Amyotrophic lateral sclerosis (abbreviated ALS, also referred to as Lou Gehrig's disease) is a form of motor neuron disease The motor neurone diseases (MND) are a group of neurological disorders that selectively affect motor neurones, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. ALS is a progressive,^[1] fatal, neurodegenerative disease Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many similarities appear which relate these diseases to caused by the degeneration of motor neurons In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system (or CNS) that project their axons outside the CNS and directly or indirectly control muscles. The motor neuron is often associated with efferent neuron, primary neuron, or alpha motor neurons, the nerve cells in the central nervous system that control voluntary muscle Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system. It is one of three major muscle types, the others being cardiac and smooth muscle. As its name suggests, most skeletal muscle is attached to bones by bundles of collagen fibers known as tendons movement. The condition is often called Lou Gehrig Henry Louis "Lou" Gehrig was an American baseball player in the 1920s and 1930s, chiefly remembered for his prowess as a hitter, his consecutive games-played record and its subsequent longevity, and the pathos of his farewell from baseball at age 36, when he was stricken with a fatal neurological disease. Popularly called "The Iron's disease in North America, after the famous New York Yankees – In 1981, a players' strike in middle of the season forced the season to be split into two halves. New York had the best record in the East Division when play was stopped and was declared the first-half division winner. Per the year's playoff format, the Yankees beat the Brewers in the division series and defeated the A's in the ALCS baseball player who was diagnosed with the disease in 1939. Today, renowned physicist Stephen Hawking Stephen William Hawking, CH, CBE, FRS, FRSA is a British theoretical physicist, whose scientific career spans over forty years. His books and public appearances have made him an academic celebrity and he is an Honorary Fellow of the Royal Society of Arts, a lifetime member of the Pontifical Academy of Sciences, and in 2009 was awarded the is the best-known living ALS patient. The disorder causes muscle weakness and atrophy throughout the body as both the upper Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle. The main effector neurons for voluntary movement lie within layer V of the and lower motor neurons Lower motor neurons are the motor neurons connecting the brainstem and spinal cord to muscle fibers, bringing the nerve impulses from the upper motor neurons out to the muscles. A lower motor neuron's axon terminates on an effector (muscle) degenerate, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, develop fasciculations A fasciculation /fəˌsɪkjʉˈleɪʃən/, or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers . Fasciculations have a variety of causes, the majority of which are benign, but can also be due to disease of (twitches) because of denervation, and eventually atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself. Hormonal and nerve inputs that maintain an organ or body part are because of that denervation. The patient may ultimately lose the ability to initiate and control all voluntary movement; bladder and bowel sphincters and the muscles responsible for eye movement are usually (but not always) spared.

Cognitive function is generally spared except in certain situations such as when ALS is associated with frontotemporal dementia Frontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe. It is one of three syndromes caused by frontotemporal lobar degeneration.^[2] 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 The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils, micturition (urination), and sexual arousal, which controls functions like sweating, generally remain functional.

Signs and symptoms

Initial

The onset of ALS may be so subtle that symptoms A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality. A symptom is subjective, observed by the patient, and not measured are frequently overlooked.^[3] 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 motor neurons, therefore these symptoms without clinical weakness or atrophy of affected muscle is likely not ALS.

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.

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 protect the airway In medicine, aspiration is the entry of secretions or foreign material into the trachea and lungs when swallowing are experienced.

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 Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia), and speaking or forming words (dysarthria Dysarthria is a motor speech disorder resulting from neurological injury, characterized by poor articulation . Any of the speech subsystems (respiration, phonation, resonance, prosody, articulation and movements of jaw and tongue) can be affected). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity Spasticity or muscular hypertonicity is a disorder of the central nervous system in which certain muscles continually receive a message to tighten and contract. The nerves leading to those muscles, unable to regulate themselves (which would provide for normal muscle tone), permanently and continually "over-fire" these commands to tighten) and exaggerated reflexes (hyperreflexia Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways . See Autonomic dysreflexia) including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign In medicine and neurology, the Babinski response to the plantar reflex is a reflex, named after Joseph Babinski , a Polish neurologist, that can identify disease of the spinal cord and brain and also exists as a primitive reflex in infants. When non-pathological, it is called the plantar reflex, while the term Babinski's sign (or Koch's sign) (the big toe extends upward and other toes spread out) 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.

Emerging

Although the sequence of emerging symptoms and the rate of disease progression vary from person to person, eventually most patients are not 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 can 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 Frontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe. It is one of three syndromes caused by frontotemporal lobar degeneration 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.

As the diaphragm and intercostal muscles (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 must decide whether to have a tracheostomy Tracheotomy and tracheostomy are surgical procedures on the neck to open a direct airway through an incision in the trachea . They are performed by paramedics, veterinarians, emergency physicians and surgeons. Both surgical and percutaneous techniques are now widely used and long term mechanical ventilation. At this point, some patients choose palliative hospice care Palliative care is any form of medical care or treatment that concentrates on reducing the severity of disease symptoms, rather than striving to halt, delay, or reverse progression of the disease itself or provide a cure. The goal is to prevent and relieve suffering and to improve quality of life for people facing serious, complex illness. Non-. Most people with ALS die of respiratory failure or pneumonia Pneumonia is an inflammatory condition of the lung. It is often characterized as including inflammation of the parenchyma of the lung and abnormal alveolar filling with fluid (consolidation and exudation). Death usually occurs within two to five years of diagnosis. Although the disease can strike at any age, most people are between forty and seventy years of age when the disease strikes and men are affected slightly more frequently than women. An estimated 5,000 people in the United States are diagnosed with the disease each year.^[4] ALS, a progressive disease, leads to death in half of the people diagnosed within three years and ninety percent within six years.

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 Multiple sclerosis is a disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. Disease onset usually occurs in young adults, and it is more common in females. It has a prevalence that ranges between 2 and 150 per 10, 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.

Cause

Evidence favors the idea of a neurodegenerative chain-reaction in all neurodegenerative disorders, in which initial cellular 'faults' produce or induce some version of a cascade failure that leads to progressive neuronal loss, eventual loss of function, and progressively more serious consequences. Given that familial ALS has been linked to a mutation on the gene coding for superoxide dismutase Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen. One of the exceedingly rare exceptions is Lactobacillus plantarum and related lactobacilli, which use a different mechanism (a critical enzyme involved in the protection of mitochondria against oxidative stress - see next section), initial theorizing has focused on oxidative stress Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. All forms of life maintain a reducing environment within their cells. This reducing environment is preserved by enzymes that maintain the, a probable but nonspecific mechanism in virtually all neurodegenerative disorders.

Oxidative stress is probably not uniform at the cellular level, and much of it is probably created (and managed) within the mitochondria In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 10 micrometers (μm) in diameter. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of, the primary chemical energy generation system in the cell. Most so-called free radicals In chemistry, radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Radicals may have positive, negative or zero charge. By convention, metals and their ions or complexes with unpaired electrons are not radicals. The unpaired electrons cause radicals to be highly chemically reactive are indeed produced in the mitochondria, but there are extensive cellular defenses against oxidative stress in the mitochondria (in which superoxide dismutase plays an important but not exclusive role). A critical issue is the emerging evidence that in aging Ageing or aging (American and Canadian English) is the accumulation of changes in an organism or object over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline. Reaction time, for example, may slow with age, while, there is probably progressive damage to mitochondrial DNA and progressive failure of the mechanisms by which the mitochondria are protected from oxidative stress. There is work suggesting that progressive damage to the mitochondria is at the central mechanism in age-related change, implying that damage to the mitochondria may be a common denominator in all age-related neurodegenerative diseases.

Most scientists and researchers, however, believe that this set of events is probably too nonspecific to explain individual neurodegenerative disorders such as ALS, and that more specific degenerative cascades at a cellular level, explaining the unique features and unique protein depositions of each neurodegenerative disorder, have yet to be outlined. However, failures in the management of oxidative stress within the mitochondria can lead to a whole cascade of undesirable effects, including acceleration of apoptosis (programmed cell death), damage to other cellular organelles, and disorders of protein folding (an area of increasing interest in ALS and many other neurodegenerative disorders).

Since neurons for the most part cannot be replaced (with some partial exceptions), any process that substantially up-regulates programmed cell death in aging within motor neuron populations will eventually lead to motor symptoms and eventual motor system failure. Evidence suggests that programmed cell death may be upregulated (as a primary cause of atrophy) in both upper and lower motor neuron populations in ALS.

A major challenge for these perspectives however is the evidence that calorie restriction Calorie restriction, or caloric restriction , is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects. CR when not associated with malnutrition, is thought to improve age-related health and to slow the aging process in some animals and fungi (thought to protect cells from oxidative stress through a variety of mechanisms but including enhanced mitochondrial biogenesis) actually accelerates ALS (see below), suggesting the apparently paradoxical possibility that upregulation of defenses against oxidative stress may play a role in neurodegeneration in ALS. All of this underlines that a final explanation for the degenerative processes of ALS remains to be established.

Despite not finding a definitive or primary cause for ALS, the onset of the disease has been linked to several factors, including: a virus; exposure to various neurotoxins or heavy metals; DNA defects; immune system abnormalities; occupational involvement in military service and elite sports (where the issue again may be toxic exposure); extreme stress; and enzyme abnormalities.

Surgeries involving the spinal cord have also been thought to play a role in the onset of ALS, possibly due to the increased burden of oxidative stress and inflammation after spinal cord injury or stress.

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 on chromosome 21 (coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS.^[5][6] This mutation is believed to be autosomal dominant Dominance in genetics is a relationship between different forms of a gene at a particular physical location (locus) on a chromosome. The most common ALS causing SOD1 mutation in North America is A4V, characterized by an exceptionally rapid progression from onset to death. 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, suggesting again an environmental or other non-genetic cause.^[7]

Some environmental causative factors have been suggested for the increased incidence in the western Pacific. Prolonged exposure to a dietary neurotoxin called BMAA is one suspected risk factor in Guam The GUAM Organization for Democracy and Economic Development is a regional organization of four post-Soviet states: Georgia, Ukraine, Azerbaijan, and Moldova>^[8]; this neurotoxin produced by cyanobacteria is one of several possible neurotoxic compounds found in the seed of the cycad Cycads are seed plants characterized by a large crown of compound leaves and a stout trunk. They are evergreen, dioecious plants having large pinnately compound leaves. They are frequently confused with and mistaken for palms or ferns, but are only distantly related to both, and instead belong to the division Cycadophyta Cycas circinalis,^[9] a tropical plant found in Guam, which was used in the human food supply during the 1950s and early 1960s.

The very high incidence of the disease among Italian soccer Association football, more commonly known as football or soccer, is a team sport played between two teams of eleven players using a spherical ball. It is widely considered to be the most popular sport in the world players (more than five times higher than normally expected) has raised the concern of a possible link between the disease and the use of pesticides on the soccer fields (several of which have been linked to neuronal toxicity).^[10][11]

According to the ALS Association, military veterans are at an increased risk of contracting ALS (again, possibly implying a link to neurotoxic chemical exposure). In its report ALS in the Military,^[12] the group pointed to an almost 60% greater chance of the disease in military veterans than the general population. The former Indian Army Chief of Staff General K.Sunderji also suffered from ALS before passing away. For Gulf War veterans, the chance is seen as twice that of veterans not deployed to the Persian Gulf in a joint study by the Veterans Affairs Administration The United States Department of Veterans Affairs is a government-run military veteran benefit system with Cabinet-level status. It is the United States government’s second largest department, after the United States Department of Defense. With a total 2009 budget of about $87.6 billion, VA employs nearly 280,000 people at hundreds of Veterans and the DOD, another epidemiologic association suggesting a link to toxic exposure.^[13][14][15]

Dietary intake of polyunsaturated fatty acids In nutrition, polyunsaturated fat, or polyunsaturated fatty acid, are fatty acids in which more than one double bond exists within the representative molecule. That is, the molecule has two or more points on its structure capable of supporting hydrogen atoms not currently part of the structure. Polyunsaturated fatty acids can assume a cis or trans (PUFA) has been shown in several studies to decrease the risk of developing ALS and other neurodegenerative disorders, probably through several mechanisms, including promotion of neurotrophins such as BDNF ^[16][17]

Pathophysiology

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 Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins. Inclusion bodies can also be hallmarks of genetic diseases, as in the case of Neuronal Inclusion bodies in in their cell bodies and axons An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma. These inclusions often contain ubiquitin Ubiquitin is a small, highly-conserved regulatory protein that is ubiquitously expressed in eukaryotes. Ubiquitination refers to the post-translational modification of a protein by the covalent attachment (via an isopeptide bond) of one or more ubiquitin monomers. The most prominent function of ubiquitin is labeling proteins for proteasomal, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), or FUS. Interestingly, these inclusions do not stain with the dyes Congo Red Congo red is the sodium salt of benzidinediazo-bis-1-naphthylamine-4-sulfonic acid . It is a secondary diazo dye. Congo red is water soluble, yielding a red colloidal solution; its solubility is better in organic solvents such as ethanol or Thioflavin S, and are therefore non-amyloid Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases aggregates.^[18][19] This is in contrast to the aggregates and plaques seen in many other neurodegenerative diseases of protein aggregation, including Alzheimer's disease Alzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Generally, it is diagnosed, Parkinson's disease Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions, Huntington's disease Huntington's disease, chorea, or disorder , is a progressive neurodegenerative genetic disorder, which affects muscle coordination and some cognitive functions, typically becoming noticeable in middle age. It is the most common genetic cause of abnormal involuntary writhing movements called chorea and is much more common in people of Western, and prion diseases Transmissible spongiform encephalopathies are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection. Mental and physical abilities deteriorate.

SOD1

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 Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen. One of the exceedingly rare exceptions is Lactobacillus plantarum and related lactobacilli, which use a different mechanism (SOD1) enzyme were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions that damage cells. Antioxidants terminate these chain reactions by that protects the body from damage caused by superoxide Superoxide is an anion with the chemical formula O2−. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature. With one unpaired electron, the superoxide ion is a free radical, and, like dioxygen, it is paramagnetic, a toxic free radical generated in the mitochondria. Free radicals In chemistry, radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. The unpaired electrons cause them to be highly chemically reactive. Radicals play an important role in combustion, atmospheric chemistry, polymerization, plasma chemistry, biochemistry, and many other chemical processes, including human 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).^[20][21]

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.^[22] 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.^[23] 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 serum and spinal fluid.^[6] 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 FDA 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. The antibiotic ceftriaxone has demonstrated an unexpected effect on glutamate and appears to be a beneficial treatment for ALS in animal models. Ceftriaxone is currently being tested in clinical trials.

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.

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, while the personal histories of many people who develop ALS do include these types of factors, as of yet, no study has produced evidence sufficient to directly implicate these factors as causes of ALS.

One possible exception is smoking which, in a study the results of which were published in 2009, was determined to be an "established" risk factor for ALS.^[24]

Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.

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.

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,^[25] syphilis^[26] and tick-borne encephalitis^[27] 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 should always obtain a second neurological opinion.

A recent study identified three proteins that are found in significantly lower concentrations in the cerebral spinal fluid of patients with ALS than in healthy individuals.^[28] Evaluating the levels of these three proteins proved 95% accurate for diagnosing ALS. Two of the three protein were identified as cystatin C (13.4 kD) and a 4.8 kD peptide fragment of VEGF (Vascular Endothelial Growth Factor). A third 6.7 kD cationic peptide has not yet been identified. These diagnostic biomarkers may be useful in making earlier diagnoses of ALS than previously possible.

Treatment

Medication

Approved drugs

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 via activation of glutamate transporters. In addition, the drug offers a wide array of other neuroprotective effects, by means of sodium and calcium channel blockades,^[29] inhibition of protein kinase C,^[30] and the promotion of NMDA (N-methyl d-aspartate) receptor antagonism.^[29][31] Clinical trials with ALS patients showed that Riluzole lengthens 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. A small, open-label study recently suggested that the drug lithium which traditionally is used for the treatment of bipolar affective disorder may slow progression in both animal models and the human form of the disease.^[32] However, further studies were terminated early for failure to replicate the initial success of the original Fornai et al. study.^[33][34][35]

Experimental drugs

A number of clinical trials are underway globally for ALS.

KNS-760704 is under clinical investigation in ALS patients. It is hoped that the drug will have a neuroprotective effect. It is the enantiomer of pramipexole, which is approved for the treatment of Parkinson's disease and restless legs syndrome.^[36] However, KNS-760704, which has been manufactured to a high degree of enantiomeric purity and which is essentially inactive at dopamine receptors, is not dose limited by the potent dopaminergic properties of pramipexole.^[37] The potential utility of KNS-760704 in ALS is being advanced in clinical studies by Knopp Neurosciences Inc. of Pittsburgh, PA.

The tetracycline antibiotic minocycline is also under investigation for the treatment of ALS among other neurological disorders. In rodents with the SOD1 gene mutation that has been associated with ALS, Minocycline was as effective as Riluzole in extending survival, and it delayed the onset of movement problems.^[38] It is thought to exert its neuroprotective effects not by affecting glutamate release as with Riluzole, but by inhibiting the release of a mitochondrial protein called cytochrome c into the body of the cell. 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 using RNAi gene silencing technology targeted at the mutant SOD1 gene.^[39] 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.

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 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.

Methylcobalamin is being studied in Japan;^[40] preliminary results show it significantly lengthens survival time of ALS patients.

Other

In addition to the use of medical intervention to treat ALS, there are other approaches that people apply to solving the problem. These include mind body methods, holistic problem solving methods, psychotherapy, hypnotherapy and nutrition related methods.

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; acupuncturists; 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.

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, depression, sleep disturbances, and constipation. Pharmacists can advise on best use of medications. This is particularly helpful with regards to patients with dysphagia, which many ALS patients experience. They would also monitor a patient's medications to reduce risk of drug interactions.

Physical therapy and special equipment such as assistive technology 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. Physiotherapists can suggest devices such as ramps, braces, walkers, and wheelchairs that help patients remain mobile. Occupational therapists can provide or recomment equipment and adaptations to enable people to retain as much 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. 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.

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.

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.^[41] 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.

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.

Both animal and human research suggest calorie restriction (CR) may be contraindicated for those with ALS. Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS.^[42] In that study, Hamadeh et al. also note two human studies^[43][44] 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."^[43]

Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits.^[45] 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.^[46]

Prognosis

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 motor neuron disease). Eventually many people with ALS are not 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 three to five years from the onset of symptoms. However, about 10–20 percent^[47] of those individuals with ALS survive 10 or more years.

Epidemiology

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.^[48] 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.

"Familial ALS" accounts for approximately 5%–10% of all ALS cases and is caused by genetic factors. Of these, approximately 1 in 10 are linked to a mutation in copper/zinc superoxide dismutase (SOD1), an enzyme responsible for scavenging free radicals. A recent study has identified a gene called FUS ("Fused in Sarcoma", ALS6) as being responsible for 1 in 20 cases of fALS.^[49][50]

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.^[51] Two more areas of increased incidence are the Kii peninsula of Japan and West Papua.^[52][53]

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,^[10] three football-playing friends in the south of England,^[54] and reports of conjugal (husband and wife) cases in the south of France,^{[55][56][57][58][59]} 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.

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 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.

History

Notable cases

Notable people living with ALS include:

• Stephen Hawking - British theoretical physicist ^[60]
• Stefano Borgonovo - Former Italian soccer player ^[61]
• Jason Becker - Rock guitarist with David Lee Roth and Cacophony ^[62][63]
• Tony Judt - British-born, US-based public intellectual and historian^[64]
• Scott LeDoux - American politician and former boxer^[65]
• Eric Lowen - American musician, in Lowen & Navarro^[66]
• Washington César Santos - Brazilian former football player^[67]
• Orlando Thomas - American football star^[68]
• Mike Porcaro - Former longtime bass player in the American rock band Toto (1982–2008)^[69]
• Lee Abramson (1970-) Bass player and composer [1]

See also

• Muscular Dystrophy Association
• ALS Association
• ALS Therapy Development Institute
• ALS Society of Canada

References

1. ^ amyotrophic lateral sclerosis at Dorland's Medical Dictionary
2. ^ Phukan J, Pender NP, Hardiman O (2007). "Cognitive impairment in amyotrophic lateral sclerosis". Lancet Neurol 6 (11): 994–1003. doi:10.1016/S1474-4422(07)70265-X. PMID 17945153. http://linkinghub.elsevier.com/retrieve/pii/S1474-4422(07)70265-X.
3. ^ "Amyotrophic Lateral Sclerosis Fact Sheet" on National Institute of Neurological Disorders and Stroke
4. ^ www.alsa.org
5. ^ Conwit, Robin A. (December 2006). "Preventing familial ALS: A clinical trial may be feasible but is an efficacy trial warranted?". Journal of the Neurological Sciences 251 (1–2): 1–2. doi:10.1016/j.jns.2006.07.009. ISSN 0022-510X. PMID 17070848.
6. ^ ^{a b} Al-Chalabi, Ammar; P. Nigel Leigh (August 2000). "Recent advances in amyotrophic lateral sclerosis". Current Opinion in Neurology 13 (4): 397–405. ISSN 1473-6551. PMID 10970056.
7. ^ "ALS Clinic at the Penn State Milton S. Hershey Medical Center". Web.archive.org. http://web.archive.org/web/20041115214832/http://www.alsphiladelphia.org/pennstatehershey/newsletters/newsletter_spring04.htm. Retrieved 2010-06-13.
8. ^ "Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease". http://www.ncbi.nlm.nih.gov/pubmed/19254284.
9. ^ Khabazian I, Bains JS, Williams DE, Cheung J, Wilson JM, Pasqualotto BA, Pelech SL, Andersen RJ, Wang YT, Liu L, Nagai A, Kim SU, Craig UK, Shaw CA (August 2002). "Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex". J. Neurochem. 82 (3): 516–28. doi:10.1046/j.1471-4159.2002.00976.x. PMID 12153476. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2002&volume=82&issue=3&spage=516. Retrieved 2009-03-13.
10. ^ ^{a b} "Sla, indagini nei club. Pesticidi nel mirino". http://www.corriere.it/sport/08_ottobre_03/sla_indagine_pesticidi_fd04f986-911c-11dd-9f28-00144f02aabc.shtml. Retrieved 2008-10-02.
11. ^ "Sla, una strage nel calcio". http://www.gazzetta.it/Calcio/Altro_Calcio/Primo_Piano/2007/11_Novembre/30/sla_3011.shtml. Retrieved 2008-10-02.
12. ^ "ALS in the Military". The ALS Association. 2007-05-17. http://www.alsa.org/files/pdf/als_military_paper.pdf. Retrieved 2008-05-01.
13. ^ "Occurrence of ALS higher in Gulf War veterans". http://www.bcm.edu/fromthelab/vol02/is10/03oct_n1.htm.
14. ^ "Veterans get ALS disability". http://www.baltimoresun.com/news/nation/bal-te.als25jul25,0,7448073.story.
15. ^ "ALS Research: Poison Dirt?". http://quest.mda.org/news/als-research-poison-dirt.
16. ^ Veldink JH, Kalmijn S, Groeneveld GJ, Wunderink W, Koster A, de Vries JH, van der Luyt J, Wokke JH, Van den Berg LH (April 2007). "Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis". J. Neurol. Neurosurg. Psychiatr. 78 (4): 367–71. doi:10.1136/jnnp.2005.083378. PMID 16648143. PMC 2077791. http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=16648143. Retrieved 2009-03-13.
17. ^ Okamoto K, Kihira T, Kondo T, Kobashi G, Washio M, Sasaki S, Yokoyama T, Miyake Y, Sakamoto N, Inaba Y, Nagai M (October 2007). "Nutritional status and risk of amyotrophic lateral sclerosis in Japan". Amyotroph Lateral Scler 8 (5): 300–4. doi:10.1080/17482960701472249. PMID 17852010. http://www.informaworld.com/openurl?genre=article&doi=10.1080/17482960701472249&magic=pubmed||1B69BA326FFE69C3F0A8F227DF8201D0. Retrieved 2009-03-13.
18. ^ Kwong LK, Uryu K, Trojanowski JQ, Lee VM (2008). "TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis". Neurosignals 16 (1): 41–51. doi:10.1159/000109758. PMID 18097159.
19. ^ Kerman A, Liu HN, Croul S, Bilbao J, Rogaeva E, Zinman L, Robertson J, Chakrabartty A (2010). "Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form". Acta Neuropathol. 119 (3): 335–44. doi:10.1007/s00401-010-0646-5. PMID 20111867.
20. ^ Reaume A, Elliott J, Hoffman E, Kowall N, Ferrante R, Siwek D, Wilcox H, Flood D, Beal M, Brown R, Scott R, Snider W (1996). "Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury". Nat Genet 13 (1): 43–7. doi:10.1038/ng0596-43. PMID 8673102.
21. ^ Bruijn L, Houseweart M, Kato S, Anderson K, Anderson S, Ohama E, Reaume A, Scott R, Cleveland D (1998). "Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1". Science 281 (5384): 1851–4. doi:10.1126/science.281.5384.1851. PMID 9743498.
22. ^ Furukawa Y, Fu R, Deng H, Siddique T, O'Halloran T (2006). "Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice". Proc Natl Acad Sci USA 103 (18): 7148–53. doi:10.1073/pnas.0602048103. PMID 16636274.
23. ^ Boillée S, Vande Velde C, Cleveland D (2006). "ALS: a disease of motor neurons and their nonneuronal neighbors". Neuron 52 (1): 39–59. doi:10.1016/j.neuron.2006.09.018. PMID 17015226.
24. ^ Armon C (2009). "Smoking may be considered an established risk factor for sporadic ALS". Neurology 73 (20): 1693–8. doi:10.1212/WNL.0b013e3181c1df48. PMID 19917993.
25. ^ Hansel Y, Ackerl M, Stanek G. (1995). "ALS-like sequelae in chronic neuroborreliosis". Wien Med Wochenschr. 145 (7-8): 186–8. PMID 7610670.
26. ^ el Alaoui-Faris M, Medejel A, al Zemmouri K, Yahyaoui M, Chkili T (1990). "Amyotrophic lateral sclerosis syndrome of syphilitic origin. 5 cases". Rev Neurol (Paris) 146 (1): 41–4. PMID 2408129.
27. ^ Umanekii KG, Dekonenko EP (1983). "Structure of progressive forms of tick-borne encephalitis". Zh Nevropatol Psikhiatr Im S S Korsakova. 83 (8): 1173–9. PMID 6414202.
28. ^ Pasinetti G, Ungar L, Lange D, Yemul S, Deng H, Yuan X, Brown R, Cudkowicz M, Newhall K, Peskind E, Marcus S, Ho L (2006). "Identification of potential CSF biomarkers in ALS". Neurology 66 (8): 1218–22. doi:10.1212/01.wnl.0000203129.82104.07. PMID 16481598.
29. ^ ^{a b} Hubert JP, Delumeau JC, Glowinski J, Prémont J, Doble A. (1994). "Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rate cultured granule cells: evidence for a dual mechanism of action". Br. J. Pharmacol. 113 (1): 261–267. PMID 7812619.
30. ^ Noh KM, Hwang JY, Shin HC, Koh JY. (2000). "A Novel Neuroprotective Mechanism of Riluzole: Direct Inhibition of Protein Kinase C". Neurobiol Dis. 7 (4): 375–383. doi:10.1006/nbdi.2000.0297. PMID 10964608.
31. ^ Beal MF, Lang AE, Ludolph AC. (2005). Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics. Cambridge: Cambridge University Press. p. 775. ISBN 0-521-81166-X. OCLC 57691713.
32. ^ Fornai F, Longone P, Cafaro L, et al. (2008). "Lithium delays progression of amyotrophic lateral sclerosis". Proc. Natl. Acad. Sci. U.S.A. 105 (6): 2052. doi:10.1073/pnas.0708022105. PMID 18250315. PMC 2538879. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18250315.
33. ^ Wicks P, Massagli M, Frost J, Macedo H, Felzer K, Heywood J. (2008). "A patient-led trial of lithium in ALS using the internet". Amyotrophic Lateral Sclerosis 9 (S1): 59.
34. ^ "Italian Trial of Lithium in ALS Stopped Early | Quest Magazine Online". Quest.mda.org. 2009-11-06. http://quest.mda.org/news/italian-trial-lithium-als-stopped-early. Retrieved 2010-06-13.
35. ^ "MDA / Quest Extra / NIH Cuts Short ALS Lithium Trial; MDA’s Trial Continues for Now". Mda.org. 2009-09-23. http://www.mda.org/publications/Quest/extra/sept09/als-lithium.html. Retrieved 2010-06-13.
36. ^ 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.
37. ^ Gribkoff V and Bozik M. KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis. CNS Neurosci Ther. 2008 Fall;14(3):215-26.
38. ^ "Minocycline Delays Onset and Slows Progression of ALS in Mice: National Institute of Neurological Disorders and Stroke (NINDS)". Ninds.nih.gov. http://www.ninds.nih.gov/news_and_events/news_articles/news_article_als_minocycline.htm. Retrieved 2010-06-13.
39. ^ Xia X, Zhou H, Huang Y, Xu Z (Sep 2006). "Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo". Neurobiol Dis. 23 (3): 578–86. doi:10.1016/j.nbd.2006.04.019. PMID 16857362.
40. ^ Izumi Y, Kaji R (October 2007). "[Clinical trials of ultra-high-dose methylcobalamin in ALS]" (in Japanese). Brain Nerve 59 (10): 1141–7. PMID 17969354.
41. ^ Sviri S, Linton DM, Van Heerden PV (Jun 2005). "Non-invasive Mechanical Ventilation Enhances Patient Autonomy in Decision-Making Regarding Chronic Ventilation". Critical Care and Resuscitation 7 (2): 116–118. PMID 16548804.
42. ^ Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA (Feb 2005). "Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse". Muscle Nerve 31 (2): 214–20. doi:10.1002/mus.20255. PMID 15625688.
43. ^ ^{a b} Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ (Jan 1996). "Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death". Am J Clin Nutr. 63 (1): 130–7. PMID 8604660. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=8604660.
44. ^ Slowie LA, Paige MS, Antel JP (Jul 1983). "Nutritional considerations in the management of patients with amyotrophic lateral sclerosis (ALS)". J Am Diet Assoc 83 (1): 44–7. PMID 6863783.
45. ^ Pedersen WA, Mattson MP (Jun 1999). "No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice". Brain Res. 833 (1): 117–20. doi:10.1016/S0006-8993(99)01471-7. PMID 10375685. http://linkinghub.elsevier.com/retrieve/pii/S0006-8993(99)01471-7.
46. ^ Zhao Z, Lange DJ, Voustianiouk A, et al. (2006). "A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis". BMC Neurosci 7: 29. doi:10.1186/1471-2202-7-29. PMID 16584562. Media report on Zhao et al..
47. ^ "The median survival time from onset to death ranges from 20 to 48 months, but 10 to 20% of ALS patients have a survival longer than 10 years." Prognostic factors in ALS: A critical review published in Amyotrophic Lateral Sclerosis Journal, 05 December 2008, Adriano Chio et al.
48. ^ "ALS Topic Overview". http://www.webmd.com/brain/tc/Amyotrophic-Lateral-Sclerosis-ALS-Topic-Overview. Retrieved 2008-05-01.
49. ^ Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (February 2009). "Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6". Science (journal) 323 (5918): 1208–11. doi:10.1126/science.1165942. PMID 19251628. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=19251628. Retrieved 2009-03-13.
50. ^ Kwiatkowski TJ, Bosco DA, LeClerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown, RH (Feb 2009). "Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis". Science 323 (5918): 1205–1208. doi:10.1126/science.1166066. PMID 19251627.
51. ^ Reed D, Labarthe D, Chen KM, Stallones R (Jan 1987). "A cohort study of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam and Rota". Am J Epidemiol. 125 (1): 92–100. PMID 3788958. http://aje.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=3788958.
52. ^ 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
53. ^ Spencer PS, Palmer VS, Ludolph AC (Aug 2005). "On the decline and etiology of high-incidence motor system disease in West Papua (southwest New Guinea)". Mov. Disord. 20 (Suppl 12): S119–26. doi:10.1002/mds.20552. PMID 16092101.
54. ^ 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
55. ^ Rachele MG, Mascia V, Tacconi P, Dessi N, Marrosu F (April 1998). "Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy". Ital J Neurol Sci. 19 (2): 97–100. doi:10.1007/BF02427565. PMID 10935845.
56. ^ Poloni M, Micheli A, Facchetti D, Mai R, Ceriani F (April 1997). "Conjugal amyotrophic lateral sclerosis: toxic clustering or change?". Ital J Neurol Sci. 18 (2): 109–12. doi:10.1007/BF01999572. PMID 9239532.
57. ^ Camu W, Cadilhac J, Billiard M. (March 1994). "Conjugal amyotrophic lateral sclerosis: a report on two couples from southern France". Neurology 44 (3 Pt 1): 547–8. PMID 8145930.
58. ^ Cornblath DR, Kurland LT, Boylan KB, Morrison L, Radhakrishnan K, Montgomery M. (November 1993). "Conjugal amyotrophic lateral sclerosis: report of a young married couple". Neurology 43 (11): 2378–80. PMID 8232960.
59. ^ Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W (November 2003). "A clustering of conjugal amyotrophic lateral sclerosis in southeastern France". Neurol. 60 (4): 553–7. doi:10.1001/archneur.60.4.553. PMID 12707069.
60. ^ "From charcot to lou gehrig: deciphering selective motor neuron death in als : Abstract : Nature Reviews Neuroscience". http://www.nature.com/nrn/journal/v2/n11/abs/nrn1101-806a.html.
61. ^ Reuters (2008-10-09). "ESPN.com - FEATURE-Soccer-Motor neurone worry hangs over Italian game". Sports.espn.go.com. http://sports.espn.go.com/espn/print?id=3634949&type=story. Retrieved 2010-06-13.
62. ^ "Jason Becker : Jason's Words". Jasonbeckerguitar.com. http://www.jasonbeckerguitar.com/jasons_words.html. Retrieved 2010-06-13.
63. ^ http://www.jasonbeckerguitar.com/downloads/tearsheets/GuitarWorldApril1991.pdf
64. ^ "Paralyzed but undaunted, Judt wills the left to a battle against inequality". Mondoweiss.net. 2009-10-20. http://mondoweiss.net/2009/10/paralyzed-but-undaunted-judt-urges-the-left-to-attack-inequality.html. Retrieved 2010-06-13.
65. ^ "Famed Minn. Boxer Battles Lou Gehrig's Disease". wcco.com. 2009-04-08. http://wcco.com/specialreports/scott.ledoux.boxer.2.979681.html. Retrieved 2010-06-13.
66. ^ "Lowen and Navarro - History". Lownav.com. http://www.lownav.com/history/index.html. Retrieved 2010-06-13.
67. ^ (Portuguese)
68. ^ Michael David Smith Lead Blogger. "Orlando Thomas Battling Lou Gehrig's Disease". NFL FanHouse. http://nfl.fanhouse.com/2007/06/10/orlando-thomas-battling-lou-gehrigs-disease/. Retrieved 2010-06-13.
69. ^ http://www.toto99.com/blog/news.php

Further reading

• "ALS Hope Foundation". http://www.alshopefoundation.org/. Retrieved 2008-06-21. "Dedicated to the care and cure of people with Lou Gehrig's Disease. (from site page us.php)"
• "Lou Gehrig: The Official Web Site". CMG Worldwide. http://www.lougehrig.com. Retrieved 2008-06-21. "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)"
• Patrick Aebischer; Ann C. Kato (November 2007). "Playing defense against Lou Gehrig's Disease" (Paper). Scientific American (Verlagsgruppe Georg von Holtzbrinck): pp. 86–93. http://www.sciam.com/article.cfm?id=playing-defense-against-l. Retrieved 2008-06-21. "Researchers have proposed potential therapies for a paralyzing disorder once thought to be untreatable (sub-title)"

External links

• ALS Association
• GeneReviews I
• GeneReviews II
• NIH Amyotrophic Lateral Sclerosis Fact Sheet
• - NPR Story
• ALS Forums - Support forum for those affected with ALS.

Categories: Motor neuron disease | Rare diseases | Unsolved problems in neuroscience | People with motor neuron disease | Deaths from motor neurone disease | Systemic atrophies primarily affecting the central nervous system | Neurodegenerative disorders

Personal tools

• New features
• Log in / create account

Namespaces

• Article
• Discussion

Variants

Views

• Read
• Edit
• View history

Actions

Search

Navigation

• Main page
• Contents
• Featured content
• Current events
• Random article

Interaction

• About Wikipedia
• Community portal
• Recent changes
• Contact Wikipedia
• Donate to Wikipedia
• Help

Toolbox

• What links here
• Related changes
• Upload file
• Special pages
• Permanent link
• Cite this page

Print/export

• Create a book
• Download as PDF
• Printable version

Languages

• العربية
• Български
• Català
• Dansk
• Deutsch
• Español
• Esperanto
• فارسی
• Français
• 한국어
• Hrvatski
• Bahasa Indonesia
• Italiano
• עברית
• ქართული
• Македонски
• Nederlands
• 日本語
• ‪Norsk (bokmål)‬
• Polski
• Português
• Русский
• Simple English
• Српски / Srpski
• Srpskohrvatski / Српскохрватски
• Suomi
• Svenska
• தமிழ்
• Türkçe
• 中文

• This page was last modified on 27 July 2010 at 00:34.
• Text is available under the Creative Commons Attribution-ShareAlike License ; additional terms may apply. See Terms of Use for details.
  Wikipedia® is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.
• Contact us

• Privacy policy
• About Wikipedia
• Disclaimers

See Also:

What Links Here:

Recently Viewed Pages:

• Home
• Weblogs: News
• Karl Ludwig Kahlbaum: Blogs
• Neuropsychiatry
• Psychiatry: Encyclopedia
• Health: Mental Health: Disorders: Personality: Chats and Forums: Directory
• Psychotherapy: Encyclopedia
• Psychiatry: Dictionary
• Cognitive: Encyclopedia
• Psychiatries: Dictionary

Most Popular Pages:

• Online Counseling: Blogs
• Keirsey Temperament Sorter: Answers
• Handwriting Analysis
• Karl Ludwig Kahlbaum: Blogs
• Bryophyte
• Weblogs: News
• Mental Status Examination: Encyclopedia
• Maudsley Bipolar Twin Study: Blogs
• Psychiatry: Dictionary
• Psychiatry: Encyclopedia

Related 'Amyotrophic Lateral Sclerosis' Searches: