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NEUROPATHIES WITH ABNORMAL MYELINATION

Clinical types   Immune   Toxins   Drugs   Hereditary   Metabolic   Mitochondrial   Infections Myelin & Schwann cell components Pathological features

Myelin Proteins J Kwon

Immune

• Acute
  • Guillain Barré
• Chronic
  • Chronic Immune Demyelinating Polyneuropathy (CIDP)
    • Symmetric
    • Multifocal
  • Multifocal Motor Neuropathy (MMN)
  • IgM vs
    • GM1 ganglioside
    • Myelin-associated Glycoprotein (MAG)
    • GALOP antigen
    • Sulfatide (with serum M-protein)
    • GM2 ganglioside
    • GD1b ganglioside: Occasional
  • POEMS Syndrome
    Polyneuropathy
    Organomegaly
    Endocrinopathy or Edema
    M-protein
    Skin changes
  • IgG vs
    • Neurofascin
    • Contactin
  • Perineuritis

Toxins

• Diphtheria
• Buckthorn
• Hexachlorophene
• Porcine aerosolized brain
• Sodium Cyanate
• Tellurium

Drugs

• Predominantly demyelinating
  • Chloroquine
  • FK506 (Tacrolimus)
  • Perhexiline
  • Procainamide
  • Zimeldine
• Mixed demyelinating & axonal
  • Amiodarone
  • Eosinophilia-Myalgia syndrome
  • Gold
  • Suramin
  • Taxol

Hereditary: See CMT syndromes

• Carbohydrate-deficient glycoprotein
• Cataracts & Facial dysmorphism
• Cockayne's syndrome
• Congenital hypomyelinating
• Congenital muscular dystrophy: Merosin deficient
• Farber's disease (Lipogranulomatosis)
• HMSN & CMT
  • Dominant: IA, IB, III, HNPP, EGR2, Thermosensitive
  • Recessive: III (Dejerine-Sottas); 4A; 4B; 4B2; 4C; 4D (LOM); 4E; 4F; HMSN-R; CNS
  • X-linked: IX
• Krabbe
• Marinesco-Sjögren
• Metachromatic Leukodystrophy
• Niemann-Pick
• Pelizaeus-Merzbacher (PLP)
• Refsum
• Prion protein (PrP27-30): Glu200Lys mutation
  • Creutzfeld-Jakob disease
  • Mouse model: Prion over expression
• Salla disease
• SOX10: Waardenburg-Shah syndrome, neurologic variant
• Tenascin-XA
  • Uneven packing of peripheral myelin sheaths
  • Ehlers-Danlos phenotype

Metabolic (unusual)

• Diabetes (? due to concurrent CIDP)
• ? Hypothyroidism
• Hepatic disorders

• MNGIE Syndrome
  Myopathy & external ophthalmoplegia
  Neuropathy
  Gastro-
  Intestinal
  Encephalopathy
• NARP Syndrome
  Neuropathy
  Ataxia
  Retinitis
  Pigmentosa

Infections

• Creutzfeld-Jakob disease
• Diphtheria
• HIV: Associated CIDP
• Leprosy: Lepromatous; Mixed axonal-demyelinating; Colonized Schwan cells

Primary Demyelinating Neuropathy: Pathologic Differential Diagnosis

• Macrophage-mediated myelin stripping: Often immune mediated ¹
  • Guillain-Barré
  • CIDP
  • Initial locations: Commonly either
    • At nodes of Ranvier
    • At paranodes
    • Along myelin internode
  • Animal model: Experimental allergic neuritis (EAN)
  • Macrophage Variants
    • Nodopathies: Macrophages not common
    • Acute Motor Axonal Neuropathy: Macrphages invade axons
• Vesicular demyelination: Myelin splitting at major dense line
  • Guillain-Barré
  • Diabetes
  • Post-mortem artefact
  • Experimental: Lead; Tellurium; Radiation
• Myelin Periodicity: Pathology
  • Uncompacted myelin: Cytoplasmic aspects of Schwann cell membrane not apposed
    • Immune
      • M-proteins: POEMS; Some IgG & IgA
      • Guillain-Barré
      • CIDP
    • Hereditary
      • HNPP
      • CMT 1B
      • CMT 4D (LOM)
    • Normal: Schmidt-Lanterman clefts
  • Widely spaced myelin
    • Appearance
      • Separation of interperiod line
        • Major dense lines separated by space contiguous with extracellular compartment
      • Most often in outer myelin lamellae
      • Also wide adaxonal gap
    • Disorders
      • Anti-MAG Syndrome
      • Anti-Sulfatide Antibody Syndrome (with serum M-protein)
• Schwann cell inclusions
  • Storage disorders
    • Farber's disease (Lipogranulomatosis)
    • Krabbe
    • Metachromatic Leukodystrophy
    • Niemann-Pick
    • Adrenoleukodystrophy
    • Cerebrotendinous Xanthomatosis
  • Toxins
    • Amiodarone
    • Chloroquine
    • Perhexiline
  • Infections: Leprosy; CMV
• Thickened myelin sheaths
  • Segmentally thickened or folded myelin sheath ± Tomaculous change
    • HNPP
    • CMT 4B
    • CMT 4C
  • Thick myelin sheath relative to axon caliber: CMT 1A with PMP-22 duplication: Early stages of disease
• Onion bulb-like structures
  • Differential diagnosis of pathology
    • Onion bulbs: Chronic demyelinating disorders
      • Pathology
        • Central region: Axons or Empty (Obsolete onion bulbs)
        • Surrounding Layers: Schwann cell processes, Basal lamina & Collagen
      • Differential diagnosis
    • Axon Swelling & then Atrophy
      • IDPN intoxication: Nerve roots (Slow transport blockade)
    • Schwann cell proliferation
      • Pseudo-onion bulbs: Multiple Schwann cell processes around axons
      • Association: Circumferential sprouts from axons; Axon loss & regeneration
    • Perineurial cells
      • Location: Endoneurium; Not neighboring axons
      • Central axon: Surrounded by Endoneurial cell inside Collagen IV
      • Association: Perineurioma
    • Basal lamina onion bulbs (BLOBs)
      • Layers
        • Basal lamina
        • Schwann cell processes
        • Little collagen
      • Axons
        • In some central areas: May be absent
        • Size: Small
        • Thinly- or Un-myelinated
      • Associations: Neurofibroma/Schwannoma Hybrid Nerve Sheath Tumors; CMT 4C
  • Chronic demyelinating disorders with onion bulbs
    • Pathology
    • Differential diagnosis
      • CMT
        • 1A with PMP-22 point mutation
        • 1B
        • HNPP
      • HMSN III (Dejerine-Sottas)
      • Refsum
      • Storage disorders: OB Variably present
        • Krabbe
        • Metachromatic Leukodystrophy
        • Cerebrotendinous Xanthomatosis
      • Immune
        • CIDP (Chronic)
        • MMN (At sites of conduction block)
      • ? Acromegaly
      • Experimental
• Hypomyelination
  • CMT 1A: Especially in older patients
  • HMSN III (Dejerine-Sottas)
  • Congenital hypomyelinating neuropathy
  • Storage disorders
    • Krabbe
    • Metachromatic Leukodystrophy
• Nerve pathology illustrations
  • Dysmyelination
    
  • Demyelination: Chronic