What is Amyotrophic Lateral Sclerosis (ALS)?

Understanding Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition characterized by degeneration of both upper and lower motor neurons in the brain and spinal cord, leading to progressive muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. 1, 2

Definition and Classification

• ALS is the most common motor neuron disease, representing approximately 85% of all motor neuron disease cases 3, 2
• The majority of ALS cases (85-90%) are sporadic, occurring without a known genetic mutation or family history 3, 2
• Familial ALS is present in only 5-10% of all ALS patients, often with an autosomal dominant inheritance pattern 4, 5
• Common genetic mutations in familial ALS include C9orf72, SOD1, FUS, and TARDBP genes 4

Pathophysiology

• ALS involves progressive degeneration of both upper motor neurons (in the brain) and lower motor neurons (in the brainstem and spinal cord) along the corticospinal tracts 1, 3
• The disease is characterized by protein deposits in the cytoplasm of motor neurons, with TDP-43 being the most common protein found in these aggregates 4
• The etiology is multifactorial, involving increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 3

Clinical Presentation

• Classical ALS presents with mixed upper and lower motor neuron signs 2:
  • Upper motor neuron signs: hypertonicity and hyperreflexia
  • Lower motor neuron signs: muscle fasciculations, weakness, and atrophy 1
• Approximately 80% of patients with bulbar-onset ALS develop dysarthria (speech difficulties) and dysphagia (swallowing difficulties) 3, 6
• The disease typically has a focal onset but subsequently spreads to different body regions 5
• In up to 50% of cases, there are extra-motor manifestations such as changes in behavior, executive dysfunction, and language problems 5
• In 10-15% of patients, cognitive problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD) 5

Diagnosis

• ALS is diagnosed by exclusion of other conditions with similar presentations 7
• Key diagnostic tests include 1, 4, 8:
  • Electromyography (EMG) and nerve conduction studies (NCS)
  • MRI of the brain and spine (mainly to exclude other conditions)
  • Laboratory tests to rule out mimicking conditions
• Common MRI findings include abnormal T2/FLAIR signal in the corticospinal tracts and abnormal T2 signal in the anterior horns ("snake eyes" appearance) in the spine 1, 3
• Diagnostic criteria require 7:
  • Progressive motor symptoms
  • Upper and lower motor neuron signs on examination
  • Clear spread of symptoms through the body
  • Exclusion of other disorders that cause similar symptoms
  • EMG compatible with lower motor neuron loss

Prognosis

• Mean survival of typical ALS patients is 3-5 years after symptom onset 3, 2
• Only 5-10% of patients live longer than 10 years 3, 2
• Respiratory failure due to respiratory muscle weakness is the most common cause of death 1

Treatment

• ALS is not curable, but treatment can improve survival, symptom control, and quality of life 4
• Riluzole is FDA-approved for the treatment of ALS 9
  • Clinical trials showed that riluzole extended survival by approximately 60-90 days compared to placebo 9
  • Recommended dosage is 50 mg twice daily, taken at least 1 hour before or 2 hours after a meal 9
• A multidisciplinary approach is essential for optimal management 4, 10:
  • Symptomatic medication for specific symptoms
  • Assistive devices to maintain function
  • Nutritional support for dysphagia and weight loss
  • Ventilation therapy for respiratory insufficiency
• Palliative care should be integrated from the time of diagnosis, with emphasis on patient autonomy, dignity, and quality of life 1

Important Considerations

• Early referral to palliative services is recommended to establish relationships with staff and address end-of-life issues before communication becomes limited 1
• Care in specialized ALS centers is recommended to ensure optimal treatment and coordination between specialists 4
• Regular monitoring of respiratory function, nutritional status, and functional abilities is essential to guide interventions 4
• Support for caregivers is crucial, as they often experience significant burden 1