What is the prognosis and what complications are associated with Amyotrophic Lateral Sclerosis (ALS)?

Prognosis and Complications of ALS

ALS has a median survival of 3-5 years from symptom onset, with bulbar-onset patients and older individuals having the shortest life expectancy, and death typically results from respiratory failure or malnutrition with dehydration. 1

Survival and Prognostic Factors

Median survival ranges from 20-48 months, but 5-10% of patients survive longer than 10 years. 1, 2

Key Prognostic Factors at Diagnosis:

• Age at onset: Each decade increase in age worsens prognosis. Median survival is 34 months for onset <60 years, 27 months for 60-75 years, and 23 months for >75 years 3
• Site of onset: Bulbar-onset patients (25-35% of cases) have the shortest survival at approximately 25 months, compared to 39 months for lower limb onset and 27 months for upper limb onset 1, 3
• Diagnostic delay: Longer time from symptom onset to diagnosis paradoxically predicts better survival, as it indicates slower disease progression 4
• Rate of progression: The speed of symptom progression pre-diagnosis is an independent predictor of overall survival 2

Nutritional Status as Prognostic Indicator:

• Weight loss >5% at diagnosis doubles mortality risk (HR 1.92, p=0.01) 1
• Each 1-point BMI loss increases death risk by 9-23% (HR 1.09-1.23) 1
• Weight loss of 10% at diagnosis increases mortality risk by 45% (HR 1.45, p=0.046) 1
• Lower serum albumin significantly increases death risk in both men (HR 1.39) and women (HR 1.73) 1
• Higher phase angle on bioimpedance reduces death risk by 20% (HR 0.80) 1

Major Complications

Respiratory Complications:

• Respiratory failure is the primary cause of death in ALS patients 1
• Progressive weakness of respiratory muscles leads to ventilatory insufficiency requiring non-invasive ventilation (NIV) 4
• NIV improves survival when implemented appropriately 2
• Lung infections occur due to increased work of breathing and aspiration risk 1

Nutritional Complications:

• Dysphagia develops in approximately 80% of bulbar-onset patients 1, 5
• Malnutrition with dehydration is a primary cause of death alongside respiratory failure 1
• Anorexia is common, attributed to psychosocial distress, depression, and polypharmacy 1
• Constipation results from weakness of abdominal/pelvic muscles, reduced physical activity, and low-fiber diet 1
• Despite reduced lean body mass, energy requirements may increase due to increased work of breathing and infections 1

Cognitive and Behavioral Complications:

• Cognitive dysfunction occurs in 20-50% of cases, mainly frontotemporal dementia 1, 5
• 10-15% meet clinical criteria for frontotemporal dementia 5
• Executive dysfunction, behavioral changes, and language problems are common extra-motor manifestations 5
• Patients with ALS-FTD are less likely to choose long-term mechanical ventilation 5

Functional Complications:

• Progressive muscle weakness and atrophy affecting limbs, bulbar muscles, and respiratory muscles 1
• Falls are frequent, particularly forward falls due to weakness of ankle extensors and lower limb muscles 6
• Inability to perform protective stepping increases fall-related injury risk 6
• Osteoporosis from progressive immobility increases fracture risk with falls 6

Clinical Phenotypes and Their Prognosis

Bulbar-Onset ALS (25-35% of patients):

• Shortest life expectancy among all phenotypes 1, 5
• Initial symptoms of dysarthria and dysphagia in 80% of cases 5
• Requires early intervention with communication devices and nutritional support 5
• Videofluoroscopy recommended at diagnosis to detect early dysphagia 5

Limb-Onset ALS (65-75% of patients):

• Better prognosis than bulbar-onset, with median survival of 27-39 months depending on upper vs. lower limb involvement 3
• Progressive weakness spreading to multiple body regions 5
• Eventually develops respiratory and bulbar symptoms 1

Treatment Effects on Survival

Riluzole:

• Extends median survival by approximately 60-90 days compared to placebo 7
• More effective in younger patients and those with longer diagnostic delay 4
• Does not improve muscle strength or neurological function 7

Gastrostomy Timing:

• Early gastrostomy (before >10% weight loss) significantly improves survival 1
• Weight loss >10% before gastrostomy increases 30-day mortality risk 2.5-fold (HR 2.514, p=0.001) 1
• Patients with <5 kg weight loss and cholesterol >220 mg/dl at PEG insertion survive 21.5 months vs. 15.3 months for those with greater weight loss (p=0.025) 1
• Gastrostomy can be performed safely even with FVC <50% if NIV support is provided 1

Non-Invasive Ventilation:

• NIV use is associated with improved survival after respiratory involvement 4, 2
• Should be considered when respiratory insufficiency develops 8

Common Pitfalls in Prognostication

• Avoid delaying gastrostomy until severe weight loss occurs - nutritional deficits may become irreversible 1
• Do not assume all patients have 3-5 year survival - 10-20% survive >10 years, requiring individualized prognostic discussions 2
• Consider cognitive status when discussing interventions - patients with FTD have different decision-making capacity and preferences 5
• Monitor for falls systematically - all patients should be screened at admission, transitions, and with any health status change 6