Amyotrophic lateral sclerosis (ALS, sometimes called Lou Gehrig's
Disease, Maladie de Charcot or motor neurone disease) is a progressive, fatal, neurodegenerative disease caused by the degeneration of motor neurons, the nerve cells in the
central nervous system that control voluntary muscle movement. The disorder causes muscle
weakness and atrophy throughout the body as both the upper and lower motor neurons degenerate and die, ceasing to send messages to muscles. Unable to function, the
muscles gradually weaken, atrophy, and develop fasciculations (twitches) because of denervation. Eventually, the brain
completely loses its ability to initiate and control voluntary movement. The disease does not necessarily debilitate the
patient's mental functioning in the same manner as Alzheimer's disease or other
neurological conditions. Rather, those suffering advanced stages of the disease may retain the same memories, personality, and
intelligence they had before its onset. Famous people to suffer from it include American baseball star Lou Gehrig, British actor David
Niven, Leeds United and England
association football manager Don Revie,
Neo-Classical metal guitarist Jason Becker, British theoretical physicist Stephen Hawking and British musicologist Stanley Sadie.
Etymology
The word amyotrophic is present Greek in origin. A means
no or negative, myo refers to muscle, and trophic means nourishment. When put
together it means "no-muscle-nourishment." Lateral identifies the
areas of the spinal cord where portions of the nerve cells that signal and control the
muscles are located. As this area degenerates it leads to scarring or hardening (sclerosis) in the region. [1]
Epidemiology, causes and risk factors
ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected.
Between 1 to 2 people per 100,000 develop ALS each year [1]. ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop
the disease. Men are affected slightly more often than women.
ALS is classified into three general groups, familial ALS, sporadic ALS and Guamanian ALS.
- "Familial ALS" accounts for approximately 5%-10% of all ALS cases and is caused by genetic factors. Of these approximately
10% are linked to a mutation in Superoxide dismutase (SOD1), a copper/zinc dependant dismutase that is responsible for scavenging free radicals.
- Most of the remaining 90-95% of cases are classified as "sporadic ALS" and have no known
hereditary component.
- A third type, called "Guamanian ALS", represents a small cluster of cases concentrated on the Pacific island of
Guam.
Although there have been reports of several "clusters" including three American
football players from the San Francisco 49ers, three soccer-playing friends in the south of England, and reports of conjugal (i.e., husband and
wife) cases in the south of France[2][3][4] [5] [6], these are statistically plausible chance
events. Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the
latter have not been firmly identified, other than a higher risk with increasing age.
Cause and risk factors
Scientists have not found a definitive cause for ALS and the onset of the disease can be linked to a variety of risk factors.
It is believed that one or more of the following factors are responsible for the majority of ALS cases. Researchers suspect a
virus, exposure to neurotoxins or heavy metals, DNA defects (especially in familial ALS), immune system abnormalities, and enzyme
abnormalities as the leading causes of the disease. There is a hereditary factor in familial ALS (FALS) however there is no known
hereditary component in the 90-95% cases diagnosed as sporadic ALS.
A few causative factors have been discovered. Prolonged exposure to a dietary neurotoxin is the suspected risk factor in
Guamanian ALS. The neurotoxin is a compound (a sterol beta-D-glucoside[7]) found in the seed of the cycad Cycas circinalis, a tropical plant found in Guam, which was used in the human food supply during
the 1950s and early 1960s. An inherited genetic defect linked to a defect on chromosome 21 is believed to cause approximately 40%
of familial ALS cases. This mutation is believed to be autosomal dominant.
The children of those diagnosed with familial ALS have a higher risk factor for developing the disease, however those who have
close family members diagnosed with sporadic ALS have no greater a risk factor than the general population [2].
According to The ALS Association, military veterans are at an increased risk of contracting
ALS. In its report ALS in the
Military, the group pointed to an almost 60% greater chance of the disease in military veterans than the general
population.
Symptoms
The onset of ALS may be so subtle that the symptoms are frequently overlooked. The earliest
symptoms may include twitching, cramping, or stiffness of muscles; muscle weakness affecting an arm or a leg; and/or slurred and
nasal speech. These general complaints then develop into more obvious weakness or atrophy that
may cause a physician to suspect ALS.
The parts of the body affected by early symptoms of ALS depend on which muscles in the body are damaged first. About 75% of
people experience "limb onset" ALS. In some of these cases, symptoms initially affect one of the legs, and patients experience
awkwardness when walking or running or they notice that they are tripping or stumbling more often. Other limb onset patients
first see the effects of the disease on 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.
About 25% of cases are "bulbar onset" ALS. These patients first notice difficulty speaking
clearly. Speech becomes garbled and slurred. Nasality and loss of volume are frequently the first symptoms. Difficulty
swallowing, and loss of tongue mobility follow. Eventually total loss of speech and the inability to protect the airway when
swallowing are experienced.
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. Patients 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 (the large toe extends upward as the sole of the foot is
stimulated) 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). Around 15–45% of
patients experience pseudobulbar affect, also known as "emotional lability", which
consists of uncontrollable laughter or crying.
To be diagnosed with ALS, patients 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 patients
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 patient's ability to eat normally and increase the risk of choking. Maintaining weight will then become a
problem. Because the disease usually does not affect cognitive abilities, patients are aware of their progressive loss of
function and may become anxious and depressed. A small percentage of patients go on to develop frontotemporal dementia characterized by profound personality changes; this is more common
amongst those with a family history of dementia. A larger proportion of patients experience mild problems with word-generation,
attention, or decision-making. Cognitive function may be affected as part of the disease process or could be related to poor
breathing at night (nocturnal hypoventilation). Health care professionals need to explain the course of the disease and describe
available treatment options so that patients can make informed decisions in advance.
As the diaphragm and intercostal muscles weaken, forced vital capacity and inspiratory pressure diminish. In bulbar onset ALS,
this may occur before significant limb weakness is apparent. Bilevel positive pressure ventilation (frequently referred to by the
tradename BiPAP) is frequently used to support breathing, first at night, and
later during the daytime as well. It is recommended that long before BiPAP becomes insufficient, patients (with the eventual help
of his/her family) must decide whether to have a tracheostomy and long term mechanical
ventilation. Most patients do not elect this route, and instead choose palliative hospice
care at this point. Most people with ALS die of respiratory failure or pneumonia, not
the disease itself.
ALS predominantly affects the motor neurons, and in the majority of cases the disease does not impair a patient's mind,
personality, intelligence, or memory. Nor does it affect a person's ability to see, smell, taste, hear, or feel touch. Control of
eye muscles is the most preserved function, although some patients with an extremely long duration of disease (20+ years) may
lose eye control too. Unlike multiple sclerosis, bladder and bowel control are
usually preserved in ALS, although as a result of immobility and diet changes, intestinal problems such as constipation can
require intensive management.
Diagnosis
No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb
is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the
patient and a series of tests to rule out other diseases. Physicians obtain the patient'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 getting progressively worse.
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 patient 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. Although these MRI scans are often normal in
patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor,
multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical
spondylosis.
Based on the patient'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 that the patient 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), Lyme disease, syphilis[8] and
tick-borne encephalitis [9]viruses can in some cases cause ALS-like symptoms. Neurological disorders such
as multiple sclerosis, post-polio
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. There have been
documented cases of a patient presenting with ALS-like symptoms, having a positive Lyme titer, and responding to antibiotics.
[10]
Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early
stages of the disease, patients may wish to obtain a second neurological opinion.
A study by researchers from Mount Sinai School of Medicine identified three proteins that are found in significantly lower
concentration in the cerebral spinal fluid of patients with ALS than in healthy individuals. This finding was published in the
February 2006 issue of Neurology. Evaluating the levels of these three proteins proved 95% accurate for diagnosing ALS. The three
protein markers are TTR, cystatin C, and the carboxyl-terminal fragment of neuroendocrine protein 7B2). These are the first
biomarkers for this disease and may be first tools for confirming diagnosis of ALS. With current methods, the average time from
onset of symptoms to diagnosis is around 12 months. Improved diagnostic markers may provide a means of early diagnosis, allowing
patients to receive relief from symptoms years earlier. [11]
Etiology
The cause of ALS is not known. An important step toward answering that question came in 1993 when scientists discovered that
mutations in the gene that produces the Cu/Zn superoxide dismutase (SOD1) enzyme
were associated with some cases (approximately 20%) of familial ALS. This enzyme is a powerful antioxidant that protects the body
from damage caused by superoxide, a toxic free radical. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. Although it is
not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of
free radicals may result from the faulty functioning of this gene. Current research, however, indicates that motor neuron death
is not likely a result of lost or compromised dismutase activity, suggesting mutant SOD1 induces toxicity in some other way (a
gain of function).[12][13]
Studies involving transgenic mice have yielded several theories about
the role of SOD1 in mutant SOD1 familial amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily
develop ALS, although they do exhibit an acceleration of age-related muscle atrophy (sarcopenia) and a shortened lifespan (see
article on superoxide dismutase). This indicates that the toxic properties of the
mutant SOD1 are a result of a gain in function rather than a loss of normal function. In addition, aggregation of proteins has
been found to be a common pathological feature of both familial and sporadic ALS (see article on proteopathy). Interestingly, in mutant SOD1 mice, aggregates (misfolded protein accumulations) of mutant
SOD1 were found only in diseased tissues, and greater amounts were detected during motor neuron degeneration.[14] It is speculated that aggregate accumulation of mutant SOD1 plays a role
in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins.[15] Any such disruption, if proven, would lend significant
credibility to the theory that aggregates are involved in mutant SOD1 toxicity. However, it is important to remember that SOD1
mutations cause only 10% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the
sporadic form of the disease. Yet, the ALS-SOD1 mice remain the best model of the disease thus far.
Studies also have focused on the role of glutamate in motor neuron degeneration.
Glutamate is one of the chemical messengers or neurotransmitters in the brain.
Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die off when they are
exposed over long periods to excessive amounts of glutamate (excitotoxicity). Now,
scientists are trying to understand what mechanisms lead to a buildup of unneeded glutamate in the spinal fluid and how this
imbalance could contribute to the development of ALS. Failure of astrocytes to sequester
glutamate from the extracellular fluid surrounding the neurones has been proposed as a possible cause of this glutamate-mediated
neurodegeneration. Riluzole is currently the only approved drug for ALS and targets glutamate
transporters. Its very modest benefit to patients has bolstered the argument that glutamate is not a primary cause of the
disease.
Autoimmune responses which occur when the body's immune system attacks normal cells have been suggested as one possible cause
for motor neuron degeneration in ALS. Some scientists theorize that antibodies may directly or indirectly impair the function of
motor neurons, interfering with the transmission of signals between the brain and muscles. More recent evidence indicates that
the nervous system's immune cells, Microglia, are heavily involved in the later stages of the disease.
In searching for the cause of ALS, researchers have also studied environmental factors such as exposure to toxic or infectious
agents. Other research has examined the possible role of dietary deficiency or trauma. However, as of yet, there is insufficient
evidence to implicate these factors as causes of ALS.
Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.
Treatment
No cure has yet been found for ALS. However, the Food and Drug
Administration (FDA) has approved the first drug treatment for the disease: Riluzole
(Rilutek). 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, and may have a greater survival benefit for those with a
bulbar onset. The drug also extends the time before a patient needs ventilation support. Riluzole does not reverse the damage
already done to motor neurons, and patients 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 patients. This supportive care
is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational,
and speech therapists; nutritionists; 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.
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 patient's
prescriptions to avoid risks of drug interactions.
Physical therapy and special equipment such as assistive technology can enhance
patients' 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 patients remain mobile.
ALS patients who have difficulty speaking may benefit from working with a speech-language pathologist. These health
professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS
progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers,
speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet
boards or yes/no signals. These methods and devices help patients communicate when they can no longer speak or produce vocal
sounds. With the help of occupational therapists, speech-generating devices can be activated by switches or mouse emulation
techniques controlled by small physical movements of, for example, the head, finger or eyes.
Patients and caregivers can learn from speech-language pathologists 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.
Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. When patients can no longer get
enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also
reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does
not prevent patients from eating food orally if they wish.
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 patient's lungs from various external sources that are applied directly to the face or body.
When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time.
Patients may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the
lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as a tracheotomy, in which a plastic breathing tube is inserted directly in the patient's 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 patient's quality of life and in cost. Although ventilation
support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be
fully informed about these considerations and the long-term effects of life without movement before they make decisions about
ventilation support. It must be pointed out that some patients under long-term tracheostomy intermittent positive pressure
ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak. This technique preserves
speech in some patients with long-term mechanical ventilation.
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. Social workers provide support such as assistance in obtaining financial aid, arranging
durable power of attorney, preparing a living will, and finding support groups for patients and caregivers. Home nurses are
available not only to provide medical care but also to teach caregivers about tasks such as maintaining respirators, giving
feedings, and moving patients to avoid painful skin problems and contractures. Home hospice nurses work in consultation with
physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain
at home. The home hospice team can also counsel patients and caregivers about end-of-life issues.
Both animal and human research suggest calorie restriction (CR) may be
contraindicated for those with ALS. Research on a transgenic mouse model
of ALS demonstrates that CR may hasten the onset of death in ALS. [16] In that study, Hamadeh et al also note two human studies[17][18] that
they indicate show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and
Antel state: "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a
consistent aspect of the illness." They go on to conclude: "We conclude that ALS patients have a chronically deficient intake of
energy and recommended augmentation of energy intake." (PMID 8604660)
Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease
and had no benefits.[19] Suggesting that a calorically
dense diet may slow ALS, a ketogenic diet in the ALS mouse model has been shown to slow
the progress of disease.[20]
The new discovery of RNAi has some promise in treating ALS. In recent studies, RNAi
has been used in lab rats to shut off specific genes that lead to ALS. Cytrx Corporation has
sponsored ALS research utilizing RNAi gene silencing technology targeted at the mutant SOD1 gene. The mutant SOD1 gene is
responsible for causing ALS in a subset of the 10% of all ALS patients who suffer from the familial, or genetic, form of the
disease. Cytrx's orally-administered drug Arimoclomol is currently in clinical evaluation as a therapeutic treatment for ALS.
Insulin-like growth factor 1 has also been studied as treatment for ALS.
Cephalon and Chiron conducted two pivotal clinical studies of IGF-1 for ALS, and although one study demonstrated efficacy, the
second was equivocal, and the product has never been approved by the FDA. In January of 2007, the Italian Ministry of Health has
requested INSMED corporation's drug, IPLEX, which is a recombinant IGF-1 with Binding Protein
3(IGF1BP3) to be used in a clinical trial for ALS patients in Italy.
Prognosis
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 have increasing problems such as delusions and/or paranoia, swallowing, and speaking
or forming words. Eventually people with ALS will not be able to stand or walk, get in or out of bed on their own, or use their
hands and arms. In later stages of the disease, individuals have difficulty breathing as the muscles of the respiratory system
weaken. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of
ALS. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. However, about 10
percent of those individuals with ALS survive for 10 or more years.
Resources
There are many organizations set up across the world to help people with ALS. Internationally there is the ALS MND alliance, in the United States there is the
ALS Association [3], the Packard Center for ALS Research at
Johns Hopkins, and staytough.fightHARD..
In the United Kingdom the Motor Neurone Disease Association, in Canada the ALS Society of Canada, and in Australia there is the
Motor Neurone Disease Association of Australia [4]. These organizations and others work to eliminate the disease with ALS patients and their families, whilst the
ALS Therapy Development Institute focuses on finding treatments for
today's patients. In addition, the ALS Association holds an annual event called The Walk to D'Feet
ALS where walkers raise awareness and money for patient services programs and research. Also, the Boston Red Sox pitcher Curt
Schilling has created a foundation for researching a treatment for the disease known as Curt's Pitch for ALS.
References
- ^ What is ALS - The ALS Association Retrieved October 24, 2006
- ^ Rachele MG, Mascia V, Tacconi P,
Dessi N, Marrosu F (1998). "Conjugal amyotrophic lateral sclerosis: a report on a couple from Sardinia, Italy.". Ital J Neurol
Sci. Apr;19 (2): 97-100. PMID: 10935845.
