Amyotrophic lateral sclerosis

"ALS" redirects here. For other uses, see ALS (disambiguation).
"Motor neurone disease" redirects here. For the broader group of diseases, see Motor neuron disease.
Amyotrophic lateral sclerosis

An MRI with increased signal in the posterior part of the internal capsule which can be tracked to the motor cortex consistent with the diagnosis of ALS.
Classification and external resources
Synonyms Lou Gehrig's disease, Charcot disease
Specialty Neurology
ICD-10 G12.2
ICD-9-CM 335.20
OMIM 105400
DiseasesDB 29148
MedlinePlus 000688
eMedicine neuro/14 emerg/24 pmr/10
Patient UK Amyotrophic lateral sclerosis
MeSH D000690
GeneReviews
Orphanet 803

Amyotrophic lateral sclerosis (ALS) is a specific disorder that involves the death of neurons.[1] In a number of countries the term motor neurone disease (MND) is commonly used,[2] while others use that term for a group of five conditions of which ALS is the most common.[3] ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscles decreasing in size.[4] This results in difficulty speaking, swallowing, and eventually breathing.[4]

The cause is not known in 90% to 95% of cases.[5] About 5–10% of cases are inherited from a person's parents.[6] About half of these genetic cases are due to one of two specific genes. It results in the death of the neurons that control voluntary muscles. The diagnosis is based on a person's signs and symptoms with testing done to rule out other potential causes.[5]

There is no known cure for ALS.[5] A medication called riluzole may extend life expectancy by about two to three months.[7] Non-invasive ventilation may result in both improved quality and length of life.[8] The disease usually starts around the age of 60 and in inherited cases around the age of 50.[6] The average survival from onset to death is three to four years.[9] About 10% survive longer than 10 years.[5] Most die from respiratory failure. In much of the world, rates of ALS are unknown.[6] In Europe and the United States, the disease affects about 2 people per 100,000 per year.[6][10]

Descriptions of the disease date back to at least 1824 by Charles Bell.[11] In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis.[11] It became well known in the United States in the 20th century when it affected the baseball player Lou Gehrig,[1] and later when Stephen Hawking gained fame for his scientific achievements.[12] In 2014, videos of the ice bucket challenge went viral on the internet and increased public awareness.[13]

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.[14]

Cognitive function is generally spared for most people, although some (about 5%) also develop frontotemporal dementia.[15] A higher proportion of people (30–50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing. Sometimes, ALS coexists in individuals who also experience dementia, degenerative muscle disorder, and degenerative bone disorder as part of a syndrome called multisystem proteinopathy.[16] Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing, sight, touch, smell, and taste.[17]

Initial symptoms

The start of ALS may be so subtle that the symptoms are overlooked.[18] The earliest symptoms of ALS are muscle weakness and/or muscle atrophy. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first.

About 75% of people contracting the disorder first experience weakness or atrophy in an arm or leg and this is known as "limb-onset" ALS. Awkwardness when walking or running or even tripping over or stumbling may be experienced and often this is marked by walking with a "dropped foot" which drags gently on the ground. Or if arm-onset, difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock may be experienced. Occasionally, the symptoms remain confined to one limb for a long period of time or for the duration of the illness; this is known as monomelic amyotrophy.

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

Over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations) although twitching is not a diagnostic symptom and more of a side effect so twitching would either occur after or accompany weakness and atrophy. Around 15–45% of people 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. For ALS to be diagnosed, symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes must be present.

Progression

Although the order and rate of symptoms varies from person to person, most people eventually are not able to walk or use their hands and arms. They also lose the ability to speak and swallow food, while most end up on a portable ventilator, called bilevel positive airway pressure. The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale Revised (ALSFRS-R)", a 12-item instrument administered as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, patients lose about 0.9 FRS points per month. A survey-based study amongst clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.[19] 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,[20][21] are mildly obese,[22] have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[23] Conversely, progression is faster and prognosis poorer in people with bulbar-onset disorder, respiratory-onset disorder, and frontotemporal dementia.[23]

The CX3CR1 allelic variants have also been shown to have an effect on the disorder's progression and life expectancy.[24]

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.[25] Guitarist Jason Becker has lived since 1989 with the disorder, while physicist Stephen Hawking has survived for more than 50 years, but they are considered unusual cases.[26]

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. 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 (EOMs). The eye movements remain unaffected largely until the later stages due to differences in the extraocular muscles compared to the skeletal muscles that are initially and readily affected. In the disease's final stages, a person's condition may resemble locked-in syndrome.[27]

Eye movement

People with ALS may have difficulty in generating voluntary fast movements of the eye.[28] The speed of eye movement is slower in people with ALS.[28] Problems in generating smooth pursuit and convergence movements have also been noted.[28] Testing the vestibulo-ocular reflex should help in identifying these problems.[29] The electrooculography (EOG) technique measures the resting potential of the retina. EOG findings in people with ALS show progressive changes that correlate with disorder progression, and provide a measurement for clinically evaluating the effects of disorder progression on oculomotor activity.[29] Additionally, EOG may allow earlier detection of problems with the eyes.

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.[30] EOMs have significantly more myogenic precursor cells than limb skeletal muscles.[30]

Causes

Genetics

About 5–10% of cases are directly inherited from a person's parents.[6] Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS.[31][32]

A defect on chromosome 21, which codes for superoxide dismutase, is associated with about 20% of familial cases of ALS, or about 2% of ALS cases overall.[33][34][35] 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 America; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS, and people with this form of the disorder survive for an average of 11 years.[36]

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,[37] and accounts for some 6% of cases of ALS among white Europeans.[38] The gene is also found in people of Filipino descent.[38]

The UBQLN2 gene encodes production of the protein ubiquilin 2 in the cell, which is a member of the ubiquilin family and controls the degradation of ubiquitinated proteins. Mutations in UBQLN2 interfere with protein degradation, leading to neurodegeneration and causing dominantly inherited, chromosome X-linked ALS and ALS/dementia.[39]

To date, a number of genetic mutations have been associated with various types of ALS. The currently known associations are:

Type OMIM Gene Locus Inheritance Remarks
ALS1 105400 SOD1 21q22.1 autosomal dominant (?), autosomal recessive (?) The most common form of familial ALS
ALS2 205100 ALS2 2q33.1 autosomal recessive (?) Juvenile-onset
ALS3 606640 (?) 18q21 (?)
ALS4 602433 SETX 9q34.13 autosomal dominant (?)
ALS5 602099 SPG11 15q15.1–q21.1 autosomal recessive (?) Juvenile onset
ALS6 608030 FUS 16p11.2 (?)
ALS7 608031 (?) 20p13 (?)
ALS8 608627 VAPB 20q13.3 autosomal dominant (?)
ALS9 611895 ANG 14q11.2 (?)
ALS10 612069 TARDBP 1p36.2 autosomal dominant (?) ALS with or without frontotemporal dementia
ALS11 612577 FIG4 6q21 (?)
ALS12 613435 OPTN 10p13 (?)
ALS13 183090 ATXN2 12q24.12 autosomal dominant (?) Spinocerebellar ataxia 2
ALS14 613954 VCP 9p13.3 (?) Recent new study shows strong link in ALS mechanism[40][41]
ALS15 300857 UBQLN2 Xp11.21 X-linked dominant (?) Described in one family[42]
ALS16 614373 SIGMAR1 9p13.3 autosomal recessive (?) Juvenile onset, very rare, described only in one family[43]
ALS17 614696 CHMP2B 3p11.2 autosomal dominant (?) Very rare, reported only in a handful of people
ALS18 614808 PFN1 17p13.2 (?) Very rare, described only in a handful of Chinese families[44]
ALS19 615515 ERBB4 2q34 autosomal dominant (?) Very rare, as of late 2013 described only in four people[45]
ALS20 615426 HNRNPA1 12q13.13 (?) Very rare, as of late 2013 described only in two people[46]
ALS21 606070 MATR3 5q31.2 autosomal dominant (?) Very rare. Formerly known as "distal myopathy type 2" (MPD2) and "vocal cord and pharyngeal dysfunction with distal myopathy" (VCPDM)
FTDALS1 105550 C9orf72 9p21.2 autosomal dominant (?) "Frontotemporal dementia and/or amyotrophic lateral sclerosis type 1". Accounts for around 6% of ALS cases among white Europeans
FTDALS2 615911 CHCHD10 22q11.23 autosomal dominant (?) "Frontotemporal dementia and/or amyotrophic lateral sclerosis type 2"
FTDALS3 616437 SQSTM1 5q35.3 autosomal dominant (?) "Frontotemporal dementia and/or amyotrophic lateral sclerosis type 3"
FTDALS4 616439 TBK1 12q14.2 autosomal dominant (?) "Frontotemporal dementia and/or amyotrophic lateral sclerosis type 4"

SOD1

In 1993, scientists discovered that mutations in the gene (SOD1) that produces the Cu-Zn superoxide dismutase (SOD1) enzyme were associated with around 20% of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disorder, some of which (such as H46R) have a very long clinical course, while others, such as A4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis) is upregulated.

A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of free radicals. A gain of SOD1 function could be toxic in other ways.[47][48]

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. This indicates 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 (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.[49] Aggregate accumulation of mutant SOD1 is suspected to play a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins.[50] 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.

An online database is available which was designed to provide both the scientific community and the wider public with up-to-date information on ALS genetics. This is known as ALSOD – website originally designed for the SOD1 gene in 1999, but since upgraded to include over 40 ALS-related genes.

Other factors

Where no family history of the disease is present – i.e., in around 90% of cases – no cause is known for ALS. Possible associations for which evidence is inconclusive include head trauma, military service, frequent drug use, and participation in contact sports.

Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the neurotransmitters in the brain. Scientists have found, compared with healthy people, people with ALS have higher levels of glutamate in their serum and spinal fluid.[34] Riluzole is currently the only FDA-approved drug for ALS and targets glutamate transporters. It only has a modest effect on survival, however, suggesting that excess glutamate is not the sole cause of the disease.

Certain studies suggested a link between sporadic ALS, specifically in athletes, and a diet enriched with branched-chain amino acids, a common dietary supplement among athletes, which cause cell hyperexcitability resembling that usually observed in people with ALS. The proposed underlying mechanism is that cell hyperexcitability results in increased calcium absorption by the cell, and thus brings about cell death of neuronal cells, which have particularly low calcium buffering capabilities.[51][52]

Some evidence supports superoxide dismutase 1 (SOD1) protein misfolding propagates between molecules in a similar fashion to prions.[53] Similarly, it has been proposed that incorporation of the cyanobacterial toxin β-methylamino-l-alanine (BMAA) leads to another prion-like protein misfolding propagation.[54][55]

Another very common factor associated with ALS is a lesion to the motor system in areas such as the frontotemporal lobes.[56] Lesions in these areas often show signs of early deficit, which can be used to predict the loss of motor function, and result in the spread of ALS.[56] The mechanisms of ALS are present long before any signs or symptoms become apparent.[57] Before any muscular atrophy becomes apparent during ALS, roughly one-third of the motor neurons must be destroyed.[57]

Many other potential risk factors including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated, but are without consistent findings.[58]

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 protein-rich inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.[59] These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), and/or FUS.[60]

Skeletal motor units

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.[61]

Differences are also noted 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.[62] EOMs affected by ALS preserve the GL and OL organization.[62] 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.[62] 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.[63] People with ALS showed preserved Lnα4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the same people.[63] Preservation of laminin expression may play a role in preserving EOM integrity in people with ALS. People with sporadic ALS (sALS) have increased levels of intracelluar calcium, causing increased neurotransmitter release.[64] Passive transfer of sera from people with sALS increases spontaneous transmitter release in spinal, but not EOM terminals;[64] therefore, EOMs are assumed to be resistant to changes in physiologic conditions typically found in ALS.

However, some effects of the disorder were noted. EOMs affected by ALS had a larger variation in fiber size compared to those in age-matched healthy controls.[62] EOMs exhibited both clustered and scattered atrophic and hypertrophic fibers that are characteristic of disorder, but these muscles showed significantly less damage compared to limb muscles from the same donors.[62] These EOMs also showed an increase in connective tissue and areas of fatty replacement in compensation of fiber loss and atrophy.[62] Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei, has been noted in ALS patients.[28] Additionally, myosin heavy chain content of the EOM fibers was altered, with a loss of normal expression of MyHCslow tonic in the GL and the OL did not contain MyHCemb, which is normally expressed in this layer.[62] 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.[62] Because EOMs are normally highly innervated, any denervation is compensated for by neighbouring axons which preserve function.[62]

Lactate and cinnamate

Lactic acid is an end product of glycolysis and is known to cause muscle fatigue. Lactate dehydrogenase (LDH) enzyme 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. EOMs that have high LDH activity are thought to be resistant to ALS.[65]

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 the extensor digitorum longus muscle in the leg.[65] In contrast, replacing glucose with exogenous lactate increases fatiguability of EDL muscles but not EOMs.[65] Fatiguability in EOMs was only found when a combination of exogenous lactacte plus cinnamate replaced glucose.[65]

Diagnosis

MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the diagnosis of ALS.

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive.[5] Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases.[5] Physicians obtain the person'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 worsening.[5]

Differential diagnosis

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.[5] One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles.[5] Certain EMG findings can support the diagnosis of ALS.[5] Another common test measures nerve conduction velocity (NCV).[5] 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. While a magnetic resonance imaging (MRI) is often normal in people with early stage 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.[5]

Based on the person'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.[5] In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.[5]

Viral infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukaemia virus (HTLV), Lyme disease,[66] syphilis[67] and tick-borne encephalitis[68] can in some cases cause ALS-like symptoms.[5] Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered.[5]

ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants.[69] 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, people should always obtain a specialist neurological opinion, so alternative diagnoses are clinically ruled out. Benign fasciculation syndrome is another condition that mimics many of the symptoms of ALS, but is accompanied by normal EMG readings and no major disablement.

However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10%.[70][71] In one study, 190 patients who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these patients (16%) had their diagnosis completely changed during the clinical observation development period.[72] In the same study, three patients had a false negative diagnosis, myasthenia gravis (MG), an autoimmune disease. MG can mimic ALS and other neurological disorders leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.[73] Myasthenic syndrome, also known as Lambert-Eaton syndrome, can mimic ALS and its initial presentation can be similar to that of MG.[74][75]

Management

Management of ALS attempts to relieve symptoms and extend life expectancy. This supportive care is best provided by multidisciplinary teams of health care professionals working with the person and their caregivers to keep them as mobile and comfortable as possible.

Medications

Riluzole (Rilutek) has been found to modestly improve survival.[76] It lengthens survival by several months, and may have a greater survival benefit for those with a bulbar onset. It also extends the time before a person needs ventilation support. People taking it must be monitored for liver damage (occurring in about 10% of people taking the drug).[77] It is approved by Food and Drug Administration (US) and recommended by the National Institute for Clinical Excellence (UK). Riluzole does not reverse damage already done to motor neurons.[78]

Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Drugs also are available to help patients with pain, depression, sleep disturbances, dysphagia, and constipation. Baclofen and diazepam are often prescribed to control the spasticity caused by ALS, and trihexyphenidyl or amitriptyline may be prescribed when people with ALS begin having trouble swallowing their saliva.[14]

Breathing support

When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive pressure ventilation, bilevel positive airway pressure (BiPAP), or biphasic cuirass ventilation (BCV) may be used to aid breathing. Such devices artificially inflate the person's lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by several positive expiratory breaths.[79] People may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as a tracheotomy, in which a plastic breathing tube is inserted directly in the person's windpipe through an opening in the neck.

Persons and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the person's quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support and have deep discussions on quality of life. Some persons under long-term tracheotomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheotomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough, though in all cases speech will be lost as the disease progresses. This technique preserves speech in some persons with long-term mechanical ventilation. Other persons may be able to use a speaking valve such as a Passey-Muir speaking valve with the assistance and guidance of a speech-language pathologist.

External ventilation machines that use the ventilation mode of BiPAP are frequently used to support breathing, initially at night, and later during the daytime, as well. The use of BPAP (more often referred to as noninvasive ventilation, NIV) is only a temporary remedy, however, and long before BPAP stops being effective, persons should decide whether to have a tracheotomy and long-term mechanical ventilation. At this point, some persons choose palliative hospice care.

Therapy

Physical therapy plays a large role in rehabilitation for individuals with ALS. Specifically, physical and occupational therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, preventing complications, and promoting functional independence.[80]

Occupational therapy and special equipment such as assistive technology can also enhance patients' independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help patients remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable people to retain as much safety and independence in activities of daily living as possible.

ALS patients who have difficulty speaking may benefit from working with a speech-language pathologist. These health professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet boards or yes/no signals.

Nutrition

Patients and caregivers can learn from dieticians how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber and fluid, and how to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. Occupational therapists can assist with recommendations for adaptive equipment to ease the physical task of self-feeding. Speech-language pathologists make food choice recommendations that are more conducive to their unique deficits and abilities. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent patients from eating food orally if they wish.

Researchers have stated, "ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake"[81] and have a severe loss of appetite.[82] Both animal[83] and human research[81] [84] suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their caloric intake. As of 2012, "a lack of robust evidence for interventions" remained for the management of weight loss.[85]

End of life care

Social workers and home care and hospice nurses help people with ALS, their families, and caregivers with the medical, emotional, and financial challenges of coping, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging 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.

Epidemiology

In much of the world, rates of ALS are unknown.[6] In Europe, the disease affects about 2.2 people per 100,000 per year.[6] In the United States, more than 5,600 are diagnosed every year, and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 people per year.[86]

ALS is classified as a rare disease, but is the most common motor neuron disease. People of all races and ethnic backgrounds are affected. One or two of 100,000 people develop ALS each year.[87] Amyotrophic lateral sclerosis affects around 30,000 Americans.[88] ALS cases are estimated at 1.2–4.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations.[89] Filipinos are second to Caucasians in terms of ALS prevalence with 1.1-2.8 per 100,000 individuals.[88]

Reports have been made of several "clusters" including three American football players from the San Francisco 49ers, more than 50 association football players in Italy,[90] three association football-playing friends in the south of England,[91] and conjugal (husband and wife) cases in the south of France.[92][93][94][95][96] Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a higher risk with increasing age.

History

Descriptions of the disease date back to at least 1824 by Charles Bell.[11]

English scientist Augustus Waller described the appearance of shriveled nerve fibers in 1850. In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot, who introduced the term amyotrophic lateral sclerosis in his 1874 paper.[11] In 1881, the article was translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System.

ALS became a cause célèbre in the United States in 1939 when baseball legend Lou Gehrig's career, and two years later, his life, were ended by the disease.[97]

In the 1950s, an epidemic occurred among the Chamorro people on Guam which bore similarities to many conditions, including ALS.[98]

By 1991, researchers had linked chromosome 21 to familial ALS (FALS). In 1993, the SOD1 gene on chromosome 21 was found to play a role in some cases of FALS. In 1996, riluzole became the first FDA-approved drug for ALS.

In 1998, the El Escorial criteria were developed as the standard for classifying ALS patient in clinical research. The next year, the revised ALS Functional Rating Scale was published and soon becomes a gold standard for rating the declines in ALS patient in clinical research. Noncoding repeat expansions in C9ORF72 were found to be a major cause of ALS and frontotemporal dementia in 2011.

Name

Amyotrophic comes from the Greek word amyotrophia: a- means "no", myo refers to "muscle", and trophia means "nourishment"; amyotrophia therefore means "no muscle nourishment," which describes the characteristic atrophy of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where affected portions of the nerve cells are located. Degeneration in this area leads to scarring or hardening ("sclerosis").

In the United Kingdom, India,[99] Australia[100] and some other Commonwealth countries the term motor neurone disease (MND) is commonly used.[2]

Society and culture

In August 2014, a challenge went viral online which was commonly known as the "ALS Ice Bucket Challenge".[101] Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US $10 (or a similar amount in their local currency) to ALS research at the ALS Association, or Motor Neurone Disease Association in the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of August 25, the Ice Bucket Challenge raised $79.7 million for the ALS Association, compared to $2.5 million raised over the same period in 2013. Many celebrities have taken part in the challenge.[102]

ALS is the central topic of the 2014 movie You're Not You, directed by George C. Wolfe, with Hilary Swank, Emmy Rossum and Josh Duhamel playing the main characters.[103]

In the Marvel Comics comic The Incredible Hulk, one storyline saw Bruce Banner, AKA the Hulk, learn that he was dying of the disease, with his unique condition meaning that his Hulk personas would permanently take over his body once his disease became too progressed for him to survive on his own. He was eventually able to find a cure with the aid of his old foe the Leader, who arranged for the damaged DNA sequences causing the disease to be replaced by healthy genes extracted from the corpse of Bruce's father, the Hulk's transformation back into Bruce integrating the repaired genes into his system. The final issue of this storyline concludes with Bruce informing the reader that there is no cure for ALS at present.[104]

Research

A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can be found at ClinicalTrials.gov. A large genetic study, called project MinE, initiated by two people with ALS is going on currently. It is a crowdfunded research project with many countries involved to discover more genes.[105] A division of the US Centers for Disease Control and Prevention maintains a registry of Americans with ALS.[106]

A phase-II trial on tirasemtiv has been completed with a follow-on phase-IIb study in progress under the name "BENEFIT-ALS". Results of the first study are available here.[107][108] The current trial is an international, placebo-controlled, multiple-center study on 680 participants. This makes it one of the largest studies to date. A phase-II trial on ozanezumab is in progress. It is a large multiple-site international research project sponsored by GlaxoSmithKline.

A phase-II clinical trial is being conducted by BrainStorm Cell Therapeutics at the Hadassah Medical Center in Israel and interim results "demonstrated a tendency toward stabilization in some parameters in the ALS Functional Rating Scale."[109][110] People in the trial have bone marrow stem cells removed and differentiated in a clean room into cells that express neurotropic factors. The cells are injected back into the same person by intrathecal and intramuscular injections. A second phase-II trial is expected to open in the United States at several institutions including the Mayo Clinic.[111]

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