What is ALS (Amyotrophic Lateral Sclerosis)?
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 is the most common motor neuron disease, representing approximately 85% of all motor neuron disease cases. 1, 2 The disease involves progressive degeneration of motor neurons along the corticospinal tracts, affecting both upper motor neurons (in the motor cortex) and lower motor neurons (in the brainstem and spinal cord). 3, 1
Pathophysiology
The underlying mechanisms are multifactorial and include:
- Increased oxidative stress 1
- Glutamate toxicity (excitotoxicity) 1, 4
- Mitochondrial dysfunction 1
- Inflammation and microglial activation 1, 4
- Apoptosis (programmed cell death) 1
- Aggregation of misfolded proteins 5
This is fundamentally a disease of axonal degeneration affecting motor neurons, not a primary muscle disorder or demyelinating disease. 1 The primary pathological process is progressive degeneration and death of the motor neurons themselves and their axons. 1
Clinical Presentation
ALS presents with mixed upper and lower motor neuron signs:
Upper motor neuron signs:
Lower motor neuron signs:
- Muscle fasciculations (visible muscle twitching) 1, 6
- Progressive muscle weakness 7
- Muscle atrophy (wasting) 1, 6
Clinical Subtypes by Onset Location
Limb-onset (spinal) ALS accounts for 65-75% of cases and presents with initial symptoms in the extremities, manifesting as progressive muscle weakness in arms or legs. 7
Bulbar-onset ALS represents 25-35% of cases, with approximately 80% of these patients developing dysarthria (speech difficulty) and dysphagia (swallowing difficulty) as primary manifestations. 1, 7 Additional bulbar symptoms include sialorrhea (drooling due to impaired swallowing of saliva) and nasal regurgitation from soft palate weakness. 1
Epidemiology and Risk Factors
Sporadic ALS represents 85-90% of all cases, occurring without known genetic mutation or family history, with an annual incidence of 1-2 per 100,000 people. 2, 7 The remaining 10-15% are familial cases, with approximately 20% of familial cases associated with mutations in the copper/zinc superoxide dismutase-1 gene. 6
Established risk factors include:
Prognosis
Mean survival is 3-5 years after symptom onset, with only 5-10% of patients living longer than 10 years. 1, 7 Respiratory failure due to respiratory muscle weakness is the most common cause of death. 1 Malnutrition with dehydration also contributes significantly to mortality. 7
Nutritional status is a major prognostic factor: malnutrition at diagnosis increases the risk of death by more than four-fold, and each 5% loss of body weight is associated with a 34% increase in mortality risk. 1
Cognitive and Behavioral Features
Up to 40-50% of ALS patients have cognitive impairment, mainly frontotemporal dementia, with extra-motor manifestations including behavioral changes, executive dysfunction, and language problems. 1, 7 This cognitive impairment significantly impacts treatment decisions, reduces compliance with non-invasive ventilation, and affects the likelihood of choosing long-term mechanical ventilation. 1
Diagnosis
There is no single diagnostic test for ALS; clinicians rely on the combination of upper and lower motor neuron signs in the same body region, confirmed by electromyography. 4, 5 The median time from symptom onset to diagnosis is 14 months. 4
MRI of the brain and spine is used primarily to exclude other conditions that can mimic ALS, though characteristic findings include abnormal T2/FLAIR signal in the corticospinal tracts and abnormal T2 signal in the anterior horns with a "snake eyes" appearance. 3, 1, 2
Treatment Approach
Riluzole is the only disease-modifying therapy approved to date, extending mean patient survival by 3-6 months. 4, 6 Beyond this modest pharmacologic intervention, management focuses on symptomatic relief and palliative care.
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 essential to establish relationships with staff and address end-of-life issues before communication becomes limited. 1
Critical management components include: