What is Amyotrophic Lateral Sclerosis (ALS)?

What is Amyotrophic Lateral Sclerosis (ALS)?

ALS is a relentlessly progressive neurodegenerative disease 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

Core Disease Characteristics

• ALS represents the most common motor neuron disease, accounting for approximately 85% of all motor neuron disease cases 1, 2
• The disease involves progressive destruction of motor neurons along the corticospinal tracts, affecting both upper motor neurons (in the brain and brainstem) and lower motor neurons (in the spinal cord and brainstem) 1, 2
• Epidemiology shows an annual incidence of 1-2 per 100,000 people with a prevalence of approximately 5.2 per 100,000 in Western countries 2, 3

Pathophysiology

• The underlying mechanisms are multifactorial, involving increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 1
• Most cases (85-90%) are sporadic without identifiable genetic cause, while 5-10% are familial with known genetic mutations 4, 2
• The pathological hallmark is loss of motor neurons with characteristic protein inclusions (TDP-43 immunoreactive inclusions in degenerating lower motor neurons) 3

Clinical Presentation

Classical ALS presents with mixed upper and lower motor neuron signs:

• Upper motor neuron signs include hypertonicity, hyperreflexia, and spasticity 1
• Lower motor neuron signs include muscle fasciculations, progressive weakness, and atrophy 1

Two main onset patterns exist:

• Limb-onset ALS (approximately two-thirds of cases) presents with focal muscle weakness and wasting in upper or lower limbs, either distally or proximally 3
• Bulbar-onset ALS is characterized by dysarthria and dysphagia in approximately 80% of affected patients, with limb symptoms typically developing within 1-2 years 1, 4, 2

Prognosis and Natural History

• Mean survival is 3-5 years after symptom onset, with bulbar-onset cases typically surviving 2-3 years and limb-onset cases 3-5 years 1, 2, 3
• Only 5-10% of patients survive longer than 10 years 1, 4
• Respiratory failure from respiratory muscle weakness is the most common cause of death 1

Diagnosis

Diagnosis relies on clinical criteria rather than a single definitive test:

• The diagnosis requires evidence of both upper and lower motor neuron damage in the same body region that cannot be explained by any other disease process 3
• Key diagnostic studies include electromyography (EMG) and nerve conduction studies to confirm lower motor neuron involvement 3, 5
• MRI of brain and spine may show abnormal T2/FLAIR signal in the corticospinal tracts and abnormal T2 signal in the anterior horns 1
• The median time from symptom onset to diagnosis is 14 months, primarily due to the need to exclude ALS-mimicking conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease 3, 6

Management Approach

Multidisciplinary palliative care should be integrated from the time of diagnosis, with emphasis on patient autonomy, dignity, and quality of life 1

Key management components include:

• Non-invasive ventilation prolongs survival and improves quality of life 3
• Nutritional support is essential for managing dysphagia and preventing weight loss 1
• Early advance care planning should address preferences regarding ventilatory support, feeding tubes, and end-of-life care 1
• Caregiver support is crucial, as caregivers experience significant burden, particularly when patients develop cognitive impairment (present in up to 40% of cases) 1

Available Pharmacologic Treatments

• Riluzole is the only drug proven to extend survival, though the benefit is modest (3-6 months mean survival extension) 3, 6
• Edaravone received FDA approval in 2017 and showed statistically significant slowing of functional decline in a specific patient population (those with early disease, preserved function, and normal respiratory capacity) 7, 5

Critical Pitfalls to Avoid

• Late referral to palliative services negatively impacts quality of life and should be avoided by initiating palliative care at diagnosis 1
• Diagnostic delays are common due to heterogeneous presentation and lack of definitive biomarkers, requiring high clinical suspicion 4
• Access to assistive equipment may be limited once patients formally receive palliative care, highlighting the need for early integration of palliative services into comprehensive multidisciplinary care 1