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{{Clinpsy}}
 
{{Clinpsy}}
{{Infobox_Disease
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| Name = Amyotrophic lateral sclerosis
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{{Infobox disease
| Image =
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| Name = Amyotrophic Lateral Sclerosis<br/>(Lou Gehrig's Disease)
| Caption =
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| Image = ALS Coronal.jpg
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| Caption = This [[Magnetic resonance imaging|MRI]] ([[Sagittal plane|parasagittal]] [[Fluid attenuated inversion recovery|FLAIR]]) demonstrates increased [[Magnetic resonance imaging|T2 signal]] within the posterior part of the [[internal capsule]] and can be tracked to the [[White matter|subcortical white matter]] of the [[motor cortex]], outlining the [[corticospinal tract]], consistent with the clinical diagnosis of ALS.
 
| DiseasesDB = 29148
 
| DiseasesDB = 29148
 
| ICD10 = {{ICD10|G|12|2|g|10}}
 
| ICD10 = {{ICD10|G|12|2|g|10}}
 
| ICD9 = {{ICD9|335.20}}
 
| ICD9 = {{ICD9|335.20}}
| ICDO =
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| ICDO =
 
| OMIM = 105400
 
| OMIM = 105400
 
| MedlinePlus = 000688
 
| MedlinePlus = 000688
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'''Amyotrophic lateral sclerosis''', or '''ALS''', is a disease marked by gradual degeneration of the nerve cells in the central nervous system that control voluntary [[muscle]] movement. The disorder causes muscle weakness and atrophy throughout the body. In ALS, both the [[upper motor neuron]]s and the [[lower motor neuron]]s degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away ([[atrophy]]), and have [[fasciculation]]s because of denervation. Eventually, the [[brain]] completely loses its ability to initiate and control voluntary movement. The disease does not necessarily debilitate the patient's mental functioning in the same manner as [[Alzheimer's disease]] does or other neurological conditions do. Instead, those suffering advanced stages of the disease may retain the same [[memory|memories]], [[Wiktionary:personality|personality]], and [[intelligence]] they had before its onset.
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'''Amyotrophic lateral sclerosis''' ('''ALS''') also referred to as '''motor neurone disease''' in some [[Commonwealth of Nations|British Commonwealth]] countries and as '''Lou Gehrig's disease's disease''' in North America is a debilitating disease with varied [[etiology (medicine)|etiology]] characterized by rapidly progressive [[weakness]], [[muscle atrophy]] and [[fasciculations]], muscle [[spasticity]], difficulty speaking ([[dysarthria]]), difficulty swallowing ([[dysphagia]]), and decline in breathing ability. ALS is the most common of the five [[motor neuron disease]]s.
   
<!-- Unsourced image removed: [[Image:lou-gehrig.jpg|thumb|250px|[[Lou Gehrig]], whose ALS was diagnosed in 1939]] -->
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==Signs and symptoms==
==Etymology==
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The disorder causes muscle weakness and atrophy throughout the body caused by degeneration of the [[upper motor neuron|upper]] and [[lower motor neuron]]s. Unable to function, the muscles weaken and [[atrophy]]. Affected individuals may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel sphincters and the muscles responsible for eye movement are usually, but not always, spared.<ref name="PubMed Health">http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001708/</ref>
The word ''[[amyotrophic]]'' is Greek in origin. ''A'' means no or negative, ''myo'' refers to [[muscle]], and ''trophic'' means nourishment. When put together it means "no-muscle-nourishment." ''[[Anatomical terms of location|Lateral]]'' identifies the areas of the [[spinal cord]] where portions of the nerve cells that signal and control the muscles are located. As this area degenerates it leads to scarring or hardening ([[sclerosis]]) in the region. <ref>[http://www.alsa.org/als/what.cfm What is ALS - The ALS Association] Retrieved [[October 24]], [[2006]]</ref>
 
   
==Epidemiology, causes and risk factors==
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Cognitive function is generally spared for most patients, although some (about 5%) also have [[frontotemporal dementia]].<ref name="pmid17945153">{{cite journal |author=Phukan J, Pender NP, Hardiman O |title=Cognitive impairment in amyotrophic lateral sclerosis |journal=Lancet Neurol |volume=6 |issue=11 |pages=994–1003 |year=2007 |pmid=17945153 |doi=10.1016/S1474-4422(07)70265-X |url=http://linkinghub.elsevier.com/retrieve/pii/S1474-4422(07)70265-X}}</ref> A higher proportion of patients (30-50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed [[neuropsychological testing]]. Sensory nerves and the [[autonomic nervous system]] are generally unaffected, meaning the majority of people with ALS will maintain sight, hearing, touch, smell, and taste.
ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. Between 1 to 2 people per 100,000 develop ALS each year [http://www.webmd.com/brain/tc/Amyotrophic-Lateral-Sclerosis-ALS-Topic-Overview]. ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop the disease. Men are affected slightly more often than women.
 
   
ALS is classified into three general groups, '''familial ALS''', '''sporadic ALS''' and '''Guamanian ALS'''. Familial ALS accounts for approximately 5%-10% of all ALS cases and is caused by genetic factors. Most of the remaining 90-95% of cases are classified as sporadic ALS and have no known hereditary component. A third type, called Guamanian ALS, represents a small cluster of cases concentrated on the Pacific island of [[Guam]]. Although there have been reports of several "clusters" including three American football players from the 49ers team, three soccer-playing friends in the south of England, and reports of conjugal (''i.e.'', husband and wife) cases in the south of France<ref name="ALS1">{{cite journal | author = Rachele MG, Mascia V, Tacconi P, Dessi N, Marrosu F | title = Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy. | journal = Ital J Neurol Sci. | volume = Apr;19 | issue = 2 | pages = 97-100 | year = 1998 | id = PMID: 10935845}}</ref><ref name="ALS2">{{cite journal | author = Poloni M, Micheli A, Facchetti D, Mai R, Ceriani F | title = Conjugal amyotrophic lateral sclerosis: toxic clustering or change?| journal = Ital J Neurol Sci. | volume = Apr;18 | issue = 2 | pages = 109-12 | year = 1997 | id = PMID: 9239532}}</ref><ref name="ALS3">{{cite journal | author = Camu W, Cadilhac J, Billiard M. | title = Conjugal amyotrophic lateral sclerosis: a report on two couples from southern France.| journal = Neurology. | volume = Mar;44 | issue = 3 Pt 1 | pages = 547-8 | year = 1994 | id = PMID: 8145930}}</ref>
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===Initial symptoms===
<ref name="ALS4">{{cite journal | author = Cornblath DR, Kurland LT, Boylan KB, Morrison L, Radhakrishnan K, Montgomery M. | title = Conjugal amyotrophic lateral sclerosis: report of a young married couple.| journal = Neurology.| volume = Nov;43 | issue = 11 | pages = 2378-80 | year = 1993 | id = PMID: 8232960}}</ref>
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The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting symptoms include muscle fasciculation (twitching), 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 disease experience "limb onset" ALS, ''i.e.'', first symptoms in the arms or legs. Patients with the leg onset form may experience awkwardness when walking or running or notice that they are tripping or stumbling, often with a "dropped foot" which drags gently along the ground. Arm-onset patients may experience difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock. Occasionally, the symptoms remain confined to one limb for a long period of time or for the whole length of the illness; this is known as [[monomelic amyotrophy]].
<ref name="9couples">{{cite journal | author = Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W | title = A clustering of conjugal amyotrophic lateral sclerosis in southeastern France. | journal = Neurol. | volume = Apr;60 | issue = 4 | pages = 553-7 | year = 2003 | id = PMID: 12707069}}</ref>, these are statistically plausible chance events. 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.
 
   
===Cause and risk factors===
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About 25% of cases are "bulbar onset" ALS. These patients first notice difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. Other symptoms include difficulty swallowing and loss of tongue mobility. A smaller proportion of patients experience "respiratory onset" ALS, where the [[intercostal]] muscles that support breathing are affected first. A small proportion of patients may also present with what appears to be [[frontotemporal dementia]], but later progresses to include more typical ALS symptoms.
   
Scientists have not found a definitive cause for ALS and the onset of the disease can be linked to a variety of risk factors. It is believed that one or more of the following factors are responsible for the majority of ALS cases. Researchers suspect a virus, exposure to neurotoxins or heavy metals, DNA defects (especially in familial ALS), immune system abnormalities, and enzyme abnormalities as the leading causes of the disease. There is a hereditary factor in familial ALS (FALS) however there are no known hereditary component in the 90%-95% cases diagnosed as sporadic ALS.
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Over time, patients 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 called [[Plantar reflex|Babinski's sign]] also 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). Around 15&ndash;45% of patients experience [[pseudobulbar affect]], also 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. To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.
   
A few causative factors have been discovered. Prolonged exposure to a dietary neurotoxin is the suspected risk factor in Guamanian ALS. The neurotoxin is an amino acid found in the seed of the [[cycad]] ''[[Cycas circinalis]]'', a tropical plant found in Guam, which was used in the human food supply during the 1950s and early 1960s. An inherited genetic defect linked to a defect on chromosome 21 is believed to cause approximately 40% of familial ALS cases. This mutation is believed to be [[autosomal dominant]].
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===Disease progression and spread===
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Although the order and rate of symptoms varies from person to person, eventually most patients are not able to walk, get out of bed on their own, or use their hands and arms. The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale (Revised)", 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 there is a high degree of variability and a small percentage of patients have much slower disease, on average, patients lose about 1 FRS point per month. Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to other parts of the body as the disease 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.
   
The children of those diagnosed with familial ALS have a higher risk factor for developing the disease, however those who have close family members diagnosed with sporadic ALS have no greater a risk factor than the general population [http://www.alsphiladelphia.org/pennstatehershey/newsletters/newsletter_spring04.htm].
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Disease progression tends to be slower in patients who are younger than 40 at onset,<ref>{{cite journal | author = M. Sabatelli, MD, F. Madia, MD, A. Conte, MD, M. Luigetti, MD, M. Zollino, MD, I. Mancuso, PhD, M. Lo Monaco, MD, G. Lippi, MD and P. Tonali, MD | title = Natural history of young-adult amyotrophic lateral sclerosis | journal = Neurology | year = 2008 | volume = 16 | issue = 71 | pages = 876–881 }}</ref> have disease restricted primarily to one limb, and those with primarily upper motor neuron symptoms.<ref name="pmid21402743">{{cite doi|10.1136/jnnp.2010.235952}}</ref> Conversely, progression is faster and prognosis poorer in patients with bulbar-onset disease, respiratory-onset disease, and frontotemporal dementia.<ref name="pmid21402743" />
   
==Symptoms==
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===Late stage disease symptoms===
The onset of ALS may be so subtle that the [[symptom]]s are frequently overlooked. The earliest symptoms may include twitching, cramping, or stiffness of muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. These general complaints then develop into more obvious weakness or [[atrophy]] that may cause a physician to suspect ALS.
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Difficulty swallowing and chewing making eating normally very difficult and increase the risk of choking or aspirating food into the lungs. In later stages of the disease, aspiration pneumonia and maintaining a healthy weight can become a significant problem and may require insertion of a feeding tube. As the diaphragm and [[intercostal muscle]]s (rib cage) that support breathing weaken, measures of lung function such as forced vital capacity and inspiratory pressure diminish. In respiratory onset ALS, this may occur before significant limb weakness is apparent. External machines such as bilevel positive pressure ventilation (frequently referred to by the tradename [[BiPAP]]) are frequently used to support breathing, first at night, and later during the daytime as well. BiPAP is only a temporary remedy, however, and it is recommended that long before BiPAP stops being effective, patients should decide whether to have a [[tracheotomy]] and long term mechanical ventilation. At this point, some patients choose [[Palliative care|palliative hospice care]]. Most people with ALS die of respiratory failure or [[pneumonia]].
   
[[Image:Babelou.jpg|thumb|250px|[[Lou Gehrig]] was forced to retire from baseball due to ALS. He is seen here on the day of his retirement ([[July 4]], [[1939]]) with former teammate [[Babe Ruth]].]]
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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.<ref>{{cite journal | author = M R Turner, M J Parton, C E Shaw, P N Leigh, A Al-Chalabi | title = Prolonged survival in motor neuron disease: a descriptive study of the King’s database 1990–2002. | journal = J Neurol Neurosurg Psychiatry | year = 2003 | volume = 74 | pages = 995–997 }}</ref> The best-known person with ALS, [[Stephen Hawking]], has lived with the disease for more than 50 years, though his is an unusual case.<ref>[http://articles.cnn.com/2009-04-20/health/hawking.als_1_als-association-lou-gehrig-s-disease-motor-neuron-disease?_s=PM:HEALTH Stephen Hawking serves as role model for ALS patients]</ref>
   
The parts of the body affected by early symptoms of ALS depend on which muscles in the body are damaged first. About 75% of people experience "limb onset" ALS. In some of these cases, symptoms initially affect one of the legs, and patients experience awkwardness when walking or running or they notice that they are tripping or stumbling more often. Other limb onset patients first see the effects of the disease on a hand or arm as they experience difficulty with simple tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock.
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==Cause==
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For patients without a family history of the disease, who include ~95% of cases, there is no known cause for ALS. Potential causes for which there is inconclusive evidence includes head trauma, military service, and participation in contact sports. Many other potential causes, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated but without consistent findings.<ref>{{cite journal | author = Sutedja NA, Fischer K, Veldink JH, van der Heijden GJ,
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Kromhout H, Heederik D, et al. | title = What we truly know about occupation as a risk factor for ALS: a critical and systematic review. | journal = Amyotrophic Lateral Sclerosis | year = 2009 | volume = 10 |pages = 295–301 }}</ref>
   
About 25% of cases are "[[bulbar onset]]" ALS. These patients first notice difficulty speaking clearly. Speech becomes garbled and slurred. Nasality and loss of volume are frequently the first symptoms. Difficulty swallowing, and loss of tongue mobility follow. Eventually total loss of speech and the disability to protect the airway when swallowing are experienced.
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There is a known hereditary factor in familial ALS (FALS), where the condition is known to run in families. Recently, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9ORF72, which is associated with ALS combined with frontotemporal dementia ALS-FTD,<ref>{{cite journal | author = Dejesus-Hernandez, M., et al., | title = Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. | journal = Neuron | year = 2011 | volume = 72 | issue = 2 | pages = 245–56 }}</ref> and accounts for some 6% of cases of ALS among white Europeans.<ref>{{cite journal | author =Majounie E., et al., | title = Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. | journal = Lancet Neurology | year = 2012 | volume = 11 | issue = 4 | pages = 323–330 }}</ref> The high degree of mutations found in patients that appeared to have "sporadic" disease, ''i.e.'' without a family history, suggests that genetics may play a more significant role than previously thought and that environmental exposures may be less relevant.
   
Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to other parts of the body as the disease progresses. Patients 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 called [[Plantar reflex|Babinski's sign]] (the large toe extends upward as the sole of the foot is stimulated) also 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). Around 15&ndash;45% of patients experience [[pseudobulbar affect]], also known as "emotional lability", which consists of uncontrollable laughter or crying.
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A defect on chromosome 21 (coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS, or about 2% of ALS cases overall.<ref>{{cite journal |last=Conwit|first=Robin A. |title=Preventing familial ALS: A clinical trial may be feasible but is an efficacy trial warranted? |journal=Journal of the Neurological Sciences |year=2006 |month=December |volume=251 |issue=1–2 |pages=1–2 |doi=10.1016/j.jns.2006.07.009 |issn=0022-510X |pmid=17070848}}</ref><ref name="advances">{{cite journal |last=Al-Chalabi |first=Ammar |coauthor=P. Nigel Leigh |title=Recent advances in amyotrophic lateral sclerosis |journal=Current Opinion in Neurology |year=2000 |month=August |volume=13 |issue=4 |pages=397–405 |doi= 10.1097/00019052-200008000-00006|issn=1473-6551 |pmid=10970056}}</ref><ref>{{cite journal |author =Battistini S, Ricci C, Lotti EM, Benigni M, Gagliardi S, Zucco R, Bondavalli M, Marcello N, Ceroni M, Cereda C |title= Severe familial ALS with a novel exon 4 mutation (L106F) in the SOD1 gene |journal=Journal of the Neurological Sciences |year=2010 |month=June|volume=293 |issue=1 |pages=112–115 |doi=10.1016/j.jns.2010.03.009 |pmid=20385392}}</ref> This mutation is believed to be [[autosomal dominant]], and has over a hundred different forms of mutation. The most common ALS-causing SOD1 mutation in North American patients is [[A4V]], characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A, is more slowly progressive than typical ALS and patients with this form of the disease survive for an average of 11 years.<ref>{{cite journal | author =Anderson P.M., et al., | title = Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation, A clinical and genealogical study of 36 patients. | journal = Brain | year = 1996 | volume = 119 | issue = | pages = 1153–1172 }}</ref>
   
To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.
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[[Mutation]]s in several genes have also been linked to various types of ALS, and the currently identified associations are shown in the table below:
   
Although the sequence of emerging symptoms and the rate of disease progression vary from person to person, eventually patients will not be able to stand or walk, get in or out of bed on their own, or use their hands and arms. Difficulty swallowing and chewing impair the patient's ability to eat normally and increase the risk of choking. Maintaining weight will then become a problem. Because the disease usually does not affect cognitive abilities, patients are aware of their progressive loss of function and may become anxious and depressed. A small percentage of patients go on to develop [[frontotemporal dementia]] characterized by profound personality changes; this is more common amongst those with a family history of dementia. A larger proportion of patients experience mild problems with word-generation, attention, or decision-making. Cognitive function may be affected as part of the disease process or could be related to poor breathing at night (nocturnal hypoventilation). Health care professionals need to explain the course of the disease and describe available treatment options so that patients can make informed decisions in advance.
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{| class="wikitable" align="center" style="width: 40em;"
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|-
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!colspan=4|Genetic associations include
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|-
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! Type
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! [[OMIM]]
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! Gene
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! Locus
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|-
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| ALS1
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| {{OMIM2|105400}}
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| ''[[SOD1]]''
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| 21q22.1
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|-
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| ALS2
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| {{OMIM2|205100}}
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| ''[[ALS2]]''
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| 2q33.1
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|-
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| ALS3
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| {{OMIM2|606640}}
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| ?
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| 18q21
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|-
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| ALS4
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| {{OMIM2|602433}}
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| ''[[SETX]]''
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| 9q34.13
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|-
  +
| ALS5
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| {{OMIM2|602099}}
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| ?
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| 15q15.1-q21.1
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|-
  +
| ALS6
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| {{OMIM2|608030}}
  +
| ''[[FUS]]''
  +
| 16p11.2
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|-
  +
| ALS7
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| {{OMIM2|608031}}
  +
| ?
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| 20p13
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|-
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| ALS8
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| {{OMIM2|608627}}
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| ''[[VAPB]]''
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| 20q13.3
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|-
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| ALS9
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| {{OMIM2|611895}}
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| ''[[Angiogenin|ANG]]''
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| 14q11.2
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|-
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| ALS10
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| {{OMIM2|612069}}
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| ''[[TARDBP]]''
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| 1p36.2
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|-
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| ALS11
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| {{OMIM2|612577}}
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| ''[[FIG4]]''
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| 6q21
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|-
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| ALS12
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| {{OMIM2|613435}}
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| ''[[OPTN]]''
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| 10p15-p14
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|-
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| ALS13
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| {{OMIM2|183090}}
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| ''[[ATXN2]]''
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| 12q24.12
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|-
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| ALS14
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| {{OMIM2|613954}}
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| ''[[Valosin-containing protein|VCP]]''
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| 9p13.3
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|}
   
As the diaphragm and intercostal muscles weaken, forced vital capacity and inspiratory pressure diminish. In bulbar onset ALS, this may occur before significant limb weakness is apparent. Bilevel positive pressure ventilation (frequently referred to by the tradename [[BiPAP]]) is frequently used to support breathing, first at night, and later during the daytime as well. It is recommended that long before BiPAP becomes insufficient, patients (with the eventual help of his/her family) must decide whether to have a tracheostomy and long term mechanical ventilation. Most patients do not elect this route, and instead choose palliative hospice care at this point. Most people with ALS die of respiratory failure or pneumonia, not the disease itself.
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==Pathophysiology==
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The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop proteinaceous [[inclusion bodies|inclusions]] in their cell bodies and [[axon]]s. This may be partly due to defects in protein degradation.<ref>{{cite journal|last=Deng|first=HX|coauthors=Chen, W, Hong, ST, Boycott, KM, Gorrie, GH, Siddique, N, Yang, Y, Fecto, F, Shi, Y, Zhai, H, Jiang, H, Hirano, M, Rampersaud, E, Jansen, GH, Donkervoort, S, Bigio, EH, Brooks, BR, Ajroud, K, Sufit, RL, Haines, JL, Mugnaini, E, Pericak-Vance, MA, Siddique, T|title=Mutations in UBQLN2 cause dominant X-linked juvenile and adult onset ALS and ALS/dementia|journal=Nature|date=2011-08-21|pmid=21857683|doi=10.1038/nature10353|volume=477|issue=7363|pages=211–5|pmc=3169705}}</ref> These inclusions often contain [[ubiquitin]], and generally incorporate one of the ALS-associated proteins: [[SOD1]], [[TDP-43|TAR DNA binding protein]] (TDP-43, or TARDBP), or [[FUS]].
   
ALS predominantly affects the motor neurons, and in the majority of cases the disease does not impair a patient's mind, personality, intelligence, or memory. Nor does it affect a person's ability to see, smell, taste, hear, or feel touch. Control of eye muscles is the most preserved function, although some patients with an extremely long duration of disease (20+ years) may lose eye control too. Unlike [[multiple sclerosis]], bladder and bowel control are usually preserved in ALS, although as a result of immobility and diet changes, intestinal problems such as constipation can require intensive management.
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===SOD1===
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{{merge to|SOD1|date=June 2012}}
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The cause of ALS is not known, though an important step toward determining the cause came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn [[superoxide dismutase]] ([[SOD1]]) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful [[antioxidant]] that protects the body from damage caused by [[superoxide]], a toxic free radical generated in the mitochondria. [[Free radicals]] are highly reactive molecules produced by cells during normal [[metabolism]] again largely by the mitochondria. Free radicals can accumulate and cause damage to both mitochondrial and nuclear DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disease, some of which have a very long clinical course (e.g. [[H46R]]), while others, such as [[A4V]], being exceptionally aggressive. Evidence suggests that failure of defenses against oxidative stress up-regulates programmed cell death (apoptosis), among many other possible consequences. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way (a gain of function).<ref name="mSOD1 gene deletion does not cause MND">{{cite journal |author=Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W |title=Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury |journal=Nat Genet |volume=13 |issue=1 |pages=43–7 |year=1996 |pmid=8673102 |doi=10.1038/ng0596-43}}</ref><ref name="wtSOD1 elevatation/elimination do not change disease course">{{cite journal |author=Bruijn L, Houseweart M, Kato S, Anderson K, Anderson S, Ohama E, Reaume A, Scott R, Cleveland D |title=Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1 |journal=Science |volume=281 |issue=5384 |pages=1851–4 |year=1998 |pmid=9743498 |doi=10.1126/science.281.5384.1851}}</ref>
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  +
Studies involving [[transgenic]] mice have yielded several theories about the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily develop ALS, although they do exhibit an acceleration of age-related muscle atrophy ([[sarcopenia]]) and a shortened lifespan (see article on [[superoxide dismutase]]). This indicates that the toxic properties of the mutant SOD1 are 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 (see article on [[proteopathy]]). Interestingly, in mutant SOD1 mice (most commonly, the [[G93A]] mutant), aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration.<ref>{{cite journal |author=Furukawa Y, Fu R, Deng H, Siddique T, O'Halloran T |title=Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice |journal=Proc Natl Acad Sci USA |volume=103 |issue=18 |pages=7148–53 |year=2006 |pmid=16636274 |doi=10.1073/pnas.0602048103 |pmc=1447524}}</ref> It is speculated that aggregate accumulation of mutant SOD1 plays a role in disrupting cellular functions by damaging [[mitochondria]], [[proteasomes]], protein folding [[chaperone (protein)|chaperone]]s, or other proteins.<ref>{{cite journal |author=Boillée S, Vande Velde C, Cleveland D |title=ALS: a disease of motor neurons and their nonneuronal neighbors |journal=Neuron |volume=52 |issue=1 |pages=39–59 |year=2006 |pmid=17015226 |doi=10.1016/j.neuron.2006.09.018}}</ref> Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. Critics have noted that in humans, SOD1 mutations 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.
  +
  +
=== Other factors ===
  +
Studies also have focused on the role of [[glutamate]] in motor neuron degeneration. Glutamate is one of the chemical messengers or [[neurotransmitters]] in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the [[blood plasma|serum]] and spinal fluid.<ref name="advances" /> [[Riluzole]] is 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.
   
 
==Diagnosis==
 
==Diagnosis==
 
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. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.
 
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. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.
   
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). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of [[peripheral neuropathy]] (damage to peripheral nerves) or [[myopathy]] (muscle disease) rather than ALS. The physician may order [[magnetic resonance imaging]] (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, [[multiple sclerosis]], a herniated disk in the neck, syringomyelia, or cervical spondylosis.
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[[File:ALS cross.jpg|thumb|MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the clinical diagnosis of ALS.]]
  +
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). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of [[peripheral neuropathy]] (damage to peripheral nerves) or [[myopathy]] (muscle disease) rather than ALS. The physician may order [[magnetic resonance imaging]] (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, [[multiple sclerosis]], a [[hernia]]ted disk in the neck, [[syringomyelia]], or cervical [[spondylosis]].
   
 
Based on the patient'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 that the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.
 
Based on the patient'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 that the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.
   
Infectious diseases such as human immunodeficiency virus ([[HIV]]), human T-cell leukemia virus ([[HTLV]]), [[Lyme disease]], [[syphilis]]<ref name="5cases">{{cite journal | author = el Alaoui-Faris M, Medejel A, al Zemmouri K, Yahyaoui M, Chkili T | title = Amyotrophic lateral sclerosis syndrome of syphilitic origin. 5 cases. | journal = Rev Neurol (Paris) | volume = 146 | issue = 1 | pages =41-4 | year = 1990 | id = PMID: 2408129}}</ref> and [[tick-borne encephalitis]] <ref name="TBE">{{cite journal | author = Umanekii KG, Dekonenko EP | title = Structure of progressive forms of tick-borne encephalitis | journal = Zh Nevropatol Psikhiatr Im S S Korsakova. | volume = 83 | issue = 8 | pages = 1173-9 | year = 1983 | id = PMID: 6414202}}</ref>viruses can in some cases cause ALS-like symptoms. Neurological disorders such as [[multiple sclerosis]], [[post-polio syndrome]], multifocal motor neuropathy, and [[spinal muscular atrophy]] also can mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis. There have been documented cases of a patient presenting with ALS-like symptoms, having a positive Lyme titer, and responding to antibiotics. <ref name="Lyme">{{cite journal | author = Hansel Y, Ackerl M, Stanek G. | title = ALS-like sequelae in chronic neuroborreliosis. | journal = Wien Med Wochenschr. | volume = 145 | issue = 7-8 | pages = 186-8 | year = 1995 | id = PMID: 7610670}}</ref>
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Infectious diseases such as human immunodeficiency virus ([[HIV]]), human T-cell leukaemia virus ([[HTLV]]), [[Lyme disease]],<ref name="Lyme">{{cite journal |author = Hansel Y, Ackerl M, Stanek G. |title = ALS-like sequelae in chronic neuroborreliosis |journal = Wien Med Wochenschr. |volume = 145 |issue = 7–8 |pages = 186–8 |year = 1995 |pmid =7610670}}</ref> [[syphilis]]<ref name="5cases">{{cite journal |author = el Alaoui-Faris M, Medejel A, al Zemmouri K, Yahyaoui M, Chkili T |title = Amyotrophic lateral sclerosis syndrome of syphilitic origin. 5 cases |journal = Rev Neurol (Paris) |volume = 146 |issue = 1 |pages =41–4 |year = 1990 |pmid =2408129}}</ref> and [[tick-borne encephalitis]]<ref name="TBE">{{cite journal |author = Umanekii KG, Dekonenko EP |title = Structure of progressive forms of tick-borne encephalitis |journal = Zh Nevropatol Psikhiatr Im S S Korsakova. |volume = 83 |issue = 8 |pages = 1173–9 |year = 1983 |pmid =6414202}}</ref> viruses can in some cases cause ALS-like symptoms. Neurological disorders such as [[multiple sclerosis]], [[post-polio syndrome]], [[multifocal motor neuropathy]], [[CIDP]], and [[spinal muscular atrophy]] can also mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.
   
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 may wish to obtain a second neurological opinion.
+
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.<ref>{{cite pmid|21412713}}</ref> 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 second neurological opinion.
   
Recently researchers from Mount Sinai School of Medicine identified three proteins that are found in significantly lower concentration in the cerebral spinal fluid of patients with ALS than in healthy individuals. Evaluating the levels of these three proteins proved 95% accurate for diagnosing ALS. These are the first biomarkers for this disease and may be first tools for confirming diagnosis of ALS published in Feb 2006's issue of Neurology. With current methods, the average time from onset of symptoms to diagnosis is around 12 months. Improved diagnostic markers may provide a means of early diagnosis, allowing patients to receive relief from symptoms years earlier. <ref name="ALS CSF biomarkers">{{cite journal |author=Pasinetti G, Ungar L, Lange D, Yemul S, Deng H, Yuan X, Brown R, Cudkowicz M, Newhall K, Peskind E, Marcus S, Ho L |title=Identification of potential CSF biomarkers in ALS |journal=Neurology |volume=66 |issue=8 |pages=1218-22 |year=2006 |id=PMID 16481598}}</ref>
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However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10%.<ref>{{cite journal|author = Eisen, A.|title = Amyotrophic lateral sclerosis: A review |journal = BCMJ | volume = 44 | issue = 7 | year = 2002 | pages = 362–366| url = http://www.bcmj.org/article/amyotrophic-lateral-sclerosis-review}}</ref><ref>{{cite doi|10.1136/jnnp.60.2.147}}</ref> 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 (15.78%) had their diagnosis completely changed, during the clinical observation development period.<ref>{{cite doi|10.1590/S0004-282X2010000600002}}</ref> In the same study, three patients had a false negative diagnoses, myasthenia gravis (MG), an auto-immune disease. MG can mimic ALS and other neurological disorders leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.<ref>{{cite pmid|22375266}}</ref> Myasthenic syndrome, also known as Lambert-Eaton syndrome (LES),can mimic ALS and its initial presentation can be similar to that of MG.<ref>http://misc.medscape.com/pi/android/medscapeapp/html/A1170810-business.html</ref><ref>http://www.lems.com/what_is_lems</ref>
   
==Etiology==
+
==Treatment==
The cause of ALS is not known. An important step toward answering that question came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn [[superoxide dismutase]] (SOD1) enzyme were associated with some cases (~20%) of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by [[superoxide]], a toxic free radical. [[Free radicals]] are highly reactive molecules produced by cells during normal [[metabolism]]. Free radicals can accumulate and cause damage to DNA and proteins within cells. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way.<ref name="mSOD1 gene deletion does not cause MND">{{cite journal |author=Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W |title=Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury |journal=Nat Genet |volume=13 |issue=1 |pages=43-7 |year=1996 |id=PMID 8673102}}</ref><ref name="wtSOD1 elevatation/elimination do not change disease course">{{cite journal |author=Bruijn L, Houseweart M, Kato S, Anderson K, Anderson S, Ohama E, Reaume A, Scott R, Cleveland D |title=Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1 |journal=Science |volume=281 |issue=5384 |pages=1851-4 |year=1998 |id=PMID 9743498}}</ref>
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===Slowing progression===
  +
[[Riluzole]] (Rilutek) is the only treatment that has been found to improve survival but only to a modest extent.<ref>{{cite journal|last=Carlesi|first=C|coauthors=Pasquali, L, Piazza, S, Lo Gerfo, A, Caldarazzo Ienco, E, Alessi, R, Fornai, F, Siciliano, G|title=Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis|journal=Archives italiennes de biologie|date=2011 Mar|volume=149|issue=1|pages=151–67|pmid=21412722|doi=10.4449/aib.v149i1.1267}}</ref> It lengthens survival by several months, and may have a greater survival benefit for those with a bulbar onset. It also extends the time before a person needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and people taking it must be monitored for liver damage (occurring in ~10% of people taking the drug).<ref>{{cite journal|last=Miller|first=RG|coauthors=Mitchell JD, Lyon M, Moore DH, G|title=Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)|journal=Cochrane Database of Systematic Reviews |year=2007|issue=1|pmid=17253460|doi=10.1002/14651858.CD001447.pub2|editor1-last=Miller|editor1-first=Robert G|pages=CD001447}}</ref> It is approved by [[Food and Drug Administration]] (FDA) and recommended by the [[National Institute for Clinical Excellence]] (NICE).
   
Studies involving [[transgenic]] mice have yielded a different theory about the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily get ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a shortened lifespan (see article on [[superoxide dismutase]]). In addition, aggregation of proteins has been found to be a common pathological feature of both familial and sporadic ALS. Interestingly, in mutant SOD1 mice, aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration.<ref>{{cite journal |author=Furukawa Y, Fu R, Deng H, Siddique T, O'Halloran T |title=Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice |journal=Proc Natl Acad Sci U S A |volume=103 |issue=18 |pages=7148-53 |year=2006 |id=PMID 16636274}}</ref> It is speculated that aggregate accumulation of mutant SOD1 plays a role in disrupting cellular functions by damaging [[mitochondria]], [[proteasomes]], protein folding [[chaperones]], or other proteins.<ref>{{cite journal |author=Boillée S, Vande Velde C, Cleveland D |title=ALS: a disease of motor neurons and their nonneuronal neighbors |journal=Neuron |volume=52 |issue=1 |pages=39-59 |year=2006 |id=PMID 17015226}}</ref> Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. However, it is important to remember that SOD1 mutations cause only 4% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. Yet, the ALS-SOD1 mice remain the best model of the disease thus far.
+
===Disease management===
  +
Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals working with patients and caregivers to keep patients as mobile and comfortable as possible.
   
Studies also have focused on the role of [[glutamate]] in motor neuron degeneration. Glutamate is one of the chemical messengers or [[neurotransmitters]] in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the [[blood plasma|serum]] and spinal fluid. Laboratory studies have demonstrated that neurons begin to die off when they are exposed over long periods to excessive amounts of glutamate ([[excitotoxicity]]). Now, scientists are trying to understand what mechanisms lead to a buildup of unneeded glutamate in the spinal fluid and how this imbalance could contribute to the development of ALS. Failure of [[astrocytes]] to sequester glutamate from the extracellular fluid surrounding the neurones has been proposed as a possible cause of this glutamate-mediated neurodegeneration.
+
====Pharmaceutical treatments====
  +
Medical professionals can prescribe medications to help reduce fatigue, ease muscle cramps, control [[spasticity]], and reduce excess [[saliva]] and [[phlegm]]. Drugs also are available to help patients with pain, [[clinical depression|depression]], sleep disturbances, [[dysphagia]], and [[constipation]]. [[Baclofen]] and [[diazepam]] are often prescribed to control the spasticity caused by ALS, and [[trihexyphenidyl]] or [[amitriptyline]] may be prescribed when ALS patients begin having trouble swallowing their saliva.<ref name="PubMed Health"/>
   
Autoimmune responses which occur when the body's immune system attacks normal cells have been suggested as one possible cause for motor neuron degeneration in ALS. Some scientists theorize that antibodies may directly or indirectly impair the function of motor neurons, interfering with the transmission of signals between the brain and muscles.
+
====Physical, occupational and speech therapy====
  +
[[Physical therapists]] and [[occupational therapists]] play 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.<ref name="Lewis & Rushanan">{{cite journal|author=Lewis, M. & Rushanan, S.|title=The role of physical therapy and occupational therapy in the treatment of Amyotrophic Lateral Sclerosis|journal=NeuroRehabilitation|year=2007|volume=22 |pages=451–461|pmid=18198431|issue=6}}</ref>
   
In searching for the cause of ALS, researchers have also studied environmental factors such as exposure to toxic or infectious agents. Other research has examined the possible role of dietary deficiency or trauma. However, as of yet, there is insufficient evidence to implicate these factors as causes of ALS.
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Occupational therapy and special equipment such as [[assistive technology]] can also enhance patients' independence and safety throughout the course of ALS. Gentle, low-impact [[aerobic exercise]] such as performing activities of daily living (ADL's), walking, [[Human swimming|swimming]], and [[Exercise bicycle|stationary bicycling]] can 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.
   
Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.
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ALS patients who have difficulty speaking may benefit from working with a [[speech-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 of [[augmentative and alternative communication]] such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as [[letter board|alphabet boards]] or yes/no signals.
   
==Treatment==
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====Feeding and nutrition====
No cure has yet been found for ALS. However, the [[Food and Drug Administration]] (FDA) has approved the first drug treatment for the disease: [[Riluzole]] (Rilutek). Riluzole is believed to reduce damage to motor neurons by decreasing the release of glutamate. Clinical trials with ALS patients showed that riluzole prolongs survival by several months, and may have a greater survival benefit for those with a bulbar onset. The drug also extends the time before a patient needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and patients taking the drug must be monitored for liver damage and other possible side effects. However, this first disease-specific therapy offers hope that the progression of ALS may one day be slowed by new medications or combinations of drugs.
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Patients and caregivers can learn from speech-language pathologists and nutritionists 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 and/or 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 a feeding tube into 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.
   
Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational, and speech therapists; nutritionists; social workers; and home care and hospice nurses. Working with patients and caregivers, these teams can design an individualized plan of medical and physical therapy and provide special equipment aimed at keeping patients as mobile and comfortable as possible.
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Researchers have stated that "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake."<ref name=Kasarskis96/> Both animal<ref>{{cite journal |author=Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA |title=Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse |journal=Muscle Nerve |volume=31 |issue=2 |pages=214–20 |year=2005 |month=Feb |pmid=15625688 |doi=10.1002/mus.20255 }}</ref> and human research<ref name=Kasarskis96>{{cite journal |author=Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ |title=Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death |journal=Am J Clin Nutr. |volume=63 |issue=1 |pages=130–7 |year=1996 |month=Jan |pmid=8604660 |doi= |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=8604660}}</ref><ref>{{cite journal |author=Slowie LA, Paige MS, Antel JP |title=Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS) |journal=J Am Diet Assoc |volume=83 |issue=1 |pages=44–7 |year=1983 |month=Jul |pmid=6863783 }}</ref> suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their calorie intake.
   
Physicians can prescribe medications to help reduce fatigue, ease muscle cramps, control [[spasticity]], and reduce excess [[saliva]] and [[phlegm]]. Drugs also are available to help patients with pain, [[clinical depression|depression]], sleep disturbances, and [[constipation]]. [[Pharmacists]] can give advice on the proper use of medications and monitor a patient's prescriptions to avoid risks of drug interactions.
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====Breathing support====
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When the muscles that assist in breathing weaken, use of ventilatory assistance ([[intermittent positive pressure ventilation]] (IPPV), [[bilevel positive airway pressure]] (BIPAP), or [[Biphasic Cuirass Ventilation|biphasic cuirass ventilation]] (BCV)) may be used to aid breathing. Such devices artificially inflate the patient'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.<ref>{{cite journal |author=Sviri S, Linton DM, Van Heerden PV |title= Non-invasive Mechanical Ventilation Enhances Patient Autonomy in Decision-Making Regarding Chronic Ventilation |journal=Critical Care and Resuscitation
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|volume=7 |issue=2 |pages=116–118 |year=2005 |month=Jun |pmid=16548804 |doi=}}</ref> Patients 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 ([[vertebrate trachea|trachea]]) and for long-term use, an operation such as a [[tracheostomy]], in which a plastic [[Tracheal tube|breathing tube]] is inserted directly in the patient's windpipe through an opening in the neck.
   
Physical therapy and special equipment can enhance patients' independence and safety throughout the course of ALS. Gentle, low-impact [[aerobic exercise]] such as walking, [[swimming]], and [[Exercise bicycle|stationary bicycling]] can 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 therapists can recommend exercises that provide these benefits without overworking muscles. Occupational therapists can suggest devices such as ramps, braces, walkers, and wheelchairs that help patients conserve energy and remain mobile.
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Patients 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 patient'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. Some patients under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough. This technique preserves speech in some patients with long-term mechanical ventilation.
   
ALS patients who have difficulty speaking may benefit from working with a speech-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 of [[augmentative and alternative communication]] such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet boards or yes/no signals. These methods and devices help patients communicate when they can no longer speak or produce vocal sounds. With the help of occupational therapists, speech-generating devices can be activated by switches or mouse emulation techniques controlled by small physical movements of, for example, the head, finger or eyes.
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====Palliative care====
  +
[[Social workers]] and home care and [[Hospice care|hospice]] nurses help patients, families, and caregivers with the medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable [[power of attorney]], preparing a [[living 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.
   
Patients and caregivers can learn from speech-language pathologists and nutritionists 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. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into 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.
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==Epidemiology==
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ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. One or two out of 100,000 people develop ALS each year.<ref>{{cite web|url=http://www.webmd.com/brain/tc/Amyotrophic-Lateral-Sclerosis-ALS-Topic-Overview |title=ALS Topic Overview |accessdate=2008-05-01| archiveurl= http://web.archive.org/web/20080501194730/http://www.webmd.com/brain/tc/amyotrophic-lateral-sclerosis-als-topic-overview| archivedate= 1 May 2008 <!--DASHBot-->| deadurl= no}}</ref> ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop the disease. Men are affected slightly more often than women.
   
When the muscles that assist in breathing weaken, use of nocturnal ventilatory assistance ([[intermittent positive pressure ventilation]] (IPPV) or [[bilevel positive airway pressure]] (BIPAP)) may be used to aid breathing during sleep. Such devices artificially inflate the patient'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.
+
Although the incidence of ALS is thought to be regionally uniform, there are three regions in the West Pacific where there has in the past been an elevated occurrence of ALS. This seems to be declining in recent decades. The largest is the area of [[Guam]] inhabited by the [[Chamorro people]], who have historically had a high incidence (as much as 143 cases per 100,000 people per year) of a condition called [[Lytico-Bodig disease]] which is a combination of ALS, Parkinsonism, and dementia.<ref>{{cite journal |author=Reed D, Labarthe D, Chen KM, Stallones R |title=A cohort study of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam and Rota |journal=Am J Epidemiol. |volume=125 |issue=1 |pages=92–100 |year=1987 |month=Jan |pmid=3788958 |url=http://aje.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3788958}}</ref> Two more areas of increased incidence are [[West Papua (region)|West Papua]] and the [[Kii Peninsula]] of Japan.<ref>S. Kuzuhara, Y. Kokubo P3-146Marked increase of parkinsonism-dementia (P-D) phenotypes in the high incidence amyotrophic lateral sclerosis (ALS) focus in the Kii peninsula of Japan. Alzheimer's and Dementia, Volume 2, Issue 3, Pages S417-S417</ref><ref>{{cite journal |author=Spencer PS, Palmer VS, Ludolph AC |title=On the decline and etiology of high-incidence motor system disease in West Papua (southwest New Guinea) |journal=Mov. Disord. |volume=20 |issue=Suppl 12 |pages=S119–26 |year=2005 |month=Aug |pmid=16092101 |doi=10.1002/mds.20552 }}</ref>
   
Patients 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 ([[vertebrate trachea|trachea]]) and for long-term use, an operation such as a [[tracheotomy]], in which a plastic breathing tube is inserted directly in the patient's windpipe through an opening in the neck. Patients 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 patient'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. It must be pointed out that some patients under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak. This technique preserves speech in some patients with long-term mechanical ventilation.
+
Although there have been reports of several "clusters" including three [[American football]] players from the [[San Francisco 49ers]], more than fifty football players in Italy,<ref name="corriere.it">{{cite web|url=http://www.corriere.it/sport/08_ottobre_03/sla_indagine_pesticidi_fd04f986-911c-11dd-9f28-00144f02aabc.shtml |title=Sla, indagini nei club. Pesticidi nel mirino |accessdate=2008-10-02| archiveurl= http://web.archive.org/web/20081003220654/http://www.corriere.it/sport/08_ottobre_03/sla_indagine_pesticidi_fd04f986-911c-11dd-9f28-00144f02aabc.shtml| archivedate= 3 October 2008 <!--DASHBot-->| deadurl= no}}</ref> three football-playing friends in the south of England,<ref>Wicks P, Abrahams S, Masi D, Hejda-Forde S, Leigh PN & Goldstein LH (2005) The Prevalence of Depression and Anxiety in MND, Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, Volume 6, Supplement 1, p. 147</ref> and reports of conjugal (husband and wife) cases in the south of France,<ref name="ALS1">{{cite journal |author=Rachele MG, Mascia V, Tacconi P, Dessi N, Marrosu F |title=Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy |journal=Ital J Neurol Sci. |volume=19 |issue=2 |pages=97–100 |year=1998 |month=April |pmid=10935845 |doi=10.1007/BF02427565}}</ref><ref name="ALS2">{{cite journal |author=Poloni M, Micheli A, Facchetti D, Mai R, Ceriani F |title=Conjugal amyotrophic lateral sclerosis: toxic clustering or change? |journal=Ital J Neurol Sci. |volume=18 |issue=2 |pages=109–12 |year=1997 |month=April |pmid=9239532 |doi=10.1007/BF01999572}}</ref><ref name="ALS3">{{cite journal |author=Camu W, Cadilhac J, Billiard M. |title=Conjugal amyotrophic lateral sclerosis: a report on two couples from southern France |journal=[[Neurology (journal)|Neurology]] |volume=44 |month=March |issue=3 Pt 1 |pages=547–8 |year=1994 |pmid=8145930}}</ref><ref name="ALS4">{{cite journal |author=Cornblath DR, Kurland LT, Boylan KB, Morrison L, Radhakrishnan K, Montgomery M. |title=Conjugal amyotrophic lateral sclerosis: report of a young married couple |journal=Neurology |volume=43 |month=November |issue=11 |pages=2378–80 |year=1993 |pmid=8232960}}</ref><ref name="9couples">{{cite journal |author=Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W |title=A clustering of conjugal amyotrophic lateral sclerosis in southeastern France |journal=Neurol. |volume=60 |month=November |issue=4 |pages=553–7 |year=2003 |pmid=12707069 |doi=10.1001/archneur.60.4.553}}</ref> these are statistically plausible chance events{{Citation needed|date=July 2011}}. 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.
   
[[Social workers]] and home care and [[hospice]] nurses help patients, families, and caregivers with the medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living 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.
+
==Etymology==
  +
''Amyotrophic'' comes from the [[Greek language]]: ''A-'' means "no", ''myo'' refers to "muscle", and ''trophic'' means "nourishment"; ''amyotrophic'' therefore means "no muscle nourishment," which describes the characteristic [[atrophy|atrophication]] of the sufferer's disused muscle tissue. ''Lateral'' identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening ("[[Sclerosis (medicine)|sclerosis]]") in the region.
   
Both animal and human research suggest [[calorie restriction]] (CR) may be contraindicated for those with ALS. Research on a [[Genetically modified organism|transgenic]] mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. <ref>Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA. ''Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse.'' Muscle Nerve. 2005 Feb;31(2):214-20. PMID 15625688.</ref> In that study, Hamadeh ''et al'' also note two human studies<ref> Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. ''Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death.'' Am J Clin Nutr. 1996 Jan;63(1):130-7. PMID 8604660.</ref><ref>Slowie LA, Paige MS, Antel JP. ''Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS).'' J Am Diet Assoc. 1983 Jul;83(1):44-7. PMID 6863783</ref> that they indicate show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state: "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They go on to conclude: "We conclude that ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake." (PMID 8604660)
+
==History==
  +
{| class="wikitable"
  +
|+Timeline
  +
!Year
  +
!Event
  +
|-
  +
|1824
  +
|Charles Bell writes a report about ALS.<ref>Tyler HR, Shefner J. Amyotrophic lateral sclerosis. Handb Clin Neurol. 1991;15:169-215. Serial publication.</ref>
  +
|-
  +
|1850
  +
|English scientist [[Augustus Volney Waller|Augustus Waller]] describes the appearance of shriveled nerve fibers
  +
|-
  +
|1869
  +
|French doctor [[Jean-Martin Charcot]] first describes ALS in scientific literature<ref>{{cite journal |doi=10.1001/archneur.58.3.512 |author=Rowland LP |title=How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot |journal=Arch. Neurol. |volume=58 |issue=3 |pages=512–5 |year=2001 |month=March |pmid=11255459 |url= http://archneur.ama-assn.org/cgi/content/extract/58/3/512}}</ref>
  +
|-
  +
|1881
  +
|"Amyotrophic Lateral Sclerosis" is translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System
  +
|-
  +
|1939
  +
|ALS becomes a ''[[cause célèbre]]'' in the [[United States]] when baseball legend [[Lou Gehrig]]'s career—and, two years later, his life—is ended by the disease. He gives his farewell speech on July 4, 1939.<ref>{{Cite web|url=http://www.lougehrig.com/about/speech.htm |title=Farewell Speech |accessdate=April 16, 2008 |last= |first= |coauthors= |date=July 4, 1939 |work= |publisher=lougehrig.com| archiveurl= http://web.archive.org/web/20080412123358/http://www.lougehrig.com/about/speech.htm| archivedate= 12 April 2008 <!--DASHBot-->| deadurl= no}}</ref>
  +
|-
  +
|1950s
  +
|ALS epidemic occurs among the Chamorro people on Guam
  +
|-
  +
|1991
  +
|Researchers link chromosome 21 to FALS (Familial ALS)
  +
|-
  +
|1993
  +
|[[SOD1]] gene on chromosome 21 found to play a role in some cases of FALS
  +
|-
  +
|1996
  +
|[[Rilutek]] becomes the first FDA-approved drug for ALS
  +
|-
  +
|1998
  +
|The El Escorial criteria is developed as the standard for classifying ALS patient in clinical research
  +
|-
  +
|1999
  +
|The revised ALS Functional Rating Scale (ALSFRS-R) is published and soon becomes a gold standard measure for rating decline in ALS patient in clinical research
  +
|-
  +
|2011
  +
|Noncoding repeat expansions in C9ORF72 are found to be a major cause of ALS and frontotemporal dementia
  +
|}
   
Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits.<ref> Pedersen WA, Mattson MP. ''No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice.'' Brain Res. 1999 Jun 26;833(1):117-20. PMID 10375685. </ref> Suggesting that a calorically dense diet may slow ALS, a [[ketogenic diet]] in the ALS mouse model has been shown to slow the progress of disease.<ref>Zhao Z, Lange DJ , Voustianiouk A, ''et al.'' ''A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis.'' [http://www.biomedcentral.com/1471-2202/7/29 BMC Neuroscience 2006, 7:29.] (PMID 16584562). [http://www.sciencedaily.com/releases/2006/04/060417104324.htm Media report on Zhao ''et al''].</ref>
+
==Clinical research==
  +
A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can be found at [[ClinicalTrials.gov]].
   
The new discovery of [[RNAi]] has some promise in curing ALS. In recent studies, RNAi has been used in lab rats to shut off specific genes that lead to ALS. [[Cytrx]] Corporation has sponsored ALS research utilizing RNAi gene silencing technology targeted at the mutant SOD1 gene. The mutant SOD1 gene is responsible for causing ALS in a subset of the 10% of all ALS patients who suffer from the familial, or genetic, form of the disease. Cytrx's orally-administered drug Arimoclomol is currently in clinical evaluation as a therapeutic treatment for ALS.
+
[[KNS-760704]] (Dexpramipexole) is under clinical investigation in ALS patients. It is hoped that the drug will have a neuroprotective effect. It is one [[enantiomer]] of [[pramipexole]], which is approved for the treatment of Parkinson's disease and restless legs syndrome.<ref>Abramova NA et al. Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma. J Neurosci Res. 2002 Feb 15;67(4):494-500.</ref> The single-enantiomer preparation is essentially inactive at dopamine receptors, is not dose limited by the potent dopaminergic properties of pramipexole.<ref>{{cite doi|10.1111/j.1755-5949.2008.00048.x}}</ref> Results of a Phase II clinical trial conducted by Knopp Neurosciences and involving 102 patients were reported in 2010; the trial found a dose-dependent slowing in loss of function.<ref>{{cite doi|10.1097/01.NT.0000384108.10957.21}}</ref> A larger phase II trial conducted by Biogen found the drug to be safe, well tolerated, and associated with a dose-dependent slowing in the decline of ALS.<ref>{{cite doi|10.1038/nm.2579}}</ref>
   
[[Insulin-like_growth_factor_1]] has also been studied as treatment for ALS. Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the second was equivocal, and the product has never been approved by the FDA. In January of 2007, the Italian Ministry of Health has requested INSMED corporation's drug, IPLEX, which is a recombinant IGF-1 with Binding Protein 3(IGF1BP3) to be used in a clinical trial for ALS patients in Italy.
+
[[Talampanel]] is being tested in ALS by [[Teva Pharmaceutical Industries]]; a Phase II trial was completed in April 2010.<ref>http://clinicaltrials.gov/ct2/show/NCT00696332?term=ALS&rank=2</ref>
   
==Research==
+
==See also==
Organization of research is as follows:<ref>ALS Research Areas, Accessed 4/20/07[http://www.alsa.org/research/topics.cfm?CFID=3824443&CFTOKEN=8979253]</ref>
+
* [[ALS Association]]
1. Clinical Trials
+
* [[ALS Society of Canada]]
2. Disease Process of ALS
+
* [[ALS Therapy Development Institute]]
a. Cell Death and Apoptosis
+
* [[Motor Neurone Disease Association]]
b. Cognitive Changes with ALS (Frontotemporal Dementia)
+
* [[Muscular Dystrophy Association]]
c. Glutamate
 
d. Inflammation
 
e. Mitochondria
 
f. SOD1 and ALS (copper zinc superoxide dismutase 1)
 
3. Environmental Factors
 
4. Genetics of ALS
 
5. Laboratory Models of ALS
 
6. Therapies for ALS
 
a. Call Targets
 
b. Gene Therapy
 
c. RNA Therapy
 
d. Stem Cells
 
e. Trophic Factors
 
f. Biomarkers
 
   
==Resources==
+
==References==
There are many organizations set up across the world to help people with ALS. Internationally there is the [http://www.alsmndalliance.org ALS MND alliance], in the United States there is the [http://www.alsa.org ALS Association] and the [http://www.alscenter.org Packard Center for ALS Research at Johns Hopkins], in the [[United Kingdom]] the [http://www.mndassociation.org/ Motor Neuron Disease Association], in [[Canada]] the [http://www.als.ca/ ALS Society of Canada], and in [[Australia]] there is the Motor Neurone Disease Association of Australia [http://www.mndaust.asn.au/]. These organizations and others work to eliminate the disease with ALS patients and their families, whilst [http://www.als.net/ The ALS Therapy Development Foundation] focuses on finding treatments for today's patients. In addition, the ALS Association holds an annual event called [http://www.alsa.org/walk/default.cfm?CFID=2221817&CFTOKEN=41813014 The Walk to D'Feet ALS] where walkers raise awareness and money for patient services programs and research. Also, the [[Boston Red Sox]] [[pitcher]] [[Curt Schilling]] has created a foundation for researching a treatment for the disease known as Curt's Pitch for ALS.
+
{{Reflist|30em}}
   
==References==
+
==Further reading==
<!------------------------------------------------------------
+
<div class="references-small>
See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a
+
* {{Cite web |url=http://www.alshopefoundation.org/ |title=ALS Hope Foundation
discussion of different citation methods and how to generate
+
|accessdate=2008-06-21
footnotes using the <ref>, </ref> and <reference /> tags
+
|quote=Dedicated to the care and cure of people with Lou Gehrig's Disease. (from site page us.php) | archiveurl= http://web.archive.org/web/20080512012521/http://www.alshopefoundation.org/| archivedate= 12 May 2008 <!--DASHBot-->| deadurl= no}}
----------------------------------------------------------- -->
+
* {{Cite web |url=http://www.lougehrig.com |title=Lou Gehrig: The Official Web Site
<div class="references-small">
+
|accessdate=2008-06-21 |publisher=CMG Worldwide
<references />
+
|quote=The Official Web site of Lou Gehrig is an informational Web site intended to honor the life, the legend and the career of Lou Gehrig. (from site page siteinfo/index.htm) | archiveurl= http://web.archive.org/web/20080509101328/http://www.lougehrig.com/| archivedate= 9 May 2008 <!--DASHBot-->| deadurl= no}}
  +
* {{Cite news |authorlink=Patrick Aebischer |author=Patrick Aebischer |coauthors=Ann C. Kato
  +
|title=Playing defense against Lou Gehrig's Disease
  +
|url=http://www.sciam.com/article.cfm?id=playing-defense-against-l |format=Paper
  +
|work=[[Scientific American]] |publisher=[[Verlagsgruppe Georg von Holtzbrinck]] |pages=86&ndash;93
  +
|date = November 2007| accessdate=2008-06-21
  +
|quote=Researchers have proposed potential therapies for a paralyzing disorder once thought to be untreatable (sub-title) }}
 
</div>
 
</div>
   
 
==External links==
 
==External links==
*[http://www.lesturnerals.org Les Turner ALS Foundation]
+
<!-- PLEASE READ
*[http://www.alsa.org ALS Association]
+
If you intend to add links to non-profit organizations, charities, or webpages that you think may be of interest to patients, please ensure you have thoroughly read and understand [[WP:EL]], Wikipedia's policies on external links. Most links are *not* suitable for wikipedia, even if they would be helpful to patients.
*[http://www.hawking.org.uk/home/hindex.html Stephen Hawking's Website]
+
-->
*[http://www.alsa.org/patient/drug.cfm?id=46 Clinical Trial of Neurodex for Pseudobulbar Affect in People with Amyotrophic Lateral Sclerosis]
+
* [https://www.nlm.nih.gov/medlineplus/amyotrophiclateralsclerosis.html Medline Plus article on ALS]
* [http://www.lougehrig.com Lou Gehrig's Website]
 
* [http://www.als-project.com ALS-Project - Free communication software for people suffering from ALS]
 
* [http://www.als.net ALS Therapy Development Foundation]
 
* [http://www.patientslikeme.com PatientsLikeMe - a free online tool for ALS patients to track and share progress]
 
* [http://www.dukealsclinic.com Duke ALS Clinic] The Muscular Dystrophy Association (MDA) has recognized the Duke ALS Clinic as one of its distinguished ALS Research and Clinical Centers.
 
* [http://www.alscenter.org Robert Packard Center for ALS Research at Johns Hopkins, a leader in ALS Research]
 
* [http://www.alsforums.com/ ALS Support Group] ALSforums is an international online support group for individuals affected by ALS (Lou Gehrig's Disease).
 
* [http://www.als.net/forum/ ALS-TDF forums] are maintained by the [[ALS Therapy Development Foundation]] and focuses on answering scientific questions pertaining to ALS
 
* [http://brain.hastypastry.net/forums/forumdisplay.php?f=77 BrainTalk communities] was one of the largest ALS/MND forums in the world but following a 2-month hardware failure is currently rebuilding its community.
 
* [http://www.build-uk.net BUILD UK] is for people affected by ALS/MND in the UK, but also has overseas members
 
* [http://www.patientslikeme.com PatientsLikeMe] is a telesocial medicine site which allows ALS/MND patients to record their symptoms and share information about treatments
 
* [http://als.clinicahealth.com The ALS Advocacy Community] is the ALS Association's online community offering. Members can partake in blogs, discussions, social network and many other features.
 
* [http://www.patrickobrienfoundation.org/ The Patrick O'Brien Foundation] A non-profit dedicated to promoting awareness of ALS, established in honor of Patrick Sean O'Brien - an artist diagnosed with ALS at the uncommonly early age of 30, who is chronicling his experience of the disease for a feature film.
 
* [http://www.misaoforacause.com Misao for a Cause] A t-shirt charity created by Misao Apparel, to help benefit those diagnosed with ALS.
 
* [http://www.3reasons.org A Ride for 3 Reasons] One man's solo ride across America on a bicycle to raise awareness and money for ALS research. Includes his daily weblog during the ride and profiles of families and individuals living with ALS.
 
 
   
''This article incorporates public domain text from [http://www.ninds.nih.gov/ The U.S. National Institute of Neurological Disorders and Stroke]'' <br>
+
{{Diseases of the nervous system|state=collapsed}}
   
{{Muscular Dystrophy}}
+
{{DEFAULTSORT:Amyotrophic Lateral Sclerosis}}
{{Diseases of the nervous system}}
+
[[Category:Motor neurone disease]]
[[Category:Deaths from motor neurone disease]]
+
[[Category:Rare diseases]]
[[Category:Proteopathy]]
 
[[Category:Motor neuron disease]]
 
 
[[Category:Unsolved problems in neuroscience]]
 
[[Category:Unsolved problems in neuroscience]]
  +
[[Category:Systemic atrophies primarily affecting the central nervous system]]
  +
[[Category:Cytoskeletal defects]]
   
 
<!--
 
<!--
  +
[[ar:التصلب العضلي الجانبي]]
 
[[bg:Амиотрофична латерална склероза]]
 
[[bg:Амиотрофична латерална склероза]]
  +
[[ca:Esclerosi lateral amiotròfica]]
  +
[[cs:Amyotrofická laterální skleróza]]
 
[[da:Amyotrofisk lateral sklerose]]
 
[[da:Amyotrofisk lateral sklerose]]
 
[[de:Amyotrophe Lateralsklerose]]
 
[[de:Amyotrophe Lateralsklerose]]
 
[[es:Esclerosis lateral amiotrófica]]
 
[[es:Esclerosis lateral amiotrófica]]
 
[[eo:Amiotrofa lateralsklerozo]]
 
[[eo:Amiotrofa lateralsklerozo]]
  +
[[fa:اسکلروز جانبی آمیوتروفیک]]
 
[[fr:Sclérose latérale amyotrophique]]
 
[[fr:Sclérose latérale amyotrophique]]
  +
[[ko:근위축성 측색 경화증]]
  +
[[hi:पेशीशोषी पार्श्व काठिन्य (एमियोट्रॉफ़िक लैटरल स्कलिरॉसिस)]]
  +
[[hr:Amiotrofična lateralna skleroza]]
  +
[[id:Sklerosis lateral amiotrofik]]
 
[[it:Sclerosi laterale amiotrofica]]
 
[[it:Sclerosi laterale amiotrofica]]
[[nl:Amyotrofische laterale sclerose]]
+
[[he:ALS]]
  +
[[ka:ამიოტროფული გვერდითი სკლეროზი]]
  +
[[mk:Амиотрофична латерална склероза]]
  +
[[nl:Amyotrofe laterale sclerose]]
 
[[ja:筋萎縮性側索硬化症]]
 
[[ja:筋萎縮性側索硬化症]]
[[no:Amyotrofisk lateral sklerose]]
+
[[no:Amyotrofisk lateralsklerose]]
 
[[pl:Stwardnienie zanikowe boczne]]
 
[[pl:Stwardnienie zanikowe boczne]]
 
[[pt:Esclerose lateral amiotrófica]]
 
[[pt:Esclerose lateral amiotrófica]]
[[simple:Amyotrophic Lateral Sclerosis]]
+
[[ru:Боковой амиотрофический склероз]]
[[fi:Amyotrofinen lateraaliskleroosi]]
+
[[simple:Amyotrophic lateral sclerosis]]
  +
[[sr:Amiotrofična lateralna skleroza]]
  +
[[sh:Amiotrofična lateralna skleroza]]
  +
[[fi:ALS-tauti]]
 
[[sv:Amyotrofisk lateralskleros]]
 
[[sv:Amyotrofisk lateralskleros]]
  +
[[tl:Amyotrophic lateral sclerosis]]
  +
[[ta:அமையோட்ரோபிக் லேட்டரல் ஸ்க்லெரோசிஸ்]]
 
[[tr:Amyotrofik lateral skleroz]]
 
[[tr:Amyotrofik lateral skleroz]]
  +
[[zh:肌萎缩性脊髓侧索硬化症]]
 
-->
 
-->
 
{{enWP|Amyotrophic lateral sclerosis}}
 
{{enWP|Amyotrophic lateral sclerosis}}

Latest revision as of 14:26, August 17, 2012

Assessment | Biopsychology | Comparative | Cognitive | Developmental | Language | Individual differences | Personality | Philosophy | Social |
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Amyotrophic Lateral Sclerosis
(Lou Gehrig's Disease)
Classification and external resources
Template:Px
This MRI (parasagittal FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule and can be tracked to the subcortical white matter of the motor cortex, outlining the corticospinal tract, consistent with the clinical diagnosis of ALS.
ICD-10 G122
ICD-9 335.20
OMIM 105400
DiseasesDB 29148
MedlinePlus 000688
eMedicine neuro/14 emerg/24 pmr/10
MeSH D000690

Amyotrophic lateral sclerosis (ALS) – also referred to as motor neurone disease in some British Commonwealth countries and as Lou Gehrig's disease's disease in North America – is a debilitating disease with varied etiology characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle spasticity, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and decline in breathing ability. ALS is the most common of the five motor neuron diseases.

Signs and symptomsEdit

The disorder causes muscle weakness and atrophy throughout the body caused by degeneration of the upper and lower motor neurons. Unable to function, the muscles weaken and atrophy. Affected individuals may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel sphincters and the muscles responsible for eye movement are usually, but not always, spared.[1]

Cognitive function is generally spared for most patients, although some (about 5%) also have frontotemporal dementia.[2] A higher proportion of patients (30-50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing. Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS will maintain sight, hearing, touch, smell, and taste.

Initial symptomsEdit

The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting symptoms include muscle fasciculation (twitching), 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 disease experience "limb onset" ALS, i.e., first symptoms in the arms or legs. Patients with the leg onset form may experience awkwardness when walking or running or notice that they are tripping or stumbling, often with a "dropped foot" which drags gently along the ground. Arm-onset patients may experience difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock. Occasionally, the symptoms remain confined to one limb for a long period of time or for the whole length of the illness; this is known as monomelic amyotrophy.

About 25% of cases are "bulbar onset" ALS. These patients first notice difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. Other symptoms include difficulty swallowing and loss of tongue mobility. A smaller proportion of patients experience "respiratory onset" ALS, where the intercostal muscles that support breathing are affected first. A small proportion of patients may also present with what appears to be frontotemporal dementia, but later progresses to include more typical ALS symptoms.

Over time, patients 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 called Babinski's sign also 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). Around 15–45% of patients experience pseudobulbar affect, also 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. To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.

Disease progression and spreadEdit

Although the order and rate of symptoms varies from person to person, eventually most patients are not able to walk, get out of bed on their own, or use their hands and arms. The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale (Revised)", 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 there is a high degree of variability and a small percentage of patients have much slower disease, on average, patients lose about 1 FRS point per month. Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to other parts of the body as the disease 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.

Disease progression tends to be slower in patients who are younger than 40 at onset,[3] have disease restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[4] Conversely, progression is faster and prognosis poorer in patients with bulbar-onset disease, respiratory-onset disease, and frontotemporal dementia.[4]

Late stage disease symptomsEdit

Difficulty swallowing and chewing making eating normally very difficult and increase the risk of choking or aspirating food into the lungs. In later stages of the disease, aspiration pneumonia and maintaining a healthy weight can become a significant problem and may require insertion of a feeding tube. As the diaphragm and intercostal muscles (rib cage) that support breathing weaken, measures of lung function such as forced vital capacity and inspiratory pressure diminish. In respiratory onset ALS, this may occur before significant limb weakness is apparent. External machines such as bilevel positive pressure ventilation (frequently referred to by the tradename BiPAP) are frequently used to support breathing, first at night, and later during the daytime as well. BiPAP is only a temporary remedy, however, and it is recommended that long before BiPAP stops being effective, patients should decide whether to have a tracheotomy and long term mechanical ventilation. At this point, some patients choose palliative hospice care. Most people with ALS die of respiratory failure or pneumonia.

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.[5] The best-known person with ALS, Stephen Hawking, has lived with the disease for more than 50 years, though his is an unusual case.[6]

CauseEdit

For patients without a family history of the disease, who include ~95% of cases, there is no known cause for ALS. Potential causes for which there is inconclusive evidence includes head trauma, military service, and participation in contact sports. Many other potential causes, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated but without consistent findings.[7]

There is a known hereditary factor in familial ALS (FALS), where the condition is known to run in families. Recently, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9ORF72, which is associated with ALS combined with frontotemporal dementia ALS-FTD,[8] and accounts for some 6% of cases of ALS among white Europeans.[9] The high degree of mutations found in patients that appeared to have "sporadic" disease, i.e. without a family history, suggests that genetics may play a more significant role than previously thought and that environmental exposures may be less relevant.

A defect on chromosome 21 (coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS, or about 2% of ALS cases overall.[10][11][12] This mutation is believed to be autosomal dominant, and has over a hundred different forms of mutation. The most common ALS-causing SOD1 mutation in North American patients is A4V, characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A, is more slowly progressive than typical ALS and patients with this form of the disease survive for an average of 11 years.[13]

Mutations in several genes have also been linked to various types of ALS, and the currently identified associations are shown in the table below:

Genetic associations include
Type OMIM Gene Locus
ALS1 105400 SOD1 21q22.1
ALS2 205100 ALS2 2q33.1
ALS3 606640  ? 18q21
ALS4 602433 SETX 9q34.13
ALS5 602099  ? 15q15.1-q21.1
ALS6 608030 FUS 16p11.2
ALS7 608031  ? 20p13
ALS8 608627 VAPB 20q13.3
ALS9 611895 ANG 14q11.2
ALS10 612069 TARDBP 1p36.2
ALS11 612577 FIG4 6q21
ALS12 613435 OPTN 10p15-p14
ALS13 183090 ATXN2 12q24.12
ALS14 613954 VCP 9p13.3

PathophysiologyEdit

The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop proteinaceous inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.[14] These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), or FUS.

SOD1Edit

Merge-arrow
It has been suggested that this article or section be merged into SOD1. (Discuss)

The cause of ALS is not known, though an important step toward determining the cause came in 1993 when scientists discovered that mutations in the gene that produces the Cu/Zn superoxide dismutase (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism again largely by the mitochondria. Free radicals can accumulate and cause damage to both mitochondrial and nuclear DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disease, some of which have a very long clinical course (e.g. H46R), while others, such as A4V, being exceptionally aggressive. Evidence suggests that failure of defenses against oxidative stress up-regulates programmed cell death (apoptosis), among many other possible consequences. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way (a gain of function).[15][16]

Studies involving transgenic mice have yielded several theories about the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily develop ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a shortened lifespan (see article on superoxide dismutase). This indicates that the toxic properties of the mutant SOD1 are 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 (see article on proteopathy). Interestingly, in mutant SOD1 mice (most commonly, the G93A mutant), aggregates (misfolded protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration.[17] It is speculated that aggregate accumulation of mutant SOD1 plays a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins.[18] Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. Critics have noted that in humans, SOD1 mutations 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.

Other factors Edit

Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid.[11] Riluzole is 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.

DiagnosisEdit

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. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.

File:ALS cross.jpg

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). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. The physician may order magnetic resonance imaging (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis.

Based on the patient'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 that the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.

Infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukaemia virus (HTLV), Lyme disease,[19] syphilis[20] and tick-borne encephalitis[21] viruses can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, and spinal muscular atrophy can also mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.

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.[22] 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 second neurological opinion.

However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10%.[23][24] 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 (15.78%) had their diagnosis completely changed, during the clinical observation development period.[25] In the same study, three patients had a false negative diagnoses, myasthenia gravis (MG), an auto-immune disease. MG can mimic ALS and other neurological disorders leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.[26] Myasthenic syndrome, also known as Lambert-Eaton syndrome (LES),can mimic ALS and its initial presentation can be similar to that of MG.[27][28]

TreatmentEdit

Slowing progressionEdit

Riluzole (Rilutek) is the only treatment that has been found to improve survival but only to a modest extent.[29] It lengthens survival by several months, and may have a greater survival benefit for those with a bulbar onset. It also extends the time before a person needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and people taking it must be monitored for liver damage (occurring in ~10% of people taking the drug).[30] It is approved by Food and Drug Administration (FDA) and recommended by the National Institute for Clinical Excellence (NICE).

Disease managementEdit

Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals working with patients and caregivers to keep patients as mobile and comfortable as possible.

Pharmaceutical treatmentsEdit

Medical professionals can prescribe medications to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Drugs also are available to help patients with pain, depression, sleep disturbances, dysphagia, and constipation. Baclofen and diazepam are often prescribed to control the spasticity caused by ALS, and trihexyphenidyl or amitriptyline may be prescribed when ALS patients begin having trouble swallowing their saliva.[1]

Physical, occupational and speech therapyEdit

Physical therapists and occupational therapists play 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.[31]

Occupational therapy and special equipment such as assistive technology can also enhance patients' independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as performing activities of daily living (ADL's), walking, swimming, and stationary bicycling can 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 a speech-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 of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet boards or yes/no signals.

Feeding and nutritionEdit

Patients and caregivers can learn from speech-language pathologists and nutritionists 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 and/or 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 a feeding tube into 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 that "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake."[32] Both animal[33] and human research[32][34] suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their calorie intake.

Breathing supportEdit

When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive pressure ventilation (IPPV), bilevel positive airway pressure (BIPAP), or biphasic cuirass ventilation (BCV)) may be used to aid breathing. Such devices artificially inflate the patient'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.[35] Patients 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 a tracheostomy, in which a plastic breathing tube is inserted directly in the patient's windpipe through an opening in the neck.

Patients 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 patient'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. Some patients under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough. This technique preserves speech in some patients with long-term mechanical ventilation.

Palliative careEdit

Social workers and home care and hospice nurses help patients, families, and caregivers with the medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living 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.

EpidemiologyEdit

ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. One or two out of 100,000 people develop ALS each year.[36] ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop the disease. Men are affected slightly more often than women.

Although the incidence of ALS is thought to be regionally uniform, there are three regions in the West Pacific where there has in the past been an elevated occurrence of ALS. This seems to be declining in recent decades. The largest is the area of Guam inhabited by the Chamorro people, who have historically had a high incidence (as much as 143 cases per 100,000 people per year) of a condition called Lytico-Bodig disease which is a combination of ALS, Parkinsonism, and dementia.[37] Two more areas of increased incidence are West Papua and the Kii Peninsula of Japan.[38][39]

Although there have been reports of several "clusters" including three American football players from the San Francisco 49ers, more than fifty football players in Italy,[40] three football-playing friends in the south of England,[41] and reports of conjugal (husband and wife) cases in the south of France,[42][43][44][45][46] these are statistically plausible chance events[citation needed]. 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.

EtymologyEdit

Amyotrophic comes from the Greek language: A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristic atrophication of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening ("sclerosis") in the region.

HistoryEdit

Timeline
Year Event
1824 Charles Bell writes a report about ALS.[47]
1850 English scientist Augustus Waller describes the appearance of shriveled nerve fibers
1869 French doctor Jean-Martin Charcot first describes ALS in scientific literature[48]
1881 "Amyotrophic Lateral Sclerosis" is translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System
1939 ALS becomes a cause célèbre in the United States when baseball legend Lou Gehrig's career—and, two years later, his life—is ended by the disease. He gives his farewell speech on July 4, 1939.[49]
1950s ALS epidemic occurs among the Chamorro people on Guam
1991 Researchers link chromosome 21 to FALS (Familial ALS)
1993 SOD1 gene on chromosome 21 found to play a role in some cases of FALS
1996 Rilutek becomes the first FDA-approved drug for ALS
1998 The El Escorial criteria is developed as the standard for classifying ALS patient in clinical research
1999 The revised ALS Functional Rating Scale (ALSFRS-R) is published and soon becomes a gold standard measure for rating decline in ALS patient in clinical research
2011 Noncoding repeat expansions in C9ORF72 are found to be a major cause of ALS and frontotemporal dementia

Clinical researchEdit

A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can be found at ClinicalTrials.gov.

KNS-760704 (Dexpramipexole) is under clinical investigation in ALS patients. It is hoped that the drug will have a neuroprotective effect. It is one enantiomer of pramipexole, which is approved for the treatment of Parkinson's disease and restless legs syndrome.[50] The single-enantiomer preparation is essentially inactive at dopamine receptors, is not dose limited by the potent dopaminergic properties of pramipexole.[51] Results of a Phase II clinical trial conducted by Knopp Neurosciences and involving 102 patients were reported in 2010; the trial found a dose-dependent slowing in loss of function.[52] A larger phase II trial conducted by Biogen found the drug to be safe, well tolerated, and associated with a dose-dependent slowing in the decline of ALS.[53]

Talampanel is being tested in ALS by Teva Pharmaceutical Industries; a Phase II trial was completed in April 2010.[54]

See alsoEdit

ReferencesEdit

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  51. DOI:10.1111/j.1755-5949.2008.00048.x
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  52. DOI:10.1097/01.NT.0000384108.10957.21
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  53. DOI:10.1038/nm.2579
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Further readingEdit

External linksEdit

  1. REDIRECT Template:CNS diseases of the nervous system
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