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CHRONIC IMMUNE POLYNEUROPATHIES: DEMYELINATING

Comparative features: Demyelinating PN Treatment strategies CIDP   Clinical features   Laboratory features   Pathology   Treatments   Variants GALOP syndrome GD1a antibody   Motor-Sensory neuropathy Multifocal motor neuropathy MAG antibody associated neuropathy Osteosclerotic Myeloma Other demyelinating neuropathies POEMS Syndrome Sulfatide antibody associated neuropathy Antibody testing Also see: Immune axonal neuropathies

Myelinated Axons: Segmental demyelination in Multifocal Motor Neuropathy (MMN)

Chronic Immune Demyelinating Polyneuropathy (CIDP)

• Epidemiology
  • Male > Female: 2:1
  • Onset age
    • Average: 50 years
    • Range: All ages
    • Childhood: ~10%; Youngest < 1 year
  • Prevalence: 1/100,000
  • Earlier onset in relapsing-remitting than monophasic/progressive group
  • Preceding event: ? Increased frequency of immunizations or infections
• 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%)
      • 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 features¹⁹: 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 Axonal loss
• 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 axonal 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%
  • Serum M-Protein: Occasional
  • 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
• Associated disorders
  • Monoclonal Antibodies (M-proteins): Some IgG & IgA; Rarely IgM
  • HIV
  • Diabetes
  • Other possible associations
    • Chronic active hepatitis (Hepatitis C); Graft-vs-host; Nephrotic syndrome;
      CNS demyelination; Lymphoma; Interferon-α treatment; TNF-α antagonists
  • Greater Frequency of HLA-B8
• 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
  • Axonal loss
    • Variable fascicular involvement
    • Patchy loss of axons
    • Loss of myelinated axons
    • Axonal 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
  • 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 (IV): 1 gram/day x5
      • Then intermittent (tapering) additional iv or oral doses (1 gram): Weekly to Monthly
    • Human Immune Globulin
      • 1g/kg/day x2; repeat q3 to 8 weeks
        
      • 400 mg/kg 1 to 2 times per week for 8 or more weeks
    • 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

CIDP: Variants

• Multifocal demyelinating CIDP⁹ (Multifocal CIDP; Lewis-Sumner¹)
  • Age range: 28 to 58 years
  • Weakness
    • Asymmetric
    • Distal > Proximal
    • Arms > Legs (78%)
    • Occasional proximal syndrome
      • 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
  
  
• Focal upper limb demyelinating CIDP^2,6
  • Onset
    • Mean = 54 years; Range 15 to 75 years
    • Rarely childhood
    • Acute or Progressive
  • Clinical
    • Weakness
      • Onset: With reduced pain
      • Single or multiple upper extremity nerves
      • Distal > Proximal
      • Asymmetric > Symmetric
      • Monomelic or Bilateral
    • Sensory
      • Paresthesias or numbness early in most
      • Pain: Often localized to peripheral nerve territory
      • Sensory loss: Usually mild, distal; Often asymmetric
    • Course: Progressive; Some stabilize or spontaneously resolve
    • Rule out: Brachial neuritis
  • Laboratory
    • Anti-GM1 ganglioside antibodies: Uncommon
    • CSF protein
      • High in 72%
      • Mean 64 mg/dL; Range 21 to 128
    • Nerve conduction studies
      • Conduction block (100%)
      • Slowing 35%;
      • CMAP amplitude: Reduced (56%)
      • Abnormal SNAPs: Some patients
  • Treatment
    • Response to Prednisone or HIG in some (> 50%)
    • Often less recovery than with generalized CIDP
  
  
• Sensory CIDP
  • Clinical
    • Sensory: Distal pansensory loss & pain
      
    • Motor: Normal or minimal distal weakness
  • Electrophysiology
    • Motor & sensory demyelination
    • Conduction block, slow NCV & long distal latency
  • Treatment: Poor response to prednisone or HIG
  
  
• 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
    • 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 reported¹⁹
  • Prognosis
    • Better for remission with relatively rapid onset
    • Worse: Axonal 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 M-protein vs β-tubulin
  • Weakness: Slowly progressive; Asymmetric
  • Hyporeflexia
  • Poor response to prednisone
  • Antigenic epitope: β-tubulin amino acids 301-314
  
  
• CIDP associated with IgG or IgA M-protein
  • Similar clinical syndrome to typical CIDP
  • Weakness: Slowly progressive; Symmetric
  • Partial response to immunotherapy
  
  
• CIDP + Diabetes mellitus⁸
  • Patient characteristics: Most similar to CIDP alone
  • Differences from CIDP
    • Age: Older (67 years)
    • Symptoms: More gait imbalance
    • Electrodiagnostic: More axonal loss
    • Treatment: Less improvement
  
  
• CIDP: Acute onset
  • Onset: Progressive over days to weeks
  • Clinical
    • Weakness: Symmetric; Proximal & Distal
    • Sensory loss: Distal
    • Tendon reflexes: Reduced
    • Course: Partial, but not complete improvement in strength over months
  • Laboratory
    • Electrodiagnostic: Prominent demyelinating features early in disease course
    • CSF protein: High
  
  
• CIDP: Subacute onset²³
  • 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 in some: May require teased fibers to document
      • Inflammation: Epineurial; Some patients
  
  
• CIDP + CNS features¹⁹
  • Frequency: Rare patients with CNS features
  • Onset
    • Age: Adult or Childhood
    • Clinical: CNS or PNS features
  • CNS features
    • Ocular
      • Papilledema: Associated with high CSF protein
      • Visual loss: Optic atrophy
    • Myelopathy
      • Tendon reflexes may be brisk
      • r/o Spinal cord compression from enlarged nerve roots
    • Ataxia
  • Rule out: Late onset dysmyelination (MLD; Krabbe)
  • Treatment: Corticosteroids
  
  
• Perineuritis
  • Usually axonal neuropathy: Occcasional demyelinating neuropathy reported
  
  

Multifocal Motor Neuropathy (MMN)³

MMN: Focal weakness   Variable finger extension

MMN: Median nerve conduction block   Weakness of thenar eminence   No atrophy

• Epidemiology
  • Male > Female: 2 to 1
  • Prevalence: 1 per 100,000
• Genetics: Higher frequency of homozygous SMN2 deletion (40%) than controls (10%)¹⁷
• Onset
  • Age
    • Mean 40 years
    • Range 25 to 70 years
    • Most between 30 and 50 years
  • Weakness
    • Arm: Distal
    • Often in distribution of individual nerve: Wrist or finger extension
• Clinical Features
• Weakness: 100%
  • Distal > Proximal (87%)
  • Asymmetric (94%)
  • Upper > Lower extremity (80%)
  • Fatigue: Occasional
  • Rare involvement: Cranial nerves 2%; Respiratory 1%
• Muscle atrophy (80%)
  • Common in some muscles: > 90%
  • Bulk may be relatively preserved in weak muscles
    • Especially when conduction block in nerve
    • More common early in disease course
• Fasciculations: 25% to 50%
• Cramps: 50%
• No upper motor neuron signs
• Sensory: Normal or minimal subjective symptoms
• Tendon reflexes
  • Preserved in proportion to strength
  • Normal in 40%
• Time course
  • Weakness
    • Slowly progressive over 1 to 30 years (90%)
    • Occasionally stepwise (10%)
    • Transient exacerbations: Weeks to months
      • Pregnancy
      • Corticosteroid treatment
  • Focal conduction block: Often persists over time
  • Axonal loss: Often progresses over years
  • Death due to disease: Rare
  • Spontaneous remission: Rare; Not when anti-GM1 antibodies present

    Conduction block Distal stimulation (Top): Large CMAP Proximal stimulation   Reduced CMAP size (to < 50%)   Reduction occurs focally along nerve

• Electrophysiology
• Motor Conduction Block: Especially
  • 50% Reduction of proximal vs distal CMAP amplitude
  • Focal
  • Location: Distal nerve segment in arm; Ulnar or Median nerves
  • May increase with activity or repeated action potentials
  • More regions with block in patients with long disease course (> 10 years)
• Other signs of demyelination (Mild)
  • Conduction velocities: Often normal between regions of block
  • Temporal dispersion: Mild
  • Distal latencies: Occasionally prolonged
• Axonal Loss
  • Motor
  • Later in disease course
  • Progressive reduction over time
• Sensory nerve conductions: Normal
• EMG
  • Distal denervation
  • Normal thoracic paraspinous muscles
• Axon physiology¹³
  • Site of conduction block: Depolarization
  • Distal to conduction block: Hyperpolarization
• Serum Autoantibodies
  • Antigens: GM1 ganglioside
  • Antibody type: IgM
  • Optimal anti-GM1 antibody testing: Covalent ELISA methodology
    • Sensitivity for MMN: >80%
    • Specificity
      • IgM Anti-GM1 antibodies common: Often present in Motor neuropathies
        • MMN or Distal LMN syndrome present in >98% of + serums
        • Occur in 37% of patients with Acute axonal motor neuropathy
      • Anti-GM1 antibodies rare
        • Never present in ALS
        • Occur in 0.3% of controls
  • See
    • Anti-GM1 antibodies
      • Clinical associations
      • Testing guidelines
    • Ganglioside structures
• Laboratory
  • Serum M-Protein: Occasional
  • CSF protein: Mildly elevated in 33%

    Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-1'Ceramide 3 | Neu5Acα2 GM1 ganglioside

  • MRI: T2 signal intensity in region of conduction block
    
• Pathology²⁴
  • Multifocal demyelination: Some biopsies
    • Segmental demyelination
    • Onion bulbs in regions of conduction block
    • ? Less common with longer disease duration
  • Motor axon loss
    • Multifocal
    • Especially larger axons
    • Regenerating clusters
    • Probably increased with disease duration
  • Inflammation: Epineurial; Perivascular
• Treatment
  • General
    • Improvement with IVIg¹⁴
      • More likely
        • When conduction block detected
        • More nerves involved
      • 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
  • 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
  • Human Immune Globulin
    • Dose: 1 g/kg/day x2 days
    • Repeat treatments: Every 2 weeks to 9 months to prevent relapse
    • Outcome
      • Useful functional improvement in 50% to 60%
      • Improvement more common with
        • Definite conduction block
        • Serum IgM binding to GM1 ganglioside
    • "Resistance" may develop over time²⁵
      • Onset: 3 to 7 years after onset of treatment
      • More frequent dosing
        • May initially maintain strength
        • Becomes less effective over time
      • 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
  • 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)

Anti-MAG IgM staining of Schwann cell cytoplasm > compact myelin in nerve

• Onset age: Usually > 50 years
• Clinical Features
  • Sensory loss (100%)
    • Distal
    • Legs > Arms
    • Symmetric
    • Panmodal
  • Weakness (70%)
    • Distal
    • Legs > > Arms
    • Symmetric
  • 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
  • Time Course: Slowly Progressive (years)
• Electrophysiology
  • Demyelination
    • Prolonged Distal Latencies (90%)
    • Slow NCV (70%)
    • Temporal dispersion of CMAPs
    • NO Conduction Block
  • Axonal Loss
    • Compound motor action potentials (CMAPs): Reduced distally
    • Sensory nerve action potentials (SNAPs): Reduced amplitude, or absent
• Serum Autoantibodies:
  • IgM vs MAG
    • Specific for demyelinating neuropathy when Western blot +
    • Peripheral nerve tissue staining
      • Schwann cell cytoplasm: Adaxonal & Abaxonal
      • Compact myelin: Moderate

        MAG Antigenic Site

        3-Sulfated (SO4) glucuronyl moiety

    • MAG protein
      • Member of immunoglobulin superfamily
      • Adhesion molecule
      • CNS more abundant than PNS
      • Present in myelinating Schwann cells
      • Required to maintain normal separation of axonal & adaxonal Schwann cell membrane
  • Serum M-Protein
    • IgM
    • Common (85%); Especially with anti-MAG titers > 30,000
    • Some with Waldenström's macroglobulinemia
  • MAG Antigenic site
    • Includes 3-Sulfated (SO₄) glucuronyl group
    • Present on several glycoproteins & glycolipids
      • MAG
      • P₀ protein
      • N-CAM
      • Sulfated glucuronyl paragloboside
• Nerve pathology
  • Demyelination

    External layers of Schwann cell (myelin) membrane are separated.

    • Segmental
    • Myelin wide spacing
    • Onion bulbs
    • Tomaculae
      • Teased fiber
      • Ultrastructure
  • Axonal loss
  • IgM deposits on peripheral nerve myelin
• Treatment: Immunosuppression
  • Cyclophosphamide (IV) & Plasma Exchange⁴
    • Treat to reduce anti-MAG antibody titers by > 70%
    • Treatment effects: Improved strength & gait; ? Sensation
  • Rituximab⁷
  • Other
    • α-interferon: May produce improved sensation
    • Prednisone: Not effective
    • IVIg: May produce short-lived small benefit in some patients¹⁸
    • Cladribine: Case reports of efficacy; Significant toxicity
    • Fludarabine: Case reports of efficacy; Significant toxicity
• Treatment: Other
  • Tremor: Gabapentin
• Variant anti-MAG clinical syndrome: Anti-MAG antibody titers < 10,000
  • Sensory loss: Small > large fiber modalities
  • Motor: Normal
  • Electrodiagnostic: Axonal loss
• MAG protein
  • 100 KDa Glycoprotein
  • 2 splice variants with different size cytoplasmic domains
  • Cell adhesion molecule
  • Immunoglobulin superfamily (Extracellular domain)
  • Zinc binding (Intracellular domain): May induce MAG dimerization

GALOP syndrome⁵

• 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

From M. Al-Lozi POEMS   Thickened, dry skin   Clubbing of fingers

POEMS Syndrome²¹

• Nosology: Other names
  • Crow-Fukase Syndrome
  • Takatsuki disease
  • PEP syndrome
• General Features
  • POEMS
    Polyneuropathy
    Organomegaly
    Endocrinopathy or Edema
    M-protein: Usually IgG or IgA λ
    Skin changes
  • Male (60% to 70%) > Female
  • Onset age: Mean 51 years; Younger than myeloma
  • Course
    • Progression over months to years
    • 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
      • Reduced
        • Fingernail clubbing
        • Extravascular volume overload
    • Death: > 50%
      • 33 month mean survival in patients who died
      • Causes
        • Heart failure
        • Capillary leak (Pleural effusion; Ascites)
        • Renal failure
        • Infection
  • Geography: ? High incidence in Japanese males
  • Partial POEMS syndromes
    • Not uncommon
    • Definition
      • Polyneuropathy
      • M-protein
      • Other systemic features
  • Treatment
    • Radiation
    • Prednisone ± Melphalan
• Polyneuropathy: Most common presenting feature
  • Onset
    • Age: Mean 45 years; Range 27 to 80 years
    • Paresthesias in feet
  • Clinical
    • Weakness
      • Initially distal
      • Symmetric
      • Progresses to involve proximal strength
      • Disabling in > 50%
    • Sensory loss: Especially vibration & touch
    • Tendon reflexes: Reduced or Absent
    • Pain: Unusual
    • Autonomic: Hyperhidrosis
    • Course: Progressive over 1 to 2 years
  • Electrophysiology¹⁵
    • Demyelination
      • NCV: Slowing more in intermediate than distal nerve segments
      • Distal latencies: Moderately prolonged
      • Conduction block: Unusual
    • Axonal Loss
      • Motor & Sensory
      • CMAPs: Small; Legs reduced more than arms
  • CSF: High protein; No cells
  • Nerve pathology
    • Axonal loss
    • Demyelination: Segmental; Thinly myeliated axons
    • Uncompacted myelin
      • Non-fusion of inner aspects of Schwann cell membranes
      • Found in 1% to 7% of myelinated axons
      • Present in 50% to 90% of POEMS biopsies
    • No inflammation
• Other systemic disorders
  • Cranial nerves
    • Most not involved
    • Papilledema: 29% to 55%
  • Skin changes
    • Hypertrichosis: Associated with endocrine disorders
    • Hyperpigmentation: Most common skin feature (47%)
    • Acrocyanosis & Plethora
    • Clubbed fingers: Associated with more extensive disease
    • White nails
    • Hemangiomas
    • Sclerodermatous changes
    • Angiomatous lesions
    • Violaceous cutaneous patch: Over bone plasmacytoma; Enlarging²²
  • Edema

    From M. Al-Lozi POEMS: Edema

    • Very common
    • Oten severe
    • Types
      • Peripheral edema
      • Ascites
      • Effusions: Anasarca
  • Endocrinopathy
    • Diabetes: Glucose intolerance (25%)
    • Hypothyroid (25%)
    • Gynecomastia (60% to 70%)
    • Amenorrhea (60% to 70%)
    • 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%)
    • Pre-retinal hemorrhages
    • Uveitis
    • Neovascularization of disk
  • Renal involvement: Occasional renal failure
    • Membranoprolifrative glomerulonephritis (MPGN)
    • Thrombotic microangiopathy
    • Mesangiolytic glomerulonephritis
  • Circulatory
    • Pulmonary hypertension
    • Thrombotic events
    • Congestive heart failure
  • Other
    • Weight loss > 10 pounds: 37%
    • Fatigue: 31%
• Associated neoplasms
  • With bone lesions (55% to 90%)
    • Myeloma
      • Osteosclerotic > Osteolytic
      • Lytic lesions may have sclerotic rim
      • Solitary lesion in 40%
  • 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
• Lab
  • Serum M-protein
    • Frequency: 75% to 84%
    • Usually IgG or IgA
    • λ light chain in more than 95%
    • IgG: 44%; Occurs more frequently with bone lesions
    • IgA: 40%; Bone lesions less frequent
    • Other
      • IgM: 1%
      • 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
        • External link: R&D
      • 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: Down-regulated in nerves
        • May explain organomegaly, skin changes & edema in POEMS
    • Erythropoetin: Levels reduced in serum
    • Proinflammatory cytokines: Increased IL-1β , IL-6 , TNF-α
    • Matrix metalloproteases: Increased MMP-1, 2, 3, 9 and TIMP
  • Sedimentation rate: Normal
  • Bone marrow: Plasmacytosis > 10% in 5% to 20%
  • CSF
    • Protein: High
    • Pressure: High
    • Cells: Normal
  • Nerve pathology
    • Demyelination: Uncompacted myelin
    • Axonal loss
    • Endoneurial vessels
      • Thickened basal lamina
      • Narrowed lumen
      • Endothelial cells: Proliferation; Tight junctions opened
  • Viral infections: ? Kaposi sarcoma-associated herpesvirus (Human herpesvirus 8)
  • Pathogenesis: Many signs associated with increased vascular permeabiltiy
• Treatment
  • Localized osteosclerotic lesions: Irradiation
  • Widespread lesions: Chemotherapy
    • Melphalan & Prednisone: Poor response
    • Melphalan, high dose (200 mg/m²) with bone marrow transplant¹⁶
  • No bone lesions: ? Cyclophosphamide
  • No benefit: Corticosteroids; IVIg
  • ? Plasma Exchange

Neuropathy with IgM binding to Sulfatide

• Clinical Features
  • Onset: Age usually > 50 years; Paresthesias
  • Sensory: Symmetric; Distal; Paraesthesias

    Carbohydrate moiety (Sulfated galactose)   Lipid moiety Ceramide
    SULFATIDE

  • Motor: Distal; Symmetric
  • Gait Disorder: 50%
  • Tremor
• Course: Slowly progressive
• Electrophysiology
  • M-Protein: Demyelinating (like MAG)
    • Prolonged distal Latency
    • Slow NCV
    • Axonal 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
  • Axonal loss
  • IgM & complement binding in nerve
• Treatment: Few Reports
  • Cyclophosphamide
  • Human Immune Globulin
  • Other: Rituximab; ? Fludarabine

Demyelinating ataxic neuropathy with IgM binding to GalNAc-GD1a and GM2 gangliosides¹⁰

• 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 Neuropathy¹¹
  • 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 Neuropathy¹²
  • 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