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 condition characterized by degeneration of both upper and lower motor neurons, typically leading to death within 3-5 years of symptom onset, with palliative care intervention recommended 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 (corticospinal tracts) and lower motor neurons (anterior horn cells) 2, 3
• Pathophysiological processes include mitochondrial dysfunction, protein aggregation, oxidative stress, excitotoxicity, inflammation, and apoptosis 2, 4
• Approximately 90% of cases are sporadic, while 10% are familial with autosomal dominant inheritance pattern 5
• 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 5, 6

Clinical Presentation

• Classical ALS presents with mixed upper and lower motor neuron signs 2:
  • Upper motor neuron signs: hypertonicity and hyperreflexia
  • Lower motor neuron signs: muscle fasciculations, weakness, and atrophy
• Approximately 80% of patients with bulbar-onset ALS develop dysarthria and dysphagia 2, 7
• The disease typically begins focally in the central nervous system and then spreads relentlessly 4
• Extra-motor manifestations occur in up to 50% of cases, including behavioral changes, executive dysfunction, and language problems 5
• In 10-15% of patients, cognitive problems are severe enough to meet the criteria for frontotemporal dementia 5

Diagnosis

• The diagnosis is based on progressive signs and symptoms of upper and lower motor neuron dysfunction 4, 8
• Key diagnostic tests include 2, 3:
  • Electromyography (EMG) and nerve conduction velocity (NCV) studies to detect lower motor neuron degeneration
  • MRI of the brain and spine to exclude other conditions and potentially show abnormal T2/FLAIR signal in the corticospinal tracts
  • Laboratory tests to exclude treatable mimics (CBC, metabolic panel, thyroid function, vitamin levels, autoimmune markers)
• MRI findings may include 3:
  • Abnormal T2/FLAIR signal in the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles
  • T2/STIR signal in the anterior horns ("snake eyes" appearance) on spine MRI
• Genetic testing should be considered, especially in cases with family history 3

Prognosis

• Mean survival is 3-5 years after symptom onset 2, 4
• Only 5-10% of patients live longer than 10 years 2, 7
• Respiratory failure due to respiratory muscle weakness is the most common cause of death 1
• Prognostic factors include age at onset, site of onset (bulbar onset has worse prognosis), and rate of progression 5, 6

Treatment

FDA-Approved Medications

• Riluzole (50 mg twice daily) is indicated for the treatment of ALS and has been shown to modestly prolong survival 9
  • Take at least 1 hour before or 2 hours after meals
  • Monitor serum aminotransferases before and during treatment
  • Not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal
• Edaravone, a free radical scavenger, is another FDA-approved medication that may slow disease progression in early stages through its cytoprotective effect 6, 10

Supportive Care

• Multidisciplinary care is essential and should include 4, 8:
  • Neurologist
  • Pulmonologist for respiratory support
  • Gastroenterologist for nutritional support
  • Physical, occupational, and speech therapists
  • Social worker and psychologist
• Ventilatory support for respiratory insufficiency 8
• Gastrostomy for patients with dysphagia and weight loss 2, 8
• Symptomatic management of spasticity, cramps, excessive salivation, and emotional lability 8

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 care provides emotional and physical support to patients and families throughout the disease course 4

Current Research and Future Directions

• Clinical trials aim to slow disease progression by targeting pathophysiological processes 8, 6
• Novel therapies being investigated include 6:
  • Neuroprotective agents with different mechanisms of action
  • Antisense oligonucleotide gene therapies
  • Stem cell injections
  • Diaphragmatic pacing

Common Pitfalls and Caveats

• Diagnostic delays are common due to the heterogeneous presentation and overlap with other neurological conditions 7
• Definitive biomarkers for ALS are still lacking, complicating early diagnosis 7
• Riluzole has significant drug interactions with CYP1A2 inhibitors and inducers 9
• Patients taking riluzole and other hepatotoxic drugs may be at increased risk for hepatotoxicity 9