What is the primary treatment for Amyotrophic Lateral Sclerosis (ALS)?

Pathology of Amyotrophic Lateral Sclerosis (ALS)

ALS is characterized by progressive degeneration of both upper and lower motor neurons along the corticospinal tracts in the brain and spinal cord, leading to relentless muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. 1, 2

Core Pathophysiological Mechanisms

The neurodegeneration in ALS involves multiple interconnected cellular pathways that ultimately lead to motor neuron death 1:

• Oxidative stress: Increased production of reactive oxygen species overwhelms cellular antioxidant defenses, damaging motor neurons 1
• Glutamate excitotoxicity: Excessive glutamate accumulation causes overstimulation of motor neurons, leading to calcium influx and cell death 1
• Mitochondrial dysfunction: Impaired energy production and increased oxidative damage within motor neurons 1
• Inflammatory processes: Neuroinflammation contributes to ongoing motor neuron injury 1
• Apoptotic pathways: Programmed cell death mechanisms are activated in affected motor neurons 1

Clinical Manifestations of Pathology

The dual motor neuron degeneration produces a characteristic mixed clinical picture 1, 2:

Upper motor neuron signs (from corticospinal tract degeneration):

• Hypertonicity and spasticity 1
• Hyperreflexia 1
• Pathological reflexes 1

Lower motor neuron signs (from anterior horn cell degeneration):

• Muscle fasciculations 1
• Progressive weakness 1
• Muscle atrophy 1

Disease Progression and Outcomes

The pathological process follows a relentless course 3, 1:

• Mean survival: 3-5 years after symptom onset 3, 1
• Long-term survival: Only 5-10% of patients live longer than 10 years 3, 1
• Primary cause of death: Respiratory failure due to respiratory muscle weakness from progressive motor neuron loss 3, 1

Cognitive and Behavioral Pathology

The pathology extends beyond pure motor systems in a substantial proportion of patients 3:

• Cognitive impairment: Up to 40% of patients develop evidence of cognitive deterioration 3
• Frontotemporal dementia: Some patients develop frank dementia with executive dysfunction, which significantly shortens survival 3
• Behavioral changes: Behavioral deficits negatively impact caregiver quality of life and increase caregiver burden 3

Epidemiology and Classification

ALS represents the most common motor neuron disease 1, 2:

• Proportion of motor neuron diseases: Approximately 85% of all motor neuron disease cases 1, 2
• Sporadic cases: 85-90% of ALS cases occur without family history 2
• Annual incidence: 1-2 per 100,000 people 2

Clinical Variants Based on Pathological Distribution

Bulbar-onset ALS: Initial pathology affects brainstem motor neurons, causing dysarthria and dysphagia in approximately 80% of these patients 1, 2

Classical ALS: Mixed upper and lower motor neuron pathology affecting both populations simultaneously 1, 2

Imaging Correlates of Pathology

MRI can demonstrate the pathological changes in ALS 1:

• Corticospinal tract changes: Abnormal T2/FLAIR signal intensity along the corticospinal tracts 1
• Anterior horn changes: Abnormal T2 signal in the anterior horns of the spinal cord 1