Motor Neuron Disease

Epidemiology

Incidence: 1/100,000

Risk factors:

  • Male (<65)
  • Age (60s – 70s)

Pathogenesis

ALS is an idiopathic neurodegenerative disorder characterised by progressive degeneration of motor neurons in the central and peripheral nervous systems.

Microscopic

  • Nuclear and glial inclusions containing ubiquitinated proteins +/- TDP-43 or FUS

Macroscopic

  • Degeneration and scarring (sclerosis) of the pyramidal tracts from their origin in the frontal cortices to the alpha motor neurons in the corticospinal tract.

 

Presentation

The classic presentation is of a progressive mixed picture of upper motor neuron and lower motor neuron weakness, often starting in a single limb. Classic ALS usually begins with distal, asymmetric limb weakness which progresses proximally to involve other limbs, bulbar muscles, and eventually the respiratory muscles.  Although sensory symptoms are possible, ALS should be thought of a purely motor disorder which mainly manifests as follows:

  • Motor
    • Limb muscles:
      • UMN: weakness, inco-ordination, spasticity
      • LMN: weakness, cramps, wasting, fasciculations
    • Bulbar muscles:
      • UMN: dysarthria, dysphagia, pseudobulbar affect
      • LMN: dysarthria, dysphagia
    • Axial muscles:
      • Head drop
      • Postural instability
    • Respiratory muscles:
      • Initially: dyspnoea on exertion, nocturnal hypoventilation
      • Later: neuromuscular respiratory failure
    • Cognitive
      • There is an association with Frontotemporal Dementia

 

 

 

Motor neuron disease can be divided into different subtypes, which may be useful for prognosis.

UMN, LMN, or both? Sites affected Prognosis
Progressive Muscular Atrophy LMN Limbs Ok
Primary Lateral Sclerosis UMN Limbs Good
Progressive Bulbar Palsy Both Bulbar muscles Poor
Flail Arm Syndrome LMN Arm Good

 

In general ALS and its subtypes progress rapidly within 5 years to death from neuromuscular respiratory failure or aspiration pneumonia due to pharyngeal weakness.

Investigation

The diagnosis of ALS relies on a combination of clinical and electrophysiological findings, and the appropriate exclusion of differential diagnoses.

Differential diagnosis

  • Brain
    • Expanding structural lesions affected pyramidal tract
    • Multiple
  • Cord
    • Cervical myeloradiculopathy
    • Hereditary spastic paraplegia
    • Kennedy disease (spinobulbar muscular atrophy)
  • Motor nerves
    • Multifocal Motor Neuropathy with conduction block
    • Infection: Lyme, HIV, polio
    • Paraneoplastic syndrome
    • Heavy metal poisoning
    • Vasculitis
    • Hyperthryoidism
  • Muscle (myopathy)
    • Idiopathic inflammatory myositis: DM, PM, inclusion body myositis
    • Benign fasciculation syndrome

 

Investigations:

  • Bloods: FBC, calcium, vasculitis screen, thyroid function tests, liver function tests, B12, serum protein electrophoresis, creatine kinase, anti-GM1 antibodies (for MMN)
  • Lumbar puncture: if there is strong suspicion of an alternative diagnosis
  • EMG: evidence of acute and/or chronic denervation
  • NCS: reduction in the number of motor axons.
  • MRI brain and spinal cord:
    • to exclude structural cortical lesions
    • to exclude cervical myelopathy

Management

ALS is a progressive disorder which leads to death within 5 years in most cases. Treatment is largely supportive although one ‘disease-modifying’ drug, riluzole, is available.

Supportive care

  • Spasticity: baclofen
  • Dysphagia: speech & language therapy, possibly alternative feeding routes (e.g. PEG) later in the disease
  • Neuromuscular respiratory failure: non-invasive ventilation, diaphragmatic pacing, tracheostomy
  • Sialorrhoea: muscarinic antagonists (e.g. hyoscine hydrobromide)

 

Riluzole

  • Mechanism: NMDA antagonist. Unclear how this leads to benefit in ALS.
  • Benefit: extends overall survival by a few months and extends tracheostomy-free survival.