Residency · Residency · Neurology

Chronic Inflammatory Demyelinating Polyneuropathy

Overview

CIDP is the most common chronic acquired demyelinating polyneuropathy, with a prevalence of 1-9 per 100,000. It follows a progressive or relapsing-remitting course over more than 8 weeks, which distinguishes it from GBS. CIDP is a treatable disorder, and early recognition with appropriate therapy can prevent irreversible axonal loss. However, there is significant concern about overdiagnosis: up to 50% of patients referred with a CIDP diagnosis may be misdiagnosed.

Clinical Features

Typical CIDP

Typical CIDP presents with symmetric proximal and distal weakness, which is unusual for neuropathies that are generally distal-predominant. Sensory involvement affects large fibers, causing impaired vibration and proprioception along with paresthesias. Reflexes are reduced or absent. The onset is gradual over at least 8 weeks, and both upper and lower extremities are affected. Cranial nerve involvement is uncommon in typical CIDP.

CIDP Variants

Distal Acquired Demyelinating Symmetric (DADS) Neuropathy presents with predominantly distal sensory greater than motor involvement. It is often associated with an IgM paraprotein and anti-MAG antibodies, tremor is common, and it is less responsive to standard CIDP treatments but may respond to rituximab.

Multifocal Acquired Demyelinating Sensory and Motor (MADSAM/Lewis-Sumner Syndrome) presents with an asymmetric, multifocal pattern mimicking mononeuropathy multiplex. Conduction block in individual nerve territories is characteristic, and it responds to standard CIDP treatments, unlike multifocal motor neuropathy.

Pure Motor CIDP presents with symmetric weakness without sensory involvement. It must be differentiated from multifocal motor neuropathy (MMN), as it responds to IVIG while corticosteroids may worsen MMN but not CIDP.

Pure Sensory CIDP causes sensory ataxia and large-fiber sensory loss without weakness. Demyelinating features on NCS confirm the diagnosis and distinguish it from sensory neuronopathy.

Focal CIDP is confined to one or two limbs, often the upper extremity, with prominent brachial plexus involvement.

<image>Clinical photographs and nerve conduction patterns comparing typical CIDP with its variants including DADS, MADSAM, and pure motor and sensory forms</image>

Diagnostic Criteria

EFNS/PNS 2021 Revised Criteria

Definite CIDP requires clinical criteria plus electrodiagnostic evidence of demyelination in at least 2 motor nerves. Probable CIDP requires electrodiagnostic features in 1 nerve or probable features in 2 nerves with supportive criteria. Possible CIDP requires clinical criteria with only 1 demyelinating feature in 1 nerve.

Electrodiagnostic Criteria for Demyelination

Motor nerve conduction velocity below 70% of the lower limit of normal, distal motor latency above 150% of the upper limit of normal, F-wave latency above 120% of the upper limit of normal or absent F-waves, conduction block (more than 50% proximal CMAP amplitude reduction for definite, 30-50% for probable), and temporal dispersion (more than 30% increase in CMAP duration between proximal and distal stimulation). These findings must be present in at least 2 nerves for a definite diagnosis.

Supportive Criteria

Supportive evidence includes CSF protein above 45 mg/dL with cell count below 10 per microliter (albuminocytologic dissociation), MRI showing gadolinium enhancement and/or hypertrophy of nerve roots, brachial plexus, or cauda equina, nerve biopsy evidence of demyelination and remyelination (onion bulb formation), objective clinical improvement with immunotherapy, and ultrasound showing nerve cross-sectional area enlargement.

The Overdiagnosis Problem

Why CIDP is Overdiagnosed

Electrodiagnostic criteria for demyelination are frequently misapplied. Technical errors on NCS (submaximal stimulation, cool limb temperature) can create artifacts resembling conduction block or slowed velocities. Diabetic neuropathy with mild demyelinating features is mistaken for CIDP. Hereditary neuropathies (CMT1) are misdiagnosed as CIDP. Patients are placed on chronic IVIG without a confirmed diagnosis, and "IVIG dependence" may reflect placebo response or natural disease fluctuation.

How to Avoid Misdiagnosis

The approach includes strictly applying electrodiagnostic criteria with proper technique, considering hereditary neuropathy if slowing is uniform without conduction block, reviewing family history and examining family members (with genetic testing if appropriate), performing structured IVIG withdrawal trials in patients with questionable diagnoses, and objectively documenting the treatment response rather than relying solely on subjective improvement.

<image>Algorithm for distinguishing true CIDP from common mimics including diabetic neuropathy, CMT1, anti-MAG neuropathy, and multifocal motor neuropathy</image>

Treatment

First-Line Therapies

IVIG is given as a 2 g/kg loading dose over 2-5 days, then 1 g/kg maintenance every 3-4 weeks. The ICE trial demonstrated efficacy over placebo with improvement in grip strength and INCAT disability score. The dose should be titrated to the lowest effective amount at the longest tolerable interval. Subcutaneous immunoglobulin (SCIg) was shown in the PATH trial to be non-inferior to IVIG for maintaining response, with improved autonomy through weekly self-administration at home and fewer systemic side effects.

Corticosteroids (oral prednisone at 1 mg/kg/day with slow taper over months, or pulsed IV methylprednisolone) have equivalent efficacy to IVIG for typical CIDP. They should be avoided in pure motor CIDP due to risk of worsening. Long-term side effects limit utility. Plasma exchange is effective for acute exacerbation or maintenance but requires central venous access and is less practical for long-term use.

Second-Line and Steroid-Sparing Agents

Azathioprine is the most commonly used steroid-sparing agent with slow onset over 3-6 months (TPMT should be checked). Mycophenolate mofetil is frequently used despite limited trial evidence. Rituximab is increasingly used, especially for anti-MAG neuropathy and refractory CIDP. Cyclophosphamide is reserved for severe refractory cases. Cyclosporine is a second-line option requiring drug level monitoring.

Treatment Strategy

Response should be assessed objectively at 3-6 months using MRC sum score, grip strength, INCAT score, and walk speed. Periodic dose reduction or withdrawal attempts are important to confirm ongoing need. Approximately 30-40% of patients may achieve drug-free remission. If no objective improvement occurs after adequate trials of 2 first-line agents, the diagnosis should be reconsidered.

Prognosis

Approximately 60-80% of patients respond to first-line immunotherapy. About 10-20% have a progressive course despite treatment. Early treatment initiation correlates with better long-term outcomes by preventing irreversible axonal loss. A relapsing-remitting course generally carries a better prognosis than chronic progressive disease. Secondary axonal damage (progressive reduction in CMAP and SNAP amplitudes) portends worse functional outcome.

<image>Nerve ultrasound images showing enlarged cross-sectional area of the median nerve at the forearm in CIDP compared with normal nerve caliber</image>

Clinical Pearls

If a patient diagnosed with GBS does not improve or worsens after 8 weeks, the diagnosis should be reclassified as acute-onset CIDP and maintenance immunotherapy initiated. The hallmark clinical feature distinguishing CIDP from most other neuropathies is significant proximal weakness; the differential for neuropathies causing proximal weakness is short (CIDP, GBS, diabetic amyotrophy, porphyria, hereditary motor neuropathies). Conduction block is the most specific electrodiagnostic feature of acquired demyelination; uniform slowing without block suggests hereditary neuropathy (CMT1). SPEP with immunofixation should always be checked in suspected CIDP because an IgM paraprotein changes both the differential diagnosis (anti-MAG neuropathy) and the treatment approach (rituximab). Corticosteroids must not be used for multifocal motor neuropathy (MMN) as they can worsen it; IVIG is the treatment of choice for MMN. Periodic IVIG withdrawal trials are important because many patients can sustain remission off therapy, and continued unnecessary IVIG is expensive and exposes patients to risks. Nerve ultrasound showing multifocal nerve enlargement supports the diagnosis and can help identify biopsy targets. A negative nerve biopsy does not exclude CIDP because the disease is patchy and the biopsy may miss affected segments.

References

• Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force. Eur J Neurol. 2021;28(11):3556-3583.
• Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study). Lancet Neurol. 2008;7(2):136-144.
• van Schaik IN, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2018;17(1):35-46.
• Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment benefit. Neurology. 2015;85(6):498-504.
• Bunschoten C, Jacobs BC, Van den Bergh PYK, et al. Progress in diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Lancet Neurol. 2019;18(8):784-794.

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