Amyotrophic Lateral Sclerosis (ALS)

Overview

ALS belongs to a group of disorders known as motor neuron diseases, characterized by the gradual deterioration and death of motor neurons. The term "amyotrophic" comes from Greek, meaning "no muscle nourishment," which refers to the muscle wasting that occurs when motor neurons can no longer send signals to muscles. "Lateral sclerosis" refers to the scarring or hardening in the lateral region of the spinal cord where affected motor neurons are located. The disease gained widespread recognition when it ended the career of baseball legend Lou Gehrig in 1939, leading to its common name in North America.

The disease affects approximately 2 per 100,000 people annually worldwide, with about 5,000 new cases diagnosed each year in the United States. Most people develop ALS between ages 55 and 75, though it can occur at any age. Men are slightly more likely to develop ALS than women, with a ratio of about 1.5:1, though this gender difference diminishes after menopause. The disease occurs in all racial and ethnic groups worldwide, with some variations in prevalence that may be attributed to genetic factors or environmental influences.

ALS is classified into two main types: sporadic and familial. Sporadic ALS, which accounts for 90-95% of cases, occurs randomly without a clear family history. Familial ALS (FALS) represents 5-10% of cases and is inherited through genetic mutations. More than 20 genes have been associated with ALS, with mutations in C9orf72, SOD1, TARDBP, and FUS being the most common. The disease's complexity extends beyond simple categorization, as it exists on a spectrum with frontotemporal dementia (FTD), with some patients experiencing cognitive and behavioral changes alongside motor symptoms. Understanding ALS requires recognizing its heterogeneous nature, variable progression rates, and the profound impact it has on patients, families, and caregivers.

Symptoms

ALS symptoms vary significantly among individuals, both in terms of initial presentation and progression rate. The disease typically begins subtly, often in one localized area, before spreading to other parts of the body. Early symptoms may be so mild that they're overlooked or attributed to normal aging or other conditions.

Motor Symptoms

• Weakness - Progressive muscle weakness, often starting in hands, feet, or limbs
• Abnormal involuntary movements - Muscle twitches (fasciculations) visible under the skin
• Leg cramps or spasms - Painful muscle cramps, especially in early stages
• Muscle stiffness and spasticity - Increased muscle tone causing rigidity
• Clumsiness and stumbling - Difficulty with fine motor tasks or walking
• Foot drop - Difficulty lifting the front part of the foot
• Hand weakness - Dropping objects, difficulty with buttons or writing

Bulbar Symptoms

• Difficulty speaking - Slurred speech (dysarthria), nasal quality, or weak voice
• Difficulty in swallowing - Problems with liquids or solids (dysphagia)
• Excessive drooling - Due to difficulty managing saliva
• Tongue fasciculations - Visible twitching of tongue muscles
• Difficulty chewing - Jaw muscle weakness
• Choking episodes - Risk of aspiration

Respiratory Symptoms

• Shortness of breath - Initially with exertion, later at rest
• Difficulty breathing when lying flat (orthopnea)
• Morning headaches - Due to overnight CO2 retention
• Fatigue and daytime sleepiness
• Weak cough - Inability to clear secretions effectively
• Frequent respiratory infections

Other Symptoms

• Uncontrollable laughing or crying (pseudobulbar affect)
• Weight loss - Due to muscle wasting and swallowing difficulties
• Cognitive changes - In 15-20% of patients
• Behavioral changes - Apathy, disinhibition, or compulsive behaviors
• Constipation - Due to reduced mobility and dietary changes
• Pain - From muscle cramps, joint immobility, or pressure points

Importantly, ALS typically does not affect the senses (sight, smell, taste, hearing, touch), bladder or bowel control, sexual function, or eye movements, which helps distinguish it from other neurological conditions.

Causes

The exact cause of ALS remains unknown in most cases, but research has identified multiple factors that contribute to motor neuron degeneration. The disease likely results from a complex interaction of genetic susceptibility and environmental triggers.

Genetic Factors

• C9orf72 gene: Most common genetic cause (40% of familial, 7% of sporadic cases)
  • Hexanucleotide repeat expansion
  • Associated with ALS-FTD spectrum
  • Variable penetrance and expression
• SOD1 gene: First identified ALS gene (20% of familial cases)
  • Over 180 mutations identified
  • Produces misfolded protein aggregates
  • Some mutations have rapid progression
• TARDBP and FUS genes: Encode RNA-binding proteins
• Other genes: UBQLN2, OPTN, VCP, SQSTM1, and others

Cellular Mechanisms

• Protein aggregation: Accumulation of misfolded proteins in motor neurons
• RNA processing defects: Disrupted RNA metabolism and transport
• Mitochondrial dysfunction: Impaired energy production in cells
• Oxidative stress: Damage from reactive oxygen species
• Glutamate excitotoxicity: Excessive stimulation damaging neurons
• Neuroinflammation: Activated microglia and astrocytes
• Axonal transport defects: Impaired cellular trafficking
• Impaired protein degradation: Accumulation of cellular waste

Environmental Factors

• Military service: Veterans have 1.5-2x higher risk
• Toxin exposure:
  • Lead and heavy metals
  • Pesticides and agricultural chemicals
  • Organic solvents
• Physical trauma: Head injuries may increase risk
• Intense physical activity: Professional athletes show higher rates
• Smoking: Associated with increased risk, especially in women
• β-methylamino-L-alanine (BMAA): Neurotoxin found in certain environments

Other Potential Factors

• Viral infections: Possible trigger in susceptible individuals
• Autoimmune responses: Antibodies against neural components
• Prion-like propagation: Spread of misfolded proteins between cells
• Epigenetic factors: Environmental influences on gene expression

Risk Factors

While ALS can affect anyone, certain factors increase the likelihood of developing the disease:

• Age: Risk increases with age
  • Most common between 55-75 years
  • Can occur in younger adults (rare in those under 30)
  • Juvenile ALS (before age 25) is very rare
• Gender:
  • Men have 1.5x higher risk before age 65
  • Risk equalizes after menopause
  • Gender differences may relate to hormonal factors
• Genetics:
  • 5-10% have familial ALS
  • 50% chance of inheriting from affected parent (dominant mutations)
  • Some genes have reduced penetrance
• Military service: Veterans of all eras at increased risk
• Geography:
  • Higher rates in Guam and parts of Japan
  • Possible environmental clusters
• Occupation:
  • Agricultural workers
  • Electrical workers
  • Professional athletes
• Lifestyle factors:
  • Smoking (especially current smokers)
  • High levels of physical activity
  • Low body mass index
• Other medical conditions:
  • Type 2 diabetes (protective effect noted)
  • High cholesterol (may be protective)

Diagnosis

Diagnosing ALS is challenging as there's no single definitive test. The process involves ruling out other conditions that mimic ALS and demonstrating progressive motor neuron degeneration. Early diagnosis is crucial for treatment planning and clinical trial eligibility.

Clinical Evaluation

• Neurological examination:
  • Muscle strength testing
  • Reflex assessment (hyperreflexia with weakness)
  • Muscle tone evaluation
  • Fasciculation observation
  • Coordination and gait assessment
• Medical history: Symptom progression, family history, exposures
• Physical examination: Overall health assessment

Electrodiagnostic Studies

• Electromyography (EMG):
  • Detects electrical activity in muscles
  • Shows denervation and reinnervation
  • Helps localize affected regions
• Nerve conduction studies:
  • Measures nerve signal speed and strength
  • Usually normal in ALS (rules out neuropathy)

Imaging Studies

• MRI of brain and spinal cord:
  • Rules out structural causes
  • May show motor cortex changes
  • Detects spinal cord compression
• PET or SPECT scans: Research settings to visualize brain metabolism

Laboratory Tests

• Blood and urine tests:
  • Thyroid function
  • Vitamin B12 levels
  • Heavy metal screening
  • Inflammatory markers
  • Creatine kinase (may be elevated)
• Lumbar puncture: CSF analysis to rule out infections or inflammation
• Genetic testing: For familial ALS or younger patients
• Muscle biopsy: Rarely needed, shows neurogenic atrophy

Diagnostic Criteria

The revised El Escorial criteria require:

• Evidence of upper motor neuron degeneration
• Evidence of lower motor neuron degeneration
• Progressive spread of symptoms
• Absence of other disease processes

Differential Diagnosis

• Multifocal motor neuropathy
• Kennedy's disease
• Primary lateral sclerosis
• Progressive muscular atrophy
• Myasthenia gravis
• Multiple sclerosis
• Cervical myelopathy

Treatment Options

While there's no cure for ALS, treatments can slow disease progression, manage symptoms, and improve quality of life. A multidisciplinary approach involving various specialists provides the best outcomes.

Disease-Modifying Medications

• Riluzole (Rilutek, Tiglutik, Exservan):
  • First FDA-approved drug for ALS (1995)
  • Reduces glutamate release
  • Extends survival by 2-3 months
  • Available as tablets, liquid, or oral film
• Edaravone (Radicava, Radicava ORS):
  • Antioxidant that may slow decline
  • IV infusion or oral suspension
  • Most effective in early disease
• Sodium phenylbutyrate/taurursodiol (Relyvrio):
  • Newest approved medication (2022)
  • May slow functional decline
  • Oral powder mixed with water

Symptomatic Management

• Muscle cramps and spasticity:
  • Baclofen, tizanidine
  • Stretching exercises
  • Physical therapy
• Excessive saliva:
  • Anticholinergic medications
  • Botulinum toxin injections
  • Suction devices
• Pseudobulbar affect:
  • Dextromethorphan/quinidine (Nuedexta)
  • SSRIs or tricyclic antidepressants
• Pain:
  • NSAIDs for musculoskeletal pain
  • Gabapentin for neuropathic pain
  • Opioids for severe pain
• Depression and anxiety: Antidepressants, counseling
• Sleep problems: Sleep positioning, medications
• Constipation: Dietary changes, laxatives

Respiratory Support

• Non-invasive ventilation (NIV/BiPAP):
  • Improves quality of life and survival
  • Initially used at night
  • Eventually may need 24-hour use
• Cough assist devices: Help clear secretions
• Tracheostomy and invasive ventilation: Personal choice
• Diaphragm pacing: Electrical stimulation of diaphragm

Nutritional Support

• Dietary modifications: Texture changes, thickened liquids
• High-calorie supplements: Prevent weight loss
• Feeding tube (PEG):
  • Maintains nutrition when swallowing unsafe
  • Best placed before respiratory compromise
  • Can still eat for pleasure if safe

Rehabilitation Therapies

• Physical therapy: Maintain mobility, prevent contractures
• Occupational therapy: Adaptive equipment, energy conservation
• Speech therapy: Communication strategies, swallowing techniques
• Respiratory therapy: Breathing exercises, airway clearance

Assistive Technologies

• Mobility aids: Canes, walkers, wheelchairs, lifts
• Communication devices:
  • Speech-generating devices
  • Eye-tracking systems
  • Brain-computer interfaces
• Environmental controls: Smart home technology
• Computer access: Modified keyboards, voice recognition

Prevention

Since the exact cause of ALS remains unknown for most cases, there are no proven prevention strategies. However, some lifestyle modifications may potentially reduce risk:

• Avoid smoking: Current smoking associated with increased risk
• Limit exposure to toxins:
  • Use protective equipment with chemicals
  • Minimize pesticide exposure
  • Avoid heavy metal exposure
• Maintain overall health:
  • Regular moderate exercise
  • Balanced nutrition
  • Adequate vitamin D levels
• Head injury prevention: Use appropriate safety equipment
• Genetic counseling: For those with family history
• Participate in research:
  • Clinical trials
  • Biomarker studies
  • Genetic research
• Early intervention: Seek evaluation for concerning symptoms

When to See a Doctor

Early evaluation is important for accurate diagnosis and treatment planning. See a healthcare provider if you experience:

• Progressive weakness in hands, arms, or legs
• Persistent muscle twitching (fasciculations)
• Difficulty speaking or slurred speech
• Difficulty swallowing liquids or solids
• Frequent tripping or dropping objects
• Unexplained muscle cramps or stiffness
• Changes in voice quality
• Shortness of breath, especially when lying down

Seek specialized evaluation from a neurologist if:

• Symptoms progressively worsen over weeks to months
• Multiple symptoms occur together
• Family history of ALS or motor neuron disease
• Symptoms interfere with daily activities
• Primary care physician recommends neurological consultation

Related Conditions

Frequently Asked Questions

References

1. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017;377(2):162-172.
2. van Es MA, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084-2098.
3. Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918-1929.
4. Feldman EL, et al. Amyotrophic lateral sclerosis. Lancet. 2022;400(10360):1363-1380.
5. Miller RG, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis. Neurology. 2009;73(15):1218-1226.