What is Amyotrophic Lateral Sclerosis (ALS) and how is it diagnosed and treated?

Amyotrophic Lateral Sclerosis (ALS): Diagnosis and Management

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease characterized by degeneration of both upper and lower motor neurons, typically leading to death within 3-5 years of symptom onset, with palliative care being essential from diagnosis to improve quality of life. 1, 2

Definition and Pathophysiology

• ALS is the most common motor neuron disease, representing approximately 85% of all motor neuron disease cases 2
• The disease involves progressive degeneration of both upper motor neurons (in the brain) and lower motor neurons (in the spinal cord) along the corticospinal tracts 2
• Pathophysiology involves multiple mechanisms including oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 2
• Approximately 90% of cases are sporadic, while 10% are familial with genetic mutations 3, 4
• The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30-50% of familial ALS and 7% of sporadic ALS 4

Clinical Presentation

• Classical ALS presents with mixed upper and lower motor neuron signs 2
• Upper motor neuron signs include hypertonicity and hyperreflexia 2
• Lower motor neuron signs include muscle fasciculations, weakness, and atrophy 2
• Approximately 80% of patients with bulbar-onset ALS develop dysarthria and dysphagia 2, 3
• Extra-motor manifestations occur in up to 50% of cases, including behavioral changes, executive dysfunction, and language problems; in 10-15% of patients, these problems meet the clinical criteria for frontotemporal dementia 4

Diagnostic Approach

• Diagnosis is based on progressive signs and symptoms of upper and lower motor neuron dysfunction 5
• Key diagnostic tests include:
  • Electromyography (EMG) and nerve conduction velocity (NCV) studies to detect lower motor neuron degeneration 6
  • MRI of the brain without IV contrast to exclude other conditions 6
  • MRI of the spine without IV contrast in certain cases to exclude structural causes 6
• Laboratory tests to exclude treatable mimics:
  • Complete blood count, chemistry profile, thyroid function tests 6
  • Vitamin B12, folate, and vitamin E levels 6
  • Serum protein electrophoresis, anti-ganglioside antibodies 6
  • Paraneoplastic antibody panel, anti-acetylcholine receptor antibodies 6
• Genetic testing for ALS-associated genes (e.g., C9orf72, SOD1, FUS, TARDBP) should be considered, especially with family history 6

Prognosis

• Mean survival is 3-5 years after symptom onset 2, 5
• Only 5-10% of patients live longer than 10 years 2, 3
• Respiratory failure due to respiratory muscle weakness is the most common cause of death 1
• Factors associated with poorer prognosis include older age at onset, bulbar onset, and rapid progression 4

Treatment

FDA-Approved Medications

• Riluzole (50 mg twice daily, taken at least 1 hour before or 2 hours after meals) is the primary FDA-approved medication for ALS treatment, though it provides only modest survival benefit of approximately 3 months 7, 8
• Edaravone, a free radical scavenger, is also FDA-approved for ALS treatment 9
• Monitoring requirements for riluzole:
  • Measure serum aminotransferases before and during treatment 7
  • Not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal 7
  • Discontinue if there is evidence of liver dysfunction 7

Supportive Care

• Multidisciplinary care is the cornerstone of management 10, 9
• Nutritional support for dysphagia and weight loss is essential 2
• Ventilatory support for respiratory insufficiency can extend life 10
• Gastrostomy for those with dysphagia helps maintain nutrition 10
• Symptomatic management for various manifestations:
  • Spasticity
  • Sialorrhea (excessive drooling)
  • Pseudobulbar affect
  • Pain
  • Depression and anxiety 10

Palliative Care

• Palliative care should be integrated from the time of diagnosis, with emphasis on patient autonomy, dignity, and quality of life 1, 2
• Early referral to palliative services is recommended to establish relationships with staff and address end-of-life issues before communication becomes limited 2
• Support for caregivers is crucial, as they often experience significant burden 2
• Hospice programs provide emotional and physical support to patients and families throughout the disease course 5

Emerging Therapies

• Current clinical trials aim to slow disease progression by targeting known pathophysiological pathways 10
• Novel approaches include:
  • Gene replacement therapies, particularly for patients with identified genetic mutations 8
  • Antisense oligonucleotide gene therapies 9
  • Stem cell injections 10, 9
  • Diaphragmatic pacing 10

Important Considerations

• Diagnostic delays are common due to the heterogeneous presentation and overlap with other neurological conditions 3
• ALS often has a focal onset but subsequently spreads to different body regions 4
• There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia 5
• The mechanisms leading to disease propagation in the brain are a current focus of research 5