Demyelinating Neuropathies

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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
- IgG vs
  - Neurofascin
  - Contactin
- Perineuritis

Toxins

Drugs

Predominantly demyelinating
Mixed demyelinating & axonal

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)

Mitochondrial

MNGIE Syndrome
NARP Syndrome

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 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
  - 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
- Toxins
- Infections: Leprosy; CMV
Thickened myelin sheaths
- Segmentally thickened or folded myelin sheath ± Tomaculous change
- Thick myelin sheath relative to axon caliber: CMT 1A with PMP-22 duplication: Early stages of disease
Tomaculae
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
    - 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 Clusters
    - Around Thinly myelinated axons
    - No 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
    - 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

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References
1. Neurology 2018;91:1051-1060, Cells 2021;10:844

11/20/2023