amyotrophic lateral sclerosis

amyotrophic lateral sclerosis
Name	Amyotrophic lateral sclerosis
Synonyms	Lou Gehrig's disease, motor neurone disease (MND)
Caption	Diagram showing upper and lower motor neuron degeneration
Field	Neurology
Symptoms	Muscle stiffness, twitching, weakness, slurred speech
Complications	Respiratory failure, Pneumonia, Malnutrition
Onset	Typically 50s–60s
Duration	Progressive
Types	Sporadic, Familial
Causes	Unknown (most), genetic (minority)
Risks	Ageing, Smoking, Military service
Diagnosis	Based on symptoms, Electromyography, Nerve conduction study
Differential	Multifocal motor neuropathy, Kennedy's disease, Cervical spondylotic myelopathy
Treatment	Riluzole, Edaravone, Sodium phenylbutyrate/taurursodiol, Non-invasive ventilation
Prognosis	2–5 year median survival from onset
Frequency	1–2 per 100,000 per year
Deaths	~5 per 100,000 per year

amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord. This leads to muscle weakness, paralysis, and ultimately respiratory failure. The disease is also known as Lou Gehrig's disease, named after the famous New York Yankees baseball player. While most cases occur sporadically, about 5-10% are familial, linked to genetic mutations.

Signs and symptoms

Initial symptoms vary but often include muscle weakness, fasciculations, and cramps in a limb. As the disease progresses, individuals develop spasticity, hyperreflexia, and Babinski sign. Bulbar onset ALS affects muscles of the head and neck, leading to dysarthria, dysphagia, and sialorrhea. The disease typically spares sensory neurons, oculomotor muscles, and sphincter control until very late stages. Cognitive and behavioral changes, often overlapping with frontotemporal dementia, occur in a significant minority.

Causes

The majority of cases are sporadic with no clear cause, though ageing is the greatest risk factor. Known environmental risk factors include smoking and a history of military service, particularly in the Gulf War. Familial ALS, accounting for 5-10% of cases, is usually inherited in an autosomal dominant pattern. Over 30 genes have been implicated, with mutations in C9orf72, SOD1, TARDBP, and FUS being the most common. The Centers for Disease Control and Prevention and the National Institutes of Health continue to fund research into potential causes.

Pathophysiology

The core pathology is the selective degeneration of upper motor neurons in the motor cortex and lower motor neurons in the brainstem and anterior horn of the spinal cord. Hallmarks include intracellular inclusions of misfolded proteins like TDP-43 and ubiquitin. Proposed mechanisms of neuronal death include excitotoxicity mediated by glutamate, oxidative stress, mitochondrial dysfunction, defective RNA metabolism, and impaired protein homeostasis. Glial cells, including astrocytes and microglia, contribute to a toxic inflammatory microenvironment.

Diagnosis

Diagnosis is primarily clinical, based on the presence of both upper and lower motor neuron signs in multiple body regions. Key supportive tests include electromyography and nerve conduction study to confirm lower motor neuron involvement and rule out mimics. Magnetic resonance imaging of the brain and spinal cord is used to exclude structural lesions like tumors or cervical spondylotic myelopathy. Diagnostic criteria, such as the revised El Escorial criteria, are used to define certainty of diagnosis. Genetic testing is recommended for those with a family history.

Management

There is no cure, so management focuses on slowing progression, symptom relief, and maintaining quality of life. Disease-modifying therapies include riluzole, edaravone, and sodium phenylbutyrate/taurursodiol. Multidisciplinary care in specialized clinics, involving neurologists, pulmonologists, and physical therapists, is standard. Non-invasive ventilation is critical for managing hypoventilation. Other interventions include percutaneous endoscopic gastrostomy for nutrition, medications for spasticity and sialorrhea, and advanced communication aids. The Food and Drug Administration has approved several therapies through accelerated pathways.

Prognosis

Prognosis is poor, with a median survival of 2 to 5 years from symptom onset. The rate of progression is variable; factors associated with shorter survival include older age at onset, bulbar onset, and short interval from onset to diagnosis. Death is usually due to respiratory failure or complications like pneumonia. Long-term survivors, such as Stephen Hawking, are exceptional and often have distinct clinical phenotypes. Prognostic discussions are a key part of care planning with patients and families.

Epidemiology

ALS has an annual incidence of 1 to 2 cases per 100,000 people and a prevalence of 4 to 6 per 100,000. Incidence increases with age, peaking between 50 and 75 years, and is slightly more common in males. Sporadic ALS accounts for 90-95% of cases globally. Certain clusters, like in the Western Pacific (Guam, Kii Peninsula), have been historically noted. Major registries, including the National ALS Registry in the United States and the European ALS Consortium, work to track epidemiology and facilitate research.

Category:Neurodegenerative disorders Category:Motor neuron diseases Category:Rare diseases