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CHRONIC IMMUNE POLYNEUROPATHIES: DEMYELINATING

Demyelinating PN
  Comparative features
  Treatment strategies

CIDP
  Clinical features
    Associated disorders
  Laboratory features
  Pathology
  Treatments
  Variants
Contactin-1
GALOP syndrome
GD1a antibody
  Motor-Sensory neuropathy
Multifocal motor neuropathy
MAG antibody associated neuropathy
Neurofascin antibodies
Osteosclerotic Myeloma
Other demyelinating neuropathies
POEMS Syndrome
Sulfatide

Antibody testing

Also see: Immune axonal neuropathies


Multifocal Motor Neuropathy (MMN)
Myelinated Axons: Segmental demyelination


CHRONIC IMMUNE DEMYELINATING NEUROPATHIES:
COMPARATIVE FEATURES
Neuropathy
(Antibody)
Clinical Features Electrophysiology Antibody M-Protein* Treatment
Chronic
Immune
Demyelinating
Polyneuropathy
(CIDP)
Motor > Sensory
Weakness:
  Proximal & Distal
  Symmetric
Onset: 1 to 80 yrs
Chronic/Relapsing
Motor + Sensory Δ
NCV: Slow
Conduction Block
Distal Latency: Long
F-waves: Slow
Targets
  β-tubulin
  Heparan sulfate

Class: IgM or IgG
Frequency: 10%
15% T-cell immunosuppression
  Prednisone
  Cyclosporine A
  Methotrexate
HIG
Plasma Exchange
Multifocal
  CIDP


Also see:
  CIDP variants
Chronic
Motor > Sensory
Weakness:
  Distal > Proximal
  Asymmetric
  Arms > Legs
Onset: 15 to 75 yrs
Motor + Sensory Δ
NCV: Slow
Conduction Block
Distal Latency: Long
F-waves: Slow
? ? T-cell immunosuppression
  Prednisone
HIG
Multifocal
Motor
Neuropathy

(MMN)
Motor only
  Distal > Proximal
  Arms > Legs
  Asymmetric
Onset: 25 to 80 yrs
Slowly progressive
Motor only
  Conduction Block
  Axon Loss: Distal

EMG: Denervation with
  disease progression
Targets
  Co-GM1, NP-9
    or NS6S


Class: IgM

Frequency: 80%
20% IVIg (Conduction block)
B-cell immunosuppression
  Cyclophosphamide ±
    Plasma Exchange
  Rituximab
Myelin-
Associated
Glycoprotein

(MAG)
Sensory > Motor
Distal; Symmetric
Gait disorder
Tremor
Onset: > 50 yrs
Slowly progressive
Motor + Sensory Δ
Distal Latency: Long
NCV: Slow
No conduction block
Axon Loss: Distal legs
Target: MAG

Class: IgM

Frequency: 100%
85% B-cell immunosuppression
  Cyclophosphamide ±
    Plasma Exchange
  Rituximab
  ? Fludarabine
  Not HIG
GALOP Gait Disorder
Sensory > Motor
Distal; Symmetric
Onset: > 50 yrs
Motor + Sensory Δ
Distal Latency: Long
NCV: Slow
No conduction block
Target
  Sulfatide in
    lipid membrane


Class: IgM
80% HIG
  Cyclophosphamide ±
    Plasma Exchange
Sulfatide Slowly progressive
Sensory > Motor
Distal; Symmetric
Onset: > 45 yrs
Distal Latency: Long
NCV: Slow
Axon Loss: Distal
Target
  Sulfatide

Class: IgM
90% HIG
Cyclophosphamide ±
    Plasma Exchange
GM2 &
GalNAc-GD1a

Sensory > Motor
Ataxia: Limb & Gait
Distal
Symmetric or
  Asymmetric
Onset: Adult
Slowly progressive
NCV: Slow
Targets
  GM2
  GalNAc-GD1a

Class: IgM
Common HIG
Polyneuropathy
Organomegaly
Endocrinopathy
M-protein
Skin changes
(POEMS)
Sensory & Motor
Symmetric
Onset: 25 to 60 yrs
NCV: Slow
Axon Loss
Target: ?

Class: IgA or IgG
90% ?
Neurofascin Sensory & Motor
Distal
Tremor
Onset: Adult
Progressive
NCV: Slow
Target
  Neurofascin

Class: IgG4
No
?
Contactin-1 Sensory & Motor
Distal or Diffuse
Onset: Adult, late
Progressive
Distal latency: Long
Conduction block
Target
  Contactin-1

Class: IgG
No Prednisone
Not HIG
* Frequency based on testing by immunofixation methodology.
Print


Chronic Immune Demyelinating Polyneuropathy (CIDP)

Clinical features
  Associated disorders
Comparative features
Laboratory features
Pathology
Treatments
Variants


Chronic Immune Demyelinating Neuropathies: Variants

β-Tubulin Ab
Childhood
CIDP
CIDP + CNS features
Contactin-1 Ab
Diabetes
IgM vs GM2 & GalNAc-GD1a
Motor
  CIDP
  MMN
  Polyradiculopathy
Multifocal
  Upper limb
  M-protein
  IgM
  IgG or IgA
Neurofascin Ab
Onset
  Acute
  Subacute
Perineuritis
POEMS
Sensory
  CIDP
  CISP Polyradiculopathy

  • Sensory, Demyelinating Polyradiculopathy (SDP; CISP) 39
    • Epidemiology: > 30 patients
    • Clinical
      • Onset age: Median 55 years; 34 to 72
      • Sensory loss
        • Gait ataxia (80%)
        • Proprioception: Reduced
        • Pan modal
        • Arms involved early or at onset: In 1st 6 months
      • Discomfort
        • Paresthesias (78%)
        • Pain (22%)
      • Cranial nerves
        • V: Sensory loss
        • III
      • Tendon reflexes
        • Absent in 36%
        • Ankle or Leg loss in others
      • Strength: Normal
      • Course
        • Progression: Over months
        • Gait aids required (30%)
      • Treatment response
        • Frequency of improvement: Common (95%)
        • Modalities: IVIg; Prednisone
        • Monophasic (78%): Treatment could be stopped
    • Laboratory
      • NCV
        • Conduction velocities: Normal or Mildly reduced
        • SNAP amplitudes: Normal (36%) or Reduced
        • Abnormal radial/Normal sural pattern (20%)
        • Motor: Normal
        • SSEP: Abnormal
      • M-protein: 20%
      • CSF: Protein high (73%), Range 36 to 140
      • Nerve biopsy
        • Axon loss
        • Demyelinating features (70%)
          • Onion bulbs
          • Myelin sheath: Thin
        • Epineurial mononuclear cell inflammation
          • T-cells & Macrophages

From: M. Al-Lozi
CISP: Lumbo-Sacral roots enhance

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

Antibodies
Clinical
Electrodiagnostic
Epidemiology
Laboratory
Pathology
Treatment
Variants & DDx

MMN: Focal weakness
  Varied finger extension

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


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

  • MAG genetics
  • 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
      • CNS more abundant than 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)
    • 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 seveere disability (50%)
    • Treatment: Immunosuppression
      • 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
  • Serum Autoantibodies
  • Nerve pathology 61
  • Variant anti-MAG clinical syndrome: Anti-MAG antibody titers < 10,000
    • Sensory loss: Small > Large fiber modalities
    • Motor: Normal
    • Electrodiagnostic: Axon loss


MAG
Antigen Cross-Reactivity
3-Sulfated (SO4)
Glucuronyl moiety (SGPG)


Myelin Pathology: MAG PN


External layers
of myelin
membrane
are separated



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

Myelin Wide spacing


GALOP syndrome 5


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
  Polyneuropathy
  Monoclonal plasmaproliferative disorder (Usually λ)
Other
Vascular endothelial growth factor (VEGF): High
Sclerotic bone lesions
Castleman’s disease
Minor diagnostic criteria: 1 needed
Organomegaly
  Spleen, Liver; Lymph nodes
Edema
  Edema, Pleural effusion, Ascites
Endocrinopathy
  Adrenal, Thyroid, Pituitary, Gonadal, Parathyroid, Pancreas
Skin Δ
  Pigmentation, Hypertrichosis, Plethora, Hemangiomata, Nail Δ


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


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


Osteosclerotic Myeloma


Antibody testing is performed at:

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


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Chemical figures by G. Lopate.

1/25/2021