CLINICAL FEATURES – CLASSIC (T-cell mediated CIDP)

• Symmetric, slowly progressive weakness in both upper and lower limbs (≥8 weeks).

• Proximal AND distal muscle weakness.

• Sensory loss: vibration & proprioception impaired earlier than pain/temperature.

• Gait difficulty: wide-based, unsteady, positive Romberg.

• Reduced or absent tendon reflexes.

• Fatigue and heaviness of limbs.

• Difficulty climbing stairs, rising from chair, lifting arms above shoulder.

• Facial weakness is uncommon but may occur.

• Cranial neuropathy rare but possible (e.g., diplopia).

• Autonomic symptoms mild (orthostatic light-headedness).

• Relapsing–remitting pattern or chronic progressive pattern.

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CLINICAL FEATURES – PARANODAL / IgG4 CIDP (Anti-NF155, CNTN1, CASPR1)

• More severe at onset compared to classic CIDP.

• Marked distal predominant weakness (more foot/toe/wrist drop).

• Tremor prominent (especially action tremor).

• Ataxic gait: sensory ataxia significantly worse.

• Poor response to IVIG (key clinical clue).

• Better response to rituximab (B-cell mediated disease).

• Cranial nerves more commonly involved than in classic CIDP.

• Sensory loss disproportionately severe, especially vibration & position sense.

• Early involvement of paranodes → rapid loss of conduction.

• May show hypertrophic nerves clinically (palpable nerve thickening in rare cases).

• Facial and bulbar symptoms more frequent in CNTN1 and CASPR1 variants.

• Autonomic symptoms can be more noticeable (urinary difficulty, constipation).

- Rare but possible in severe axonal variants.

- Leads to hypoventilation and need for ventilatory support.

- Loss of proprioception → inability to stand or walk without support.

- Higher impact in paranodal/IgG4 variants.

- Due to delayed diagnosis or inadequate treatment.

- Axonal loss leads to irreversible weakness or sensory loss.

- Orthostatic hypotension, gastrointestinal dysmotility, sweating abnormalities.

- More common in IgG4-positive variants (e.g., anti–CNTN1).

- Neuropathic pain, burning dysesthesia, or deep aching pain.

- Often needs long-term management.

- Long-term steroids → osteoporosis, diabetes, Cushingoid features.

- IVIG → thrombosis, renal dysfunction.

- Plasmapheresis → hypotension, electrolyte imbalance.

- Rituximab → infusion reactions, infection risk.

- Due to muscle weakness + sensory loss + poor balance.

- Thyroiditis, type 1 diabetes, MGUS, other dysimmune disorders.

- Particularly in IgG4-positive (anti-NF155, CNTN1, CASPR1) where

IVIG often fails and B-cell–targeted therapy is required.

Guillain–Barré Syndrome (GBS):

Acute onset (<4 weeks), often post-infectious.

More rapid progression than CIDP.

MMN (Multifocal Motor Neuropathy):

Pure motor involvement.

Asymmetric weakness.

Conduction block but no sensory loss.

Diabetic Polyneuropathy:

Slowly progressive.

Sensory > motor.

History of diabetes.

POEMS syndrome:

Polyneuropathy with organomegaly and M-protein.

Hereditary demyelinating neuropathies (CMT):

Family history.

Slow lifelong progression.

Foot deformities.

Vitamin B12 deficiency:

Subacute combined degeneration.

Macrocytosis.

Paraneoplastic neuropathy:

Associated with cancers (lymphoma, lung, GI).

Rapid declines.

Myasthenia/ALS:

Mismatch between motor & sensory pattern.

Normal sensory NCS in ALS.

Acute onset (<4 weeks), often post-infectious, cranial nerve involvement more common.

Pure motor, asymmetric, conduction block; anti-GM1 antibodies; responds to IVIG (not steroids).

Distal sensory ataxia, tremor, slow progression; IgM paraproteinemia; demyelination has distinctive pattern.

(Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, disialosyl antibodies).

Sensory ataxia + ophthalmoplegia + IgM paraprotein.

Polyneuropathy + organomegaly + endocrinopathy + monoclonal protein + skin changes; sclerotic bone lesions.

TNF-α inhibitors, immune checkpoint inhibitors, chemotherapy agents.

Lyme disease, diphtheria, HIV, hepatitis B/C — look for systemic clues & serology.

Slowly progressive, pes cavus, family history, uniform slowing on NCS.

Recurrent compressive mononeuropathies; PMP22 deletion; conduction block.

Progressive sensory-motor + autonomic dysfunction; biopsy positive for amyloid.

Diabetic or non-diabetic lumbosacral radiculoplexus neuropathy, B6 toxicity, renal failure-related neuropathy, chemotherapy-induced neuropathy.

Painful asymmetric neuropathy, systemic symptoms, abnormal imaging/biopsy.

Autonomic dysfunction, proteinuria, cardiomyopathy; biopsy with Congo red positivity.

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Key antigens include P0, PMP22, MBP (peripheral variant), NF155, CNTN1 etc. These antigens do not exist in bone or muscle.

Failure of regulatory T-cells (Tregs) → autoreactive T-cells escape suppression → target PNS myelin.

Peripheral nerves express MHC-II under inflammatory stress → allows CD4 T-cells to bind and attack → muscles and bones do NOT do this.

Infections, vaccines, trauma, or unknown triggers break the BNB → immune cells suddenly "see" myelin proteins → attack begins.

Myelin basic protein (MBP) and P0 have strong T-cell epitopes that induce inflammation.

PNS is more accessible to immune cells; bone and muscle are less immunogenic and protected.

These IgG4-mediated nodopathies target proteins only present in nodes of Ranvier — nowhere else in the body.

Each autoimmune condition has its own antigenic target — CIDP's target happens to be myelin.

Nerve conduction studies (NCS):

• hallmark test for CIDP

• shows demyelination pattern:

– prolonged distal motor latencies

– slowed conduction velocities

– temporal dispersion

– conduction block (>50% drop in CMAP amplitude between segments)

– absent or prolonged F-waves

• sensory nerve action potentials may be reduced or absent

Electromyography (EMG):

• may show chronic denervation + reinnervation

• helps exclude axonal neuropathies

Cerebrospinal fluid (CSF):

• classic finding: albuminocytologic dissociation

– high protein (>45–55 mg/dL)

– normal WBC (<10 cells/mm³)

• seen in ~90% of classic CIDP but may be normal in IgG4/paranodal type

MRI (spine / brachial plexus):

• nerve-root hypertrophy

• gadolinium enhancement of cauda equina or plexus

• thickened peripheral nerves in long-standing disease

Ultrasound of peripheral nerves:

• nerve enlargement (cross-sectional area ↑)

• non-uniform enlargement in classic CIDP

• uniform enlargement in hereditary neuropathies → helps differentiate

Blood tests (to exclude mimics):

• HbA1c / glucose (diabetes neuropathy)

• Vitamin B12, folate

• Thyroid profile

• Serum electrophoresis + immunofixation (rule out MGUS, myeloma)

• ANA, ANCA, ENA panel

• HIV, hepatitis B/C, Lyme (region-specific)

Autoantibody testing (important new category):

• Anti-NF155 (IgG4)

• Anti-NF186

• Anti-CNTN1 (IgG4)

• Anti-CASPR1

• strongly associated with *paranodal / nodal antibody-positive CIDP*

• these patients respond poorly to IVIG but better to Rituximab

Nerve biopsy (rarely needed):

• segmental demyelination + remyelination (“onion bulb” formation)

• macrophage-mediated demyelination

• indicated only when diagnosis uncertain, or suspected vasculitis

DISTINGUISHING FEATURES – CLASSIC vs IgG4 CIDP

• Classic CIDP → IVIG-responsive, no specific autoantibody.

• IgG4 CIDP → IVIG-nonresponsive, requires rituximab.

• Classic → more proximal weakness.

• IgG4 → more distal weakness + tremor + sensory ataxia.

• Classic → T-cell mediated demyelination.

• IgG4 → antibody-mediated disruption of paranodal proteins.

• Classic → mild sensory loss.

• IgG4 → severe sensory ataxia.

• Classic → chronic course.

• IgG4 → often subacute and more aggressive early phase.

CLASSIC CIDP — T-cell + Macrophage Mediated Demyelination

• Breakdown of peripheral nerve immune tolerance → activation of autoreactive CD4+ T cells.

• CD4+ Th1 and Th17 cells cross the blood–nerve barrier and release pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17).

• Macrophages penetrate Schwann-cell basal lamina → strip compact myelin → “macrophage-mediated demyelination.”

• Complement activation contributes to Schwann-cell injury.

• Demyelination causes conduction block, slowed nerve conduction velocity, and dispersed CMAPs.

• Chronic cycles of demyelination → remyelination → onion-bulb formation → visible on nerve biopsy.

• Blood–nerve barrier becomes leaky due to inflammatory cytokines.

IGG4 PARANODAL CIDP — Autoantibody-Mediated (NF155 / CNTN1 / CASPR1)

• Autoantibodies are IgG4 isotype → functionally monovalent → do NOT fix complement.

• The paranode normally anchors myelin loops to the axonal membrane (septate junction).

• Binding of IgG4 autoantibodies → disrupts axo–glial adhesion → detaches myelin loops from the axolemma.

• No macrophage infiltration, no complement deposition.

• Sodium-channel clusters at the node become disorganized → severe conduction block.

• Pathology is “nodopathy/paranodopathy,” not classical demyelination.

• Rituximab is effective because depletion of B cells removes the source of IgG4 autoantibodies.

KEY DIFFERENCES — Classic vs IgG4 CIDP

• Classic responds to IVIG, steroids, plasmapheresis.

• IgG4 variants respond best to rituximab; IVIG often fails.

• IgG4 CIDP shows severe ataxia, tremor, early disability due to paranodal dysfunction.

CIDP is an autoimmune demyelinating neuropathy with multifactorial triggers; no specific environmental or lifestyle factor has been reliably linked to disease onset. Prevention focuses on avoiding known treatment-related complications rather than preventing the disease itself.

Supportive recommendations:

• Early recognition of symptoms → prevents long-term disability through timely treatment.

• Optimizing general immune health (adequate sleep, nutrition) – general advice; NOT proven to prevent CIDP.

• Controlling diabetes, thyroid disease, and other metabolic disorders – helps avoid worsening neuropathy but does not prevent CIDP.

• Avoid unnecessary immune-suppressing medications unless prescribed.

• For patients receiving steroids → monitor glucose, BP, cataracts, infection risk.

• For patients on IVIG → ensure adequate hydration; monitor for thrombosis or renal injury.

• For patients on immunosuppressants → regular CBC & LFT monitoring to prevent complications.

Positive Romberg sign

Broad-based gait

Distal muscle wasting in long-standing cases

Reduced or absent ankle, knee, biceps reflexes

Nerve conduction slowing (demyelination)

Mild tremor (less common)

Poor coordination due to nodal dysfunction

Nerve enlargement on ultrasound (often marked)

CSF protein may be extremely high

Reflexes absent even when strength seems relatively preserved early

Loss of vibration sense + proprioception early

Often anti-NF155 positive (IgG4 subclass)

CIDP is caused by immune-mediated attack on peripheral nerve myelin and Schwann-cell structures. Both humoral and cellular mechanisms contribute.

Arms and legs affected equally

Numbness, tingling, “pins & needles” in feet/hands

Gait imbalance—worsening in dark or uneven surfaces

Reduced endurance during daily activities

Facial weakness rarely

Mild back pain radiating to legs

Autonomic symptoms usually mild (dryness, constipation)

Poor temperature sensation; burning or cold dysesthesia

Grip weakness more prominent than proximal weakness

Severe sensory loss in soles → stamping gait

Frequent tripping due to loss of position sense

Occasional neuropathic pain (less in NF155, more in CNTN1)

Diplopia or bulbar symptoms very rare

Autonomic dysfunction uncommon

Prednisolone or pulsed dexamethasone reduces T-cell–mediated inflammation of peripheral myelin.

Useful in classic CIDP but less effective in nodal/paranodal IgG4 variants.

IVIG modulates Fc-receptors, neutralises pathogenic antibodies, and down-regulates inflammatory cascades.

Most effective in IgG4-positive nodal variants and classic CIDP with good early response.

Removes circulating pathogenic antibodies and complement factors.

Highly effective in rapidly progressive or severe weakness or when IVIG fails.

Many patients relapse when therapy is stopped, so a slow taper or spaced IVIG cycles is required.

Goal is functional stability with minimum dose.

Azathioprine, mycophenolate, cyclosporine or methotrexate used as steroid-sparing agents.

Do not work fast; usually take 3 to 6 months before benefit.

Most effective for CNTN1, NF155, NF186, CASPR1 antibody-positive CIDP.

Targets B-cells producing IgG4; dramatic improvement possible when classic therapy fails.

Used in severe aggressive disease unresponsive to IVIG, steroids or rituximab.

Requires careful monitoring due to toxicity.

Strengthening and gait training improve functional recovery.

Prevents contractures, foot drop, fatigue and long-term disability.

Neuropathic pain may require pregabalin, gabapentin or amitriptyline.

Avoid excessive sedatives in severely weak patients.

Watch for steroid complications, IVIG-related aseptic meningitis and thrombotic events, and relapse after dose reduction.