CIDP

Definitions

• Acquired demyelinating disorder of the peripheral nerves and nerve roots

• Distinct from AIDP which is a demyelinating form of GBS

• CIDP by definition continues to progress or have relapses beyond 8 weeks

Epidemiology

• Prevalence – 1.9/100,000

• Increases with age – 6.7/100,000 in elderly

• Onset age

o Average: 50 years

o Childhood: ~10%; Youngest < 1 year

• Males>females 2:1

Pathogenesis

• Precipitating factors

o Vaccination or infection within 6 weeks of symptoms in 32% of patients

• Increased relapse rate in pregnancy

• Both cellular and humoral immune factors thought to be involved

Variants and related conditions

• There are varying opinions as to what is a variant of CIDP vs a separate disease

• One view is that:

o DADS and MADSAM are CIDP variants

o MMN, Anti-MAG, POEMS are separate diseases

	CIDP	DADS	MADSAM	MMN
Symmetric	Y	Y	N	N
Motor	Y++	+/- distal	Y	Y
Sensory	Y+	Y++	Y	N
Treatment	IVIG or steroids	Poor treatment response	IVIG or steroids	IVIG
Antibodies	Nil	Anti-MAG		Anti-GM1
Elevated CSF protein	Common	Common	Infrequent (34%)
Prevalence		24-35%	8-15%

Variants

DADS (Distal Acquired Demyelinating Symmetrical Neuropathy)

• Distal, predominantly sensory, large fibre ataxic neuropathy

• Generally respond poorly to immunotherapy (but it is still recommended to try it)

• Some texts state classify this as a CIDP variant and denote a separate condition if associated with monoclonal IgM (especially anti-MAG) – see below

MADSAM (Multifocal Acquired Demyelinating Sensory and Motor Neuropathy)

(Lewis-Sumner Syndrome)

• Asymmetric

• Upper limb dominant

• Motor and sensory

• Responds to treatment

Related conditions

Anti-MAG Neuropathy

• Some classify this as part of DADS

• Distal, predominantly sensory, large fibre ataxic neuropathy

• Progressive over years or decades

• NCS often show a disproportionate prolongation of distal latencies (compared to normal CIDP)

• CSF protein frequently elevated (90%)

• Positive for Anti-MAG antibodies

o Anti-MAG antibodies can be positive in a number of other neuropathies, significant if very high

o Anti-MAG deposits on nerve biopsy can confirm diagnosis

• 12–35% have Waldenstrom macroglobulinaemia or B‑cell lymphoma that requires bone marrow biopsy for diagnosis

• Do not respond to steroids or IVIG – need rituximab or other chemotherapy agent

MMN (Multifocal Motor Neuropathy)

• Asymmetric

• Upper limb dominant

• Motor only

• Often positive for Anti-GM1 antibodies

POEMS Syndrome Associated Neuropathy

• Symmetric, ascending sensorimotor neuropathy

• Progressive weakness and sensory loss

• Often painful

• Systemic manifestations include hepatosplenomegaly, enlarged lymph nodes, diabetes or glucose intolerance, gynaecomastia, impotence, hypothyroidism, hyperpigmentation, skin thickening, acrocyanosis, angiomas, peripheral oedema, ascites, pleural effusions, papilloedema, thrombocytosis, and polycythemia

• Electrodiagnostic findings indicate both demyelination and axonal loss, with two-thirds of patients meeting the definite EFNS–PNS criteria for demyelinating polyneuropathy. Electrodiagnostic changes are more uniform than those found in CIDP

• Often elevated CSF protein

DDX:

• Multifocal motor Neuropathy

• Anti-MAG Neuropathy

Systemic conditions

• Paraprotein associated neuropathy

o MGUS

o CLL

o Walderstrom’s

o Myeloma

o POEMS

• Hereditary demyelinating neuropathy

o E.g. CMT 1

• Infective

o HIV

o Hepatitis B/C

• DM

• Autoimmune inflammatory disease

o SLE

o Sarcoidosis

o Autoimmune hepatitis

o IBD

• Thyrotoxicosis

• Nephrotic syndrome

• Medications:

o Anti-TNFalpha agents

o Immune checkpoint inhibitors

Clinical manifestations

• Majority have chronic course

o 1/3 have chronic relapsing-remitting course

• Symmetrical typically but can be asymmetric

• Motor changes usually predominate but sensory changes are present in most cases

o Distal and proximal equally involved

• Pain

• Ataxia

• Cranial nerve/bulbar involvement in ~10-20%

• Clinical variants

o Focal and multifocal

o Chronic sensory demyelinating polyneuropathy

o Pure motor pattern

o CIDP in DM

o Postural and action tremor

o CNS involvement

• Examination

o Globally reduced or absent reflexes

Diagnosis

Suggested diagnostic criteria

• (Modified from EFNS, 2010)

Clinical Inclusion Criteria

• Typical CIDP

o Progression over at least two months

o Symmetric

o Proximal and distal

o Involvement of upper and lower limbs

o Motor weakness and sensory symptoms

o Reduced deep tendon reflexes throughout

• Atypical CIDP – one of:

o Predominantly distal

o Asymmetric

o Focal

o Pure motor

o Pure sensory

• Exclusion criteria

o Alternative cause identified

o Hereditary neuropathy

o Anti-MAG antibodies

o Prominent sphincter disturbance

o Evidence of MMN

Supportive

• Increased cerebrospinal fluid protein without pleocytosis

• Nerve conduction evidence of a demyelinating neuropathy (not meeting full criteria below)

• Nerve biopsy evidence of segmental demyelination with or without inflammation

• MRI showing gadolinium enhancement and/or hypertrophy of the cauda equina, lumbosacral or cervical nerve roots, or the brachial or lumbosacral plexuses

• Objective evidence of improvement with immunomodulatory treatment

Definitions

• Definite

o Clinical criteria positive, no exclusions and definite NCS criteria (below)

o Probable NCS criteria and at least one supportive criteria

o Possible NCS criteria and at least 2 supportive criteria

• Probable

o Clinical criteria positive, no exclusions and probable NCS criteria (below)

o Possible NCS criteria and at least 1 supportive criteria

• Possible

o Clinical criteria with possible NCS criteria

NCS

EFNS NCS Criteria

• Definite – at least one of:

1. Distal motor latencies prolonged >150% ULN (2 or more nerves, not at entrapment sites)

2. Motor conduction velocity slowed <70% LLN (2 or more nerves, not at entrapment sites)

3. Late responses prolonged: F-reponse or H-reflex latency prolonged >130% ULN

4. Absence of F waves (in two nerves), as long as CMAP amplitude >20% LLN AND at least one other criteria is met.

5. Conduction block, >50% amplitude reduction, as long as the distal CMAP amplitude >20% LLN, in two nerves or in one nerve AND at least one other criteria is met.

6. Temporal dispersion of CMAP: Prox/distal CMAP duration ratio >1.30 in 2 or more nerves

7. Temporal dispersion with distal CMAP duration increased in at elast one nerve (median >6.6, Ulnar >6.7, Peroneal >7.6, Tibial >8.8) AND at least one other criteria is met.

• Probable:

· Conduction block - >30% amplitude reduction(excluding posterior tibial), as long as the distal CMAP amplitude >20% LLN in 2 nerves, OR in one nerve AND at least one of the other criteria met

• Possible:

· As for definite but only demonstrated in one nerve

American Criteria -NCS – demonstrate 3 of the following:

1. Distal motor latencies prolonged >130% ULN (2 or more nerves, not at entrapment sites)

2. Motor conduction velocity slowed <75% LLN (2 or more nerves, not at entrapment sites)

3. Late responses prolonged: F-reponse or H-reflex latency prolonged >130% ULN

4. Conduction block and or temporal dispersion of CMAP (one or more nerves)

o Unequivocal conduction block: Prox/distal CMAP area ratio <0.5

o Possible conduction block: Prox/distal CMAP area ratio <0.7

o Temporal dispersion: Prox/distal CMAP duration ratio >1.15

CSF

• Raised protein (however normal in 14%)

Nerve biopsy

• Teased fibre analysis to determine demyelination and inflammation

MRI of Nerve roots

• May show increased T2 signal in nerves if relapsing-remitting course and longer disease duration.

Other investigations to exclude associated diseases (from EFNS guidelines):

• Recommended studies

o Serum and urine paraprotein detection by immunofixation

o Fasting blood glucose

o Complete blood count

o Renal function

o Liver function

o Antinuclear factor

o Thyroid function

• Studies to be performed if clinically indicated

o Skeletal survey

o Oral glucose tolerance test

o Borrelia burgdorferi serology

o C reactive protein

o Extractable nuclear antigen antibodies

o Chest radiograph

o Angiotensin-converting enzyme

o HIV antibody

• To detect hereditary neuropathy

o Examination of parents and siblings

o Appropriate gene testing (especially PMP22 duplication and connexin 32 mutations)

o Nerve biopsy

Treatment

IVIG

• NNT = 3 to “improve disability” in one patient

• Overall patient response ~70%

• Improves disability for 2-6 weeks

• Potentially more rapid relief

• ?Less likely than steroids to produce a remission – 85% required ongoing Rx at 3.5 years

• TIALS:

o ICE study – IVIG vs placebo

o ?IMC IVIG vs IVMP

o PATH trial (Lancet 2018)

- SCIG (0.4g/kg/week vs 0.2g/kg/week) vs placebo

- Relapse rate – 33% vs 40% vs 63%

- Higher relapse rates in extension trial with low dose SCIG

- SE: skin reactions and headache

• Dosing:

o IVIG most trials used 2g/kg over 4 days then 0.4-1g/kg every 3-4 weeks

o SCIG 0.2-0.4g/kg/week (70kg pt – 14g-28g weekly)

- Maximum 10g/site

Steroids

• Long used but paucity of trials

• One trial showed similar effects to IVIG (?IMC trial)

• Some suggestion of increased remission rate

• High dose tapering over 12 weeks

• TRIALS:

o PREDICT trial – 40mg dexamethasone monthly pulse vs daily pred – similar effectiveness

Plasma exchange

• Effective in short term treatment in small trials

Other

• Other immunosuppressants used without consistent benefit

• FORCIDP – fingolimod vs IVIG – negative trial

Prognosis

• 2/3 respond to initial treatment

• 10-15% resistant to all treatment

• Complete remission in ~25%

• Severe long term disability in ~15%