Amyotrophic

Lateral Sclerosis

U.S. DEPARTMENT OF HEALTH

AND HUMAN SERVICES
Public Health Service
National Institutes of Health

Amyotrophic Lateral
Sclerosis

What is amyotrophic lateral sclerosis?

myotrophic lateral sclerosis (ALS),

sometimes called Lou Gehrigs disease,
is a rapidly progressive, invariably fatal
neurological disease that attacks the nerve
cells (neurons) responsible for controlling
voluntary muscles (muscle action we are able
to control, such as those in the arms, legs,
and face). The disease belongs to a group
of disorders known as motor neuron diseases,
which are characterized by the gradual
degeneration and death of motor neurons.
Motor neurons are nerve cells located in the
brain, brain stem, and spinal cord that serve
as controlling units and vital communication
links between the nervous system and the
voluntary muscles of the body. Messages
from motor neurons in the brain (called
upper motor neurons) are transmitted to
motor neurons in the spinal cord (called
lower motor neurons) and from them to
particular muscles. In ALS, both the upper
motor neurons and the lower motor neurons
degenerate or die, and stop sending messages
to muscles. Unable to function, the muscles
gradually weaken, waste away (atrophy), and
have very fine twitches (called fasciculations).
Eventually, the ability of the brain to start
and control voluntary movement is lost.
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ALS causes weakness with a wide range

of disabilities (see section titled What are
the symptoms?). Eventually, all muscles
under voluntary control are affected, and
individuals lose their strength and the ability
to move their arms, legs, and body. When
muscles in the diaphragm and chest wall fail,
people lose the ability to breathe without
ventilatory support. Most people with ALS
die from respiratory failure, usually within
3 to 5 years from the onset of symptoms.
However, about 10 percent of those with
ALS survive for 10 or more years.
Although the disease usually does not impair
a persons mind or intelligence, several
recent studies suggest that some persons
with ALS may have depression or alterations
in cognitive functions involving decisionmaking and memory.
ALS does not affect a persons ability to
see, smell, taste, hear, or recognize touch.
Patients usually maintain control of eye
muscles and bladder and bowel functions,
although in the late stages of the disease
most individuals will need help getting to
and from the bathroom.
Who gets ALS?

s many as 20,000-30,000 people in

the United States have ALS, and
an estimated 5,000 people in the U.S. are
diagnosed with the disease each year. ALS
is one of the most common neuromuscular
diseases worldwide, and people of all races
and ethnic backgrounds are affected.

ALS most commonly strikes people between

40 and 60 years of age, but younger and older
people also can develop the disease. Men are
affected more often than women.
In 90 to 95 percent of all ALS cases, the
disease occurs apparently at random with no
clearly associated risk factors. Individuals
with this sporadic form of the disease do
not have a family history of ALS, and their
family members are not considered to be
at increased risk for developing it.
About 5 to 10 percent of all ALS cases are
inherited. The familial form of ALS usually
results from a pattern of inheritance that
requires only one parent to carry the gene
responsible for the disease. Mutations in
more than a dozen genes have been found
to cause familial ALS.
About one-third of all familial cases (and
a small percentage of sporadic cases)
result from a defect in a gene known as
chromosome 9 open reading frame 72, or
C9orf72. The function of this gene is still
unknown. Another 20 percent of familial
cases result from mutations in the gene that
encodes the enzyme copper-zinc superoxide
dismutase 1 (SOD1).
What are the symptoms?

he onset of ALS may be so subtle that the

symptoms are overlooked. The earliest
symptoms may include fasciculations, cramps,
tight and stiff muscles (spasticity), muscle
weakness affecting an arm or a leg, slurred
and nasal speech, or difficulty chewing or

swallowing. These general complaints then

develop into more obvious weakness or
atrophy that may cause a physician to
suspect ALS.
The parts of the body showing early
symptoms of ALS depend on which muscles
in the body are affected. Many individuals
first see the effects of the disease in a hand
or arm as they experience difficulty with
simple tasks requiring manual dexterity
such as buttoning a shirt, writing, or turning
a key in a lock. In other cases, symptoms
initially affect one of the legs, and people
experience awkwardness when walking or
running or they notice that they are tripping
or stumbling more often. When symptoms
begin in the arms or legs, it is referred to as
limb onset ALS. Other individuals first
notice speech problems, termed bulbar
onset ALS.
Regardless of the part of the body first
affected by the disease, muscle weakness
and atrophy spread to other parts of the body
as the disease progresses. Individuals may
develop problems with moving, swallowing
(dysphagia), and speaking or forming words
(dysarthria). Symptoms of upper motor
neuron involvement include spasticity and
exaggerated reflexes (hyperreflexia) including
an overactive gag reflex. An abnormal reflex
commonly called Babinskis sign (the large
toe extends upward as the sole of the foot is
stimulated in a certain way) also indicates
upper motor neuron damage. Symptoms of
lower motor neuron degeneration include
muscle weakness and atrophy, muscle
cramps, and fasciculations.
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To be diagnosed with ALS, people must

have signs and symptoms of both upper
and lower motor neuron damage that
cannot be attributed to other causes.
Although the sequence of emerging
symptoms and the rate of disease progression
vary from person to person, eventually
individuals will not be able to stand or
walk, get in or out of bed on their own,
or use their hands and arms. Difficulty
swallowing and chewing impair the persons
ability to eat normally and increase the risk
of choking. Maintaining weight will then
become a problem. Because cognitive
abilities are relatively intact, people are
aware of their progressive loss of function
and may become anxious and depressed.
A small percentage of individuals may
experience problems with memory or
decision-making, and there is growing
evidence that some may even develop a
form of dementia over time. Health care
professionals need to explain the course
of the disease and describe available
treatment options so that people can make
informed decisions in advance. In later
stages of the disease, individuals have
difficulty breathing as the muscles of the
respiratory system weaken. They eventually
lose the ability to breathe on their own and
must depend on ventilatory support for
survival. Affected individuals also face an
increased risk of pneumonia during later
stages of ALS.

How is ALS diagnosed?

o one test can provide a definitive

diagnosis of ALS, although the presence
of upper and lower motor neuron signs is
strongly suggestive. Instead, the diagnosis
of ALS is primarily based on the symptoms
and signs the physician observes in the
patient and a series of tests to rule out other
diseases. Physicians obtain the individuals
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 getting progressively worse.
Since ALS symptoms in the early stages
of the disease 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
is a nerve conduction study (NCS), which
measures electrical energy by assessing
the nerves ability to send a signal). Specific
abnormalities in the NCS and EMG may
suggest, for example, that the individual has
a form of peripheral neuropathy (damage
to peripheral nerves) or myopathy (muscle
disease) rather than ALS. The physician
may order magnetic resonance imaging
(MRI), a noninvasive procedure that uses
a magnetic field and radio waves to take
detailed images of the brain and spinal
cord. Standard MRI scans are normal in

people with ALS. However, they can reveal

evidence of other problems that may be
causing the symptoms, such as a spinal
cord tumor, a herniated disk in the neck that
compresses the spinal cord, syringomyelia
(a cyst in the spinal cord), or cervical
spondylosis (abnormal wear affecting
the spine in the neck).
Based on the persons 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 that the individual
may have a myopathy rather than ALS,
a muscle biopsy may be performed.
Infectious diseases such as human
immunodeficiency virus (HIV), human
T-cell leukemia virus (HTLV), polio, West
Nile virus, and Lyme disease can in some
cases cause ALS-like symptoms. Neurological
disorders such as multiple sclerosis, postpolio syndrome, multifocal motor neuropathy,
and spinal muscular atrophy also can mimic
certain facets of the disease and should be
considered by physicians attempting to make
a diagnosis. Fasciculations, the fine rippling
movements in the muscle, and muscle
cramps also occur in benign conditions.
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, individuals may wish
to obtain a second neurological opinion.

What causes ALS?

he cause of ALS is not known, and

scientists do not yet know why ALS
strikes some people and not others. An
important step toward answering this
question was made in 1993 when scientists
supported by the National Institute of
Neurological Disorders and Stroke (NINDS)
discovered that mutations in the gene that
produces the SOD1 enzyme were associated
with some cases of familial ALS. Although it
is still not clear how mutations in the SOD1
gene lead to motor neuron degeneration,
there is increasing evidence that mutant
SOD1 protein can become toxic.
Since then, over a dozen additional genetic
mutations have been identified, many through
NINDS-supported research, and each of these
gene discoveries has provided new insights
into possible mechanisms of ALS.
For example, the discovery of certain
genetic mutations involved in ALS suggests
that changes in the processing of RNA
molecules (involved with functions including
gene regulation and activity) may lead to
ALS-related motor neuron degeneration.
Other gene mutations implicate defects in
protein recycling. And still others point to
possible defects in the structure and shape
of motor neurons, as well as increased
susceptibility to environmental toxins.

Overall, it is becoming increasingly clear

that a number of cellular defects can lead
to motor neuron degeneration in ALS.
Another research advance was made in
2011 when scientists found that a defect in
the C9orf72 gene is not only present in a
significant subset of ALS patients but also
in some patients who suffer from a type
of frontotemporal dementia (FTD). This
observation provides evidence for genetic
ties between these two neurodegenerative
disorders. In fact, some researchers are
proposing that ALS and some forms of
FTD are related disorders with genetic,
clinical, and pathological overlap.
In searching for the cause of ALS,
researchers are also studying the role of
environmental factors such as exposure to
toxic or infectious agents, as well as physical
trauma or behavioral and occupational
factors. For example, studies of populations
of military personnel who were deployed
to the Gulf region during the 1991 war
show that those veterans were more likely
to develop ALS compared to military
personnel who were not in the region.
Future research may show that many
factors, including a genetic predisposition,
are involved in the development of ALS.

How is ALS treated?

o cure has yet been found for

ALS. However, the Food and Drug
Administration (FDA) approved the first
drug treatment for the diseaseriluzole
(Rilutek)in 1995. Riluzole is believed
to reduce damage to motor neurons by
decreasing the release of glutamate.
Clinical trials with ALS patients showed
that riluzole prolongs survival by several
months, mainly in those with difficulty
swallowing. The drug also extends the
time before an individual needs ventilation
support. Riluzole does not reverse the damage
already done to motor neurons, and persons
taking the drug must be monitored for liver
damage and other possible side effects.
However, this first disease-specific therapy
offers hope that the progression of ALS
may one day be slowed by new medications
or combinations of drugs.
Other treatments for ALS are designed to
relieve symptoms and improve the quality
of life for individuals with the disorder.
This supportive care is best provided by
multidisciplinary teams of health care
professionals such as physicians; pharmacists;
physical, occupational, and speech therapists;
nutritionists; and social workers and home
care and hospice nurses. Working with
patients and caregivers, these teams can
design an individualized plan of medical
and physical therapy and provide special
equipment aimed at keeping patients as
mobile and comfortable as possible.

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Physicians can prescribe medications to help

reduce fatigue, ease muscle cramps, control
spasticity, and reduce excess saliva and phlegm.
Drugs also are available to help patients with
pain, depression, sleep disturbances, and
constipation. Pharmacists can give advice on
the proper use of medications and monitor
a patients prescriptions to avoid risks of
drug interactions.
Physical therapy and special equipment
can enhance an individuals independence
and safety throughout the course of ALS.
Gentle, low-impact aerobic exercise such as
walking, swimming, and stationary bicycling
can strengthen unaffected muscles, improve
cardiovascular health, and help patients fight
fatigue and depression. Range of motion and
stretching exercises can help prevent painful
spasticity and shortening (contracture) of
muscles. Physical therapists can recommend
exercises that provide these benefits without
overworking muscles. Occupational therapists
can suggest devices such as ramps, braces,
walkers, and wheelchairs that help individuals
conserve energy and remain mobile.
People with ALS who have difficulty
speaking may benefit from working with a
speech therapist. These health professionals
can teach individuals adaptive strategies
such as techniques to help them speak louder
and more clearly. As ALS progresses, speech
therapists can help people develop ways for
responding to yes-or-no questions with their
eyes or by other nonverbal means and can
recommend aids such as speech synthesizers
and computer-based communication systems.
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These methods and devices help people

communicate when they can no longer
speak or produce vocal sounds.
Nutritional support is an important part of
the care of people with ALS. Individuals and
caregivers can learn from speech therapists
and nutritionists how to plan and prepare
numerous small meals throughout the day
that provide enough calories, fiber, and fluid
and how to avoid foods that are difficult to
swallow. People may begin using suction
devices to remove excess fluids or saliva and
prevent choking. When individuals can no
longer get enough nourishment from eating,
doctors may advise inserting a feeding
tube into the stomach. The use of a feeding
tube also reduces the risk of choking and
pneumonia that can result from inhaling
liquids into the lungs. The tube is not painful
and does not prevent individuals from eating
food orally if they wish.
When the muscles that assist in breathing
weaken, use of nocturnal ventilatory assistance
(intermittent positive pressure ventilation
[IPPV] or bilevel positive airway pressure
[BIPAP]) may be used to aid breathing during
sleep. Such devices artificially inflate the
persons lungs from various external sources
that are applied directly to the face or body.
Individuals with ALS will have breathing
tests on a regular basis to determine when to
start non-invasive ventilation (NIV). When
muscles are no longer able to maintain
normal oxygen and carbon dioxide levels,
these devices may be used full-time.

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Individuals may eventually consider forms

of mechanical ventilation (respirators) in
which a machine inflates and deflates the
lungs. To be effective, this may require a
tube that passes from the nose or mouth to
the windpipe (trachea) and for long-term
use, an operation such as a tracheostomy, in
which a plastic breathing tube is inserted
directly in the patients windpipe through
an opening in the neck. Patients and their
families should consider several factors
when deciding whether and when to use one
of these options. Ventilation devices differ
in their effect on the persons quality of life
and in cost. Although ventilation support can
ease problems with breathing and prolong
survival, it does not affect the progression of
ALS. People need to be fully informed about
these considerations and the long-term effects
of life without movement before they make
decisions about ventilation support.
Social workers and home care and hospice
nurses help patients, families, and caregivers
with the medical, emotional, and financial
challenges of coping with ALS, particularly
during the final stages of the disease.
Respiratory therapists can help caregivers
with tasks such as operating and maintaining
respirators, and home care nurses are available
not only to provide medical care but also to
teach caregivers about giving tube feedings
and moving patients to avoid painful skin
problems and contractures. Home hospice
nurses work in consultation with physicians
to ensure proper medication and pain control.

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What research is being done?

he National Institute of Neurological

Disorders and Stroke, part of the National
Institutes of Health, is the Federal Governments
leading supporter of biomedical research on
ALS. The goals of this research are to find
the cause or causes of ALS, understand the
mechanisms involved in the progression of
the disease, and develop effective treatments.
Scientists are seeking to understand the
mechanisms that selectively trigger motor
neurons to degenerate in ALS, and to find
effective approaches to halt the processes
leading to cell death. This work includes
studies in animals to identify the molecular
means by which ALS-causing gene mutations
lead to the destruction of neurons. To this
end, scientists have developed models of
ALS in a variety of animal species, including
fruit flies, zebrafish, and rodents. Initially,
these genetically modified animal models
focused on mutations in the SOD1 gene
but more recently, models harboring other
ALS-causing mutations also have been
developed. Research in these models suggests
that depending on the gene mutation, motor
neuron death is caused by a variety of
cellular defects, including in the processing
of RNA molecules and recycling of proteins,
as well as impaired energy metabolism, and
hyperactivation of motor neurons. Increasing
evidence also suggests that various types of
glial support cells and inflammation cells of
the nervous system play an important role in
the disease.

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Overall, the work in familial ALS is already

leading to a greater understanding of
the more common sporadic form of the
disease. Because familial ALS is virtually
indistinguishable from sporadic ALS
clinically, some researchers believe that
familial ALS genes may also be involved in
sporadic ALS. For example, recent research
has shown that the defect in the C9orf72
gene found in familial ALS is also present
in a small percentage of sporadic ALS cases.
Further, there is evidence that mutant SOD1
is present in spinal cord tissue in some
sporadic cases of ALS.
Another active area of research is the
development of innovative cell culture
systems to serve as patient-derived model
systems for ALS research. For example,
scientists have developed ways of inducing
skin cells from individuals with ALS into
becoming pluripotent stem cells (cells that
are capable of becoming all the different
cell types of the body). In the case of ALS,
researchers have been able to convert
pluripotent stem cells derived from skin into
becoming motor neurons and other cell types
that may be involved in the disease. NINDS
is supporting research on the development
of pluripotent cell lines for a number of
neurodegenerative diseases, including ALS.
Scientists are also working to develop
biomarkers for ALS that could serve as
tools for diagnosis, as markers of disease
progression, or correlated with therapeutic
targets. Such biomarkers can be molecules
derived from a bodily fluid (such as spinal
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fluid), an imaging assay of the brain or spinal

cord, or an electrophysiological measure
of nerve and muscle ability to process an
electrical signal.
Potential therapies for ALS are being
investigated in a range of animal models,
especially in rodent models. This work
involves the testing of drug-like compounds,
gene therapy approaches, antibodies and
cell-based therapies. In addition, at any given
time, a number of exploratory treatments
are in clinical testing in ALS patients.
Investigators are optimistic that these
and other basic, translational, and clinical
research studies will eventually lead to new
and more effective treatments for ALS.
How can I help research?

he NINDS and the Centers of Disease

Control and Prevention/ Agency for Toxic
Substances and Disease Registry (CDC/
ATSDR) are committed to studies of disease
patterns or risk factors among persons with
ALS in order to better understand the causes
of ALS, the mechanisms involved in the
progression of the disease, and to develop
effective treatments. The National ALS
Registry, a program to collect, manage, and
analyze data about persons with ALS, was
launched in October 2010 and is actively
enrolling individuals with the disease.
The Registry includes data from national
databases as well as de-identified information
provided by persons with ALS. All collected
information is kept confidential. Persons

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living with ALS who choose to participate

can add their information to the Registry by
visiting www.cdc.gov/als.
Clinical trials offer hope for many people
and an opportunity to help researchers find
better ways to safely detect, treat, or prevent
disease. Many neurological disorders dont
have good treatment options. By participating
in a clinical trial, individuals with an illness
or disease can greatly affect their life and
those of others affected by a neurological
disorder. For information about finding and
participating in clinical trials, visit NIH
Clinical Research Trials and You at www.nih.
gov/health/clinicaltrials. Use the search terms
amyotrophic lateral sclerosis or ALS AND
(your state) to locate trials in your area.
The NINDS contributes to the support of
the Human Brain and Spinal Fluid Resource
Center in Los Angeles. This bank supplies
investigators around the world with tissue
from patients with neurological and other
disorders. Tissue from individuals with ALS
is needed to enable scientists to study this
disorder more intensely. Prospective donors
may contact:
Human Brain and Spinal Fluid Resource Center
Neurology Research
W. Los Angeles Healthcare Center
11301 Wilshire Blvd. (127A)
Building 212, Room 16
Los Angeles, CA 90073
310-268-3536
www.brainbank.ucla.edu

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Where can I get more information?

or more information on neurological

disorders or research programs funded
by the National Institute of Neurological
Disorders and Stroke, contact the Institutes
Brain Resources and Information Network
(BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
800-352-9424
www.ninds.nih.gov
Information also is available from the
following organizations:
The ALS Association
1275 K Street, N.W., Suite 1050
Washington, DC 20005
202-407-8580
800-782-4747
www.alsa.org
ALS Therapy Development Institute
300 Technology Square, Suite 400
Cambridge, MA 02139
617-441-7200
www.als.net
Les Turner ALS Foundation
5550 West Touhy Avenue, Suite 302
Skokie, IL 60077-3254
847-679-3311
888-257-1107
www.lesturnerals.org

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Muscular Dystrophy Association

3300 East Sunrise Drive
Tucson, AZ 85718-3208
800-572-1717
www.mda.org
PRIZE4LIFE
P.O. Box 425783
Cambridge, MA 02142
617-500-7527
www.prize4life.org
Project ALS
3960 Broadway, Suite 420
New York, NY 10032
212-420-7382
800-603-0270
www.projectals.org

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NIH . . . Turning Discovery Into Health

Prepared by:
Office of Communications and Public Liaison
National Institute of Neurological
Disorders and Stroke
National Institutes of Health
Department of Health and Human Services
Bethesda, Maryland 20892 -2540

NIH Publication No. 13 - 916

May 2013