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. 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), leading to progressive muscle weakness and paralysis 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 autosomal dominant inheritance pattern 3
• 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 3

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
• Presentation varies based on site of onset:
  • Bulbar-onset: approximately 80% develop dysarthria and dysphagia 2, 4
  • Limb-onset: weakness and atrophy typically beginning in distal limbs 3
• The disease begins focally in the central nervous system and then spreads relentlessly 5
• Extra-motor manifestations occur in up to 50% of cases, including behavioral changes, executive dysfunction, and language problems 3
• In 10-15% of patients, cognitive problems are severe enough to meet criteria for frontotemporal dementia (FTD) 3

Diagnosis

• Diagnosis is based on history of painless progressive weakness with examination findings of upper and lower motor neuron dysfunction 6
• Key diagnostic tests include:
  • Electromyography (EMG) and nerve conduction velocity (NCV) studies are cornerstone tests for diagnosing ALS, detecting lower motor neuron degeneration 7
  • MRI of brain and spine to exclude other conditions and potentially show abnormal T2/FLAIR signal in the corticospinal tracts 2, 7
  • Laboratory tests to exclude treatable mimics, including CBC, chemistry profile, thyroid function, vitamin levels, and autoimmune markers 7
  • Cerebrospinal fluid examination may be performed to exclude infectious, inflammatory, or neoplastic causes 7
  • Genetic testing for ALS-associated genes (e.g., C9orf72, SOD1, FUS, TARDBP) should be considered, especially with family history 7

Prognosis

• Mean survival is 3-5 years after symptom onset 2
• Only 5-10% of patients live longer than 10 years 2, 4
• 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 3

Treatment

1. FDA-approved medications:

   • Riluzole (50 mg twice daily) is indicated for ALS treatment and has been shown to modestly prolong survival 8, 9
   • Edaravone, a free radical scavenger, may halt progression in early stages through its cytoprotective effect 6, 10

2. Symptomatic management:

   • Respiratory support: Non-invasive ventilation for respiratory insufficiency 9
   • Nutritional support: Gastrostomy for dysphagia and weight loss 2, 9
   • Symptomatic treatments for spasticity, sialorrhea, pseudobulbar affect, and pain 9

3. Multidisciplinary care:

   • A multidisciplinary approach involving neurologists, pulmonologists, gastroenterologists, speech therapists, physical therapists, and palliative care specialists 1, 3
   • Regular monitoring of respiratory function and nutritional status 2

4. 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

Emerging Therapies

• Current clinical trials aim to slow disease progression by targeting known pathophysiological pathways or genetic defects 5, 6
• Approaches include:
  • Antisense oligonucleotide gene therapies 6
  • Stem cell therapies 6
  • Targeting muscle proteins such as Nogo 5
  • Addressing energetic balance and abnormal gene products 5

Important Considerations

• Monitor serum aminotransferases before and during riluzole treatment 8
• Riluzole is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal 8
• Watch for neutropenia in patients taking riluzole; advise patients to report any febrile illness 8
• Discontinue riluzole if interstitial lung disease develops 8
• Most common adverse reactions to riluzole include asthenia, nausea, dizziness, decreased lung function, and abdominal pain 8