Array ( [0] => {{Short description|Rare neurodegenerative disease}} [1] => {{About|the neurodegenerative disease|other uses|ALS (disambiguation)}} [2] => {{Redirect-multi|2|Motor neuron disease|Motor neurone disease|a group of muscle-wasting disorders|Motor neuron diseases}} [3] => {{Good article}} [4] => {{Use dmy dates|date=September 2020}} [5] => {{infobox medical condition (new) [6] => | name = Amyotrophic lateral sclerosis [7] => | synonyms = {{ubl|Motor neurone disease (MND)|[[Lou Gehrig]]'s disease|[[Jean-Martin Charcot|Charcot's disease]]}} [8] => | image = ALS Affected neurons and muscles.png [9] => | caption = Parts of the [[nervous system]] affected by ALS, causing progressive symptoms in [[skeletal muscles]] throughout the body [10] => | field = [[Neurology]] [11] => | symptoms = '''Early''': [[spasticity|Stiff muscles]], [[fasciculation|muscle twitches]], gradual increasing weakness
'''Later''': Difficulty in [[dysarthria|speaking]], [[dysphagia|swallowing]], and [[shortness of breath|breathing]]; [[respiratory failure]] 10–15% experience [[frontotemporal dementia]] [12] => | complications = [[Falling (accident)]]; [[Respiratory failure]]; [[Pneumonia]]; [[Malnutrition]] [13] => | onset = 45–75 years [14] => | duration = [15] => | causes = Unknown (about 85%), genetic (about 15%) [16] => | risks = Genetic risk factors; age; [[Male|male sex]]; heavy metals; organic chemicals; smoking; electric shock; physical exercise; head injury [17] => | diagnosis = Clinical diagnosis of exclusion based on progressive symptoms of upper and lower motor neuron degeneration in which no other explanation can be found. Supportive evidence from [[electromyography]], [[genetic testing]], and [[neuroimaging]] [18] => | differential = [[Multifocal motor neuropathy]], [[Kennedy's disease]], [[Hereditary spastic paraplegia]], [[Nerve compression syndrome]], [[Diabetic neuropathy]], [[Post-polio syndrome]], [[Myasthenia gravis]], [[Multiple sclerosis]]{{cite journal | vauthors = Kwan J, Vullaganti M | title = Amyotrophic lateral sclerosis mimics | journal = Muscle & Nerve | volume = 66 | issue = 3 | pages = 240–252 | date = September 2022 | pmid = 35607838 | doi = 10.1002/mus.27567 | s2cid = 249014375 }} [19] => | prevention = [20] => | treatment = [[Walker (mobility)]]; [[Wheelchair]]; [[Non-invasive ventilation]]; [[Feeding tube]]; [[Augmentative and alternative communication]]; symptomatic management [21] => | medication = [[Riluzole]], [[Edaravone]], [[Sodium phenylbutyrate/ursodoxicoltaurine]], [[Tofersen]], [[Dextromethorphan/quinidine]] [22] => | prognosis = Life expectancy highly variable but typically 2–4 years after diagnosis{{cite journal | vauthors = Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, Feldman EL | title = Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis | journal = The Lancet. Neurology | volume = 21 | issue = 5 | pages = 480–493 | date = May 2022 | pmid = 35334233 | pmc = 9513753 | doi = 10.1016/S1474-4422(21)00465-8 }} [23] => | frequency = {{Plain list| [24] => * Incidence: 1.6/100,000 individuals per year [25] => * Prevalence: 4.4/100,000 living individuals [26] => * Lifetime risk: 1 in 400 individuals{{cite journal | vauthors = Ryan M, Heverin M, McLaughlin RL, Hardiman O | title = Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis | journal = JAMA Neurology | volume = 76 | issue = 11 | pages = 1367–1374 | date = November 2019 | pmid = 31329211 | pmc = 6646974 | doi = 10.1001/jamaneurol.2019.2044 }} [27] => }} [28] => | deaths = [29] => | alt = Diagram of a human nervous system highlighting the brain, spinal cord, motor neurons, and muscles of the body affected by ALS [30] => }} [31] => [32] => [33] => '''Amyotrophic lateral sclerosis''' ('''ALS'''), also known as '''motor neurone disease''' ('''MND''') or '''Lou Gehrig's disease''' in the United States, is a rare but terminal [[neurodegenerative disease|neurodegenerative disorder]] that results in the progressive loss of both upper and lower [[motor neuron]]s that normally control [[Skeletal muscle|voluntary muscle]] contraction. ALS is the most common form of the [[motor neuron diseases]].{{Cite web |title=Motor Neuron Diseases Fact Sheet |url=https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/motor-neuron-diseases-fact-sheet |url-status=live |archive-url=https://web.archive.org/web/20201010105651/https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Motor-Neuron-Diseases-Fact-Sheet |archive-date=10 October 2020 |access-date=27 October 2020 |website=www.ninds.nih.gov |publisher=National Institute of Neurological Disorders and Stroke}} ALS often presents in its early stages with gradual muscle [[Spasticity|stiffness]], [[Fasciculation|twitches]], [[Muscle weakness|weakness]], and [[Muscle atrophy|wasting]].{{Cite web |title=Amyotrophic Lateral Sclerosis (ALS) Fact Sheet |url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet |url-status=live |archive-url=https://web.archive.org/web/20170105002627/http://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet |archive-date=5 January 2017 |access-date=22 October 2020 |publisher=National Institute of Neurological Disorders and Stroke}} Motor neuron loss typically continues until the abilities to eat, speak, move, and, lastly, breathe are all lost. While only 15% of people with ALS also fully develop [[frontotemporal dementia]], an estimated 50% face at least some minor difficulties with [[cognitive disorder|thinking]] and [[behavior]].{{cite journal |vauthors=van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, van den Berg LH |date=November 2017 |title=Amyotrophic lateral sclerosis |journal=Lancet |volume=390 |issue=10107 |pages=2084–2098 |doi=10.1016/S0140-6736(17)31287-4 |pmid=28552366 |s2cid=24483077}} Depending on which of the aforementioned symptoms develops first, ALS is classified as ''limb-onset'' (begins with weakness in the arms or legs) or ''bulbar-onset'' (begins with difficulty in [[dysarthria|speaking]] or [[dysphagia|swallowing]]).{{cite journal |display-authors=6 |vauthors=Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH |date=October 2017 |title=Amyotrophic lateral sclerosis |url=http://eprints.whiterose.ac.uk/122838/1/WR_ALS-Hardiman_V3_EDITED_FOR_AUTHOR_APPROVAL_FINAL_APPROVED-1.pdf |url-status=live |journal=Nature Reviews. Disease Primers |volume=3 |issue=17071 |pages=17071 |doi=10.1038/nrdp.2017.71 |pmid=28980624 |s2cid=1002680 |archive-url=https://web.archive.org/web/20201201185718/http://eprints.whiterose.ac.uk/122838/1/WR_ALS-Hardiman_V3_EDITED_FOR_AUTHOR_APPROVAL_FINAL_APPROVED-1.pdf |archive-date=1 December 2020 |access-date=20 December 2019}} [34] => [35] => [36] => Most cases of ALS (about 90% to 95%) have [[idiopathic|no known cause]], and are known as ''sporadic ALS''.{{cite web |title=Understanding ALS |url=https://www.als.org/understanding-als |publisher=The ALS Association |language=en |access-date=28 October 2020 |archive-date=26 October 2020 |archive-url=https://web.archive.org/web/20201026133033/https://www.als.org/understanding-als |url-status=live}} However, both [[genetics|genetic]] and [[environmental factors]] are believed to be involved.{{cite journal | vauthors = Wingo TS, Cutler DJ, Yarab N, Kelly CM, Glass JD | title = The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27985 | year = 2011 | pmid = 22132186 | pmc = 3222666 | doi = 10.1371/journal.pone.0027985 | bibcode = 2011PLoSO...627985W | doi-access = free }} The remaining 5% to 10% of cases have a genetic cause, often linked to a [[Family history (medicine)|history of the disease in the family]], and these are known as ''familial ALS'' (hereditary).{{cite web |title=Amyotrophic lateral sclerosis |url=https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis/ |website=MedlinePlus Genetics |access-date=7 August 2023 |language=en}} About half of these genetic cases are due to disease-causing variants in one of four specific [[gene]]s. The [[diagnosis]] is based on a person's [[signs and symptoms]], with testing conducted to rule out other potential causes. [37] => [38] => [39] => There is no known cure for ALS. The goal of treatment is to slow the disease progression, and improve symptoms. Treatments that slow ALS include [[riluzole]] (extends life by two to three months) and [[sodium phenylbutyrate/ursodoxicoltaurine]] (extends life by around seven months).{{cite journal | vauthors = Heo YA | title = Sodium Phenylbutyrate and Ursodoxicoltaurine: First Approval | journal = CNS Drugs | volume = 36 | issue = 9 | pages = 1007–1013 | date = September 2022 | pmid = 35907175 | doi = 10.1007/s40263-022-00945-x | s2cid = 251162676 | url = https://figshare.com/articles/online_resource/Sodium_Phenylbutyrate_and_Ursodoxicoltaurine_First_Approval/20327265 }} [[Non-invasive ventilation]] may result in both improved quality, and length of life.{{cite journal | vauthors = Hobson EV, McDermott CJ | title = Supportive and symptomatic management of amyotrophic lateral sclerosis | journal = Nature Reviews. Neurology | volume = 12 | issue = 9 | pages = 526–538 | date = September 2016 | pmid = 27514291 | doi = 10.1038/nrneurol.2016.111 | url = http://eprints.whiterose.ac.uk/104445/1/16.pdf | access-date = 20 December 2019 | url-status = live | s2cid = 8547381 | archive-url = https://web.archive.org/web/20201201183335/http://eprints.whiterose.ac.uk/104445/1/16.pdf | archive-date = 1 December 2020 }} [[Mechanical ventilation]] can prolong survival but does not stop disease progression.{{cite journal | vauthors = Soriani MH, Desnuelle C | title = Care management in amyotrophic lateral sclerosis | journal = Revue Neurologique | volume = 173 | issue = 5 | pages = 288–299 | date = May 2017 | pmid = 28461024 | doi = 10.1016/j.neurol.2017.03.031 }} A [[feeding tube]] may help maintain weight and nutrition.{{cite journal | vauthors = Connolly S, Galvin M, Hardiman O | title = End-of-life management in patients with amyotrophic lateral sclerosis | journal = The Lancet. Neurology | volume = 14 | issue = 4 | pages = 435–442 | date = April 2015 | pmid = 25728958 | doi = 10.1016/S1474-4422(14)70221-2 | s2cid = 34109901 }} Death is usually caused by respiratory failure.{{cite journal | vauthors = Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC | display-authors = 6 | title = Amyotrophic lateral sclerosis | journal = Lancet | volume = 377 | issue = 9769 | pages = 942–955 | date = March 2011 | pmid = 21296405 | doi = 10.1016/s0140-6736(10)61156-7 | doi-access = free }} The disease can affect people of any age, but usually starts around the age of 60. The average survival from onset to death is two to four years, though this can vary, and about 10% of those affected survive longer than ten years.{{cite journal | vauthors = Pupillo E, Messina P, Logroscino G, Beghi E | title = Long-term survival in amyotrophic lateral sclerosis: a population-based study | journal = Annals of Neurology | volume = 75 | issue = 2 | pages = 287–297 | date = February 2014 | pmid = 24382602 | doi = 10.1002/ana.24096 | s2cid = 205345019 }} [40] => [41] => [42] => Descriptions of the disease date back to at least 1824 by [[Charles Bell]]. In 1869, the connection between the symptoms and the underlying neurological problems was first described by French neurologist [[Jean-Martin Charcot]], who in 1874 began using the term ''amyotrophic lateral sclerosis''.{{cite journal | vauthors = Rowland LP | title = How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot | journal = Archives of Neurology | volume = 58 | issue = 3 | pages = 512–515 | date = March 2001 | pmid = 11255459 | doi = 10.1001/archneur.58.3.512 }} [43] => {{TOC limit|3}} [44] => [45] => ==Classification== [46] => ALS is a [[motor neuron diseases|motor neuron disease]], which is a group of [[neurological disorder]]s that selectively affect [[motor neuron]]s, the cells that control [[Skeletal muscle|voluntary muscles]] of the body. Other motor neuron diseases include [[primary lateral sclerosis]] (PLS), [[progressive muscular atrophy]] (PMA), [[progressive bulbar palsy]], [[pseudobulbar palsy]], and [[monomelic amyotrophy]] (MMA).{{cite web|url=https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/661720689|title=8B60 Motor neuron disease|website=ICD-11 for Mortality and Morbidity Statistics|publisher=World Health Organization|access-date=2019-01-24|archive-date=1 August 2018|archive-url=https://archive.today/20180801205234/https://icd.who.int/browse11/l-m/en%23/http://id.who.int/icd/entity/294762853#/http://id.who.int/icd/entity/661720689|url-status=live}} [47] => [48] => As a disease, ALS itself can be classified in a few different ways: by which part of the motor neurons are affected; by the parts of the body first affected; whether it is genetic; and the age at which it started. Each individual diagnosed with the condition will sit at a unique place at the intersection of these complex and overlapping subtypes, which presents a challenge to diagnosis, understanding, and prognosis.{{cite journal | vauthors = van Eenennaam RM, Koppenol LS, Kruithof WJ, Kruitwagen-van Reenen ET, Pieters S, van Es MA, van den Berg LH, Visser-Meily JM, Beelen A | display-authors = 6 | title = Discussing Personalized Prognosis Empowers Patients with Amyotrophic Lateral Sclerosis to Regain Control over Their Future: A Qualitative Study | journal = Brain Sciences | volume = 11 | issue = 12 | pages = 1597 | date = November 2021 | pmid = 34942899 | pmc = 8699408 | doi = 10.3390/brainsci11121597 | doi-access = free }} [49] => [50] => ===Subtypes of motor neuron disease=== [51] => [[File:Illustration of the motor neuron tract descending from primary motor cortex, via spinal cord, to skeletal muscle.jpg|thumb|Classic ALS involves neurons in the brain and spinal cord ([[upper motor neuron]]s, highlighted red), as well as the [[lower motor neuron]]s, which go from the spinal cord to the muscles, highlighted teal.{{cite journal | vauthors = Grad LI, Rouleau GA, Ravits J, Cashman NR | title = Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS) | journal = Cold Spring Harbor Perspectives in Medicine | volume = 7 | issue = 8 | page = a024117 | date = August 2017 | pmid = 28003278 | pmc = 5538408 | doi = 10.1101/cshperspect.a024117 | doi-access = free }} ]] [52] => ALS can be classified by the types of motor neurons that are affected. To successfully control any voluntary muscle in the body, a signal must be sent from the [[motor cortex]] in the brain down the [[upper motor neuron]] as it travels down the spinal cord. There, it connects via a [[synapse]] to the [[lower motor neuron]] which connects to the muscle itself. Damage to either the upper or lower motor neuron, as it makes its way from the brain to muscle, causes different types of symptoms. Damage to the upper motor neuron typically causes [[spasticity]] including stiffness and increased [[tendon reflex]]es, and/or [[clonus]], while damage to the lower motor neuron typically causes [[muscle weakness|weakness]], [[Muscular atrophy#Pathophysiology|muscle atrophy]], and [[fasciculation]]s.{{cite book | vauthors = Arora RD, Khan YS | chapter = Motor Neuron Disease |date=2023 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK560774/ | title = StatPearls |access-date=2023-08-27 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32809609 }} [53] => [54] => Classical, or classic ALS, involves degeneration to both the [[upper motor neuron]]s in the brain and the [[lower motor neuron]]s in the spinal cord. [[Primary lateral sclerosis]] (PLS) involves degeneration of only the upper motor neurons, and [[progressive muscular atrophy]] (PMA) involves only the lower motor neurons. There is debate over whether PLS and PMA are separate diseases or simply variants of ALS. [55] => {| class="wikitable" [56] => |+ [57] => !Main ALS Subtypes [58] => ![[Upper motor neuron]] degeneration [59] => ![[Lower motor neuron]] degeneration [60] => |- [61] => |Classical ALS [62] => |Yes [63] => |Yes [64] => |- [65] => |Primary lateral sclerosis (PLS) [66] => |Yes [67] => |No [68] => |- [69] => |Progressive muscular atrophy (PMA) [70] => |No [71] => |Yes [72] => |} [73] => Classical ALS accounts for about 70% of all cases of ALS and can be subdivided into where symptoms first appear as these are usually focussed to one region of the body at initial presentation before later spread. ''Limb-onset'' ALS (also known as spinal-onset) and ''bulbar-onset'' ALS. Limb-onset ALS begins with weakness in the hands, arms, feet, and/or legs and accounts for about two-thirds of all classical ALS cases. Bulbar-onset ALS begins with weakness in the muscles of speech, chewing, and swallowing and accounts for about 25% of classical ALS cases. A rarer type of classical ALS affecting around 3% of patients is respiratory-onset, in which the initial symptoms are difficulty breathing ([[dyspnea]]) upon exertion, at rest, or while lying flat ([[orthopnea]]).{{cite journal | vauthors = Gautier G, Verschueren A, Monnier A, Attarian S, Salort-Campana E, Pouget J | title = ALS with respiratory onset: clinical features and effects of non-invasive ventilation on the prognosis | journal = Amyotrophic Lateral Sclerosis | volume = 11 | issue = 4 | pages = 379–382 | date = August 2010 | pmid = 20001486 | doi = 10.3109/17482960903426543 | s2cid = 27672209 }} [74] => [75] => [[Primary lateral sclerosis]] (PLS) is a subtype of the overall ALS category which accounts for about 5% of all cases and only affects the upper motor neurons in the arms, legs, and bulbar region.{{cite journal | vauthors = Swinnen B, Robberecht W | title = The phenotypic variability of amyotrophic lateral sclerosis | journal = Nature Reviews. Neurology | volume = 10 | issue = 11 | pages = 661–670 | date = November 2014 | pmid = 25311585 | doi = 10.1038/nrneurol.2014.184 | url = https://lirias.kuleuven.be/handle/123456789/469667 | url-status = live | access-date = 22 August 2018 | s2cid = 205516010 | archive-url = https://web.archive.org/web/20181231043137/https://limo.libis.be/primo-explore/fulldisplay?docid=LIRIAS548693&context=L&vid=Lirias&search_scope=Lirias&tab=default_tab&lang=en_US&fromSitemap=1 | archive-date = 31 December 2018 }} However, more than 75% of people with apparent PLS go on to later develop lower motor neuron signs within four years of symptom onset, meaning that a definitive diagnosis of PLS cannot be made until several years have passed.{{cite journal | vauthors = Al-Chalabi A, Hardiman O, Kiernan MC, Chiò A, Rix-Brooks B, van den Berg LH | title = Amyotrophic lateral sclerosis: moving towards a new classification system | journal = The Lancet. Neurology | volume = 15 | issue = 11 | pages = 1182–1194 | date = October 2016 | pmid = 27647646 | doi = 10.1016/S1474-4422(16)30199-5 | hdl-access = free | s2cid = 45285510 | hdl = 2318/1636249 }} PLS has a better prognosis than classical ALS, as it progresses slower, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss than classical ALS. [76] => [77] => [[Progressive muscular atrophy]] (PMA) is another subtype that accounts for about 5% of the overall ALS category and affects lower motor neurons in the arms, legs, and bulbar region. While PMA is associated with longer survival on average than classical ALS, it is still progressive over time, eventually leading to respiratory failure and death. As with PLS developing into classical ALS, PMA can also develop into classical ALS over time if the lower motor neuron involvement progresses to include upper motor neurons, in which case the diagnosis might be changed to classic ALS. [78] => [79] => ===Rare isolated variants of ALS=== [80] => Isolated variants of ALS have symptoms that are limited to a single region for at least a year; they progress more slowly than classical ALS and are associated with longer survival. These regional variants of ALS can only be considered as a diagnosis should the initial symptoms fail to spread to other spinal cord regions for an extended period of time (at least 12 months).{{cite journal | vauthors = Jawdat O, Statland JM, Barohn RJ, Katz JS, Dimachkie MM | title = Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis) | journal = Neurologic Clinics | volume = 33 | issue = 4 | pages = 775–785 | date = November 2015 | pmid = 26515621 | pmc = 4629514 | doi = 10.1016/j.ncl.2015.07.003 }} Flail arm syndrome is characterized by lower motor neuron damage affecting the arm muscles, typically starting with the upper arms symmetrically and progressing downwards to the hands.{{cite journal | vauthors = Masrori P, Van Damme P | title = Amyotrophic lateral sclerosis: a clinical review | journal = European Journal of Neurology | volume = 27 | issue = 10 | pages = 1918–1929 | date = October 2020 | pmid = 32526057 | pmc = 7540334 | doi = 10.1111/ene.14393 }} Flail leg syndrome is characterized by lower motor neuron damage leading to asymmetrical weakness and wasting in the legs starting around the feet. Isolated bulbar palsy is characterized by upper or lower motor neuron damage in the bulbar region (in the absence of limb symptoms for at least 20 months),{{cite journal | vauthors = Zhang H, Chen L, Tian J, Fan D | title = Disease duration of progression is helpful in identifying isolated bulbar palsy of amyotrophic lateral sclerosis | journal = BMC Neurology | volume = 21 | issue = 1 | pages = 405 | date = October 2021 | pmid = 34686150 | pmc = 8532334 | doi = 10.1186/s12883-021-02438-8 | doi-access = free }} leading to gradual onset of difficulty with speech ([[dysarthria]]) and swallowing ([[dysphagia]]). [81] => [82] => [[File:ALS subtypes UMN LMN distribution.png|thumb|Illustration showing the range of upper and lower motor neuron involvement in the two most common types of ALS (top row) and three of the most common rare subtypes of ALS (bottom row)]] [83] => [84] => ===Age of onset=== [85] => ALS can also be classified based on the age of onset. While the peak age of onset is 58 to 63 for sporadic ALS and 47 to 52 for genetic ALS, about 10% of all cases of ALS begin before age 45 ("young-onset" ALS), and about 1% of all cases begin before age 25 ("juvenile" ALS). People who develop young-onset ALS are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of the disease. Juvenile ALS is more likely to be genetic in origin than adult-onset ALS; the most common genes associated with juvenile ALS are ''[[FUS (gene)|FUS]]'', ''[[ALS2]]'', and ''[[SETX]]''.{{cite journal | vauthors = Lehky T, Grunseich C | title = Juvenile Amyotrophic Lateral Sclerosis: A Review | journal = Genes | volume = 12 | issue = 12 | pages = 1935 | date = November 2021 | pmid = 34946884 | pmc = 8701111 | doi = 10.3390/genes12121935 | doi-access = free }} Although most people with juvenile ALS live longer than those with adult-onset ALS, some of them have specific mutations in [[FUS (gene)|FUS]] and ''[[SOD1]]'' that are associated with a poor prognosis.{{cite journal | vauthors = Teoh HL, Carey K, Sampaio H, Mowat D, Roscioli T, Farrar M | title = Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy | journal = Neural Plasticity | volume = 2017 | pages = 6509493 | date = 2017 | pmid = 28634552 | pmc = 5467325 | doi = 10.1155/2017/6509493 | doi-access = free }} Late onset (after age 65) is generally associated with a more rapid functional decline and shorter survival.{{cite journal | vauthors = Tard C, Defebvre L, Moreau C, Devos D, Danel-Brunaud V | title = Clinical features of amyotrophic lateral sclerosis and their prognostic value | journal = Revue Neurologique | volume = 173 | issue = 5 | pages = 263–272 | date = May 2017 | pmid = 28477850 | doi = 10.1016/j.neurol.2017.03.029 }} [86] => [87] => == Signs and symptoms == [88] => The disorder causes muscle weakness, [[atrophy]], and [[Spasticity|muscle spasms]] throughout the body due to the degeneration of the upper motor and lower motor neurons. [[Sensory neuron|Sensory nerves]] and the [[autonomic nervous system]] are generally unaffected, meaning the majority of people with ALS maintain [[hearing]], [[Visual perception|sight]], [[Somatosensory system|touch]], [[Olfaction|smell]], and [[taste]]. [89] => [90] => === Initial symptoms === [91] => The start of ALS may be so subtle that the symptoms are overlooked. The earliest symptoms of ALS are muscle weakness or muscle atrophy, typically on one side of the body. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first.{{cite journal | vauthors = Ravits J, Appel S, Baloh RH, Barohn R, Brooks BR, Elman L, Floeter MK, Henderson C, Lomen-Hoerth C, Macklis JD, McCluskey L, Mitsumoto H, Przedborski S, Rothstein J, Trojanowski JQ, van den Berg LH, Ringel S | display-authors = 6 | title = Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis | journal = Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration | volume = 14 | issue= Suppl 1 | pages = 5–18 | date = May 2013 | pmid = 23678876 | pmc = 3779649 | doi = 10.3109/21678421.2013.778548 }} [92] => [93] => In limb-onset ALS, the first symptoms are in the arms or the legs. If the legs are affected first, people may experience awkwardness, tripping, or stumbling when walking or running; this is often marked by walking with a "[[Foot drop|dropped foot]]" that drags gently on the ground. If the arms are affected first, they may experience difficulty with tasks requiring manual dexterity, such as buttoning a shirt, writing, or turning a key in a lock.{{cite web |date=15 January 2018 |title=Motor neurone disease |url=https://www.nhs.uk/conditions/motor-neurone-disease/ |url-status=live |archive-url=https://web.archive.org/web/20141229064258/http://www.nhs.uk/conditions/Motor-neurone-disease/Pages/Introduction.aspx |archive-date=29 December 2014 |access-date=24 October 2020 |publisher=National Health Service |language=en |location=UK}} [94] => [95] => In bulbar-onset ALS, the first symptoms are difficulty speaking or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty with swallowing and loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS, where the [[intercostal muscle]]s that support breathing are affected first. [96] => [97] => Over time, people experience increasing difficulty moving, swallowing ([[dysphagia]]), and speaking or forming words ([[dysarthria]]). Symptoms of upper motor neuron involvement include tight and stiff muscles ([[spasticity]]) and exaggerated reflexes ([[hyperreflexia]]), including an overactive gag reflex. While the disease does not cause pain directly, pain is a symptom experienced by most people with ALS caused by reduced mobility.{{cite journal | vauthors = Chiò A, Mora G, Lauria G | title = Pain in amyotrophic lateral sclerosis | journal = The Lancet. Neurology | volume = 16 | issue = 2 | pages = 144–157 | date = February 2017 | pmid = 27964824 | doi = 10.1016/S1474-4422(16)30358-1 | arxiv = 1607.02870 | s2cid = 38905437 }} Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin ([[fasciculation]]s). [98] => [99] => === Progression === [100] => Although the initial site of symptoms and subsequent rate of disability progression vary from person to person, the initially affected body region is usually the most affected over time, and symptoms usually spread to a neighbouring body region. For example, symptoms starting in one arm usually spread next to either the opposite arm or to the leg on the same side. Bulbar-onset patients most typically get their next symptoms in their arms rather than legs, arm-onset patients typically spreads to the legs before the bulbar region, and leg-onset patients typically spread to the arms rather than the bulbar region.{{cite journal | vauthors = Gromicho M, Figueiral M, Uysal H, Grosskreutz J, Kuzma-Kozakiewicz M, Pinto S, Petri S, Madeira S, Swash M, de Carvalho M | display-authors = 6 | title = Spreading in ALS: The relative impact of upper and lower motor neuron involvement | journal = Annals of Clinical and Translational Neurology | volume = 7 | issue = 7 | pages = 1181–1192 | date = July 2020 | pmid = 32558369 | pmc = 7359118 | doi = 10.1002/acn3.51098 }} Over time, regardless of where symptoms began, most people eventually lose the ability to walk or use their hands and arms independently. Less consistently, they may lose the ability to speak and to swallow food. It is the eventual development of weakness of the respiratory muscles, with the loss of ability to cough and to breathe without support, that is ultimately life-shortening in ALS. [101] => [102] => The rate of progression can be measured using the [[ALS Functional Rating Scale - Revised]] (ALSFRS-R), a 12-item instrument survey administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability).{{cite journal | vauthors = Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A | title = The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III) | journal = Journal of the Neurological Sciences | volume = 169 | issue = 1–2 | pages = 13–21 | date = October 1999 | pmid = 10540002 | doi = 10.1016/s0022-510x(99)00210-5 | s2cid = 7057926 }} The ALSFRS-R is the most frequently used outcome measure in clinical trials{{cite journal | vauthors = Wong C, Stavrou M, Elliott E, Gregory JM, Leigh N, Pinto AA, Williams TL, Chataway J, Swingler R, Parmar MK, Stallard N, Weir CJ, Parker RA, Chaouch A, Hamdalla H, Ealing J, Gorrie G, Morrison I, Duncan C, Connelly P, Carod-Artal FJ, Davenport R, Reitboeck PG, Radunovic A, Srinivasan V, Preston J, Mehta AR, Leighton D, Glasmacher S, Beswick E, Williamson J, Stenson A, Weaver C, Newton J, Lyle D, Dakin R, Macleod M, Pal S, Chandran S | display-authors = 6 | title = Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective | journal = Brain Communications | volume = 3 | issue = 4 | pages = fcab242 | date = 2021 | pmid = 34901853 | pmc = 8659356 | doi = 10.1093/braincomms/fcab242 }} and is used by doctors to track disease progression.{{cite journal | vauthors = Creemers H, Grupstra H, Nollet F, van den Berg LH, Beelen A | title = Prognostic factors for the course of functional status of patients with ALS: a systematic review | journal = Journal of Neurology | volume = 262 | issue = 6 | pages = 1407–1423 | date = June 2015 | pmid = 25385051 | doi = 10.1007/s00415-014-7564-8 | s2cid = 31734765 }} Though the degree of variability is high and a small percentage of people have a much slower progression, on average people with ALS lose about 1 ALSFRS-R point per month.{{cite journal | vauthors = Atassi N, Berry J, Shui A, Zach N, Sherman A, Sinani E, Walker J, Katsovskiy I, Schoenfeld D, Cudkowicz M, Leitner M | display-authors = 6 | title = The PRO-ACT database: design, initial analyses, and predictive features | journal = Neurology | volume = 83 | issue = 19 | pages = 1719–1725 | date = November 2014 | pmid = 25298304 | pmc = 4239834 | doi = 10.1212/WNL.0000000000000951 }} Brief periods of stabilization ("plateaus") and even small reversals in ALSFRS-R score are not uncommon, due to the fact the tool is subjective, can be affected by medication, and different forms of compensation for changes in function.{{cite journal | vauthors = Bedlack RS, Vaughan T, Wicks P, Heywood J, Sinani E, Selsov R, Macklin EA, Schoenfeld D, Cudkowicz M, Sherman A | display-authors = 6 | title = How common are ALS plateaus and reversals? | journal = Neurology | volume = 86 | issue = 9 | pages = 808–812 | date = March 2016 | pmid = 26658909 | pmc = 4793781 | doi = 10.1212/WNL.0000000000002251 }} However, it is rare (<1%) for these improvements to be large (i.e. greater than 4 ALSFRS-R points) or sustained (i.e. greater than 12 months). A survey-based study among clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful, which is the most common threshold used to determine whether a new treatment is working in clinical trials.{{cite journal | vauthors = Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Cudkowicz ME | title = Clinical significance in the change of decline in ALSFRS-R | journal = Amyotrophic Lateral Sclerosis | volume = 11 | issue = 1–2 | pages = 178–180 | year = 2010 | pmid = 19634063 | doi = 10.3109/17482960903093710 | type = Journal Article | s2cid = 207619689 }} [103] => [104] => === Late stage disease management === [105] => Difficulties with chewing and swallowing make eating very difficult ([[dysphagia]]) and increase the risk of choking or of [[Pulmonary aspiration|aspirating]] food into the lungs.{{cite journal | vauthors = Yunusova Y, Plowman EK, Green JR, Barnett C, Bede P | title = Clinical Measures of Bulbar Dysfunction in ALS | journal = Frontiers in Neurology | volume = 10 | pages = 106 | date = 2019 | pmid = 30837936 | pmc = 6389633 | doi = 10.3389/fneur.2019.00106 | doi-access = free }} In later stages of the disorder, [[aspiration pneumonia]] can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and [[intercostal muscle]]s of the [[rib cage]] that support breathing weaken, measures of [[Spirometry|lung function]] such as [[vital capacity]] and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, known as [[locked-in syndrome]]. Bladder and bowel function are usually spared, meaning [[Urinary incontinence|urinary]] and [[fecal incontinence]] are uncommon, although trouble getting to a toilet can lead to difficulties. The [[extraocular muscles]] responsible for eye movement are usually spared,{{cite journal | vauthors = Lui AJ, Byl NN | title = A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis | journal = Journal of Neurologic Physical Therapy | volume = 33 | issue = 2 | pages = 68–87 | date = June 2009 | pmid = 19556916 | doi = 10.1097/NPT.0b013e31819912d0 | s2cid = 7650356 | doi-access = free }} meaning the use of [[eye tracking]] technology to support [[Augmentative and alternative communication|augmentative communication]] is often feasible, albeit slow, and needs may change over time.{{cite journal | vauthors = Beukelman D, Fager S, Nordness A | title = Communication Support for People with ALS | journal = Neurology Research International | volume = 2011 | pages = 714693 | date = 2011 | pmid = 21603029 | pmc = 3096454 | doi = 10.1155/2011/714693 | doi-access = free }} Despite these challenges, many people in an advanced state of disease report satisfactory wellbeing and quality of life.{{cite journal | vauthors = Kuzma-Kozakiewicz M, Andersen PM, Ciecwierska K, Vázquez C, Helczyk O, Loose M, Uttner I, Ludolph AC, Lulé D | display-authors = 6 | title = An observational study on quality of life and preferences to sustain life in locked-in state | journal = Neurology | volume = 93 | issue = 10 | pages = e938–e945 | date = September 2019 | pmid = 31391247 | pmc = 6745736 | doi = 10.1212/WNL.0000000000008064 }} [106] => [107] => === Prognosis, staging, and survival === [108] => [109] => Although respiratory support using [[non-invasive ventilation]] can ease problems with breathing and prolong survival,{{cite journal | vauthors = O'Brien D, Stavroulakis T, Baxter S, Norman P, Bianchi S, Elliott M, Johnson M, Clowes M, Garcia-Sánchez A, Hobson E, McDermott C | display-authors = 6 | title = The optimisation of noninvasive ventilation in amyotrophic lateral sclerosis: a systematic review | journal = The European Respiratory Journal | volume = 54 | issue = 3 | pages = 1900261 | date = September 2019 | pmid = 31273038 | doi = 10.1183/13993003.00261-2019 | s2cid = 195805546 | doi-access = free }} it does not affect the progression rate of ALS. Most people with ALS die between two and four years after the diagnosis. Around 50% of people with ALS die within 30 months of their symptoms beginning, about 20% live between five and ten years, and about 10% survive for 10 years or longer. [110] => [111] => The most common cause of death among people with ALS is [[respiratory failure]], often accelerated by [[pneumonia]]. Most ALS patients die at home after a period of worsening difficulty breathing, a decline in their nutritional status, or a rapid worsening of symptoms.{{cite journal | vauthors = Bede P, Oliver D, Stodart J, van den Berg L, Simmons Z, O Brannagáin D, Borasio GD, Hardiman O | display-authors = 6 | title = Palliative care in amyotrophic lateral sclerosis: a review of current international guidelines and initiatives | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 82 | issue = 4 | pages = 413–418 | date = April 2011 | pmid = 21297150 | doi = 10.1136/jnnp.2010.232637 | url = https://epub.ub.uni-muenchen.de/21892/ | access-date = 30 April 2023 | url-status = live | s2cid = 7043837 | archive-url = https://web.archive.org/web/20230528133749/https://epub.ub.uni-muenchen.de/21892/ | archive-date = 28 May 2023 | hdl = 2262/59035 | hdl-access = free }} Sudden death or acute respiratory distress are uncommon.{{cite journal | vauthors = Corcia P, Pradat PF, Salachas F, Bruneteau G, Forestier N, Seilhean D, Hauw JJ, Meininger V | display-authors = 6 | title = Causes of death in a post-mortem series of ALS patients | journal = Amyotrophic Lateral Sclerosis | volume = 9 | issue = 1 | pages = 59–62 | date = 2008-01-01 | pmid = 17924236 | doi = 10.1080/17482960701656940 | s2cid = 40367873 }} Access to [[palliative care]] is recommended from an early stage to explore options, ensure psychosocial support for the patient and caregivers, and to discuss [[advance healthcare directive]]s. [112] => [113] => As with [[cancer staging]], ALS has staging systems numbered between 1 and 4 that are used for research purposes in clinical trials. Two very similar staging systems emerged around a similar time, the King's staging system and Milano-Torino (MiToS) functional staging.{{cite journal | vauthors = Fang T, Al Khleifat A, Stahl DR, Lazo La Torre C, Murphy C, Young C, Shaw PJ, Leigh PN, Al-Chalabi A | display-authors = 6 | title = Comparison of the King's and MiToS staging systems for ALS | journal = Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration | volume = 18 | issue = 3–4 | pages = 227–232 | date = May 2017 | pmid = 28054828 | pmc = 5425622 | doi = 10.1080/21678421.2016.1265565 }} [114] => {| class="wikitable" [115] => |+ style="text-align: left;" |Kings ALS staging system and prognosis at each stage [116] => ! [117] => !Stage 1 [118] => !Stage 2 [119] => !Stage 3 [120] => !Stage 4 [121] => |- [122] => |Stage description [123] => |Symptom onset, involvement of the first region [124] => |2A: Diagnosis [125] => 2B: Involvement of the second region [126] => |Involvement of the third region [127] => |4A: Need for a feeding tube [128] => 4B: Need for non-invasive ventilation [129] => |- [130] => |Median time to stage [131] => |13.5 months [132] => |17.7 months [133] => |23.3 months [134] => |4A: 17.7 months [135] => 4B: 30.3 months [136] => |} [137] => [138] => {| class="wikitable" [139] => |+ style="text-align: left;" | MiToS ALS staging system and prognosis at each stage [140] => ! [141] => !Stage 0 [142] => !Stage 1 [143] => !Stage 2 [144] => !Stage 3 [145] => !Stage 4 [146] => !Stage 5 [147] => |- [148] => |Stage description [149] => |No loss of a functional domain [150] => |Loss of 1 domain [151] => |Loss of 2 domains [152] => |Loss of 3 domains [153] => |Loss of 4 domains [154] => |Death [155] => |- [156] => |Probability of death at each stage [157] => |7% [158] => |26% [159] => |33% [160] => |33% [161] => |86% [162] => | [163] => |} [164] => [165] => Providing individual patients with a precise prognosis is not currently possible, though research is underway to provide statistical models on the basis of prognostic factors including age at onset, progression rate, site of onset, and presence of [[frontotemporal dementia]]. Those with a bulbar onset have a worse prognosis than limb-onset ALS; a population-based study found that bulbar-onset ALS patients had a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset ALS patients had a median survival of 2.6 years and a 10-year survival rate of 13%.{{cite journal | vauthors = Chiò A, Calvo A, Moglia C, Mazzini L, Mora G | title = Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 82 | issue = 7 | pages = 740–746 | date = July 2011 | pmid = 21402743 | doi = 10.1136/jnnp.2010.235952 | url = https://hal.archives-ouvertes.fr/hal-00623289/file/PEER_stage2_10.1136%252Fjnnp.2010.235952.pdf | access-date = 4 August 2022 | url-status = live | s2cid = 13416164 | archive-url = https://web.archive.org/web/20221124232146/https://hal.archives-ouvertes.fr/hal-00623289/file/PEER_stage2_10.1136%2Fjnnp.2010.235952.pdf | archive-date = 24 November 2022 }} Those with respiratory-onset ALS had a shorter median survival of 1.4 years and 0% survival at 10 years. While [[astrophysics|astrophysicist]] [[Stephen Hawking]] lived for 55 more years following his diagnosis, his was an unusual case.{{cite web | vauthors = Landau E |url=http://www.cnn.com/2009/HEALTH/04/20/hawking.als/index.html |title=Stephen Hawking serves as role model for ALS patients |publisher=CNN |date=20 September 2009 |url-status=live |archive-url=https://web.archive.org/web/20160815000537/http://www.cnn.com/2009/HEALTH/04/20/hawking.als/index.html |archive-date=15 August 2016}} [166] => [167] => === Cognitive, emotional, and behavioral symptoms === [168] => [[Cognitive disorder|Cognitive impairment]] or behavioral dysfunction is present in 30–50% of individuals with ALS,{{cite journal | vauthors = Martin S, Al Khleifat A, Al-Chalabi A | title = What causes amyotrophic lateral sclerosis? | journal = F1000Research | volume = 6 | pages = 371 | date = 2017 | pmid = 28408982 | pmc = 5373425 | doi = 10.12688/f1000research.10476.1 | doi-access = free }} and can appear more frequently in later stages of the disease.{{cite journal | vauthors = Crockford C, Newton J, Lonergan K, Chiwera T, Booth T, Chandran S, Colville S, Heverin M, Mays I, Pal S, Pender N, Pinto-Grau M, Radakovic R, Shaw CE, Stephenson L, Swingler R, Vajda A, Al-Chalabi A, Hardiman O, Abrahams S | display-authors = 6 | title = ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS | journal = Neurology | volume = 91 | issue = 15 | pages = e1370–e1380 | date = October 2018 | pmid = 30209236 | pmc = 6177274 | doi = 10.1212/WNL.0000000000006317 }} [[Language disorder|Language dysfunction]], [[executive dysfunction]], and troubles with [[social cognition]] and [[verbal memory]] are the most commonly reported cognitive symptoms in ALS. Cognitive impairment is found more frequently in patients with C9orf72 gene repeat expansions, bulbar onset, bulbar symptoms, [[Family history (medicine)|family history]] of ALS, and/or a predominantly upper motor neuron phenotype.{{cite journal | vauthors = Yang T, Hou Y, Li C, Cao B, Cheng Y, Wei Q, Zhang L, Shang H | display-authors = 6 | title = Risk factors for cognitive impairment in amyotrophic lateral sclerosis: a systematic review and meta-analysis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 92 | issue = 7 | pages = 688–693 | date = July 2021 | pmid = 33563800 | doi = 10.1136/jnnp-2020-325701 | s2cid = 231858696 }} [169] => [170] => [[Pseudobulbar affect|Emotional lability]] is a symptom in which patients cry, smile, yawn, or laugh, either in the absence of emotional stimuli, or when they are feeling the opposite emotion to that being expressed;{{cite journal | vauthors = Wicks P | title = Excessive yawning is common in the bulbar-onset form of ALS | journal = Acta Psychiatrica Scandinavica | volume = 116 | issue = 1 | pages = 76; author reply 76-76; author reply 77 | date = July 2007 | pmid = 17559605 | doi = 10.1111/j.1600-0447.2007.01025.x | s2cid = 12807996 }} it is experienced by about half of ALS patients and is more common in those with bulbar-onset ALS. While relatively benign relative to other symptoms, it can cause increased stigma and social isolation as people around the patient struggle to react appropriately to what can be frequent and inappropriate outbursts in public.{{cite journal | vauthors = Sauvé WM | title = Recognizing and treating pseudobulbar affect | journal = CNS Spectrums | volume = 21 | issue = S1 | pages = 34–44 | date = December 2016 | pmid = 28044945 | doi = 10.1017/S1092852916000791 | s2cid = 21066800 }} [171] => [172] => In addition to mild changes in cognition that may only emerge during neuropsychological testing, around 10–15% of individuals have signs of [[frontotemporal dementia]] (FTD). [[Perseveration|Repeating phrases or gestures]], apathy, and [[disinhibition|loss of inhibition]] are the most frequently reported behavioral features of ALS.{{cite journal | vauthors = Raaphorst J, Beeldman E, De Visser M, De Haan RJ, Schmand B | title = A systematic review of behavioural changes in motor neuron disease | journal = Amyotrophic Lateral Sclerosis | volume = 13 | issue = 6 | pages = 493–501 | date = October 2012 | pmid = 22424127 | doi = 10.3109/17482968.2012.656652 | s2cid = 22224140 }} ALS and FTD are now considered to be part of a common disease spectrum (ALS–FTD) because of genetic, clinical, and pathological similarities.{{cite journal | vauthors = Couratier P, Corcia P, Lautrette G, Nicol M, Marin B | title = ALS and frontotemporal dementia belong to a common disease spectrum | journal = Revue Neurologique | volume = 173 | issue = 5 | pages = 273–279 | date = May 2017 | pmid = 28449882 | doi = 10.1016/j.neurol.2017.04.001 }} Genetically, repeat expansions in the C9orf72 gene account for about 40% of genetic ALS and 25% of genetic FTD.{{cite journal | vauthors = Renton AE, Chiò A, Traynor BJ | title = State of play in amyotrophic lateral sclerosis genetics | journal = Nature Neuroscience | volume = 17 | issue = 1 | pages = 17–23 | date = January 2014 | pmid = 24369373 | pmc = 4544832 | doi = 10.1038/nn.3584 | hdl = 2318/156177 }} [173] => [174] => Cognitive and behavioral issues are associated with poorer prognosis as they may reduce adherence to medical advice, and deficits in empathy and social cognition which may increase caregiver burden.{{cite journal | vauthors = Beeldman E, Raaphorst J, Klein Twennaar M, de Visser M, Schmand BA, de Haan RJ | title = The cognitive profile of ALS: a systematic review and meta-analysis update | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 87 | issue = 6 | pages = 611–619 | date = June 2016 | pmid = 26283685 | doi = 10.1136/jnnp-2015-310734 | s2cid = 22082109 }} [175] => [176] => == Cause == [177] => [178] => It is not known what causes sporadic ALS, hence it is described as an [[idiopathic disease]]. Though its exact cause is unknown, genetic and environmental factors are thought to be of roughly equal importance. The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause ALS. A multi-step [[liability threshold model]] for ALS proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life.{{cite journal | vauthors = Al-Chalabi A, Hardiman O | title = The epidemiology of ALS: a conspiracy of genes, environment and time | journal = Nature Reviews. Neurology | volume = 9 | issue = 11 | pages = 617–628 | date = November 2013 | pmid = 24126629 | doi = 10.1038/nrneurol.2013.203 | s2cid = 25040863 }} ALS can strike at any age, but its likelihood increases with age.{{Cite web |title=Amyotrophic lateral sclerosis (ALS) - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/syc-20354022 |access-date=2022-04-06 |website=Mayo Clinic |language=en |archive-date=6 April 2022 |archive-url=https://web.archive.org/web/20220406073949/https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/syc-20354022 |url-status=live}} Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis.{{Cite web |title=Who Gets ALS? |url=https://www.als.org/understanding-als/who-gets-als |access-date=2022-04-06 |website=The ALS Association |language=en |archive-date=6 April 2022 |archive-url=https://web.archive.org/web/20220406153827/https://www.als.org/understanding-als/who-gets-als |url-status=live}} ALS is 20% more common in men than women, but this difference in sex distribution is no longer present in patients with onset after age 70. [179] => [180] => === Genetics and genetic testing === [181] => {{Main|Genetics of amyotrophic lateral sclerosis}} [182] => [183] => While they appear identical clinically and pathologically,{{cite journal | vauthors = He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA | title = Amyotrophic Lateral Sclerosis Genetic Studies: From Genome-wide Association Mapping to Genome Sequencing | journal = The Neuroscientist | volume = 21 | issue = 6 | pages = 599–615 | date = December 2015 | pmid = 25378359 | doi = 10.1177/1073858414555404 | url = https://eprints.qut.edu.au/110861/2/UQ351652_OA.pdf | url-status = live | access-date = 20 December 2019 | s2cid = 3437565 | archive-url = https://web.archive.org/web/20200507233727/https://eprints.qut.edu.au/110861/2/UQ351652_OA.pdf | archive-date = 7 May 2020 }} ALS can be classified as being either familial or sporadic, depending on whether there is a known family history of the disease and/or whether an ALS-associated genetic mutation has been identified via genetic testing.{{cite journal | vauthors = McNeill A, Amador MD, Bekker H, Clarke A, Crook A, Cummings C, McEwen A, McDermott C, Quarrell O, Renieri A, Roggenbuck J, Salmon K, Volk A, Weishaupt J | display-authors = 6 | title = Predictive genetic testing for Motor neuron disease: time for a guideline? | journal = European Journal of Human Genetics | volume = 30 | issue = 6 | pages = 635–636 | date = June 2022 | pmid = 35379930 | pmc = 9177585 | doi = 10.1038/s41431-022-01093-y }} Familial ALS is thought to account for 10–15% of cases overall and can include [[Monogenic (genetics)|monogenic]], [[oligogenic inheritance|oligogenic]], and [[Polygenic inheritance|polygenic]] modes of inheritance.{{cite journal | vauthors = Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, Feldman EL | title = Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis | journal = The Lancet. Neurology | volume = 21 | issue = 5 | pages = 465–479 | date = May 2022 | pmid = 35334234 | pmc = 9513754 | doi = 10.1016/S1474-4422(21)00414-2 }} [184] => [185] => There is considerable variation among clinicians on how to approach genetic testing in ALS, and only about half discuss the possibility of genetic inheritance with their patients, particularly if there is no discernible family history of the disease.{{cite journal | vauthors = De Oliveira HM, Soma A, Baker MR, Turner MR, Talbot K, Williams TL | title = A survey of current practice in genetic testing in amyotrophic lateral sclerosis in the UK and Republic of Ireland: implications for future planning | journal = Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration | volume = 24 | issue = 5–6 | pages = 405–413 | date = August 2023 | pmid = 36458618 | doi = 10.1080/21678421.2022.2150556 | s2cid = 254150195 | doi-access = free }} In the past, genetic counseling and testing was only offered to those with obviously familial ALS. But it is increasingly recognized that cases of sporadic ALS may also be due to disease-causing [[de novo mutation]]s in ''[[SOD1]]'', or ''[[C9orf72]]'',{{cite journal | vauthors = Müller K, Oh KW, Nordin A, Panthi S, Kim SH, Nordin F, Freischmidt A, Ludolph AC, Ki CS, Forsberg K, Weishaupt J, Kim YE, Andersen PM | display-authors = 6 | title = De novo mutations in ''SOD1'' are a cause of ALS | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 93 | issue = 2 | pages = 201–206 | date = February 2022 | pmid = 34518333 | pmc = 8784989 | doi = 10.1136/jnnp-2021-327520 }} an incomplete family history, or incomplete [[penetrance]], meaning that a patient's ancestors carried the gene but did not express the disease in their lifetimes. The lack of positive family history may be caused by lack of historical records, having a smaller family, older generations dying earlier of causes other than ALS, genetic [[Non-paternity event|non-paternity]], and uncertainty over whether certain neuropsychiatric conditions (e.g. [[frontotemporal dementia]], other forms of [[dementia]], suicide, psychosis, [[schizophrenia]]) should be considered significant when determining a family history. There have been calls in the research community to routinely counsel and test all diagnosed ALS patients for familial ALS,{{cite journal | vauthors = McNeill A, Amador MD, Bekker H, Clarke A, Crook A, Cummings C, McEwen A, McDermott C, Quarrell O, Renieri A, Roggenbuck J, Salmon K, Volk A, Weishaupt J | display-authors = 6 | title = Predictive genetic testing for Motor neuron disease: time for a guideline? | journal = European Journal of Human Genetics | volume = 30 | issue = 6 | pages = 635–636 | date = June 2022 | pmid = 35379930 | pmc = 9177585 | doi = 10.1038/s41431-022-01093-y | collaboration = International Alliance of ALS/MND Associations }} particularly as there is now a licensed gene therapy ([[tofersen]]) specifically targeted to carriers of SOD-1 ALS. A shortage of genetic counselors and limited clinical capacity to see such at-risk individuals makes this challenging in practice, as does the unequal access to genetic testing around the world.{{cite journal | vauthors = Salmon K, Kiernan MC, Kim SH, Andersen PM, Chio A, van den Berg LH, Van Damme P, Al-Chalabi A, Lillo P, Andrews JA, Genge A | display-authors = 6 | title = The importance of offering early genetic testing in everyone with amyotrophic lateral sclerosis | journal = Brain | volume = 145 | issue = 4 | pages = 1207–1210 | date = May 2022 | pmid = 35020823 | pmc = 9129091 | doi = 10.1093/brain/awab472 | url = https://academic.oup.com/brain/article/145/4/1207/6501632 | access-date = 27 May 2023 | url-status = live | archive-url = https://web.archive.org/web/20230527172816/https://academic.oup.com/brain/article/145/4/1207/6501632 | archive-date = 27 May 2023 }} [186] => [187] => More than 40 genes have been associated with ALS, of which four account for nearly half of familial cases, and around 5% of sporadic cases: ''[[C9orf72]]'' (40% of familial cases, 7% sporadic), ''[[SOD1]]'' (12% of familial cases, 1-2% sporadic), ''[[FUS (gene)|FUS]]'' (4% of familial cases, 1% sporadic), and ''[[TARDBP]]'' (4% of familial cases, 1% sporadic), with the remaining genes mostly accounting for fewer than 1% of either familial or sporadic cases. ALS genes identified to date explain the cause of about 70% of familial ALS and about 15% of sporadic ALS. Overall, first-degree relatives of an individual with ALS have a ~1% risk of developing ALS themselves. [188] => [189] => === Environmental and other factors === [190] => The multi-step hypothesis suggests the disease is caused by some interaction between an individual's genetic risk factors and their cumulative lifetime of exposures to environmental factors, termed their [[exposome]]. The most consistent lifetime exposures associated with developing ALS (other than genetic mutations) include heavy metals (e.g. [[lead]] and [[Mercury (element)|mercury]]), chemicals (e.g. [[pesticide]]s and [[solvent]]s), [[Electrical injury|electric shock]], [[Injury|physical injury]] (including [[head injury]]), and [[smoking]] (in men more than women).{{cite journal | vauthors = Wang MD, Little J, Gomes J, Cashman NR, Krewski D | title = Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis | journal = Neurotoxicology | volume = 61 | pages = 101–130 | date = July 2017 | pmid = 27377857 | doi = 10.1016/j.neuro.2016.06.015 | url = https://linkinghub.elsevier.com/retrieve/pii/S0161813X16301164 | access-date = 27 May 2023 | url-status = live | s2cid = 33604904 | archive-url = https://web.archive.org/web/20221117202809/https://linkinghub.elsevier.com/retrieve/pii/S0161813X16301164 | archive-date = 17 November 2022 }} Overall these effects are small, with each exposure in isolation only increasing the likelihood of a very rare condition by a small amount. For instance an individual's lifetime risk of developing ALS might go from "1 in 400" without an exposure to between "1 in 300" and "1 in 200" if they were exposed to heavy metals. A range of other exposures have weaker evidence supporting them and include participation in [[professional sports]], having a lower [[body mass index]], lower [[educational attainment]], manual occupations, military service, exposure to [[Beta-Methylamino-L-alanine|Beta-N-methylamino-L-alanin]] (BMAA), and viral infections. [191] => [192] => Although some personality traits, such as [[openness to experience|openness]],{{cite journal | vauthors = Grossman AB, Levin BE, Bradley WG | title = Premorbid personality characteristics of patients with ALS | journal = Amyotrophic Lateral Sclerosis | volume = 7 | issue = 1 | pages = 27–31 | date = March 2006 | pmid = 16546756 | doi = 10.1080/14660820510012004 | s2cid = 20998807 }} [[agreeableness]]{{cite journal | vauthors = Parkin Kullmann JA, Hayes S, Pamphlett R | title = Are people with amyotrophic lateral sclerosis (ALS) particularly nice? An international online case-control study of the Big Five personality factors | journal = Brain and Behavior | volume = 8 | issue = 10 | pages = e01119 | date = October 2018 | pmid = 30239176 | pmc = 6192405 | doi = 10.1002/brb3.1119 }} and [[conscientiousness]] appear remarkably common among patients with ALS, it remains open whether personality can increase susceptibility to ALS directly.{{cite journal | vauthors = Mehl T, Jordan B, Zierz S | title = "Patients with amyotrophic lateral sclerosis (ALS) are usually nice persons"-How physicians experienced in ALS see the personality characteristics of their patients | journal = Brain and Behavior | volume = 7 | issue = 1 | pages = e00599 | date = January 2017 | pmid = 28127517 | pmc = 5256182 | doi = 10.1002/brb3.599 }} Instead, genetic factors giving rise to personality might simultaneously predispose people to developing ALS, or [193] => the above personality traits might underlie lifestyle choices which are in turn risk factors for ALS. [194] => [195] => == Pathophysiology == [196] => ===Neuropathology=== [197] => Upon examination at autopsy, features of the disease that can be [[Gross pathology|seen with the naked eye]] include skeletal [[muscle atrophy]], motor cortex atrophy, [[Sclerosis (medicine)|sclerosis]] of the [[corticospinal tract|corticospinal]] and [[corticobulbar tract]]s, thinning of the [[hypoglossal nerve]]s (which control the tongue), and thinning of the [[anterior roots]] of the spinal cord. [198] => [199] => The defining feature of ALS is the death of both upper motor neurons (located in the [[motor cortex]] of the brain) and lower motor neurons (located in the brainstem and spinal cord).{{cite journal | vauthors = Robberecht W, Philips T | title = The changing scene of amyotrophic lateral sclerosis | journal = Nature Reviews. Neuroscience | volume = 14 | issue = 4 | pages = 248–264 | date = April 2013 | pmid = 23463272 | doi = 10.1038/nrn3430 | s2cid = 208941 }} In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well.{{cite journal | vauthors = Brown RH, Al-Chalabi A | title = Amyotrophic Lateral Sclerosis | journal = The New England Journal of Medicine | volume = 377 | issue = 2 | pages = 162–172 | date = July 2017 | pmid = 28700839 | doi = 10.1056/NEJMra1603471 | url = https://kclpure.kcl.ac.uk/portal/en/publications/amyotrophic-lateral-sclerosis(70a10b6b-0121-46ae-896b-7108a6666dcb).html | url-status = live | access-date = 20 December 2019 | s2cid = 205117619 | archive-url = https://web.archive.org/web/20210225022352/https://kclpure.kcl.ac.uk/portal/en/publications/amyotrophic-lateral-sclerosis(70a10b6b-0121-46ae-896b-7108a6666dcb).html | archive-date = 25 February 2021 }} The pathological hallmark of ALS is the presence of [[inclusion bodies]] (abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor neurons. In about 97% of people with ALS, the main component of the inclusion bodies is [[TDP-43]] protein; however, in those with ''SOD1'' or ''FUS'' mutations, the main component of the inclusion bodies{{cite journal | vauthors = Okamoto K, Mizuno Y, Fujita Y | title = Bunina bodies in amyotrophic lateral sclerosis | journal = Neuropathology | volume = 28 | issue = 2 | pages = 109–115 | date = April 2008 | pmid = 18069968 | doi = 10.1111/j.1440-1789.2007.00873.x | s2cid = 34398467 }}{{cite journal | vauthors = White JA, Banerjee R, Gunawardena S | title = Axonal Transport and Neurodegeneration: How Marine Drugs Can Be Used for the Development of Therapeutics | journal = Marine Drugs | volume = 14 | issue = 5 | page = 102 | date = May 2016 | pmid = 27213408 | pmc = 4882576 | doi = 10.3390/md14050102 | doi-access = free }} is SOD1 protein or FUS protein, respectively. [[Prion]]-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others. The [[glymphatic system]] may also be involved in the [[pathogenesis]] of ALS.{{cite journal | vauthors = Ng Kee Kwong KC, Mehta AR, Nedergaard M, Chandran S | title = Defining novel functions for cerebrospinal fluid in ALS pathophysiology | journal = Acta Neuropathologica Communications | volume = 8 | issue = 1 | pages = 140 | date = August 2020 | pmid = 32819425 | pmc = 7439665 | doi = 10.1186/s40478-020-01018-0 | doi-access = free }} [200] => [201] => ===Biochemistry=== [202] => [[File:ALS Disease Pathology and Proposed Disease Mechanisms.jpg|thumb|upright=1.2|This figure shows ten proposed disease mechanisms for ALS and the genes associated with them.{{cite journal | vauthors = Van Damme P, Robberecht W, Van Den Bosch L | title = Modelling amyotrophic lateral sclerosis: progress and possibilities | journal = Disease Models & Mechanisms | volume = 10 | issue = 5 | pages = 537–549 | date = May 2017 | pmid = 28468939 | pmc = 5451175 | doi = 10.1242/dmm.029058 }}]] [203] => [204] => It is still not fully understood why neurons die in ALS, but this [[neurodegeneration]] is thought to involve many different cellular and molecular processes. The genes known to be involved in ALS can be grouped into three general categories based on their normal function: protein degradation, the [[cytoskeleton]], and RNA processing.{{cite journal | vauthors = Alsultan AA, Waller R, Heath PR, Kirby J | title = The genetics of amyotrophic lateral sclerosis: current insights | journal = Degenerative Neurological and Neuromuscular Disease | volume = 6 | pages = 49–64 | date = 2016 | pmid = 30050368 | pmc = 6053097 | doi = 10.2147/DNND.S84956 | doi-access = free }} Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of [[wild-type]] (normal) SOD1 protein are common in sporadic ALS. It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner. Other protein degradation genes that can cause ALS when mutated include ''[[Valosin-containing protein|VCP]]'', ''[[Optineurin|OPTN]]'', ''[[TBK1 (gene)|TBK1]]'', and ''[[SQSTM1]]''. Three genes implicated in ALS that are important for maintaining the cytoskeleton and for axonal transport include ''[[DCTN1]]'', ''[[PFN1]]'', and ''[[TUBA4A]]''. [205] => [206] => There are a number of ALS genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein, a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of ALS; however, mutations in ''TARDBP'', the gene that codes for TDP-43, are a rare cause of ALS. ''FUS'' codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated. It is thought that mutations in ''TARDBP'' and ''FUS'' increase the binding affinity of the low-complexity domain, causing their respective proteins to aggregate in the cytoplasm.{{cite journal | vauthors = Shang Y, Huang EJ | title = Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis | journal = Brain Research | volume = 1647 | pages = 65–78 | date = September 2016 | pmid = 27033831 | pmc = 5003642 | doi = 10.1016/j.brainres.2016.03.036 }} Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal proteins both within and between cells in a prion-like manner. This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo normal processing. Other RNA metabolism genes associated with ALS include ''[[angiogenin|ANG]]'', ''[[SETX]]'', and ''[[MATR3]]''. [207] => [208] => ''C9orf72'' is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over);{{cite journal | vauthors = Nguyen HP, Van Broeckhoven C, van der Zee J | title = ALS Genes in the Genomic Era and their Implications for FTD | journal = Trends in Genetics | volume = 34 | issue = 6 | pages = 404–423 | date = June 2018 | pmid = 29605155 | doi = 10.1016/j.tig.2018.03.001 | doi-access = free | hdl = 10067/1514730151162165141 | hdl-access = free }} people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS.{{cite journal | vauthors = Gitler AD, Tsuiji H | title = There has been an awakening: Emerging mechanisms of C9orf72 mutations in FTD/ALS | journal = Brain Research | volume = 1647 | pages = 19–29 | date = September 2016 | pmid = 27059391 | pmc = 5003651 | doi = 10.1016/j.brainres.2016.04.004 }} The three mechanisms of disease associated with these ''C9orf72'' repeats are deposition of RNA transcripts in the nucleus, translation of the RNA into toxic dipeptide repeat proteins in the cytoplasm, and decreased levels of the normal C9orf72 protein. Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in ''C9orf72''-ALS using human [[Induced pluripotent stem cells|induced pluripotent stem cell]] (iPSC) technologies coupled with [[CRISPR/Cas9-mediated genome editing|CRISPR/Cas9]] gene-editing, and human post-mortem spinal cord tissue examination.{{cite journal | vauthors = Mehta AR, Gregory JM, Dando O, Carter RN, Burr K, Nanda J, Story D, McDade K, Smith C, Morton NM, Mahad DJ, Hardingham GE, Chandran S, Selvaraj BT | display-authors = 6 | title = Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis | journal = Acta Neuropathologica | volume = 141 | issue = 2 | pages = 257–279 | date = February 2021 | pmid = 33398403 | pmc = 7847443 | doi = 10.1007/s00401-020-02252-5 | doi-access = free }} [209] => [210] => [[Excitotoxicity]], or nerve cell death caused by high levels of intracellular calcium due to excessive stimulation by the excitatory [[neurotransmitter]] [[glutamate]], is a mechanism thought to be common to all forms of ALS. Motor neurons are more sensitive to excitotoxicity than other types of neurons because they have a lower calcium-buffering capacity and a type of glutamate receptor (the [[AMPA receptor]]) that is more permeable to calcium. In ALS, there are decreased levels of excitatory amino acid transporter 2 ([[EAAT2]]), which is the main transporter that removes glutamate from the synapse; this leads to increased synaptic glutamate levels and excitotoxicity. [[Riluzole]], a drug that modestly prolongs survival in ALS, inhibits glutamate release from pre-synaptic neurons; however, it is unclear if this mechanism is responsible for its therapeutic effect. [211] => [212] => == Diagnosis == [213] => [[File:ALS cross.jpg|thumb|upright=1.2|An [[MRI of the brain]] (axial [[Fluid-attenuated inversion recovery|FLAIR]]) looking at a person as if from above that shows increased [[Spin-spin relaxation|''T2'']] signal as a small white region within the [[Internal capsule#Posterior limb|posterior part of the internal capsule]] around the center of the image, consistent with the diagnosis of ALS]] [214] => No single test can provide a definite diagnosis of ALS. Instead, the diagnosis of ALS is primarily made based on a physician's clinical assessment after ruling out other diseases. Physicians often obtain the person's full [[medical history]] and conduct neurologic examinations at regular intervals to assess whether signs and symptoms such as muscle weakness, [[muscle atrophy]], [[hyperreflexia]], [[Plantar reflex|Babinski's sign]], and spasticity are worsening. A number of biomarkers are being studied for the condition, but as of 2023 are not in general medical use.{{cite journal | vauthors = Verber NS, Shepheard SR, Sassani M, McDonough HE, Moore SA, Alix JJ, Wilkinson ID, Jenkins TM, Shaw PJ | display-authors = 6 | title = Biomarkers in Motor Neuron Disease: A State of the Art Review | journal = Frontiers in Neurology | volume = 10 | pages = 291 | date = 2019 | pmid = 31001186 | pmc = 6456669 | doi = 10.3389/fneur.2019.00291 | doi-access = free }}[[File:ALS Coronal.jpg|thumb|An [[MRI of the brain]] looking at a person from side-on that shows [[T2-weighted|increased T2 signal]] as a white region in the posterior part of the [[internal capsule]] that can be tracked to the [[motor cortex]], consistent with the diagnosis of ALS ]] [215] => [216] => ===Differential diagnosis=== [217] => Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is [[electromyography]] (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures [[nerve conduction velocity]] (NCV).{{cite journal | vauthors = Joyce NC, Carter GT | title = Electrodiagnosis in persons with amyotrophic lateral sclerosis | journal = PM&R | volume = 5 | issue = 5 Suppl | pages = S89–S95 | date = May 2013 | pmid = 23523708 | pmc = 4590769 | doi = 10.1016/j.pmrj.2013.03.020 }} Specific abnormalities in the NCV results may suggest, for example, that the person has a form of [[peripheral neuropathy]] (damage to peripheral nerves) or [[myopathy]] (muscle disease) rather than ALS. While a [[magnetic resonance imaging]] (MRI) is often normal in people with early-stage ALS, it can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, [[multiple sclerosis]], a [[herniated disc]] in the neck, [[syringomyelia]], or cervical [[spondylosis]]. [218] => [219] => Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood and [[urine]] samples to eliminate the possibility of other diseases, as well as routine laboratory tests. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed. [220] => [221] => A number of infectious diseases can sometimes cause ALS-like symptoms, including human immunodeficiency virus ([[HIV]]), [[human T-lymphotropic virus]] (HTLV), [[Lyme disease]], and [[syphilis]]. Neurological disorders such as multiple sclerosis, [[post-polio syndrome]], [[multifocal motor neuropathy]], [[Chronic inflammatory demyelinating polyneuropathy|CIDP]], [[spinal muscular atrophy]], and [[spinal and bulbar muscular atrophy]] can also mimic certain aspects of the disease and should be considered. [222] => [223] => ALS must be differentiated from the "ALS mimic syndromes", which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants.{{cite journal | vauthors = Silani V, Messina S, Poletti B, Morelli C, Doretti A, Ticozzi N, Maderna L | title = The diagnosis of Amyotrophic lateral sclerosis in 2010 | journal = Archives Italiennes de Biologie | volume = 149 | issue = 1 | pages = 5–27 | date = March 2011 | pmid = 21412713 | doi = 10.4449/aib.v149i1.1260 }} Because the prognosis of ALS and closely related subtypes of motor neuron disease are generally poor, neurologists may carry out investigations to evaluate and exclude other diagnostic possibilities. Disorders of the [[neuromuscular junction]], such as [[myasthenia gravis]] (MG) and [[Lambert–Eaton myasthenic syndrome]], may also mimic ALS, although this rarely presents diagnostic difficulty over time.{{cite web | vauthors = Stickler DE | veditors = Lorenzo N |url=http://misc.medscape.com/pi/android/medscapeapp/html/A1170810-business.html |title=Lambert-Eaton Myasthenic Syndrome (LEMS) |publisher=Misc.medscape.com |access-date=18 April 2013 |url-status=live |archive-url=https://web.archive.org/web/20130514014534/http://misc.medscape.com/pi/android/medscapeapp/html/A1170810-business.html |archive-date=14 May 2013}}{{cite web |url=http://www.lems.com/what_is_lems | work = LEMS.com | title = Lambert-Eaton Myasthenic Syndrome: About |publisher=BioMarin Pharmaceutical Inc. |access-date=18 April 2013 |url-status=dead |archive-url=https://web.archive.org/web/20130120025113/http://www.lems.com/what_is_lems |archive-date=20 January 2013}} [[Benign fasciculation syndrome]] and [[cramp fasciculation syndrome]] may also, occasionally, mimic some of the early symptoms of ALS. Nonetheless, the absence of other neurological features that develop inexorably with ALS means that, over time, the distinction will not present any difficulty to the experienced neurologist; where doubt remains, EMG may be helpful.{{cite journal | vauthors = Mills KR | title = Characteristics of fasciculations in amyotrophic lateral sclerosis and the benign fasciculation syndrome | journal = Brain | volume = 133 | issue = 11 | pages = 3458–3469 | date = November 2010 | pmid = 20959307 | doi = 10.1093/brain/awq290 | doi-access = free }} [224] => [225] => == Management == [226] => [227] => There is no cure for ALS. Management focuses on treating symptoms and providing supportive care, with the goal of improving quality of life and prolonging survival. This care is best provided by multidisciplinary teams of healthcare professionals; attending a multidisciplinary ALS clinic is associated with longer survival, fewer hospitalizations, and improved quality of life. [228] => [229] => [[Non-invasive ventilation]] (NIV) is the main treatment for respiratory failure in ALS. In people with normal bulbar function, it prolongs survival by about seven months and improves quality of life. One study found that NIV is ineffective for people with poor bulbar function while another suggested that it may provide a modest survival benefit. Many people with ALS have difficulty tolerating NIV. Invasive ventilation is an option for people with advanced ALS when NIV is not enough to manage their symptoms. While invasive ventilation prolongs survival, disease progression and functional decline continue. It may decrease the quality of life of people with ALS or their caregivers. Invasive ventilation is more commonly used in Japan than in North America or Europe. [230] => [231] => [[File:Per Villand.jpg|alt=Person with ALS and their assistive technologies|thumb|A person with late-stage ALS with a range of assistive technologies to support movement (power wheelchair), breathing (invasive ventilation), and communication (eye tracker and computer)]] [232] => [233] => Physical therapy can promote functional independence through an aerobic, range of motion, and stretching exercises. Occupational therapy can assist with activities of daily living through adaptive equipment. Speech therapy can assist people with ALS who have difficulty speaking. Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life. Initially, difficulty swallowing (dysphagia) can be managed by dietary changes and swallowing techniques. A [[feeding tube]] should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water. The feeding tube is usually inserted by [[percutaneous endoscopic gastrostomy]] (PEG). There is weak evidence that PEG tubes improve survival.{{cite journal | vauthors = Sulistyo A, Abrahao A, Freitas ME, Ritsma B, Zinman L | title = Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 8 | pages = CD004030 | date = August 2023 | pmid = 37579081 | pmc = 10413437 | doi = 10.1002/14651858.CD004030.pub4 | pmc-embargo-date = August 10, 2024 }} PEG insertion is usually performed with the intent of improving quality of life. [234] => [235] => [[Palliative care]] should begin shortly after someone is diagnosed with ALS. Discussion of end-of-life issues gives people with ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Hospice care can improve symptom management at the end of life and increases the likelihood of a peaceful death. In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety. [236] => [237] => === Medications === [238] => [239] => ====Disease-slowing treatments==== [240] => [[File:Riluzole2DACS.svg|thumb|upright=1.2|Chemical structure of [[riluzole]], a medication that prolongs survival by 2–3 months{{cite journal | vauthors = Miller RG, Mitchell JD, Moore DH | title = Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 3 | pages = CD001447 | date = March 2012 | pmid = 22419278 | pmc = 7055506 | doi = 10.1002/14651858.CD001447.pub3 }}]] [241] => [[Riluzole]] has been found to modestly prolong survival by about 2–3 months.{{cite journal | vauthors = Carlesi C, Pasquali L, Piazza S, Lo Gerfo A, Caldarazzo Ienco E, Alessi R, Fornai F, Siciliano G | display-authors = 6 | title = Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis | journal = Archives Italiennes de Biologie | volume = 149 | issue = 1 | pages = 151–167 | date = March 2011 | pmid = 21412722 | doi = 10.4449/aib.v149i1.1267 }} It may have a greater survival benefit for those with [[bulbar-onset ALS]]. It may work by decreasing release of the excitatory [[neurotransmitter]] [[Glutamate (neurotransmitter)|glutamate]] from pre-synaptic neurons. The most common side effects are nausea and a lack of energy ([[asthenia]]). People with ALS should begin treatment with riluzole as soon as possible following their diagnosis.{{cite journal | vauthors = Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chio A, Van Damme P, Hardiman O, Kollewe K, Morrison KE, Petri S, Pradat PF, Silani V, Tomik B, Wasner M, Weber M | display-authors = 6 | title = EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force | journal = European Journal of Neurology | volume = 19 | issue = 3 | pages = 360–375 | date = March 2012 | pmid = 21914052 | doi = 10.1111/j.1468-1331.2011.03501.x | s2cid = 5746940 | doi-access = free }} Riluzole is available as a tablet, liquid, or dissolvable oral film.{{Cite web |title=FDA-Approved Drugs for Treating ALS |url=https://www.als.org/navigating-als/living-with-als/fda-approved-drugs |access-date=2023-04-25 |website=The ALS Association |language=en |archive-date=25 April 2023 |archive-url=https://web.archive.org/web/20230425205601/https://www.als.org/navigating-als/living-with-als/fda-approved-drugs |url-status=live}} [242] => [243] => [[Edaravone]] has been shown to modestly slow the decline in function in a small group of people with early-stage ALS.{{cite journal | title = Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial | journal = The Lancet. Neurology | volume = 16 | issue = 7 | pages = 505–512 | date = July 2017 | pmid = 28522181 | doi = 10.1016/S1474-4422(17)30115-1 | doi-access = free | last1 = Abe | first1 = Koji | last2 = Aoki | first2 = Masashi | last3 = Tsuji | first3 = Shoji | last4 = Itoyama | first4 = Yasuto | last5 = Sobue | first5 = Gen | last6 = Togo | first6 = Masanori | last7 = Hamada | first7 = Chikuma | last8 = Tanaka | first8 = Masahiko | last9 = Akimoto | first9 = Makoto | last10 = Nakamura | first10 = Kazue | last11 = Takahashi | first11 = Fumihiro | last12 = Kondo | first12 = Kazuoki | last13 = Yoshino | first13 = Hiide | last14 = Abe | first14 = Koji | last15 = Aoki | first15 = Masashi | last16 = Tsuji | first16 = Shoji | last17 = Itoyama | first17 = Yasuto | last18 = Sobue | first18 = Gen | last19 = Togo | first19 = Masanori | last20 = Hamada | first20 = Chikuma | last21 = Sasaki | first21 = Hidenao | last22 = Yabe | first22 = Ichiro | last23 = Doi | first23 = Shizuki | last24 = Warita | first24 = Hitoshi | last25 = Imai | first25 = Takashi | last26 = Ito | first26 = Hiroaki | last27 = Fukuchi | first27 = Mitsumasa | last28 = Osumi | first28 = Etsuko | last29 = Wada | first29 = Manabu | last30 = Nakano | first30 = Imaharu | display-authors = 1 }}{{cite journal | vauthors = Dorst J, Ludolph AC, Huebers A | title = Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis | journal = Therapeutic Advances in Neurological Disorders | volume = 11 | pages = 1756285617734734 | year = 2018 | pmid = 29399045 | pmc = 5784546 | doi = 10.1177/1756285617734734 | doi-access = free }} It may work by protecting motor neurons from [[oxidative stress]].{{cite journal | vauthors = Takei K, Watanabe K, Yuki S, Akimoto M, Sakata T, Palumbo J | title = Edaravone and its clinical development for amyotrophic lateral sclerosis | journal = Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration | volume = 18 | issue = sup1 | pages = 5–10 | date = October 2017 | pmid = 28872907 | doi = 10.1080/21678421.2017.1353101 | doi-access = free }} The most common side effects are bruising and gait disturbance. Edaravone is available as an intravenous infusion or as an oral suspension.{{Cite web |author=Center for Drug Evaluation and Research |date=2022-06-16 |title=FDA Approves Oral Form for the treatment of adults with amyotrophic lateral sclerosis (ALS) |url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-oral-form-treatment-adults-amyotrophic-lateral-sclerosis-als |publisher=U.S. Food and Drug Administration |language=en |access-date=25 April 2023 |archive-date=12 May 2022 |archive-url=https://web.archive.org/web/20220512203805/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-oral-form-treatment-adults-amyotrophic-lateral-sclerosis-als |url-status=live}} [244] => [245] => [[Sodium phenylbutyrate/ursodoxicoltaurine|AMX0035]] (Relyvrio) is a combination of [[sodium phenylbutyrate]] and [[Tauroursodeoxycholic acid|taurursodiol]], which was initially shown to prolong the survival of patients by an average of six months.{{Cite web |title=AMX0035 (RELYVRIO) |url=https://www.als.org/navigating-als/living-with-als/fda-approved-drugs/amx0035 |access-date=2023-04-25 |website=The ALS Association |language=en |archive-date=25 April 2023 |archive-url=https://web.archive.org/web/20230425205603/https://www.als.org/navigating-als/living-with-als/fda-approved-drugs/amx0035 |url-status=live}} Relyvrio was withdrawn by the manufacturer in April 2024{{Cite web |date=2024-04-04 |title=ALS drug will be pulled from US market after study showed patients didn't benefit |url=https://apnews.com/article/relyvrio-amylyx-als-drug-fda-5fca44189f7e33f7645cb8d019197442 |access-date=2024-04-04 |website=AP News |language=en}} following the completion of the Phase 3 PHOENIX trial{{Cite report |url=https://clinicaltrials.gov/study/NCT05021536 |title=A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of AMX0035 Versus Placebo for 48-week Treatment of Adult Patients With Amyotrophic Lateral Sclerosis (ALS) |last=Amylyx Pharmaceuticals Inc. |date=2023-01-04 |publisher=clinicaltrials.gov |issue=NCT05021536}} which did not show substantial benefit to ALS patients. [246] => [247] => [[Tofersen]] (Qalsody) is an [[antisense oligonucleotide]] that was approved for medical use in the United States in April 2023, for the treatment of SOD1-associated ALS.{{cite press release | title=FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene | publisher=U.S. [[Food and Drug Administration]] (FDA) | date=25 April 2023 | url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene | access-date=25 April 2023 | archive-date=25 April 2023 | archive-url=https://web.archive.org/web/20230425172813/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene | url-status=live}} In a study of 108 patients with SOD1-associated ALS there was a non-significant trend towards a slowing of progression, as well as a significant reduction in neurofilament light chain,{{cite journal | vauthors = Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S | display-authors = 6 | title = Trial of Antisense Oligonucleotide Tofersen for ''SOD1'' ALS | journal = The New England Journal of Medicine | volume = 387 | issue = 12 | pages = 1099–1110 | date = September 2022 | pmid = 36129998 | doi = 10.1056/NEJMoa2204705 | s2cid = 252438252 | doi-access = free }} a putative ALS biomarker thought to indicate neuronal damage.{{cite journal | vauthors = Lu CH, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N, Giovannoni G, Fratta P, Sidle K, Fish M, Orrell R, Howard R, Talbot K, Greensmith L, Kuhle J, Turner MR, Malaspina A | display-authors = 6 | title = Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis | journal = Neurology | volume = 84 | issue = 22 | pages = 2247–2257 | date = June 2015 | pmid = 25934855 | pmc = 4456658 | doi = 10.1212/WNL.0000000000001642 }} A follow-up study and open-label extension suggested that earlier treatment initiation had a beneficial effect on slowing disease progression. Tofersen is available as an intrathecal injection into the [[lumbar cistern]] at the base of the spine. [248] => [249] => ===== Symptomatic treatments ===== [250] => [251] => Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and [[phlegm]].{{cite journal | vauthors = Orrell RW | title = Motor neuron disease: systematic reviews of treatment for ALS and SMA | journal = British Medical Bulletin | volume = 93 | pages = 145–159 | date = 2010 | pmid = 20015852 | doi = 10.1093/bmb/ldp049 | doi-access = free }} [[Gabapentin]], [[pregabalin]], and [[tricyclic antidepressants]] (e.g., [[amitriptyline]]) can be used for neuropathic pain, while nonsteroidal anti-inflammatory drugs ([[NSAIDs]]), [[acetaminophen]], and [[opioid]]s can be used for nociceptive pain. [252] => [253] => Depression can be treated with [[selective serotonin reuptake inhibitor]]s (SSRIs) or tricyclic antidepressants, while [[benzodiazepines]] can be used for anxiety. There are no medications to treat cognitive impairment/frontotemporal dementia (FTD); however, SSRIs and antipsychotics can help treat some of the symptoms of FTD. [[Baclofen]] and [[tizanidine]] are the most commonly used oral drugs for treating spasticity; an [[intrathecal]] baclofen pump can be used for severe spasticity. [[Atropine]], [[scopolamine]], amitriptyline or [[glycopyrrolate]] may be prescribed when people with ALS begin having trouble swallowing their saliva ([[sialorrhea]]). [254] => [255] => A 2017 review concluded that [[mexiletine]] is safe and effective for treating cramps in ALS based on a randomized controlled trial from 2016. [256] => [257] => === Breathing support === [258] => [259] => ==== Non-invasive ventilation ==== [260] => [[File:BIPAP.JPG|thumb|upright=1.2|left|[[Non-invasive ventilation]] supports breathing with a face or nasal mask connected to a ventilator.]] [261] => [262] => [[Non-invasive ventilation]] (NIV) is the primary treatment for respiratory failure in ALS and was the first treatment shown to improve both survival and quality of life. NIV uses a face or nasal mask connected to a ventilator that provides intermittent positive pressure to support breathing. Continuous positive pressure is not recommended for people with ALS because it makes breathing more difficult. Initially, NIV is used only at night because the first sign of respiratory failure is decreased gas exchange ([[hypoventilation]]) during sleep; symptoms associated with this nocturnal hypoventilation include interrupted sleep, anxiety, morning headaches, and daytime fatigue. As the disease progresses, people with ALS develop shortness of breath when lying down, during physical activity or talking, and eventually at rest.{{cite journal | vauthors = Paganoni S, Karam C, Joyce N, Bedlack R, Carter GT | title = Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis | journal = NeuroRehabilitation | volume = 37 | issue = 1 | pages = 53–68 | date = 2015 | pmid = 26409693 | pmc = 5223769 | doi = 10.3233/NRE-151240 }} Other symptoms include poor concentration, poor memory, confusion, respiratory tract infections, and a weak cough. Respiratory failure is the most common cause of death in ALS. [263] => [264] => It is important to monitor the respiratory function of people with ALS every three months because beginning NIV soon after the start of respiratory symptoms is associated with increased survival. This involves asking the person with ALS if they have any respiratory symptoms and measuring their respiratory function. The most commonly used measurement is upright [[forced vital capacity]] (FVC), but it is a poor detector of early respiratory failure and is not a good choice for those with bulbar symptoms, as they have difficulty maintaining a tight seal around the mouthpiece. Measuring FVC while the person is lying on their back (supine FVC) is a more accurate measure of diaphragm weakness than upright FVC.{{cite journal | vauthors = Ahmed RM, Newcombe RE, Piper AJ, Lewis SJ, Yee BJ, Kiernan MC, Grunstein RR | title = Sleep disorders and respiratory function in amyotrophic lateral sclerosis | journal = Sleep Medicine Reviews | volume = 26 | pages = 33–42 | date = April 2016 | pmid = 26166297 | doi = 10.1016/j.smrv.2015.05.007 }} Sniff nasal inspiratory pressure (SNIP) is a rapid, convenient test of diaphragm strength that is not affected by bulbar muscle weakness. If someone with ALS has signs and symptoms of respiratory failure, they should undergo daytime [[blood gas analysis]] to look for [[hypoxemia]] (low oxygen in the blood) and [[hypercapnia]] (too much carbon dioxide in the blood). If their daytime blood gas analysis is normal, they should then have nocturnal [[pulse oximetry]] to look for hypoxemia during sleep. [265] => [266] => Non-invasive ventilation prolongs survival longer than riluzole.{{cite journal | vauthors = Pinto S, Carvalho M | title = Breathing new life into treatment advances for respiratory failure in amyotrophic lateral sclerosis patients | journal = Neurodegenerative Disease Management | volume = 4 | issue = 1 | pages = 83–102 | date = 2014 | pmid = 24640982 | doi = 10.2217/nmt.13.74 }} A 2006 randomized controlled trial found that NIV prolongs survival by about 48 days and improves the quality of life; however, it also found that some people with ALS benefit more from this intervention than others. For those with normal or only moderately impaired bulbar function, NIV prolongs survival by about seven months and significantly improves the quality of life. For those with poor bulbar function, NIV neither prolongs survival nor improves the quality of life, though it does improve some sleep-related symptoms.{{cite journal | vauthors = Radunovic A, Annane D, Rafiq MK, Brassington R, Mustfa N | title = Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD004427 | date = October 2017 | pmid = 28982219 | pmc = 6485636 | doi = 10.1002/14651858.CD004427.pub4 }} Despite the clear benefits of NIV, about 25–30% of all people with ALS are unable to tolerate it, especially those with cognitive impairment or bulbar dysfunction. Results from a large 2015 cohort study suggest that NIV may prolong survival in those with bulbar weakness, so NIV should be offered to all people with ALS, even if it is likely that they will have difficulty tolerating it. [267] => [268] => ==== Invasive ventilation ==== [269] => Invasive ventilation bypasses the nose and mouth (the upper airways) by making a cut in the trachea ([[tracheostomy]]) and inserting a [[tracheal tube|tube]] connected to a ventilator. It is an option for people with advanced ALS whose respiratory symptoms are poorly managed despite continuous NIV use. While invasive ventilation prolongs survival, especially for those younger than 60, it does not treat the underlying neurodegenerative process. The person with ALS will continue to lose motor function, making communication increasingly difficult and sometimes leading to [[locked-in syndrome]], in which they are completely paralyzed except for their eye muscles. About half of the people with ALS who choose to undergo invasive ventilation report a decrease in their quality of life but most still consider it to be satisfactory. However, invasive ventilation imposes a heavy burden on caregivers and may decrease their quality of life. Attitudes toward invasive ventilation vary from country to country; about 30% of people with ALS in Japan choose invasive ventilation, versus less than 5% in North America and Europe.{{cite journal | vauthors = Eisen A, Krieger C | title = Ethical considerations in the management of amyotrophic lateral sclerosis | journal = Progress in Neurobiology | volume = 110 | pages = 45–53 | date = November 2013 | pmid = 23735671 | doi = 10.1016/j.pneurobio.2013.05.001 | s2cid = 26282198 }} [270] => [271] => ===Therapy=== [272] => [[File:Using a head mounted laser to point to a communication board.jpg|alt=A man with ALS communicates with his wife by pointing to letters and words with a head mounted laser pointer.|thumb|left|upright=1.2|A man with ALS communicates by pointing to letters and words using a head-mounted laser pointer.]] [273] => [274] => [[Physical therapy]] plays a large role in rehabilitation for individuals with ALS. Specifically, physical, occupational, and speech therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing, preventing complications, and promoting functional independence.{{cite journal | vauthors = Lewis M, Rushanan S | title = The role of physical therapy and occupational therapy in the treatment of amyotrophic lateral sclerosis | journal = NeuroRehabilitation | volume = 22 | issue = 6 | pages = 451–461 | year = 2007 | pmid = 18198431 | doi = 10.3233/NRE-2007-22608 }}{{cite web|title=Amyotrophic Lateral Sclerosis (ALS)|url=http://www.asha.org/public/speech/disorders/ALS/|archive-url=https://web.archive.org/web/20120802064043/http://www.asha.org/public/speech/disorders/ALS/|url-status=dead|archive-date=2 August 2012|publisher=American Speech-Language-Hearing Association, Rockville, MD|access-date=30 November 2016}} [275] => [276] => Occupational therapy and special equipment such as [[assistive technology]] can also enhance people's independence and safety throughout the course of ALS. Gentle, low-impact [[aerobic exercise]] such as performing activities of daily living, walking, swimming, and [[Stationary bicycle|stationary bicycling]] can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful [[spasticity]] and shortening (contracture) of muscles.{{cite journal | vauthors = Majmudar S, Wu J, Paganoni S | title = Rehabilitation in amyotrophic lateral sclerosis: why it matters | journal = Muscle & Nerve | volume = 50 | issue = 1 | pages = 4–13 | date = July 2014 | pmid = 24510737 | pmc = 4433000 | doi = 10.1002/mus.24202 }} Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles because muscle exhaustion can lead to a worsening of symptoms associated with ALS, rather than providing help to people with ALS. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help people remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable ALS people to retain as much safety and independence in activities of daily living as possible.{{cite journal | vauthors = Arbesman M, Sheard K | title = Systematic review of the effectiveness of occupational therapy-related interventions for people with amyotrophic lateral sclerosis | journal = The American Journal of Occupational Therapy | volume = 68 | issue = 1 | pages = 20–26 | year = 2014 | pmid = 24367951 | doi = 10.5014/ajot.2014.008649 | doi-access = free }} Since respiratory insufficiency is the primary cause of mortality, physical therapists can help improve respiratory outcomes in people with ALS by implementing pulmonary physical therapy. This includes inspiratory muscle training, lung volume recruitment training, and manual assisted cough therapy aimed at increasing respiratory muscle strength as well as increasing survival rates.{{cite journal | vauthors = Macpherson CE, Bassile CC | title = Pulmonary Physical Therapy Techniques to Enhance Survival in Amyotrophic Lateral Sclerosis: A Systematic Review | journal = Journal of Neurologic Physical Therapy | volume = 40 | issue = 3 | pages = 165–175 | date = July 2016 | pmid = 27164308 | doi = 10.1097/NPT.0000000000000136 | s2cid = 7279853 }} [277] => [278] => People with ALS who have difficulty speaking or swallowing may benefit from working with a [[Speech-language pathology|speech-language pathologist]]. These health professionals can teach people adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of [[augmentative and alternative communication]] such as voice amplifiers, speech-generating devices (or voice output communication devices) or low-tech communication techniques such as head-mounted laser pointers, [[Letter board#Communication Board|alphabet boards]] or yes/no signals. [279] => [280] => ===Nutrition=== [281] => [[File:Percutaneous endoscopic gastrostomy-tube.jpg|thumb|A [[gastrostomy]] tube is placed through the wall of the abdomen into the stomach.]] [282] => Preventing [[weight loss]] and [[malnutrition]] in people with ALS improves both survival and quality of life. Weight loss in ALS is often caused by muscle wasting and increased resting energy expenditure. Weight loss may also be secondary to reduced food intake since [[dysphagia]] develops in about 85% of people with ALS at some point over the course of their disease. Therefore, regular periodic assessment of the weight and swallowing ability in people with ALS is very important. Dysphagia is often initially managed via dietary changes and modified swallowing techniques. People with ALS are often instructed to avoid dry or chewy foods in their diet and instead have meals that are soft, moist, and easy to swallow. Switching to thick liquids (like fruit nectar or smoothies) or adding thickeners (to thin fluids like water and coffee) may also help people facing difficulty swallowing liquids. There is tentative evidence that high-calorie diets may prevent further weight loss and improve survival, but more research is still needed. [283] => [284] => A [[feeding tube]] should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water. This can take the form of a [[gastrostomy]] tube, in which a tube is placed through the wall of the abdomen into the stomach, or (less commonly) a [[nasogastric tube]], in which a tube is placed through the nose and down the esophagus into the stomach. A gastrostomy tube is more appropriate for long-term use than a nasogastric tube, which is uncomfortable and can cause esophageal ulcers. The feeding tube is usually inserted by a [[percutaneous endoscopic gastrostomy]] procedure (PEG). While there is weak evidence that PEG tubes improve survival in people with ALS, no [[Randomized controlled trial|randomized controlled trials]] (RCTs) have yet been conducted to indicate whether enteral tube feeding has benefits compared to continuation of feeding by mouth. Nevertheless, PEG tubes are still offered with the intent of improving the person's quality of life by sustaining nutrition, hydration status, and medication intake. [285] => [286] => ===End-of-life care=== [287] => [[Palliative care]], which relieves symptoms and improves the quality of life without treating the underlying disease, should begin shortly after someone is diagnosed with ALS. Early discussion of end-of-life issues gives people with ALS time to reflect on their preferences for [[end-of-life care]] and can help avoid unwanted interventions or procedures. Once they have been fully informed about all aspects of various life-prolonging measures, they can fill out [[advance directive]]s indicating their attitude toward noninvasive ventilation, invasive ventilation, and feeding tubes. Late in the disease course, difficulty speaking due to muscle weakness ([[dysarthria]]) and cognitive dysfunction may impair their ability to communicate their wishes regarding care. Continued failure to solicit the preferences of the person with ALS may lead to unplanned and potentially unwanted emergency interventions, such as invasive ventilation. If people with ALS or their family members are reluctant to discuss end-of-life issues, it may be useful to use the introduction of gastrostomy or noninvasive ventilation as an opportunity to bring up the subject. [288] => [289] => [[Hospice care]], or palliative care at the end of life, is especially important in ALS because it helps to optimize the management of symptoms and increases the likelihood of a peaceful death. It is unclear exactly when the end-of-life phase begins in ALS, but it is associated with significant difficulty moving, communicating, and, in some cases, thinking. Although many people with ALS fear choking to death (suffocating), they can be reassured that this occurs rarely, less than 1% of the time.{{cite journal | vauthors = Spataro R, Lo Re M, Piccoli T, Piccoli F, La Bella V | title = Causes and place of death in Italian patients with amyotrophic lateral sclerosis | journal = Acta Neurologica Scandinavica | volume = 122 | issue = 3 | pages = 217–223 | date = September 2010 | pmid = 20078446 | doi = 10.1111/j.1600-0404.2009.01290.x | s2cid = 26479278 | doi-access = free }} Most patients die at home, and in the final days of life, opioids can be used to treat pain and [[dyspnea]], while [[benzodiazepine]]s can be used to treat anxiety. [290] => [291] => ==Epidemiology== [292] => ALS is the most common [[motor neuron diseases|motor neuron disease]] in adults and the third most common [[neurodegenerative disease]] after [[Alzheimer's disease]] and [[Parkinson's disease]].{{cite book | vauthors = Checkoway H, Lundin JI, Kelada SN | year = 2011 | chapter = Chapter 22: Neurodegenerative diseases | veditors = Rothman N, Hainaut P, Schulte P, Smith M, Boffetta P, Perera F | title = Molecular Epidemiology: Principles and Practices | publisher = International Agency for Research on Cancer | pages = 408–409 | isbn = 978-9283221630}} Worldwide the number of people who develop ALS yearly is estimated to be 1.9 people per 100,000 per year, while the number of people who have ALS at any given time is estimated to be about 4.5 people per 100,000.{{cite journal | vauthors = Chiò A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA | title = Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature | journal = Neuroepidemiology | volume = 41 | issue = 2 | pages = 118–130 | date = 2013 | pmid = 23860588 | pmc = 4049265 | doi = 10.1159/000351153 }} In Europe, the number of new cases a year is about 2.6 people per 100,000, while the number affected is 7–9 people per 100,000.{{cite journal | vauthors = Hardiman O, Al-Chalabi A, Brayne C, Beghi E, van den Berg LH, Chio A, Martin S, Logroscino G, Rooney J | display-authors = 6 | title = The changing picture of amyotrophic lateral sclerosis: lessons from European registers | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 88 | issue = 7 | pages = 557–563 | date = July 2017 | pmid = 28285264 | doi = 10.1136/jnnp-2016-314495 | url = https://kclpure.kcl.ac.uk/portal/en/publications/the-changing-picture-of-amyotrophic-lateral-sclerosis(93e2a283-3125-4464-88ed-009897be906c).html | url-status = live | access-date = 22 August 2018 | s2cid = 52871105 | archive-url = https://web.archive.org/web/20191221151144/https://kclpure.kcl.ac.uk/portal/en/publications/the-changing-picture-of-amyotrophic-lateral-sclerosis(93e2a283-3125-4464-88ed-009897be906c).html | archive-date = 21 December 2019 | hdl = 2318/1633611 | hdl-access = free }} The lifetime risk of developing ALS is 1:350 for European men and 1:400 for European women. Men have a higher risk mainly because spinal-onset ALS is more common in men than women. The number of those with ALS in the United States in 2015 was 5.2 people per 100,000, and was higher in whites, males, and people over 60 years old.{{cite journal | vauthors = Mehta P, Kaye W, Raymond J, Punjani R, Larson T, Cohen J, Muravov O, Horton K | display-authors = 6 | title = Prevalence of Amyotrophic Lateral Sclerosis - United States, 2015 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 67 | issue = 46 | pages = 1285–1289 | date = November 2018 | pmid = 30462626 | pmc = 5858037 | doi = 10.15585/mmwr.mm6746a1 }} The number of new cases is about 0.8 people per 100,000 per year in east Asia and about 0.7 people per 100,000 per year in south Asia. About 80% of ALS epidemiology studies have been conducted in Europe and the United States, mostly in people of northern European descent. There is not enough information to determine the rates of ALS in much of the world, including Africa, parts of Asia, India, Russia, and South America. There are several geographic clusters in the Western Pacific where the prevalence of ALS was reported to be 50–100 times higher than the rest of the world, including [[Guam]], the [[Kii Peninsula]] of Japan, and [[Western New Guinea]]. The incidence in these areas has decreased since the 1960s;{{cite journal | vauthors = Wijesekera LC, Leigh PN | title = Amyotrophic lateral sclerosis | journal = Orphanet Journal of Rare Diseases | volume = 4 | issue = 4 | pages = 3 | date = February 2009 | pmid = 19192301 | pmc = 2656493 | doi = 10.1186/1750-1172-4-3 | doi-access = free }} the cause remains unknown. [293] => [[File:Prevalence of ALS in the United States by age group, 2012-2015.jpg|thumb|upright=1.5|Estimated prevalence of ALS in the United States by age group, 2012–2015]] [294] => People of all races and ethnic backgrounds may be affected by ALS, but it is more common in whites than in Africans, Asians, or Hispanics.{{cite journal | vauthors = Arthur KC, Calvo A, Price TR, Geiger JT, Chiò A, Traynor BJ | title = Projected increase in amyotrophic lateral sclerosis from 2015 to 2040 | journal = Nature Communications | volume = 7 | issue = 12408 | pages = 12408 | date = August 2016 | pmid = 27510634 | pmc = 4987527 | doi = 10.1038/ncomms12408 | bibcode = 2016NatCo...712408A }} In the United States in 2015, the prevalence of ALS in whites was 5.4 people per 100,000, while the prevalence in blacks was 2.3 people per 100,000. The Midwest had the highest prevalence of the four US Census regions with 5.5 people per 100,000, followed by the Northeast (5.1), the South (4.7), and the West (4.4). The Midwest and Northeast likely had a higher prevalence of ALS because they have a higher proportion of whites than the South and West. Ethnically mixed populations may be at a lower risk of developing ALS; a study in Cuba found that people of mixed ancestry were less likely to die from ALS than whites or blacks. There are also differences in the genetics of ALS between different ethnic groups; the most common ALS gene in Europe is ''C9orf72'', followed by ''SOD1'', ''TARDBP'', and ''FUS'', while the most common ALS gene in Asia is ''SOD1'', followed by ''FUS'', ''C9orf72'', and ''TARDBP''.{{cite journal | vauthors = Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP | title = Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 88 | issue = 7 | pages = 540–549 | date = July 2017 | pmid = 28057713 | doi = 10.1136/jnnp-2016-315018 | s2cid = 41974606 }} [295] => [296] => ALS can affect people at any age, but the peak incidence is between 50 and 75 years and decreases dramatically after 80 years. The reason for the decreased incidence in the elderly is unclear. One thought is that people who survive into their 80s may not be genetically susceptible to developing ALS; alternatively, ALS in the elderly might go undiagnosed because of [[comorbidities]] (other diseases they have), difficulty seeing a neurologist, or dying quickly from an aggressive form of ALS.{{cite journal | vauthors = Luna J, Logroscino G, Couratier P, Marin B | title = Current issues in ALS epidemiology: Variation of ALS occurrence between populations and physical activity as a risk factor | journal = Revue Neurologique | volume = 173 | issue = 5 | pages = 244–253 | date = May 2017 | pmid = 28477849 | doi = 10.1016/j.neurol.2017.03.035 }} In the United States in 2015, the lowest prevalence was in the 18–39 age group, while the highest prevalence was in the 70–79 age group. Sporadic ALS usually starts around the ages of 58 to 63 years, while genetic ALS starts earlier, usually around 47 to 52 years. The number of ALS cases worldwide is projected to increase from 222,801 in 2015 to 376,674 in 2040, an increase of 69%. This will largely be due to the aging of the world's population, especially in developing countries. [297] => [298] => ==History== [299] => [[File:Jean-Martin Charcot.jpg|thumb|upright|The French neurologist [[Jean-Martin Charcot]] coined the term ''amyotrophic lateral sclerosis'' in 1874.]] [300] => [[File:1923 Lou Gehrig.png|thumb|upright|American baseball player [[Lou Gehrig]]. In some countries, especially the United States, ALS is called "Lou Gehrig's disease".]] [301] => Descriptions of the disease date back to at least 1824 by [[Charles Bell]]. In 1850, [[François-Amilcar Aran]] was the first to describe a disorder he named "progressive muscular atrophy", a form of ALS in which only the lower motor neurons are affected.{{cite journal | vauthors = Visser J, de Jong JM, de Visser M | title = The history of progressive muscular atrophy: syndrome or disease? | journal = Neurology | volume = 70 | issue = 9 | pages = 723–727 | date = February 2008 | pmid = 18299524 | doi = 10.1212/01.wnl.0000302187.20239.93 | s2cid = 22629725 }} In 1869, the connection between the symptoms and the underlying neurological problems were first described by [[Jean-Martin Charcot]], who initially introduced the term ''amyotrophic lateral sclerosis'' in his 1874 paper. Flail arm syndrome, a regional variant of ALS, was first described by [[Alfred Vulpian]] in 1886. Flail leg syndrome, another regional variant of ALS, was first described by [[Pierre Marie]] and his student Patrikios in 1918.{{cite journal | vauthors = Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, Willey E, Ampong MA, Ellis CM, Shaw CE, Al-Chalabi A, Leigh PN | display-authors = 6 | title = Natural history and clinical features of the flail arm and flail leg ALS variants | journal = Neurology | volume = 72 | issue = 12 | pages = 1087–1094 | date = March 2009 | pmid = 19307543 | pmc = 2821838 | doi = 10.1212/01.wnl.0000345041.83406.a2 }} [302] => [303] => ===Diagnostic criteria=== [304] => In the 1950s, [[electrodiagnostic testing]] (EMG) and [[nerve conduction velocity]] (NCV) testing began to be used to evaluate clinically suspected ALS. In 1969 [[Electromyography#History|Edward H. Lambert]] published the first EMG/NCS diagnostic criteria for ALS, consisting of four findings he considered to strongly support the diagnosis.{{cite journal | vauthors = Wilbourn AJ | title = Clinical neurophysiology in the diagnosis of amyotrophic lateral sclerosis: the Lambert and the El Escorial criteria | journal = Journal of the Neurological Sciences | volume = 160 | issue = Supplement 1 | pages = S25–S29 | date = October 1998 | pmid = 9851644 | doi = 10.1016/s0022-510x(98)00194-4 | s2cid = 32884687 }} Since then a number of diagnostic criteria have been developed, which are mostly in use for research purposes for inclusion/exclusion criteria, and to stratify patients for analysis in trials. Research diagnostic criteria for ALS include the "El Escorial" in 1994,{{cite journal | vauthors = Brooks BR | title = El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors | journal = Journal of the Neurological Sciences | volume = 124 | issue = Supplement | pages = 96–107 | date = July 1994 | pmid = 7807156 | doi = 10.1016/0022-510x(94)90191-0 | s2cid = 32678612 }} revised in 1998.{{cite journal | vauthors = Brooks BR, Miller RG, Swash M, Munsat TL | title = El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis | journal = Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders | volume = 1 | issue = 5 | pages = 293–299 | date = December 2000 | pmid = 11464847 | doi = 10.1080/146608200300079536 | s2cid = 22725949 }} In 2006, the "Awaji" criteria proposed using EMG and NCV tests to help diagnose ALS earlier,{{cite journal | vauthors = de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M | display-authors = 6 | title = Electrodiagnostic criteria for diagnosis of ALS | journal = Clinical Neurophysiology | volume = 119 | issue = 3 | pages = 497–503 | date = March 2008 | pmid = 18164242 | doi = 10.1016/j.clinph.2007.09.143 | s2cid = 14851649 }} and most recently the "Gold Coast" criteria in 2019.{{cite journal | vauthors = Shefner JM, Al-Chalabi A, Baker MR, Cui LY, de Carvalho M, Eisen A, Grosskreutz J, Hardiman O, Henderson R, Matamala JM, Mitsumoto H, Paulus W, Simon N, Swash M, Talbot K, Turner MR, Ugawa Y, van den Berg LH, Verdugo R, Vucic S, Kaji R, Burke D, Kiernan MC | display-authors = 6 | title = A proposal for new diagnostic criteria for ALS | journal = Clinical Neurophysiology | volume = 131 | issue = 8 | pages = 1975–1978 | date = August 2020 | pmid = 32387049 | doi = 10.1016/j.clinph.2020.04.005 | s2cid = 215823371 | doi-access = free | hdl = 10451/48432 | hdl-access = free }} [305] => [306] => ===Name=== [307] => {{See also|Motor neuron diseases}} [308] => ''Amyotrophic'' comes from [[Greek language|Greek]]: ''a-'' means "no", ''myo-'' (from ''mûs'') refers to "muscle", and ''trophḗ'' means "nourishment". Therefore, ''[[amyotrophy]]'' means "muscle malnourishment" or the wasting of muscle tissue.{{cite web | url = https://www.mda.org/disease/amyotrophic-lateral-sclerosis | title = ALS: Amyotrophic Lateral Sclerosis | author = | website = Muscular Dystrophy Association | archive-url = https://web.archive.org/web/20180806173221/https://www.mda.org/disease/amyotrophic-lateral-sclerosis | archive-date = 6 August 2018 | url-status=live | access-date = 23 December 2018 | date = 18 December 2015}} ''Lateral'' identifies the locations in the spinal cord of the affected motor neurons. ''[[Sclerosis (medicine)|Sclerosis]]'' means "scarring" or "hardening" and refers to the death of the motor neurons in the spinal cord.{{cite web | url = http://www.alsa.org/about-als/what-is-als.html | title = What is ALS? | author = | website = The ALS Association | archive-url = https://web.archive.org/web/20181221191534/http://www.alsa.org/about-als/what-is-als.html | archive-date = 21 December 2018 | url-status=live | access-date = 23 December 2018}} [309] => [310] => ALS is sometimes referred to as ''Charcot's disease'' (not to be confused with [[Charcot–Marie–Tooth disease]] or [[Charcot joint disease]]), because [[Jean-Martin Charcot]] was the first to connect the clinical symptoms with the pathology seen at autopsy.{{cite journal | vauthors = Goetz CG | title = Amyotrophic lateral sclerosis: early contributions of Jean-Martin Charcot | journal = Muscle & Nerve | volume = 23 | issue = 3 | pages = 336–343 | date = March 2000 | pmid = 10679709 | doi = 10.1002/(SICI)1097-4598(200003)23:3<336::AID-MUS4>3.0.CO;2-L | s2cid = 5917354 }} The British neurologist [[Russell Brain]] coined the term ''motor neurone disease'' in 1933 to reflect his belief that ALS, progressive bulbar palsy, and progressive muscular atrophy were all different forms of the same disease.{{cite book | vauthors = Gordon PH | year = 2006 | chapter = Chapter 1: History of ALS | veditors = Mitsumoto H, Przedborski S, Gordon PH | title = Amyotrophic Lateral Sclerosis | publisher = CRC Press | page = 9 | isbn = 978-0824729240}} In some countries, especially the United States, ALS is called ''Lou Gehrig's disease''{{cite journal | vauthors = Teive HA, Lima PM, Germiniani FM, Munhoz RP | title = What's in a name? Problems, facts and controversies regarding neurological eponyms | journal = Arquivos de Neuro-Psiquiatria | volume = 74 | issue = 5 | pages = 423–425 | date = May 2016 | pmid = 27191240 | doi = 10.1590/0004-282X20160040 | doi-access = free }} after the American [[baseball]] player [[Lou Gehrig]], who developed ALS in 1938.{{cite journal | vauthors = Gordon PH | title = Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials | journal = Aging and Disease | volume = 4 | issue = 5 | pages = 295–310 | date = October 2013 | pmid = 24124634 | pmc = 3794725 | doi = 10.14336/AD.2013.0400295 }} [311] => [312] => In the United States and continental Europe, the term ''ALS'' (as well as ''Lou Gehrig's disease'' in the US) refers to all forms of the disease, including "classical" ALS, [[progressive bulbar palsy]], [[progressive muscular atrophy]], and [[primary lateral sclerosis]].{{cite journal | vauthors = Huynh W, Simon NG, Grosskreutz J, Turner MR, Vucic S, Kiernan MC | title = Assessment of the upper motor neuron in amyotrophic lateral sclerosis | journal = Clinical Neurophysiology | volume = 127 | issue = 7 | pages = 2643–2660 | date = July 2016 | pmid = 27291884 | doi = 10.1016/j.clinph.2016.04.025 | s2cid = 3757685 | doi-access = free }} In the United Kingdom and Australia, the term ''motor neurone disease'' refers to all forms of the disease while ''ALS'' only refers to "classical" ALS, meaning the form with both upper and lower motor neuron involvement. [313] => [314] => == Society and culture == [315] => [[File:ALS Ice Bucket Challenge.ogv|thumb|left|upright=1.2|A student demonstrating the ice bucket challenge]] [316] => {{See also|List of people with motor neuron disease}} [317] => In addition to the baseball player [[Lou Gehrig]] and the theoretical physicist [[Stephen Hawking]] (who notably lived longer than any other known person with the condition) a number of other notable individuals have or have had ALS. People with ALS have been featured in high-profile works such as the memoir ''[[Tuesdays with Morrie]]'' and the critically acclaimed motion picture ''[[The Theory of Everything (2014 film)|The Theory of Everything]]''. [318] => [319] => In August 2014 the "[[Ice Bucket Challenge]]" to raise money for ALS research went [[Viral phenomenon|viral]] online.{{cite news | vauthors = Alexander E | date = 20 August 2014 | title=George Bush delivers possibly the best ALS ice bucket challenge yet| url=https://www.independent.co.uk/news/people/george-bush-delivers-possibly-the-best-als-ice-bucket-challenge-yet-9680934.html| work=The Independent|access-date=20 August 2014| archive-url=https://web.archive.org/web/20140821095115/http://www.independent.co.uk/news/people/george-bush-delivers-possibly-the-best-als-ice-bucket-challenge-yet-9680934.html| archive-date=21 August 2014}} Participants filmed themselves filling a bucket full of ice water and pouring it onto themselves; they then nominated other individuals to do the same. Many participants donated to ALS research at the [[ALS Association]], the [[ALS Therapy Development Institute]], [[ALS Society of Canada]], or [[Motor Neurone Disease Association]] in the UK.{{cite journal | vauthors = Wicks P | title = The ALS ice bucket challenge - can a splash of water reinvigorate a field? | journal = Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration | volume = 15 | issue = 7–8 | pages = 479–480 | date = December 2014 | pmid = 25431828 | doi = 10.3109/21678421.2014.984725 | s2cid = 207581186 | doi-access = free }} [320] => {{clear left}} [321] => [322] => == References == [323] => {{Source-attribution|{{Cite web |title=Amyotrophic Lateral Sclerosis Fact Sheet |url=http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophiclateralsclerosis.htm |archive-url=https://web.archive.org/web/20041118185803/http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophiclateralsclerosis.htm |archive-date=2004-11-18}}}}{{reflist}} [324] => [325] => == External links == [326] => {{Commons category-inline}} [327] => [329] => * [https://www.als.org/ ALS Association Official Website] [330] => * [https://www.als.net/ ALS Therapy Development Institute] [331] => * [https://www.als-mnd.org/ International Alliance of ALS/MND Associations] [332] => * [https://symposium.mndassociation.org/ International Symposium on ALS/MND] [333] => [334] => {{Medical resources [335] => | DiseasesDB = 29148 [336] => | ICD11 = {{ICD11|8B60.0}} [337] => | ICD10 = {{ICD10|G12.2}} [338] => | ICD10CM = {{ICD10CM|G12.21}} [339] => | ICD9 = {{ICD9|335.20}} [340] => | ICDO = [341] => | OMIM = 105400 [342] => | MedlinePlus = 000688 [343] => | eMedicineSubj = neuro [344] => | eMedicineTopic = 14 [345] => | eMedicine_mult = {{eMedicine2|emerg|24}} {{eMedicine2|pmr|10}} [346] => | MeshID = D000690 [347] => | GeneReviewsName = Amyotrophic lateral sclerosis [348] => | GeneReviewsNBK = NBK1450 [349] => | Orphanet = 803 [350] => | Scholia = Q206901 [351] => |RP=amyotrophic-lateral-sclerosis-3}} [352] => [353] => {{CNS diseases of the nervous system|state=collapsed}} [354] => {{Amyotrophic lateral sclerosis}} [355] => {{Authority control}} [356] => [357] => [[Category:Amyotrophic lateral sclerosis| ]] [358] => [[Category:Motor neuron diseases]] [359] => [[Category:Rare diseases]] [360] => [[Category:Unsolved problems in neuroscience]] [361] => [[Category:Systemic atrophies primarily affecting the central nervous system]] [362] => [[Category:Cytoskeletal defects]] [363] => [[Category:Wikipedia medicine articles ready to translate]] [364] => [[Category:Neuromuscular disorders]] [365] => [[Category:Wikipedia neurology articles ready to translate]] [366] => [[Category:Idiopathic diseases]] [] => )
good wiki

ALS

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease in the United States, is a rare but terminal neurodegenerative disorder that results in the progressive loss of both upper and lower motor neurons that normally control voluntary muscle contraction. ALS is the most common form of the motor neuron diseases.

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