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Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis – Clinical Features, Pathophysiology and Management Christophe Coupé 1 and Paul H Gordon 2 1. Clinician Psychologist; 2. Visiting Neurologist and Researcher, Centre référent maladie rare SLA, Département des Maladies du Système Nerveux, Hôpital de la Pitié-Salpêtrière, Paris, France Abstract Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot 145 years ago, is an age-related neurodegenerative disorder that leads to destruction of motor neurons. The disease begins focally in the central nervous system then spreads inexorably. The clinical diagnosis, defined by progressive upper and lower motor neuron findings, is confirmed by electromyogram. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of progressive weakness and respiratory failure less than 3 years from symptom onset. Like other neurodegenerative diseases, ALS is thought to have genetic and environmental causes. Five to 10  % of cases are inherited. Genetic factors, age, tobacco use and athleticism may contribute to sporadic ALS, but major causes are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. One medication, riluzole, which was approved in 1996, prolongs survival by several months. Numerous ensuing clinical trials have been negative. Researchers currently aim to slow disease progression by targeting known pathophysiological pathways. Approaches under examination are directed at muscle protein, energetic balance, cell replacement and protein aggregation. Until the causes and more robust neuroprotective agents are identified, symptomatic therapies can help improve expectancy and quality of life. Palliative care ensures dignity in advanced stages. Keywords Amyotrophic lateral sclerosis, neurodegeneration, epidemiology, pathophysiology, diagnosis, treatment Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: We thank Professor Vincent Meininger, the director of the Paris ALS Centre in the tradition of Charcot, for his leadership, dedication to this difficult disease and friendship. Received: 22 April 2013 Accepted: 26 April 2013 Citation: European Neurological Review, 2013;8(1):38–44 Correspondence: Paul H Gordon, Département des Maladies du Système Nerveux, Centre référent maladie rare SLA, Hôpital de la Pitié-Salpêtrière, 47-83, Boulevard de l’Hôpital, 75651, Paris France, Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of upper (UMN) and lower (LMN) motor neurons in the brain and spinal cord. Rare in its own right, ALS is the most common form of motor neuron disease (MND). Primary lateral sclerosis, a disease isolated to UMNs, makes up 1–3 %, and progressive muscular atrophy, limited to LMNs, approximately 10  % of MND. Predominance of UMN features probably carries a better prognosis, even for patients with ALS. 1 Incidence rates for ALS range from 1.2–4.0 per 100,000 person years in Caucasians. 2–5 The rate may be lower in some minority populations 6 and historically as much as 100 times higher in the western Pacific (Guam, Japan’s Kii Peninsula, western New Guinea). 7 Incidence increases with age, peaking between 70 and 80 years and is thought to be more common in men than women. 8,9 ALS begins in limb or bulbar muscles and then spreads to contiguous and eventually respiratory, myotomes. Survival ranges from months to decades, but is usually less than 3 years from when symptoms first appear. 10 Jean-Martin Charcot, the father of neurology, used the clinico- anatomical method that he devised to describe the clinical and pathological features of ALS during series of lectures in the 1860s and 1870s. 11 The methodology available to Charcot was primitive by today’s standards, but his approach was so insightful, becoming the 38 foundation of the field he formed, that his original descriptions are considered accurate today. Sir William Gowers and Lord Russell Brain made major contributions in the UK, labelling the malady MND instead of ALS because they believed that all patients have pathology of both UMNs and LMNs, either during life or at autopsy. Few American neurologists early in the 20th Century meant that the illness was largely overlooked in the New World until 1939 when the notable first baseman for the New York Yankees was diagnosed with ALS. Called the “iron horse” for playing 2,130 consecutive games over 14 years, Gehrig first exhibited signs in 1938. 12,13 Several weeks into the 1939 season, he removed himself from the lineup, no longer able to play. Gehrig died two years later, having participating in an early clinical trial. 14 ALS still uses Gehrig’s name as its eponym in the US; MND is used in the UK, whereas ALS is preferred in France and the US. ALS is almost as mysterious today as it was in the first part of the 20th Century. There are no known causes for most patients and no cures. Genetic mutations account for some of the 5–10  % of cases that are inherited (familial ALS [fALS]), usually in a Mendelian trait. Sporadic ALS (sALS) is thought to have both genetic and environmental influences, but the principle causes await discovery. Once the disease begins, a number of processes transpire in both neurons and surrounding glial cells; how these processes interact is an area of active research. 15 As in other © Touch M Edi cal ME d ia 2013