Amyotrophic Lateral Sclerosis

Detailed Overview

The disease manifests as a spectrum, often beginning with focal, asymmetric weakness in the limbs (limb-onset) or bulbar musculature (bulbar-onset). Bulbar onset carries a poorer prognosis due to earlier compromise of swallowing and airway protection. Histopathologically, ALS is characterized by ubiquitinated cytoplasmic inclusions of TDP-43 in degenerating neurons. Frontotemporal dementia (FTD) is present in up to 15% of patients, underscoring a continuum between FTD and ALS, particularly driven by C9orf72 mutations.

Epidemiology & Demographics

Incidence is ~2 per 100,000 person-years. Peak age of onset is 55 to 75 years. Slight male predominance (1.5:1) in sporadic cases, though this gender gap narrows with age.

Etiological Mechanism

Sporadic ALS (sALS) comprises 90% of cases with an unknown etiology. Familial ALS (fALS) comprises 10% and is primarily inherited in an autosomal dominant pattern. The most common genetic mutations are hexanucleotide repeat expansions in C9orf72 (40% of fALS) and mutations in superoxide dismutase 1 (SOD1) (20% of fALS).

Primary Causes

Genetic mutations (C9orf72, SOD1, TARDBP, FUS) cause aberrant protein aggregation, oxidative stress, impaired axonal transport, and glutamate excitotoxicity.

• Age: Risk strongly increases past the age of 50.
• Family History: Having a first-degree relative with ALS or Frontotemporal Dementia increases risk.
• Military Service: Veterans deployed to the Gulf War showed a statistically significant increased incidence, possibly linked to environmental exposures.

Defective clearance of glutamate by astrocytic EAAT2 transporters leads to glutamate-induced excitotoxicity, driving massive intracellular calcium influx and motor neuron death. Intracellularly, abnormal aggregation of RNA-binding proteins (principally TDP-43) disrupts RNA processing. Wallerian degeneration of the corticospinal tracts leads to lateral column sclerosis (the 'lateral sclerosis'), while anterior horn cell death causes muscle denervation and atrophy (the 'amyotrophy').

Characteristic Clinical Presentation

• Asymmetric Limb Weakness: Commonly presenting as foot drop, difficulty turning keys, or trouble gripping objects.
• Bulbar Symptoms: Dysarthria (slurred speech), dysphagia (difficulty swallowing), and sialorrhea (drooling).
• Fasciculations and Cramps: Spontaneous, involuntary muscle twitching and severe cramping, especially at night.

Physical Examination Signs

• UMN Signs: Hyperreflexia (3+ to 4+), positive Babinski sign, spasticity, Hoffmann sign.
• LMN Signs: Profound muscle atrophy, visible fasciculations, hyporeflexia in severely wasted limbs.
• Pseudobulbar Affect: Inappropriate laughing or crying due to UMN bulbar pathway degeneration.

• Type 2 Respiratory Failure: Hypercapnic failure due to progressive diaphragmatic weakness.
• Deep Vein Thrombosis: High risk of DVT and subsequent PE due to profound immobility.

Diagnostic Criteria & Guidelines

The revised El Escorial criteria require evidence of LMN degeneration by clinical, electrophysiological, or neuropathological exam; evidence of UMN degeneration by clinical exam; and progressive spread of symptoms within a region or to other regions. It requires the absence of electrophysiological/pathological evidence of other diseases.

Differential Diagnosis

• Cervical Spondylotic Myelopathy (can mimic UMN/LMN mix)
• Multifocal Motor Neuropathy (MMN)
• Primary Lateral Sclerosis (pure UMN)
• Spinal Muscular Atrophy (pure LMN)

Laboratory Tests & Biomarkers

• Serum Creatine Kinase (CK): Mildly elevated (usually < 1000 U/L) due to active muscle denervation.
• Neurofilament Light Chain (NfL): Significantly elevated in CSF and serum, correlating with rapid progression.

Imaging Modalities & Findings

• MRI Brain/Spine:
• Electromyography (EMG):

• Early
  Weakness restricted to one body region (e.g., hand weakness or isolated foot drop). Independence maintained.
• Middle
  Weakness spreads to multiple regions. Mobility requires assistive devices (e.g., AFO, wheelchair). Mild respiratory muscle weakness (FVC 70-80%).
• Late
  Severe quadriplegia and bulbar palsy. Vital capacity falls < 50%. Dependent for all ADLs and nutrition (PEG placement).

Second-Line & Adjunctive Therapy

Symptom management: Dextromethorphan/quinidine (Nuedexta) 20 mg/10 mg PO BID for pseudobulbar affect. Glycopyrrolate 1-2 mg PO TID or botulinum toxin to salivary glands for sialorrhea. Baclofen 10-20 mg PO TID for spasticity. Tofersen 100 mg intrathecally every 28 days for adults with SOD1-mutated ALS.

Surgical & Procedural Management

Percutaneous Endoscopic Gastrostomy (PEG) tube placement for enteral nutrition when dysphagia causes significant weight loss or aspiration, ideally placed while FVC is still > 50%. Tracheostomy with invasive mechanical ventilation is an option for end-stage disease but involves complex ethical and quality-of-life decisions.

Recommended Lifestyle Changes

• Consultation with a speech-language pathologist for communication devices (e.g., eye-tracking technology) and swallow evaluation.
• Work with physical and occupational therapy for assistive equipment (wheelchairs, orthotics) to maximize independence.

Patient Counseling & Advice

Early discussions regarding advance directives, living wills, and preferences regarding PEG tubes and mechanical ventilation are essential before bulbar or respiratory muscles profoundly fail.

Follow-Up & Monitoring Schedule

Multidisciplinary ALS clinic visits every 3 months. Serial monitoring of Forced Vital Capacity (FVC) and Maximum Inspiratory Pressure (MIP) to assess respiratory muscle function.

Preventive Strategies

No known preventive measures. Genetic counseling is advised for patients with a strong family history of ALS or FTD.

Median survival is 3 to 5 years from symptom onset. 10-20% of patients survive longer than 10 years (especially those with earlier onset or pure upper motor neuron variants). Death is invariably due to respiratory failure or aspiration pneumonia.