Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, was first described by Bell in 1830, and named by Charcot in 1874. A translation of amyotrophic lateral sclerosis is:
|lateral:||pertaining to side (of spinal cord)|
|sclerosis:||hardening of (lateral aspect of spinal cord)|
The term amyotrophic refers to the loss of nerve cells called lower motor neurons (which project from the spinal cord to the muscle), and the term lateral sclerosis refers to the loss of nerve cells called upper motor neurons (which project from the brain to the lateral part of the spinal cord). Upper and lower motor neurons are necessary for muscle contraction and movement.
ALS is a progressive disorder of the nervous system which causes degeneration in both upper and lower motor neurons and results in muscle weakness. The loss of lower motor neurons leads to weakness, twitching of muscles (fasciculations) and loss of muscle bulk (atrophy). The loss of upper motor neurons causes stiffness, cramping and weakness.
Involvement of only lower or only upper motor neurons is not the same as ALS. When the lower motor neuron extending from the spinal cord to the muscle is compromised, the condition can be termed motor neuron disease or spinal or progressive muscular atrophy. When the lower motor neuron extending from the brainstem to the muscles of speech and swallowing are compromised, the condition is termed progressive bulbar palsy. Involvement of only the upper motor neurons results in a condition known as primary lateral sclerosis. Spinal or progressive muscular atrophy, progressive bulbar palsy, and primary lateral sclerosis alone are not considered the same as a diagnosis of ALS.
ALS refers to involvement of both lower and upper motor neurons, and diagnostic efforts are aimed at establishing the involvement of both motor neuron systems. While motor function is profoundly affected in ALS, the disease leaves sensation intact. In approximately 50 percent of ALS cases, mild cognitive changes are present primarily involving executive functions, including judgement capabilities. At present, there is no known cause or cure.
The course of ALS is extremely variable. In the majority of patients, the weakness progresses over a three- to five-year period. A small number of patients progress more rapidly over a one year period. In 20 percent of patients, the progression is slow and the course is over five years or longer. At present, the reason for this variation is unknown, and it is difficult to predict the rate of progression in any single patient.
Not all muscles are involved. For example, eye muscles and muscles involving bladder and bowel control are usually spared. Sexual function also remains intact. Heart and intestines are not affected. Other nerve cells are spared so that vision, hearing, taste, smell and skin sensations remain normal.
ALS occurs in all races, but affects men more frequently than women in a ratio of approximately two to one. After the age of 60, the ratio of men to women approaches one to one.
One to two out of every one hundred thousand people will develop the disease each year, except in selected areas of the Kii peninsula of Japan, Guam, and western New Guinea, where the incidence is much higher.
The average age of onset is 53 to 57 years. Approximately eighty percent of cases begin between the ages of 40 to 70 years, with about ten percent of patients younger and about ten percent older than these limits.
The major symptom affecting patients with ALS is muscle weakness. The onset of weakness is usually difficult to establish because the disease may be present for a number of months or years before an individual seeks medical attention. In the earliest stages, the patient may merely have a mild decrease in endurance. Others may complain of fatigue, stiffness in the legs, jumping and twitching of the muscles, or cramping.
Twenty percent of patients will have voice compromise as an initial complaint, and note hoarseness, slurring of words or a nasal quality in the voice. Often these symptoms are dismissed and attributed to "working too hard," to emotional stress, or to a previous injury or surgery.
As the symptoms of ALS become more apparent, patients may notice weakness of the arms and hands, which results in difficulty performing daily activities such as buttoning or zipping clothing, handwriting, and opening jars or doors. ALS may also cause weakness of the legs and feet, which may first be noted when walking over uneven surfaces or for long distances.
As other muscles become involved, the patient will notice further compromise in overall endurance and increasing difficulty in performing activities of daily living. Progressive weakness of the arms and hands may result in difficulty in performing tasks such as cutting meat and holding articles, and weakness of the shoulders may make it difficult to raise the arms to brush the hair or remove articles from a high shelf. Atrophy (a wasting of muscle mass) and/or increasing stiffness of muscles may become apparent. Weakness of the legs and hips will make it more difficult to climb up and down the stairs, rise from a chair or walk safely.
If the weakness continues to progress, the loss of function in the arms and legs will have a major effect on lifestyle. Falls may occur and lead to the need for a wheelchair not only to assure safety, but also to prolong endurance and to maintain independence. At this point, performance of daily tasks and self-care may require the help of assistive devices and/or a family member.
In some patients, the muscles for voice production may become involved, resulting in hoarseness or slurred speech. Subsequently, the muscles of swallowing can become affected, and patients may have difficulty handling clear liquids and certain foods.
ALS may also cause weakness of the respiratory muscles, which in an early phase may go undetected. The respiratory system can be considered to have a ventilatory phase (air sacs and bronchial tubes), a circulatory phase (where the exchange of gases occurs), and a mechanical phase (determined by the muscles of respiration and by the compliance (stiffness) of the lungs. Different disease processes may involve one or more phases of the respiratory system.
For example, bronchitis causes significant disturbances of the ventilatory phase, whereas blood clots to the lung (pulmonary emboli) primarily affect the circulatory phase. ALS may directly or indirectly affect all phases of the respiratory system.
Certain measurements of the respiratory system can monitor the mechanical phase of respiration. The vital capacity (total amount of air that can be moved in or out of the lung) is the most frequent measurement made. This can easily be accomplished by exhaling into a spirometer. A decrease in the vital capacity in ALS is usually a reflection of neuromuscular weakness, provided the intrinsic lung function is normal. The vital capacity can be monitored as needed to assess the status of the mechanical phase of respiration.
An ineffective cough may result if there is failure of the mechanical phase of respiration. This will lead to an accumulation of secretions in the bronchial tubes. With increasing airway secretions, a reduction in the ventilatory phase of respiration may occur. Progressive ventilatory deterioration results in low oxygen levels in the blood and a build-up of carbon dioxide. These abnormalities cause a sensation of breathlessness and decreased energy levels.
With accumulation of airway secretions or aspiration of food or liquids, an overgrowth of bacteria develops which can result in pneumonia (infection of the lungs). Not only does pneumonia aggravate the ventilatory phase of respiration, it also causes changes in the circulatory phase of respiration, resulting in reduced blood oxygen levels. From the time of diagnosis, infections or changes in the respiratory status are of paramount concern and must be promptly treated.
While weakness is the main feature of ALS, not all muscles are involved. The muscles involved for sexual, bowel, and bladder function are usually spared. Eye muscles, as well as those of the heart and intestines, are not affected. Vision, hearing, taste, smell and sensation remain normal.
Pain is not a generally recognized symptom of ALS. However, in some patients, discomfort may occur due to muscle cramping or to decreased muscle tone around the joints which leads to stress on unsupported ligaments. Stretching exercises, medication and a prevention program are usually effective in alleviating these symptoms.
The patient's medical history, physical examination, and neurological examination are usually sufficient to suggest the diagnosis of amyotrophic lateral sclerosis (ALS). However, it is still important to conduct a full investigation to exclude other conditions and to permit a detailed understanding of the areas involved by the disease. Since no single laboratory test or procedure can establish the diagnosis, every effort must be made to be certain that a treatable condition resembling ALS is not overlooked. A complete diagnostic workup usually includes most, if not all, of the following tests and procedures:
NCV (nerve conduction velocity)
Because no single electrodiagnostic test provides complete information, a combination of EMG, NCV, and neuromuscular transmission studies are usually necessary to determine the involvement of motor neurons, nerves, or muscles. Electrodiagnostic tests may recognize abnormal nerve and muscle activity early in the course of the disease when the physical examination is only minimally changed.
The purpose of these tests in ALS is to:
During an EMG, electrical potentials derived from contracting and non-contracting muscle fibers are recorded from a small disposable needle electrode and are displayed on an oscilloscope screen. The amplified electrical activity may also be heard through a loudspeaker. Insertion of the needle may be uncomfortable, but causes no long term complications.
Depending on the stage of ALS, varying degrees of abnormalities are seen on EMG. These include small involuntary muscle contractions, known as fibrillations and positive sharp waves, as well as a reduction in the number of voluntary motor units. Spontaneous muscle twitches (fasciculations) are also detected by EMG.
Reduced motor units
Because the remaining healthy motor neurons can reinnervate the denervated muscles, long-duration polyphasic units indicative of such a reinnervation process may be seen, especially in more slowly progressive cases. This process also causes a grouping together of muscle fiber types, which can be seen on a muscle biopsy. Single fiber EMG technique may show decreased fiber densities as a manifestation of reinnervation.
Nerve conduction velocity (NCV) measurements determine the time required for an impulse (evoked by electrical stimulation) to traverse a known length of nerve. In ALS, this speed is usually normal, but occasionally may be slightly slowed. Significant slowing indicates damage to peripheral nerves, and suggests a cause other than ALS.
In some patients with otherwise typical ALS, a decrement of motor unit potentials after repetitive stimulation is seen, which resembles another neuromuscular disease called myasthenia gravis. An experienced electromyographer is usually able to distinguish between ALS and other neuromuscular diseases, but at times denervation changes (fibrillations and sharp waves) encountered in other neuromuscular diseases may create diagnostic confusion.
In addition to routine blood and urine tests, the following should be performed:
Bottom=abnormal protein pattern
Because cervical spine disease (spondylosis) may cause pressure on the spinal cord and the nerve roots, this condition may give signs of weakness, wasting, and muscle twitching of the arms, along with increased stiffness in the legs. All patients presenting with these symptoms should undergo routine neck x-rays as well as MRI (magnetic resonance imaging) and/or myelogram of the cervical spine. If these investigations show definite evidence of cervical root or spinal cord compromise, surgical decompression may halt progression of the difficulties and possibly produce improvement. The MRI and myelogram will also detect other conditions of the spinal cord such as a tumor (i.e. meningioma) or another process (i.e. syringomyelia), which may mimic some of the clinical symptoms and signs of ALS.
The usefulness of the muscle biopsy in ALS is greatest when unusual or atypical features are present or symptoms are predominantly ascribable to the proximal muscles. The muscle biopsy assists in investigating the differential diagnostic possibilities in ALS. Diagnostic muscle pathology, especially in disorders of lower motor neurons, is based primarily on evaluation of fresh frozen sections of muscle stained by routine methods and reacted for certain enzymes.
In ALS, a muscle that is mildly weak is the best choice for biopsy. As a general rule, it is better to perform the biopsy in the quadriceps muscle (upper leg) and avoid muscles which may be involved by unrelated processes (e.g., entrapment of nerves, nerve root lesions, or direct trauma). A muscle which has been the site of recent injections, trauma, or EMG should not be selected for biopsy.
The muscle biopsy is performed using local anesthesia, eliminating the risk of general anesthesia. After exposing the muscle by a small incision, three to four small pieces are removed, a process which may involve moderate discomfort. The specimens are immediately taken to the laboratory for processing and stained for routine histological stains and histochemical reactions.
The muscle changes seen in diseases of lower motor neurons, nerve roots, or peripheral nerves are associated with a characteristic set of pathological changes on biopsy. However, the muscle biopsy does not distinguish between damage to the motor neuron and damage to the peripheral nerve and as a result, the biopsy can not per se make a specific diagnosis of ALS. The illustrations below compare normal muscle with the typical changes seen in ALS muscle:
Polygonal fiber shape
Atrophic, angulated fibers
The majority of patients diagnosed with amyotrophic lateral sclerosis do not have a history of ALS in any of their immediate family members (grandparents, parents, siblings). These cases (90 percent of all ALS patients) are considered to be sporadic occurrences of the disease. Neither the cause nor the specific mechanism of motor neuron loss in sporadic ALS has been defined, but several theories have been proposed to explain motor neuron injury.
This theory is based on the fact that glutamate, an amino acid present in proteins, can cause neuronal cell death when present in high concentration. The specific evidence for the excitotoxic theory comes from the demonstration of decreased levels of glutamate in ALS spinal cord, with the assumption that glutamate must have been released and must have been present in high concentrations that would have been toxic. In addition, there is a decreased ability of glutamate to be taken up in fractions of spinal cord tissue of ALS patients taken at autopsy. Such data would suggest once again that glutamate might have been elevated as a result of a failure of uptake. However, the changes in glutamate could also be secondary to damage or loss of motor neurons. Thus, it is not clear what triggers the release of glutamate and the failure of glutamate uptake. Nevertheless, the fact that glutamate can be toxic for motor neurons does suggest that glutamate may play a role, if not in causing ALS, then possibly as a participant in motor neuron injury.
Tissue studies of patients with sporadic ALS have documented the presence of biochemical markers of oxidative cellular injury. Altered proteins (such as nitrated or carbonylated proteins) are detected in higher concentrations in sporadic ALS spinal cords than in disease control specimens. Furthermore, mitochondrial changes, which are associated with the production of free radicals, are also present in sporadic ALS motor terminals. What triggers these changes, and what causes the increase in free radicals, is not currently defined.
The presence of abnormal levels of calcium inside the cell can be visualized (as a yellow color) using a laser scanning confocal microscope
Increasing evidence supports a role for immune system activation and inflammation in ALS patients. An animal model of motor neuron disease shows early activation of the immune system before symptom onset. There is also a significant infiltration of immune cells around motor neurons and motor nerve fiber tracts in the spinal cord of ALS patients. Studies also suggest that motor neuron injury requires the interaction of other cells within the nervous system, and these cells include immune cells. Further understanding of the "communication" between motor neurons and these immune cells in association with motor neuron injury should help define new generations of potential therapies.
It is entirely possible that excitotoxicity, free radicals and immune-inflammation could all contribute to motor neuron cell injury and death. Immune activation can lead to increased free radical release, which can lead to increases in calcium entry in the cell, increased glutamate release and subsequent toxicity. In turn, glutamate and calcium toxicity can also lead to free radical release and immune activation. Therefore, there is likely a "communal" process occurring in ALS that involves these mechanisms, and other theorized mechanisms as well.
IGF-1 may play a role in regeneration and repair of damaged motor neurons
Recent research has documented that the growth and maintenance of motor neurons are dependent on protein nutritive hormones called neurotrophic factors. Insulin like growth factor-1 (IGF-1), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) are all examples of such neurotrophic factors, which have been documented to influence motor neuron development and maintenance. In addition, such factors appear to influence the regenerative and repair capacity of motor neurons. IGF-1 is now considered to be the major factor which produces sprouting of nerves in man. These neurotrophic factors have considerable potential in motor neuron repair and could possibly function as neuroprotective agents and play a meaningful role in therapy.
Familial ALS is rare, occurring in only 10 percent of all cases. Most studies indicate that the disease in this small group of patients is inherited as a dominant genetic trait. This means that you do not have a familial form of ALS if your immediate family members have not been affected (e.g., parents, brothers, sisters or grandparents). This assumes that your grandparents and parents have not died at an early age before the manifestations of the disease could occur. If a distant relative has a similar problem, familial ALS is a reasonable concern, but would be difficult to establish. Even if ALS is established in a relative, it may well be coincidental.
The genetic defect has been discovered for 20 percent of the cases of familial ALS (two percent of all ALS cases). A defect in the enzyme Cu/Zn superoxide dismutase (SOD-1) may result in a change in free radicals and subsequent destruction of the motor neuron. This enzyme defect is inherited on chromosome 21. However, 80 percent of patients with familial ALS (eight percent of all ALS cases) do not have a defect on chromosome 21 or in SOD-1, and the specific genetic alteration is undefined.
Several different forms of lower motor neuron disease without upper motor neuron disease have been described as Spinal Muscular Atrophy Type I, Type II, or Type III. This condition usually occurs in the first two decades of life. It is known that this disorder can be inherited and is due to a defect on chromosome 5. The specific genetic abnormality has not been defined.
Another form of lower motor neuron disease is inherited on the X-chromosome and is seen primarily in males. This disorder, called X-Linked Spinal and Bulbar Muscular Atrophy or Kennedy's disease, is associated with limb weakness, speech and swallowing difficulty, as well as enlargement of the breasts and testicular atrophy. It is associated with an abnormality in the DNA characterized by nucleotide repeats attached to the androgen receptor gene. The exact explanation for the motor neuron loss in this disorder is not known.
Despite the lack of definitive information about the cause and specific cure for ALS, there is much that can be done in the way of symptomatic therapy. Too often the patient has initially encountered the negative attitude that "there is nothing that can be done." Patients feel totally abandoned by this attitude, and may lose their most important asset, namely the courage and willingness to fight their disease. In fact, such a statement could not be further from the truth. Despite the absence of a cure, there is much that can be done.
The major symptom affecting ALS patients is muscle weakness. Adaptive devices for specific limb weakness can be of great benefit in improving independence. Correcting footdrop with a lightweight ankle-foot orthosis can be helpful to minimize falls and maintain endurance.
The prevention of falls due to muscle weakness is a major concern. Modification of bathrooms and attention to sites in the home, where falls might occur, are important. Canes, walkers and eventually wheelchairs may be necessary to maintain endurance, prolong independence and avoid injury. The goal is to maintain ambulation as long as it is safe.
For the upper extremity, there are numerous assistive devices for improving or maintaining the ability to perform daily activities. These range from simple devices such as button hooks, zipper pulls and built-up utensils to long-handled reachers and automatic book page turners. There are also various splints which may increase grip strength and improve finger dexterity.
Regular exercise can be of considerable help from both a physical and a psychological point of view. There is evidence that disuse can increase weakness in already affected muscles. Consequently, patients should be encouraged to participate in regular, individualized exercise programs, but never to the point of exhaustion. Exercises should not include weight-lifting or resistance training. Stationary bicycle riding, walking on even surfaces and water exercises may be appropriate in the beginning. Exercise, in combination with medication, also has been reported to be beneficial in minimizing spasticity. Exercise should be moderate, and never to the point of fatigue.
Pain is not a generally recognized symptom of ALS, but weakness may put excessive stress on joints, causing discomfort. Under these circumstances, anti-inflammatory medication may be of value in alleviating the discomfort. When the pain is due to pressure, especially with prolonged sitting or lying in one position, changes in position and devices such as "egg-crate" mattresses to decrease weight on pressure points may be of help. Cramps may also be severe enough to cause pain and interfere with sleep. Stretching exercises may be of value, but medication may be ultimately required.
Good nutrition is important to everyone. A variety of foods should be selected from the basic four food groups:
Sometimes eating enough of the right foods is not easy. Generally, no change in diet is needed and simply eating a balanced diet to meet the challenge of nourishing the body and maintaining weight is sufficient. However, if swallowing problems occur, changes in the consistency of foods may be required. A dietitian can devise an individual program to provide adequate protein and calories while conforming to an individual's swallowing capability. If a patient has a tendency to feel full sooner than before or becomes tired while eating, then consuming smaller meals along with high protein, high calorie snacks between meals is helpful.
It is important that the diet provide enough nutrients — proteins, fats, carbohydrates, vitamins, and minerals. An adequate, well-balanced diet should provide all of these. Occasionally, loss of appetite and change in swallowing abilities may reduce the intake of needed nutrients. Taking a multivitamin may help stimulate the appetite and provide the nutrients missing in the diet. A vitamin should never be taken instead of eating a balanced diet, but as an additional supplement, and only with the approval of a physician. Vitamin and mineral intake can also be enhanced by drinking fruit and vegetable juices and by eating fresh fruits and whole grain breads either at mealtime or as a nutritious snack.
Periodic checks on the weight will assure that the present diet is providing enough calories to maintain weight. If not, intervention in the form of alternative means of feeding can provide adequate nutrition and relief from swallowing difficulties.
The therapy of respiratory dysfunction in ALS is primarily aimed at general supportive measures. All infections should be promptly treated with antibiotics. If low blood oxygen levels are documented, supplemental oxygen is given. In patients with swallowing difficulties, diets are provided to minimize the chance of aspiration. If oral or pharyngeal secretions become excessive, drugs that decrease saliva production or suction devices to remove secretions may be beneficial. To minimize muscle fatigue that may aggravate diaphragmatic muscle weakness, adequate nutrition must be given, chemical imbalances corrected, breathing exercises maintained, and medication used as needed. In addition, patients may benefit from using non-invasive ventilation with machines directed at opening the lungs and improving oxygen and carbon dioxide exchange. Respiratory status is carefully monitored in ALS patients by a pulmonologist and respiratory therapy team.
Increased saliva may be a source of embarrassment in the ALS patient, and may increase the likelihood of choking spells. The major problem is usually the inability of the patient to swallow saliva. A number of different therapies are available, but most of them have undesirable side effects. The use of a tissue to wipe the saliva from the mouth may provide the simplest solution to this most difficult problem. A suction machine with an oral suction tube is also useful for removal of saliva that cannot be swallowed.
Another social problem is inappropriate crying and laughing — the so-called pseudobulbar affect associated with upper motor neuron dysfunction. It is important to realize that such emotional lability is not an indication of severe depression or a psychological problem. Several medications can help alleviate this frustrating condition.
A major problem that may develop in some ALS patients is slurred speech. If the patient has difficulty communicating verbally, but can still write, a "magic" slate (erasable writing pad) is effective and convenient. There are numerous communication devices available on the market. The decision for alternative communication devices should be carefully considered. Advice should be sought from the speech pathologist and physician with input from the family and patient as to the best means of meeting this challenge. The speech pathologist assists the patient in choosing an alternative communication device.
One of the many ways of providing therapy for the diverse problems of the patient with ALS is through a specialized clinic. ALS patients may benefit from many different health professionals such as a neurologist, pulmonary specialist, occupational therapist, physical therapist, speech pathologist, neuropsychologist, dietitian, nurses, respiratory therapist, social workers and representatives from the Muscular Dystrophy Association. A specialized clinic enables the ALS patient to see all of these professionals in one visit. Most ALS patients draw great support from the milieu of the clinic and find that encounters with other ALS patients are very comforting, and are as important to their psychological well being as their encounters with professionals.
There has been an increased awareness of the role of oxidative stress and free radicals in neurodegenerative diseases. Some cases of familial ALS are linked to mutations in the gene that detoxifies one of the most potent oxidant free radicals, superoxide. Genetically engineered mice with this abnormal gene show the same clinical features observed in the human condition: motor neuron loss and oxidative damage. A recent experiment using this animal model shows that adding vitamin E to their food delays onset of clinical disease and slows progression, but does not prolong survival. It is thought that antioxidants such as vitamin E, vitamin C and beta-carotene may protect nerve cells from damage by toxic free radicals. However, the specific benefits of these compounds have not been tested scientifically in patients with ALS. Side effects should be minimal. High doses of beta-carotene can cause yellowing of the skin, first appearing on the palm and on the soles of feet. This will normally disappear if dosage is reduced or discontinued.
Because of the prognosis associated with ALS, you will more than likely experience a period of emotional change after the diagnosis is first made. Many people find that their goals and priorities change as they learn how their illness affects their accustomed lifestyles and the people around them. Typical concerns include financial matters, altering your daily environment to maximize your personal well-being and independence, and your own and your family's adjustment to your symptoms and prognosis.
Although there is no single "right way" to cope with ALS, certain styles of coping do seem to work effectively. These strategies include learning how to pace yourself, changing priorities, and redefining independence. All three have in common a focus on quality of time and conservation of energy. Being successful usually requires that you learn not only a new way of doing things, but also a new way of thinking about what you do.
Many patients find that an impartial "ear," such as a clergyman or a counselor, helps them to clarify for themselves what they want to accomplish and how to go about it. Support groups, such as those through the Muscular Dystrophy Association, are also available.
Do not demand of yourself a perpetually positive outlook, or require of yourself that nothing about you change. One of the keys to adjustment to ALS is flexibility as it applies to your work, your family and friends, and yourself.
The Muscular Dystrophy Association (MDA), one of the nation’s largest voluntary health agencies, provides comprehensive services for patients with amyotrophic lateral sclerosis. Working hand in hand with those affected by the disease, specialists at the MDA clinics offer services such as:
MDA/ALS Clinical Center
Methodist Neurological Institute
6560 Fannin, Suite 802
Houston, TX 77030
Director: Dr. Stanley H. Appel
While MDA/ALS centers offer highly focused programs of research and medical management directed at combating ALS, the MDA also offers a full program of clinical services for ALS patients at all of its 230 hospital-affiliated clinics across the country, including the opportunity for participation in clinical trials of experimental therapies. Send e-mail to the MDA National Headquarters to locate the clinic in your area.
Go to MDA's home page and access 500 library files with the latest research, resources and other information about neuromuscular diseases; personal networking opportunities; weekly chat sessions; special "Ask the Experts" online researcher/physician conferences; and more on the MDA Forum.