ALS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease and Charcot disease,

is a specificdisorder that involves the death of neurons.[1] In the United Kingdom 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 muscle wasting. This results in

difficulty speaking, swallowing, and eventually breathing.[4]

The cause is not known in 90% to 95% of cases.[4] About 5–10% of cases are inherited from a

person's parents.[5]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.[4]

There is no cure for ALS.[4] A medication called riluzole may extend life expectancy by about two to

three months.[6] Non-invasive ventilation  may result in both improved quality and length of life.[7] The

disease usually starts around the age of 60 and in inherited cases around the age of 50. [5] The

average survival from onset to death is three to four years.[8] About 10% survive longer than 10

years.[4] Most die from respiratory failure. In much of the world, rates of ALS are unknown.[5] In

Europe and the United States, the disease affects about 2 people per 100,000 per year. [5][9]

Descriptions of the disease date back to at least 1824 by Charles Bell.[10] 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.[10] 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.[11] In 2014 videos of the ice

bucket challenge went viral on the internet and increased public awareness.[12]

Contents

  

1   Signs and symptoms

o 1.1   Initial symptoms

o 1.2   Progression

o 1.3   Late stages

o 1.4   Eye movement

2   Causes

o 2.1   Genetics

o 2.2   Other factors

3   Pathophysiology

o 3.1   Skeletal motor units

o 3.2   Lactate and cinnamate

4   Diagnosis

5   Management

o 5.1   Medications

o 5.2   Breathing support

o 5.3   Therapy

o 5.4   Nutrition

o 5.5   Palliative care

6   Epidemiology

7   History

o 7.1   Etymology

8   Society and culture

9   Research

10   References

11   External links

Signs and symptomsThe 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.[13]

Cognitive function is generally spared for most people, although some (about 5%) also

develop frontotemporal dementia.[14] A higher proportion of people (30–50%) also have more subtle

cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing.

Infrequently, ALS coexists in individuals who also experience dementia, degenerative muscle

disorder, and degenerative bone disorder as part of a syndrome called multisystem proteinopathy.

[15] Sensory nerves and the autonomic nervous system are generally unaffected, meaning the

majority of people with ALS maintain hearing, sight, touch, smell, and taste.[16]

Initial symptoms

The start of ALS may be so subtle that the symptoms are overlooked.[17] 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.[citation needed] 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.[18] 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,[19][20] are mildly

obese,[21] have disorder restricted primarily to one limb, and those with primarily upper motor neuron

symptoms.[22] Conversely, progression is faster and prognosis poorer in people with bulbar-onset

disorder, respiratory-onset disorder, and frontotemporal dementia.[22]

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

and life expectancy.[23]

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.[24] 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.[25]

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.[26]

Eye movement

People with ALS may have difficulty in generating voluntary fast movements of the eye.[27] The speed

of eye movement is slower in people with ALS.[27] Problems in generating smooth pursuit and

convergence movements have also been noted.[27] Testing the vestibulo-ocular reflex should help in

identifying these problems.[28]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.[28] 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.[29] EOMs have significantly more myogenic precursor cells than limb skeletal

muscles.[29]

Causes[

Genetics

About 5–10% of cases are directly inherited from a person's parents.[5] Overall, first-degree

relatives of an individual with ALS have a 1% risk of developing ALS.[30][31]

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.[32][33][34] 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.[35]

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

people of Filipino descent.[37]

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.[38]

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

known associations are:

Type OMIM Gene Locus Remarks

ALS1 105400 SOD1 21q22.1The most common form of familial

ALS

ALS2 205100 ALS2 2q33.1

ALS3 606640  ? 18q21

ALS4 602433 SETX 9q34.13

ALS5 602099  ? 15q15.1–q21.1 Juvenile onset

ALS6 608030 FUS 16p11.2

ALS7 608031  ? 20p13

ALS8 608627 VAPB 20q13.3

ALS9 611895 ANG 14q11.2

ALS10 612069 TARDBP 1p36.2

ALS11 612577 FIG4 6q21

ALS12 613435 OPTN 10p13

ALS13 183090 ATXN2 12q24.12

ALS14 613954 VCP 9p13.3Recent new study shows strong

link in ALS mechanism[15][39]

ALS15 300857 UBQLN2 Xp11.23–p11.1 Described in one family[40]

ALS16 614373 SIGMAR1 9p13.3Juvenile onset, very rare,

described only in one family[41]

ALS17 614696 CHMP2B 3p11Very rare, reported only in a

handful of people

ALS18 614808 PFN1 17p13.3Very rare, described only in a

handful of Chinese families[42]

ALS19 615515 ERBB4 2q34Very rare, as of late 2013

described only in four people[43]

ALS20 615426 HNRNPA1 12q13Very rare, as of late 2013

described only in two people[44]

ALS-FTD 105550 C9orf72 9p21.2Accounts for around 6% of ALS

cases among white Europeans

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.[45][46]

Studies involving transgenic mice have yielded several theories about the role of SOD1 in mutant

SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1gene 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 G93Amutant), aggregates (misfolded

protein accumulations) of mutant SOD1 were found only in diseased tissues, and greater amounts

were detected during motor neuron degeneration.[47] 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.[48] 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[edit]

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.[medical citation needed]

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.[33] 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. [49]

[50]

Some evidence supports superoxide dismutase 1 (SOD1) protein misfolding propagates between

molecules in a similar fashion to prions.[51] Similarly, it has been proposed that incorporation of the

cyanobacterial toxin β-methylamino-l-alanine (BMAA) leads to another prion-like protein misfolding

propagation.[52][53]

Another very common factor associated with ALS is a lesion to the motor system in areas such as

the frontotemporal lobes.[54] 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.[54] The mechanisms of ALS

are present long before any signs or symptoms become apparent.[55] Before any muscular atrophy

becomes apparent during ALS, roughly one-third of the motor neurons must be destroyed.[55]

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.[56]

Pathophysiology[edit]

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.[57] These inclusions often contain ubiquitin, and generally incorporate one of the ALS-

associated proteins: SOD1, TAR DNA binding protein (TDP-43, or TARDBP), and/orFUS.[58]

Skeletal motor units[edit]

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.[59]

One neural fiber connects with only one or two muscle fibers

No ocular stretch reflexes, despite being rich in muscle spindles

No recurrent inhibition

No special fast-twitch or slow-twitch muscles

All eye motor neurons participate equally in all types of eye movements—not specialized for

saccades or smooth pursuit

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. [60] EOMs

affected by ALS preserve the GL and OL organization.[60] 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.[60] 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.[61] People with ALS showed preserved

Lnα4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the

same people.[61] 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.[62] Passive transfer of sera from people with sALS

increases spontaneous transmitter release in spinal, but not EOM terminals;[62] 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.[60]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.[60] These EOMs

also showed an increase in connective tissue and areas of fatty replacement in compensation of

fiber loss and atrophy.[60] Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei,

has been noted in ALS patients.[27]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.[60] 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.[60] Because EOMs are normally highly

innervated, any denervation is compensated for by neighbouring axons which preserve function.[60]

Lactate and cinnamate[edit]

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.[63]

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.[63] In contrast,

replacing glucose with exogenous lactate increases fatiguability of EDL muscles but not EOMs.

[63] Fatiguability in EOMs was only found when a combination of exogenous lactacte plus cinnamate

replaced glucose.[63]

Diagnosis[edit]

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.[4] Instead, the diagnosis of ALS is primarily

based on the symptoms and signs the physicianobserves in the person and a series of tests to rule

out other diseases.[4] Physicians obtain the person's full medical historyand usually conduct a

neurologic examination at regular intervals to assess whether symptoms such as muscle weakness,

atrophy of muscles, hyperreflexia, and spasticity are worsening.[4]

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.[4] One of these tests is electromyography(EMG), a special recording technique that

detects electrical activity in muscles.[4] Certain EMG findings can support the diagnosis of ALS.[4] Another common test measures nerve conduction velocity (NCV).[4] Specific abnormalities in the

NCV results may suggest, for example, that the patient has a form of peripheral

neuropathy (damage to peripheral nerves) ormyopathy (muscle disease) rather than ALS. While

a magnetic resonance imaging (MRI) is often normal in people 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.[4]

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.[4] In some cases, for example, if a physician suspects the person

may have a myopathy rather than ALS, a muscle biopsy may be performed.[4]

Viral infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukaemia

virus (HTLV), Lyme disease,[64] syphilis [65]  and tick-borne encephalitis [66]  can in some cases cause

ALS-like symptoms.[4] 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.[4]

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.[67] 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 specialist neurological opinion, so alternative

diagnoses are clinically ruled out.

However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS

clinics is less than 10%.[68][69] 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.[70] 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.[71] Myasthenic syndrome, also known as Lambert-Eaton syndrome, can mimic ALS and its

initial presentation can be similar to that of MG.[72][73]

Management[edit]

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[edit]

Riluzole (Rilutek) has been found to modestly improve survival.[74] It lengthens survival by several

months, and may have a greater survival benefit for those with abulbar 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).[75] 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.[76]

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.[13]

Breathing support[edit]

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.[77] 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[edit]

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.[78]

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 ofaugmentative 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[edit]

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"[79] and have a severe loss of appetite.[80] Both

animal[81] and human research[79][unreliable medical source?] [82][unreliable medical source?] 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. [83]

Palliative care[edit]

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[edit]

In much of the world, rates of ALS are unknown.[5] In Europe, the disease affects about 2.2 people

per 100,000 per year.[5] 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.[84]

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.[85] Amyotrophic lateral sclerosis affects around 30,000 Americans.[86] ALS cases are estimated at 1.2–

4.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations.[87] Filipinos are second to Caucasians in terms of ALS prevalence with 1.1-2.8 per 100,000

individuals.[86]

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,[88] three association

football-playing friends in the south of England,[89] and conjugal (husband and wife) cases in the

south of France.[90][91][92][93][94] 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[edit]

Descriptions of the disease date back to at least 1824 by Charles Bell.[10]

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.[10] 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.[95]

In the 1950s, an ALS epidemic occurred among the Chamorro people on Guam.[96]

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.

Etymology

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").

Society and cultureSee also: Category:People with motor neurone disease

In August 2014, a challenge went viral online which was commonly known as the "ALS Ice Bucket

Challenge".[97] 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.[98]

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.[99]

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.[100]

Research[edit]

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, calledproject 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.[101] A division of the US Centers for Disease Control and Prevention maintains

a registry of Americans with ALS.[102]

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.[103][unreliable medical source?][104][verification

needed] 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 byGlaxoSmithKline.

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."[105][106] 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.[107]