What is amyotrophic lateral sclerosis?

What is Amyotrophic Lateral Sclerosis (ALS)?

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease characterized by degeneration of both upper and lower motor neurons in the brain and spinal cord, leading to progressive muscle weakness, paralysis, and typically death within 3-5 years of symptom onset. 1

Disease Classification and Epidemiology

ALS is the most common motor neuron disease, representing approximately 85% of all motor neuron disease cases. 1 The disease affects approximately 1-2 per 100,000 people annually, with relatively uniform distribution across Western countries. 2 About 85-90% of cases are sporadic (occurring without known genetic mutation or family history), while 10-15% are familial with autosomal dominant inheritance patterns. 1, 3

The mean age of onset is approximately 60 years, with a slight male predominance (male-to-female ratio approximately 1.5:1). 2

Pathophysiology

The fundamental pathological process involves progressive degeneration and death of motor neurons along the corticospinal tracts, from the motor cortex through the brainstem to the spinal cord. 1 This is primarily an axonal degenerative disease, not a demyelinating condition—any demyelination observed on imaging is secondary to the primary axonal degeneration. 1

The etiology is multifactorial, involving:

• Increased oxidative stress 1
• Glutamate excitotoxicity 4
• Mitochondrial dysfunction 1
• Inflammation and microglial activation 5
• Apoptosis (programmed cell death) 1

Genetic factors include mutations in the SOD1 gene (20% of familial cases), TARDBP/TDP-43 gene (2-5% of familial cases), and most commonly, hexanucleotide repeat expansions in the C9orf72 gene (30-50% of familial ALS and 7% of sporadic ALS). 2, 3

Clinical Presentation

ALS presents in two main patterns based on site of onset:

Limb-Onset (Spinal) ALS (65-75% of cases)

• Initial symptoms involve progressive muscle weakness in arms or legs 6
• Weakness may start distally or proximally in the extremities 2
• Spasticity gradually develops in weakened, atrophic limbs, affecting manual dexterity and gait 2
• Muscle fasciculations, weakness, and atrophy reflect lower motor neuron involvement 1

Bulbar-Onset ALS (25-35% of cases)

• Approximately 80% develop dysarthria (speech difficulty) and dysphagia (swallowing difficulty) as primary manifestations 1, 6
• Sialorrhea (drooling) occurs due to impaired swallowing of saliva 1
• Nasal regurgitation from soft palate weakness 1
• Limb symptoms typically develop within 1-2 years of bulbar onset 2

Mixed Upper and Lower Motor Neuron Signs

The hallmark of ALS is the combination of:

• Upper motor neuron signs: Hypertonicity, hyperreflexia, spasticity 1
• Lower motor neuron signs: Muscle fasciculations, weakness, atrophy 1

Extra-Motor Manifestations

Up to 40-50% of patients develop cognitive impairment, primarily frontotemporal dementia, with behavioral changes, executive dysfunction, and language problems. 6, 3 This cognitive involvement significantly impacts treatment decisions, advance care planning, and compliance with interventions like non-invasive ventilation. 1

Diagnostic Approach

Diagnosis relies on clinical history, examination, electromyography, and exclusion of ALS-mimicking conditions. 2 There are no definitive biomarkers for ALS, which contributes to diagnostic delays. 6

Key Diagnostic Tests

MRI of the brain without IV contrast is the usually appropriate initial imaging study. 7 Common MRI findings include:

• Abnormal T2/FLAIR signal anywhere within the corticospinal tracts (most frequently in the posterior limb of internal capsule and cerebral peduncles), corresponding to axonal degeneration and gliosis 7
• Abnormal hypointensity on T2*-weighted or susceptibility-weighted imaging in the precentral gyrus, which is highly sensitive and specific for ALS 7
• "Snake eyes" appearance on spinal MRI showing abnormal T2 signal in the anterior horns, reflecting lower motor neuron disease 1

MRI of the spine without IV contrast may be appropriate in certain patients to exclude structural, infectious, or neoplastic mimics of motor neuron disease. 7

Electromyography and nerve conduction studies are key diagnostic tests. 8 The diagnosis requires signs of both upper and lower motor neuron damage not explained by any other disease process. 2

Conditions to Exclude

Critical ALS-mimics that must be ruled out include:

• Cervical spondylotic myelopathies 2
• Multifocal motor neuropathy 2
• Kennedy's disease 2
• Structural lesions, infections, or neoplasms of the spine 7

Prognosis

Mean survival is 3-5 years after symptom onset, with only 5-10% of patients living longer than 10 years. 1, 6 Bulbar-onset cases typically have shorter survival (2-3 years) compared to limb-onset cases (3-5 years). 2

Respiratory failure due to respiratory muscle weakness is the most common cause of death. 1 Malnutrition and dehydration also contribute significantly to mortality. 6

Prognostic Factors

• Nutritional status is a major prognostic factor: Malnutrition at diagnosis increases the risk of death by more than four-fold 1
• Each 5% loss of body weight is associated with a 34% increase in mortality risk 1
• A reduction of one BMI point corresponds to a 24% higher risk of death 1
• Performing gastrostomy after more than 10% weight loss markedly raises mortality (relative risk 4.18) 1

Management Principles

The cornerstone of ALS management is multidisciplinary supportive and palliative care, which should be integrated from the time of diagnosis. 1, 2 There is considerable evidence that multidisciplinary care improves both survival and quality of life. 1

Disease-Modifying Treatment

Riluzole is the only drug that has been shown to extend survival, though the effect is modest (extending mean survival by 3-6 months). 2, 5

Respiratory Management

Non-invasive ventilation (NIV) prolongs survival and improves quality of life. 2 However, NIV compliance may be reduced in patients with cognitive impairment, so cognitive function should be assessed before recommending this intervention. 1

Nutritional Support

Nutritional support is essential and should be initiated early. 1 Key interventions include:

• Modification of food texture to prevent aspiration 1
• Chin-tuck posture to protect airways 1
• Gastrostomy (PEG) placement before severe respiratory compromise develops 1
• Videofluoroscopy should be performed at the time of ALS diagnosis to detect early dysphagia signs, as aspiration may occur without clinical signs. 1
• Implement structured dysphagia screening every 3 months using the Eating Assessment Tool-10 (EAT-10), which achieves approximately 86% sensitivity and 76% specificity 1

Advance Care Planning

Advance directive discussions should be initiated early in the disease course, ideally at diagnosis, before communication becomes limited. 1 This includes discussions about ventilatory support, feeding tubes, and end-of-life care preferences. 1

Caregiver Support

Structured caregiver support including counseling, support groups, and crisis management systems should be implemented from diagnosis, as caregiver burden is substantial and worsens with behavioral deficits in patients. 1

Critical Pitfalls to Avoid

• Late referral to palliative services is the most common and harmful error, negatively impacting quality of life for both patients and caregivers 1
• Delaying videofluoroscopy assessment can lead to silent aspiration 1
• Performing gastrostomy after significant weight loss (>10%) markedly increases mortality 1
• Failing to assess cognitive function before recommending NIV, as cognitive impairment reduces compliance 1
• Using the Harris-Benedict equation to prescribe calories, as it is unreliable for individual ALS patients (limits of agreement -677 to +591 kcal/day) 1