Wag lang maki-USO Basa basa din Amyotrophic lateral sclerosis From Wikipedia, the free encyclopedia ALS redirects here. For other uses, see ALS (disambiguation). Motor neurone disease redirects here. For a broader group of diseases that affect motor neurons, see Motor neuron disease. Amyotrophic Lateral Sclerosis (ALS) Classification and external resources ALS Coronal.jpg This MRI (parasagittal FLAIR) demonstrates increased T1 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. However, typically MRI is unremarkable in a patient with ALS. ICD-10 G12.2 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 (MND), Lou Gehrigs disease in the United States, and rarely Charcot disease—is a neurodegenerative disease with various causes. ALS is characterised by muscle spasticity, rapidly progressive weakness due to muscle atrophy, and difficulty in speaking (dysarthria), swallowing (dysphagia), and breathing (dyspnea). ALS is the most common of the five motor neuron diseases. In the U.S., more than 5,600 are diagnosed every year, and up to 30,000 Americans are currently affected. ALS is responsible for 2 deaths per 100,000 people.[1] Median survival time from onset to death is 39 months, and only 4% survive longer than 10 years, although rare cases survive 50 years or more. Most die from respiratory failure, usually within three to five years from onset of symptoms.[2] Contents 1 Signs and symptoms 1.1 Initial symptoms 1.2 Progression 1.3 Late stages 2 Extraocular and skeletal motor units 2.1 Eye movement impairment 2.2 Roles of lactate and cinnamate 3 Causes 3.1 Genetics 3.1.1 SOD1 3.2 Other factors 4 Pathophysiology 5 Diagnosis 6 Management 6.1 Medications 6.2 Therapy 6.3 Nutrition 6.4 Breathing support 6.5 Palliative care 7 Epidemiology 8 History 8.1 Etymology 9 Clinical research 10 Charity fundraising 11 See also 12 References 13 External links Signs and symptoms The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and the muscles responsible for eye movement are usually spared until the final stages of the disorder.[3] Cognitive function is generally spared for most patients, although some (about 5%) also develop frontotemporal dementia.[4] A higher proportion of patients (30–50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing. Infrequently ALS coexists in individuals who also experience dementia, degenerative muscle disorder, and degenerative bone disorder as part of a syndrome called multisystem proteinopathy.[5] Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS will maintain hearing, sight, touch, smell, and taste.[6] Initial symptoms The earliest symptoms of ALS are typically obvious weakness and/or muscle atrophy. Other presenting symptoms include trouble swallowing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first. About 75% of people contracting the disorder 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 Babinskis 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, a neurological disorder 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.[citation needed] 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. Progression Although the order and rate of symptoms varies from person to person, eventually most patients are not able to walk or use their hands and arms. They also lose the ability to speak and swallow food, while most end up on a portable ventilator, called a BiPAP. The rate of progression can be measured using an outcome measure called the ALS Functional Rating Scale Revised (ALSFRS-R), a 12-item instrument administered as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). Though there is a high degree of variability and a small percentage of patients have much slower disorder, on average, patients lose about 0.9 FRS point per month. A survey-based study amongst clinicians showed that they rated a 20% change in the slope of the ALSFRS-R would be clinically meaningful.[7] Regardless of the part of the body first affected by the disorder, muscle weakness and atrophy spread to other parts of the body as the disorder progresses. In limb-onset ALS, symptoms usually spread from the affected limb to the opposite limb before affecting a new body region, whereas in bulbar-onset ALS symptoms typically spread to the arms before the legs. Disorder progression tends to be slower in patients who are younger than 40 at onset,[8][9] are mildly obese,[10] have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[11] Conversely, progression is faster and prognosis poorer in patients with bulbar-onset disorder, respiratory-onset disorder, and fronto-temporal dementia.[11] CX3CR1 allelic variants have also been shown to modify the survival time and the progression of patients.[12] Late stages 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.[2] Guitarist Jason Becker has lived since 1989 with the disorder, while physicist Stephen Hawking has survived for more than 50 years, but theyre considered unusual cases.[13] Difficulty in chewing and swallowing makes eating very difficult and increases the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory onset ALS, this may occur before significant limb weakness is apparent. External ventilation machines that use the ventilation mode of bilevel positive airway pressure (BiPAP) are frequently used to support breathing, initially at night, and later during the daytime as well. The use of BPAP (more often referred to as non-invasive ventilation, NIV) is only a temporary remedy, however, and it is recommended that long before BPAP 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. In late stages the oculomotor nerve that controls the movements of the eye, can be affected as can the extraocular muscles. The eye movements remain unaffected largely until the later stages due to differences in the extraocular muscles compared to the skeletal muscles that are initially and readily affected. Finally, patient condition may be mimicking locked-in syndrome.[14] Extraocular and skeletal motor units Main article: Extraocular muscles Despite sharing fixed sequences of recruitment, extraocular muscles (EOMs) and skeletal muscles exhibit different characteristics. The following are characteristics of EOMs that differ from skeletal motor units.[15] One neural fiber connects with only 1 or 2 muscle fibers No ocular stretch reflexes, despite being rich in muscle spindles No recurrent inhibition No special fast-twitch or slow-twitch muscles All eye motor neurons participate equally in all types of eye movements—not specialized for saccades or smooth pursuit There are also noted differences between healthy and affected EOMs. EOMs from postmortem donors preserved their cytoarchitecture, as compared to limb muscles. Healthy EOMs consist of a central global layer (GL) facing the globe and a thin orbital layer (OL) facing the walls of the orbit.[16] EOMs affected by ALS preserve the GL and OL organization.[16] EOMs possess the neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and these neuroprotective factors are also preserved in EOMs affected by ALS.[16] Laminin is a structural protein typically found in the neuromuscular junction (NMJ). Lnα4 is a laminin isoform that is a hallmark of skeletal muscle NMJs.[17] Patients with ALS showed preserved Lnα4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the same patients.[17] Preservation of laminin expression may play a role in preserving EOM integrity in ALS patients. Patients with sporadic ALS (sALS) have increased levels of intracelluar calcium, causing increased neurotransmitter release.[18] Passive transfer of sera from sALS patients increases spontaneous transmitter release in spinal but not EOM terminals;[18] therefore, it is assumed that EOMs are resistant to changes in physiologic conditions typically found in ALS. However, some effects of the disorder were noted. EOMs affected by ALS had a larger variation in fiber size compared to those in age-matched healthy controls.[16] EOMs exhibited both clustered and scattered atrophic and hypertrophic fibers that are characteristic of disorder; however, these muscles showed significantly less damage compared to limb muscles from the same donors.[16] These EOMs also showed an increase in connective tissue and areas of fatty replacement in compensation of fiber loss and atrophy.[16] Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei, has been noted in ALS patients.[19] Additionally, there was altered myosin heavy chain content of the EOM fibers, with a loss of normal expression of MyHCslow tonic in the GL and the OL did not contain MyHCemb, which is normally expressed in this layer.[16] This change may represent a change in innervation pattern that may include reinnervation by a different type of motor neuron or loss of multiple innervations. Changes in MyHCslow and MyHCemb are the only fiber changes seen in EOMs, leaving the EOM fiber composition relatively normal.[16] Because EOMs are normally highly innervated, any denervation, is compensated for by neighbouring axons which preserve function.[16] Eye movement impairment Patients with ALS may have difficulty in generating voluntary saccades, fast movements of the eye.[19] Saccade velocity is significantly slower in patients with ALS.[19] Problems in generating smooth pursuit and convergence movements have also been noted in patients with ALS.[19] Testing the vestibulo-ocular reflex (VOR) should help in identifying these deficits in ALS patients.[20] Electrooculography (EOG) is a technique that measures the resting potential of the retina. EOG findings in patients with ALS show progressive changes that correlate with disorder progression, and provide a measurement for clinically evaluating the effects of disorder progression on oculomotor activity.[20] Additionally, EOG may allow earlier, subclinical, detection of oculomotor abnormalities in patients with ALS. The embryonic lineage of EOMs differs from that of somite-derived muscles. EOMs are unique because they continuously remodel through life and maintain a population of active satellite cells during aging.[21] EOMs have significantly more myogenic precursor cells than limb skeletal muscles.[21] Roles of lactate and cinnamate Lactic acid is an end product of glycolysis and is known to cause muscle fatigue. Lactate dehydrogenase (LDH) is an enzyme that exerts its effects bidirectionally and is able to oxidize lactate into pyruvate so it can be used in the Krebs Cycle. In EOM, lactate sustains muscle contraction during increased activity levels. EOM that have high LDH activity are thought to be resistant to ALS.[22] Cinnamate is a blocker of lactate transport and exogenous lactate on fatigue resistance. Cinnamate is able to cause fatigue in EOM, while decreasing EOM endurance and residual force; however, cinnamate has no effect on extensor digitorum longus muscle, a muscle in the leg.[22] In contrast, replacing glucose with exogenous lactate increases fatiguability of EDL muscles but not EOM.[22] Fatiguability in EOM was only found when a combination of exogenous lactacte plus cinnamate replaced glucose.[22] Causes Genetics There is a known hereditary factor in familial ALS, where the condition is known to run in families. A defect on chromosome 21, which codes for superoxide dismutase, is associated with approximately 20% of familial cases of ALS, or about 2% of ALS cases overall.[23][24][25] This mutation is believed to be transmitted in an autosomal dominant manner, and has over a hundred different forms of mutation. The most common ALS-causing mutation is a mutant SOD1 gene, seen in North American patients; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS and patients with this form of the disorder survive for an average of 11 years.[26] In 2011, 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,[27] and accounts for some 6% of cases of ALS among white Europeans.[28] The gene is also found in people of Filipino descent.[28] The worlds largest genetic study, called project MinE, initiated by two ALS patients is currently ongoing. It is a crowdfunded research project with many countries involved to discover more genes.[29]
Posted on: Thu, 28 Aug 2014 13:32:17 +0000
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