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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 & ONION-LIKE BULBS

General features   Subtypes   BLOBs   Early   Large   Very large   Obsolete   Schwann cell process   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
• Structures within onion bulb
  • General Orientation
    • Circumferential
    • Around axon, if one is present
  • Components
    • Schwann cell processes: Contain NCAM & P0 protein; "Denervated"
    • Basal lamina: Stains for Collagen IV; Between Schwann cell processes
    • Collagen
    • Fibroblast processes: May surround onion bulb
• Associated axon
  • Location: 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 bulb distribution
    • Often separated from each other by increased endomysial connective tissue
  • Congenital Hypomyelinating Neuropathies
    • BLOBs: Onion bulbs have more Schwann cell basal lamina & fewer Schwann cell processes
  • Obsolete (Burnt-out) 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
  • Often similar in hereditary & immune, acquired demyelinating disorders
• 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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Electron micrograph: From Robert Schmidt MD

Onion Bulbs: Circumferential Layer Components   Schwann cell processes   Schwann cell basal lamina   Collagen: Between Schwann cell components   Fibroblast processes: May form outer layer Axons in Onion Bulbs   General location: Central   Sizes: Large or Intermediate   Absent: See obsolete onion bulbs   Myelination: Varied     Normal     Thin or Abnormal     None Electron micrograph: From Robert Schmidt MD

Electron micrograph: From Robert Schmidt MD

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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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Onion Bulbs: Ultrastructure

CIDP, Childhood onset

From: Robert Schmidt MD

Onion bulbs, Large: Several layers surround thinly myelinated axons
  Layers include
    Schwann cell processes
    Schwann cell basal lamina
    Connective tissue
  Outer rim: My be fibroblast process
  Central axon: Thinly myelinated

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Onion Bulbs: Around thinly myelinated axons

From: Robert Schmidt MD

Onion bulbs, Large: Several layers surround thinly myelinated axons
  Layers include
    Schwann cell processes
    Schwann cell basal lamina
    Connective tissue
  Outer rim: My be fibroblast process
  Central axon: Thinly myelinated

From: Robert Schmidt MD

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Cells within Onion Bulbs

From: Robert Schmidt MD

Schwann cells & Macrophages within onion bulb layers

From: Robert Schmidt MD

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Macrophage: Between onion bulb layers

From: Robert Schmidt MD

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Onion Bulbs: Around demyelinated axons

From: Robert Schmidt MD

Onion bulbs, Large: Several layers surround demyelinated axons
  Layers include
    Schwann cell processes
    Schwann cell basal lamina
    Connective tissue
  Outer rim: My be fibroblast process
  Central axon: Unmyelinated

From: Robert Schmidt MD

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Schwann cell processes surround demyelinated axon

From: Robert Schmidt MD

From: Robert Schmidt MD

Onion bulbs around demyelinated axon

From: Robert Schmidt MD

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Onion Bulbs, Obsolete: Central axons are lost (Above)

From: Robert Schmidt MD

From: Robert Schmidt MD

Onion bulbs, Obsolete
  Multiple layers contain: Schwann cells alternating with collagen
  Associated central axon is: Lost

From: Robert Schmidt MD

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From: Robert Schmidt MD

Pale Schwann cell processes in onion bulb

From: Robert Schmidt MD

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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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Onion Bulbs, Early

Onion bulbs, Incompletely formed
  Schwann cell processes: Long, uninterrupted
  Surround 3 thinly myelinated axons

From: Robert Schmidt MD

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

Toluidine blue

Possible Onion bulbs, thin: Around myelinated axons (Arrow)
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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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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Return to Normal nerve biopsies
Return to Biopsy illustrations
Return to Neuromuscular Home Page
Return to Nerve biopsy
Return to Demyelinating neuropathies
Return to Active demyelination

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

1/19/2026