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| '''For patient information, click [[Amyotrophic lateral sclerosis (patient information)|here]]'''
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| | {{Amyotrophic lateral sclerosis}} |
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| {{SK}} ALS; Lou-Gehrig's disease; maladie de Charcot
| | ==[[Amyotrophic lateral sclerosis overview|Overview]]== |
| | Amyotrophic Lateral Sclerosis is a chronic progressive neurological disease that affects both upper and lower motor neurons. It presents with muscle spasms, fasciculation, weakness and which could ultimately lead to muscles paralysis. ALS is diagnosed clinically, however additional testing with electromyography to confirm muscle denervation. Laboratory tests might be required to rule out other reversible causes of weakness. ALS has a poor prognosis with death usually due to respiratory complications with a median survival of 3-5 years. ALS is managed by a multidisciplinary care setting with fewer disease modifying agents to date. |
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| ==Overview== | | ==[[Amyotrophic lateral sclerosis historical perspective|Historical Perspective]]== |
| | Amyotrophic Lateral Sclerosis was first described by French neurologist Jean-Martin Charcot in his Tuesday lectures in late 1860 and then a publication in 1874. He is also known as the ''' Father of Amyotrophic Lateral Sclerosis''' because of his devotion to the disease. He complied 50 years of previous work on muscle weakness. He was the first scientist to link the disease to its specific pathology. |
| | <ref name="pmid26515617">{{cite journal| author=Katz JS, Dimachkie MM, Barohn RJ| title=Amyotrophic Lateral Sclerosis: A Historical Perspective. | journal=Neurol Clin | year= 2015 | volume= 33 | issue= 4 | pages= 727-34 | pmid=26515617 | doi=10.1016/j.ncl.2015.07.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26515617 }} </ref> |
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| '''Amyotrophic Lateral Sclerosis''' is a progressive, usually fatal, [[neurodegenerative disease]] caused by the degeneration of [[motor neurons]], the nerve cells in the central nervous system that control [[voluntary muscle]] movement. As a [[motor neuron disease]], the disorder causes muscle weakness and atrophy throughout the body as both the [[upper motor neuron|upper]] and [[lower motor neuron]]s degenerate, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, develop [[fasciculation]]s (twitches) because of denervation, and eventually [[atrophy]] due to that denervation. The patient may ultimately lose the ability to initiate and control all voluntary movement except of the eyes.
| | ==[[Amyotrophic lateral sclerosis classification|Classification]]== |
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| Cognitive function is generally spared except in certain situations such as when ALS is associated with [[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> However, there are reports of more subtle cognitive changes of the frontotemporal type in many patients when detailed neuropsychological testing is employed. Sensory nerves and the [[autonomic nervous system]], which controls functions like sweating, generally remain functional.
| | ==[[Amyotrophic lateral sclerosis pathophysiology|Pathophysiology]]== |
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| ==Etymology== | | ==[[Amyotrophic lateral sclerosis causes|Causes]]== |
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| The word ''amyotrophic'' is present 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>
| | ==[[Amyotrophic lateral sclerosis differential diagnosis|Differentiating Amyotrophic lateral sclerosis from other Diseases]]== |
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| ==History of amyotrophic lateral sclerosis== | | ==[[Amyotrophic lateral sclerosis epidemiology and demographics|Epidemiology and Demographics]]== |
| * 1850 - English scientist [[Augustus Waller]] describes the appearance of shriveled nerve fibers
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| * 1869 - French doctor [[Jean-Martin Charcot]] first describes ALS in scientific literature
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| * 1881 - "On Amyotrophic Lateral Sclerosis" gets translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System
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| * 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.
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| * 1950s - ALS epidemic occurs among the Chamorro people on Guam
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| * 1991 - Researchers link chromosome 21 to FALS (Familial ALS)
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| * 1993 - SOD1 gene on chromosome 21 found to play a role in some cases of FALS
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| * 1996 - Rilutek® becomes the first FDA-approved drug for ALS
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| * 1998 - El Escorial is developed as the standard for confirming ALS
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| * 2001 - Alsin gene on chromosome 2 found to cause ALS2
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| ==Epidemiology, causes and risk factors== | | ==[[Amyotrophic lateral sclerosis risk factors|Risk Factors]]== |
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| 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.
| | ==[[Amyotrophic lateral sclerosis screening|Screening]]== |
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| ALS is classified into three general groups, '''familial ALS''', '''sporadic ALS''' and '''Guamanian ALS'''.
| | ==[[Amyotrophic lateral sclerosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| * "Familial ALS" accounts for approximately 5%-10% of all ALS cases and is caused by genetic factors. Of these approximately 10% are linked to a mutation in [[Superoxide dismutase]] (SOD1), a copper/zinc dependant dismutase that is responsible for scavenging free radicals.
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| * Most of the remaining 90-95% of cases are classified as "sporadic ALS" and have no known hereditary component.
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| * A third type, called "Guamanian ALS", represents a small cluster of cases concentrated on the Pacific island of Guam.
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| Although there have been reports of several "clusters" including three American football players from the San Francisco 49ers, 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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| <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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| <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.
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| ===Cause and risk factors===
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| Scientists have not found a definitive cause for ALS and the onset of the disease has been linked to several factors, including: a virus; exposure to neurotoxins or heavy metals; DNA defects; immune system abnormalities; and enzyme abnormalities. There is a known hereditary factor in familial ALS (FALS); however, there is no known hereditary component in the 90-95% cases diagnosed as sporadic ALS. An inherited genetic defect linked to a defect on chromosome 21 is believed to cause approximately 40% of familial cases of ALS. This mutation is believed to be [[autosomal dominant]]. 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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| Some causative factors have been suggested for the increased incidence in the western Pacific. Prolonged exposure to a dietary neurotoxin is one suspected risk factor in Guam; the neurotoxin is a compound found in the seed of the [[cycad]] ''[[Cycas circinalis]]'',<ref>Bains J, et al. (2002). "Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex".<I>J. Neurochem</I>. <B>82</B>(3):516-28. PMID: 12153476.</ref> a tropical plant found in Guam, which was used in the human food supply during the 1950s and early 1960s.
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| According to the [[ALS Association]], military veterans are at an increased risk of contracting ALS. In its report ALS in the Military,<ref>{{cite web| url=http://www.alsa.org/files/pdf/als_military_paper.pdf |title=ALS in the Military |accessdate=2008-05-01 |publisher=The [[ALS Association]] |date=2007-05-17}}</ref> the group pointed to an almost 60% greater chance of the disease in military veterans than the general population. For Gulf War veterans, the chance is seen as twice that of the general population in a joint study by the [[United States Department of Veterans Affairs|Veterans Affairs Administration]] and the DOD.
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| ==Symptoms==
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| ===Initial symptoms===
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| The onset of ALS may be so subtle that the [[symptom]]s are frequently overlooked. The earliest symptoms are obvious weakness and/or muscle atrophy. This is followed by twitching, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The twitching, cramping, etc. associated with ALS is a result of the dying muscle, therefore these symptoms without clinical weakness or atrophy of affected muscle is likely not ALS.
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| 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 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. Occasionally the symptoms remain confined to one limb; this is known as [[monomelic amyotrophy]].
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| 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 inability to [[Pulmonary aspiration|protect the airway]] when swallowing are experienced.
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| 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 15–45% 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.
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| 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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| ===Emerging symptoms===
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| 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 among 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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| As the diaphragm and [[intercostal muscle]]s (rib cage) 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 their families) must decide whether to have a [[tracheostomy]] and long term mechanical ventilation. Most patients do not elect this route, and instead choose [[Palliative care|palliative hospice care]] at this point. Most people with ALS die of respiratory failure or [[pneumonia]], not the disease itself.
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| 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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| ==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.
| | [[Amyotrophic lateral sclerosis diagnostic evaluation|Diagnostic Evaluation]] | [[Amyotrophic lateral sclerosis history and symptoms|History and Symptoms]] | [[Amyotrophic lateral sclerosis physical examination|Physical Examination]] | [[Amyotrophic lateral sclerosis laboratory findings|Laboratory Findings]] | [[Amyotrophic lateral sclerosis electrocardiogram|Electrocardiogram]] | [[Amyotrophic lateral sclerosis x ray|X Ray]] | [[Amyotrophic lateral sclerosis CT|CT]] | [[Amyotrophic lateral sclerosis MRI|MRI]] | [[Amyotrophic lateral sclerosis echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Amyotrophic lateral sclerosis other imaging findings|Other Imaging Findings]] | [[Amyotrophic lateral sclerosis other diagnostic studies|Other Diagnostic Studies]] |
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| 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]].
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| 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.
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| Infectious diseases such as human immunodeficiency virus ([[HIV]]), human T-cell leukaemia 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 | 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, 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 | pmid = : 7610670}}</ref> Lyme disease is particularly difficult to diagnose.
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| 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.
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| A study by 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. This finding was published in the February 2006 issue of [[Neurology (journal) |Neurology]]. Evaluating the levels of these three proteins proved 95% accurate for diagnosing ALS. The three protein markers are TTR, cystatin C, and the carboxyl-terminal fragment of neuroendocrine protein 7B2). These are the first biomarkers for this disease and may be first tools for confirming diagnosis of ALS. 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 |pmid=16481598 |doi=10.1212/01.wnl.0000203129.82104.07}}</ref>
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| ==Etiology==
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| 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 (approximately 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 (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 |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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| 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, 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 10% 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.
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| 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. [[Riluzole]] is currently the only approved drug for ALS and targets glutamate transporters. Its very modest benefit to patients has bolstered the argument that glutamate is not a primary cause of the disease. | |
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| 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. More recent evidence indicates that the nervous system's immune cells, Microglia, are heavily involved in the later stages of the disease.
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| 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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| Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.
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| ==Treatment== | | ==Treatment== |
| 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.
| | [[Amyotrophic lateral sclerosis medical therapy|Medical Therapy]] | [[Amyotrophic lateral sclerosis surgery|Surgery]] | [[Amyotrophic lateral sclerosis primary prevention|Primary Prevention]] | [[Amyotrophic lateral sclerosis secondary prevention|Secondary Prevention]] | [[Amyotrophic lateral sclerosis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Amyotrophic lateral sclerosis future or investigational therapies|Future or Investigational Therapies]] |
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| 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.
| | ==Case Studies== |
| | [[Amyotrophic lateral sclerosis case study|Case #1]] |
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| 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.
| | ==Related Chapters== |
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| 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 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 remain mobile.
| | *[[Muscular Dystrophy Association]] |
| | | *[[ALS Association]] |
| 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.
| | *[[ALS Therapy Development Institute]] |
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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. 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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| 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.
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| 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.
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| 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.
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| 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)
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| 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>
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| The new discovery of [[RNAi]] has some promise in treating 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.
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| [[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.
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| ==Prognosis==
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| Regardless of the part of the body first affected by the disease, it is usual for muscle weakness and atrophy to spread to other parts of the body as the disease progresses. It is important to remember that some patients with ALS have an arrested course with no progression beyond a certain point despite extensive follow-up. Such a pattern is particularly true for young males with predominant upper limb weakness especially on one side (so-called monomelic or Hirayama type mother neuron disease). Eventually people with ALS will not be able to stand or walk, get in or out of bed on their own, or use their hands and arms. In later stages of the disease, individuals have difficulty breathing as the muscles of the respiratory system weaken. Although ventilation 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 3 to 5 years from the onset of symptoms. However, about 10 percent of those individuals with ALS survive for 10 or more years.
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| ==Resources==
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| ===United States===
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| * [http://www.neurology.emory.edu/als Emory ALS Center]
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| * [[ALS Association]]
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| * [[Muscular Dystrophy Association]] [http://www.als-mda.org]
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| * [http://www.alscenter.org Packard Center for ALS Research at Johns Hopkins]
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| * [[ALS Therapy Development Institute]] (ALS TDI), a non-profit biotechnology company focused on finding viable treatment and a cure
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| ===International===
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| * [http://www.alsmndalliance.org ALS MND alliance]
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| ===United Kingdom===
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| * [http://www.mndassociation.org/ Motor Neurone Disease Association]
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| ===Canada===
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| * [http://www.als.ca/ ALS Society of Canada]
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| ===Australia===
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| * Motor Neurone Disease Association of Australia [http://www.mndaust.asn.au/]
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| ==Awareness and fundraising events==
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| * [http://www.rideforlife.com The Ride For Life], founded in 1998 by ALS patient and former teacher Chris Pendergast. Chris and other ALS patients made a wheelchair ride from Yankee Stadium to Washington D.C.—a 350-mile journey. The ride continues annually and, in recent years, has centered on the New York Metro area. Their mission is to raise public awareness of ALS, help fund research, support ALS patients and their families, and provide the ALS community with the latest ALS related news, information and inspiration. Since 1998, Ride for Life has earned nearly 3 million dollars for ALS research and patient services.
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| * Augie's Quest [http://www.augiesquest.org] was started by fitness pioneer Augie Nieto in cooperation with the Muscular Dystrophy Association after his diagnosis with the disease. Augie's Quest and [[ALS Therapy Development Institute|ALS TDI]] entered into the largest private funding collaboration in the history of the disease, $36 million, in 2006. All funds raised through Augie's Quest events go 100% to ALS research.
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| * [http://www.alsa.org/walk/default.cfm?CFID=2221817&CFTOKEN=41813014 The Walk to D'Feet ALS] held annually by the ALS Association, where walkers raise awareness and money to fight and cure ALS.
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| * [http://www.prize4life.org Prize 4 Life], a group of recent Harvard Business School graduates founded Prize4Life, a nonprofit to turbo charge ALS research because one or their classmates, Avi Kremer, MBA 2007 and Chairman of Prize4Life, was diagnosed with this fatal illness in the fall of 2004. Prize4Life is a results-oriented nonprofit founded to accelerate ALS/MND research by offering substantial prizes to scientists who solve the most critical scientific problems preventing the discovery of an effective ALS/MND treatment. The Prize4Life concept is inspired by other prize awards for stimulating research, such as the X-Prize for commercial space travel and DNA-decoding, the U.S. government’s H-Prize for hydrogen renewable energy, and Eli Lilly’s venture, InnoCentive, which outsources difficult R&D problems to a distributed network of scientists using prizes.
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| ==See also==
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| * [[Muscular Dystrophy Association]] | |
| * [[ALS Association]] | |
| * [[ALS Therapy Development Institute]] | |
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| ==External links==
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| *[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.
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| * [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.
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| *[http://www.alsa.org ALS Association]
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| * [http://www.als-project.com ALS-Project - Free communication software for people suffering from ALS]
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| * [http://www.alsforums.com/ ALS Support Group] ALSforums is an international online support group for individuals affected by ALS (Lou Gehrig's Disease).
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| *[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
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| *[http://www.als.net ALS Therapy Development Foundation]; see also ''So Much So Fast'' below
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| *[http://www.alswarriorpoet.com ALS Warrior Poet] Blazeman Foundation, founded by the late Job Blaise, the first person with ALS to compete and finish the Ironman triathalon.
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| *[http://www.alsa.org/patient/drug.cfm?id=46 Clinical Trial of Neurodex for Pseudobulbar Affect in People with Amyotrophic Lateral Sclerosis]
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| *[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.
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| *[http://www.build-uk.net BUILD UK] is for people affected by ALS/MND in the UK, but also has overseas members
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| *[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.
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| *[http://www.extrahands.org Extra Hands for ALS]
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| *[http://www.lesturnerals.org Les Turner ALS Foundation]
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| * [http://www.lougehrig.com Lou Gehrig's Website]
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| *[http://www.misaoforacause.com Misao for a Cause] A t-shirt charity created by Misao Apparel, to help benefit those diagnosed with ALS.
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| *[http://www.patientslikeme.com PatientsLikeMe] is a telesocial medicine site which allows ALS/MND patients to record their symptoms and share information about treatments
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| *[http://www.alscenter.org Robert Packard Center for ALS Research at Johns Hopkins, a leader in ALS Research]
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| *[http://www.westcityfilms.com/smsf.html So Much So Fast] A documentary about ALS and one family's race to find a cure; aired on [http://www.pbs.org/wgbh/pages/frontline/somuchsofast/ PBS's Frontline] in May 2007
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| *[http://www.hawking.org.uk/home/hindex.html Stephen Hawking's Website]
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| *[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.
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| *[http://www.waronals.com War on ALS] Official Site of Team Blazeman, founded in honor of the late Jon Blais.
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|
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|
| ==References== | | ==References== |
| {{Reflist|2}} | | {{reflist|2}} |
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| == General Muscular Dystrophy ==
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| *[http://www.mdaeurope.org Muscular Dystrophy Association Europe]
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| ''This article incorporates in public domain text from [http://www.ninds.nih.gov/ The U.S. National Institute of Neurological Disorders and Stroke]'' <br>
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| {{Diseases of the nervous system}} | | {{Diseases of the nervous system}} |
| {{SIB}}
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| [[bg:Амиотрофична латерална склероза]]
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| [[ca:Esclerosi lateral amiotròfica]]
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| [[da:Amyotrofisk lateral sklerose]]
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| [[de:Amyotrophe Lateralsklerose]]
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| [[es:Esclerosis lateral amiotrófica]]
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| [[eo:Amiotrofa lateralsklerozo]]
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| [[fr:Sclérose latérale amyotrophique]]
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| [[hr:Amiotrofična lateralna skleroza]]
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| [[it:Sclerosi laterale amiotrofica]]
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| [[he:ALS]]
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| [[ka:ამიოტროფიული ლატერალური სკლეროზი]]
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| [[nl:Amyotrofische laterale sclerose]]
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| [[ja:筋萎縮性側索硬化症]]
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| [[no:Amyotrofisk lateral sklerose]]
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| [[pl:Stwardnienie zanikowe boczne]]
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| [[pt:Esclerose lateral amiotrófica]]
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| [[ru:Боковой амиотрофический склероз]]
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| [[simple:Amyotrophic Lateral Sclerosis]]
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| [[sh:Amiotrofična lateralna skleroza]]
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| [[fi:ALS-tauti]]
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| [[sv:Amyotrofisk lateralskleros]]
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| [[ta:அமையோட்ரோபிக் லேட்டரல் ஸ்க்லெரோசிஸ்]]
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| [[tr:Amyotrofik lateral skleroz]]
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| [[zh:肌肉萎縮性側索硬化症]]
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|
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| | [[Category:Neurology]] |
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| | {{WS}} |
| {{WH}} | | {{WH}} |
| {{WS}}
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| [[Category:Motor neuron disease]]
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| [[Category:Neurology]]
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| [[Category:Disease]]
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| [[Category:Overview complete]]
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