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CHRONIC IMMUNE PERIPHERAL NERVE MYELINOPATHIES (CIPNM)

CIPNM   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 Neuropathies with Myelin pathology Osteosclerotic Myeloma POEMS Syndrome Antibody tests Also see: Immune axonal neuropathies

Multifocal Motor Neuropathy (MMN) Myelinated Axons: Segmental demyelination

Chronic Immune Demyelinating Polyneuropathy (CIDP)

• 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
            • Chronic Immune Demyelinating Polyneuropathies
            • vs: typical CIDP
              • Weakness: More distal
              • NCV: More slowing; Longer motor distal latencies
              • Treatment: Rituximab; Less response to IVIg & Corticosteroids
          • Pan-Neurofascin IgG antibodies
            • Acute onset: GBS-like or CIDP-like polyneuropathies
            • Nerve pathology: Redundant myelin
          • IgG Neurofascin-186 antibodies: Acute onset polyneuropathies
            • GBS-like syndromes
            • More distal weakness
          • 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%): Nephrotic syndrome
            • Diabetes (10% to 60%) ⁷⁶
          • Treatment response
            • Prednisone: Some response in 65% to 70%
            • IVIg: No response in 40%; Even responders need additional treatment
            • Rituximab (90% response) 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
            • IgG₄ common
            • Some correlation of titers with initial disability
            • Many disappear after treatment
          • Serum Contactin-1 levels: Reduced vs normal
          • Serum Neurofilament Light levels
            • Initial: Often high
            • May fall after successful treatment
          • MRI: Proximal nerve enlargement or enhancement
          • Nerve pathology
            • Axon loss
            • Axo-glial detachment
            • Remyelination
          • Proteinuria: 50%
    • 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
    • Other demyelinating neuropathies
    • Other immune demyelinating neuropathies
    • HMSN & HNPP
    • CIDP variant
• 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

• 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
      • Typical CIDP
      • Upper limb CIDP
      • Motor CIDP
    • 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%)
    • Often in distribution of individual nerve: Wrist or finger extension
    • 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 MYD88L265P 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 CXCR4S338X 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 MAG P0 protein NCAM1 Sulfated glucuronyl paragloboside 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 C5b-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

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
    Polyneuropathy
    Organomegaly
    Endocrinopathy or Edema
    M-protein: Usually IgG or IgA & λ type
    Skin changes
  • 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
    • λ light chain: 92% to 100%
    • IgG: 25% to 44%; Occurs more frequently with bone lesions
    • IgA: 40% to 70%; Bone lesions less frequent
    • Other
      • IgM: 1%
      • λ light chain only: 5%
      • Clonal λ disorder in bone lesion or marrow: 12%
    • 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
  • Acute neuropathy with IgM binding to GalNAc-GD1a
  • Acute motor neuropathy with IgG binding to GalNAc-GD1a
  • Chronic motor neuropathy with IgG binding to GalNAc-GD1a

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