Amyotrophic lateral sclerosis

Classification

ALS is a motor neuron disease, also spelled "motor neurone disease", which is a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy.

ALS itself can be classified a few different ways: by how fast the disease progresses (slow vs fast progressors), by whether it is inherited or sporadic, and by where it starts. Most commonly (~70% of the time) the limbs are affected first. In this case, neurons in the brain (upper motor neurons) and in the spinal cord (lower motor neurons) are dying and this form is called "limb onset". In about 25% of cases, muscles in the face, mouth, and throat are affected first because motor neurons in the part of the brain stem called the medulla oblongata (formerly called the "bulb") start to die first along with lower motor neurons. This form is called "bulbar onset". In about 5% of cases muscles in the trunk of the body are affected first. In all cases the disease spreads and affects other regions. The symptoms may also be limited to one spinal region. This form carries a longer survival time than classic onset ALS.

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.

Cognitive or behavioral dysfunction is present in up to half of individuals with ALS. Around half of people with ALS will experience mild changes in cognition and behavior, and 10–15% will show signs of frontotemporal dementia. Repeating phrases or gestures, apathy, and loss of inhibition are frequently reported behavioral features of ALS. Language dysfunction, executive dysfunction, and troubles with social cognition and verbal memory are the most commonly reported cognitive symptoms in ALS; a meta-analysis found no relationship between dysfunction and disease severity. However, cognitive and behavioral dysfunctions have been found to correlate with reduced survival in people with ALS and increased caregiver burden; this may be due in part to deficits in social cognition. About half the people who have ALS experience emotional lability, in which they cry or laugh for no reason.

Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing, sight, touch, smell, and taste.

Initial symptoms

The start of ALS may be so subtle that the symptoms are overlooked. The earliest symptoms of ALS are muscle weakness 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; 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.

In limb-onset ALS, people first experience 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.

In 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.

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.

Progression

Although the order and rate of symptoms vary from person to person, the disease eventually spreads to unaffected regions and the affected regions become more affected. Most people eventually are not able to walk or use their hands and arms, lose the ability to speak and swallow food and their own saliva, and begin to lose the ability to cough and to breathe on their own.

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 self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability); it is the most commonly used outcome measure in clinical trials and is used by doctors to track disease progression. Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, people with ALS 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.

Disorder progression tends to be slower in people who are younger than 40 at onset, are mildly obese, have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms. Conversely, progression is faster and prognosis poorer in people with bulbar-onset disorder, respiratory-onset disorder, and frontotemporal dementia.

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

Late stages

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.

Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die between two and four years after the diagnosis. Around half of people with ALS die within 30 months of their symptoms beginning, and about 20% of people with ALS live between 5 years and 10 years after symptoms begin. 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.

Most people with ALS die in their own home, with their breath failing while they sleep; people rarely choke to death.

Genetics

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

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. 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.

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, and accounts for some 6% of cases of ALS among white Europeans.

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.

SNPs in the VEGF gene have been identified has a risk factor for ALS.

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

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.

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.

Head injury

While moderate to severe traumatic brain injury is a risk for ALS, it is unclear if mild traumatic brain injury increases rates.

In 1994 the National Institute for Occupational Safety and Health (NIOSH) reported a nonsignificant increase in nervous system disorders due to four cases of ALS among National Football League (NFL) players. It was unclear if this was due to chance or not. Another study from 2012 also found a possible increase in ALS in NFL football players. An older study did not find an increased risk among high school football players. A 2007 review found an increased risk among soccer players. ALS may also occur more often among the US military veterans however the reason is unknown. This may be due to head injury.

After the 2012 report was released, some NFL players involved in the legal settlement with the NFL complained that the NFL, which initially agreed to pay $765 million, was not doing enough to help players. The judge in the case concurred, and the NFL then agreed to pay an unlimited amount of damages for players found to have ALS, Parkinson’s disease, Alzheimer’s disease and dementia.

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 military service, frequent drug use, and participation in contact sports. Studies on military history and ALS frequency are inconsistent, but suggest a positive correlation. Various factors that have been proposed include exposure to environmental toxins (evidenced by geographical deployment studies) as well as alcohol and tobacco use during military service.

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. Riluzole, which targets glutamate transporters, is currently the only FDA-approved drug for treatment of ALS. It has only 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.

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

Another very common factor associated with ALS is a lesion to the motor system in areas such as the frontotemporal lobes. 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. The mechanisms of ALS are present long before any signs or symptoms become apparent. Before any muscular atrophy becomes apparent during ALS, roughly one-third of the motor neurons must be destroyed.

Other potential risk factors including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock have been investigated but are without consistent findings. There is a tentative association with exposure to a number of pesticides including the organochlorine insecticides aldrin, dieldrin, DDT, and toxaphene.

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. These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), or FUS. The mutant SOD1 may also contribute to motor neuron cell death through generating free radicals.

Excitotoxicity, or cell death caused by high levels of intracellular calcium caused by excessive activity of excitatory neurotransmitters, may be a mechanism of ALS. This concept has been supported by increased glutamate and dysfunctional glutamate transporter–RNA in cerebrospinal fluid of those with ALS. This is further supported by the only effective treatment being an anti-glutaminergic drug (Riluzole), as well as the poor ability to buffer calcium in motor neurons relative to other neurons.

Neurofilament accumulation in axons has been observed in sporadic cases of ALS as well as in SOD1 patients, possibly interfering with axonal transport, leading to cell death from SOD1 toxicity.

Research

Mitochondrial abnormalities, such as increased free radical production and impaired ATP production, have been observed but these mechanisms are unproven causes of ALS. SOD1 and TDP-43 mutations may play a role in causing mitochondria dysfunction.

Increased markers of oxidative stress have been observed in sporadic cases of ALS, including 8-Oxo-2'-deoxyguanosine and 4-Hydroxynonenal. This hypothesis is further supported by various risk factors observed for ALS, such as trauma and exposure to certain chemicals that may play a role in increasing oxidative stress. However, failed trials with anti-oxidants and methodological limitation limit the hypothesis. One proposed mechanism of ALS incorporating both the genetic mutations of RNA binding proteins and oxidative stress, suggests that with age cells lose their ability to buffer against the genetic changes due to increasing oxidative stress resulting in the death of sensitive cells. A possible mechanism for dysregulation of glutaminergic neurotransmission may be through excessive oxidative stress of astrocytes.

Given the co-occurrence and symptomatic overlap with frontotemporal dementia, they may share an underlying pathophysiology, such as dysreguated microRNA activity(possibly originating in a TDP-43 mutation.) However authors cautioned against assuming a causal role of microRNA dysregulation.

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 person and a series of tests to rule out other diseases. 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.

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. 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 person 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, it 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 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. In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.

Viral infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV), Lyme disease, syphilis and tick-borne encephalitis can in some cases cause ALS-like symptoms. 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.

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. 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 in order to rule out alternative diagnoses. 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.

Most cases of ALS, however, are readily diagnosed, and the error rate of diagnosis in large ALS clinics is less than 10%. In one study, 190 people who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these people (16%) had their diagnosis completely changed during the clinical observation development period. In the same study, three people 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. Myasthenic syndrome, also known as Lambert–Eaton syndrome, can mimic ALS, and its initial presentation can be similar to that of MG.

Management

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

Medications

Riluzole has been found to modestly improve survival by approximately two to three months. It 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). 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.

In 2015 edaravone was approved for treatment ALS in Japan and drug obtained Orphan Drug Designation in the EU and USA.

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 people 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.

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. 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. People 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 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, 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, improving speech and swallowing, preventing complications, and promoting functional independence.

Occupational therapy and special equipment such as assistive technology can also enhance people's 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 people 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 people remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable ALS people to retain as much safety and independence in activities of daily living as possible.

People with ALS who have difficulty speaking may benefit from working with a speech-language pathologist. These health professionals can teach people 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) or low-tech communication techniques such as head mounted laser pointers, alphabet boards or yes/no signals.

Nutrition

People with ALS 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. People 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 people with ALS 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 people 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" and have a severe loss of appetite. Both animal and human research 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.

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 people 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 people with ALS who wish to remain at home. The home hospice team can also counsel people with ALS and caregivers about end-of-life issues.

Epidemiology

In much of the world, rates of ALS are unknown. In Europe, the disease affects about 2.2 people per 100,000 per year. In the United States, more than 5,600 are diagnosed every year (over 1.87 per 100,000 per year), and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 people per year.

ALS is classified as a rare disease, designated by the FDA as an “orphan” disease (affecting fewer than 200,000 people in the United States), 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. Amyotrophic lateral sclerosis affects around 30,000 Americans. ALS cases are estimated at 1.2–4.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations. Filipinos are second to Caucasians in terms of ALS prevalence with 1.1-2.8 per 100,000 individuals.

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, three association football-playing friends in the south of England, and conjugal (husband and wife) cases in the south of France. 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.

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 initially introduced the term amyotrophic lateral sclerosis in his 1874 paper. 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.

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

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 people with ALS in clinical research. The next year, the revised ALS Functional Rating Scale was published and soon becomes a gold standard for 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 Commonwealth countries, the term "motor neurone disease" (MND) is commonly used.

Society and culture

In August 2014, a challenge went viral online which was commonly known as the "ALS Ice Bucket Challenge". 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 July 2015, the Ice Bucket Challenge had raised $115 million for the ALS Association. Many celebrities have taken part in the challenge. The Ice Bucket Challenge was credited with helping to raise funds that contributed to the discovery that the gene NEK1 may potentially contribute to the development for ALS.

ALS has been discussed and depicted late in the second season of Stargate Universe science fiction series, particularly in episode "Epilogue (Part 2)", which first aired on 25 April 2011.

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.

New York filmmaker and ALS advocate Patrick Sean O'Brien self-directed an autobiographical documentary Transfatty Lives on his initial diagnosis of ALS in 2005. In the spring of 2015, the documentary was released. As of late 2016, O'Brien was continuing his film tour and fundraiser events via a motion-sensing device and computer through which he speaks.

Research

Repetitive transcranial magnetic stimulation had been studied in ALS in small and poorly designed clinical trials; as of 2013, there was insufficient evidence to know if rTMS is safe or effective for ALS.

One 2016 review of stem cell therapy trials found tentative evidence that intraspinal stem cell implantation was relatively safe and possibly effective. A 2016 Cochrane review of cell based therapies found that there was insufficient evidence to speculate about efficacy.

Masitinib has been approved as an orphan medication in Europe and the United States with studies ongoing as of 2016. Medications tested but without evidence for efficacy include lamotrigine, dextromethorphan, gabapentin, BCAAs, Vitamin E, acetylcysteine, selegiline, amantadine, cyclophosphamide, various neurotrophic factors, and creatine. Beta-adrenergic agonist drugs have been proposed as a treatment for their effects on muscle growth and neuroprotection, but there is insufficient research in humans to determine their efficacy.