Pathology of peripheral neuropathies

Tests for peripheral neuropathy

• Electromyography
  • measures electrical impulses in muscle at rest & when contracting
  • Differentiates between muscle and nerve disorders
• Nerve conduction velocity
  • assess the degree of damage in the larger nerve fibres due to myelin loss
  • Slow transmission –> myelin damage   
  • Decrease strength of impulse -> axonal degeneration
• Nerve biopsy
  • invasive
  • sural nerves (unmyelinated nerve)
• Skin biopsy
  • assess damage present in small fibres
  • nerve conduction tests cannot assess these

Approach to peripheral nerve diseases

Consider whether the pathology is:

• Primary damage to Schwann cells/myelin
  • Acute inflammatory demyelinating polyradiculoneuropathy (GBS)
  • Chronic inflmamatory demyelinating polyradiculoneuropath
  • Paraprotein neuropathy
  • Charcot-Marie-Tooth type 1
• Damage to neuron/axon
  • Damage affecting predominantly small unmyelinated fibres 
    • amyloid
    • diabetes mellitus
    • HIV
  • Affecting all axonal population
    • vasculitis
    • CMT type 2

Pathology of demyelination

• Axon damaged
• Neural bodies intact
• Conduction block
  • conduction velocity decreases

Patterns of axonal pathology

1. Wallerian degeneration
   • In transected axon
     • distal portion undergoes disintegration & degradation
   • Limited recovery & regeneration
   • Neuronal body
     • chromatolysis
       • activation of protein synthesis to help regenerate axon
   • Examples:
     • trauma
     • infarction
       • diabetic mononeuropathy
       • vasculitis
     • neoplastic infiltration
2. Distal axonopathy
   • Degeneration of axon and myelin starts in the most distal part of the axon
   • Axon dies back (retrograde)
     • ‘stocking-glove’ sensory
     • motor deficit
   • Caused by neuronal body pathology
     • resulting in inability to sustain the metabolic needs of the axon
   • Examples
     • drugs
     • toxins
     • organophosphates
     • diabetic polyneuropathy*
     • alcohol
     • vitamin deficiency
     • uraemia
     • malignancy

Classification of peripheral neuropathy

By etiology

1. Inflammatory neuropathies
   • Immune-mediated
   • Examples
     • Gullain-Barre Syndrome
     • chronic inflammatory demyelinating polyradiculoneuropathy
2. Infectious
   • Examples
     • Leprosy (Hansen’s disease)
     • Diptheria
     • Varicella-zoster
3. Hereditary
   • Examples
     • Charcot-Marie-Tooth 1,2 and X
4. Acquired metabolic & toxic neuropathies
   • Examples
     • Diabetes mellitus
     • vitamin deficiency
     • liver disease
     • alcohol
     • malignancy
     • paraneoplastic

By site of pathology

• Affecting Schwann cells/myelin
  • Acute inflammatory demyelinating polyradiculoneuropathy (GBS)
  • Chronic inflmamatory demyelinating polyradiculoneuropathy
  • Paraprotein neuropathy
  • Charcot-Marie-Tooth type 1
• Affecting the neurons/axons
  • Damage affecting predominantly small unmyelinated fibres 
  • Example
    • Amyloid
    • Diabetes mellitus
    • HIV
• Affecting all axonal population
  • Vasculitis
  • CMT type 2

_____________________________________________________________________

DEMYELINATING DISEASES

Acute inflammatory demyelinating polyradiculoneuropathy

• General
  • Also known as: Guillain-Barre Syndrome
  • T-cell mediated immune response & humoral response
• Clinical features
  • Rapidly evolving
    • Ascending symmetrical weakness
    • Areflexia
  • Variable autonomic dysfunction
  • Mild sensory sign
  • Mostly preceded by an acute flu-like illness
    • complication of influenzae infection
• Important features
  • Ascending paralysis
  • Loss of deep tendon reflexes
  • Decreased nerve conduction
  • Increase in CSF protein
    • Little cell increase
• Infectious agents implicated include
  • Campylobacter jejuni
  • CMV
  • EBV
  • Mycoplasma pneumoniae
  • Influenzae virus
• Microscopic pathology picture:
  • Endoneurial lymphocytic inflammation
    • macrophage infiltration
    • MACROPHAGE mediated DEMYELINATION
  • More severe in the nerve roots
    • more subtle in the periphery
    • Axonal damage when disease is severe
  • Electron microscopy
    • macrophage penetrating basement membrane of Schwann cells
    • Stripping myelin sheath away
    • Remyelination can occur
• Plasmapharesis is effective in some cases

Chronic inflmamatory demyelinating polyradiculoneuropathy

• Classical Triad
  • Symmetrical proximal & distal weakness
    • for more than 2 months
  • Loss of large fibre modalities

  Loss of deep tendon reflexes

Hereditary Sensory and Motor Neuropathy (HSMN)

• General
  • Also known as Charcot-Marie-Tooth type 1
• Clinical features
  • Slowly progressive distal weakness
  • Usually begin in childhood
  • Muscle atrophy and sensory impairment
  • Dominance of distal lower extremities signs and symptom
  • Hammertoes
    • 
  • Pes caves
    • high arch
  • Nerve enlargement (hypertrophy)
    • If nerves palpable and tremors = CMT type 1
  • Very slow disease with normal longevity
• Pathology
  • Decrease numbers of large & small myelinated fibres
  • Onion bulb formation
  • Increase in calibre of affected nerves
    • nerve hypertrophy
  • Axonal form (CMT2)
    • no onion bulb, but regenerative axonal clusters
  • Genetic mutation of myelin related proteins

Paraprotein neuropathy

• Neuropathy associated with a monoclonal gammopathy
• Incidence
  • > 50 yrs
  • male
• Clinical features
  • Mild slowly progressive symmetrical distal weakness
  • Painful with severe sensory loss & paresthesia
• Diagnosis
  • Monoclonal IgM with anti-MAG (myelin-associated glycoprotein activity)
• Pathology
  • Non-specific myelin & axonal loss
  • POEMS syndrome
    • polyneuropathy
    • organomegaly
    • endocrinopathy
    • M protein
    • skin changes

_____________________________________________________________________

AXONAL DISEASES

Amyloid neuropathy

• General
  • Hereditary/acquired
• Important features
  • Small fibre neuropathy
    • pain
    • temperature
    • autonomic dysfunction*
• Clinical features
  • Painful dysesthesias
  • Bowel & bladder dysfunction
  • Impotence
  • Orthostasis
  • Cardiac & renal abnomalites
• Pathology
  • Biopsy abdominal fatpad
    • Amyloid deposition in endomerium & vascular wall
    • Large myelinated fibres are preserved

Diabetic polyneuropathy

• Cause
  • diabetes mellitus
• Most common pattern
  • length-dependent axonal sensorimotor polyneuropathy
• Manifest as
  • PAIN and PARESTHESIAS
• Clincal features
  • Start in distal lower extremities
    • longest nerve fibres
  • Gait abnormality
  • Autonomic abnormality
    • ‘diabetic autonomic neuropathy
  • Sensory dysfunction distal extremity
    • glove & stocking numbness
  • weakness of distal lower extremity
• Pathology
  • Axonal neuropathy
  • Loss of large, small & unmyelinated fibres
  • Entirely NON-SPECIFIC
• Pathophysiology
  • Nerve ischaemia
    • due to diabetic microangiopathy
    • poor blood flow
    • may easily develop ulceration

• Skin biopsy to assess small-nerve fibres
  • Easy to perform
  • Provides information on small nerve fibres
    • not possible with sural nerve biopsy
    • nor with routine neurophysiological testing
  • Can demonstrate subclinical neuropathy
    • eg. in diabetic patients

_____________________________________________________________________

Hansen’s disease

• Causal organism
  • Mycobacterium leprae
• Pathology
  • In Lepromatous leprosy
    • Schwann cells are invaded by the mycobacteria
    • Increase in Th2 cytokines: IL3, IL5, IL10
    • Increase CD8 cells
  • In Tuberculoid leprosy
    • active cell mediated immune response
      • injures cutaneous nerves
      • including axons, schwann cells & myelin
    • Increase Th1 cytokines: IL2, IFNγ, TNFβ
    • Histology:
      • granulomatous inflammation, scanty bacilli
• Clinical features
  • Pain fibres affected
    • loss of sensation

Traumatic neuroma

• Non-neoplastic
• Occurs at proximal end of severed nerve
  • trauma
  • surgery
• Clinical features
  • Firm nodule, painful or tender
    • Reactive proliferation of schwann cells, axons & fibrous ce
      lls

Tumours of peripheral nerves

Neurofibroma

• Cutaneous/ in Peripheral nerve
• Plexiform type
  • only seen in Neurofibromatosis Type1 (NF1)
• Tumours in NF1 are more likely to become malignant
  • Malignant tumours are called
    • Malignant Peripheral Nerve Sheath tumours (MPNST)
• Histology
  • Spindle shaped cells
  • Serpentine nuclei
  • Schwann cells, axons, fibroblastic cells and perineurial cells are present

Schwannoma

• Arise from Schwann cells
• Histology
  • True encapsulation
  • Antoni type A & Antoni type B areas
  • Verocay bodies
• Multiple tumours seen in NF2
  • Benign
• Malignant counterpart is MPNST