published their initial guideline on the management of CIDP in 2005 [
European Federation of Neurological Societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the peripheral nerve society.
European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision.
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision.
] has been the gold standard for diagnosis and treatment of CIDP. Criteria published in the 2010 guideline have been used for patient enrolment in almost all clinical trials of CIDP [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Using available clinical evidence, the guideline taskforce attempted to make practical sense of the diagnosis and management of typical CIDP and its variants. Major changes to the diagnostic terminology include replacing the term ‘atypical’ CIDP with four well-characterized CIDP variants, and specifying clinical, electrodiagnostic and supportive diagnostic criteria for typical CIDP and each CIDP variant [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
The diagnosis of CIDP in patients who present with weakness and sensory disturbances is often complex, and involves distinguishing it from other conditions that mimic CIDP [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Traditionally, CIDP was viewed as a single neuropathy that was distinct from other neuropathies such as GBS, monoclonal gammopathy of undetermined significance (MGUS), POEMS (polyneuropathy- organomegaly-endocrinopathy-M-protein-skin changes) syndrome, multifocal motor neuropathy (MMN) and vasculitis. A more modern view recognizes several subgroups within the CIDP spectrum. In 2019, Bunschoten et al. proposed a spectrum that included typical CIDP and distal, multifocal/focal, motor and sensory CIDP variants, with some overlap with immunoglobulin IgG4 nodal-paranodal antibody neuropathies and monoclonal gammopathies [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Fig. 1Changes in the spectrum of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on the 2021 second revision of the European Academy of Neurology/Peripheral Nerve Society guideline [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Red text/ovals indicate changes made in the 2021 guideline. Ig immunoglobulin, MAG myelin-associated glycoprotein, MGUS monoclonal gammopathy of undetermined significance. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Acute-onset CIDP continues to be included as a subtype of typical CIDP. Conversely, autoimmune nodopathies [i.e., antibodies against contactin associated protein 1 (Caspr1), contactin 1 (CNTN1), neurofascin (NF)-186 and NF155], anti-myelin associated glycoprotein (MAG) neuropathy, POEMS syndrome and MMN are not included as part of the CIDP syndrome (Fig. 1), as they have distinct clinical, laboratory, electrodiagnostic, pathological and treatment features [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
] is also currently considered to be separate from CIDP (Fig. 1), as it is not clearly a demyelinating CIDP variant, and requires further investigation [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
], the term ‘typical CIDP’ is retained but the term ‘CIDP variants’ replaces ‘atypical CIDP’, with well-characterized CIDP variants —distal, multifocal/focal, pure motor and pure sensory CIDP (Fig. 1) — being added. All forms of CIDP have some common features, including progression or relapse over a period of >8 weeks, areflexia, nerve changes indicative of segmental demyelination and, generally, a response to immunomodulation with intravenous immunoglobulin (IVIg), corticosteroids or plasma exchange. However, the pathogenic mechanisms and clinical presentation may differ between variants, with each form having some unique characteristics that modify their differential diagnosis. To that end, the 2021 guidelines include tables of differential diagnostic considerations for each variant as well as tables that advise on diagnostic investigations useful in evaluating each potential variant (Table 1, Table 2 and Fig. 2).
Table 1Red flags and examples of potential alternative diagnoses for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on the second revision of the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Especially the presence of contactin-associated protein 1 (Caspr1), neurofascin (NF) 155 or contactin (CNTN) 1 IgG4 antibodies. Autoimmune nodopathies is the term proposed by the EAN/PNS taskforce for conditions associated with antibodies against these nodal-paranodal cell-adhesion molecules. These conditions are also referred to as nodo-paranodopathies.
); diabetes (possible diabetic NP); IgA or IgG monoclonal gammopathy (possible multiple myeloma, AL amyloidosis, POEMS syndrome)
GBS; multiple myeloma; osteosclerotic myeloma; POEMS syndrome; AL amyloidosis, ATTRv-PN; HIV-related NP; hepatic NP; uraemic NP; actual or functional vitamin B12 deficiency, autoimmune nodopathy
Especially the presence of contactin-associated protein 1 (Caspr1), neurofascin (NF) 155 or contactin (CNTN) 1 IgG4 antibodies. Autoimmune nodopathies is the term proposed by the EAN/PNS taskforce for conditions associated with antibodies against these nodal-paranodal cell-adhesion molecules. These conditions are also referred to as nodo-paranodopathies.
Especially the presence of contactin-associated protein 1 (Caspr1), neurofascin (NF) 155 or contactin (CNTN) 1 IgG4 antibodies. Autoimmune nodopathies is the term proposed by the EAN/PNS taskforce for conditions associated with antibodies against these nodal-paranodal cell-adhesion molecules. These conditions are also referred to as nodo-paranodopathies.
Also known as Lewis-Sumner syndrome, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), multifocal acquired demyelinating NP with persistent conduction block, multifocal inflammatory demyelinating NP.
Pain (possible diabetic radiculopathy/plexopathy, neuralgic amyotrophy); normal sensation (possible MMN); only 1 nerve in 1 limb affected (possible nerve entrapment/tumour); family history of HNPP; signs of vasculitis (possible vasculitis NP)
Dyspnoea, dysarthria and dysphagia (possible MND, myasthenia gravis); family history of hereditary motor NPs; asymmetrical weakness at onset (possible MMN); elevated serum creatine kinase levels (possible myositis)
Family history of hereditary motor NP; diabetes (possible diabetic NP); vitamin B12 deficiency, chemotherapy (possible sensory neuronopathy); IgM monoclonal gammopathy (possible anti-MAG NP); normal motor and sensory conduction (possible CISP)
CANVAS; CISP; dorsal column lesions (due to paraneoplastic syndromes, syphilis, or copper or vitamin B12 deficiency); hereditary sensory NPs; idiopathic sensory NP; sensory NP; toxic NPs (e.g., due to chemotherapy or vitamin B6 toxicity)
a Especially the presence of contactin-associated protein 1 (Caspr1), neurofascin (NF) 155 or contactin (CNTN) 1 IgG4 antibodies. Autoimmune nodopathies is the term proposed by the EAN/PNS taskforce for conditions associated with antibodies against these nodal-paranodal cell-adhesion molecules. These conditions are also referred to as nodo-paranodopathies.
b Also known as distal acquired demyelinating symmetric NP (DADS).
c Also known as Lewis-Sumner syndrome, multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), multifocal acquired demyelinating NP with persistent conduction block, multifocal inflammatory demyelinating NP.
Table 2Summary of clinical and electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on the second revision of the European Academy of Neurology/Peripheral Nerve Society guideline [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Features strongly supportive of demyelination include ≥1 of the following: motor distal latency ↑ to ≥50% above ULN in 2 nerves (except that due to carpal tunnel syndrome); ↓ in motor conduction velocity to ≥30% below the LLN in 2 nerves; ↑ in F-wave latency to ≥20% of ULN (≥50% if the amplitude of distal negative peak CMAP <80% of LLN); absence of F-waves in 2 nerves (in nerves with a distal negative peak CMAP amplitude ≥20% of LLN) + ≥1 other demyelinating parameter in ≥1 other nerve; motor conduction block (≥30% ↓ of the proximal relative to distal negative peak CMAP amplitude, excluding the tibial nerves, and distal negative peak CMAP amplitude ≥20% of LLN in 2 nerves; or in 1 nerve + ≥1 demyelinating parameter in ≥1 other nerve except absence of F-waves in ≥1 other nerve); abnormal temporal dispersion (>30% ↑ in duration between the proximal and distal negative peak CMAP in ≥2 nerves [≥100% ↑ in the tibial nerve]); or distal CMAP duration ↑ in ≥1 nerve (median, ulnar, peroneal and tibial values at low frequency filter bandpass of 2, 5, 10 or 20 Hz) + ≥1 other demyelinating parameter in ≥1 other nerve.
Sensory conduction abnormalities include ≥1 of the following in 2 nerves: ↑ in distal latency; ↓ SNAP amplitude, or slowed conduction velocity outside of normal limits.
Typical CIDP
Symmetrical in 4 limbs, proximal and distal
In ≥2 limbs
Met in ≥2
Abnormal in ≥2
Typical CIDP
Met in 1
Abnormal in ≥2
Possible typical CIDP (upgrade to typical CIDP if 2 SC
Normal motor nerve conduction studies plus either: sensory nerve conduction velocity < 80% of LLN (for SNAP amplitude >80% of LLN) or < 70% of LLN (for SNAP amplitude <80% of LLN) in ≥2 nerves (median, ulnar, radial, sural nerve); or sural sparing pattern (abnormal median or radial SNAP with normal sural nerve SNAP) [excluding carpal tunnel syndrome].
a Features strongly supportive of demyelination include ≥1 of the following: motor distal latency ↑ to ≥50% above ULN in 2 nerves (except that due to carpal tunnel syndrome); ↓ in motor conduction velocity to ≥30% below the LLN in 2 nerves; ↑ in F-wave latency to ≥20% of ULN (≥50% if the amplitude of distal negative peak CMAP <80% of LLN); absence of F-waves in 2 nerves (in nerves with a distal negative peak CMAP amplitude ≥20% of LLN) + ≥1 other demyelinating parameter in ≥1 other nerve; motor conduction block (≥30% ↓ of the proximal relative to distal negative peak CMAP amplitude, excluding the tibial nerves, and distal negative peak CMAP amplitude ≥20% of LLN in 2 nerves; or in 1 nerve + ≥1 demyelinating parameter in ≥1 other nerve except absence of F-waves in ≥1 other nerve); abnormal temporal dispersion (>30% ↑ in duration between the proximal and distal negative peak CMAP in ≥2 nerves [≥100% ↑ in the tibial nerve]); or distal CMAP duration ↑ in ≥1 nerve (median, ulnar, peroneal and tibial values at low frequency filter bandpass of 2, 5, 10 or 20 Hz) + ≥1 other demyelinating parameter in ≥1 other nerve.
b Sensory conduction abnormalities include ≥1 of the following in 2 nerves: ↑ in distal latency; ↓ SNAP amplitude, or slowed conduction velocity outside of normal limits.
c Includes objective treatment response and findings from nerve ultrasound, nerve MRI, nerve biopsy and cerebrospinal fluid.
d Normal motor nerve conduction studies plus either: sensory nerve conduction velocity < 80% of LLN (for SNAP amplitude >80% of LLN) or < 70% of LLN (for SNAP amplitude <80% of LLN) in ≥2 nerves (median, ulnar, radial, sural nerve); or sural sparing pattern (abnormal median or radial SNAP with normal sural nerve SNAP) [excluding carpal tunnel syndrome].
Fig. 2Summary of key steps in the differential diagnosis of typical and variant chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on the 2021 second revision of the European Academy of Neurology/Peripheral Nerve Society guideline [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. In the figures, green indicates motor-sensory, blue indicates motor and red indicates sensory involvement. Caspr contactin-associated protein, CNTN contactin, NF neurofascin. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
], the levels of diagnostic certainty have been reduced to two (CIDP and possible CIDP) from three (definite, probable, possible CIDP) in the 2010 guideline [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. This is evaluated by assessing whether the patient exhibits weakness and sensory disturbance in keeping with typical or variant CIDP. It is necessary to identify the clinical phenotype of CIDP based on its motor and sensory characteristics due to differences in their ‘red flags’ and differential diagnoses (Table 1) and diagnostic workflow (Fig. 2 and Table 2).
3.1.1 Typical CIDP
Typical CIDP is the most common form of CIDP. It presents with symmetrical motor and sensory signs and symptoms affecting at least two limbs that follow a progressive or relapsing-remitting pattern for ≥8 weeks [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. On examination, there is proximal and distal muscle weakness of the upper and lower limbs, sensory involvement and absence or reduced tendon reflexes in all limbs. The 2009 Koski criteria for CIDP noted that the typical CIDP phenotype (symmetrical proximal and distal weakness with areflexia) was virtually pathognomonic for CIDP, with nerve conduction studies confirming, but not adding to, diagnostic accuracy [
Acute CIDP develops more rapidly, with considerable weakness within 4 weeks, and initially may be diagnosed as GBS. However, unlike patients with GBS, patients will continue to deteriorate for ≥8 weeks or relapse three or more times after initial improvement [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. The upper limbs may also be affected by distal sensory loss and weakness.
Importantly, patients with distal neuropathy who have IgM paraprotein and anti-MAG antibodies (i.e., anti-MAG neuropathy) are not classified as distal CIDP [
]. Anti-MAG neuropathy is not considered to be a type of CIDP, as electrodiagnostic and pathological findings are specific in most patients, and it does not usually respond to IVIg or corticosteroids [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Testing for anti-MAG may, therefore, be a useful additional investigation in differentiating distal CIDP from anti-MAG neuropathies. Furthermore, a recently developed diagnostic score may prove useful in discriminating between patients with anti-Mag neuropathy and those with anti-MAG antibodies with a CIDP-like presentation, thus aiding in the treatment of these conditions [
P.E. Doneddu, M. Ruiz, E. Bianchi, G. Liberatore, F. Manganelli, D. Cocito, G. Cosentino, L. Benedetti, G.A. Marfia, M. Filosto, C. Briani, C. Giannotta, E. Nobile-Orazio, A diagnostic score for anti-myelin-associated-glycoprotein neuropathy or chronic inflammatory demyelinating polyradiculoneuropathy in patients with anti-myelin-associated-glycoprotein antibody, Eur. J. Neurol. n/a(n/a). doi:https://doi.org/10.1111/ene.15296.
In patients with distal CIDP with lambda light chain associated IgA or IgG paraproteins, testing of vascular endothelial growth factor (VEGF) serum levels can help differentiate distal CIDP from suspected POEMS syndrome.
3.1.3 Multifocal CIDP
Multifocal CIDP presents with motor and sensory symptoms that are usually asymmetrical and predominant in the upper limbs [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Relative to other types of CIDP, the cranial nerves, including oculomotor, trigeminal, facial, vagal and hypoglossal nerves, are probably more frequently involved [
Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy?.
]. Antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA) tests may help differentiate multifocal/focal CIDP from other diseases; for example, the presence of positive ANA indicates mononeuropathy multiplex rather than CIDP.
3.1.4 Motor CIDP
Motor CIDP presents with relatively symmetric proximal and distal weakness, and normal sensation (both clinically and electrodiagnostically [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Motor chronic inflammatory demyelinating polyneuropathy (CIDP) in 17 patients: clinical characteristics, electrophysiological study, and response to treatment.
Motor chronic inflammatory demyelinating polyneuropathy (CIDP) in 17 patients: clinical characteristics, electrophysiological study, and response to treatment.
], similar to patients with MMN. Although the reason for this deterioration is currently unknown, the use of corticosteroids should be avoided in motor CIDP and IVIg is considered first-line treatment [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Creatine kinase levels, muscle biopsy and anti-acetylcholine receptor antibody testing may be useful in differentiating this variant from other possible conditions (Table 1). Other disorders that must be considered in the differential diagnoses are various genetic and non-genetic forms of motor neuron disease (MND). To diagnose motor CIDP, it is necessary to identify conduction abnormalities that meet EAN/PNS CIDP criteria.
3.1.5 Sensory CIDP
Sensory CIDP presents with sensory signs and symptoms that are symmetrical in four limbs, without the presence of motor weakness [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. In patients with clinical signs of sensory CIDP who show motor nerve conduction slowing or motor conduction block, the variant is known as sensory-predominant CIDP [
Importantly, sensory CIDP is often a transient clinical stage that precedes the appearance of motor weakness. In long-term follow-up studies, approximately 70% of patients with sensory CIDP eventually developed motor weakness [
Development of weakness in patients with chronic inflammatory demyelinating polyneuropathy and only sensory symptoms at presentation: a long-term follow-up study.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
], they have not yet been evaluated in randomized clinical trials in patients with sensory CIDP.
3.2 Electrodiagnostic criteria
If the clinical criteria for CIDP are met, the second question is ‘Do nerve conduction studies indicate demyelination?’ In the 2021 EAN/PNS guideline [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
], the taskforce chose to include both motor and sensory conduction criteria to support the clinical diagnosis of typical and variant CIDP (Table 2), due to the long-standing clinical experience, widespread availability and relative inexpensiveness of electrodiagnostic testing.
The motor conduction criteria in the 2021 guidelines [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
] reduction of the proximal relative to distal negative peak amplitude; 3) distal compound muscle action potential duration prolongation is defined as median, ulnar, peroneal and tibial values at low frequency filter bandpass of 2, 5, 10 or 20 Hz [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
]. Importantly, the 2021 guidelines expanded the 2010 electrodiagnostic criteria by including sensory nerve conduction criteria specific for CIDP and defining criteria specific for its variants (Table 2).
3.2.1 Typical CIDP
The diagnosis of typical CIDP is made when the patient meets the clinical criteria and the motor conduction criteria are met in at least two nerves and sensory abnormalities are present in at least two nerves [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. If motor conduction criteria are met in only one nerve and sensory conduction abnormalities are present in at least two nerves, a diagnosis of possible CIDP can be made (upgradeable to CIDP if at least two supportive criteria are met) (Table 2).
As up to one-fifth of patients with clinically typical CIDP do not fulfil minimal electrodiagnostic criteria for possible CIDP (one nerve abnormality), such patients may be diagnosed as possible typical CIDP if they show an objective response to any of the three proven CIDP treatments (IVIg, corticosteroids and plasma exchange) along with at least one other supportive criterion (Table 2) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
A clinical diagnosis of distal CIDP is confirmed if motor conduction criteria are fulfilled in at least two upper limb nerves and sensory conduction abnormalities are present in at least two nerves [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. The distal negative peak compound muscle action potential amplitude should be ≥1 mV. If other criteria are met, but motor criteria are met in only one upper limb nerve or two lower limb nerves, the diagnosis is possible distal CIDP.
3.2.3 Multifocal/focal CIDP
A clinical diagnosis of multifocal CIDP is confirmed if motor conduction criteria are met in at least two nerves in at least two limbs with sensory conduction abnormalities present in at least two nerves of the affected limbs [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. If other criteria are met but motor criteria are fulfilled in only one nerve, the maximum certainty of the diagnosis is possible multifocal CIDP.
A clinical diagnosis of focal CIDP is confirmed if motor conduction criteria are met in at least two nerves in one limb with sensory conduction abnormalities present in at least two nerves of the affected limb [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. If motor and sensory conduction criteria are fulfilled in only one nerve, the maximum certainty of the diagnosis is possible focal CIDP.
3.2.4 Motor and motor-predominant CIDP
A clinical diagnosis of motor CIDP is confirmed if motor conduction criteria are fulfilled in at least two nerves and sensory conduction is normal in all of at least four nerves (median, ulnar, radial, and sural) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. If other criteria are met but motor criteria are fulfilled in only one nerve, the diagnosis is possible motor CIDP.
If sensory conduction abnormalities are present in two nerves, the diagnosis is motor-predominant CIDP if motor conduction criteria are fulfilled in least two nerves, and possible motor-predominant CIDP if motor conduction criteria are fulfilled in only one nerve [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
A diagnosis of possible sensory CIDP can be made if sensory conduction abnormalities are found in two nerves and motor conduction is normal in all of at least four nerves (median, ulnar, peroneal, and tibial) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
In patients with motor conduction abnormalities in addition to sensory conduction abnormalities in two nerves, the diagnosis is sensory-predominant CIDP if motor conduction criteria are fulfilled in two nerves, and possible sensory-predominant CIDP if motor conduction criteria are fulfilled in one nerve [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
If clinical and electrodiagnostic criteria allow only for a diagnosis of possible CIDP, several additional tests – cerebrospinal fluid (CSF) analysis, nerve ultrasound, nerve magnetic resonance imaging (MRI), nerve biopsy and objective treatment response – can be performed to support the diagnosis (Table 2) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. However, based on assessments of their diagnostic accuracy, these tests cannot be used as primary diagnostic criteria for CIDP.
3.3.1 Cerebrospinal fluid analysis
CSF analysis may not be as useful as previously thought in the diagnosis of CIDP. Due to its unproven independent diagnostic value in typical CIDP and its uncertain sensitivity in CIDP variants [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. However, CSF analysis should be considered to exclude other diagnoses or to support a diagnosis of CIDP when 1) the diagnostic criteria for possible CIDP but not CIDP are met; 2) the patient has weakness and sensory disturbances with an acute or subacute onset; 3) there is a suspected or possible infectious or malignant cause.
High CSF protein levels are generally used as a positive indicator of CIDP. However, elevated levels of protein in the CSF should be interpreted cautiously in patients with diabetes or those aged >50 years (due to their higher normal CSF protein levels [
]). A diagnosis of CIDP or possible CIDP should not be made based on an elevated CSF protein in the absence of clinical and/or electrodiagnosis criteria (due to the risk of misdiagnosis [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. On the other hand, normal CSF protein levels do not exclude a diagnosis of CIDP or a response to immune treatment.
Unfortunately, rigorous cut-off values for CSF protein levels in CIDP cannot be established due to the lack of sufficient data. The clinical experience of the physician and the laboratory's normative CSF protein values should be relied upon to guide the diagnosis. Nonetheless, very high CSF protein levels (i.e., ≥1 g/L) strongly suggest the presence of CIDP [
As nerve enlargement is not specific to CIDP, nerve ultrasound has only moderate diagnostic accuracy in CIDP and is considered a supportive criterion [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Nerve ultrasound has the advantages of being a non-invasive, easily-repeated, relatively low-cost procedure that is widely available. However, interpreting the results requires expertise, practice and the establishment of intra-laboratory normal values.
Parameters evaluated during nerve ultrasound include the cross-sectional nerve size, fascicle size, nerve vascularity, echogenicity and epineurium thickness [
]. A diagnosis of CIDP may be more likely if there is nerve enlargement in at least two sites in proximal median nerve segments and/or the brachial plexus [
A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.
]. Normative values for the cross-sectional area of the median nerve are available, with nerve enlargement being shown by values of >10 mm2 at the forearm, >13 mm2 at the upper arm, >9 mm2 for the interscalene (trunks) and > 12 mm2 for nerve roots [
Although not featured in the 2021 CIDP guideline, muscle ultrasound may provide additional information. In a recent study in 80 patients with typical or variant CIDP [
], distal muscles showed increased echointensity, indicating fibrosis and fatty infiltration due to secondary axonal damage, which correlated with disease severity. Fasciculations, which are a potential marker of active axonal damage, were frequently observed in distal muscles. Although further studies on specificity and sensitivity are required, echointensity information from muscle ultrasound may prove to be a prognostic, and potentially even diagnostic, marker for CIDP.
3.3.3 Nerve MRI
Nerve MRI is a supportive criterion in patients fulfilling the diagnostic criteria for possible CIDP when nerve ultrasound is not available or when nerve ultrasound results are non-contributory [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
A diagnosis of CIDP may be more likely if there is nerve enlargement and/or increased signal intensity of nerve roots on T2-weighted MRI sequences (DIXON/STIR, coronal and sagittal planes) [
A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.
]. Preferably, evaluation includes a quantitative assessment of spinal nerve root sizes (nerve root diameter immediately next to the ganglion, measured as coronal plane height with a cut-off value of >5 mm) or semi-quantitative scoring of abnormalities of the spinal nerve roots and trunks as normal, possibly abnormal or clearly abnormal [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. However, as nerve enlargement and increased signal intensity are associated with conditions that mimic CIDP, it is important to consider other potential diagnoses.
Nerve ultrasound is currently preferred over nerve MRI due to the low inter-rater reliability, lack of objective cut-off values, relatively high cost and selection bias of nerve MRI in current studies [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. However, the value of nerve MRI in the differential diagnosis of CIDP may improve as its specificity is enhanced by more precise measurement criteria. In a systematic comparison of the nerve architecture of the brachial plexus in a recent study [
Quantitative magnetic resonance imaging of the brachial plexus shows specific changes in nerve architecture in chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and motor neuron disease.
], significant differences in quantitative MRI parameters were shown between patients with CIDP, MMN and MND, which may reflect differences in underlying pathophysiological mechanisms. The investigators took great care in precisely measuring the nerve root and calculating the values, which may be necessary when determining which measurements to take with nerve MRI.
3.3.4 Immunological testing
Testing for serum monoclonal proteins is strongly advised in patients with clinical suspicion of CIDP, with further evaluation recommended if a gammopathy is found [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. As monoclonal gammopathies can be associated with neuropathies presenting a clinical picture resembling CIDP (e.g., anti-MAG IgM paraproteinemic neuropathy, POEMS syndrome, multiple myeloma), it is vital that the neurological and oncological conditions are correctly identified to enable appropriate treatment [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Nodal/paranodal or MAG antibody testing should be considered in patients who fulfil criteria for CIDP and present with particular characteristics or do not respond well to proven effective treatments [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Antibody testing is associated with relatively low costs, and positive results have significant implications for diagnosis and treatment; however, nodal/paranodal antibody testing is not widely available.
Testing for nodal and paranodal autoantibodies in patients with clinical suspicion of CIDP should be considered when nodal and paranodal (anti-NF155, anti-CNTN1, anti-Caspr1) and possibly anti-NF140/186) antibody testing is available and meets quality standards [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. The proviso for ‘availability’ and ‘quality standards’ is included in recognition that not all laboratories can provide such testing. Clinical hints of paranodopathies include an onset similar to that of GBS, tremor and poor response to IVIg and corticosteroids. Antibodies to the proteins of the paranodal complex, including anti-NF155/−86, anti-CNTN1 and anti-Caspr1, may be present [
]. The predominant antibody subtype may be IgG4 (not complement dependent) or, in more acute cases, IgG3 (complement dependent). The screening test is serum binding on teased nerve fibres, with results confirmed by a specific enzyme-linked immunosorbent assay (ELISA). The importance of correctly diagnosing paranodopathies is highlighted by the case of a 30-year-old male who developed severe progressive distal neuropathic pain and sensory deficits, was diagnosed with CIDP and, despite IVIg treatment, was unable to walk within a few months [
]. Binding assays showed autoantibodies against Caspr1 with IgG4 as the predominant autoantibody subclass. Following four cycles of rituximab, which has proven effectiveness in treating paranodopathies [
All patients fulfilling CIDP diagnostic criteria should be tested for a paraprotein. Patients who are IgM-positive should undergo anti-MAG antibody testing. Anti-MAG antibody testing is widely available, with Bühlmann test ELISA and locally validated ELISA, Western blot or immunohistochemistry assays being recommended. A high anti-MAG antibody titre (>7000 Bühlmann units) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. Due to their low diagnostic accuracy, invasive nature and the availability of other diagnostic means, their use should be limited to unusual cases when all other investigations are non-diagnostic [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. For example, macrophage clusters around vessels are markedly increased in patients with CIDP relative to patients with hereditary neuropathies and healthy controls, suggesting a possible diagnostic marker for CIDP [
]. Currently, however, nerve biopsies should be used only in carefully selected patients when CIDP is suspected but cannot be confirmed with clinical, laboratory, imaging and electrodiagnostic studies, there is little or no response to treatment, skilled and specialized physicians and laboratories are available, and symptoms are severe enough to justify the potential complications.
3.3.6 Treatment response
A response to treatment with a standard immunomodulatory agent may assist in confirming a diagnosis of CIDP, as IVIg (high-certainty evidence), and corticosteroids and plasma exchange (both moderate-certainty evidence) have been shown to improve impairment [
]. Objective treatment response is considered to be a supportive diagnostic criterion for CIDP in patients in whom clinical, electrodiagnostic and other supportive criteria allow only for a diagnosis of possible CIDP (Table 2) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
As current immunomodulatory treatments are not specific for CIDP, treatment response must be considered carefully in tandem with clinical and electrophysiological evidence to avoid over-diagnosing CIDP [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. In patients with possible CIDP, an objective response to treatment increases the probability of a CIDP diagnosis, but a response could also occur if another autoimmune condition was present. Importantly, treatment failure may or may not indicate a misdiagnosis of CIDP, as failure may be due to other causes such as inadequate treatment dosage or duration [
]. In patients who do not respond to at least one of the three proven effective CIDP treatments, it is appropriate to review the CIDP diagnosis and consider other conditions before considering other immunosuppressive therapies.
The guideline defines an objective treatment response as an improvement in at least one measure of disability and at least one measure of impairment. Although the changes required to define improvement have not been adequately validated, those which have been used in clinical trials can serve as a guide (Table 3) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Table 3Examples of disability and impairment scales that may be used to assess an objective response to treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.
Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.
Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.
Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
]. In this article, we reviewed key diagnostic-related revisions in the guideline including the addition of four well-characterized CIDP variants, changes in specific clinical, electrodiagnostic (including the addition of sensory conduction criteria) and supportive criteria for typical CIDP and each of the CIDP variants, and revisions in the levels of diagnostic certainty for typical and variant CIDP.
Improvements in the guidelines for the diagnosis of CIDP were necessary, as CIDP, especially the variant forms, continued to be commonly over- or under-diagnosed [
]. Problems associated with misdiagnosis include not recognizing the key clinical signs, especially of CIDP variants, misinterpretation of nerve conduction studies, lack of adherence to electrodiagnostic criteria, over-reliance on supportive findings such as CSF protein levels, and failure to exclude other causes of polyneuropathy.
The addition to the guidelines of specific criteria for the four variant forms of CIDP should aid in the diagnosis of these conditions. Although typical CIDP with its proximal and distal weakness may be relatively easy to diagnose, it is more difficult to diagnose CIDP variants. For example, in a review of the accuracy of CIDP diagnosis in 59 patients [
], 28 patients (47%) were misdiagnosed. All patients with typical CIDP were accurately diagnosed, meeting the 2010 EFNS/PNS diagnostic requirements for CIDP [
European Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.
European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision.
Despite recent advances in the understanding of CIDP, many questions remain about its diagnosis and treatment, as well as other related aspects (e.g., epidemiology and healthcare burden). To reduce the high rates of over- and under-diagnosis of CIDP, it is vital that neuromuscular experts carefully review an individual's clinical findings and electrophysiological test results, and factor in supportive diagnostic criteria when considering a diagnosis of CIDP.
Supportive criteria include an objective response to treatment with one of the three immunomodulatory agents (i.e., IVIg, corticosteroids and plasma exchange) that have proven effective in the treatment of CIDP. However, as other auto-immune conditions may also respond to these treatments, treatment response as a supportive diagnostic criteria needs to be considered carefully along with the clinical and electrophysiological findings. Furthermore, as a fraction of non-responders to at least one of these treatments may still have CIDP, additional testing is needed to rule out disorders that mimic CIDP before considering other immunosuppressive treatment strategies. Despite extensive efforts to objectify treatment response, there are clinical scenarios that cannot be addressed by clinical measures alone [
]. A treatment response test can be diagnostically convenient when the differential diagnosis is narrow and there is a high probability of improvement as assessed by a measurable objective outcome; however, problems occur when ‘benefit’ is loosely defined [
]. Questions still remain regarding how treatment response should be defined, how long each treatment should be continued and how many of the treatment options should be used before deciding that a lack of treatment response has occurred.
It is hoped that future studies will establish diagnostic biomarkers that can aid in the differential diagnosis of CIDP and other neuropathic disorders, thereby further improving the diagnostic criteria. The establishment of biomarker criteria could also serve as a surrogate marker for treatment response and disease progression in clinical trials, as well as in clinical practice.
5. Conclusion
In conclusion, use of the diagnostic criteria in the revised 2021 EAN/PNS guideline should enable more accurate diagnosis and treatment of CIDP and its variants in clinical practice. In addition, it will allow patient populations to be appropriately defined in clinical trials, thereby improving our understanding of CIDP. The revised guideline still needs to be validated and its strengths and weaknesses assessed. Until then, we need to utilize the revised guideline, recognize pitfalls that can lead to a delayed or incorrect diagnosis of CIDP, and be particularly vigilant before diagnosing a CIDP variant.
Contributions
All authors contributed equally to this publication in concept, writing and editing.
Funding
The manuscript was developed from the proceedings of a Grifols-sponsored virtual symposium, held on 2 November 2021 as part of the 2021 Peripheral Nerve Society Virtual Event.
Disclosures
R. Lewis is a consultant for Annexon, Argenx, CSL Behring, Grifols, J & J, Roche, Pfizer, Sanofi and Takeda, and has received honoraria from Akcea, Alnylam and Medscape.
P. A. van Doorn is a consultant for Annexon, Argenx, Hansa, Immunic, Roche, and Sanofi; has received honoraria from Grifols (all honoraria paid to the Erasmus MC research fund); and has received unrestricted research grants from the Netherlands Organisation for Health Research and Development (ZonMW), Baxter/Shire, Grifols, Prinses Beatrix Spierfonds, and Sanquin.
C. Sommer is a consultant for Alnylam, Air Liquide, Bayer, Immunic, Ipsen, LFB, Merz, Pfizer, Roche and Takeda, and has received honoraria from Alnylam, CSL Behring, Grifols, Lilly, Merck, Novartis, Pfizer and TEVA.
Acknowledgements
Editorial assistance was provided by Katherine Lyseng-Williamson on behalf of Content Ed Net (Madrid, Spain) with funding from Grifols SA (Barcelona, Spain).
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European Federation of Neurological Societies/peripheral nerve society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the peripheral nerve society.
European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
European Federation of Neurological Societies/Peripheral Nerve Society
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European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision.
European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision.
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Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy?.
Motor chronic inflammatory demyelinating polyneuropathy (CIDP) in 17 patients: clinical characteristics, electrophysiological study, and response to treatment.
Development of weakness in patients with chronic inflammatory demyelinating polyneuropathy and only sensory symptoms at presentation: a long-term follow-up study.
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