ALS - Wikipedia

ALS - Wikipedia
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Rare neurodegenerative disease
This article is about the neurodegenerative disease. For other uses, see
ALS (disambiguation)
"Motor neuron disease" and "Motor neurone disease" redirect here. For a group of muscle-wasting disorders, see
Motor neuron diseases
Medical condition
Amyotrophic lateral sclerosis
Other names
Motor neuron disease (MND)
Lou Gehrig
's disease
Charcot
's disease
Parts of the
nervous system
affected by ALS, causing progressive symptoms in
skeletal muscles
throughout the body
Specialty
Neurology
Symptoms
Early
Stiff muscles
muscle twitches
, gradual increasing weakness
Late
: Difficulty in
speaking
swallowing
, and
breathing
respiratory failure
Rare
frontotemporal dementia
Complications
Falling
Respiratory failure
Pneumonia
Malnutrition
Usual onset
45–75 years
Causes
Unknown (90% to 95%) or genetic (5% to 10%)
Risk factors
Genetic risk factors, age,
male sex
, heavy metals, organic chemicals, smoking, electric shock, head injury
Diagnostic method
Clinical diagnosis of exclusion based on progressive symptoms of upper and lower motor neuron degeneration for which no other explanation can be found. Supportive evidence from
electromyography
genetic testing
, and
neuroimaging
Differential diagnosis
Multifocal motor neuropathy
Kennedy's disease
hereditary spastic paraplegia
nerve compression syndrome
diabetic neuropathy
post-polio syndrome
myasthenia gravis
multiple sclerosis
Treatment
Walker
wheelchair
non-invasive ventilation
feeding tube
augmentative and alternative communication
, symptomatic management
Medication
Riluzole
edaravone
tofersen
dextromethorphan/quinidine
Prognosis
Life expectancy is highly variable, but typically 2–4 years after diagnosis
Frequency
Incidence: 1.6/100,000 individuals per year
Prevalence: 4.4/100,000 living individuals
Lifetime risk: 1 in 400 individuals
Amyotrophic lateral sclerosis
ALS
), also known as
motor neuron disease
MND
) or
Lou Gehrig's disease
, is a rare
terminal
neurodegenerative disease
defined by the progressive loss of both upper and lower
motor neurons
that normally control
voluntary muscle
contraction. ALS is the most common of the
motor neuron diseases
ALS often presents in its early stages with gradual muscle
stiffness
twitches
weakness
, and
wasting
. Motor neuron loss typically continues until the ability to eat, speak, move, and breathe without mechanical support is lost.
It is estimated that at least 50% of people with ALS experience significant changes in
thinking
and
behavior
, with 15% of individuals going on to develop
frontotemporal dementia
10
An ALS
diagnosis
is made based on a person's
signs and symptoms
, with additional testing conducted to rule out other potential causes.
Depending on which areas of the body are affected first, ALS may be classified as
limb-onset
(beginning with weakness in the arms or legs) or
bulbar-onset
(beginning with difficulty in
speaking
or
swallowing
). Respiratory onset occurs in approximately 1%–3% of cases.
11
Most cases of ALS (about 90–95%) have
no known cause
and are known as
sporadic ALS
12
Genetic
autoimmune
13
and
environmental factors
are believed to be involved in the onset of ALS.
14
Approximately 5–10% of ALS cases have a known genetic cause and often linked to a
family history
of ALS; such cases are known as
familial ALS
or hereditary ALS.
15
Mutations in the C9orf72 gene represent the most common known genetic cause of familial ALS and are also found in a subset of sporadic cases.
16
Four disease-linked
genes
are responsible for approximately half of all genetic cases.
17
There is no known cure for ALS.
The goal of treatment is to slow the disease progression and improve symptoms.
10
FDA
-approved treatments that slow the progression of ALS include
riluzole
and
edaravone
18
Non-invasive ventilation
may result in both improved quality and length of life.
Mechanical ventilation
can prolong survival but does not stop disease progression.
19
feeding tube
may help maintain weight and nutrition.
20
Death is usually caused by respiratory failure. The disease can affect people of any age, but usually starts around the age of 60.
21
The average survival from onset to death is two to four years, though this can vary; about 10% of those affected survive longer than ten years.
22
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 French neurologist
Jean-Martin Charcot
, who in 1874 began using the term
amyotrophic lateral sclerosis
23
Classification
edit
ALS is a
motor neuron disease
, which is a group of
neurological disorders
that selectively affect
motor neurons
, the cells that control
voluntary muscles
of the body.
Related motor neuron diseases, sometimes characterized as ALS variants rather than distinct entities, include
primary lateral sclerosis
(PLS),
progressive muscular atrophy
(PMA),
progressive bulbar palsy
pseudobulbar palsy
, and
monomelic amyotrophy
(MMA).
24
As a disease, ALS may be classified in several different ways: by which part of the motor neurons is affected; by the parts of the body first affected; whether it is genetic; and by the age at which it started. Each individual diagnosed with the condition will sit at a unique place at the intersection of these complex and overlapping subtypes, which presents a challenge to diagnosis, understanding, and prognosis.
25
Subtypes of disease
edit
Classic ALS involves neurons in the brain and spinal cord (
upper motor neurons
, highlighted red), as well as the
lower motor neurons
, which go from the spinal cord to the muscles, highlighted teal.
26
ALS can be classified by the types of motor neurons that are affected.
To successfully control any voluntary muscle in the body, a signal must be sent from the
motor cortex
in the brain down the
upper motor neuron
as it travels down the spinal cord. There, it connects via a
synapse
to the
lower motor neuron
, which connects to the muscle itself. Damage to either the upper or lower motor neuron, as it makes its way from the brain to the muscle, causes different types of symptoms.
26
Damage to the upper motor neuron typically causes
spasticity
including stiffness and increased
tendon reflexes
or
clonus
, while damage to the lower motor neuron typically causes
weakness
muscle atrophy
, and
fasciculations
27
Classical or classic ALS involves degeneration to both the
upper motor neurons
in the brain and the
lower motor neurons
in the spinal cord.
Primary lateral sclerosis
(PLS) involves degeneration of primarily the upper motor neurons, and
progressive muscular atrophy
(PMA) involves the lower motor neurons primarily. There is debate over whether PLS and PMA are separate diseases or variants of ALS.
10
Main ALS subtypes
Upper motor neuron
degeneration
Lower motor neuron
degeneration
Classical ALS
Yes
Yes
Primary lateral sclerosis (PLS)
Yes
No
Progressive muscular atrophy (PMA)
No
Yes
Illustration showing the range of upper and lower motor neuron involvement in the two most common types of ALS (top row) and three of the most common rare subtypes of ALS (bottom row)
Classical ALS accounts for about 70% of all cases of ALS and can be subdivided into cases where symptoms first appear, as these are usually focused on one region of the body at initial presentation before later spread.
Limb-onset
ALS (also known as spinal-onset) and
bulbar-onset
ALS.
10
Limb-onset ALS begins with weakness in the hands, arms, feet, and/or legs
11
and accounts for about two-thirds of all classical ALS cases.
10
Bulbar-onset ALS begins with weakness in the muscles of speech, chewing, and swallowing
26
and accounts for about 25% of classical ALS cases.
A rarer type of classical ALS affecting about 3% of patients is respiratory-onset,
10
in which the initial symptoms are difficulty breathing (
dyspnea
) upon exertion, at rest, or while lying flat (
orthopnea
).
28
Primary lateral sclerosis
(PLS) accounts for about 5% of all ALS cases and only affects the upper motor neurons in the arms, legs, and bulbar region.
29
However, more than 75% of people with apparent PLS go on to later develop lower motor neuron signs within four years of symptom onset, meaning that a definitive diagnosis of PLS cannot be made until several years have passed.
30
PLS has a better prognosis than classical ALS, as it progresses more slowly, results in less functional decline, does not affect the ability to breathe, and causes less severe weight loss than classical ALS.
29
Progressive muscular atrophy
(PMA) accounts for about 5% of all ALS cases and affects lower motor neurons in the arms, legs, and bulbar region.
29
While PMA is associated with longer survival on average than classical ALS, it is still progressive over time, eventually leading to respiratory failure and death.
10
As with PLS, PMA can also develop into classical ALS over time if the lower motor neuron involvement progresses to include upper motor neurons, in which case the diagnosis might be changed to classic ALS.
30
Regionally isolated variants
edit
Rarely, ALS symptoms may be limited to a single region of the body for an extended period of time. The disease typically progresses more slowly than classical ALS and is associated with longer survival.
These regional variants of ALS can only be considered as a diagnosis should the initial symptoms fail to spread to other spinal cord regions for at least 12 months.
31
Flail arm syndrome
is characterized by lower motor neuron damage affecting the arm muscles, typically starting with the upper arms symmetrically and progressing downwards to the hands. Flail leg syndrome is characterized by lower motor neuron damage leading to asymmetrical weakness and wasting in the legs starting around the feet.
Isolated bulbar palsy is characterized by upper or lower motor neuron damage in the bulbar region (in the absence of limb symptoms for at least 20 months),
32
leading to gradual onset of difficulty with speech (
dysarthria
) and swallowing (
dysphagia
).
Age of onset
edit
ALS can also be classified based on the age of onset. People with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS.
33
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).
26
People who develop young-onset ALS are more likely to be male, less likely to have bulbar onset of symptoms, and more likely to have a slower progression of the disease.
30
Juvenile ALS is more likely to be genetic in origin than adult-onset ALS; the most common genes associated with juvenile ALS are
FUS
ALS2
, and
SETX
34
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.
35
Late onset (after age 65) is generally associated with a more rapid functional decline and shorter survival.
36
Signs and symptoms
edit
The disorder causes muscle weakness,
atrophy
, and
muscle spasms
throughout the body due to the degeneration of the upper motor and lower motor neurons.
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
edit
Early signs of ALS may be so subtle that the symptoms are overlooked.
The earliest symptoms of ALS are muscle weakness or muscle atrophy, typically on one side of the body. 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.
37
In limb-onset ALS, the first symptoms are in the 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.
38
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.
21
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.
26
While the disease does not cause pain directly, pain is a symptom experienced by most people with ALS, caused by reduced mobility, and possibly also some sensory nerve dysfunction.
39
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
).
27
Progression
edit
Although the initial site of symptoms and subsequent rate of disability progression vary from person to person, the initially affected body region is usually the most affected over time, and symptoms usually spread to a neighbouring body region. For example, symptoms starting in one arm usually spread to either the opposite arm or to the leg on the same side.
26
Bulbar-onset patients most typically experience their next symptoms in their arms rather than legs, arm-onset patients typically spread to the legs before the bulbar region, and leg-onset patients typically spread to the arms rather than the bulbar region.
40
Over time, regardless of where symptoms began, most people eventually lose the ability to walk or use their hands and arms independently. They may also lose the ability to speak and to swallow food. It is the eventual development of weakness of the respiratory muscles, with the loss of ability to cough and to breathe without mechanical support, that is ultimately life-shortening in ALS.
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).
41
The ALSFRS-R is the most frequently used outcome measure in clinical trials
42
and is used by doctors to track disease progression.
43
On average, people with ALS lose about 1 ALSFRS-R point per month.
44
Brief periods of stabilization ("plateaus") and even small reversals in ALSFRS-R score are not uncommon, owing to the subjective nature of scoring, effects of symptomatic medication, and patients' own compensations for changes in function. However, it is rare (<1%) for these improvements to be large (i.e. greater than 4 ALSFRS-R points) or sustained (i.e. greater than 12 months).
45
A survey-based study among clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful, hence its common usage as a threshold to determine efficacy of new treatments in clinical trials.
46
Late-stage disease management
edit
Difficulties with chewing and swallowing make eating very difficult (
dysphagia
) and increase 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.
47
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. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement,
known as
locked-in syndrome
. Bladder and bowel function are usually spared, meaning
urinary
and
fecal incontinence
are uncommon, although trouble getting to a toilet can lead to difficulties. The
extraocular muscles
responsible for eye movement are usually spared,
48
meaning the use of
eye tracking
technology to support
augmentative communication
is often feasible.
49
Despite these challenges, many people in an advanced state of disease report satisfactory well-being and quality of life with these supportive measures.
50
Prognosis, staging, and survival
edit
Although respiratory support using
non-invasive ventilation
can ease problems with breathing and prolong survival,
51
it does not affect the progression rate of ALS. Most people with ALS die between two and four years after the diagnosis.
About 50% of people with ALS die within 30 months of their symptoms beginning, about 20% live between five and ten years,
21
and about 10% survive for 10 years or longer.
22
The most common cause of death among people with ALS is
respiratory failure
, often accelerated by
pneumonia
21
Most ALS patients die at home after a period of worsening difficulty breathing, a decline in their nutritional status, or a rapid worsening of symptoms.
52
Sudden death or acute respiratory distress are uncommon.
53
Access to
palliative care
is recommended from an early stage to explore options, ensure psychosocial support for the patient and caregivers, and to discuss
advance healthcare directives
52
As with
cancer staging
, ALS has staging systems numbered between 1 and 4 that are used for research purposes in clinical trials.
Two very similar staging systems emerged around a similar time: the King's staging system and Milano-Torino (MiToS) functional staging.
54
Kings ALS staging system and prognosis at each stage
Stage 1
Stage 2
Stage 3
Stage 4
Stage description
Symptom onset, involvement of the first region
2A: Diagnosis
2B: Involvement of the second region
Involvement of the third region
4A: Need for a feeding tube
4B: Need for non-invasive ventilation
Median time to stage
13.5 months
17.7 months
23.3 months
4A: 17.7 months
4B: 30.3 months
MiToS ALS staging system and prognosis at each stage
Stage 0
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
Stage description
No loss of a functional domain
Loss of 1 domain
Loss of 2 domains
Loss of 3 domains
Loss of 4 domains
Death
Probability of death at each stage
7%
26%
33%
33%
86%
N/A
Providing individual patients with a precise prognosis is not currently possible, though research is underway to provide statistical models on the basis of prognostic factors, including age at onset, progression rate, site of onset, and presence of
frontotemporal dementia
Bulbar-onset ALS typically has a worse prognosis than limb-onset ALS; a population-based study found that bulbar-onset ALS patients had a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset ALS patients had a median survival of 2.6 years and a 10-year survival rate of 13%.
55
Those with respiratory-onset ALS had a shorter median survival of 1.4 years and 0% survival at 10 years.
55
Though notable
astrophysicist
Stephen Hawking
lived for 55 more years following his diagnosis, his case was an unusual one.
56
Cognitive, emotional, and behavioral symptoms
edit
Cognitive impairment
or behavioral dysfunction is present in 30–50% of individuals with ALS,
57
and can appear more frequently in later stages of the disease.
Language dysfunction
executive dysfunction
, and troubles with
social cognition
and
verbal memory
are the most commonly reported cognitive symptoms in ALS.
58
Cognitive impairment is found more frequently in patients with
C9orf72
gene repeat expansions, bulbar onset, bulbar symptoms,
family history
of ALS and/or a predominantly upper motor neuron phenotype.
59
Pseudobulbar affect
and emotional lability are a type of symptom in which patients cry, smile, yawn, or laugh, either in the absence of emotional stimuli, or when they are feeling the opposite emotion to that being expressed.
60
Approximately half of ALS patients experience this; it is more common in those with bulbar-onset ALS.
While more or less benign relative to other symptoms, it can cause increased stigma and social isolation as people around the patient struggle to react appropriately to what can be frequent and inappropriate outbursts in public.
61
In addition to mild changes in cognition that may only emerge during neuropsychological testing, around 10–15% of individuals have signs of
frontotemporal dementia
(FTD).
Repeating phrases or gestures
, apathy, and
loss of inhibition
are the most frequently reported behavioral features of ALS.
62
ALS and FTD are now considered to be part of a common disease spectrum (ALS–FTD) because of genetic, clinical, and pathological similarities.
63
Cognitive and behavioral issues are associated with a poorer prognosis as they may reduce adherence to medical advice and deficits in empathy and social cognition, which may increase caregiver burden.
64
Cause
edit
Sporadic ALS has no known cause and is described as an
idiopathic disease
21
Though its exact cause is unknown, genetic and environmental factors are thought to be of roughly equal importance.
14
The genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause ALS. A multi-step
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.
65
ALS can strike at any age, but its likelihood increases with age.
66
Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. ALS is 20% more common in men than women,
67
but this difference in sex distribution is no longer present in patients with onset after age 70.
66
Genetics and genetic testing
edit
Main article:
Genetics of amyotrophic lateral sclerosis
ALS can be classified as either familial or sporadic, depending on whether there is a known family history of the disease and/or whether an ALS-associated genetic mutation has been identified via genetic testing.
68
69
Familial ALS is thought to account for 10–15% of cases overall and can include
monogenic
oligogenic
, and
polygenic
modes of inheritance.
17
There is considerable variation among clinicians on whether to conduct genetic testing in ALS, particularly if there is no discernible family history of the disease.
70
In the past, genetic counseling and testing was only offered to those with obviously familial ALS.
17
It is increasingly recognized that cases of sporadic ALS may also be due to disease-causing
de novo mutations
in
SOD1
, or
C9orf72
71
or inherited mutations which were overlooked due to incomplete family history or incomplete
penetrance
. The lack of positive family history may be caused by lack of historical records, having a smaller family, older generations dying earlier of causes other than ALS, genetic
non-paternity
, and uncertainty over whether certain neuropsychiatric conditions (e.g.
frontotemporal dementia
, other forms of
dementia
suicide
psychosis
schizophrenia
) should be considered significant when determining a family history.
17
There have been calls in the research community to routinely counsel and test all diagnosed ALS patients for familial ALS,
72
especially due to the availability of gene therapy (
tofersen
) for carriers of SOD1 ALS. A shortage of genetic counselors and limited clinical capacity to see such at-risk individuals make this challenging in practice, as does the unequal access to genetic testing around the world.
73
More than 40 genes have been associated with ALS, of which four account for nearly half of familial cases, and around 5% of sporadic cases:
C9orf72
(40% of familial cases, 7% sporadic),
SOD1
(12% of familial cases, 1–2% sporadic),
FUS
(4% of familial cases, 1% sporadic), and
TARDBP
(4% of familial cases, 1% sporadic), with the remaining genes mostly accounting for fewer than 1% of either familial or sporadic cases.
17
Notably, repeat expansions in the C9orf72 gene account for about 40% of genetic ALS and 25% of genetic FTD, leading to the redefinition of ALS and FTD as lying on a shared disease spectrum.
74
ALS genes identified to date explain the cause of 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 themselves.
17
SOD (superoxide dismutase)
refers to a group of enzymes that target and reduce the presence of harmful
reactive oxygen species (ROS)
to protect cells. Subsequently, SOD enzymes are often critical in ensuring appropriate conditions for neuronal/neural pathway development
75
SOD1
, a subspecies within the main SOD gene family, is a metalloenzyme characterized by the two main metal groups it contains—Zinc (Zn) and Copper (Cu). The
Cu-Zn superoxide dismutase
metabolizes superoxide radicals to oxygen and hydrogen peroxide, defending organisms against oxygen toxicity. Various gene inhibition and knockdown experiments in model organisms such as
Drosophila melanogaster
have indicated the key role of SOD enzyme activity in neuronal remodeling.
76
SOD gene mutation has been linked to inhibited motor function and ability, as well as a decreased capacity for affected organisms to function and perform physical behaviors normally due to dysfunctional movement and muscle degeneration.
76
These downregulated transcripts are responsible for mediating axon extension and guidance functions; mutations in SOD1 genes are linked with neuronal defects/neuroinflammation similar to the symptoms of ALS.
77
Environmental and other factors
edit
The multi-step hypothesis suggests the disease is caused by some interaction between an individual's genetic risk factors and their cumulative lifetime of exposures to environmental factors, termed their
exposome
17
The most consistent lifetime exposures associated with developing ALS (other than genetic mutations) include heavy metals (e.g.
lead
and
mercury
), chemicals (e.g.
pesticides
and
solvents
),
electric shock
physical injury
(including
head injury
), and
smoking
(in men more than women). Generally, the effect of each exposure is relatively small. For instance, an individual's lifetime risk of developing ALS might increase from "1 in 400" without exposure to between "1 in 300" and "1 in 200" if they were exposed to heavy metals.
78
Some industries are heavily dependent upon the use or exposure to these environmental factors, which may increase employees' susceptibility. For example, agricultural tasks may involve as many as 5 such risk factors
79
excluding workers' smoking habits. A range of other factors have weaker evidence supporting them and include participation in
professional sports
, having a lower
body mass index
, lower
educational attainment
, manual occupations, military service, exposure to
beta-Methylamino-L-alanine
(BMAA), and viral infections.
78
Although some personality traits, such as
openness
80
agreeableness
and
conscientiousness
81
appear remarkably common among patients with ALS, it remains open whether personality can increase susceptibility to ALS directly.
82
Instead, genetic factors giving rise to personality might simultaneously predispose people to develop ALS,
80
or the above personality traits might underlie lifestyle choices which are in turn risk factors for ALS.
81
Viruses and retrotransposons
edit
Many ALS patients have substantially increased expression of
endogenous retroviruses
(HERVs), which are remnants of infections that may have happened early in human evolution and remained integrated in the
human genome
. Similarly, about one in five people with ALS had high levels of
retrotransposon
activation and dysfunction of
TDP-43
, a protein which regulates human gene expression and inhibits activation of retroviral genes. Preliminary data suggest that
antiviral therapy
may be used to treat ALS and related diseases.
83
84
Autoimmune processes
edit
Multiple studies have provided evidence suggesting that motor neurons in ALS patients may be susceptible to inflammatory responses driven by autoreactive immune cells.
85
In 1991, researchers with
Baylor College of Medicine
found that antibodies could be used to target motor neurons in a mouse model, leading to limb weakness and other symptoms similar to ALS symptoms in humans.
86
In 2025, researchers at
Columbia University Medical School
and
La Jolla Institute for Immunology
published the first study showing inflammatory T cells targeting a specific antigen (vulnerable site) on motor neurons in patients with ALS.
87
Pathophysiology
edit
Neuropathology
edit
Upon examination at autopsy, 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.
11
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).
88
In ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the brain die as well.
89
The pathological hallmark of ALS is the presence of
inclusion bodies
(abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor neurons. In about 97% of people with ALS, the main component of the inclusion bodies is
TDP-43
protein;
11
however, in those with
SOD1
or
FUS
mutations, the main component of the inclusion bodies
90
91
is SOD1 or FUS protein, respectively.
Prion
-like propagation of misfolded proteins from cell to cell may explain why ALS starts in one area and spreads to others.
26
The
glymphatic system
may also be involved in the
pathogenesis
of ALS.
92
Biochemistry
edit
This figure shows ten proposed disease mechanisms for ALS and the genes associated with them.
93
Neurodegeneration
in ALS is thought to involve many different cellular and molecular processes.
10
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.
94
Mutant SOD1 protein forms intracellular aggregations that inhibit protein degradation. Cytoplasmic aggregations of
wild-type
(normal) SOD1 protein are common in sporadic ALS.
89
It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner.
11
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 cytoskeletal maintenance and axonal transport
11
include
DCTN1
PFN1
, and
TUBA4A
89
Several ALS genes encode RNA-binding proteins. The first to be discovered was TDP-43 protein,
89
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.
11
FUS
codes for FUS, another RNA-binding protein with a similar function to TDP-43, which can cause ALS when mutated.
74
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.
95
Once these mutant RNA-binding proteins are misfolded and aggregated, they may be able to misfold normal proteins both within and between cells in a prion-like manner.
89
This also leads to decreased levels of RNA-binding protein in the nucleus, which may mean that their target RNA transcripts do not undergo normal processing.
96
Other RNA metabolism genes associated with ALS include
ANG
SETX
, and
MATR3
11
C9orf72
is the most commonly mutated gene in ALS and causes motor neuron death through several mechanisms.
89
The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over);
97
people with up to 30 repeats are considered normal, while people with hundreds or thousands of repeats can have familial ALS, frontotemporal dementia, or sometimes sporadic ALS.
98
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.
89
Mitochondrial bioenergetic dysfunction leading to dysfunctional motor neuron axonal homeostasis (reduced axonal length and fast axonal transport of mitochondrial cargo) has been shown to occur in
C9orf72
-ALS using human
induced pluripotent stem cell
(iPSC) technologies coupled with
CRISPR/Cas9
gene-editing, and human post-mortem spinal cord tissue examination.
99
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 presynaptic neurons. However, it is unclear if this mechanism is responsible for its therapeutic effect.
11
Diagnosis
edit
An
MRI of the brain
(axial
FLAIR
) looking at a person as if from below that shows increased
signal as a small white region within the
posterior part of the internal capsule
around the center of the image, consistent with the diagnosis of ALS
No single test can provide a definite diagnosis of ALS.
Instead, the diagnosis of ALS is primarily made based on a physician's clinical assessment after ruling out other diseases.
Physicians often obtain the person's full
medical history
and conduct neurologic examinations at regular intervals to assess whether signs and symptoms such as muscle weakness,
muscle atrophy
hyperreflexia
Babinski's sign
, and spasticity are worsening.
Many biomarkers are being studied for the condition, but as of 2023 are not in general medical use.
100
An
MRI of the brain
looking at a person from side-on that shows
increased T2 signal
as a white region in the posterior part of the
internal capsule
that can be tracked to the
motor cortex
, consistent with the diagnosis of ALS
Differential diagnosis
edit
Because symptoms of ALS can be similar to those of a wide variety of other 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).
101
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 disc
in the neck,
syringomyelia
, or cervical
spondylosis
Based on the person's symptoms and findings 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.
Several infectious diseases can sometimes cause ALS-like symptoms, including human immunodeficiency virus (
HIV
),
human T-lymphotropic virus
(HTLV),
Lyme disease
, and
syphilis
10
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.
102
Because the prognosis of ALS and closely related subtypes of motor neuron disease is generally poor, neurologists may carry out investigations to evaluate and exclude other diagnostic possibilities. Disorders of the
neuromuscular junction
, such as
myasthenia gravis
(MG) and
Lambert–Eaton myasthenic syndrome
, may also mimic ALS, although this rarely presents diagnostic difficulty over time.
103
104
Benign fasciculation syndrome
and
cramp fasciculation syndrome
may also occasionally mimic some of the early symptoms of ALS. Nonetheless, the absence of other neurological features that develop inexorably with ALS means that, over time, the distinction will not present any difficulty to the experienced neurologist; where doubt remains, EMG may be helpful.
105
Management
edit
There is no known cure for ALS. Management focuses on treating symptoms and providing supportive care to improve quality of life and prolong survival.
10
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.
Non-invasive ventilation
(NIV) is the main treatment for respiratory failure in ALS.
11
In people with normal bulbar function, it prolongs survival by about seven months and improves the quality of life. One study found that NIV is ineffective for people with poor bulbar function
106
while another suggested that it may provide a modest survival benefit.
10
Many people with ALS have difficulty tolerating NIV.
107
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.
20
19
Invasive ventilation is more commonly used in Japan than in North America or Europe.
108
A person with late-stage ALS with a range of assistive technologies to support movement (power wheelchair), breathing (invasive ventilation), and communication (eye tracker and computer)
Physical therapy can promote functional independence
109
110
through aerobic, range of motion, and stretching exercises.
111
Occupational therapy can assist with activities of daily living through adaptive equipment.
112
Speech therapy can assist people with ALS who have difficulty speaking.
110
Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life.
10
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.
11
The feeding tube is usually inserted by
percutaneous endoscopic gastrostomy
(PEG). There is weak evidence that PEG tubes improve survival.
113
PEG insertion is usually performed with the intent of improving quality of life.
20
Palliative care
should begin shortly after someone is diagnosed with ALS.
114
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 increase the likelihood of a peaceful death.
20
In the final days of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.
19
Medications
edit
Disease-slowing treatments
edit
Chemical structure of
riluzole
, a medication that prolongs survival by 2–3 months
115
Riluzole
has been found to modestly prolong survival by about 2–3 months.
116
115
It may have a greater survival benefit for those with bulbar-onset ALS.
115
It may work by decreasing release of the excitatory
neurotransmitter
glutamate
from pre-synaptic neurons.
11
The most common side effects are nausea and a lack of energy (
asthenia
).
115
People with ALS should begin treatment with riluzole as soon as possible following their diagnosis.
114
Riluzole is available as a tablet, liquid, or dissolvable oral film.
18
Edaravone
has been shown to modestly slow the decline in function in a small group of people with early-stage ALS.
117
118
It may work by protecting motor neurons from
oxidative stress
119
The most common side effects are bruising and gait disturbance.
118
Edaravone is available as an intravenous infusion or as an oral suspension.
120
Tofersen
(Qalsody) is an
antisense oligonucleotide
that was approved for medical use in the United States in April 2023 for the treatment of SOD1-associated ALS.
121
In a study of 108 patients with SOD1-associated ALS there was a non-significant trend towards a slowing of progression, as well as a significant reduction in neurofilament light chain,
122
a putative ALS biomarker thought to indicate neuronal damage.
123
A follow-up study and open-label extension suggested that earlier treatment initiation had a beneficial effect on slowing disease progression. Tofersen is available as an intrathecal injection into the
lumbar cistern
at the base of the spine.
121
Symptomatic treatments
edit
Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and
phlegm
111
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.
39
Depression can be treated with
selective serotonin reuptake inhibitors
(SSRIs) or tricyclic antidepressants,
11
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.
11
Baclofen
and
tizanidine
are the most commonly used oral drugs for treating spasticity; an
intrathecal
baclofen pump can be used for severe spasticity
11
, and
mexiletine
is safe and effective for treating cramps.
118
Atropine
scopolamine
, amitriptyline, or
glycopyrrolate
may be prescribed when people with ALS begin having trouble swallowing their saliva (
sialorrhea
).
11
Breathing support
edit
Non-invasive ventilation
edit
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
11
and was the first treatment shown to improve both survival and quality of life.
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.
19
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.
107
As the disease progresses, people with ALS develop shortness of breath when lying down, during physical activity or talking, and eventually at rest.
124
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.
107
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).
19
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.
125
A 2006 randomized controlled trial found that NIV prolongs survival by about 48 days and improves the 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 the quality of life. For those with poor bulbar function, NIV neither prolongs survival nor improves the quality of life, though it does improve some sleep-related symptoms.
106
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.
107
Results from a large 2015 cohort study suggest that NIV may prolong survival in those with bulbar weakness, so NIV should be offered to all people with ALS, even if it is likely that they will have difficulty tolerating it.
10
Invasive ventilation
edit
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.
19
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.
19
About half of the people with ALS who choose to undergo invasive ventilation report a decrease in their quality of life,
20
but most still consider it to be satisfactory. However, invasive ventilation imposes a heavy burden on caregivers and may decrease their quality of life.
19
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.
108
Therapy
edit
A man with ALS communicates by pointing to letters and words using a head-mounted laser pointer mounted on his glasses.
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.
109
110
Occupational therapy and special equipment such as
assistive technology
can also enhance people's independence and safety throughout ALS.
112
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.
126
Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles because muscle exhaustion can lead to a worsening of symptoms associated with ALS, rather than providing help to people with ALS.
111
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 people with ALS to retain as much safety and independence in activities of daily living as possible.
112
Since respiratory insufficiency is the primary cause of mortality, physical therapists can help improve respiratory outcomes in people with ALS by implementing pulmonary physical therapy. This includes inspiratory muscle training, lung volume recruitment training, and manual assisted cough therapy aimed at increasing respiratory muscle strength as well as increasing survival rates.
127
People with ALS who have difficulty speaking or swallowing 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.
110
Nutrition
edit
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.
10
Weight loss in ALS is often caused by muscle wasting and increased resting energy expenditure. Weight loss may also be secondary to reduced food intake since
dysphagia
develops in about 85% of people with ALS at some point throughout their disease course.
19
Therefore, regular periodic assessment of the weight and swallowing ability in people with ALS is very important.
Dysphagia is often initially managed via dietary changes and modified swallowing techniques.
11
People with ALS are often instructed to avoid dry or chewy foods in their diet and instead have meals that are soft, moist, and easy to swallow.
124
Switching to thick liquids (like fruit nectar or smoothies) or adding thickeners (to thin fluids like water and coffee) may also help people facing difficulty swallowing liquids. There is tentative evidence that high-calorie diets may prevent further weight loss and improve survival,
118
but more research is still needed.
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.
11
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 (less commonly) a
nasogastric tube
, in which a tube is placed through the nose and down the esophagus into the stomach.
19
A gastrostomy tube is more appropriate for long-term use
than a nasogastric tube, which is uncomfortable and can cause esophageal ulcers.
19
The feeding tube is usually inserted by a
percutaneous endoscopic gastrostomy
procedure (PEG). While there is weak evidence that PEG tubes improve survival in people with ALS, no
randomized controlled trials
(RCTs) have yet been conducted to indicate whether enteral tube feeding has benefits compared to continuation of feeding by mouth.
113
Nevertheless, PEG tubes are still offered with the intent of improving the person's quality of life
20
by sustaining nutrition, hydration status, and medication intake.
End-of-life care
edit
Palliative care
, which relieves symptoms and improves the quality of life without treating the underlying disease, should begin shortly after someone is diagnosed with ALS.
114
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.
20
Once they have been fully informed about all aspects of various life-prolonging measures, they can fill out
advance directives
indicating their attitude toward noninvasive ventilation, invasive ventilation, and feeding tubes.
118
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.
11
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.
20
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.
20
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.
11
Although many people with ALS fear choking to death (suffocating),
20
they can be reassured that this occurs rarely, less than 1% of the time.
128
Most patients die at home,
20
and in the final days of life, opioids can be used to treat pain and
dyspnea
, while
benzodiazepines
can be used to treat anxiety.
19
Epidemiology
edit
ALS is the most common
motor neuron disease
in adults and the third most common
neurodegenerative disease
74
after
Alzheimer's disease
and
Parkinson's disease
129
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.
130
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.
131
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.
65
The number of people 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.
132
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.
11
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.
65
There are several geographic clusters in the Western Pacific where the prevalence of ALS was reported to be 50–100 times higher than in 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.
65
Estimated prevalence of ALS in the United States by age group, 2012–2015
132
People of all races and ethnic backgrounds may be affected by ALS,
132
but it is more common in whites than in Africans, Asians, or Hispanics.
133
In the United States in 2015, the prevalence of ALS in whites was 5.4 people per 100,000, while the prevalence in African Americans 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.
132
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.
134
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
135
ALS can affect people at any age,
57
but the peak incidence is between 50 and 75 years
10
and decreases dramatically after 80 years.
21
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.
134
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.
132
Sporadic ALS usually starts around the ages of 58 to 63 years, while genetic ALS starts earlier, usually around 47 to 52 years.
21
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.
133
History
edit
The French neurologist
Jean-Martin Charcot
coined the term
amyotrophic lateral sclerosis
in 1874.
23
American baseball player
Lou Gehrig
. In some countries, especially the United States, ALS is also called "Lou Gehrig's disease".
136
Descriptions of the disease date back to at least 1824 by
Charles Bell
23
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.
137
138
In 1869, the connection between the symptoms and the underlying neurological problems was first described by
Jean-Martin Charcot
, who initially introduced the term
amyotrophic lateral sclerosis
in his 1874 paper.
23
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.
139
Diagnostic criteria
edit
In the 1950s,
electrodiagnostic testing
(EMG) and
nerve conduction velocity
(NCV) testing 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.
140
Since then, several diagnostic criteria have been developed, which are mostly in use for research purposes for inclusion/exclusion criteria, and to stratify patients for analysis in trials. Research diagnostic criteria for ALS include the "El Escorial" in 1994,
141
revised in 1998.
142
In 2006, the "Awaji" criteria proposed using EMG and NCV tests to help diagnose ALS earlier,
143
and most recently, the "Gold Coast" criteria in 2019 simplified diagnosis, included cognitive change, and no longer required multiple regions to be affected.
144
Name
edit
See also:
Motor neuron diseases
Amyotrophic
is derived from
Greek
a-
means "no",
myo-
(from
mûs
) refers to "muscle", and
trophḗ
means "nourishment". Therefore,
amyotrophy
means "muscle malnourishment"
145
or the wasting of muscle tissue.
146
Lateral
identifies the locations in the spinal cord of the affected motor neurons.
Sclerosis
means "scarring" or "hardening" and refers to the death of the motor neurons in the spinal cord.
145
ALS is sometimes referred to as
Charcot's disease
(not to be confused with
Charcot–Marie–Tooth disease
or
Charcot joint disease
), because
Jean-Martin Charcot
was the first to connect the clinical symptoms with the pathology seen at autopsy.
147
The British neurologist
Russell Brain
coined the term
motor neuron disease
in 1933 to reflect his belief that ALS, progressive bulbar palsy, and progressive muscular atrophy were all different forms of the same disease.
148
In some countries, especially the United States, ALS is called
Lou Gehrig's disease
136
after the American
baseball
player
Lou Gehrig
, who was diagnosed with ALS in 1939.
149
In the United States and continental Europe, the term
ALS
(as well as
Lou Gehrig's disease
in the US) refers to all forms of the disease, including "classical" ALS,
progressive bulbar palsy
progressive muscular atrophy
, and
primary lateral sclerosis
36
In the United Kingdom and Australia, the term
motor neuron disease
refers to all forms of the disease, while
ALS
only refers to "classical" ALS, meaning the form with both upper and lower motor neuron involvement.
150
Society and culture
edit
See also:
List of people with motor neuron disease
A student demonstrating the ice bucket challenge
In addition to the baseball player
Lou Gehrig
, several notable individuals have or have had ALS. Theoretical physicist
Stephen Hawking
, who notably lived longer than any other known person with the condition, was the subject of the critically acclaimed biopic
The Theory of Everything
. American sociology professor and ALS patient
Morrie Schwartz
was the subject of the memoir
Tuesdays with Morrie
and the
film of the same name
In August 2014, the "
Ice Bucket Challenge
" to raise money for ALS research went
viral
online.
151
Participants filmed themselves filling a bucket full of ice water and pouring it onto themselves; they then nominated other individuals to do the same. Many participants donated to ALS research at the
ALS Association
, the
ALS Therapy Development Institute
ALS Society of Canada
, or
Motor Neurone Disease Association
in the UK.
152
References
edit
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Masrori P, Van Damme P (October 2020).
"Amyotrophic lateral sclerosis: a clinical review"
European Journal of Neurology
27
(10):
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doi
10.1111/ene.14393
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7540334
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32526057
"Amyotrophic Lateral Sclerosis (ALS) Fact Sheet"
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. Retrieved
22 October
2020
Kwan J, Vullaganti M (September 2022). "Amyotrophic lateral sclerosis mimics".
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(3):
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Hobson EV, McDermott CJ (September 2016).
"Supportive and symptomatic management of amyotrophic lateral sclerosis"
(PDF)
Nature Reviews. Neurology
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(9):
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10.1038/nrneurol.2016.111
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27514291
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8547381
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. Retrieved
20 December
2019
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"Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis"
The Lancet. Neurology
21
(5):
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493.
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PMC
9513753
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35334233
Ryan M, Heverin M, McLaughlin RL, Hardiman O (November 2019).
"Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis"
JAMA Neurology
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(11):
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1374.
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10.1001/jamaneurol.2019.2044
PMC
6646974
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31329211
"Motor Neuron Diseases Fact Sheet"
www.ninds.nih.gov
. National Institute of Neurological Disorders and Stroke. Archived from
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. Retrieved
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