Immune Demyelinating PN

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CHRONIC IMMUNE POLYNEUROPATHIES: MYELIN PATHOLOGY

Demyelinating PN
Comparative features
Treatment strategies

CIDP
Clinical features
Associated disorders
Laboratory features
Pathology
Treatments
Variants
Antibodies
Contactin-1
GALOP syndrome
GD1a: Motor-Sensory neuropathy
GD1b: CANOMAD; CANDA
GM1: Multifocal motor neuropathy
Lgi-4
MAG associated neuropathy
Neurofascin
Sulfatide
Osteosclerotic Myeloma
Other demyelinating neuropathies
POEMS Syndrome

Antibody testing

Also see: Immune axonal neuropathies

Multifocal Motor Neuropathy (MMN)
Myelinated Axons: Segmental demyelination

Chronic Immune Polyneuropathies with Myelin Pathology (CIPM) COMPARATIVE FEATURES
Neuropathy (Antibody)	Clinical Features	Electrophysiology	Antibody	M-Protein*	Treatment
Chronic Immune Demyelinating Polyneuropathy (CIDP)	Motor > Sensory Weakness: Proximal & Distal Symmetric Onset: 1 to 80 yrs Chronic/Relapsing	Motor + Sensory Δ NCV: Slow Conduction Block Distal Latency: Long F-waves: Slow	Targets β-tubulin Heparan sulfate Class: IgM or IgG Frequency: 10%	15%	T-cell immunosuppression Prednisone Cyclosporine A Methotrexate HIG Plasma Exchange
Multifocal CIDP Also see: CIDP variants	Chronic Motor > Sensory Weakness: Distal > Proximal Asymmetric Arms > Legs Onset: 15 to 75 yrs	Motor + Sensory Δ NCV: Slow Conduction Block Distal Latency: Long F-waves: Slow	?	?	T-cell immunosuppression Prednisone HIG
Multifocal Motor Neuropathy (MMN)	Motor only Distal > Proximal Arms > Legs Asymmetric Onset: 25 to 80 yrs Slowly progressive	Motor only Conduction Block Axon Loss: Distal EMG: Denervation with disease progression	Targets Co-GM1, NP-9 or NS6S Class: IgM Frequency: 80%	20%	IVIg (Conduction block) B-cell immunosuppression Cyclophosphamide ± Plasma Exchange Rituximab
Myelin- Associated Glycoprotein (MAG)	Sensory > Motor Distal; Symmetric Gait disorder Tremor Onset: > 50 yrs Slowly progressive	Motor + Sensory Δ Distal Latency: Long NCV: Slow No conduction block Axon Loss: Distal legs	Target: MAG M-protein Class: IgM Frequency: 95%	85%	B-cell immunosuppression Cyclophosphamide ± Plasma Exchange Rituximab ? Fludarabine Not HIG
Polyneuropathy Organomegaly Endocrinopathy M-protein Skin changes (POEMS)	Sensory & Motor Symmetric Onset: 25 to 60 yrs	NCV: Slow Axon Loss	Target: ? M-protein Class: IgA or IgG	100%	Irradiation (Local lesions) Chemotherapy Stem cell transplant
Neurofascin	Sensory & Motor Distal Tremor Onset: Adult Progressive	NCV: Slow	Target Neurofascin Class: IgG₄	No	Rituximab Corticosteroids
Contactin-1	Sensory & Motor Distal or Diffuse Onset: Adult, late Progressive	Distal latency: Long Conduction block	Target Contactin-1 Class: IgG	No	Prednisone Not HIG
Less prominent Demyelinating Features
GALOP	Gait Disorder Sensory > Motor Distal; Symmetric Onset: > 50 yrs	Motor + Sensory Δ Distal Latency: Long NCV: Slow No conduction block	Target Sulfatide in lipid membrane Class: IgM	80%	HIG Cyclophosphamide ± Plasma Exchange
Sulfatide	Slowly progressive Sensory > Motor Distal; Symmetric Onset: > 45 yrs	Distal Latency: Long NCV: Slow Axon Loss: Distal	Target Sulfatide Class: IgM	90%	HIG Cyclophosphamide ± Plasma Exchange
GM2 & GalNAc-GD1a	Sensory > Motor Ataxia: Limb & Gait Distal Symmetric or Asymmetric Onset: Adult Slowly progressive	NCV: Slow	Targets GM2 GalNAc-GD1a Class: IgM	Common	HIG

* Frequency based on testing by immunofixation methodology.
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Chronic Immune Demyelinating Polyneuropathy (CIDP)

Clinical features
Associated disorders
Comparative features
Laboratory features
Pathology
Treatments
Variants

Epidemiology
- Male > Female: 2:1
- Onset age
  - Average: 50 years
  - Range: All ages
  - Childhood: ~10%; Youngest < 1 year
- Prevalence: 1.2 to 7.7/100,000
- Earlier onset in relapsing-remitting than monophasic/progressive group
- Preceding events
  - ? Increased frequency of immunizations or infections
  - Drug treatment
    - Tumor necrosis factor (TNF)-α antagonists (Etanercept; Infliximab)
    - PD-1 antibody
- Genetic associations
  - Polymorphic GA repeat in SH2D2A
    - SH2D2A: T-cell-specific adapter protein; Involved in negative control of T-cell activation
  - Protease inhibitor type M3 allele
Clinical Features: Motor > Sensory
- Onset
  - Slowly progressive: Weeks to Months
  - Occasionally
    - Acute: Days to weeks
    - Subacute: 4 to 8 weeks
- Weakness
  - Proximal + Distal
  - Symmetric (except in CIDP variants)
  - May be more prominent than muscle atrophy
  - Most disabling feature
- Sensory
  - Loss
    - All modalities
    - Distribution: Legs > Arms; Distal
    - Mild: Rarely disabling
  - Pain: 20%; Especially in sensory variant
- Autonomic: Occasional patients with
  - Micturition change: Voiding difficulty or urgency
  - Horner's syndrome
- Tendon reflexes: Reduced or absent early in course in arms & legs in 90%
- Nerve hypertrophy
  - < 10% clinically apparent
  - Detectable by MRI (50% to 80%)
    - In roots & brachial or lumbar plexus
    - Gadolinium enhancement (T₂)
    - Radiology
  - Cranial nerves occasionally involved
  - More common with: Relapsing-remitting course; Longer disease duration
  - Associated with: Onion bulbs in peripheral nerve
  - No relation to age, sex, time from last relapse, type of therapy or disability status
- Cranial nerves
  - Ocasional, Mild, Symmetric
  - Weakness of VII, X, XII
- Intention tremor: Occasional patients
- CNS features ¹⁹: Rare patients
- Time course: Variable types
  - Chronic progressive: 60%
    - Months (> 2) to years
    - Often reach plateau
    - Onset age: Older; Mean 51 years
  - Relapsing: 30%
    - Onset age: Younger; Mean 27 years
  - Acute onset: Weeks to 2 months; 15%
  - Monophasic with remission: Especially children
- Prognosis worse with
  - Progressive course
  - CNS involvement
  - Pathology: More Axon loss
- Associated disorders
  - Monoclonal Antibodies (M-proteins)
  - HIV
  - Diabetes: 20% to 30%; HbA1C high; ~2x increased frequency
  - Other possible associations
    - Infections: Chronic active hepatitis (Hepatitis C)
    - Immune
      - Graft-vs-Host
      - CNS demyelination
      - Systemic
        
        General: 15%; 3x higher than general population
        
        Nephrotic syndrome: Neurofascin antibodies
        
        Thyroiditis
        
        Rheumatic
    - Neoplasms ⁵⁴
      - Hematologic: Lymphoma, Non-Hodgkins; Melanoma
      - Solid tumors (9%)
    - Drugs: Interferon-α treatment; TNF-α antagonists
  - Greater Frequency of HLA-B8
Laboratory features
- Electrophysiology
  - Conduction Block
  - Slow Nerve Conduction Velocities
    - < 80% of lower limit of normal
    - Variable velocities among nerves
      - Differential diagnosis: HNPP; CMT X
    - Motor & Sensory
  - CMAP changes
    - Temporal dispersion
    - Prolonged Distal latencies
  - F-waves
    - Impersistence
    - Prolonged latencies
  - Amplitude of sensory potentials: Correlates poorly with degree of axon loss
- Serum Autoantibodies
  - IgM & IgG vs Tubulin (10%)
    - Binding epitope: Tubulin amino acids 301 to 314
    - Clinical syndrome: Asymmetric CIDP
  - IgM vs Heparan Sulfate
    - Clinical syndrome: CIDP with acute onset
  - IgG binding to Schwann cell processes (non-myelinating, cultured) & neurites (distal tips) ²⁰
    - CIDP frequency: 26%
    - Control frequency 8%
  - IgG (IgG₄) & IgM binding to Neurofascin (NF140, NF155, NF186) ⁴¹
    - Neurofascin
      - Adhesion molecule
      - Locations & Tissue binding patterns
        
        PNS
        
        General location: Nodes of Ranvier
        Neurofascin-155: Glial cells at Paranodes
        Neurofascin 140 & 186: Axons at Nodes of Ranvier & initial segments
        
        CNS: Neuropil of cerebellum, brain & brainstem
    - Clinical syndromes
      - Demyelinating neuropathy/Nodopathy: Chronic
        
        Frequency: 4%; IgG or IgM vs Neurofascin-155
        Distal predominant weakness; Pain; Treatment refractory: Neurofascin-155 IgG₄ antibody ⁷²
        Acute onset, Chronic ⁷³: NF-186 antibody
      - Polyneuropathy with Sensory Ataxia & Sub-acute onset ± Demyelination: NF-140/186 antibody
      - Combined central & peripheral demyelination (CCPD)
      - IgM vs NF-155 ⁵⁶: Chronic or Acute Neuropathy
      - GBS-like, Acute onset, Monophasic polyneuropathies: Neurofascin-186
      - Multiple sclerosis-like
      - Neurofascin genetic disorder: NEDCPMD
    - Pathology: Nodopathies
    - Antibody properties
      - Location: Serum ± CSF
      - Types
        
        IgG₄ vs Neurofascin-155
        
        Most commonly reported with chronic demyelinating polyneuropathies
        
        Pan-Neurofascin IgG antibodies: Acute onset polyneuropathies
        IgG Neurofascin-186 antibodies: Acute onset polyneuropathies; GBS-like syndromes
        IgM vs NF-155
  - IgG binding to Contactin-1 (CNTN1) ³⁷
    - Antibody
      - IgG binding to: CNTN1 or CNTN1/CASPR1 complex
      - Antibody types ⁵⁷
        
        IgG₄: CIDP-variant syndromes
        
        Binding to paranodal domains
        
        Induce nodal damage
        
        IgG₂: CIDP-variant & GBS
        
        IgG₃: During acute onset; Induce conduction block
        IgG₁: Fewer pathogenic effects
        Other: Acute sensory polyradiculopathy (AISP)
      - Tissue binding: Ventral > Dorsal roots
    - Epidemiology
      - 17 patients described
      - Antibody frequency in demyelinating PN: 2.4% to 6%
    - Contactin-1 protein
      - Disease: Lethal Congenital Myopathy
    - Polyneuropathy ⁷⁵
      - Clinical
        
        Male: 75%
        Onset
        
        Patient ages: 2 to 76 years; Mean 50 years
        Subacute: Over 8 to 12 weeks; Initial diagnosis may be GBS
        
        General
        
        Most patients with sensory-motor syndromes
        
        Few patients with predominatly sensory or motor
        
        Weakness
        
        Distal (87%), Proximal (74%), or Diffuse
        
        Legs often > Arms
        Symmetric
        
        May be mild or severe
        
        Sensory
        
        Ataxia (70%)
        Paresthesias
        
        Loss
        
        Modalities: Large & Small fiber
        
        Distal > Proximal
        
        Often severe
        
        Pain (20%)
        
        Tendon reflexes: Reduced
        Tremor
        Course: Progressive
        Systemic: Renal (35%)
        Treatment response
        
        Prednisone: Some response in 65% to 70?
        IVIg: No response in 40%
        Rituximab (90%) ⁴⁶
      - Laboratory
        
        NCV
        
        Axon loss: Early; CMAP amplitudes reduced
        
        Distal latencies: Prolonged
        Conduction block
        Velocities, Motor: Reduced; 19 to 30 M/s
        Temporal dispersion
        SNAPs: Reduced or Absent
        
        CSF
        
        Protein: 46 to 75
        
        Cells: 1 to 10
        
        CNTN1 antibodies
        
        Some correlation of titers with disability
        
        May disappear after treatment
        
        Serum Contactin-1 levels: Low
        Neurofilament light levels: Often high
        Nerve pathology
        
        Axon loss
        
        Axo-glial detachment
        
        Remyelination
  - IgG binding to Contactin-associated protein 1 (Caspr; CNTNAP1) ⁴⁹
    - Antibody
      - IgG binding to CNTNAP1
      - Antibody types
        
        IgG₃: GBS patient
        
        IgG₄: CIDP patient
      - Tissue binding: Paranodal regions of axons; Small DRG neurons
    - Epidemiology: 15 patients, 1% to 2% of CIDP-like syndromes
    - Caspr protein
      - Complexed with: Neurofascin-155; Contactin-1 (CNTN1)
      - Axon locations: Paranodes
    - Polyneuropathies
      - Clinical
        
        Patient ages: 30 years (CIDP); 69 years (GBS)
        
        Prodrome: Infections 10 days before onset
        
        Pain: Distal arms & legs; Back
        
        Sensory loss: Distal
        Weakness: Distal > Proximal
        Treatment: Most benefit from Rituximab in CIDP patient
      - NCV
        
        Distal motor latency: Prolonged
        
        SNAP amplitudes: Normal amplitude
        
        CMAP amplitudes: Normal or Reduced
        
        Conduction velocities: 12 to 34 m/s
        F-waves: Long latency
      - Nerve pathology (CIDP)
        
        Damage to nodal & paranodal region
        
        Axon loss
        
        No demyelination
  - IgG binding to LM1 glycolipid ³⁸
    - IgG binding to LM1 alone or LM1/GM1 or LM1/GD1b complexes
    - Epidemiology: Frequency in demyelinating neuropathies = 10%
    - May also occur in GBS-like disorders
    - CIDP: Clinical associations
      - Ataxia (67%)
      - Age: Older
      - No cranial nerve features (Face, Bulbar, EOM paresis)
      - Corticosteroid treatment: Commonly responsive
  - IgG or IgA M-protein
    - Clinical: Typical CIDP
    - Frequency: Occasional
  - Serum CK: High in 27% ⁴⁸
  - Chemokines & Cytokines: Serum levels ⁴⁵
    - Hepatocyte growth factor
      - High in CIDP, not multifocal CIDP
      - Patients often respond to corticosteroid treatment
    - Other high levels: TNF-α, MIP-1β, IL-1β; Th-1
  - CSF
    - High protein (> 90%)
    - No (< 10) cells: Exceptions are HIV & Lyme associated disease
  - MRI
    - CNS: Abnormal in 5%
    - Spinal roots & plexus
      - Hypertrophy: Especially cases of long duration
      - Gadolinium enhancement: In active disease; Very common in children
- Rule-out
Pathology: Nerve biopsy not necessary for diagnosis
- Location: Spinal roots & Peripheral nerves
- Inflammation: 25% to 50%; Mild
  - Locations: Epineurial & endoneurial; Perivascular; Rarely perineurial
  - T-cells: 25%; Perivascular
    - Most patients with normal #s of T-cells
    - High T-cells more common: Females; Severe disease; Very high CSF protein
  - Macrophages: Activated; Upregulated MHC Class II expression
- Demyelination: Macrophage mediated
  - Multifocal: Especially with active demyelination
  - Segmental
  - Thin myelin sheaths
  - Differential fascicular involvement: Some
  - Onion bulbs in chronic cases (20%)
  - Tomacula: Occasional
- Remyelination
  - Few lamellae of loosely compacted myelin
  - Schwann cell cytoplasm rich in organelles
  - Schwann cell mitoses
- Edema: Endoneurial; Subperineurial
- Axon loss
  - Variable fascicular involvement
  - Patchy loss of axons
  - Loss of myelinated axons
  - Axon regeneration (20%)
- Active demyelination: Macrophage mediated myelin stripping
  - Macrophage process breaching basal lamina & between myelin lamellae: Visible in minority
  - Unmyelinated larger axons
  - Edema: Subperineurial & Endoneurial
- Teased nerve: Segmental demyelination; Irregular internode length
- Skin biopsy: Intraepidermal axons ⁷⁰
  - Reduced numbers: Non-length dependent pattern
  - More loss with: Increased disability; Disease instability
- Muscle
  - Denervation
  - Type I muscle fiber predominance
Treatment
- Try individual therapies sequentially
- Response to one does not predict efficacy of others
- Therapeutic modalities
  - Prednisone: 60 to 100 mg/day p.o., then taper
    - Start taper after: 3 to 6 months; or clinical improvement begins
    - Taper slowly
      1. Initially by 5 mg on alternate days q2 to 4 weeks until 80 mg and 10 mg
      2. Then by 2.5 mg on alternate days q2 weeks to 80 mg and 0 mg
      3. Then taper high day dose by 5 mg q 4 weeks until 40 mg and 0 mg
      4. Then by 2.5 mg q4 weeks
      5. Minimum dosage is qod if possible
    - Many CIDP patients will relapse if Prednisone is stopped without additional immunosuppression
  - Methylprednisolone (Solumedrol; IV): 1 gram/day x5
    - Then intermittent (tapering) additional iv or oral doses (1 gram): Weekly to Monthly
  - Human Immune Globulin
    - Initial dose: 1g/kg/day x2
    - Follow-up: Repeat doses of 400mg/kg to 2g/kg, as needed, every 1 week to 4 months
    - Other dosages: 400 mg/kg 1 to 2 times per week for 8 or more weeks
    - Responsiveness to HIG in Japanese associated with TAG1 (Contactin 2) ³⁰
      - GAT haplotype: Present in 57% of responders & 34% of non-responders
  - Cyclosporine A
    - Initial treatment when prednisone not indicated
    - Dose: 2.5 mg/kg b.i.d., then taper to monimum effective dose
  - Plasma Exchange
  - Azathioprine:
    - To lower corticosteroid or Cyclosporine dosage
    - Dose: 2.5 to 3 mg/kg
  - Methotrexate: 7.5 to 25 mg p.o. on weekends
  - Cyclophosphamide: Monthly IV pulse x 6; For refractory patients
  - ? Interferon α 2A
- Likelihood of treatment dependence increased ⁴²
  - Multifocal deficit
  - No reduction in nerve size
  - Longer delay to effective treatment
  - IVIg treatment (vs corticosteroids)

Chronic Immune Demyelinating Neuropathies: Variants

β-Tubulin Ab
Childhood
CIDP
CIDP + CNS (CCPD)
Contactin-1 Ab
Diabetes
IgM vs GM2 & GalNAc-GD1a
Motor
CIDP
MMN
Polyradiculopathy
Multifocal
Upper limb

M-protein
IgM
IgG or IgA
Neurofascin Ab
Onset
Acute
Subacute
Perineuritis
POEMS
Sensory
CIDP
CISP Polyradiculopathy

Multifocal CIDP ⁹
- Nosology
  - Multifocal CIDP
  - Lewis-Sumner ¹
  - MADSAM
  - Also see: Upper limb CIDP
- Age range: 28 to 58 years
- Weakness
  - Asymmetric
  - Distal > Proximal
  - Arms > Legs (78%)
  - Proximal syndrome: Occasional
    - Phrenic nerve: Diphragm weakness; Respiratory insufficiency
    - Suprascapular nerve: Infraspinatus ± Supraspinatus weakness
    - Other scattered distal & proximal muscles
- Sensory loss: Distal; Pansensory; Rarely severe or disabling
- Tendon reflexes: Focal loss
- Course: Slowly progressive, or Relapsing-Remitting
- Laboratory
  - Electrophysiology
    - Multifocal conduction block
    - Nerve conduction velocities: Variably slow
    - Distal latencies: Variably prolonged
  - CSF protein: High but usually < 100 mg/dL
  - IgM anti-GM1 antibodies: Never
  - MRI: Swollen nerves in brachial plexus with high T2 signal
  - Nerve pathology
    - ± Demyelination (Patchy)
    - Differential fascicular loss of axons
- Treatment: Prednisone; HIG
Multifocal upper limb CIDP ^2, ⁶
- Male:Female = 1.9:1
- Onset
  - Mean = 43 to 54 years; Range 9 to 75 years
  - Rarely childhood
  - Acute or Progressive
  - Distal
- Clinical
  - Weakness
    - Onset: May be motor, sensory, or both; With reduced pain
    - Single or multiple upper extremity nerves
    - Distal > Proximal
    - Asymmetric > Symmetric
    - Monomelic or Bilateral
  - Sensory
    - Paresthesias or numbness early in most
    - Pain: 22%; Often localized to peripheral nerve territory
    - Sensory loss: Usually mild, distal; Often asymmetric
  - Tendon reflexes: Often reduced in involved limb(s)
  - Course
    - Progressive: To legs in 25%
    - Some stabilize or spontaneously resolve
  - Cranial nerves: 17%; Optic; III; VII
  - Rule out: Brachial neuritis
- Laboratory
  - Anti-GM1 ganglioside antibodies: Uncommon
  - CSF protein
    - High in 40% to 72%
    - Mean 64 mg/dL; Range 21 to 128
  - Nerve conduction studies
    - Conduction block (100%): Proximal or Distal segments
    - Velocity Slowing 35%
    - CMAP amplitude: Reduced (56%)
    - Abnormal SNAPs: Some patients; Up to 83%
    - Leg involvement: 34%
  - MRI
    - Usually normal
    - May have brachial plexus lesions
- Treatment
  - Response to Prednisone or HIG in some (> 50%)
  - Often less recovery than with generalized CIDP
Motor predominant CIDP ³⁶
- Clinical
  - Onset
    - Age: 8 to 24 years
    - Weakness: Progressive over 1 to 6 months
  - Weakness
    - Distal > Proximal
    - Symmetric
    - Arm predominant or Arms & Legs
    - May be exacerbated by heat (Uhthoff-like phenomenon)
  - Sensory exam: Normal
  - Tendon reflexes: Diffusely absent
- Laboratory
  - Nerve conduction studies
    - Motor: Distal & F-wave latency long; Conduction block; NCV slowed (17 to 33 M/s
    - Sensory: Normal or reduced SNAP amplitudes
  - CSF: Protein high
  - GM1 antibodies: Not present
- Differential diagnosis: Multifocal motor neuropathy
Motor, Demyelinating Polyradiculopathy ⁴⁰
- Epidemiology: 1 patient
- Clinical
  - Onset: Back pain
  - Weakness
    - Legs: Distal > Proximal
    - Arms: Normal
  - Sensory: Normal
  - Tendon reflexes: Absent at ankles
  - Bowel & Bladder: Normal
  - Course: Slow progression over 10 years
  - Treatment: Improvement with plasma exchange, not IVIg
- Laboratory
  - MRI: Cauda equina hypertrophy; Radicular enhancement
  - NCV
    - Sensory NCV: Normal
    - Motor amplitudes: Leg CMAPs normal or reduced
    - Conduction velocities: Normal
    - F-waves: Absent or Prolonged
  - EMG: Denervation in legs, Proximal & Distal
  - CSF protein: High (100)
  - Serum CK: 370
  - Nerve root biopsy
    - Onion bulbs
    - Axon loss
    - No inflammation
Sensory CIDP ⁵⁰
- Clinical
  - Onset age: Adult; Range 25 to 75 years
  - Sensory
    - Loss
      - Distal predominant
      - Legs > Arms (50%) > Face (25%)
      - Pansensory or Small fiber
      - Ataxia: Some patients; Rule out IgM vs GD1b or MAG
    - Pain
    - Paresthesias: Distal > Proximal
  - Motor: Normal or Minimal distal weakness
  - Tendon reflexes: Absent, Reduced or a few Normal
  - Treatment: Poor response to prednisone or HIG
- Laboratory
  - Electrophysiology (NCV): Motor & Sensory demyelination
    - Motor
      - Conduction block
      - NCV: Slow
      - Distal latency: Long
      - F-wave latencies: Prolonged
      - CMAP amplitudes: Mildly reduced
    - Sensory: NCV Slow
    - SSEP: Proximal conduction abnormalities
  - MRI
    - Nerve roots: Contrast enhance & Enlarged
  - CSF
    - Protein high (73%):? Range 36 to 140 mg/dL)
  - M-protein 15% (Rule out POEMS)
  - Nerve biopsy
    - Axon loss
    - Hypomyelinated axons (70%)
    - Onion bulbs (30%)

Sensory, Demyelinating Polyradiculopathy (SDP; CISP) ³⁹
- Epidemiology: > 80 patients
- Clinical
  - Onset
    - Age: Median 55 to 60 years; 18 to 80
    - Gait disorder
  - Sensory loss
    - Gait ataxia (80%): Falls 57%; Gait aids 25%
    - Proprioception: Reduced (97%)
    - Pan-modal
    - Arms: Involved early (1st 6 months) or at onset
  - Discomfort
    - Paresthesias (78%)
    - Pain (5% to 22%)
  - Cranial nerves
    - V: Sensory loss
    - III
  - Tendon reflexes
    - Absent in 85%
    - Ankle or Leg loss in others
  - Strength: Normal
  - Course
    - Progression: Months to Years
    - Gait aids required (30%)
  - Treatment response
    - Frequency of improvement
      - Common (95%)
      - Gait improved
    - Modalities: IVIg; Prednisone
    - Monophasic (78%): Treatment could be stopped
  - Variant syndrome: CISP+
    - Weakness: Distal legs, Mild
    - NCV: Mild changes
      - F-waves long
      - NCV mildly slow
      - Sural SNAP present
    - SSEP: Nerve root involvement
- Laboratory: CISP
  - NCV
    - Conduction velocities: Normal or Mildly reduced
    - SNAP amplitudes: Normal (36%) or Reduced
    - Abnormal radial/Normal sural pattern (20%)
    - Motor: Normal
    - SSEP: Nerve root involvement
  - M-protein: 20%
  - CSF
    - Protein: High (90%), Range 36 to 140
    - Cells: Lymphocytes (10%)
  - MRI
    - Nerve roots: Enhancement, Thick, Clumped
    - CNS demyelination (15%)
  - Nerve biopsy
    - Axon loss: Large > Small myelinated
    - Demyelinating features (70%)
      - Onion bulbs in proximal nerves
    - Inflammation: Scattered endoneurial cells
      - Onion bulbs
      - Myelin sheath: Thin
    - Epineurial mononuclear cell inflammation
      - T-cells & Macrophages

From: M. Al-Lozi

CISP: Lumbo-Sacral roots enhance

Childhood CIDP
- Prevalence: ~ 1 in 300,000; Male > Female
- Preceding infections or vaccinations: 54%
- Onset: Childhood to Teens; Rarely infancy
- Course: Several patterns
  - Monophasic: 25%
    - Peak disability < 3 months
    - Off medications in < 1 year
  - Chronic
    - Persistent weakness & disability
    - Require continued immunosuppression
  - Acute onset: 25%
  - Relapsing: Often treatment related
- Clinical patterns
  - Overall
  - Weakness: Proximal + Distal; Usually symmetric
  - Sensory loss: Pansensory; Distal; Symmetric
  - Tendon reflexes: Reduced or Absent
  - Other: Rare clinical CNS features
- Disease Associations
  - Comparison with adult CIDP: Less with M-proteins & Diabetes
  - CNS changes: Rarely reported ¹⁹
  - Other systems: Renal; Hearing ²⁸
- Prognosis
  - Better for remission with relatively rapid onset
  - Worse: Axon loss
- Laboratory
  - Pathology
    - Similar to adult CIDP
    - Chronic cases may have prominent demyelinating features
  - MRI: Gadolinium enhancement of roots very common; Occasional CNS changes
  - Nerve conduction: Similar to adult CIDP
- Treatment
  - Corticosteroids: Response in > 90%
  - IVIg: Response in > 80%
  - Methotrexate: 2nd line treatment
CIDP + IgM vs β-Tubulin
- Clinical
  - Weakness: Slowly progressive; Asymmetric
  - Hyporeflexia
  - Poor response to prednisone
- Laboratory
  - Antigenic epitope: β-tubulin amino acids 301-314
  - IgM M-protein: Common
CIDP associated with M-proteins ⁶⁵
- Frequency: 12% to 30%
- IgG or IgA
  - Frequency: 6%
  - Clinical syndrome
    - Similar to typical CIDP
    - Onset age: Older
    - Weakness: Slowly progressive; Symmetric
    - Cranial nerve involvement: More common
    - Response to immunotherapy: Partial or Good
  - Antibody targets: None described
- IgM
  - Up to 6%
  - Motor CIDP: More frequent
  - Antibody binding: MAG; GM1; β-Tubulin
CIDP + Diabetes mellitus ⁸^,⁶⁴^,⁶⁵
- Epidemiology: Diabetes prevalence in CIDP
  - 14% to 20%
  - 2x more than expected
- Patient characteristics: Most similar to CIDP alone
- Comparison to CIDP in general
  - Clinical
    - Onset Age: Older (8 years)
    - Examination: Generally similar to no diabetes
    - "Typical" form: More frequent
    - Possibly more common: Gait imbalance; Autonomic
    - Disability frequency & Severity: Similar or More
  - Electrodiagnostic: More axon loss
  - Treatment: Less, or Similar, improvement
CIDP: Acute onset (CIDP-AO) ³²
- Onset: Progressive over days to weeks
- Clinical
  - Weakness
    - Symmetric
    - Proximal & Distal
    - Uncommon: Face, Tongue, Eye movements, Respiratory failure
    - Less severe than GBS
  - Sensory loss: Distal
  - Tendon reflexes: Reduced
  - Course
    - Slower progression to nadir than GBS
    - Partial, but not complete improvement in strength over months
    - Treatment related exacerbations
      - Common
      - Time of first exacerbation: Median 18 days; Range 10 to 54 days
      - Especially > 8 weeks after onset
      - May occur ≥ 3 times
- Laboratory
  - Electrodiagnostic
    - Prominent demyelinating features early in disease course
    - More slowing of motor nerve conduction velocity than GBS
    - Conduction block (30%)
    - EMG denervation (75%)
  - CSF protein: High
  - Antibodies: IgG anti-glycolipid uncommon
CIDP: Subacute onset (CIDP-SO; SIDP) ²³
- Male > Female: 2 to 1
- Onset
  - Age: Childhood or Adult
  - Progressive over 4 to 8 weeks
  - Antecedent infection (38%)
- Clinical
  - Weakness (80%)
    - Symmetric (90%)
    - Proximal & Distal
  - Sensory loss (80%): Distal
  - Tendon reflexes: Reduced
  - Course
    - Improvement with corticosteroid treatment
    - Few relapses
- Laboratory
  - Electrodiagnostic: Demyelination
    - NCV: Slow
    - Terminal latency: Prolonged (50%)
    - Conduction block: 50%
    - Temporal dispersion: 50%
    - Sensory: Absent SNAPs
  - CSF protein: High
  - Nerve biopsy
    - Demyelination: Some patients
    - Inflammation: Epineurial; Some patients
    - Subperineurial edema
CCPD: CIDP + CNS involvement ¹⁹
- Frequency: Rare CIDP patients with CNS features
- Clinical
  - Onset
    - Age: Adult or Childhood; Mean 39 years
    - Acute in 64%
    - Clinical: CNS or PNS features
    - Prodromal infection: 10% to 65%
  - Ocular
    - Papilledema: Associated with high CSF protein
    - Visual loss: Optic atrophy
  - Myelopathy
    - Tendon reflexes: May be brisk
    - Sphincter disorders (58%)
    - r/o Spinal cord compression from enlarged nerve roots
  - Ataxia (10%)
  - Weakness (80%)
    - Legs > Arms
    - Distal
  - Sensory loss
    - 2 patterns
      - Spinal level
      - Distal extremity
    - Pan-modal
  - Tendon reflexes: Reduced 60%; Increased 15% to 25%
  - PNS features: Also see CIDP+
  - Course
    - Progressive or Relapsing
    - Disability: May be severe
  - Treatment: Corticosteroids; Rituximab; IVIg
  - Rule out: Dysmyelination, late onset (MLD; Krabbe)
- Laboratory
  - Antibodies, serum
    - Neurofascin 155: IgG (Some IgG₄) (20%)
    - AQP4 (20% to 37%)
    - MAG
  - Brain MRI: Demyelination (25%)
  - NCV
    - CMAP amplitude: Reduced (75%)
    - SNAP amplitude: Reduced (50%)
    - Motor CV: Slow (50%)
    - F-wave & H-reflex latencies: Prolonged
  - Oligoclonal bands (36%)
  - CNS MRI: T2 lesions (90%); Spine > Brain
- CCPD Variant: Multiple sclerosis + CIDP ²⁷
  - MS duration at onset: 4 to 22 years
  - Clinical
    - Weakness: Distal > Proximal
    - Sensory loss: Distal; Pan-modal
    - Tendon reflexes: Reduced or Absent
    - CNS
      - Cerebellar: Ataxia; Nystagmus
      - Demyelination
  - CSF protein: > 120 mg/dL
  - Nerve conduction studies: Demyelinating neuropathy
  - Treatment: IVIg; Corticosteroids
- CCPD Variant: Focal CNS myelin loss: 1 patient
  - CNS: Focal mass-like lesion
  - Weakness: Mild; Distal
  - Sensory loss: Mild vibration
  - Tendon reflexes: Normal
  - NCV: Slow; Long distal latency
Demyelinating neuropathy/Nodopathy, Chronic: Distal predominant weakness; Tremor; Treatment Refractory; NF-155 IgG₄ Ab ⁴³^,⁷²
- Clinical
  - Onset
    - Ages: 4 to 72 years; Mean 31 to 45 years
    - Subacute: Often
    - Younger than Ab- CIDP or MAG PN
  - Weakness (95%)
    - Distal > Proximal
    - More severe than Ab- CIDP
  - Sensory
    - Loss
      - Ataxia (74%)
      - Modalities: Small & Large fiber
    - Paresthesias (85%)
    - Some patients
      - Pain
      - Pseudoathetosis
  - Tremor (42% to 75%)
    - High amplitude
    - Low frequency
    - Postural & Intention
  - Autonomic (45%): Sudomotor
  - Tendon reflexes: Reduced or Lost
  - CNS: CCPD; Cerebellar (20%)
  - Course
    - Chronic: Progressive
    - Onset: May be rapid
    - Gait disorder: Common
    - Relapses
  - Treatments
    - IVIg refractory: 30% to 80% no response; Less response with repeat treatments
    - Corticosteroids: Partial or Transient response (50%)
    - Rituximab ⁴⁶
  - Other clinical syndromes: Neurofascin antibodies
- Laboratory
  - Antibody
    - Target: Neurofascin-155 (NF155)
    - Types
      - IgG₄ ⁵⁹
        
        Frequency: 25% to 60% of Nf155 Ab
        Skin biopsy: Morphological changes at paranodes
      - Other antibody types
        
        Clinical: Features more similar to Ab- CIDP
        
        May be less specific for CIDP
    - Location: Serum
    - Neural tissue staining
      - PNS: Paranodes
      - CNS: Hippocampus; Cerebellar molecular layer
    - Also see: IgM vs Neurofascin-155
  - CSF
    - Protein: Higher than Ab- CIDP
    - Cells: Low or Normal
    - Upregulation of type 2 helper T (Th2) cell cytokines
  - HLA association
    - DRB1*15:01 & DRB1*15:02: 77% vs 17% in other CIDP ⁵⁵
    - HLA-DQB1 06:01 or 06:02
  - Electrodiagnostic
    - Distribution of abnormalities: Bilateral
    - CMAP amplitudes: Reduced; More axon loss than Ab- CIDP
    - NCV
      - Slower than Ab- CIDP
      - Especially: Median motor <24 m/s or Ulnar motor<26 m/s
    - Distal latency: Prolonged; Ulnar DL > 7.4 ms
    - EMG: Less denervation than expected
    - Sural: NCV range 21 to 47 M/s; May be normal
  - Nerve imaging
    - Root enlargement/Enhancement (80%)
  - Nerve pathology ⁵¹
    - Axon loss
      - Myelinated ± Unmyelinated, axons
      - Ovoids: Occasional
      - May be intrafascicular & interfascicular variation
    - Subperineurial edema (50%)
    - Paranodal pathology
      - Axo-glial detachment (Detachment of terminal myelin loops from axolemma)
        
        Common
        
        More with greater axon degeneration
        
        Loss of paranodal transverse bands
      - Swellings (50%)
    - Myelin: More pathology in proximal nerves
      - Segmental demyelination: Some; Present at consecutive internodes; Paranodal
      - Sheath thickness: Reduced in some
      - No: Onion bulbs or Macrophage mediated demyelination
    - Inflammation (10% to 80%): Epineurial
    - Axon regeneration
Polyneuropathy with Sensory Ataxia & Sub-acute onset ± Demyelination ⁵³
- Epidemiology: 5 patients
- Clinical
  - Onset
    - Age: 2 to 75 years
    - Course: Often sub-acute
  - Sensory ataxia (80%)
  - Weakness: Proximal or Diffuse; Symmetric
  - Disability: May be severe at disease nadir
  - Pain: No
  - Tremor: No
  - Treatment response: IVIg (60%); Corticosteroids (60%)
  - Systemic: Associated immune disorders
    - Retroperitoneal fibrosis
    - Nephrotic syndrome
    - Anti-Ro/SSA antibodies
  - CNS: No demyelination
- Laboratory
  - Antibody
    - Target: Neurofascin-140 or 186
    - Type: IgG₄ > IgG₃
    - Location: Serum
    - Neural tissue staining
      - PNS: Node of Ranvier
    - Titers may be reduced after recovery
  - NCV
    - Axon loss
    - Demyelination (60%): Conduction block
  - CSF: Protein High
Polyneuropathies with serum IgM binding to Neurofascin-155 ⁵⁶
- Epidemiology: 5 patients
- Clinical
  - Onset age: 22 to 76 years
  - Disease course: Chronic or Acute
  - Weakness: Arms & Legs; Distal predominant
  - Tremor: Most patients
  - Sensory: Loss; Pain
  - Treatment response: IVIg in 60%
- Laboratory
  - NCV: Distal & F-wave latencies prolonged
  - CSF protein: Normal to High
  - Skin biopsy: Small fibers normal or slightly reduced
  - Antibody target
    - Neurofascin-155
    - Also see: IgG vs Neurofascin-155
Perineuritis
- Usually axonal neuropathy: Occcasional demyelinating neuropathy reported

Multifocal Motor Neuropathy (MMN) & Immune Motor Neuropathies (IMN) ^3,¹⁴

Antibodies
Clinical
Electrodiagnostic
Epidemiology
Laboratory
Pathology
Treatment
Variants & DDx

MMN: Focal weakness
Finger extension: Involvement varied

MMN: Median nerve conduction block
Thenar eminence: Weakness
No atrophy early in disease

Epidemiology
- Male > Female: 2 to 1
- Prevalence: 0.29 to 1 per 100,000 (~ 5% to 10% of ALS prevalence)
- Drug treatment association: TNF-α antagonists, anecdotal reports
Genetics
- Higher frequency of homozygous SMN2 deletion (40%) than controls (10%) ¹⁷
Clinical Features

Onset
- Age
  - Mean 40 years
    - Males: 38 years
    - Females: 45 years
  - Range 6 to 80 years
  - Most between 30 and 50 years
  - Children: 5 patients ≤ 12 years ⁵⁸
- Weakness
  - Arm: Distal (61%)
  - Other: Distal leg (34%); Upper arm (5%)
Weakness: 100%
- Distribution
  - Distal > Proximal (87%)
  - Asymmetric (94%)
  - Upper > Lower extremity (80%)
  - Arms: Finger & Wrist dorsiflexion
  - Legs: Ankle dorsiflexion
  - Rare involvement: Cranial nerves 2%; Respiratory 1%
- Severe (20%)
- Fatigue (50%)
- Exacerbated by
  - Cold ³⁴
  - Corticosteroid treatment
Muscle atrophy (80%)
- Common in some muscles: > 90%
- Bulk may be relatively preserved in weak muscles: More common
  - Early in disease course
  - Conduction block in nerve
Spontaneous motor activity
- Fasciculations: 25% to 50%
- Cramps: 50%
No upper motor neuron signs
Sensory
- Subjective symptoms: Normal or Minimal
- Vibratory loss: Present in some patients; May progress oveer time
Tendon reflexes
- Preserved in proportion to strength
- Normal: 40%
- Brisk: 8%
Time course ⁶⁰
- Weakness
  - Slowly progressive over 1 to 30 years (90%)
  - Occasionally stepwise or acute onset (10%)
  - More with: Serum IgM vs GM1 ganglioside
  - Transient exacerbations: Weeks to months
    - Pregnancy
    - Corticosteroid treatment
  - Progression often occurs despite Ig treatment
  - More progression: More initial weakness; Lost tendon reflexes on initial exam
- Focal conduction block: Often persists over time
- Axon loss: Often progresses over years
- Death due to disease: Rare
- Spontaneous remission: Rare; Not when anti-GM1 antibodies present

Electrophysiology

Motor Conduction Block

Frequency in immune motor neuropathies: 60%
General features
- 50% Reduction of proximal vs distal CMAP amplitude
- Focal
- Location: Distal nerve segment in arm
  - Most common: Ulnar (80%); Median (77%)
  - Other: Radial (~40%)
  - Occasional: Proximal between Erb's point & axilla; Musculocutaneous nerve
- Most reproducible: Ulnar or Median nerves
- May increase with: Activity; Repeated action potentials
- More regions with block: Patients with long disease course (> 10 years)
Possible mechanisms of conduction block
- Demyelination: CIDP; Nerve compression
- Na⁺ channel block: Tetrodotoxin; GM1 antibodies
- Axon depolarization: Ischemia; High extracellular K⁺
- Axon hyperpolarization: Post-Ischemia; Long train of action potentials
Conduction block may be activity dependent
- Activity causes axon hyperpolarization
  - Long impulse trains: Activate Na⁺-K⁺ pump
    - Pump exchange: Net outward flow of cations
      - Intracellular to Extracellular: 3 Na⁺ ions
      - Extracellular to Intracellular: 2 K⁺ ions
    - Pump activation builds up positive ion charge extracellularly
      - Produces membrane hyperpolarization
  - Brief impulse trains: Activate slow K⁺ channels
- Demyelinated nodes: Na⁺-K⁺ Pump is more activated than normal
- Membrane hyperpolarization
  - Driving current may fail to reach elevated threshhold
  - Causes transient conduction block
- Symptom & Sign: Fatigue in affected muscles
Conduction block: Technical features
- Variably defined
  - 15% to 50% reduction in CMAP amplitude at proximal compared to distal stimulation
- Conduction block may go undetected unless multiple segments in several nerves are tested
- Finding of conduction block is most reliable
  - Change is focal
  - Location: Distal nerve segment other than regions of entrapment
- Rule outt: Temporal dispersion & phase cancellation over long nerve segments
Axon physiology ¹³
- Site of conduction block: Depolarization
- Distal to conduction block: Hyperpolarization
- Possible physiology of selective motor conduction block
  - Motor axons more susceptible to hyperpolarization than sensory axons
  - Safety factor of sensory axons may be higher than motor axons
    - Due to low threshhold persistent Na⁺ channels

Conduction block, Motor
Distal stimulation (Top)
Large CMAP
Proximal stimulation (Below)
Reduced CMAP size (to < 50%)
Reduction location: Focal along nerve

Other signs of demyelination (Mild)
- Conduction velocities: Often normal between regions of block
- Temporal dispersion: Mild
- Distal latencies: Occasionally prolonged
Axon Loss
- Motor
- Later in disease course
- Progressive reduction over time
- Associated with more severe disability
Sensory nerve conductions ²⁹
- Frequency of reduced SNAP amplitudes: 20%
- Reduced SNAP amplitudes more common in patients with
  - More severe disease
  - More prominent axon loss
  - Longer disease course
EMG: Denervation
- Distal muscles: 93%
- Thoracic paraspinous muscles: 30% to 50%

Motor neuropathies: Serum Autoantibodies

Antibody type: IgM

Antigens

GM1 ganglioside

IgM GM1 antibody cross-reactivity
- Some: Bind only to GM1 ganglioside
- Others: Also bind to GA1 & GD1b
Clinical
- Sensitivity for MMN: 35% to 50%
- IgM anti-GM1 antibodies common
  - Often present in Motor neuropathies
    - Chronic: MMN & Distal LMN syndromes
    - AMAN 37%
- Controls: Anti-GM1 antibodies rare
  - ALS (< 1%)
  - CIDP
  - Controls (0.3%)
Anti-GM1 antibody testing methods
- Covalent GM1 ELISA: More specific
Other anti-GM1 antibodies: Bind to GM1 ganglioside only with
- GM1 in Lipid environment
- GM1 in Mixture with other gangliosides
See
- Anti-GM1 antibodies
  - Clinical associations
  - Testing guidelines
- Ganglioside structures

NP-9 antigen (GM1 ganglioside in lipid environment)

NS6S Heparin Disaccharide ³¹

Frequency in motor neuropathies: 43%
GM1 or NS6S antibodies in motor neuropathies: 64%
Specificity: Rare in ALS (2%) or CIDP
False positives: With associated Sensory neuropathies

GalNAc-GD1a ganglioside

GM2 ganglioside

Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-1'Ceramide
                  3
                  |
           Neu5Acα2

GM1 ganglioside

Laboratory
- Serum M-Protein: Occasional
- CSF protein: Mildly elevated in 33%
- MRI: T2 signal intensity in region of conduction block
Pathology ²⁴
- Axon loss
  - Multifocal
  - Especially larger axons
  - Regenerating axon clusters
  - Probably increased with disease duration
- Multifocal Demyelination: Some biopsies
  - Segmental demyelination
  - Onion bulbs in regions of conduction block
  - ? Less common with longer disease duration
  - Rule out: Multifocal CIDP
- Inflammation: Epineurial; Perivascular
MMN: Treatment
- General
  - Improvement with IVIg ¹⁴
    - More likely
      - When conduction block detected
      - More nerves involved
      - Shorter disease duration
    - May occur in mildly or severely weak patients
  - Improvement rare or less prominent in patients with uncertain diagnosis of MMN
    - Paraspinous denervation
    - Prominent muscle atrophy
- Human Immune Globulin
  - Dose: 1 g/kg/day x2 days
  - Repeat treatments: Every 2 weeks to 9 months, as needed to prevent relapse
  - Outcome
    - Improvement
      - Useful functional: 50% to 60%
      - Some increased strength: Up to 94%
    - Improvement more common with
      - Definite conduction block
      - Serum IgM binding to GM1 ganglioside
  - "Resistance" may develop over time ^14,²⁵
    - Onset: 3 to 7 years after onset of treatment
    - More frequent dosing
      - May initially maintain strength
      - Becomes less effective over time
    - Higher dose needed: Commonly increases by ~50%
    - Related to axon loss occurring during IVIg treatment: Decline in CMAP amplitude
    - May be reversed by concurrent treatment with Rituximab or cyclophosphamide
  - See: Treatment Protocol
- Cyclophosphamide
  - 1 gm/M² per month x 6 ± Preceding Plasma Exchange x2
  - Indications
  - See Protocol
  - Outcome
    - Improvement in 80%
      - Especially when titers of anti-GM1 antibodies reduced
    - Onset of improvement after 3 to 6 months
    - Duration of improvement: 1 to 5 years
- Rituximab: May be useful; Few side effects
- ? Interferon-β1a: Minor improvement
- Other: ? Fludarabine
- NOT Prednisone: Prednisone may cause increased weakness
Variant syndrome: Distal lower motor syndrome with anti-GM1 antibodies
Differential Diagnosis
- ALS with few upper motor neuron signs: Primary muscular atrophy (PMA)
- SMN^T or SMN^C deletions
- Distal SMA
- Acquired lower motor neuron disorders
See History and Differential Diagnosis

Neuropathy with IgM binding to Myelin-Associated Glycoprotein (MAG) ⁶⁷

Epidemiology
- Prevalence: 0.28 to 0.42 per 100,000
- Prevalence vs CIDP: 15%
- Male predominance: 1.5x to 3.6x
Genetics
- MAG neuropathy: Hematologic cells ⁷¹
  - MYD88^L265P variant
    - Frequency: 60% to 73% of IgM MAG
    - No association with clinical features
    - Waldenström
      - Frequency: 90%
      - May predict treatment response to ibrutinib
    - Marginal zone lymphomas: Rare
  - CXCR4_S338X variant
    - IgM MAG neuropathy: Not present
    - IgM MGUS: 16% to 35%
    - Waldenström: 43%
- MAG mutations
MAG protein
- Glycoprotein (100 KDa)
  - N-linked glycosylation sites (8) scattered along extracellular region
  - N-linked glycans: Provide hydrophilic groups important for proper folding
- Protein type
  - Member of immunoglobulin superfamily (Extracellular domain)
  - siglecs: Contain immunoglobulin-like domains; Have sialic acids attached
- 2 splice variants
  - Cytoplasmic domains: Different size
  - Extracellular domains: Same
- Locations
  - Myelin protein: < 1% in CNS & PNS
  - Present in myelinating Schwann cells & Oligodendrocytes
  - Subcellular: Schwann cell membranes
    - Uncompacted myelin
    - Paranodal terminal myelin loops
    - Schmidt-Lanterman incisures of PNS myelin
    - Periaxonal cytoplasmic collar membrane
- Functions
  - Cell adhesion molecule
  - Maintains normal separation of axonal & adaxonal Schwann cell membranes
  - Zinc binding (Intracellular domain): May induce MAG dimerization
  - Inhibits axon regeneration
    - Mechanism: Binds to NOGO receptor (NgR)
    - Co-receptor for MAG signalling: p75 (NTR; NGFR)
  - Neurofilament phosphorylation signaling
    - Activation of
      - Cyclin dependent kinase 5 (cdk5)
      - Extracellular ERK1/2 protein kinase pathway
    - Phosphorylated neurofilaments: Increased
      - Increased axonal caliber
- Inherited disorder: SPG 75, Recessive
Neuropathy: Clinical Features (MAG antibody+ by ELISA & Western blot)
- Epidemiology: Males 70% to 80%
- Onset
  - Age: Usually > 50 years; Mean 67 years; Range 46 to 87 years
  - Sensory
  - Gait ataxia
- Sensory loss (100%)
  - Distal
  - Legs > Arms
  - Symmetric
  - Panmodal
- Pain (28%)
- Weakness (50% to 70%)
  - Distal
  - Legs > > Arms
  - Symmetric (80%)
- Gait disorder (70%)
  - Tandem gait: Poor
  - Onset: Early in neuropathy syndrome
  - Often most disabling feature
  - Frequently improves with treatment
- Tremor (30%)
  - Intention
  - Arms > Legs
  - Onset: Develops later in disease course
  - Poor response to treatment
  - May cause prominent disability: Fine movements of hands
- Tendon reflexes: Reduced, Legs > Arms
- Course
  - Time Course: Slowly Progressive (Years)
  - May progress to severe disability
    - 5 years 16%
    - 10 years 24%
    - 15 years 50%
- Treatment: Immunosuppression
  - General biomarker: Improvement more likely ⁶⁹
    - MAG antibody titers: Reduced by > 50%
    - Serum IgM or M-protein levels: Reduced by > 50%
  - Rituximab ⁷
    - Treat to reduce serum IgM & anti-MAG antibody titers by > 50%
    - Treatment effects: Improved strength & gait; ? Sensation
    - More response
      - IgM levels & MAG Ab titers reduced by > 50%
      - Electrodiagnostic: Less severe ⁶⁶
  - Cyclophosphamide (IV) & Plasma Exchange ⁴
    - Treat to reduce anti-MAG antibody titers by > 70%
    - Treatment effects: Improved strength & gait; ? Sensation
  - Other
    - α-interferon: May produce improved sensation
    - Prednisone: Not effective
    - IVIg: May produce short-lived small benefit in some patients ¹⁸
    - Cladribine: Case reports of efficacy; Significant toxicity
    - Fludarabine: Case reports of efficacy; Significant toxicity
    - Ibrutinib ⁶²
- Treatment: Other
  - Tremor: Gabapentin
Electrophysiology
- Myelination abnormal
  - Prolonged Distal Latencies (90%)
  - Slow NCV (70%)
  - Temporal dispersion of CMAPs
  - NO Conduction Block
- Axon Loss
  - Compound motor action potentials (CMAPs): Reduced distally
  - Sensory nerve action potentials (SNAPs): Reduced amplitude, or absent
Serum Autoantibodies
- IgM vs MAG
  - Indications for testing
  - Specific for demyelinating neuropathy when Western blot +
  - Peripheral nerve tissue staining
    - Schwann cell cytoplasm: Adaxonal & Abaxonal
    - Compact myelin: Moderate
- Serum M-Protein
  - IgM
  - κ 80%; λ 20%
  - Common (85% to 100%); Especially with anti-MAG titers > 30,000
  - Some with Waldenström's macroglobulinemia
- MAG Antibody: Antigen Cross-Reactivity
  - 3-Sulfated (SO₄) glucuronyl group: Present on glycoproteins & glycolipids
  - TS-HDS
  - Phosphacan ⁶³
    - Disability: More with greater relative binding to phosphacan
  - Neurofascin-155
- MAG antibody: Pathogenic effects
Nerve pathology ⁶¹
- Myelin
  - Myelin wide spacing
    - Outer myelin layers
    - Preferentially in: Paranodal & Juxtaparanodal regions
    - External link
  - Humoral Immune
    - IgM deposition
    - C3d, but no C_5b-9, on myelin sheath surfaces ⁷⁴
  - Tomaculae: Myelin folding
    - Teased fiber
    - Ultrastructure
  - Uncommon features
    - Segmental demyelination
    - Onion bulbs
- Node of Ranvier
  - KCNQ2 channels: Absent or Reduced
  - Caspr1, Contactin 1, Neurofascin at node: Lengths
    - Increased
    - Longer with: Higher MAG antibody titer
    - Correlate negatively with: NCV
  - Na⁺ channels: Reduced at widened nodes of Ranvier
- Axons
  - Loss: Myelinated axons, Large > Small
  - Neurofilament spacing: Reduced
- IgM deposits
  - Peripheral nerve myelin
  - Paranodal loops: Outer part
  - Schmidt-Lanterman incisures
  - Not on: Periaxonal membrane
Variant anti-MAG clinical syndrome: Anti-MAG antibody titers < 10,000
- Sensory loss: Small > Large fiber modalities
- Motor: Normal
- Electrodiagnostic: Axon loss

MAG Antibodies
Antigen Cross-Reactivity

3-Sulfated (SO₄)
Glucuronyl moiety (SGPG)

TS-HDS

Myelin Pathology: MAG PN
External layers of myelin membrane are separated

Compare to Uncompacted myelin

Anti-MAG IgM antibody binding to PN myelin
Schwann cell cytoplasm > Compact myelin

Myelin Wide spacing

GALOP syndrome ⁵

Gait disorder
Autoantibody
Late-age
Onset
Polyneuropathy
Clinical Features
- Gait Disorder: Ataxic; Positive Romberg
- Polyneuropathy: Sensory > Motor; Symmetric
Electrophysiology: Demyelinating with M-Protein; Others Axonal
Serum Autoantibodies: IgM vs Central Myelin Antigen (CMA)
Serum M-Protein: Common (80%); IgM
Treatment
- Cyclophosphamide
- Human Immune Globulin

POEMS Syndrome ²¹

General
Laboratory
Nosology
Polyneuropathy
Pathology

Systemic
Edema
Endocrine
Organomegaly
Treatment

From M. Al-Lozi
POEMS: Skin
Thick, Dry
Clubbing of fingers

From M. Al-Lozi

POEMS: Edema

POEMS
Major diagnostic criteria: 3 needed
Mandatory (2)
Polyneuropathy
Plasma cell proliferative disorder, Monoclonal (λ >> κ)
Other (1)
Vascular endothelial growth factor (VEGF): High
Sclerotic bone lesions
Castleman�s disease

Minor diagnostic criteria: 1 needed
Organomegaly
Spleen, Liver; Lymph nodes
Extravascular volume ↑
Edema, Pleural effusion, Ascites
Endocrinopathy
Adrenal, Thyroid, Pituitary, Gonadal, Parathyroid, Pancreas
Skin Δ
Pigmentation, Hypertrichosis, Plethora, Hemangioma, Nail Δ
Eye: Papilledema
Hematologic: Thrombocytosis/Polycythemia

Other features
Clubbing, Weight loss, Hyperhidrosis, Diarrhea,
Pulmonary hypertension/Restrictive lung disease
Thrombotic diatheses; Vitamin B12: Low

Variant syndrome
Castleman disease: No clonal plasma cell disorder

Nosology: Other names
- Crow-Fukase Syndrome
- Takatsuki disease
- PEP syndrome
- Osteosclerotic myeloma
General Features
- POEMS
- Partial POEMS syndromes
  - Not uncommon
  - Definition
    - Polyneuropathy
    - M-protein
    - Other systemic features
- Epidemiology
  - Male (60% to 70%) > Female
  - Geography
    - ? High incidence in Japanese & Asian males
    - Frequency in Japan: 0.3 per 100,000
- Course
  - Onset age
    - Mean 51 years
    - Range: 21 to 84 years
    - Younger than myeloma
  - Progression
    - Usual: Over months to years
    - Some patients: Acute or Subacute
  - Addition of new features over time
    - Frequency: 18%
    - More common with urine M-protein
  - Eventual severe disability in many
  - Survival
    - Mean: 33 to 165 months
    - 5 year survival
      - Older literature: 60%
      - More recent studies: 90%
    - Reduced
      - Fingernail clubbing
      - Extravascular volume overload
      - Clonal specfic heavy/light chain ratio abnormal ⁴⁷
      - No stem cell transplantation
      - No reduction in vascular endothelial growth factor levels after treatment
  - Death: > 50%
    - 33 month mean survival in patients who died
    - Causes
      - Heart failure
      - Capillary leak (Pleural effusion; Ascites)
      - Renal failure
      - Infection
Polyneuropathy: Most common presenting feature
- Clinical
  - Onset
    - Age: Mean 45 to 51 years; Range 27 to 80 years
    - Paresthesias: Feet ± Hands
    - Presenting feature in 50% to 95%
  - Neuropathy: General pattern
    - Length dependent: Distal > Proximal
    - Symmetric
    - Sensory + Motor
  - Weakness
    - Initially distal
    - Symmetric
    - Progresses to involve proximal strength
    - Disabling in > 50%
  - Sensory loss: Especially vibration & touch
  - Tendon reflexes: Reduced or Absent
  - Pain & Discomfort
    - Frequency: 20% to 75%
    - "Tight" sensations in legs
  - Autonomic: Hyperhidrosis
  - Course
    - Usual: Progressive over months to years
    - Wheelchair: 50% to 70% < 1 year; Range 2 weeks to 51 months
    - Some patients (5%): GBS-like onset ³³
    - More rapid with associated ascites
    - Castleman disease variant: Milder
- Electrophysiology ¹⁵
  - Demyelination
    - NCV: Slowing more in intermediate than distal nerve segments
    - Distal latencies: Moderately prolonged; Less than CIDP or MAG
    - Conduction block: Unusual (< 10%)
    - Temporal dispersion: Uncommon
  - Axon loss
    - Motor & Sensory
    - CMAPs: Small; Legs reduced more than arms
    - Occurs somewhat after demyelinating features
- Nerve pathology
Other systemic disorders
- Cranial nerves
  - Most not involved
  - Papilledema: 24% to 55%
- Pachymeningitis (70%): Cerebral or Spinal
- Skin changes
  - Hypertrichosis: Associated with endocrine disorders
  - Hyperpigmentation: Most common skin feature (47% to 93%)
  - Acrocyanosis & Plethora
  - Clubbed fingers: Associated with more extensive disease
  - White nails
  - Hemangiomas: Glomeruloid, Multiple; Trunk & Arms
  - Sclerodermatous changes
  - Angiomatous lesions
  - Violaceous cutaneous patch: Over bone plasmacytoma; Enlarging ²²
- Edema
  - Very common: 24% to 89%
  - Oten severe
  - Types
    - Peripheral edema
    - Ascites
    - Effusions: Anasarca
- Endocrinopathy
  - Diabetes: Glucose intolerance (25%)
  - Hypothyroid (25%)
  - Gynecomastia (60% to 70%)
  - Amenorrhea (60% to 70%)
  - Hypogonadotrophic Hypogonadism
    - Impotence (70% to 80%)
    - Erectile dysfunction
  - Pituitary-adrenal dysfunction (16%)
- Organomegaly
  - Liver (50% to 80%)
  - Spleen (40%): Less common with bone lesions
  - Lymph nodes (65%): Associated with Castleman's disease
- Ocular involvement
  - Optic: Disc swelling (50% to 84%); Neuropathy
  - Pre-retinal hemorrhages
  - Uveitis
  - Neovascularization of disk
- Renal involvement: Somerenal failure
  - Membranoprolifrative glomerulonephritis (MPGN)
  - Thrombotic microangiopathy
  - Mesangiolytic glomerulonephritis
- Circulatory
  - Pulmonary hypertension
  - Thrombotic events
    - Thrombocytosis
    - Polycythemia
  - Congestive heart failure
- Other
  - Weight loss > 10 pounds: 37%
  - Fatigue: 31%
Associated neoplasms
- With bone lesions
  - Myeloma
    - Osteosclerotic > Osteolytic
    - Lytic lesions may have sclerotic rim
    - Solitary lesion in 40%
  - Frequency: 58% to 97%: Lower in Japan
  - Osteosclerotic only: 47% to 81%
- Without bone lesions (10% to 45%)
  - Castleman disease
    - Angiofollicular lymph node hyperplasia
    - Multicentric plasma cell variant
  - Extramedullary plasmacytoma
  - M-protein
  - Polyclonal protein alone
  - Rarely develop classic myeloma
Treatment
- Irradiation: Localized osteosclerotic lesions
- Widespread lesions: Chemotherapy
  - Stem cell transplantation: Probably most effective
  - Melphalan & Prednisone: Poor response
  - Melphalan, high dose (200 mg/m²) + Bone marrow transplant ¹⁶
  - Lenalidomide (low dose) (10 mg daily) & Dexamethasone (40 mg, once-weekly) ⁴⁴
  - Other
    - Bortezomib ⁵² + Doxorubicin
    - Thalidomide
    - Bevacizumab: Anti-VEGF
- No bone lesions: ? Cyclophosphamide + Rituximab
- No benefit: Corticosteroids; Azathioprine; ? Plasma Exchange
- IVIg: Anecdotal reports of benefit for acute-onset neuropathy
Lab
- Serum M-protein
  - Frequency: 75% to 84%
  - Usually IgG or IgA
  - Low quantitative levels of M-protein: Requires immunofixation to detect in 40%
- Serum factors
  - Vascular Endothelial Growth Factor (VEGF) ²⁶
    - VEGF actions
      - Cytokine
      - Causes angiogenesis
      - Increases vascular permeability
      - Activates coagulation
    - VEGF in POEMS
      - High levels of VEGF & VEGF165 isoform in serum but not CSF
      - Highly expressed in blood vessels & some non-myelin forming Schwann cells
      - May return to normal with treatment
      - VEGF2 receptor (VEGFR2): Down-regulated in nerves & serum (sVEGFR2)
      - May explain organomegaly, skin changes & edema in POEMS
    - VEGF in serum in other disorders
      - Increased early in: Systemic sclerosis (Scleroderma)
      - Mildly increased on some immune neuropathies: GBS; CIDP; IgM M-protein related
  - Erythropoetin: Levels reduced in serum
  - Proinflammatory cytokines: Increased IL-1β , IL-6 , TNF-α
  - Matrix metalloproteases: Increased MMP-1, 2, 3, 9 and TIMP
- Hematologic
  - Sedimentation rate: Normal
  - Thrombocytosis: 35% to 53%
  - Polycythemia: 20%
  - Bone marrow
    - Plasmacytosis > 10% in 5% to 20%
    - Plasma cells
      - Lambda light chain restricted 95%
      - Immunoglobulin light chain variable gene usage (IGLV1)
      - Stereotypic mutations: IGLV1-40 & IGV1-44 genes
      - VEGF: High
- CSF
  - Protein: High
  - Pressure: High
  - Cells: Normal
- Ultrasound: Nerves diffusely enlarged
- Nerve pathology ⁶⁸
  - Axons
    - Loss
      - Reduced numbers of large & small myelinated axons
      - Compared to CIDP
        
        More abundant loss
        Diffuse: vs Multifocal in CIDP
    - Active Wallerian degeneration ³⁵
      - Scattered axons
      - Some patients
  - Myelin
    - Thin sheaths
    - Segmental demyelination
    - Uncompacted
      - Definition: Non-fusion of inner aspects of Schwann cell membranes
      - Frequency
        
        1% to 7% of myelinated axons
        
        Present in 50% to 90% of POEMS biopsies
      - Pathology
      - Compare to: Myelin wide-spacing
    - Uncommon or Not present
      - Onion bulbs: Smaller & fewer than CIDP
  - Endoneurial vessels
    - Thickened basal lamina
    - Narrowed lumen
    - Endothelial cells: Proliferation; Tight junctions opened
  - Epineurial small vessels: Increased numbers
  - Inflammation: Some biopsies; Mostly epineurial
- Head MRI: Meningeal thickening (70%); White matter lesions (41%)
- Viral infections: ? Kaposi sarcoma-associated herpesvirus (Human herpesvirus 8)
- Pathogenesis: Many signs associated with increased vascular permeabiltiy

Neuropathy with IgM binding to Sulfatide

Clinical Features
- Onset: Age usually > 50 years; Paresthesias
- Sensory: Symmetric; Distal; Paraesthesias
- Motor: Distal; Symmetric
- Gait Disorder: 50%
- Tremor
Course: Slowly progressive
Electrophysiology
- M-Protein: Demyelinating (like MAG)
  - Prolonged distal Latency
  - Slow NCV
  - Axon Loss
  - Low motor amplitudes
- No M-protein
  - Axonal
  - Less motor loss
  - More pain & paresthesias
Serum Autoantibody: IgM vs Sulfatide
Serum M-Protein: Occasional
Pathology
- Myelin: Widely spaced lamellae
- Axon loss
- IgM & complement binding in nerve
Treatment: Few Reports
- Cyclophosphamide
- Human Immune Globulin
- Other: Rituximab; ? Fludarabine

Carbohydrate moiety (Sulfated galactose)	Lipid moiety
	Ceramide

SULFATIDE

Demyelinating ataxic neuropathy with IgM binding to GalNAc-GD1a and GM2 gangliosides ¹⁰

Onset
- Adult
- Gait: Ataxia
- Sensory loss: Distal
Clinical
- Sensory loss: Pan-modal; Symmetric; Distal; Romberg +
- Weakness: Mild; Distal; Symmetric or Asymmetric
- Cerebellar: Dysmetria; Wide based gait
- Tendon reflexes: Absent
- Course: Slowly progressive over years
Laboratory
- Electrodiagnostic testing: Demyelinating neuropathy
  - NCV: Slow; Usually 20 to 30 M/s
  - Conduction block
- Serum M-protein: IgM κ
- Serum IgM binding: GalNAc-GD1a & GM2 gangliosides
Treatment
- IVIg: Frequent dosing
- No benefit: Corticosteroids, Cyclophosphamide
Also see

Neuropathies (Chronic) with IgM binding to GD1a, GM3 & GT1b gangliosides

Motor-Sensory Neuropathy ¹¹
- Onset
  - 7th decade
  - Weakness & Numbness
- Clinical
  - Sensory loss: Symmetric; Distal; Especially temperature
  - Weakness: Mild; Distal > Proximal; Symmetric
  - Tendon reflexes: Reduced
  - Course: Slowly progressive over years
- Laboratory
  - Electrodiagnostic testing: Demyelinating neuropathy
    - Distal latencies: Prolonged
    - Nerve conduction velocities: Slow; Variable
    - F-waves: Absent
  - Serum M-protein: None detected; IgM antibodies all κ type
  - Serum IgM binding: Anti-GD1a antibodies
    - GD1a ganglioside: Neu5Acα2-3Galβ- moiety
    - Cross-reactivity: GT1b & GM3 gangliosides
Motor Neuropathy ¹²
- Onset
  - 8th decade
  - Weakness in hands
- Clinical
  - Weakness: Diffuse; Evolving to respiratory failure
  - Fasciculations
  - Tendon reflexes: Absent
  - Sensation: Normal; Mild symptomatic numbness
  - Progression: Rapid; Over 2 years
  - Treatment: Plasma exchange; Corticosteroids probably not effective
- Laboratory
  - Serum M-protein: IgM κ
  - Serum IgM binding: Anti-GD1a antibodies
    - GD1a ganglioside: Neu5Acα2-3Galβ- moiety
    - Cross-reactivity: GT1b, GM3 & GM2 gangliosides
  - Electrodiagnostic testing: Motor neuropathy
    - CMAPs: Normal amplitude; ? Conduction block
    - Nerve conduction velocities: Normal or Mildly slowed
    - F-waves: Prolonged
  - Nerve pathology
    - Loss of myelinated axons
    - Thinly myelinated axons
Also see: AMAN

Osteosclerotic Myeloma

Antibody testing is performed at:

NEUROMUSCULAR CLINICAL LABORATORY: Washington University
Box 8111 - Neurology
660 South Euclid Avenue
St. Louis, MO 63110
Phone: 314-362-6981
Fax: 314-362-2826
e-mail: pestronka@neuro.wustl.edu