What are the risk factors and complications of amyotrophic lateral sclerosis (ALS)?

Risk Factors and Complications of Amyotrophic Lateral Sclerosis (ALS)

Risk Factors for Developing ALS

The only established risk factors for developing ALS are older age, male gender, and a family history of ALS. 1

Genetic Risk Factors

• Familial ALS accounts for 10% of cases and follows an autosomal dominant inheritance pattern. 2
• The C9orf72 hexanucleotide repeat expansion is the most common genetic cause, responsible for 30-50% of familial ALS and 7% of sporadic ALS. 2
• Other common causal genes include SOD1, FUS, and TARDBP, though genetic factors may be underestimated even in patients without family history. 3

Physical Activity as a Risk Factor

The evidence regarding physical activity as a risk factor remains conflicting and inconclusive:

• A systematic review from 2002-2006 concluded that physical activity is probably not a risk factor for developing ALS. 4
• However, an observational study of 636 sporadic ALS patients found higher risk with increased leisure time physical activity (sports, hobbies), though no association with occupational physical activity or dose-response relationship was identified. 4
• A Swedish study of over 8 million men followed for 20 years found an association between cardiovascular fitness at baseline and death from ALS at an early age. 4
• The current interpretation is that ALS may be promoted by a genetic profile or lifestyle mode related to physical fitness rather than physical activity itself. 4

Major Complications and Causes of Mortality

Respiratory Failure

Respiratory failure due to respiratory muscle weakness is the most common cause of death in ALS, with mean survival of 3-5 years after symptom onset. 5

• Only 5-10% of patients survive longer than 10 years. 5, 6
• Bulbar-onset ALS has significantly worse prognosis, with median survival of approximately 25-28 months compared to 44 months for spinal-onset patients with dysphagia. 7

Nutritional Complications

Malnutrition at diagnosis increases the risk of death by more than four-fold, making nutritional status a major prognostic factor. 5

• Each 5% loss of body weight is associated with a 34% increase in mortality risk. 5
• A reduction of one BMI point corresponds to a 24% higher risk of death. 5
• Weight loss and malnutrition develop in 0-21% of patients at diagnosis and worsen progressively. 7
• Performing gastrostomy (PEG) after more than 10% weight loss markedly raises mortality (relative risk 4.18; 95% CI 2.72-6.42). 5

Dysphagia and Aspiration

Approximately 80% of patients with bulbar-onset ALS develop dysarthria and dysphagia, which can lead to aspiration pneumonia and malnutrition. 5, 6

• Aspiration pneumonia occurs in 11.4-13% of bulbar ALS cases and represents a leading cause of mortality. 7
• Both oral and pharyngeal stages of swallowing may be compromised, and aspiration can be present even without clinical aspiration signs or subjective complaints. 5
• Silent aspiration is a critical pitfall—videofluoroscopy should be performed at diagnosis to detect early dysphagia even in asymptomatic patients. 5, 7

Cognitive and Behavioral Complications

Up to 40-50% of ALS patients have extra-motor manifestations including behavioral changes, executive dysfunction, and language problems. 5, 2

• In 10-15% of patients, cognitive problems are severe enough to meet clinical criteria for frontotemporal dementia (FTD). 2
• Cognitive impairment reduces likelihood of choosing long-term mechanical ventilation and decreases non-invasive ventilation (NIV) compliance. 5
• Patients with executive dysfunction are at higher risk of falls, choking episodes, and injuries. 7
• The C9orf72 expansion is a frequent cause of both ALS and frontotemporal dementia, emphasizing the molecular overlap. 2

Infection-Related Complications

• In patients receiving home parenteral nutrition, catheter-related bloodstream infection can be fatal—one study reported death from this complication in at least one patient, with another suspected case. 4
• Mean survival time for advanced ALS patients on home parenteral nutrition was only 3.5 ± 2.4 months, with 24 of 30 patients dying from respiratory failure. 4

Critical Prognostic Markers

Phase angle measured by bioelectrical impedance analysis (BIA) is a validated prognostic marker—every 1-degree decrease predicts a 68% increase in mortality risk. 5

• Higher fat mass during disease improves survival, with a 10% risk reduction for each 2.5 kg increase in fat mass. 5
• Neurofilament light chain (NF-L) is being investigated as a biomarker for estimating prognosis. 3

Common Pitfalls in ALS Management

Late referral to palliative services is the most common and harmful error, negatively impacting quality of life for both patients and caregivers. 5, 7

• Equipment and service delays can result in catastrophic safety risks—all requests for equipment and services should be considered urgent and handled expeditiously. 7
• Delaying videofluoroscopy assessment can lead to silent aspiration, as aspiration may occur without observable clinical signs. 5
• Refusing gastrostomy when forced vital capacity (FVC) falls below 30% is recommended, as PEG placement should occur before respiratory function significantly deteriorates, ideally when FVC remains >50% of predicted. 7