L20 Neuromuscular Disease

• Peripheral neuropathy


  Diseases of peripheral nerves; including sensory, motor, autonomic or mixed nerves, as well as dorsal or ventral nerve roots in the spinal cord, and cranial nerves
• Peripheral neuropathy


  • Can affect a single nerve (mononeuropathy), multiple sites of a single nerve (mononeuropathy multiplex), and multiple nerves (polyneuropathy)
• Nerve cell body damage

  • Demyelination
  • Axonal degeneration
• Causes of peripheral neuropathy


  • Inflammatory
  • Infectious
  • Ischaemic
  • Metabolic
  • Hereditary
  • Toxic
  • Trauma
• Healing in peripheral neuropathy

  • Demyelination may lead to remyelination, and axon transection may lead to axonal degeneration and then regeneration
  • If the cell body of the motor or sensory neuron is lost, the axon will degenerate, and no regeneration can occur
• Guillain-Barré syndrome (GBS)


  An example of a peripheral neuropathy, caused by inflammation targeting the myelin or axon depending on the GBS subtype
• Aetiology of GBS


  • Thought to be an immune-mediated neuropathy, but the specific cause is not completely understood
  • Most cases (2/3) preceded by flu-like illness that resolves prior to disease onset
  • Associated with infections by Campylobacter jejuni, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Mycoplasma, HIV, and prior vaccination

  
• GBS


  • Characterized by weakness starting in the distal limbs and advancing proximally, potentially resulting in fatal respiratory muscle paralysis
• GBS subtypes


  • Acute Inflammatory Demyelinating Polyneuropathy
  • Acute Motor Axonal Neuropathy
• Pathogenesis of GBS


  • Hallmark feature is inflammation of peripheral nerves, induced by cross-reactive autoantibodies, inflammatory infiltration, and/or complement activation
  • Molecular mimicry induces the production of cross-reactive autoantibodies targeting myelin (AIDP) or axons (AMAN)
  • Nerve sheath infiltration by T lymphocytes, macrophages, and plasma cells, particular in AIDP subtype
  • May involve antibody-mediated complement activation, particular in AMAN subtype
  • Inflammation is most intense on spinal and cranial motor nerve roots, and adjacent nerve segments

  
• Clinical presentation of GBS

  • Peripheral numbness, tingling, and pain, with progressive weakness of the legs and/or arms
  • Around half of patients have cranial nerve involvement, with weakness of face muscles, and swallowing difficulties
  • Around a quarter of patients develop weakness of breathing muscles, potentially leading to respiratory failure
• Prognosis of GBS


  May recover with axonal regeneration/remyelination, may result in permanent disability, or may be fatal (~5%)
• Diabetic neuropathy


  ~50% of patients with diabetes mellitus have peripheral neuropathy, most commonly (~80%) with a presentation of symmetrical peripheral neuropathy
• Clinical presentation of diabetic neuropathy

  • Symmetrical peripheral neuropathy, predominantly affecting the feet and hands
  • Mononeuropathy with sudden footdrop or wristdrop
  • Autonomic with incontinence and impotence
• Pathogenesis of diabetic neuropathy

  • Direct effect of diabetes on neurons is undetermined, but involves demyelination and axonal degeneration
  • Arteriolosclerosis and ischaemic nerve damage
• Motor neuron diseases (MNDs)


  A group of progressive neurological disorders characterised by selective degeneration of motor neurons responsible for voluntary muscle activity; such as speaking, walking, breathing, and swallowing
• Types of MNDs


  • Amyotrophic lateral sclerosis (ALS)
  • Primary lateral sclerosis (PLS)
  • Progressive muscular atrophy (PMA)
  • Progressive bulbar palsy (PBP)
  • Pseudobulbar palsy
  • Monomelic amyotrophy (MMA)
• Amyotrophic lateral sclerosis (ALS)


  The most common type of motor neuron disease, usually affecting both the upper and lower motor neurons (Classical)
• Aetiology of ALS


  • ~90% idiopathic, meaning cause unknown
  • ~10% Genetic (e.g. C9orf72, SOD1 mutations)
• Pathogenesis of ALS


  • Several theories have been postulated as to how ALS begins in the motor neurons, such as axonal dysfunction and cytotoxicity
  • Lateral Sclerosis: Death of upper motor neurons leads to degeneration of the corticospinal tracts running in the lateral portion of the spinal cord, resulting in motor weakness
  • Neurogenic Atrophy aka Amyotrophy: Atrophy of the spinal nerve roots leads to skeletal muscle denervation, atrophy, weakness, and fasciculations (spontaneous involuntary twitch)
• Cause of death in ALS

  The most common cause of death in ALS is recurrent chest infections, resulting from failure of respiratory muscles and an inability to clear mucus
• Multiple sclerosis (MS)


  A chronic demyelinating disorder of the CNS characterised by neurologic deficits, and is the most common demyelinating disorder
• Aetiology of MS


  • A strong link with EBV infection was recently identified, particular in patients that have previously had glandular fever
  • May also involve genetics (e.g. HLA-DRB1), other infections (e.g. HHV-6, Measles), or gut microflora
  • Other risk factors include low vitamin D, smoking, and obesity in childhood and/or adolescence
• "Before Epstein-Barr virus (EBV) infection, the risk of MS is negligible. Infection with EBV increases the risk more than 30-fold."
• Pathogenesis of MS


  • MS is an autoimmune disease caused by T and B lymphocytes targeting myelin antigens, possibly due to molecular mimicry
  • Early Phase: Autoimmune inflammation, inducing demyelination with some remyelination
  • Late Phase: Axonal degeneration from chronic demyelination, gliosis with astrocytes (similar to healing the brain from a stroke!)
• MRI of MS


  • T2-FLAIR MRI: Multiple hyperintense focal demyelinating lesions
  • T1-Weighted MRI with IV Contrast: Indicating increased BBB permeability
• Gross pathology of MS

  • Plaque of demyelination adjacent to cerebral ventricle
• Histology of MS


  • Myelin Stain: Pale zones of demyelination
  • Silver Stain: Less intense staining in demyelinated area from axonal degeneration
• Epidemiology of MS


  • More common in women, average age of onset around 20-40 years old, with particularly high prevalence in North America, Scandinavia, Western Europe, and Australia/NZ
  • People who move to these high prevalence regions before the age of 15 are at increased risk compared to those who move after this age
• Clinical presentation of MS

  • Manifestations: Motor weakness, Sensory loss, Visual disturbances, Loss of coordination, Vertigo
  • Prognosis: There is no cure for MS, patients develop progressive neurological disability
  • Corticosteroids and/or plasmapheresis may improve long term prognosis
  • EBV therapeutic vaccination/anti-virals?