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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

Demyelinated axons Macrophage-mediated myelin stripping 1 Often immune mediated 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) CMT IB: P0 (MPZ) mutations Schwann cell inclusions Storage disorders Farber's disease (Lipogranulomatosis) Krabbe Metachromatic Leukodystrophy Niemann-Pick Adrenoleukodystrophy Cerebrotendinous Xanthomatosis Toxins Amiodarone Chloroquine Perhexiline Infections: Leprosy; CMV Thick myelin sheaths Segmentally thickened or folded myelin sheath ± Tomaculae HNPP CMT 4B CMT 4C CMT 4H Thick myelin sheath relative to axon caliber CMT 1A with PMP-22 duplication: Early stages of disease Axon atrophy 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 Axon Swelling & then Atrophy IDPN intoxication: Nerve roots (Slow transport blockade) Differential diagnosis Schwann cell process proliferation Pseudo-onion bulbs: Multiple Schwann cell processes around axons Associations Circumferential unmyelinated axons within circumferential Schwann cell layers Axon loss & Regeneration Focal, persistent demyelination Basal lamina onion bulbs (BLOBs) Layers Basal lamina: Double layers Collagen: Between Basal lamina layers Schwann cell processes Few; Within layers of basal lamina Center of BLOB: May surround neighboring axon Axons In some central areas: May be absent Size: Small Myelin: Thin or None Associations Neurofibroma/Schwannoma Hybrid Nerve Sheath Tumors CMT 4C Congenital Hypomyelinating Neuropathy Nerve Pathology Regenerating axon within Büngner band cells Surrounding Schwann cell processes are compact with little ingterruption by basal lamina or collagen Central Axons: Intermediate-sized with increased organelles Collagen Bulbs Surround: Thinly myelinated axons No (or Few) other associated cells or structures Perineurial cells surrounding axons Location: Endoneurium; Not neighboring axons Central axon Unmyelinated, or thinly myelinated Surrounded by Endoneurial cell inside Collagen IV Association: Perineurioma 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