NeurologyTier 1Disease (DEADMAN)

Chronic inflammatory demyelinating polyneuropathy

Description

Acquired, immune-mediated demyelinating polyradiculoneuropathy
Broadly symmetric, PROXIMAL AND distal weakness + sensory loss, areflexia, progressing over >8 weeks
- Proximal weakness in a neuropathy is the giveaway - length-dependent axonal neuropathies do not do it
Course: progressive, relapsing-remitting, or monophasic
Treatment-responsive - the reason it must be separated from the axonal neuropathies

Variants (EAN/PNS 2021 nomenclature)

Variant	Pattern
Typical CIDP	Symmetric proximal + distal, sensorimotor, areflexia
Distal (DADS)	Distal, sensory-predominant; often IgM paraprotein + anti-MAG**
Multifocal (MADSAM / Lewis-Sumner)	Asymmetric, multiple nerve territories, upper limb onset
Focal	One limb or plexus
Motor	Pure motor - *use IVIg first; steroids can worsen it*
Sensory	Pure sensory, ataxia; may develop motor involvement later

Autoimmune nodopathies are now a separate disease, not a CIDP variant
- IgG4 antibodies to neurofascin-155, contactin-1, CASPR1, neurofascin-140/186
- Phenotype: very high CSF protein, tremor, sensory ataxia, acute aggressive onset, nephrotic syndrome (CNTN1)
- *Respond poorly to IVIg - go to rituximab*

Epidemiology

Prevalence ~1-9/100,000; incidence ~0.3-1.6/100,000/yr
M>F ~2:1; mean onset 50s (any age)
~2x more common in diabetes - and much harder to diagnose there
Over-diagnosis is a documented problem - up to ~half of referred "CIDP" does not meet criteria; usually a diabetic or hereditary neuropathy on immunoglobulin

Aetiopathogenesis

Autoimmune attack on myelin and the node/paranode of peripheral nerves and roots
- Both cellular (T cell, macrophage-mediated demyelination) and humoral mechanisms
- No single antigen identified in most cases - hence no diagnostic serology for typical CIDP
Macrophage-mediated segmental demyelination -> repeated demyelination/remyelination -> onion-bulb formation, nerve hypertrophy
Secondary axonal loss accumulates with time - this is the irreversible component
Antibody-defined subgroups (~10%): IgG4 anti-NF155/CNTN1/CASPR1 disrupt the paranodal axoglial junction rather than causing demyelination
- IgG4 does not fix complement -> explains IVIg failure and rituximab response
Melanoma-associated CIDP - a rare true paraneoplastic form; tumour cells share carbohydrate epitopes with Schwann cells
No preceding infection in most (unlike GBS)

Diagnosis

Clinical criteria

Progression over >8 weeks (GBS <=4 weeks; 4-8 weeks = "acute-onset CIDP", the group that keeps relapsing after IVIg for apparent GBS)
Symmetric proximal and distal weakness of arms and legs
Absent or reduced reflexes in all four limbs
Sensory involvement (large fibre - vibration, proprioception; sensory ataxia)
+/- cranial nerve involvement, tremor, nerve hypertrophy

CIDP vs GBS

	GBS	CIDP
Nadir	<=4 weeks	>8 weeks
Preceding infection	Common (Campylobacter, CMV, EBV)	Uncommon
Autonomic involvement	Common	Rare
Facial weakness	Common	Less common
Respiratory failure/ventilation	~20-30%	Rare
Prominent early sensory signs	Less	More - and predict conversion to CIDP
Treatment	IVIg or PLEX; steroids ineffective	IVIg, steroids, or PLEX

Nerve conduction studies - the diagnostic core

Demyelinating features in >=2 nerves:

Slowed motor conduction velocity
Prolonged distal motor latency
Prolonged or absent F-wave latency (proximal/root demyelination)
Partial motor conduction block and abnormal temporal dispersion
Needle EMG relatively normal early - a subacute demyelinating picture with conduction block and a quiet EMG is CIDP until proven otherwise
Late: secondary axonal loss with denervation and reduced CMAP amplitudes

Supportive tests

CSF: raised protein with a normal cell count (albuminocytological dissociation)
- Cells >10/microL should make you look for HIV, Lyme disease, sarcoidosis or lymphoma
MRI with gadolinium - hypertrophy and enhancement of roots, plexus and cauda equina
Nerve ultrasound - enlarged cross-sectional area, proximal segments; helps separate CIDP from CMT (uniform vs multifocal enlargement)
Objective response to immunotherapy - a formal supportive criterion
Nerve biopsy - rarely needed now; reserve for atypical cases or suspected vasculitis/amyloid

Every case needs

SPEP + serum free light chains + immunofixation - do not skip; a paraprotein changes the diagnosis
HbA1c/OGTT, TSH, B12, HIV, hepatitis B and C, ANA/ENA, ACE
Anti-MAG if distal sensory-predominant with IgM paraprotein
Nodal/paranodal antibodies (NF155, CNTN1, CASPR1, NF140/186) if atypical, aggressive, tremulous or IVIg-refractory
Skeletal survey + VEGF if POEMS suspected

Paraproteinaemic mimics - the key differential

	Features
Anti-MAG neuropathy	IgM kappa; distal, sensory, ataxic, tremor; very prolonged distal latencies. Poor response to IVIg
POEMS	Polyneuropathy, Organomegaly, Endocrinopathy, M-protein (lambda), Skin changes; osteosclerotic myeloma; inc VEGF; papilloedema, effusions. Treat the plasma cell clone, not the nerve
Waldenstrom	IgM; ~half anti-MAG positive; hyperviscosity
Cryoglobulinaemia	Distal sensorimotor + Raynaud + purpura; hepatitis C
AL amyloid	Painful small-fibre + autonomic neuropathy, carpal tunnel, cardiac and renal involvement. Axonal, not demyelinating
Hereditary (CMT1)	Lifelong, pes cavus, family history, uniform slowing, no conduction block

Management

A. Induction - three first-line options, chosen by phenotype

	Use when	Dose
IVIg	Fastest onset; first-line in motor CIDP; preferred in diabetes, brittle patients, pregnancy	2 g/kg over 2-5 days
Corticosteroid	Cheap, higher rate of long-term remission; avoid in pure motor CIDP - may worsen it	Prednisolone 60 mg daily, or pulsed dexamethasone 40 mg x4 days monthly / IV methylprednisolone 500 mg-1 g monthly
Plasma exchange	If IVIg and steroids fail, or rapid deterioration	5 exchanges over 2 weeks; benefit is short-lived, needs a maintenance plan

Assess response objectively at ~4-6 weeks - grip dynamometry, INCAT disability, MRC sum score, timed walk
- "He feels a bit better" is not a response. Document a measure before starting
No response to one first-line agent -> try another before calling it refractory

B. Maintenance

IVIg ~1 g/kg every 3 weeks, or subcutaneous immunoglobulin - equally recommended; SCIg avoids peak-trough fluctuation and infusion-day burden
Taper to the lowest effective dose and periodically attempt withdrawal - a proportion are in remission and still being infused; immunoglobulin is a scarce and expensive resource
Steroid-sparing agents (azathioprine, methotrexate, mycophenolate, ciclosporin) - weak evidence, used pragmatically

C. Refractory or antibody-defined disease

Confirm the diagnosis first - most "refractory CIDP" is not CIDP
Autoimmune nodopathy (anti-NF155/CNTN1/CASPR1) -> rituximab, not more IVIg
Efgartigimod (FcRn inhibitor, subcutaneous with hyaluronidase) - approved for adults with progressive or relapsing active CIDP previously treated with steroids or immunoglobulin; reduces relapse risk (ADHERE)
Cyclophosphamide, autologous haematopoietic stem cell transplantation in highly selected refractory cases

D. Everything that is not immunotherapy

Physiotherapy and occupational therapy - strength, gait, aids, orthoses (AFO for foot drop)
Neuropathic pain: amitriptyline, duloxetine, pregabalin or gabapentin
Falls prevention, driving assessment, vocational support
Steroid care: bone protection, glucose, PJP prophylaxis, gastroprotection
IVIg care: pre-hydration, check IgA (anaphylaxis risk), thrombosis risk, haemolysis, aseptic meningitis, renal function
Vaccination before immunosuppression

Associations

Diabetes mellitus - ~2x risk
MGUS and other paraproteinaemias (usually IgM kappa), Waldenstrom macroglobulinaemia, POEMS
Lymphoma, and rarely other malignancy; melanoma-associated CIDP
Hepatitis C; HIV/AIDS (CSF pleocytosis is the clue)
Inflammatory bowel disease
Connective tissue disease - SLE, Sjogren's
Solid organ transplantation and graft-versus-host disease
Chronic active hepatitis, thyroid disease, sarcoidosis
TNF inhibitors and checkpoint inhibitors can precipitate a CIDP-like neuropathy

Natural history & complications

Untreated: progressive disability; a minority follow a monophasic course
~60-80% respond to first-line therapy; most need long-term maintenance
~25-30% achieve sustained drug-free remission - which is why periodic withdrawal trials matter
Relapsing course commoner in younger patients; chronic progressive course commoner in older patients and carries worse outcome
Secondary axonal loss is the driver of permanent disability - reflected by low CMAP amplitudes and muscle wasting
- Delayed treatment converts a reversible demyelinating problem into a fixed axonal one
~10% remain significantly disabled or wheelchair-dependent; mortality is low but not zero

Poor prognostic markers

Older age at onset, chronic progressive (rather than relapsing) course
Marked axonal loss on NCS/EMG at diagnosis
Nodopathy antibodies, IgM paraprotein/anti-MAG
Delay from onset to treatment

Monitor

Objective strength and disability scores at each infusion cycle - these drive dose and withdrawal decisions
Repeat NCS if the phenotype changes
Steroid and immunoglobulin toxicity; annual reassessment of ongoing need

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