Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis
PaulWicks · CC BY-SA 4.0 · source
Name	Amyotrophic lateral sclerosis
Field	Neurology
Synonyms	ALS; Motor neuron disease; Lou Gehrig's disease
Symptoms	Progressive muscle weakness, fasciculations, dysarthria, dysphagia, respiratory failure
Complications	Respiratory failure, pneumonia, malnutrition, cognitive impairment
Onset	Mid to late adulthood
Causes	Genetic mutations (e.g., SOD1, C9orf72), environmental factors
Diagnosis	Clinical examination, electromyography, neuroimaging, genetic testing
Treatment	Riluzole, edaravone, multidisciplinary care, supportive therapies
Prognosis	Median survival 3–5 years from symptom onset

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder affecting upper and lower motor neurons, leading to muscle weakness, atrophy, and eventual respiratory failure. First described in the 19th century and popularized in the 20th century by public figures, the disease has been studied across neurology, genetics, and rehabilitation medicine. Management emphasizes multidisciplinary supportive care while research explores genetic, molecular, and immunologic mechanisms.

Signs and symptoms

Early clinical features include asymmetric limb weakness and muscle wasting, often beginning in a hand or foot, accompanied by muscle fasciculations and cramps. Patients develop progressive dysarthria and dysphagia as bulbar motor neurons are involved, and respiratory compromise emerges later, necessitating noninvasive ventilation in advanced stages. Cognitive and behavioral changes consistent with frontotemporal dementia can occur, producing executive dysfunction, language impairment, and behavioral disinhibition noted in some cohorts. Physical examination shows combined upper motor neuron signs (spasticity, hyperreflexia, Babinski sign) and lower motor neuron signs (atrophy, fasciculations), which inform referral to specialists and allied health teams.

Causes and pathophysiology

Both sporadic and familial forms exist, with pathogenic variants in genes such as SOD1, C9orf72, TARDBP, and FUS implicated in familial cases. Molecular mechanisms proposed include protein misfolding and aggregation, RNA metabolism dysfunction, impaired axonal transport, excitotoxicity mediated by glutamate, mitochondrial dysfunction, and neuroinflammation involving microglia and astrocytes. Environmental associations have been investigated in veterans, athletes, and clusters in specific regions, prompting study of toxins, heavy metals, smoking, and occupational exposures. Pathological hallmarks include degeneration of corticospinal tracts and anterior horn cells, with inclusions containing TDP-43 or other aberrant proteins documented at autopsy.

Diagnosis

Diagnosis rests on clinical criteria supported by electrophysiology and imaging; recognized frameworks such as the El Escorial and Awaji criteria combine upper and lower motor neuron signs across regions. Electromyography demonstrates ongoing denervation and reinnervation, while MRI of the brain and spinal cord is used to exclude mimics such as cervical spondylotic myelopathy, multiple sclerosis, or structural lesions. Laboratory testing, including serum and cerebrospinal fluid studies, evaluates metabolic, infectious, and autoimmune differentials; targeted genetic testing is offered when family history or phenotype suggests inherited forms. Neurologists collaborate with speech-language pathologists, pulmonologists, and genetic counselors to confirm diagnosis and plan care.

Management and treatment

There is no cure; disease-modifying agents approved in some jurisdictions include riluzole and edaravone, which modestly affect survival or functional decline. Multidisciplinary clinics coordinate interventions from physiotherapy, occupational therapy, and speech therapy to preserve function, prevent complications, and implement assistive devices such as wheelchairs, communication aids, and percutaneous gastrostomy. Respiratory management uses noninvasive ventilation and, when chosen, invasive ventilation via tracheostomy; palliative care and advance care planning are integral, involving ethics consultations when needed. Symptom-directed pharmacotherapy addresses spasticity, sialorrhea, pain, pseudobulbar affect, and mood disorders, and caregivers receive training through home health services and social work support.

Prognosis and complications

Prognosis varies; median survival is often cited as 3–5 years from symptom onset, though a subset of patients experiences slower progression over a decade or more. Respiratory failure is the most common cause of mortality, with aspiration pneumonia, malnutrition, and immobility-related complications contributing to morbidity. Cognitive impairment linked to frontotemporal dementia correlates with altered decision-making and caregiver burden. Prognostic indicators include age at onset, site of onset (bulbar onset has poorer prognosis), rapid early progression, and presence of respiratory compromise at presentation.

Epidemiology

Incidence rates vary internationally, commonly reported around 1–3 per 100,000 person-years, with prevalence estimates influenced by survival duration. The disorder primarily affects adults, with peak incidence in middle to late adulthood; familial forms account for approximately 5–10% of cases, while the remainder are sporadic. Epidemiological studies have examined geographic clusters, veteran cohorts, and population differences across continents, prompting registries and surveillance programs in multiple countries to track trends and risk factors.

Research directions and experimental therapies

Active research spans gene therapy, antisense oligonucleotides targeting SOD1 and C9orf72, stem cell–based approaches, immunomodulatory strategies, and small molecules addressing proteostasis, RNA processing, and mitochondrial function. Clinical trials involve biomarkers from neurofilament light chain assays, advanced neuroimaging, and electrophysiologic metrics to evaluate therapeutic effect and stratify participants. Collaborative consortia, patient advocacy organizations, and industry partners drive translational efforts and adaptive trial designs to accelerate candidate therapies toward regulatory review and clinical implementation.

Category:Neurodegenerative disorders