Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with a life expectancy of approximately 3 years after symptom onset, but the range of survival extends from a few months for some to decades for approximately 5% of patients. There is no clear cause in the majority of cases and just one medication, riluzole, has been shown to modestly prolong survival. Research has identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, generation of free radicals, excitotoxicity, inflammation and apoptosis, but for most patients the underlying cause is unknown. While ALS is considered to be a complex genetic disorder in which multiple genes in combination with environmental exposures combine to render a person susceptible, few genetic or environmental risks have been discovered to date. The diagnosis is based on the history and examination showing progressive upper and lower motor neuron findings. The electromyogram can help confirm the diagnosis, and additional tests are used to exclude other conditions. Published practice parameters guide the care of patients with ALS. Until the elucidation of aetiologies leads to the development of more robust neuroprotective agents, both pharmacological and nonpharmacological treatments are directed at maintaining quality of life and prolonging life to the greatest extent possible. Riluzole, ventilatory support for those with respiratory insufficiency, gastrostomy for those with dysphagia and multidisciplinary care may help extend life. The off-label use of many symptomatic agents can have a meaningful impact for those with the illness. Palliative care ensures dignity toward the end stages of the disease. Clinical trials currently aim to slow disease progression by testing drugs that impact one or more of the processes that are initiated after disease onset. Novel therapies currently in trials include potential neuroprotective agents with differing mechanisms of action, vaccine therapies, stem cell injections and diaphragmatic pacing.