What is the trajectory of Amyotrophic Lateral Sclerosis (ALS)?

Trajectory of Amyotrophic Lateral Sclerosis (ALS)

ALS is a relentlessly progressive neurodegenerative disease with a mean survival of 3-5 years from diagnosis, with only 5-10% of patients living longer than 10 years, ultimately resulting in respiratory failure and death. 1

Disease Onset and Progression

ALS presents in two main forms:

1. Bulbar onset (25-35% of patients):

   • Initial symptoms affect speech and swallowing
   • Almost 80% develop dysarthria and dysphagia
   • Associated with shorter life expectancy, especially in older patients 1

2. Spinal/limb onset (65-75% of patients):

   • Initial symptoms include muscle weakness in limbs
   • Progressive muscle wasting and fasciculations 2

Clinical Manifestations

The disease is characterized by a combination of:

• Upper motor neuron signs: Hypertonicity/spasticity, hyperreflexia, pyramidal tract signs 2
• Lower motor neuron signs: Muscle fasciculations, weakness, and atrophy 2
• Progressive spread: Symptoms spread from one body region to others over time 2
• Absence of sensory abnormalities: A key diagnostic feature 2

Disease Progression Timeline

1. Early Stage:

   • Focal weakness in one body region
   • Mild functional limitations
   • Weight loss begins (a 5% weight loss at diagnosis increases death risk by 14-30%) 1

2. Middle Stage:

   • Spreading weakness to multiple body regions
   • Increasing difficulty with activities of daily living
   • Development of dysphagia (even in patients without obvious bulbar symptoms) 2
   • Nutritional challenges emerge 1

3. Advanced Stage:

   • Widespread paralysis
   • Respiratory compromise
   • Complete dependence for activities of daily living
   • Potential cognitive dysfunction (20-50% of cases), mainly frontotemporal dementia 1

4. Terminal Stage:

   • Respiratory failure
   • Malnutrition with dehydration
   • These are the primary causes of death 1

Prognostic Factors

Several factors influence the disease trajectory:

• Age at onset: Older age associated with shorter survival 1
• Site of onset: Bulbar onset has worse prognosis 1
• Weight loss: A critical prognostic indicator
  • 5% weight loss increases death risk by 14-30%
  • 10% weight loss increases death risk by 45% 1
• BMI: Lower BMI at baseline associated with reduced survival 1
• Respiratory function: Decline predicts shorter survival 1

Treatment Impact on Trajectory

Current FDA-approved medications can modestly alter the disease trajectory:

• Riluzole: Extends survival by approximately 60-90 days 3
• Edaravone: Slows functional decline as measured by ALSFRS-R scores 4

However, these treatments do not fundamentally change the progressive nature of the disease or provide significant improvements in muscle strength and neurological function 3.

Palliative Care Considerations

The European Federation of Neurological Sciences recommends:

• A palliative care approach should be adopted from the time of diagnosis
• Early referral to palliative services is essential, before communication becomes limited 1
• Despite these recommendations, management of terminal ALS is often unsatisfactory, with only 30% of palliative units in the UK providing ALS care 1

Important Clinical Pitfalls

1. Delayed diagnosis: ALS is often diagnosed after symptoms have been present for some time, limiting treatment window
2. Overlooking dysphagia: Even patients without obvious bulbar symptoms may have swallowing abnormalities detectable on videofluoroscopy 2
3. Late palliative care referral: This is common and negatively impacts quality of life 1
4. Inadequate respiratory planning: Failure to discuss ventilation options early in the disease course
5. Neglecting nutritional status: Weight loss is a critical prognostic factor that requires regular monitoring 1

The trajectory of ALS is characterized by inevitable progression, but quality of life can be significantly improved through early multidisciplinary intervention, proactive symptom management, and timely palliative care integration.