| Amyotrophic lateral sclerosis | |
|---|---|
| Other names | Lou Gehrig's disease, Charcot's disease, motor neurone disease (MND) |
 | |
| An MRI with increased signal in the posterior part of the internal capsule that can be tracked to the motor cortex, consistent with the diagnosis of ALS | |
| Specialty | Neurology |
| Symptoms | Stiff muscles, muscle twitching, gradually worsening weakness |
| Complications | Difficulty in speaking, swallowing, breathing |
| Usual onset | 50s–60s |
| Causes | Unknown (most), inherited (few) |
| Diagnostic method | Based on symptoms |
| Treatment | Non-invasive ventilation |
| Medication | Riluzole, edaravone |
| Prognosis | Life expectancy 2–4 years |
| Frequency | 2.6/100,000 per year (Europe) |
Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease, is a specific disease that causes the death of neurons controlling voluntary muscles. Some also use the term motor neuron disease for a group of conditions of which ALS is the most common. ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscles decreasing in size. It may begin with weakness in the arms or legs, or with difficulty speaking or swallowing. About half of the people affected develop at least mild difficulties with thinking and behavior and most people experience pain. Most eventually lose the ability to walk, use their hands, speak, swallow, and breathe.
The cause is not known in 90% to 95% of cases, but is believed to involve both genetic and environmental factors. The remaining 5–10% of cases are inherited from a person's parents. About half of these genetic cases are due to one of two specific genes. The underlying mechanism involves damage to both upper and lower motor neurons. The diagnosis is based on a person's signs and symptoms, with testing done to rule out other potential causes.
No cure for ALS is known. The goal of treatment is to improve symptoms. A medication called riluzole may extend life by about two to three months. Non-invasive ventilation may result in both improved quality and length of life. Mechanical ventilation can prolong survival but does not stop disease progression. A feeding tube may help. The disease can affect people of any age, but usually starts around the age of 60 and in inherited cases around the age of 50. The average survival from onset to death is two to four years, though this can vary, and about 10% survive longer than 10 years. Most die from respiratory failure. In Europe, the disease affects about two to three people per 100,000 per year. Rates in much of the world are unclear. In the United States, it is more common in white people than black people.
Descriptions of the disease date back to at least 1824 by Charles Bell. In 1869, the connection between the symptoms and the underlying neurological problems was first described by Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis. It became well known in the United States in the 20th century when in 1939 it affected baseball player Lou Gehrig and later worldwide following the 1963 diagnosis of cosmologist Stephen Hawking. The first ALS gene was discovered in 1993 while the first animal model was developed in 1994. In 2014, videos of the Ice Bucket Challenge went viral on the Internet and increased public awareness of the condition.
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. Motor neuron diseases include amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), progressive bulbar palsy, pseudobulbar palsy, and monomelic amyotrophy (MMA).
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.
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 most cases the disease spreads and affects other spinal cord
regions. A few people with ALS have symptoms that are limited to one
spinal cord region for at least 12 to 24 months before spreading to a
second region; these regional variants of ALS are associated with a
better prognosis.
Classical ALS, PLS, and PMA
Typical or "classical" ALS involves neurons in the brain (upper motor neurons) and in the spinal cord (lower motor neurons).
ALS can be classified by the types of motor neurons that are
affected. Typical or "classical" ALS involves neurons in the brain (upper motor neurons) and in the spinal cord (lower motor neurons).
Primary lateral sclerosis (PLS) involves only upper motor neurons, and
progressive muscular atrophy (PMA) involves only lower motor neurons.
There is debate over whether PLS and PMA are separate diseases or simply
variants of ALS.
Classic ALS accounts for about 70% of all cases of ALS and can be subdivided into spinal-onset and bulbar-onset ALS. Spinal-onset ALS, also called limb-onset ALS, begins with weakness in the arms and legs and accounts for about two-thirds of all cases of classic ALS. Bulbar-onset ALS begins with weakness in the muscles of speech, chewing, and swallowing and accounts for about one-third of all cases of classic ALS.
It is associated with a worse prognosis than spinal-onset ALS; a
population-based study found that bulbar-onset ALS has a median survival
of 2.0 years and a 10-year survival rate of 3%, while spinal-onset ALS
has a median survival of 2.6 years and a 10-year survival rate of 13%.
Primary lateral sclerosis (PLS) accounts for about 5% of all cases of ALS and affects upper motor neurons in the arms and legs.
However, more than 75% of people with apparent PLS develop lower motor
neuron signs within four years of symptom onset, meaning that a definite
diagnosis of PLS cannot be made until then.
PLS has a better prognosis than classic ALS, as it progresses slower,
results in less functional decline, does not affect the ability to
breathe, and causes less severe weight loss.
Progressive muscular atrophy (PMA) accounts for about 5% of all
cases of ALS and affects lower motor neurons in the arms and legs.
While PMA is associated with longer survival on average than classic
ALS, it still progresses to other spinal cord regions over time,
eventually leading to respiratory failure and death. Upper motor neuron signs can develop late in the course of PMA, in which case the diagnosis might be changed to classic ALS.
Regional variants
Regional
variants of ALS have symptoms that are limited to a single spinal cord
region for at least a year; they progress slower than classic ALS and
are associated with longer survival. Examples include flail arm
syndrome, flail leg syndrome, and isolated bulbar ALS. Flail arm
syndrome and flail leg syndrome are often considered to be regional
variants of PMA because they only involve lower motor neurons. Isolated
bulbar ALS can involve upper or lower motor neurons. These regional
variants of ALS cannot be diagnosed at the onset of symptoms; a failure
of the disease to spread to other spinal cord regions for an extended
period of time (at least 12 months) must be observed.
Flail arm syndrome, also called brachial amyotrophic diplegia,
is characterized by lower motor neuron damage in the cervical spinal
cord only, leading to gradual onset of weakness in the proximal arm
muscles and decreased or absent reflexes. Flail leg syndrome, also
called leg amyotrophic diplegia,
is characterized by lower motor neuron damage in the lumbosacral spinal
cord only, leading to gradual onset of weakness in the legs and
decreased or absent reflexes. Isolated bulbar ALS is characterized by
upper or lower motor neuron damage in the bulbar region only, leading to
gradual onset of difficulty with speech (dysarthria) and swallowing (dysphagia); breathing
(respiration) is generally preserved, at least initially. Two small
studies have shown that people with isolated bulbar ALS may live longer
than people with bulbar-onset ALS.
Age of onset
ALS
can also be classified based on the age of onset. While the peak age of
onset is 58 to 63 for sporadic ALS and 47 to 52 for familial ALS,
about 10% of all cases of ALS begin before age 45 ("young-onset" ALS),
and about 1% of all cases begin before age 25 (juvenile ALS).
People who develop young-onset ALS are more likely to be male, less
likely to have a bulbar onset of symptoms, and more likely to have a
slower progression of disease. Juvenile ALS is more likely to be familial than adult-onset ALS; genes known to be associated with juvenile ALS include ALS2, SETX, SPG11, FUS, and SIGMAR1. Although most people with juvenile ALS live longer than those with adult-onset ALS, some of them have specific mutations in FUS and SOD1 that are associated with a poor prognosis. Late onset (after age 65) is associated with a more rapid functional decline and shorter survival.
Respiratory onset
Respiratory-onset ALS is a rare variant that accounts for about 3% of all cases of ALS, in which the initial symptoms are difficulty breathing (dyspnea) with exertion, at rest, or while lying down (orthopnea). Spinal and bulbar symptoms tend to be mild or absent at the beginning. It is more common in males.
Respiratory-onset ALS has the worst prognosis of any ALS variant; in a
population-based study, those with respiratory-onset had a median
survival of 1.4 years and 0% survival at 10 years.
Signs and symptoms
The disorder causes muscle weakness, atrophy, and muscle spasms
throughout the body due to the degeneration of the upper motor 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 extraocular muscles (the muscles responsible for eye movement) are usually spared until the final stages of the disease.
Cognitive or behavioral dysfunction is present in 30–50% 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; it is more common in those with bulbar-onset ALS.
Pain is a symptom experienced by most people with ALS and can take the form of neuropathic pain (pain caused by nerve damage), spasticity, muscle cramps, and nociceptive pain caused by reduced mobility and muscle weakness; examples of nociceptive pain in ALS include contractures (permanent shortening of a muscle or joint), neck pain, back pain, shoulder pain, and pressure ulcers.
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, the first symptoms are in arms or the legs. If
the legs are affected first, people may experience awkwardness,
tripping, or stumbling when walking or running; this is often marked by
walking with a "dropped foot"
that drags gently on the ground. If the arms are affected first, they
may experience difficulty with tasks requiring manual dexterity, such as
buttoning a shirt, writing, or turning a key in a lock.
In bulbar-onset ALS, the first symptoms are difficulty speaking
or swallowing. Speech may become slurred, nasal in character, or
quieter. There may be difficulty with 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). However, twitching is more of a side effect than a
diagnostic symptom; it either occurs after or accompanies weakness and
atrophy.
Progression
Although
the initial symptoms and rate of progression 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 the "ALS Functional
Rating Scale Revised (ALSFRS-R)", a 12-item instrument survey
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 among clinicians
showed that they rated a 20% change in the slope of the ALSFRS-R as
being clinically meaningful.
Disease progression tends to be slower in people who are younger than 40 at onset, are mildly obese, have symptoms 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 ALS, respiratory-onset ALS and frontotemporal dementia.
Late stages
Difficulties
with chewing and swallowing make 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.[5]
Around half of people with ALS die within 30 months of their symptoms
beginning, and about 20% of people with ALS live between five and 10
years after symptoms begin. Guitarist Jason Becker has lived since 1989 with the disorder, while cosmologist Stephen Hawking lived for 55 more years following his diagnosis, but they are considered unusual cases.
Most people with ALS die in their own home, with their breath stopping while they sleep.
Cause
Though the
exact cause of ALS is unknown, genetic factors and environmental factors
are thought to be of roughly equal importance.
The genetic factors are better understood than the environmental
factors; no specific environmental factor has been definitively shown to
cause ALS. A liability threshold model
for ALS proposes that cellular damage accumulates over time due to
genetic factors present at birth and exposure to environmental risks
throughout life.
Genetics
ALS can be classified as familial or sporadic, depending on whether or not there is a family history of the disease.
There is no consensus among neurologists on the exact definition of
familial ALS. The strictest definition is that a person with ALS must
have two or more first-degree relatives
(children, siblings, or parents) who also have ALS. A less strict
definition is that a person with ALS must have at least one first-degree
or second-degree relative (grandparents, grandchildren, aunts, uncles, nephews, nieces or half-siblings) who also has ALS. Familial ALS is usually said to account for 10% of all cases of ALS, though estimates range from 5% to 20%. Higher estimates use a broader definition of familial ALS and examine the family history of people with ALS more thoroughly.
In sporadic ALS, there is no family history of the disease. Sporadic ALS and familial ALS appear identical clinically and pathologically and are similar genetically; about 10% of people with sporadic ALS have mutations in genes that are known to cause familial ALS.
In light of these parallels, the term "sporadic ALS" has been
criticized as misleading because it implies that cases of sporadic ALS
are only caused by environmental factors; the term "isolated ALS" has
been suggested as a more accurate alternative.
More than 20 genes have been associated with familial ALS, of which four account for the majority of familial cases: C9orf72 (40%), SOD1 (20%), FUS (1–5%), and TARDBP (1–5%). The genetics of familial ALS are better understood than the genetics of sporadic ALS; as of 2016, the known ALS genes explained about 70% of familial ALS and about 15% of sporadic ALS. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS. ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.
ALS and frontotemporal dementia (FTD) are now considered to be
part of a common disease spectrum (FTD–ALS) because of genetic,
clinical, and pathological similarities. Genetically, C9orf72 repeat expansions account for about 40% of familial ALS and 25% of familial FTD.
Clinically, 50% of people with ALS have some cognitive or behavioral
impairments and 5–15% have FTD, while 40% of people with FTD have some
motor neuron symptoms and 12.5% have ALS. Pathologically, abnormal aggregations of TDP-43 protein are seen in up to 97% of ALS patients and up to 50% of FTD patients. Other genes known to cause FTD-ALS include CHCHD10, SQSTM1, and TBK1.
Environmental factors
Where
no family history of the disease is present — around 90% of cases — no
cause is known. Possible associations for which evidence is inconclusive
include military service and smoking. Although studies on military history and ALS frequency are inconsistent, there is weak evidence for a positive correlation. Various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service.
A 2016 review of 16 meta-analyses concluded that there was
convincing evidence for an association with chronic occupational
exposure to lead;
suggestive evidence for farming, exposure to heavy metals other than
lead, beta-carotene intake, and head injury; and weak evidence for
omega-three fatty acid intake, exposure to extremely low frequency
electromagnetic fields, pesticides, and serum uric acid.
In a 2017 study by the United States Centers for Disease Control and Prevention analyzing U.S. deaths from 1985 to 2011, occupations correlated with ALS deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs.
Other potential risk factors remain unconfirmed, including chemical
exposure, electromagnetic field exposure, occupation, physical trauma,
and electric shock. There is a tentative association with exposure to various pesticides, including the organochlorine insecticides aldrin, dieldrin, DDT, and toxaphene.
Head injury
A 2015 review found that moderate to severe traumatic brain injury is a risk factor for ALS, but whether mild traumatic brain injury increases rates was unclear.
A 2017 meta-analysis found an association between head injuries and
ALS; however, this association disappeared when the authors considered
the possibility of reverse causation, which is the idea that head
injuries are an early symptom of undiagnosed ALS, rather than the cause
of ALS.
Physical activity
A number of reviews have found no relationship between the amount of physical activity and the risk of developing ALS.
A 2009 review found that the evidence for physical activity as a risk
factor for ALS was limited, conflicting, and of insufficient quality to
come to a firm conclusion.
A 2014 review concluded that physical activity in general is not a risk
factor for ALS, that soccer and American football are possibly
associated with ALS, and that there was not enough evidence to say
whether or not physically demanding occupations are associated with ALS.
A 2016 review found the evidence inconclusive and noted that
differences in study design make it difficult to compare studies, as
they do not use the same measures of physical activity or the same
diagnostic criteria for ALS.
Sports
Both
soccer and American football have been identified as risk factors for
ALS in several studies, although this association is based on small
numbers of ALS cases. A 2012 retrospective cohort study of 3,439 former NFL
players found that their risk of dying from neurodegenerative causes
was three times higher than the general US population, and their risk of
dying from ALS or Alzheimer's disease was four times higher.
However, this increased risk was calculated on the basis of two deaths
from Alzheimer's disease and six deaths from ALS out of 334 deaths total
in this cohort, meaning that this study does not definitively prove
that playing American football is a risk factor for ALS. Some NFL players thought to have died from ALS may have actually had chronic traumatic encephalopathy
(CTE), a neurodegenerative disorder associated with multiple head
injuries that can present with symptoms that are very similar to ALS.
Soccer was identified as a possible risk factor for ALS in a
retrospective cohort study of 24,000 Italian soccer players who played
between 1960 and 1996. There were 375 deaths in this group, including
eight from ALS. Based on this information and the incidence of ALS, it
was calculated that the soccer players were 11 times more likely to die
from ALS than the general Italian population.
However, this calculation has been criticized for relying on an
inappropriately low number of expected cases of ALS in the cohort.
When the lifetime risk of developing ALS was used to predict the number
of expected cases, soccer players were no more likely to die of ALS
than the general population.
Smoking
Smoking is possibly associated with ALS. A 2009 review concluded that smoking was an established risk factor for ALS.
A 2010 systematic review and meta-analysis concluded that there was not
a strong association between smoking and ALS, but that smoking might be
associated with a higher risk of ALS in women.
A 2011 meta-analysis concluded that smoking increases the risk of ALS
versus never smoking. Among smokers, the younger they started smoking,
the more likely they were to get ALS; however, neither the number of
years smoked nor the number of cigarettes smoked per day affected their
risk of developing ALS.
Pathophysiology
Neuropathology
The defining feature of ALS is the death of both upper motor neurons (located in the motor cortex of the brain) and lower motor neurons (located in the brainstem and spinal cord). In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well. The pathological hallmark of ALS is the presence of inclusion bodies
(abnormal aggregations of protein) in the cytoplasm of motor neurons.
In about 97% of people with ALS, the main component of the inclusion
bodies is TDP-43 protein; however, in those with SOD1 or FUS mutations, the main component is SOD1 protein or FUS protein, respectively. The gross pathology
of ALS, which are features of the disease that can be seen with the
naked eye, include skeletal muscle atrophy, motor cortex atrophy,
sclerosis of the corticospinal and corticobulbar tracts, thinning of the hypoglossal nerves (which control the tongue), and thinning of the anterior roots of the spinal cord.
Besides for the death of motor neurons, two other characteristics
common to most ALS variants are focal initial pathology, meaning that
symptoms start in a single spinal cord region, and progressive
continuous spread, meaning that symptoms spread to additional regions
over time. Prion-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others.
Biochemistry
This figure shows ten proposed disease mechanisms for ALS and the genes associated with them.
It is still not fully understood why neurons die in ALS, but this neurodegeneration is thought to involve many different cellular and molecular processes.
The genes known to be involved in ALS can be grouped into three general
categories based on their normal function: protein degradation, the cytoskeleton,
and RNA processing. Mutant SOD1 protein forms intracellular
aggregations that inhibit protein degradation. Cytoplasmic aggregations
of wild-type (normal) SOD1 protein are common in sporadic ALS.
It is thought that misfolded mutant SOD1 can cause misfolding and
aggregation of wild-type SOD1 in neighboring neurons in a prion-like
manner. Other protein degradation genes that can cause ALS when mutated include VCP, OPTN, TBK1, and SQSTM1. Three genes implicated in ALS that are important for maintaining the cytoskeleton and for axonal transport include DCTN1, PFN1, and TUBA4A.
There are a number of ALS genes that encode for RNA-binding proteins. The first to be discovered was TDP-43 protein, a nuclear protein that aggregates in the cytoplasm of motor neurons in almost all cases of ALS; however, mutations in TARDBP, the gene that codes for TDP-43, are a rare cause of ALS. FUS codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated. It is thought that mutations in TARDBP and FUS
increase the binding affinity of the low-complexity domain, causing
their respective proteins to aggregate in the cytoplasm. Once these
mutant RNA-binding proteins are misfolded and aggregated, they may be
able to misfold normal protein both within and between cells in a
prion-like manner.
This also leads to decreased levels of RNA-binding protein in the
nucleus, which may mean that their target RNA transcripts do not undergo
the normal processing. Other RNA metabolism genes associated with ALS
include ANG, SETX, and MATR3.
C9orf72 is the most commonly mutated gene in ALS and causes motor neuron death through a number of mechanisms. The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over);
people with 30 repeats are normal, while people with hundreds or
thousands of repeats can have familial ALS, frontotemporal dementia, or
sometimes sporadic ALS. The three mechanisms of disease associated with
these C9orf72 repeats are deposition of RNA transcripts in the
nucleus, translation of the RNA into toxic dipeptide repeat proteins in
the cytoplasm, and decreased levels of the normal C9orf72 protein.
Excitotoxicity,
or nerve cell death caused by high levels of intracellular calcium due
to excessive stimulation by the excitatory neurotransmitter glutamate,
is a mechanism thought to be common to all forms of ALS. Motor neurons
are more sensitive to excitotoxicity than other types of neurons because
they have a lower calcium-buffering capacity and a type of glutamate
receptor (the AMPA receptor) that is more permeable to calcium. In ALS, there are decreased levels of excitatory amino acid transporter 2 (EAAT2),
which is the main transporter that removes glutamate from the synapse;
this leads to increased synaptic glutamate levels and excitotoxicity.
Riluzole, a drug that modestly prolongs survival in ALS, inhibits
glutamate release from pre-synaptic neurons; however, it is unclear if
this mechanism is responsible for its therapeutic effect.
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. 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. A number of biomarkers are being studied for the condition, but so far are not in general medical use.
Diagnostic criteria
The diagnosis of ALS is based on the El Escorial Revised criteria and the Awaji criteria.
The original El Escorial criteria had four levels of diagnostic
certainty, based on how many of the four spinal cord regions were
involved: bulbar, cervical, thoracic, and lumbar. Definite ALS was
defined as upper motor neuron (UMN) and lower motor neuron (LMN) signs
in three spinal cord regions, probable ALS as UMN and LMN signs in two
regions, possible ALS as UMN and LMN signs in only one region, and
suspected ALS as LMN signs only. The El Escorial Revised criteria, also
known as the Airlie House criteria, dropped the "suspected ALS" category
and added a "laboratory-supported probable ALS" category. The Awaji
criteria give abnormal EMG tests the same weight as clinical signs of
LMN dysfunction in making the diagnosis of ALS,
thus making the "laboratory-supported probable ALS" category
unnecessary. The only three categories in the Awaji criteria are
definite ALS, probable ALS, and possible ALS.
The El Escorial Revised criteria are specific for ALS, which
means that someone who meets the criteria is very likely to have ALS;
however, they are not especially sensitive for ALS, which means that
someone who does not meet the criteria can still have ALS. Their
sensitivity is particularly poor in the early stages of ALS. The Awaji
criteria have better sensitivity than the El Escorial Revised criteria,
especially for bulbar-onset ALS.
A 2012 meta-analysis found that the El Escorial Revised criteria had a
sensitivity of 62.2%, while the Awaji criteria had a sensitivity of
81.1%; both sets of criteria had a specificity of about 98%. The El Escorial criteria were designed to standardize patient groups for clinical trials
but are not as useful in clinical practice; possible ALS as described
by the El Escorial criteria is almost always clinically ALS.
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.
A number of infectious diseases can sometimes cause ALS-like symptoms, including human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), Lyme disease, and syphilis. 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 with ALS symptoms should always obtain a specialist
neurological opinion in order to rule out alternative diagnoses. Myasthenic syndrome, also known as Lambert–Eaton syndrome, can mimic ALS, and its initial presentation can be similar to that of myasthenia gravis (MG), a treatable autoimmune disease sometimes mistaken for ALS. Benign fasciculation syndrome
is another condition that mimics some of the early symptoms of ALS, but
is accompanied by normal EMG readings and no major disablement.
Most cases of ALS, however, are correctly diagnosed, with the error rate of diagnosis in large ALS clinics being less than 10%.
One study examined 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 of MG,
which can mimic ALS and other neurological disorders, leading to a delay
in diagnosis and treatment. MG is eminently treatable; ALS is not.
Management
There
is no cure for ALS. Management focuses on treating symptoms and
providing supportive care, with the goal of improving quality of life
and prolonging survival.
This care is best provided by multidisciplinary teams of healthcare
professionals; attending a multidisciplinary ALS clinic is associated
with longer survival, fewer hospitalizations, and improved quality of
life. Riluzole prolongs survival by about 2–3 months. Edaravone slows functional decline slightly in a small number of people with ALS; it is expensive and must be administered by daily IV infusions that may decrease quality of life. Other medications may be used to manage other symptoms.
Non-invasive ventilation (NIV) is the main treatment for respiratory failure in ALS.
In people with normal bulbar function, it prolongs survival by about
seven months and improves quality of life. One study found that NIV is
ineffective for people with poor bulbar function while another suggested that it may provide a modest survival benefit. Many people with ALS have difficulty tolerating NIV. Invasive ventilation is an option for people with advanced ALS when NIV is not enough to manage their symptoms. While invasive ventilation prolongs survival, disease progression and functional decline continue. It may decrease the quality of life of people with ALS or their caregivers. Invasive ventilation is more commonly used in Japan than North America or Europe.
Physical therapy can promote functional independence through aerobic, range of motion, and stretching exercises. Occupational therapy can assist with activities of daily living through adaptive equipment. Speech therapy can assist people with ALS who have difficulty speaking. Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life. Initially, difficulty swallowing (dysphagia) can be managed by dietary changes and swallowing techniques. A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water. The feeding tube is usually inserted by percutaneous endoscopic gastrostomy (PEG). There is weak evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life.
Palliative care should begin shortly after someone is diagnosed with ALS.
Discussion of end-of-life issues gives people with ALS time to reflect
on their preferences for end-of-life care and can help avoid unwanted
interventions or procedures. Hospice care can improve symptom management
at the end of life and increases the likelihood of a peaceful death. In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.
Medications
Chemical structure of riluzole, a medication that prolongs survival by 2–3 months
Riluzole has been found to modestly prolong survival by about 2–3 months. It may have a greater survival benefit for those with bulbar-onset ALS. Riluzole's mechanism of action is poorly understood. It may work by decreasing release of the excitatory neurotransmitter glutamate from pre-synaptic neurons. The most common side effects are nausea and a lack of energy (asthenia).
People with ALS should begin treatment with riluzole as soon as
possible following their diagnosis, according to guidelines from the European Federation of Neurological Societies.
Edaravone
has been shown to modestly slow the decline in function (as measured by
the Revised ALS Functional Rating Scale) in a small group of people
with early-stage ALS who meet very strict criteria; there is no evidence that edaravone is effective in all people with ALS. Its mechanism of action in ALS is unknown. It may work by protecting motor neurons from oxidative stress. The most common side effects are bruising and gait disturbance.
Treatment with edaravone is expensive (about $140,000 per year in the
United States); it is also intensive and requires daily hour-long IV
infusions for 10 days in a two-week period, followed by two weeks off
the drug. Fatigue from these daily infusions or from daily travel to an
infusion center may decrease quality of life. There is debate over whether all people with ALS should receive edaravone.
People with ALS should be made aware of the time commitment, high cost,
and limited therapeutic benefit before beginning treatment.
Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Gabapentin, pregabalin, and tricyclic antidepressants (e.g., amitriptyline) can be used for neuropathic pain, while nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids can be used for nociceptive pain. Depression can be treated with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants, while benzodiazepines can be used for anxiety.
There are no medications to treat cognitive impairment/frontotemporal
dementia (FTD); however, SSRIs and antipsychotics can help treat some of
the symptoms of FTD. Baclofen and tizanidine are the most commonly used oral drugs for treating spasticity; an intrathecal baclofen pump can be used for severe spasticity. Atropine, scopolamine, amitriptyline or glycopyrrolate may be prescribed when people with ALS begin having trouble swallowing their saliva (sialorrhea).
A 2012 review found no evidence that medications are effective at
reducing muscle cramps experienced by people with ALS; however, many of
the 20 studies analyzed were too small to come to a definite conclusion
about efficacy. A 2017 review concluded that mexiletine was safe and effective for treating cramps in ALS based on a randomized controlled trial from 2016.
Breathing support
Non-invasive ventilation
Non-invasive ventilation supports breathing with a face or nasal mask connected to a ventilator.
Non-invasive ventilation (NIV) is the primary treatment for respiratory failure in ALS and was the first treatment shown to improve both survival and quality of life in people with ALS.
NIV uses a face or nasal mask connected to a ventilator that provides
intermittent positive pressure to support breathing. Continuous positive
pressure is not recommended for people with ALS because it makes
breathing more difficult. Initially, NIV is used only at night because the first sign of respiratory failure is decreased gas exchange (hypoventilation)
during sleep; symptoms associated with this nocturnal hypoventilation
include interrupted sleep, anxiety, morning headaches, and daytime
fatigue. As the disease progresses, people with ALS develop shortness of
breath when lying down, during physical activity or talking, and
eventually at rest.
Other symptoms include poor concentration, poor memory, confusion,
respiratory tract infections, and a weak cough. Respiratory failure is
the most common cause of death in ALS.
It is important to monitor the respiratory function of people
with ALS every three months, because beginning NIV soon after the start
of respiratory symptoms is associated with increased survival. This
involves asking the person with ALS if they have any respiratory
symptoms and measuring their respiratory function. The most commonly used measurement is upright forced vital capacity
(FVC), but it is a poor detector of early respiratory failure and is
not a good choice for those with bulbar symptoms, as they have
difficulty maintaining a tight seal around the mouthpiece. Measuring FVC
while the person is lying on their back (supine FVC) is a more accurate
measure of diaphragm weakness than upright FVC.
Sniff nasal inspiratory pressure (SNIP) is a rapid, convenient test of
diaphragm strength that is not affected by bulbar muscle weakness. If someone with ALS has signs and symptoms of respiratory failure, they should undergo daytime blood gas analysis to look for hypoxemia (low oxygen in the blood) and hypercapnia (too much carbon dioxide in the blood). If their daytime blood gas analysis is normal, they should then have nocturnal pulse oximetry to look for hypoxemia during sleep.
Non-invasive ventilation prolongs survival longer than riluzole. A
2006 randomized controlled trial found that NIV prolongs survival by
about 48 days and improves quality of life; however, it also found that
some people with ALS benefit more from this intervention than others.
For those with normal or only moderately impaired bulbar function, NIV
prolongs survival by about seven months and significantly improves
quality of life. For those with poor bulbar function, NIV neither
prolongs survival nor improves quality of life, though it does improve
some sleep-related symptoms.
Despite the clear benefits of NIV, about 25–30% of all people with ALS
are unable to tolerate it, especially those with cognitive impairment or
bulbar dysfunction.
Results from a large 2015 cohort study suggest that NIV may prolong
survival in those with bulbar weakness, and so NIV should be offered to
all people with ALS, even if it is likely that they will have difficulty
tolerating it.
Invasive ventilation
Invasive ventilation bypasses the nose and mouth (the upper airways) by making a cut in the trachea (tracheostomy) and inserting a tube connected to a ventilator. It is an option for people with advanced ALS whose respiratory symptoms are poorly managed despite continuous NIV use.
While invasive ventilation prolongs survival, especially for those
younger than 60, it does not treat the underlying neurodegenerative
process. The person with ALS will continue to lose motor function,
making communication increasingly difficult and sometimes leading to locked-in syndrome, in which they are completely paralyzed except for their eye muscles. About half of the people with ALS who choose to undergo invasive ventilation report a decrease in their quality of life
but most still consider it to be satisfactory. However, invasive
ventilation imposes a heavy burden on caregivers and may decrease their
quality of life.
Attitudes toward invasive ventilation vary from country to country;
about 30% of people with ALS in Japan choose invasive ventilation,
versus less than 5% in North America and Europe.
Therapy
A man with ALS communicates by pointing to letters and words using a head-mounted laser pointer.
Physical therapy
plays a large role in rehabilitation for individuals with ALS.
Specifically, physical, occupational, and speech 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, because muscle exhaustion can lead to worsening of
symptoms associated with ALS, rather than providing help to people with
ALS.
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
A gastrostomy tube is placed through the wall of the abdomen into the stomach.
Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life.
Weight loss in ALS is caused by muscle wasting due to motor neuron
death, increased resting energy expenditure, and decreased food intake.
Difficulty swallowing (dysphagia) develops in about 85% of people with
ALS at some point over the course of their disease and is a major cause
of decreased food intake, leading to malnutrition and weight loss. It is important to regularly assess the weight and swallowing ability of people with ALS. Initially, dysphagia can be managed by dietary changes and modified swallowing techniques.
Difficulty swallowing liquids usually develops first and can be managed
by switching to thicker liquids like fruit nectar or smoothies, or by
adding fluid thickeners to thin fluids like water and coffee. People
with ALS should eat soft, moist foods, which tend to be easier to
swallow than dry, crumbly, or chewy foods. They should also be instructed on proper head posture during swallowing, which can make swallowing easier. There is tentative evidence that high-calorie diets may prevent further weight loss and improve survival.
A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely swallow food and water. This can take the form of a gastrostomy tube, in which a tube is placed through the wall of the abdomen into the stomach, or a nasogastric tube, in which a tube is placed through the nose and down the esophagus into the stomach. A gastrostomy tube is more appropriate for long-term use than a nasogastric tube, which is uncomfortable and can cause esophageal ulcers. The feeding tube is usually inserted by percutaneous endoscopic gastrostomy
(PEG). There is some evidence that a PEG tube should be inserted before
vital capacity drops below 50% of expected, as a low vital capacity may
be associated with a higher risk of complications. However, a large
2015 study showed that PEG insertion is safe in people with advanced ALS
and low vital capacities, as long as they are on NIV during the
procedure.
There is weak evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life by sustaining nutrition and medication intake. This reduces the risk of weight loss and dehydration, and can decrease anxiety from extended mealtimes and decreased oral food intake.
End-of-life care
Palliative care,
which relieves symptoms and improves quality of life without treating
the underlying disease, should begin shortly after someone is diagnosed
with ALS.
Early discussion of end-of-life issues gives people with ALS time to
reflect on their preferences for end-of-life care and can help avoid
unwanted interventions or procedures. Once they have been fully informed about all aspects of various life-prolonging measures, they can fill out advanced directives indicating their attitude toward noninvasive ventilation, invasive ventilation, and feeding tubes.
Late in the disease course, difficulty speaking due to muscle weakness
(dysarthria) and cognitive dysfunction may impair their ability to
communicate their wishes regarding care.
Continued failure to solicit the preferences of the person with ALS may
lead to unplanned and potentially unwanted emergency interventions,
such as invasive ventilation. If people with ALS or their family members
are reluctant to discuss end-of-life issues, it may be useful to use
the introduction of gastrostomy or noninvasive ventilation as an
opportunity to bring up the subject.
Hospice care,
or palliative care at the end of life, is especially important in ALS
because it helps to optimize the management of symptoms and increases
the likelihood of a peaceful death.
It is unclear exactly when the end-of-life phase begins in ALS, but it
is associated with significant difficulty moving, communicating, and,
in some cases, thinking. Although many people with ALS fear choking to death (suffocating), they can be reassured that this occurs rarely, about 0–3% of the time. About 90% of people with ALS die peacefully. In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.
Epidemiology
ALS is the most common motor neuron disease in adults and the third most common neurodegenerative disease after Alzheimer's disease and Parkinson's disease.
Worldwide the number of people who develop ALS yearly is estimated to
be 1.9 people per 100,000 per year, while the number of people who have
ALS at any given time is estimated to be about 4.5 people per 100,000. In Europe, the number of new cases a year is about 2.6 people per 100,000, while the number affected is 7–9 people per 100,000.
The lifetime risk of developing ALS is 1:350 for European men and 1:400
for European women. Men have a higher risk mainly because spinal-onset
ALS is more common in men than women.
The number of those with ALS in the United States in 2015 was 5.2
people per 100,000, and was higher in whites, males, and people over 60
years old.
The number of new cases is about 0.8 people per 100,000 per year in
east Asia and about 0.7 people per 100,000 per year in south Asia. About
80% of ALS epidemiology studies have been conducted in Europe and the
United States, mostly in people of northern European descent.
There is not enough information to determine the rates of ALS in much
of the world, including Africa, parts of Asia, India, Russia, and South
America.
There are several geographic clusters in the Western Pacific where the
prevalence of ALS was reported to be 50–100 times higher than the rest
of the world, including Guam, the Kii Peninsula of Japan, and Western New Guinea. The incidence in these areas has decreased since the 1960s; the cause remains unknown.
People of all races and ethnic backgrounds may be affected by ALS, but it is more common in whites than in Africans, Asians, or Hispanics.
In the United States in 2015, the prevalence of ALS in whites was 5.4
people per 100,000, while the prevalence in blacks was 2.3 people per
100,000. The Midwest had the highest prevalence of the four US Census
regions with 5.5 people per 100,000, followed by the Northeast (5.1),
the South (4.7), and the West (4.4). The Midwest and Northeast likely
had a higher prevalence of ALS because they have a higher proportion of
whites than the South and West.
Ethnically mixed populations may be at a lower risk of developing ALS; a
study in Cuba found that people of mixed ancestry were less likely to
die from ALS than whites or blacks. There are also differences in the genetics of ALS between different ethnic groups; the most common ALS gene in Europe is C9orf72, followed by SOD1, TARDBP, and FUS, while the most common ALS gene in Asia is SOD1, followed by FUS, C9orf72, and TARDBP.
Estimated prevalence of ALS in the United States by age group, 2012–2015
ALS can affect people at any age, but the peak incidence is between 50–75 years and decreases dramatically after 80 years.
The reason for the decreased incidence in the elderly is unclear. One
thought is that people who survive into their 80s may not be genetically
susceptible to developing ALS; alternatively, ALS in the elderly might
go undiagnosed because of comorbidities (other diseases they have), difficulty seeing a neurologist, or dying quickly from an aggressive form of ALS.
In the United States in 2015, the lowest prevalence was in the 18–39
age group, while the highest prevalence was in the 70–79 age group.
Sporadic ALS usually starts around the ages of 58 to 63 years, while
familial ALS starts earlier, usually around 47 to 52 years.
The number of ALS cases worldwide is projected to increase from 222,801
in 2015 to 376,674 in 2040, an increase of 69%. This will largely be
due to the aging of the world's population, especially in developing
countries.
History
The French neurologist Jean-Martin Charcot coined the term amyotrophic lateral sclerosis in 1874.
Descriptions of the disease date back to at least 1824 by Charles Bell. In 1850, François-Amilcar Aran
was the first to describe a disorder he named "progressive muscular
atrophy", a form of ALS in which only the lower motor neurons are
affected. 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. Flail arm syndrome, a regional variant of ALS, was first described by Alfred Vulpian in 1886. Flail leg syndrome, another regional variant of ALS, was first described by Pierre Marie and his student Patrikios in 1918.
In 1945, American naval doctors reported that ALS was 100 times more prevalent among the Chamorro people of Guam
than in the rest of the world. In 1956 the variant of ALS endemic to
Guam was named "amyotrophic lateral sclerosis/parkinsonism dementia
complex" (ALS/PDC), as it had the typical symptoms of ALS accompanied by
parkinsonism-like symptoms; the name in the local language is lytico-bodig disease.
Despite a number of genetic and environmental studies, the cause of
ALS/PDC remains unknown. Rates peaked in the early 1950s and steadily
declined thereafter, and by 1985 the incidence of ALS/PDC in Guam was
about the same as the rest of the world.
The first gene to be associated with ALS was SOD1, which was identified in 1993. This led to the development of the first animal model of ALS, the transgenic SOD1 mouse, in 1994.
In December 1995, riluzole became the first FDA-approved drug for ALS.
It was then approved in Europe in 1996 and in Japan in 1998.
In 1996, the ALS Functional Rating Scale (ALSFRS) was first published;
it was a 10-item questionnaire that measured the ability of people with
ALS to perform activities of daily living.
In 1999, the scale was changed to give more weight to respiratory
symptoms. The resulting Revised ALS Functional Rating Scale (ALSFRS-R)
is a 12-item questionnaire that replaces the single question about
breathing with a question each about dyspnea, orthopnea, and respiratory
insufficiency.
In 2006, it was discovered that the protein TDP-43 is a major
component of the inclusion bodies seen in both ALS and frontotemporal
dementia (FTD), which provided evidence that ALS and FTD are part of a
common disease spectrum. This led to the discovery in 2008 that
mutations in TARDBP, the gene that codes for TDP-43, are a cause of familial ALS. In 2011, noncoding repeat expansions in C9orf72 were found to be a major cause of ALS and FTD. Edaravone was approved to treat ALS in Japan and South Korea in 2015 and in the United States in 2017. As of 2017, it has not been approved to treat ALS in Europe.
Diagnostic criteria
In the 1950s, electrodiagnostic testing (EMG and NCV) began to be used to evaluate clinically suspected ALS. In 1969 Edward H. Lambert
published the first EMG/NCS diagnostic criteria for ALS, consisting of
four findings he considered to strongly support the diagnosis. In 1990, the World Federation of Neurology (WFN) held a meeting at El Escorial,
Spain, to come up with precise diagnostic criteria for ALS to help
standardize clinical trials; the resulting "El Escorial" criteria were
published in 1994. In 1998, the WFN held another meeting to revise the criteria at Airlie House in Warrenton, Virginia; the resulting "Airlie House" or "El Escorial Revised" criteria were published in 2000. In 2006, a meeting was held on Awaji Island
in Japan to discuss how to use EMG and NCV tests to help diagnose ALS
earlier; the resulting "Awaji" criteria were published in 2008.
Name
In some countries, especially the United States, ALS is called "Lou Gehrig's disease".
Other names for ALS include Charcot's disease, Lou Gehrig's disease, and motor neurone disease. Amyotrophic comes from the Greek word amyotrophia: a- means "no", myo refers to "muscle", and trophia means "nourishment". Therefore, amyotrophia means "no muscle nourishment," which describes the loss of signals motor neurons usually send to muscle cells; this leads to the characteristic muscle atrophy seen in people with ALS. Lateral identifies the areas in a person's spinal cord where the affected motor neurons that control muscle are located. Sclerosis means "scarring" or "hardening" and refers to the death of the motor neurons in the spinal cord.
ALS is sometimes referred to as "Charcot's disease" because
Jean-Martin Charcot was the first to connect the clinical symptoms with
the pathology seen at autopsy. The term is ambiguous and can also refer
to Charcot–Marie–Tooth disease and Charcot joint disease. The British neurologist Russell Brain
coined the term "motor neurone disease" in 1933 to reflect his belief
that ALS, progressive bulbar palsy, and progressive muscular atrophy
were all different forms of the same disease. In some countries, especially the United States, ALS is called "Lou Gehrig's disease", after the famous American baseball player Lou Gehrig, who developed ALS in 1938, had to stop playing baseball in 1939, and died from it in 1941.
In the United States, the terms "ALS" or "Lou Gehrig's disease"
refer to all forms of the disease, including classical ALS, progressive
bulbar palsy, progressive muscular atrophy, and primary lateral
sclerosis. In Europe, the term "ALS" also refers to all forms of the disease.
In the United Kingdom and Australia, the term "motor neurone disease"
refers to all forms of the disease, and "ALS" only refers to classical
ALS, meaning the form with both upper and lower motor neuron
involvement.
Society and culture
In August 2014, a challenge went viral online, 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, the ALS Therapy Development Institute, ALS Society of Canada 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.
Research
Model organisms
Some of the most common models used to study ALS.
Many different organisms are used as models for studying ALS, including Saccharomyces cerevisiae (a species of yeast), Caenorhabditis elegans (a roundworm), Drosophila melanogaster (the common fruit fly), Danio rerio (the zebrafish), Mus musculus (the house mouse), and Rattus norvegicus (the common rat).
None of these models perfectly represents ALS in humans, partly because
most animal models are based on gene overexpression, meaning that
multiple copies of the mutant human gene are inserted into the
transgenic model, and partly because the human nervous system is very
different from that of other animals.
The first animal model for ALS was the SOD1G93A transgenic mouse, which was developed in 1994. It expresses about 20–24 copies of the mutant human SOD1 gene and reproduces most of the clinical and pathological findings seen in ALS. Although there are now over 20 different SOD1 mouse models, the SOD1G93A model remains both the most widely used SOD1 mouse model and the most widely used ALS mouse model overall. Much of the present understanding of ALS pathophysiology came from studying mouse models that overexpress mutant SOD1, especially SOD1G93A mice. However, many drug targets that were shown to be effective in the SOD1G93A transgenic mouse failed in clinical trials in humans; other SOD1 models have had similar problems. Most of these drugs were identified as potentially effective based on a single study in a rodent SOD1 model and then failed in clinical trials in patients who primarily had sporadic ALS. It is thought that these clinical trials failed because SOD1 mutations account for only 2% of all ALS cases and because the pathology of SOD1
ALS is thought to be distinct from all other types of ALS; it lacks the
abnormal aggregations of TDP-43 protein or FUS protein seen in nearly
all other cases of ALS.
As of 2018, there are about 20 TARDBP mouse models, a dozen FUS mouse models, and a number of C9orf72, PFN1, and UBQLN2 mouse models. There are also new methods of developing animal models, including viral transgenesis, in which viruses are used to deliver mutant genes to an animal model, and CRISPR/Cas9,
which can be used to give an animal model multiple mutated genes. Both
of these methods are faster and cheaper than traditional methods of
genetically engineering mice; they also allow scientists to study the
effects of a mutation in mice of different genetic backgrounds, which
better represents the genetic diversity seen in humans.
Cellular models used to study ALS include the yeast Saccharomyces cerevisiae and rat or mouse motor neurons in culture. Small-animal models include the fruit fly, the roundworm C. elegans,
and the zebrafish. Of the three, the fruit fly is the most widely used;
it has a rapid life-cycle, short lifespan, a sophisticated nervous
system, and many genetic tools available. C. elegans has a short
life-cycle, is easy to manipulate genetically, and has a simple but
well-understood nervous system. The zebrafish has transparent embryos
that can be injected with DNA or RNA and has a lifespan of up to two
years. Induced pluripotent stem cells (iPSCs) can be used to convert skin fibroblasts into motor neurons.
It is now possible to generate iPSCs from people with ALS, which can
then be converted into spinal motor neurons, which are useful for
studying disease mechanisms and for testing potential drugs for ALS.
iPSCs allow sporadic ALS to be modeled, which cannot be done with animal
models.
Treatments
From the 1960s until 2014, about 50 drugs for ALS were tested in randomized controlled trials (RCTs);
of these, riluzole was the only one that showed a slight benefit in
improving survival. Drugs tested and not shown to be effective in
clinical trials in humans include antiviral drugs, anti-excitotoxic
drugs, growth factors, neurotrophic factors, anti-inflammatory drugs,
antioxidants, anti-apoptotic drugs, and drugs to improve mitochondria
function.
An analysis of 23 large phase II and phase III RCTs that failed
between 2004 and 2014 concluded that there were many potential reasons
for their lack of success. These trials in humans went ahead on the
basis of positive results in SOD1 transgenic mice, which are not a good animal model for sporadic ALS. Additionally, in most preclinical studies the SOD1
mice were given the drug during the presymptomatic stage; this makes
the results less likely to apply to people with ALS, who begin treatment
well after their symptoms begin. Positive results in small phase II
studies in humans could also be misleading and lead to failure in phase
III trials. Other potential issues included the drug not reaching its
intended site of action in the central nervous system and drug interactions between the study drug and riluzole.
Repetitive transcranial magnetic stimulation had been studied in ALS in small and poorly designed clinical trials; as of 2013, evidence was insufficient to know whether 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 drug in Europe and the United States, with studies ongoing as of 2016. Beta-adrenergic agonist
drugs have been proposed as a treatment for their effects on muscle
growth and neuroprotection, but research in humans is insufficient to
determine their efficacy.
Cause
With the discovery that TDP-43, FUS, and C9orf72 can cause ALS as well as related forms of frontotemporal dementia (FTD/ALS)
there has been intense effort to understand how these mutations cause
disease, and whether other protein dysfunction may be important. As of
2013 it appeared that differences in the methylation
of arginine residues in FUS protein may be relevant, and methylation
status may be a way to distinguish some forms of FTD from ALS.
