ABSTRACT

At this time, Amyotrophic Lateral Sclerosis(ALS) is a very confusing and elusive disorder. While the clinical presentation and diagnosis of ALS dates back to the early 1900’s, with Charcot being the first to scientifically report and document his findings, there simply has not been definitive evidence since that time for the etiology for ALS. This fundamental problem has befuddled the most qualified researchers and its ensuing answer has eluded the most clever experiments for some 80 years.

This paper is being written to address some of the most plausible candidate causes which have come to the forefront of ALS research in the last few years. This paper will also try to tackle the formidable task of possibly uniting some of the findings and results of experiments from all over the world in the last 4 years. While an exact, definitive etiology, treatment, or answer is not possible at this time, there does seem to be a few underlying trends and findings that have reinforced their own importance. These are the findings that will be evaluated and will hopefully act as a genesis for, perhaps a premature, minimally complete conclusion of the available pool of knowledge that has been amassed on ALS. In addition to this, possible treatment, including pharmacological intervention, will be reviewed.

INTRODUCTION

ALS is a disease of the skeletal muscular motor neurons throughout the nervous system that usually affects both upper and lower motor neurons. The progressive wasting and weakness of muscles that have lost their nerve supply is a characteristic sign of lower motor neuron damage; signs of spasticity and exaggerated reflexes are indications of damage to the upper motor neurons. Most of the time, ALS occurs sporadically (85%), with estimates ranging from 5-15% for the familial. The average age of onset is roughly 60. Even so, much more attention is giving to younger, healthy individuals who succumb to the disease.

The typical history usually involves early recognition of an onset of clumsiness in the hands and fingers, with a weakness in the legs soon to follow. There is also bulbar involvement that usually manifests in problems with speech and swallowing. This bulbar involvement is interesting in that it may be cytologically distinct from the corticospinal manifestation. The degenerative process itself is unforgivingly progressive, except for a few permanent plateaus, and for all reasonable assessments, will yield a fatal outcome. Even so, it should be noted that patients most often do not die from ALS, but from secondary causes such as infection and pneumonia.

When considering ALS, the relevant question is not what has been proposed as the causative agent, but what has not been proposed. Over the years, there has been a myriad of theories concerning the etiology of ALS, some with a valid premise and decent evidence, and others being way off the mark. Some of the theories that have been advanced include viruses, actions of specific neurotoxins or heavy metals, failure of DNA repair mechanisms, altered axonal transport, or some type of unusual autoimmune disease. With a significant volume of scientific literature being devoted to ALS ‘progress’ each year, it becomes painfully obvious how confusing it is to extract one or two well warranted theories from all that is available. Inevitably, it comes down to which experiments provide the best means by which to infer from, how relevant individual experiments and conclusions actually are concerning ALS, and which author(s) the reader believes to be most competent. With these fail-safes in mind, the body of this paper will examine the theory of a faulty glutamate transporter as a causative agent for ALS. This view, which seems to be the most agreed upon view as of late, will be contrasted with the possibility that ALS is the aftermath of some unusual autoimmune disorder.

BODY

The glutamate theory holds that glutamate, the primary excitatory neurotransmitter in the brain, can exert specific neurotoxic effects to motor neurons after prolonged exposure, and/or an exposure to relatively high levels of extracellular glutamate, and perhaps, aspartate. Supporting this hypothesis, are the recent findings of increased cerebral spinal fluid concentrations of glutamate and aspartate. Physiologically, the primary mechanism for the inactivation of glutamate is simply its removal from the extracellular space via a sodium-dependent transport system in astrocytes and neurons. This system has high and low affinity carriers, with the low affinity carriers being generally responsible for normal metabolic activities. The high affinity carrier is responsible for the clearance of glutamate from the synaptic cleft. The crux of the theory lies with this point, that the glutamate transport system, for some unknown reason, becomes nonfunctional with a concomitant rise in the extracellular, pathogenic glutamate concentration. Exactly how increased levels of glutamate actually cause or induce a pathological environment for nerve cells, has not been demonstrated. The most likely method of glutamate excitotoxicity is probably its ability to short--circuit or disable cellular second messenger systems(cAMP, phosphotidylinositol, xanthanine oxidase, and calcium and/or sodium channels).

In support of this hypothesis, and along with many other backing experiments, are the results of a unique, and expertly planned experiment set up by Rothstein and his colleagues. They developed a model that would demonstrate the effects of slow, long term neurologic exposure to elevated glutamate levels. All previous experiments along these same lines always addressed the effects of glutamate from a rapid, large dose exposure type experiment. Thus, this experiment that cultured organotypic spinal cord slices, gave unique insight to the effects of long-term exposure to elevated glutamate levels. This experiment was set up to chronically block the glutamate carrier, and thus, cause the extracellular levels of glutamate to slowly rise. What Rothstein found, was that neuronal toxicity was selectively prevented by non--N-methyl-D-aspartate(NMDA) glutamate receptor antagonists and glutamate synthesis or release inhibitors, but not by NMDA receptor antagonists. Thus, the selective inhibition of glutamate transport yields a model of clinically relevant slow neurotoxicity via non--NMDA receptors. It should be noted, that although these findings seem remarkably significant, it has not been demonstrated how non--NMDA antagonists produce their effect at the post-synaptic level, or how release inhibitors actually exert their inhibition pre-synaptically. Actually, there is evidence that the non-NMDA antagonists do not competitively interact with glutamate receptors post-synaptically and exert their blocking effect in an unknown way.

Recently, it has been proposed that drugs that have glutamatergic effects should be considered for possible treatment of ALS. Next to the side-chain amino acids, Riluzole (RP 54274) has gained the most attention for its glutamatergic effects. It is not completely known how Riluzole works. Two possibilities are that it may inhibit acetylcholine dependent sodium channels, or block the formation of the cyclic GMP that is evoked via glutamic acid. In any event, Riluzole has been shown to significantly effect the rates of survival and muscular deterioration in patients in a randomized, double-blind clinical trial. In an unknown way, Riluzole pre-synaptically inhibits the release of glutamate and interferes post-synaptically with the effects of excitatory amino acids(and by another study, specifically glutamate). Once again, this is not a direct effect of competition, but more likely an indirect influence over a voltage-dependent sodium channel or a G--protein.

Autoimmunity has long been proposed as an etiologic agent for ALS, yet, in the last decade, has lost favor with the scientific community. This loss of interest is due mainly to one unexplainable paradox. If autoimmunity is at play with the pathogenesis of ALS, why then is there not swelling and inflammation? And, why don’t patients respond to immunosuppressive therapy? Because of lack of evidence for the basis for these two anomalies, most of the ALS researchers have lost interest. Even so, there are two aspects in particular of the autoimmune theory that must be addressed.

Monoclonal paraproteinemia seems to be disproportionately frequent with ALS patients, and there is also an increase in frequency of antibodies to the neuronal ganglioside, GM-1. How these results should be interpreted is unclear. But, it has been proposed that these antibodies may be able to pierce the blood-brain barrier at the motor-nerve terminal where it is weak. From here, the antibodies could travel retrograde to the cell body and cause dysfunction. Actually, this hypothesis may be the naive proposal of the long-standing retroviral manifestation. A persistent viral infection may be the cause of the apparent autoimmune action. In light of this, Smith and his Baylor team reported antibodies to muscle long type calcium channels in 38 of 48 patients.

The proponents of the autoimmune hypothesis realize that there are some unexplainable problems with the theory. If the antibodies attack calcium channels, there should be a deficit with muscular calcium channels. This is a problem because ALS is restricted to motor neurons and spares muscles. And on a larger scale, if antibodies are indicated, why are only motor neurons affected? Finally, it is possible that the antibody involvement, when present, is simply in response to the defects of the neuron caused by a different mechanism.

PROBLEMS

There are many problems associated with the varying theories of ALS. First of all, if there is an autoimmune component; why doesn’t it conform to the confines of normal autoimmune symptoms and pathogenesis? Secondly, why would an antibody response, that presumably is coming from a common genesis, affect only a very selective few cells? This is also the most outstanding problem with the glutamate excitotoxicity hypothesis. There is no logical reason why the glutamate toxicity is confined to only upper and lower motor neurons. Glutamate is all but ubiquitous in the CNS, so why the specificity? An aside as a possible explanation for this specificity would be that there are different subgroups of glutamate receptors. This idea, that is all it is, may have some truth due to the fact that Riluzole treatment seems to be much more effective when given to patients with bulbar onset ALS, whereas treatment of patients with limb onset was not as significant. Finally, there is the problem of the chicken or the egg. Simply, does the excitotoxicity create a situation that would lead to an antibody response, or does the immune response somehow disable the glutamate transporter and create the neurotoxicity. The literature is convincing for both arguments. There is also the problem of heavy metal poisoning. The Chamorro’s of Guam give convincing evidence for some environmental, presumably heavy metal, etiology.

CONCLUSION

It is obvious at this time that the etiology of ALS is not definitively substantiated. There are many theories, each with merit and results that do seem genuine and significant, but there is no hard-fast proof for any of them. Recently, the glutamate excitotoxicity theory has gained wide acceptance, as well it should, but the cause for this abnormality is totally unknown. Even if the glutamate theory is indeed correct, is there a efficient way to diagnose and prevent degeneration with pharmacological intervention. As new drugs show promise, the hopes of a complete cure in the near future does not look forthcoming.

In any event, more and more is being learned about ALS, and many of the other neurological degenerative diseases, every day. With new techniques, increasing sensitivity of the instruments and some thoughtful insight, ALS may someday be a mere ‘curable’ disease. For the time being though, the outlook for ALS has been best summed up by the statement, "It is obviously difficult to put all of this together in a coherent theory."

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