What is Amyotrophic Lateral Sclerosis (ALS)?

Amyotrophic Lateral Sclerosis (ALS): Comprehensive Overview

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

Definition and Classification

• ALS is the most common motor neuron disease, representing approximately 85% of all motor neuron disease cases 1, 2
• The majority of ALS cases (85-90%) are sporadic, with an annual incidence of 1-2 per 100,000 people 2
• Sporadic ALS occurs without a known genetic mutation or family history, while familial ALS accounts for approximately 10% of cases 3

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
• The etiology is multifactorial, involving increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 1
• Genetic factors play a role, with mutations in SOD1 or C9orf72 genes identified in some cases, particularly in familial ALS 4
• Excessive free radicals (reactive oxygen species) contribute to neuronal damage through peroxidation of unsaturated fatty acids in neuronal cells 4

Clinical Presentation

• Classical ALS presents with mixed upper and lower motor neuron signs 1:
  • Upper motor neuron signs: hypertonicity and hyperreflexia 1
  • Lower motor neuron signs: muscle fasciculations, weakness, and atrophy 1
• Approximately 80% of patients with bulbar-onset ALS develop dysarthria and dysphagia 1, 3
• Other presentations may include:
  • Upper motor neuron predominant ALS with prominent spasticity 3
  • Lower motor neuron predominant ALS with prominent muscle atrophy 3
  • Behavioral changes and cognitive difficulties in some patients 4, 5

Diagnosis

• Diagnosis is primarily clinical, based on history of painless progressive weakness and examination findings of upper and lower motor neuron dysfunction 6
• Key diagnostic tests include 1:
  • MRI of the brain and spine (may show abnormal T2/FLAIR signal in the corticospinal tracts and abnormal T2 signal in the anterior horns)
  • Electromyography (EMG) and nerve conduction studies (NCS) are essential diagnostic tools 7
• No definitive biomarkers for ALS are currently available, complicating early diagnosis 3
• Diagnostic delays are common due to the heterogeneous presentation and overlap with other neurological conditions 3
• The median time from symptom onset to diagnosis is approximately 14 months 5

Prognosis

• Mean survival of typical ALS patients is 3-5 years after symptom onset 1, 2
• Only 5-10% of patients live longer than 10 years 1, 3
• Respiratory failure due to respiratory muscle weakness is the most common cause of death 1
• Slowly progressive forms of ALS may be associated with longer survival (5-10 years from symptom onset) 3

Treatment

• FDA-approved medications with modest benefits include 6:
  • Riluzole: a glutamate receptor antagonist that extends mean patient survival by 3-6 months 6, 5
  • Edaravone: a free radical scavenger that halts disease progression in early stages through its cytoprotective effect 4, 6
• Multidisciplinary care is the cornerstone of management 1, 3:
  • Nutritional support for dysphagia and weight loss 1
  • Respiratory support as disease progresses 1
  • Symptomatic management of spasticity, cramps, and other symptoms 5

Palliative Care Approach

• Palliative care should be integrated from the time of diagnosis, with emphasis on patient autonomy, dignity, and quality of life 1
• Early referral to palliative services is recommended to establish relationships with staff and address end-of-life issues before communication becomes limited 1
• Advance care planning should be initiated early, including discussions about advance directives, ventilatory support, feeding tubes, and end-of-life care 1
• Support for caregivers is crucial, as they often experience significant burden 1

Important Considerations and Pitfalls

• Up to 40% of patients with ALS have evidence of cognitive impairment, which may affect treatment decisions and compliance 1
• Late referral to palliative services is common and negatively impacts quality of life 1
• Access to assistive equipment might be limited once the patient formally receives palliative care, highlighting the need for early integration of palliative care into multidisciplinary care 1
• Despite evidence supporting multidisciplinary care improving both survival and quality of life, integration of palliative care in ALS management varies considerably across healthcare systems 1