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PERIPHERAL NERVE: Chronic Demyelination

CIDP Demyelination   Active   Demyelinated axons   Focal, Persistent   Segmental Hypomyelination Large nerves MMN Onion bulbs Subperineurial edema: CIDP Teased fibers Tomaculae

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MYELIN PATHOLOGY

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Myelin Loss: On Preserved Larger Axons

Neurofilament stain Large & Small axons: Present; Reduced numbers

VvG stain Myelin: Mostly absent

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Myelin loss: From preserved larger axons   Few remaining myelinated axons are small with thin myelin sheath Toluidine blue stain Few myelinated axons	Toluidine blue stain Demyelinated large axons, Scattered (Arrow) Demyelinated axons often have surrrounding Schwann cells
Toluidine blue stain     Onion bulb, Early (Arrow): Reduplicated basal lamina

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Segmental Demyelination & Remyelination

Segmental Demyelination with Remyelination (Top)
  Internodes (3)
    Short
    Different
      Lengths
      Thicknesses
Control Myelinated Axon (Bottom)
  Myelin internode
    Long

Teased Axons

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Myelinated Axons: Segmental Demyelination
  Myelination is absent or thin in some internodes but not others

Teased Axons

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Myelinated Axons: Segmental Demyelination
  Myelination of internode is thin to the left of the Node of Ranvier but normal on the right side

Teased Axons

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CIDP: Distal Motor Axons
  Segmental Demyalination
  Internode widening
  Distal Axons
    Thin
    Absent myelin
    Collateral sprouts: Reinnervate denervated NMJs

P0-Silver-Esterase stain

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Myelin pathology: Multifocal Motor Neuropathy

P0-Silver-Esterase stain

  Above: Segmental demyelination (Arrow) of a distal motor axon in Multifocal motor neuropathy
    Arrow points to small region of myelin in area of segemental demyelination
    Fragment of neuromuscular junction (Blue stain) is at left

  Below: Normally myelinated distal motor axon in muscle
    Arrow points normal short myelin internode on distal motor axon

P0-Silver-Esterase stain

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Hypomyelinated Axons

See: PMP-22 point mutation

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VvG stain

Endoneurium
  Cellular
  Some increased connective tissue space
  No myelin

VvG stain

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Large axons: Many present with no surrounding myelin space
Small axons: Mildly reduced numbers

Neurofilament stain

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Toluidine blue stain

Axons
  Many with very thin surrounding myelin
  Schwann cell nuclei often directly neighbor thinly myelinated axons

Toluidine blue stain

Axons
  Many with very thin surrounding myelin
  Schwann cell nuclei often directly neighbor thinly myelinated axons
Endomysial connective tissue
  Increased between axons

Toluidine blue stain

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ONION BULBS

General features   BLOBs   Early   Large   Obsolete   Molecular Also see   CIDP   CMT 1   Large nerves Differential Diagnosis   Pseudo-Onion bulbs   Perineurioma

Gombault 1889

Dejerine & Sottas 1893

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Onion Bulbs

• Definition
  • Circumferentially arranged layers of
    • Schwann cell processes
    • Schwann cell Basal lamina
    • Collagen
  • Location: Around axon, or region of axon loss
• History
  • Early illustrations: Gombault (1889) & Dejerine + Sottas (1893) (Above)
• Cause
  • Demyelination & Remyelination: Repeated episodes
  • Schwann cell proliferation
• Development
  • Remyelination: New Schwann cells add to, or replace, residual Schwann cell
  • Onion bulb formation
    • Source: Schwann cells & Processes
      • Detatch from axon
      • Generate cells & processes that form onion bulb layers
• Structure
  • Larger axons: Surrounded by NCAM containing Schwann cells & Basal lamina
  • Similar in hereditary & immune, acquired demyelinating disorders
• Structures within onion bulb
  • Orientation: Circumferential; around axon, if one is present
  • Schwann cells: Contain NCAM & P0 protein; "Denervated"
  • Basal lamina: Stains for Collagen IV; Between Schwann cell processes
  • Collagen strands
• Associated axon
  • In center of onion bulb
  • Size: Larger size; or May be several, smaller regenerated axons
  • Myelin sheath: Around axon; Inside onion bulb; Often thin for axon size, or absent
  • Some onion bulbs have no central axon = "Obsolete onion bulbs"
• Other features
  • Individual onion bulbs: Often separated from others by increased endomysial connective tissue
  • Congenital Hypomyelinating Neuropathies: Onion bulbs have more basal lamina & fewer Schwann cell processes
  • Burnt-out or Obsolete onion bulbs
    • Loss of central axon within onion bulb
    • Eventual loss of associated Schwann cells
  • Nerve size
    • Often large: Due to presence of onion bulb & increased endomysial connective tissue
• Differential Diagnosis
  • Structural
  • Related disorders
• Acquired vs Inherited disorders: Patterns of OB distribution ¹
  • Around most axons: More common with inherited neuropathies
  • Around scattered axons: Common with acquired neuropathies
  • Clustered in regions of nerve: Acquired or inherited neuropathies

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Onion Bulbs, Early

Toluidine blue

Onion bulbs, thin: Around myelinated axons (Arrow)

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Toluidine blue Onion bulbs, Early Extra layers of Basal lamina, Collagen & Schwann cell processes around thinly or normally myelinated axons.

Electron micrograph: From Robert Schmidt MD

Two patterns of Early onion bulbs: Surrounding
  Thinly myelinated, around nerve fibers (Above)
    Often related to demyelination
  More thickly myelinated, irregular-shaped myelinated axons (Below)
    May be related to changes in axon size or regeneration

Toluidine blue

Onion bulbs, rudamentary (Arrows)
  Schwann cell processes & Collagen
  May partially surround irregular-shaped myelinated axons

Toluidine blue

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Onion Bulbs: Large, Late

Also see: CMT1A

Dejerine & Sottas 1893

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Toluidine blue stains of plastic nerve sections	Onion bulbs, Large Multiple Connective tissue layers & Schwann cell processes around thinly myelinated axons. Onion bulbs may contain 0, 1, or several, axons. Toluidine blue stains of plastic nerve sections
Onion bulbs, Large Several layers of Basal lamina, Connective tissue & Schwann cell processess around thinly myelinated axons.

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Electron micrographs: From Robert Schmidt MD Onion Bulbs: Obsolete Onion bulbs   Multiple layers contain: Schwann cells alternating with collagen   Associated axon is: Lost

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Onion bulbs: Molecular composition

Neurofilament stain (Green) + NCAM stain (Red)

Axons in onion bulbs
  Surrounded by NCAM containing Schwann cells
Schwann cells in Onion Bulbs
  Contain both NCAM (Above) & P0 (Below) (Similar to Büngner band cells)

Neurofilament stain (Green) + P0 stain (Red)

Schwann cells in Onion Bulbs
  Contain both NCAM & P0 (All onion bulb cells cells costain (Below; Yellow))
  Similar to Büngner band cells

NCAM stain (Green) + P0 stain (Red)

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Also see
  Pseudo-onion bulbs
    Perineurioma
    Schwann cells & Circumferential Axon Sprouts

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Chronic Immune Demyelinating Polyneuropathy (CIDP): Adult

Other CIDP pathology Adult Childhood Demyelinated axons Demyelination, Active Differential fascicular Δ Onion bulbs Segmental demyelination Sub-acute onset Thin myelin sheaths Tomacula

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Remaining axons   Thinly myelinated   Reduced numbers		Onion bulbs: Small	Subperineurial edema

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Sensory CIDP: MRI

Cervical Spinal Cord & Roots: Enlargement & Contrast enhancement of Anterior & Posterior (Arrow) Roots

T1 with contrast

T1 with contrast

T2

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Enlargement of Cervical Roots & Brachial plexus (Arrow) T1 with contrast

Contrast enhanced Lumbar Roots (Arrow) T1 with contrast Lumbar Roots (L4-L5) T2

From: Sri Krishna Alapati

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References
1. Muscle Nerve 2019;59:665-670

4/28/2024