[Editor's note: This article is from 2007. Some newer treatments and current statistics are not included here. See further information on BrainWeb]
sections include: how ALS works, patterns of ALS, treatment and care
In the United States, amyotrophic lateral sclerosis (ALS) is often called Lou Gehrig’s disease, after the renown baseball player who died of the condition in 1936. In France, ALS is called Charcot disease for the physician who first described it. “Motor neuron disease” is yet another name for the condition, because it affects the nerve cells that control movement, as opposed to those involved in sensation.
Whatever its name, the hallmarks of ALS are the degeneration and disappearance of the motor neurons. People affected by the disease gradually lose the ability to control voluntary movements. Almost all the symptoms of ALS are due to the resulting weakness. There are no sensory aberrations: no pain, numbness, or feelings of “pins and needles.” The problems may start with clumsiness of the hands or, if the legs become weak, difficulty walking. Sometimes the muscles used in speech and swallowing are affected, so slurred speech may be another early manifestation. Other common symptoms are twitching muscles or cramps. Involuntary movements are not affected, so there are no problems with the stomach, intestines, or bladder. Sometimes people who are developing ALS, or their family members, fear that they have had a stroke (ischemic, hemorraghic). More often, they are mystified by the symptoms.
Once ALS symptoms start, they become gradually worse and spread from one part of the body to another. The course is progressive, with no evident plateaus or periods of improvement. The disease produces increasingly severe disability. The average life expectancy with ALS after onset of symptoms is three to five years; about 20 percent of patients live more than five years. Progress in research has accelerated in the last decade, improving our hope for developing a cure, but we do not have one yet.
How ALS Works
ALS always affects the lower motor neurons, which send out the nerves that control the skeletal (voluntary) muscles. Motor neurons in the lower part of the brain control the tongue, speech, and swallowing. Lower motor neurons in the spinal cord are also affected, leading to weakness, wasting, and twitching, or “fasciculation,” of muscles in the limbs. The normal function of muscle is dependent on receiving connections from lower motor neurons, and in their absence muscle degenerates.
Additionally, ALS affects neurons in other parts of the brain that control movement. One set lies in the motor cortex: the upper motor neurons, which send fibers down to the lower motor neurons. If these are malfunctioning, a person suffers stiffness and clumsiness of the arms and legs, with overactive tendon jerks. Among the signs that clearly indicate difficulties in the upper motor neurons, doctors find two especially helpful:
- Babinski sign: normally when a doctor strokes the sole of a person’s foot, the big toe moves down. If the big toe goes up instead, that is a sign of malfunctioning upper motor neurons.
- Hoffmann sign: when the doctor flicks the tip of a person’s finger, the muscles normally do not react. If the person’s upper motor neurons are not working properly, that finger quickly flexes.
The clinical diagnosis of ALS is accurate in about 95 percent of all patients. Physicians take a history and do a neurological examination, supplementing that information with findings in the electromyogram (EMG) that confirm the lower motor neuron disorder. Nerve conduction tests exclude diseases of the peripheral nerves that can simulate ALS. Other procedures used include magnetic resonance imaging (MRI), lumbar puncture for examination of the cerebrospinal fluid, tests for antibodies that might attack nerves, and DNA tests if there is a family history of the condition. To diagnose the disease, a doctor must see signs of problems in the lower motor neurons; the diagnosis becomes more certain if, as in most cases, there are also upper motor neuron signs.
All these tests yield clues to ALS, but the diagnosis can be proven only by autopsy. This postmortem procedure can be done so that it does not alter the appearance of the body. It is of vital importance in confirming the diagnosis and also providing tissues crucial for research into what causes the disease and thus what may be effective treatment.
The nerve cells of people who die from ALS show abnormal structures called Bunina bodies. In addition, their muscle cells show accumulations of ubiquitin, a protein that seems to mark each cell for destruction through a process called apoptosis. The more we learn about these structures, the more likely it is that we will be able to intervene and spare the cells from premature death.
We do not know the cause of the nerve cell degeneration in ALS, but several possible abnormalities may lead to the death of motor neurons. Most researchers now favor an explanation called excitotoxicity, whereby accumulations of the amino acid glutamate overstimulate the cells. Other theories blame the formation of free radicals or the excessive accumulation of normal neuronal structures called neurofilaments, which may block the transport of essential nutrients within the nerve cell. Researchers are investigating all of these theories in hopes of finding a way to prevent or treat and reverse ALS.
Patterns of ALS
About 25,000 people have ALS in the United States on any day. This contrasts with 500,000 to 1 million people with Parkinson’s disease, and 4 million with Alzheimer’s disease. But life expectancy is the shortest with ALS.
Most people with ALS suffer no loss of intellectual functions. About 5 percent to 10 percent suffer a particular kind of cognitive loss called frontotemporal dementia; this affects memory and other brain functions needed for normal daily life.
About 95 percent of all cases of ALS are sporadic, meaning that no relatives of the affected person have had the disease. The cause of sporadic ALS is not known. The only clear risk factor is advancing age. There are almost no cases before age 20; 10 percent to 20 percent of people with ALS develop it before 40; and after that age, the frequency increases with each decade. Men are slightly more likely to be affected than women. Some studies have found evidence that occupation, trauma, and rural life are factors in ALS, but this evidence is inconsistent. A form of the disease may be associated with cancers, and viral infections have also been suspected without consistent proof.
The remaining 10 percent of all cases of ALS are familial, usually in the pattern called autosomal dominant. Every child of a person with this type of ALS has a 50 percent chance of developing the disease. In 1993 one form of familial ALS was found to be associated with mutations in the gene for an enzyme called superoxide dismutase. This discovery opened the gates for a flood of research pointing to different mechanisms that could cause ALS in both sporadic and familial forms. We should learn even more about the overall disease when we isolate the causes of other forms of familial and nonfamilial ALS.
Treatment and Care
As ALS advances, the person requires more and more help with daily tasks: walking, sitting up, eating, going to the bathroom. The final stages of the disease are characterized by paralysis of limb muscles, inability to speak or swallow, and finally inability to breathe. The challenge to the ALS care team is to keep the patient comfortable by treating these symptoms as necessary. There are effective ways to help patients who have difficulty communicating, swallowing, or breathing. Throughout the country ALS centers have been formed, bringing together the skills of neurologists, nurse clinicians, physical therapists, respiratory specialists, psychiatrists, clergy, and hospice workers. In most of these centers, a neurologist leads the team. These facilities are the best resource for families facing the multiple challenges of ALS.
Such a grave disease brings nonmedical problems as well. Both patients and their families face the emotional challenges of dealing with the disability and looking ahead to further deterioration. Financial problems arise because a person with ALS cannot work and needs a full-time caregiver, either another member of the family, who must forgo earning money, or a paid professional. Legal questions may complicate the picture. No aspect of family life is spared. The guiding principle of managing the disease is patient autonomy, and medical teams must provide people with ALS and their families with the information they need to make choices. Ultimately the choice is between living as long as possible while depending on a mechanical ventilator, or using a hospice service to be as comfortable as possible without prolonging life.
The Food and Drug Administration has approved only one drug for the treatment of ALS: riluzole (Rilutek). It works against glutamate, the natural amino acid that plays a normal role in the excitatory functions of motor neurons and is thought to accumulate in ALS. Riluzole is believed to extend the life of a person with ALS by an average of three to six months, but there is no visible effect—there is no improvement either in symptoms or quality of life. Frustrated by this limited benefit, researchers are running trials of many new drugs, hoping to find a more effective treatment. Many patients are drawn to participating in these experiments in the hope that they’ll be among the first ALS sufferers to be cured, or that their experiences will help others. People with ALS are also often lured to alternative medicine; many take vitamin E or selenium, for instance. Unfortunately, these therapies have not been shown to be helpful.
The prospect for discovering better treatments for ALS in the coming decades is excellent. In what was once a totally neglected field, neuroscientists are now actively engaged in several lines of work that could lead to therapies. It is worth remembering that doctors once perceived pernicious anemia and its neurological form, combined system degeneration, as inescapably fatal. Once researchers determined that this disease was caused by a deficiency of vitamin B12, the entire picture changed. Now we can measure vitamin B12 in the blood and readily correct low levels with injections. That severe disease has virtually disappeared. ALS may not turn out to have such a simple cause, but with hard work and a little luck we will surely find effective solutions. We are confident that ALS will prove to be a treatable disease.
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