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

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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

image

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

  • Laboratory studies
    • Endoneurial inflammation
    • Onion-bulb formation in semithin sections
      • due to repeated demyelination & remyelination

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

image

  • 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

image

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

image 

  • 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

image

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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

image

image

  • 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

image

  • 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

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