a neurodegenerative disease with upper and lower motor neuron dysfunction.

Epidemiology

• Mean age of onset is 65 years.

Etiology

Pathophysiology

• Classically affects the entire motor neuron system at two or more levels (both upper and lower motor neuron degeneration).
  • Upper motor neurons in the precentral gyrus and, frequently, prefrontal cortex
  • Lower motor neurons in the anterior horn of the spinal cord and brainstem
• Pathology
  • UMN: degeneration & atrophy of lateral corticospinal tracts, precentral gyrus
  • LMN: degeneration of anterior horn (thin anterior roots) & cranial nerve motor nuclei
  • Muscle: denervation atrophy (angular fibers with crowded nuclei)

Clinical features

General disease characteristics

• Both upper motor neuron (UMN) and lower motor neuron (LMN) signs are present (see Upper motor neuron (UMN) injury vs. lower motor neuron (LMN) injury)
• Constant disease progression: it usually starts in one arm and/or leg then progresses to the contralateral side

Early symptoms

• Symptoms are highly variable and potentially non-specific (e.g., subtle vocal changes or difficulties grasping objects)
• Asymmetric limb weakness, often beginning with weakness in the hands and feet
• Bulbar symptoms such as dysarthria, dysphagia, and tongue atrophy (20% of cases at disease onset)
• Pseudobulbar palsy with pseudobulbar affect may develop.
• Fasciculations, cramps, and muscle stiffness
• Weight loss
• Split hand sign: a wasting pattern in which the muscles of the thenar eminence atrophy due to degeneration of the lateral portion of the anterior horn of the spinal cord

Late symptoms

• Cognitive impairment (approx. 15% of ALS patients meet the criteria for frontotemporal dementia)
• Autonomic symptoms (e.g., constipation, bladder dysfunction) may develop; the mechanism of development is unclear.
• Life-threatening symptoms
  • Respiratory failure due to paralysis of respiratory muscles
  • Dysphagia due to bulbar weakness or pseudobulbar palsy

Diagnosis

• Electromyography
  • Denervation: fibrillations, positive sharp waves, and large amplitudes
  • Fasciculations

Differential Diagnosis

• Myasthenia gravis
  • Weakness improves with acetylcholinesterase inhibitors
  • No UMN or LMN signs

Treatment

• Riluzole
  • A sodium-channel blocker that inhibits glutamate release in the CNS and decreases glutamate excitotoxicity
  • Prolongs survival and slows functional decline in patients with ALS (on average, for 3 months)
• Edaravone
  • A free radical scavenger
  • Has been shown to slow functional decline in some patients with ALS