(1) MS is an autoimmune disease of cerebral tissues, in which the myelin sheath of Oligocendrocytes [OLI] are attacked by T-lymphocytes reacting to mimicry (assumed allergy) (+). (2) The disease is characterized by destructive and repairing phases (+); (3) however, other than commonly perceived, both of these processes are occurring during the whole phase of the disease, during a long phase before clinical symptoms of the disease becomes evident (?) and (4) even in an unknown number of patients in whom the condition is never diagnosed (and therefore, from a philosophical point of view cannot be understood as a disease) (?). (5) These processes take place at a rather diffuse basis and clinical symptoms, therefore, represent merely the visible tip of the iceberg above the sealevel (?). (6) Disruption of the blood-brain barrier [BBB] is not only a consequence of MS (+); it first enables lymphocytes to cross to an area where they are normally absent and get in contact to myelin and its degradation products myelobasic protein [MBP] and myelo-oligodentric glycoprotein [MOG], possibly among other substances to be considered "foreign" (?). (7) This is a self-amplifying process: the more BBB-defects, the more exposure and the more autoimmune response, including not only myelin damage but also further BBB disruption (?). (8) On the other hand, important repair mechanisms are also active, and their level of activity decided by both endogenous and exogenous factors (+). (9) Local destruction is in itself a triggering factor for repair mechanisms (?). Not neglecting the necessity for models of the processes active in MS, these are for non-specialists uncomprehensive and also - for necessary simplification purposes - reflects the process studied by their creators. Having difficulty in surveying the various cellular and humoral factors, I have started to characterize these ironically as "good" or "bad." (link to MS_MODEL following later).
(10) There is no single and simplified treatment of MS but, to a certain degree, some factors (elements) may be influenced in various direction, at best producing a resting phase, at worst the condition which caused you to look into this page. (11) Both the destructive and repairing processes can be regarded physiological processes. It is almost (with a few exceptions, e.g., the beta-interferons [IFB]) impossible to direct therapy only to the most diseased areas (+). An attempt to ameliorate the first and/or augment the second of these processes can, therefore, be expected to a varity of adverse effects (?). (12) It might be possible, however, that a brief process can modify events before it is overshadowed by adverse effects; this can be assumed for the short therapy (3-4 weeks) with glucocorticoids (+), and (13) it remains to my understanding a tempting dosage schedule for the therapy of matrix metalloproteinase inhibitors [MMP-I] (?), in addition to what is already achieved with IFBs (+). (14) The MMP-I's may then act more importantly in reducing the allergenic provocation (in closing the BBB) than their repairing properties for stimulation of remyelinization (?), but adverse effects are explained by MMPs physiological role.
It should at latest yet be clear that I, in posing this
hypothesis, feel free from any obligation to document my claims with studies
(although they are, in fact, based on such). Worse, any hypothesis is also
a bias, colouring the perception of all further reading, in part with the
effect of understanding confirmation of the hypothesis by selection of
confirmative studies. With the vaste amount of literature available, incomprehensive
to any survey, I have decided to take this risk and hope not to forget
about it.
Therapeutic aspects deduced from the hypothesis:
Quite a number of aspects could be considered according to this hypothesis:
Blood-brain barrier defects may be one goal in the therapy. However, it is hardly possible to separate this target from other immunological impacts of the suggested therapeutics. On the other hand, there seems to be a smaller basis for reducing the damage done by means of antioxidant therapy (which is easily accessible and therefore widely used). Fortunately, any adverse effects of such therapy are largely and only mildly economical.
Both a reduction of negative exogenous factors and the addition of positive exogenous factors seems possible, reviewed separately in Environmental Exposure. Among the available options, this one must range very high.
Control of the most active phases (with glucocorticoids or MMP-I) can be assumed to diminish progression in the long run, even though this is not the opinion expressed in studies about pulsation therapy with glucocorticoids. Similarly, immunosuppressive or immunomodulating agents have been shown to enhance the disease activity (without actually stopping it).
A stimulation of remyelinization is what all MS-patients hopes for. It is easier to imagine that a physiologically occurring process may be further promoted than it is to believe in the creation of a new therapeutic concept. Local destruction is in itself a triggering factor for repair mechanisms, making it an option to simulate such a destruction without actually imposing it. Substances and means for remyelinization has been studied and reviewed repeatedly. They are currently not reviewed here because I haven't got the feeling that any of the many stimulating hormones or humoral substances have gone beyond the testing phase (please protest if reasonable); moreover, nearly anything else that (perhaps) works, is claimed to do so partly by means of remyelinization.
It is intriguing to search for therapeutic attitudes from other autoimmune diseases also characterized by destructive and repairing phases. Both of these processes are occurring during the whole phase of the disease on a rather diffuse basis.
Reduction of causative agents (e.g., microorganisms) is only possible if such remains as causative agents, which is controversial and may stay that way while it could be true for some and not for all - and studies consider only all or none.
Reduction of stress may be very effective and is indeed suggested for the acutely diseased patient. Even if current study methodology do not support such an attitude (while stress is impossible to measure and the concept does not fit into current study models), it may indeed be the most valuable therapy of those currently available. However, expressing the wish is not enough. The looming disease progression as well as economical and sociological aspects are brought into the mind of the patient along with the MS diagnosis. For that reason, any belief in a method is in itself working for the therapy selected and should not be contradicted by medical recognitions ("if it makes you happy, you should do it!").
Another therapeutic aspect is to reduce the contact to myelin and its degradation products MBP and MOG (and others?). This is attempted in the inducement of toleration ("vaccination"). However, the attempt may fire back and give rise to an even more violent response, leaving an uncomfortable uncertainty as to whether the parient may profit or actually be damaged by the attempt. It is highly likely that an unspecific immunological "irritation" bears the basis for many therapies, in particular those which are effective in so mild disease that a therapy might be challenged.
Unfortunately, it is almost impossible to direct therapy only to the most diseased areas. This is bound to influence the adverse effects in as far as therapeutic effects are directed towards physiological processes. However, some factors, both transplanted cells and growth factors, seem to exert their effect only in damaged areas, but these attempts are probably not yet ripe for human use. Also the duration of "pulsation-therapy" which has been defined to 4 weeks or less with glucocorticoids will hardly be any longer once MMP-I are utilized, provided these are not specifically active towards disease processes.
A number of therapeutical issues are not supported in this model, but that may be due to my difficulties in understanding them, rather than their inactivity. Predominantly, these relate to cellular factors and other dramatic therapeutic aspects which can only be considered when the risk of their use is balanced with their potential benefits (plasmapheresis, bone marrow transplant, injection of stem cells).
Revised September 11, 2001