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SPECIFIC MEDICAL THERAPY
No known treatment stops or improves the symptoms of ALS or halts the progression of the classic disease. Recent studies have suggested that some agents may slow the progression of the illness, but this is based on statistical analyses of populations using an agent and comparing them with a placebo-treated population. Nevertheless, for the first time in our study of this illness, there are drugs that have a rational basis for use in this disease and have shown evidence that they do indeed affect the course of the illness. To understand the rationale of the use of these agents, we should review essential aspects of current theories ofpathogenesis.
Excitotoxieity Theory and Glutamate Receptor Blockers
The excitotoxicity theory has been reviewed extensively elsewhere (16). Glutamate is an excitotoxic amino acid that when present in the extracellular fluid is potentially toxic to nerve cells. It is increased in the cerebrospinal fluid of patients with ALS (17). Such patients may have a defect in the ability to efficiently clear glutamate released into the extracellular space (18). The use of medications to block receptors for glutamate may interfere with its neurotoxicity. Rilutek (or riluzole) is the only approved medication for the treatment of patients with ALS. It blocks the toxic effect of glutamate in many animal models and has been shown to be effective in two clinical trials in ALS patients. One trial demonstrated an improved survival in patients with bulbar-onset disease but not limb-onset (19). A second trial showed significantly prolonged survival, but its effect was unexplained because there was no significant change in strength, respiratory function, or bulbar function in these patients compared with placebo. The most effective dose was 50 mg by mouth twice daily (20). Gabapentin (Neurontin) is also known to have antiglutamate effects. A recent double-blind placebo-controlled study showed that 2,400 mg of neurontin showed a trend but not statistically significant effect on the rate of deterioration. The drug is usually well tolerated, and a larger study is planned (21).
Neurotrophic Factor Deficiency
Another hypothesis is that patients with ALS have a deficiency of one or more nerve growth factors or neurotrophins critical for neuronal functioning. There are many different types ofneurotrophins that support a wide array of function and cell types. These include motor neurons, muscle, sensory neurons, or sympathetic neurons. Adding nerve growth factor to nerve cultures dramatically promotes neuronal survival. In the chick embryo, NCF promotes survival of motor neurons and impedes normal programmed cell death during development by excessive amounts. When nerves are transected, adding nerve growth factors will enhance the rate of regrowth.
There have been several clinical trials of neurotrophic factors, and many are still ongoing. Ciliary neurotrophic factor was found to be ineffective in a large-scale trial (22). Higher doses proved to be too toxic to complete another study. Brain-derived nerve growth factor showed no clinical effect in a large multicenter, double-blind, placebo-controlled trial. Insulin-like growth factor type 1 (IGF-1) has shown conflicting results. One study showed a statistically significant change in the rate of progression in patients receiving high-dose IGF-1 (23), measured by the Appel ALS score (8), and a statistically significant slowing of progression of bulbar and limb weakness was also demonstrated. IGF-1 improved quality of life, but paradoxically, the improvement was not statistically significant in the motor portion of this analysis. A second trial in Europe using IGF-1 showed no effect (24). There was, however, a trend toward slowing in the treated group. An ipso facto survival analysis showed that IGF-1 promoted survival in patients taking this drug. Food and Drug Administration approval of this drug is pending at the time of this manuscript preparation.
Antioxidant Therapy
Because of recent evidence of impaired oxidative processes in FALS, attempts to treat patients with agents that interfere with oxidative processes have been of interest. Most investigators promote the use of high-dose vitamins known for their antioxidative properties, especially vitamin E (2,000 U/day), vitamin C (2,000 mg/day), and beta-carotene (25,000 U/day). Selegiline (Eldepryl) has been found to be ineffective as has W-acetyl cysteine (25-27).
Autoimmunity
There is circumstantial evidence to implicate a role for autoimmune processes in ALS. The apparently excessive prevalence of lymphoma and paraproteinemia in patients with ALS suggests an association. One group has reported lymphocytes and activated macrophages in ALS spinal cord and the presence of IgG within ALS motor neurons. IgG from patients with ALS interact with L-type calcium channels and promote entry of calcium into the cell (28). Increased intracellular calcium may overwhelm the intracellular control systems for oxidative processes and contribute to the process of cellular destruction. However, several therapeutic trials have used immunosuppressant agents, including cyclophosphamide, intravenous immunoglobulin, prednisone, cyclosporin, and total body irradiation. None have proven effective. Calcium channel blockers have also proven to be ineffective (29).
Future advances will continue to make symptomatic care better in ALS and give hope that an understanding of what causes this disease is near, clearing the way for an effective therapy that does not slow progression but stops or reverses the process (30).
REFERENCES
An extensive reference list can be found in Motor Disorders, edited by David S. Younger, MD, Lippincott Williams & Wilkins, 1999, pg. 367.
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