Amyotrophic lateral sclerosisFrom Wikipedia, the free encyclopedia"ALS" redirects here. For other uses, seeALS (disambiguation)."Motor neurone disease" redirects here. For the broader group of diseases, seeMotor neuron disease.Amyotrophic lateral sclerosis

AnMRIwith increasedsignalin the posterior part of theinternal capsulewhich can be tracked to themotor cortexconsistent with the diagnosis of ALS.

Classification and external resources

ICD-10G12.2

ICD-9335.20

OMIM105400

DiseasesDB29148

MedlinePlus000688

eMedicineneuro/14emerg/24pmr/10

Patient UKAmyotrophic lateral sclerosis

MeSHD000690

Amyotrophic lateral sclerosis(ALS), also known asLou Gehrig's diseaseandCharcot disease, is a specificdisorder that involves the death of neurons.[1]In the United Kingdom the termmotor neurone disease(MND) is commonly used,[2]while others usethat termfor a group of five conditions of which ALS is the most common.[3]ALS is characterized bystiff muscles,muscle twitching, and gradually worsening weakness due tomuscle wasting. This results in difficultyspeaking,swallowing, and eventuallybreathing.[4]The cause is not known in 90% to 95% of cases.[4]About 510% of cases areinheritedfrom a person's parents.[5]About half of these genetic cases are due to one of two specificgenes. It results in the death of the neurons that controlvoluntary muscles. The diagnosis is based on a person's signs and symptoms with testing done to rule out other potential causes.[4]There is no cure for ALS.[4]A medication calledriluzolemay extend life expectancy by about two to three months.[6]Non-invasive ventilationmay result in both improved quality and length of life.[7]The disease usually starts around the age of 60 and in inherited cases around the age of 50.[5]The average survival from onset to death is three to four years.[8]About 10% survive longer than 10 years.[4]Most die from respiratory failure. In much of the world, rates of ALS are unknown.[5]In Europe and the United States, the disease affects about 2 people per 100,000 per year.[5][9]Descriptions of the disease date back to at least 1824 byCharles Bell.[10]In 1869, the connection between the symptoms and the underlying neurological problems were first described byJean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis.[10]It became well known in the United States when it affected the famous baseball playerLou Gehrig,[1]and in the 20th century whenStephen Hawkinggained fame for his scientific achievements.[11]In 2014 videos of theice bucket challengewent viral on the internet and increased public awareness.[12]Contents[hide] 1Signs and symptoms 1.1Initial symptoms 1.2Progression 1.3Late stages 1.4Eye movement 2Causes 2.1Genetics 2.1.1SOD1 2.2Other factors 3Pathophysiology 3.1Skeletal motor units 3.2Lactate and cinnamate 4Diagnosis 5Management 5.1Medications 5.2Breathing support 5.3Therapy 5.4Nutrition 5.5Palliative care 6Epidemiology 7History 7.1Etymology 8Society and culture 9Research 10References 11External linksSigns and symptoms[edit]The disorder causes muscle weakness andatrophythroughout the body due to the degeneration of theupperandlower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and themuscles responsible for eye movementare usually spared until the final stages of the disorder.[13]Cognitive functionis generally spared for most people, although some (about 5%) also developfrontotemporal dementia.[14]A higher proportion of people (3050%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailedneuropsychological testing. Infrequently, ALS coexists in individuals who also experience dementia, degenerative muscle disorder, and degenerative bone disorder as part of a syndrome calledmultisystem proteinopathy.[15]Sensory nervesand theautonomic nervous systemare generally unaffected, meaning the majority of people with ALS maintainhearing,sight,touch,smell, andtaste.[16]Initial symptoms[edit]The start of ALS may be so subtle that the symptoms are overlooked.[17]The earliest symptoms of ALS are muscle weakness and/or muscle atrophy. Other presenting symptoms include trouble swallowing, breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/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.About 75% of people contracting the disorder first experience weakness or atrophy in an arm or leg and this is known as "limb-onset" ALS. Awkwardness when walking or running or even tripping over or stumbling may be experienced and often this is marked by walking with a "dropped foot" which drags gently on the ground. Or if arm-onset, difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock may be experienced. Occasionally, the symptoms remain confined to one limb for a long period of time or for the duration of the illness; this is known asmonomelic amyotrophy.About 25% of cases begin asprogressive bulbar palsytermed "bulbar-onset" ALS. Initial symptoms will mainly be of difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty in swallowing and loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS, where theintercostal musclesthat support breathing are affected first. A small proportion of people may also present with what appears to befrontotemporal dementia, but later progresses to include more typical ALS symptoms.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. An abnormal reflex commonly calledBabinski's signalso indicates upper motor neuron damage. 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 (fasciculations) although twitching is not a diagnostic symptom and more of a side effect so twitching would either occur after or accompany weakness and atrophy. Around 1545% of people experiencepseudobulbar affect, aneurological disorderalso known as "emotional lability", which consists of uncontrollable laughter, crying, or smiling, attributable to degeneration of bulbar upper motor neurons, resulting in exaggeration of motor expressions of emotion.[citation needed]For ALS to be diagnosed, symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes must be present.Progression[edit]Although the order and rate of symptoms varies from person to person, most people eventually are not able to walk or use their hands and arms. They also lose the ability to speak and swallow food, while most end up on a portableventilator, called a BiPAP. The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale Revised (ALSFRS-R)", a 12-item instrument administered as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, patients lose about 0.9 FRS points per month. A survey-based study amongst clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.[18]Regardless of the part of the body first affected by the disorder, muscle weakness and atrophy spread to other parts of the body as the disorder progresses. In limb-onset ALS, symptoms usually spread from the affected limb to the opposite limb before affecting a new body region, whereas in bulbar-onset ALS, symptoms typically spread to the arms before the legs.Disorder progression tends to be slower in patients who are younger than 40 at onset,[19][20]are mildly obese,[21]have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[22]Conversely, progression is faster and prognosis poorer in people with bulbar-onset disorder, respiratory-onset disorder, and frontotemporal dementia.[22]TheCX3CR1allelicvariants have also been shown to have an effect on the disorder's progression and life expectancy.[23]Late stages[edit]Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die from respiratory failure, usually within three to five years from the onset of symptoms. The median survival time from onset to death is around 39 months, and only 4% survive longer than 10 years.[24]GuitaristJason Beckerhas lived since 1989 with the disorder, while physicistStephen Hawkinghas survived for more than 50 years, but they are considered unusual cases.[25]Difficulty in chewing and swallowing makes eating very difficult and increases the risk of choking or of aspirating food into the lungs. In later stages of the disorder,aspiration pneumoniacan develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm andintercostal musclesof therib cagethat support breathing weaken, measures oflung functionsuch asvital capacityand inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. Most people with ALS die of respiratory failure orpneumonia.In late stages, theoculomotor nervethat controls the movements of the eye can be affected as can theextraocular muscles(EOMs). The eye movements remain unaffected largely until the later stages due to differences in the extraocular muscles compared to the skeletal muscles that are initially and readily affected. In the disease's final stages, a person's condition may resemblelocked-in syndrome.[26]Eye movement[edit]People with ALS may have difficulty in generating voluntaryfast movements of the eye.[27]The speed of eye movement is slower in people with ALS.[27]Problems in generatingsmooth pursuitand convergence movements have also been noted.[27]Testing thevestibulo-ocular reflexshould help in identifying these problems.[28]Theelectrooculography(EOG) technique measures theresting potentialof theretina. EOG findings in people with ALS show progressive changes that correlate with disorder progression, and provide a measurement for clinically evaluating the effects of disorder progression on oculomotor activity.[28]Additionally, EOG may allow earlier detection of problems with the eyes.The embryonic lineage ofEOMsdiffers from that ofsomite-derived muscles. EOMs are unique because they continuously remodel through life and maintain a population of activesatellite cellsduring aging.[29]EOMs have significantly more myogenic precursor cells than limb skeletal muscles.[29]Causes[edit]Genetics[edit]About 510% of cases are directly inherited from a person's parents.[5]Overall,first-degree relativesof an individual with ALS have a 1% risk of developing ALS.[30][31]A defect onchromosome 21, which codes forsuperoxide dismutase, is associated with about 20% of familial cases of ALS, or about 2% of ALS cases overall.[32][33][34]This mutation is believed to be transmitted in anautosomal dominantmanner, and has over a hundred different forms of mutation. The most common ALS-causing mutation is a mutantSOD1gene, seen in North America; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries,D90A-SOD1, is more slowly progressive than typical ALS, and people with this form of the disorder survive for an average of 11 years.[35]In 2011, a genetic abnormality known as a hexanucleotide repeat was found in a region calledC9orf72, which is associated with ALS combined with frontotemporal dementia ALS-FTD,[36]and accounts for some 6% of cases of ALS among white Europeans.[37]The gene is also found in people ofFilipinodescent.[37]TheUBQLN2gene encodes production of the protein ubiquilin 2 in the cell, which is a member of the ubiquilin family and controls the degradation of ubiquitinated proteins. Mutations inUBQLN2interfere with protein degradation, leading to neurodegeneration and causing dominantly inherited, chromosome X-linked ALS and ALS/dementia.[38]To date, a number of genetic mutations have been associated with various types of ALS. The currently known associations are:TypeOMIMGeneLocusRemarks

ALS1105400SOD121q22.1The most common form of familial ALS

ALS2205100ALS22q33.1

ALS3606640?18q21

ALS4602433SETX9q34.13

ALS5602099?15q15.1q21.1Juvenile onset

ALS6608030FUS16p11.2

ALS7608031?20p13

ALS8608627VAPB20q13.3

ALS9611895ANG14q11.2

ALS10612069TARDBP1p36.2

ALS11612577FIG46q21

ALS12613435OPTN10p13

ALS13183090ATXN212q24.12

ALS14613954VCP9p13.3Recent new study shows strong link in ALS mechanism[15][39]

ALS15300857UBQLN2Xp11.23p11.1Described in one family[40]

ALS16614373SIGMAR19p13.3Juvenile onset, very rare, described only in one family[41]

ALS17614696CHMP2B3p11Very rare, reported only in a handful of people

ALS18614808PFN117p13.3Very rare, described only in a handful of Chinese families[42]

ALS19615515ERBB42q34Very rare, as of late 2013 described only in four people[43]

ALS20615426HNRNPA112q13Very rare, as of late 2013 described only in two people[44]

ALS-FTD105550C9orf729p21.2Accounts for around 6% of ALS cases among white Europeans

SOD1[edit]In 1993, scientists discovered that mutations in the gene (SOD1) that produces theCu-Znsuperoxide dismutase(SOD1) enzyme were associated with around 20% of familial ALS. This enzyme is a powerfulantioxidantthat protects the body from damage caused bysuperoxide, a toxic free radical generated in the mitochondria.Free radicalsare highly reactive molecules produced by cells during normalmetabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. To date, over 110 different mutations inSOD1have been linked with the disorder, some of which (such asH46R) have a very long clinical course, while others, such asA4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis) is upregulated.A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of free radicals. A gain of SOD1 function could be toxic in other ways.[45][46]Studies involvingtransgenicmice have yielded several theories about the role ofSOD1in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking theSOD1gene entirely do not customarily develop ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a shortened lifespan. This indicates the toxic properties of the mutantSOD1are a result of a gain in function rather than a loss of normal function. In addition, aggregation of proteins has been found to be a common pathological feature of both familial and sporadic ALS (proteopathy). Interestingly, in mutantSOD1mice (most commonly, theG93Amutant), aggregates (misfolded protein accumulations) of mutantSOD1were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration.[47]Aggregate accumulation of mutantSOD1is suspected to play a role in disrupting cellular functions by damagingmitochondria,proteasomes, protein foldingchaperones, or other proteins.[48]Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutantSOD1toxicity. Critics have noted that in humans,SOD1mutations cause only 2% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. To date, the ALS-SOD1 mice remain the best model of the disease for preclinical studies, but it is hoped that more useful models will be developed.An online database is available which was designed to provide both thescientific communityand the wider public with up-to-date information on ALS genetics. This is known as ALSOD website originally designed for theSOD1gene in 1999, but since upgraded to include over 40 ALS-related genes.Other factors[edit]Where no family history of the disease is presenti.e., in around 90% of cases no cause is known for ALS. Possible associations for which evidence is inconclusive include head trauma, military service, frequent drug use, and participation in contact sports.[medical citation needed]Studies also have focused on the role ofglutamatein motor neuron degeneration. Glutamate is one of theneurotransmittersin the brain. Scientists have found, compared with healthy people, people with ALS have higher levels of glutamate in theirserumand spinal fluid.[33]Riluzoleis currently the only FDA-approved drug for ALS and targets glutamate transporters. It only has a modest effect on survival, however, suggesting that excess glutamate is not the sole cause of the disease.Certain studies suggested a link between sporadic ALS, specifically in athletes, and a diet enriched withbranched-chain amino acids, a common dietary supplement among athletes, which cause cell hyperexcitability resembling that usually observed in people with ALS. The proposed underlying mechanism is that cell hyperexcitability results in increased calcium absorption by the cell, and thus brings about cell death of neuronal cells, which have particularly low calcium buffering capabilities.[49][50]Some evidence supports superoxide dismutase 1 (SOD1) protein misfolding propagates between molecules in a similar fashion toprions.[51]Similarly, it has been proposed that incorporation of the cyanobacterial toxin -methylamino-l-alanine (BMAA) leads to anotherprion-like protein misfolding propagation.[52][53]Another very common factor associated with ALS is alesionto the motor system in areas such as the frontotemporal lobes.[54]Lesions in these areas often show signs of early deficit, which can be used to predict the loss ofmotor function, and result in the spread of ALS.[54]The mechanisms of ALS are present long before any signs or symptoms become apparent.[55]Before any muscular atrophy becomes apparent during ALS, roughly one-third of themotor neuronsmust be destroyed.[55]Many other potential risk factors including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated, but are without consistent findings.[56]Pathophysiology[edit]The defining feature of ALS is the death of bothupperandlower motor neuronsin the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-richinclusionsin their cell bodies andaxons. This may be partly due to defects in protein degradation.[57]These inclusions often containubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1,TAR DNA binding protein(TDP-43, or TARDBP), and/orFUS.[58]Skeletal motor units[edit]Despite sharing fixed sequences of recruitment, extraocular muscles (EOMs) and skeletal muscles exhibit different characteristics. The following are characteristics of EOMs that differ from skeletal motor units.[59] One neural fiber connects with only one or two muscle fibers No ocularstretch reflexes, despite being rich inmuscle spindles No recurrent inhibition No special fast-twitch or slow-twitch muscles All eye motor neurons participate equally in all types of eye movementsnot specialized for saccades or smooth pursuitDifferences are also noted between healthy and affected EOMs. EOMs from postmortem donors preserved theircytoarchitecture, as compared to limb muscles. Healthy EOMs consist of a central global layer (GL) facing the globe and a thin orbital layer (OL) facing the walls of the orbit.[60]EOMs affected by ALS preserve the GL and OL organization.[60]EOMs possess the neurotrophic factorsbrain-derived neurotrophic factor(BDNF) andglial cell line-derived neurotrophic factor(GDNF), and these neuroprotective factors are also preserved in EOMs affected by ALS.[60]Lamininis a structural protein typically found in theneuromuscular junction(NMJ). Ln4 is a laminin isoform that is a hallmark of skeletal muscle NMJs.[61]People with ALS showed preserved Ln4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the same people.[61]Preservation of laminin expression may play a role in preserving EOM integrity in people with ALS. People with sporadic ALS (sALS) have increased levels of intracelluar calcium, causing increasedneurotransmitterrelease.[62]Passive transfer of sera from people with sALS increases spontaneous transmitter release in spinal, but not EOM terminals;[62]therefore, EOMs are assumed to be resistant to changes in physiologic conditions typically found in ALS.However, some effects of the disorder were noted. EOMs affected by ALS had a larger variation in fiber size compared to those in age-matched healthy controls.[60]EOMs exhibited both clustered and scattered atrophic andhypertrophicfibers that are characteristic of disorder, but these muscles showed significantly less damage compared to limb muscles from the same donors.[60]These EOMs also showed an increase inconnective tissueand areas of fatty replacement in compensation of fiber loss and atrophy.[60]Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei, has been noted in ALS patients.[27]Additionally,myosin heavy chaincontent of the EOM fibers was altered, with a loss of normal expression of MyHCslow tonic in the GL and the OL did not contain MyHCemb, which is normally expressed in this layer.[60]This change may represent a change in innervation pattern that may include reinnervation by a different type of motor neuron or loss of multiple innervations. Changes in MyHCslow and MyHCemb are the only fiber changes seen in EOMs, leaving the EOM fiber composition relatively normal.[60]Because EOMs are normally highly innervated, any denervation is compensated for by neighbouring axons which preserve function.[60]Lactate and cinnamate[edit]Lactic acidis an end product ofglycolysisand is known to cause muscle fatigue.Lactate dehydrogenase(LDH) enzyme exerts its effects bidirectionally and is able to oxidize lactate intopyruvateso it can be used in theKrebs cycle. In EOM, lactate sustains muscle contraction during increased activity levels. EOMs that have high LDH activity are thought to be resistant to ALS.[63]Cinnamateis a blocker of lactate transport and exogenous lactate on fatigue resistance. Cinnamate is able to cause fatigue in EOM, while decreasing EOM endurance and residual force; however, cinnamate has no effect on theextensor digitorum longus musclein the leg.[63]In contrast, replacingglucosewith exogenous lactate increases fatiguability of EDL muscles but not EOMs.[63]Fatiguability in EOMs was only found when a combination of exogenous lactacte plus cinnamate replaced glucose.[63]Diagnosis[edit]

MRI (axialFLAIR) demonstrates increasedT2signal within theposterior part of the internal capsule, consistent with the diagnosis of ALS.No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive.[4]Instead, the diagnosis of ALS is primarily based on the symptoms and signs thephysicianobserves in the person and a series of tests to rule out other diseases.[4]Physicians obtain the person's fullmedical historyand usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles,hyperreflexia, and spasticity are worsening.[4]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.[4]One of these tests iselectromyography(EMG), a special recording technique that detects electrical activity in muscles.[4]Certain EMG findings can support the diagnosis of ALS.[4]Another common test measuresnerve conduction velocity(NCV).[4]Specific abnormalities in the NCV results may suggest, for example, that the patient has a form ofperipheral neuropathy(damage to peripheral nerves) ormyopathy(muscle disease) rather than ALS. While amagnetic resonance imaging(MRI) is often normal in people with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor,multiple sclerosis, aherniateddisk in the neck,syringomyelia, or cervicalspondylosis.[4]Based on the person's symptoms and findings from the examination and from these tests, the physician may order tests on blood andurinesamples to eliminate the possibility of other diseases, as well as routine laboratory tests.[4]In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.[4]Viralinfectious diseasessuch as human immunodeficiency virus (HIV), human T-cell leukaemia virus (HTLV),Lyme disease,[64]syphilis[65]andtick-borne encephalitis[66]can in some cases cause ALS-like symptoms.[4]Neurological disorders such as multiple sclerosis,post-polio syndrome,multifocal motor neuropathy,CIDP,spinal muscular atrophy, andspinal and bulbar muscular atrophycan also mimic certain aspects of the disease and should be considered.[4]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.[67]Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, patients should always obtain a specialist neurological opinion, so alternative diagnoses are clinically ruled out.However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10%.[68][69]In one study, 190 patients who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these patients (16%) had their diagnosis completely changed during the clinical observation development period.[70]In the same study, three patients had a false negative diagnosis,myasthenia gravis(MG), an autoimmune disease. MG can mimic ALS and other neurological disorders leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.[71]Myasthenic syndrome, also known as Lambert-Eaton syndrome, can mimic ALS and its initial presentation can be similar to that of MG.[72][73]Management[edit]Management of ALS attempts to relieve symptoms and extend life expectancy. This supportive care is best provided by multidisciplinary teams of health care professionals working with the person and their caregivers to keep them as mobile and comfortable as possible.Medications[edit]Riluzole(Rilutek) has been found to modestly improve survival.[74]It lengthens survival by several months, and may have a greater survival benefit for those with abulbaronset. It also extends the time before a person needs ventilation support. People taking it must be monitored for liver damage (occurring in about 10% of people taking the drug).[75]It is approved byFood and Drug Administration(US) and recommended by theNational Institute for Clinical Excellence(UK). Riluzole does not reverse damage already done to motor neurons.[76]Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva andphlegm. Drugs also are available to help patients with pain, depression, sleep disturbances, dysphagia, and constipation.Baclofenanddiazepamare often prescribed to control the spasticity caused by ALS, andtrihexyphenidyloramitriptylinemay be prescribed when people with ALS begin having trouble swallowing their saliva.[13]Breathing support[edit]When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive pressure ventilation,bilevel positive airway pressure(BiPAP), orbiphasic cuirass ventilation(BCV) may be used to aid breathing. Such devices artificially inflate the person's lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by several positive expiratory breaths.[77]People may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as atracheotomy, in which a plasticbreathing tubeis inserted directly in the person's windpipe through an opening in the neck.Persons and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the person's quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support and have deep discussions on quality of life. Some persons under long-term tracheotomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheotomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough, though in all cases speech will be lost as the disease progresses. This technique preserves speech in some persons with long-term mechanical ventilation. Other persons may be able to use a speaking valve such as a Passey-Muir speaking valve with the assistance and guidance of a speech-language pathologist.External ventilation machines that use the ventilation mode of BiPAP are frequently used to support breathing, initially at night, and later during the daytime, as well. The use of BPAP (more often referred to as noninvasive ventilation, NIV) is only a temporary remedy, however, and long before BPAP stops being effective, persons should decide whether to have atracheotomyand long-term mechanical ventilation. At this point, some persons choosepalliative hospice care.Therapy[edit]Physical therapyplays a large role in rehabilitation for individuals with ALS. Specifically, physical and occupational therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, preventing complications, and promoting functional independence.[78]Occupational therapy and special equipment such asassistive technologycan also enhance patients' independence and safety throughout the course of ALS. Gentle, low-impactaerobic exercisesuch as performing activities of daily living, walking, swimming, andstationary bicyclingcan strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help patients remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable people to retain as much safety and independence in activities of daily living as possible.ALS patients who have difficulty speaking may benefit from working with aspeech-language pathologist. These health professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use ofaugmentative and alternative communicationsuch as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such asalphabet boardsor yes/no signals.Nutrition[edit]Patients and caregivers can learn from dieticians how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. Occupational therapists can assist with recommendations for adaptive equipment to ease the physical task of self-feeding. Speech-language pathologists make food choice recommendations that are more conducive to their unique deficits and abilities. When patients can no longer get enough nourishment from eating, doctors may advise inserting afeeding tubeinto the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent patients from eating food orally if they wish.Researchers have stated, "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake"[79]and have a severe loss of appetite.[80]Both animal[81]and human research[79][unreliable medical source?][82][unreliable medical source?]suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their caloric intake. As of 2012, "a lack of robust evidence for interventions" remained for the management of weight loss.[83]Palliative care[edit]Social workersand home care andhospicenurses help people with ALS, their families, and caregivers with the medical, emotional, and financial challenges of coping, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durablepower of attorney, preparing aliving will, and finding support groups for patients and caregivers. Home nurses are available not only to provide medical care, but also to teach caregivers about tasks such as maintaining respirators, giving feedings, and moving patients to avoid painful skin problems and contractures. Home hospice nurses work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain at home. The home hospice team can also counsel patients and caregivers about end-of-life issues.Epidemiology[edit]In much of the world, rates of ALS are unknown.[5]In Europe, the disease affects about 2.2 people per 100,000 per year.[5]In the United States, more than 5,600 are diagnosed every year, and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 people per year.[84]ALS is classified as a rare disease, but is the most common motor neuron disease. People of all races and ethnic backgrounds are affected. One or two of 100,000 people develop ALS each year.[85]Amyotrophic lateral sclerosis affects around 30,000 Americans.[86]ALS cases are estimated at 1.24.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations.[87]Filipinosare second to Caucasians in terms of ALS prevalence with 1.1-2.8 per 100,000 individuals.[86]Reports have been made of several "clusters" including threeAmerican footballplayers from theSan Francisco 49ers, more than 50association footballplayers in Italy,[88]three association football-playing friends in the south of England,[89]and conjugal (husband and wife) cases in the south of France.[90][91][92][93][94]Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a higher risk with increasing age.History[edit]Descriptions of the disease date back to at least 1824 byCharles Bell.[10]It became well known in the United States when it affected famous baseball playerLou Gehrig,[95]and later when theice bucket challengebecame popular in 2014.[96]English scientistAugustus Wallerdescribed the appearance of shriveled nerve fibers in 1850. In 1869, the connection between the symptoms and the underlying neurological problems were first described byJean-Martin Charcot, who introduced the termamyotrophic lateral sclerosisin his 1874 paper.[10]In 1881, the article was translated into English and published in a three-volume edition ofLectures on the Diseases of the Nervous System.ALS became acause clbrein the United States in 1939 when baseball legendLou Gehrig's career, and two years later, his life, was ended by the disease.[95]In the 1950s, an ALSepidemicoccurred among theChamorro peopleonGuam.By 1991, researchers had linked chromosome 21 to familial ALS (FALS). In 1993, theSOD1gene on chromosome 21 was found to play a role in some cases of FALS. In 1996, riluzole became the first FDA-approved drug for ALS.In 1998, the El Escorial criteria were developed as the standard for classifying ALS patient in clinical research. The next year, the revised ALS Functional Rating Scale was published and soon becomes a gold standard for rating the declines in ALS patient in clinical research. Noncoding repeat expansions inC9ORF72were found to be a major cause of ALS and frontotemporal dementia in 2011.Etymology[edit]Amyotrophic comes from theGreekwordamyotrophia:a-means "no",myorefers to "muscle", andtrophiameans "nourishment";amyotrophiatherefore means "no muscle nourishment," which describes the characteristicatrophyof the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where affected portions of the nerve cells are located. Degeneration in this area leads to scarring or hardening ("sclerosis").Society and culture[edit]See also:Category:People with motor neurone diseaseIn August 2014, a challenge wentviralonline which was commonly known as the "ALS Ice Bucket Challenge".[96]Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US$10 (or a similar amount in their local currency) to ALS research at theALS Association, orMotor Neurone Disease Associationin the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of August 25, the Ice Bucket Challenge raised $79.7 million for the ALS Association, compared to $2.5 million raised over the same period in 2013. Many celebrities have taken part in the challenge.[97]ALS is the central topic of the 2014 movieYou're Not You, directed byGeorge C. Wolfe, withHilary Swank,Emmy RossumandJosh Duhamelplaying the main characters.[98]Research[edit]A number ofclinical trialsare underway globally for ALS; a comprehensive listing of trials in the US can be found atClinicalTrials.gov. The world's largest genetic study, calledproject MinE, initiated by two people with ALS is going on currently. It is a crowdfunded research project with many countries involved to discover more genes.[99]A phase-II trial on tirasemtiv has been completed with a follow-on phase-IIb study in progress under the name "BENEFIT-ALS". Results of the first study are available here.[100][unreliable medical source?][101][verification needed]The current trial is an international, placebo-controlled, multiple-center study on 680 participants. This makes it one of the largest studies to date. A phase-II trial onozanezumabis in progress. It is a large multiple-site international research project sponsored byGlaxoSmithKline.A phase-II clinical trial is being conducted by BrainStorm Cell Therapeutics at theHadassah Medical Centerin Israel and interim results "demonstrated a tendency toward stabilization in some parameters in the ALS Functional Rating Scale."[102][103]People in the trial have bone marrow stem cells removed and differentiated in a clean room into cells that express neurotropic factors. The cells are injected back into the same person by intrathecal and intramuscular injections. A second phase-II trial is expected to open in the United States at several institutions including theMayo Clinic.[104]References[edit]1. ^Jump up to:abKelly, Evelyn B. (2013).Encyclopedia of human genetics and disease. Santa Barbara, Calif.: Greenwood. pp.7980.ISBN978-0-313-38713-5.2. Jump up^"Motor neurone disease".http://www.nhs.uk/. Retrieved2 January2015.3. Jump up^Ellison, edited by Seth Love, David N. Louis, David W. 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