Causes of ALS Remain Mysterious

New York Yankee Lou Gehrig was known as "the Iron Horse of Baseball" for his legendary home run power and durability.

But despite his extraordinary strength, he succumbed in 1941 to a still mysterious and deadly disease. The condition is now commonly called "Lou Gehrig's Disease" and technically known as Amyotrophic Lateral Sclerosis.

Despite major advances in understanding how ALS affects the body, "The precise cause or causes of ALS at this time remain unknown," says Paul Barkhaus, MD, Medical College of Wisconsin Professor of Neurology and Director of Neuromuscular Diseases at the Milwaukee Veterans Administration Medical Center. Dr. Barkhaus also serves as the Director of the Froedtert & The Medical College of Wisconsin ALS Clinic. The Clinic recently became the only program in the state recognized by the ALS Association as a designated ALS clinic.

An Attack on Motor Neurons
What remains clear, though, is that ALS causes the death of the motor nerve cells that transmit messages from the brain to the muscles, and is ultimately fatal. The disease progressively weakens the patient and shuts down the nervous system's messages to more and more muscles, particularly those controlling breathing.

The body has two sets of motor nerve cells, explains Dr. Barkhaus. The upper motor nerve cells are located over the frontal the part of the brain and regulate tone and modulation of muscle movements of the lower motor neurons. The lower motor neurons travel from the brain stem at the base of the brain throughout the spinal cord, reaching down to the lower back and controlling movements of the tongue, face, voicebox, lungs, arms, and legs.

In amyotrophic lateral sclerosis, the tracts that carry the upper motor neuron impulses to the lower motor neurons degenerate and eventually "sclerose," or harden. The fibers that normally would carry brain signals become replaced by tissues that fail to conduct the brain's messages.

While a variety of causative mechanisms are being explored, one contributing mechanism in ALS is thought to be "excitotoxicity," or an excess of chemical stimulation from the neurotransmitter glutamate, which is released from cells surrounding the motor neurons. The excess of glutamate is thought to hasten the degeneration of the motor neuron cells.

A set of largely undetectable changes usually takes place before a patient notices a decline in strength. "There's an attrition factor with the weakening of motor neurons," says Dr. Barkhaus. "You can lose about 1/3 of your lower motor neurons in a slowly progressive process before you notice it because of the body's compensatory mechanism of reinnervation of muscle cells by other surviving lower motor neurons."

ALS Symptoms Vary
ALS symptoms vary widely between individuals. "The particular symptoms of ALS depend on the specific levels or regions (brainstem, cervical, thoracic, and lumbosacral) of the motor nerve cells that it attacks first," he states. "It may affect the legs before the arms or vice versa and may be symmetric in weakness or asymmetric. In some individuals it may begin in the extremities, while in others, particularly older adults, it may first affect the muscles that control speech and swallowing."

If ALS first attacks the upper motor neurons, "The signs are more subtle and harder to pick up on symptomatically," Dr, Barkhaus observes. Such signs might include abnormal tendon reflexes, increased muscle tone, and sometimes exaggerated or inappropriate emotional responses that are totally beyond the control of the ALS victims. If the lower motor neurons are involved, there are more obvious symptoms in terms of muscle twitching, decrease in muscle bulk, and significant weakness.

Other Causes Must Be Ruled Out
Dr. Barkhaus emphatically cautions against self-diagnosing ALS based on symptoms like involuntary muscle twitching, which often occur in otherwise normal people. "Generalized symptoms may include reduced tolerance to exertion or exercise, muscle cramping, or twitching and rapid onset of fatigue when performing ordinary tasks.

ALS can only be properly diagnosed as after thorough clinical evaluation and testing, says Dr. Barkhaus. "There are a number of potential symptoms that may herald the onset of the disease, depending on the part of the body that is affected first," he notes.

"If the lower extremities are affected first, then problems with walking and balance may be the initial problems. In the instance of the upper extremities, symptoms might include reduced dexterity or weakness in the hands. If the disease begins in the muscles of the head and neck, then problems such as difficulties with speech or eating may be initial complaints. Rarely does ALS begin with problems in the respiratory muscles."

A variety of other, less serious conditions can explain many of the symptoms people might attribute to ALS. "The testing used to diagnose ALS is essentially a strategy of excluding other conditions," says Dr. Barkhaus. "If ALS is under consideration, then it is important for the patient to be seen at a center that is experienced with this disease." Such centers apply strict criteria - established by the World Federation of Neurology Research Group on ensure high consistency and accuracy in the diagnosis of ALS.

"Since there are no laboratory tests specific to unequivocally diagnose this disease, the diagnosis remains clinical, with a laboratory support, mainly from a procedure known as an EMG (electromyogram)", says Dr. Barkhaus. However, even the EMG may not be totally conclusive in isolation from other testing. EMGs can show changes in the electrical signals generated by a muscle.

Also, blood tests are typically performed to rule out other causes of similar symptoms that may mimic ALS. "Since ALS is a progressive, life-limiting illness, it is very important to be as accurate as possible in the diagnosis, given the impact it has on patients and their families," says Dr. Barkhaus.

Hope in Research
The long-term prognosis for an ALS victim still points to continued deterioration and eventual death over a period of years, but widespread advances in research offer hope for the future.

"Currently a lot of work is being devoted to stem cell research," Dr. Barkhaus says. "I know that the issue of stem cell research is lightning-charged with emotion and politics," he acknowledges. But he views such work, with appropriate institutional and ethical regulation, as a potentially life-giving field of research. "Stem cells have the potential for developing into anything with the right stimulus and environment, including motor neurons."

In addition, the development of new medications might allow patients to function at a higher level than they would without the drugs.

Studies have also shown that working with a multi-disciplinary clinic increases quality of life. "With a multi-disciplinary approach, the patient benefits from the teamwork of collaborative management," says Dr. Barkhaus. In the Froedtert & The Medical College of Wisconsin ALS Clinic, "We help patients to make the best of their lives for as long as possible."

Patients Direct Care
"I like to emphasize to the patients and their families that the patient is the 'captain of the team' and that we are essentially coaches who are attempting to provide the best advice possible in handling problems as they arise," says Dr. Barkhaus. "Management of this disease is a process that will evolve over time, and strategies will change as the disease progresses."

Family involvement in coping with ALS is crucial. "It is important to involve family, as the disease has a significant impact on individual's family, particularly those directly involved with care-giving," says Dr. Barkhaus. "This can be an important source of stress for both the patient and care-givers within families and might need to be monitored and managed."

The local Wisconsin Chapter of the ALS Association provides additional help, not only in raising money for research, but also in providing loans for medical equipment and other activities such as support groups for the patients and their caregivers.

The Wisconsin Chapter of the ALS Association is a major sponsor of the ALS Clinic Program at Froedtert Hospital. The Association also sponsors annual symposia for patients and families and contributes educational materials to the Medical College of Wisconsin Medical Library.

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.