Amyotrophic Lateral Sclerosis
A fatal disease involving progressive destruction of both upper and lower motor neurons, causing devastating muscle weakness, paralysis, and death via respiratory failure usually within 3-5 years.
Emergency Management: Acute hypercapnic respiratory failure necessitating BiPAP or intubation. Use of supplemental oxygen without non-invasive ventilation in hypercapnic ALS patients can worsen CO2 retention and lead to coma.
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease characterized by the concomitant degeneration of both upper motor neurons (UMN) in the motor cortex and lower motor neurons (LMN) in the brainstem and spinal cord. It selectively destroys motor pathways while sparing extraocular muscles and sphincter control. The resulting progressive muscle weakness ultimately leads to respiratory failure.
Detailed Overview
The disease manifests as a spectrum, often beginning with focal, asymmetric weakness in the limbs (limb-onset) or bulbar musculature (bulbar-onset). Bulbar onset carries a poorer prognosis due to earlier compromise of swallowing and airway protection. Histopathologically, ALS is characterized by ubiquitinated cytoplasmic inclusions of TDP-43 in degenerating neurons. Frontotemporal dementia (FTD) is present in up to 15% of patients, underscoring a continuum between FTD and ALS, particularly driven by C9orf72 mutations.
Epidemiology & Demographics
Incidence is ~2 per 100,000 person-years. Peak age of onset is 55 to 75 years. Slight male predominance (1.5:1) in sporadic cases, though this gender gap narrows with age.
Etiological Mechanism
Sporadic ALS (sALS) comprises 90% of cases with an unknown etiology. Familial ALS (fALS) comprises 10% and is primarily inherited in an autosomal dominant pattern. The most common genetic mutations are hexanucleotide repeat expansions in C9orf72 (40% of fALS) and mutations in superoxide dismutase 1 (SOD1) (20% of fALS).
Primary Causes
Genetic mutations (C9orf72, SOD1, TARDBP, FUS) cause aberrant protein aggregation, oxidative stress, impaired axonal transport, and glutamate excitotoxicity.
Defective clearance of glutamate by astrocytic EAAT2 transporters leads to glutamate-induced excitotoxicity, driving massive intracellular calcium influx and motor neuron death. Intracellularly, abnormal aggregation of RNA-binding proteins (principally TDP-43) disrupts RNA processing. Wallerian degeneration of the corticospinal tracts leads to lateral column sclerosis (the 'lateral sclerosis'), while anterior horn cell death causes muscle denervation and atrophy (the 'amyotrophy').
Diagnostic Criteria & Guidelines
The revised El Escorial criteria require evidence of LMN degeneration by clinical, electrophysiological, or neuropathological exam; evidence of UMN degeneration by clinical exam; and progressive spread of symptoms within a region or to other regions. It requires the absence of electrophysiological/pathological evidence of other diseases.
Riluzole 50 mg PO BID (a glutamate antagonist that prolongs survival by ~2-3 months). Check LFTs monthly for the first 3 months. Edaravone 60 mg IV daily for 14 days followed by a 14-day drug-free period (a free-radical scavenger shown to slow functional decline in early-stage disease). Non-Invasive Positive Pressure Ventilation (NIPPV/BiPAP) when FVC drops below 50% significantly extends survival.
Second-Line & Adjunctive Therapy
Symptom management: Dextromethorphan/quinidine (Nuedexta) 20 mg/10 mg PO BID for pseudobulbar affect. Glycopyrrolate 1-2 mg PO TID or botulinum toxin to salivary glands for sialorrhea. Baclofen 10-20 mg PO TID for spasticity. Tofersen 100 mg intrathecally every 28 days for adults with SOD1-mutated ALS.
Surgical & Procedural Management
Percutaneous Endoscopic Gastrostomy (PEG) tube placement for enteral nutrition when dysphagia causes significant weight loss or aspiration, ideally placed while FVC is still > 50%. Tracheostomy with invasive mechanical ventilation is an option for end-stage disease but involves complex ethical and quality-of-life decisions.
Patient Counseling & Advice
Early discussions regarding advance directives, living wills, and preferences regarding PEG tubes and mechanical ventilation are essential before bulbar or respiratory muscles profoundly fail.
Follow-Up & Monitoring Schedule
Multidisciplinary ALS clinic visits every 3 months. Serial monitoring of Forced Vital Capacity (FVC) and Maximum Inspiratory Pressure (MIP) to assess respiratory muscle function.
Preventive Strategies
No known preventive measures. Genetic counseling is advised for patients with a strong family history of ALS or FTD.
Median survival is 3 to 5 years from symptom onset. 10-20% of patients survive longer than 10 years (especially those with earlier onset or pure upper motor neuron variants). Death is invariably due to respiratory failure or aspiration pneumonia.