Multiple Sklerose: Grundlagen und Hypothesen der modernen Ursachenforschung

Summary

The majority of investigators considers an exogenous, probably infectious agent as the cause of multiple sclerosis (MS). There is also widespread agreement, however, that it must be an agent with unusual properties, and that a particular immunological reaction is prerequisite for the manifestation of the disease. The key words of this concept are “slow virus infection” and “auto-immunity”.

The development leading to the socalled neuroallergic theory and its basic aspects are summarized.

The chemical analysis of myelin composition under normal and pathological conditions has yielded divergent results, partly due to the lack of adequate correlation of biochemical data and histopathology. Further confirmation of findings, that areas of white matter not affected by the demyelinating process have altered myelin composition, would be pathologically significant as a indication, that an (acquired ?) pathochemical situation precedes the morphological features of MS.

The delayed sensitivity reaction found in EAE, with an antigen-antibody response in regional lymph nodes, evolved the concept, that a cell-bound reaction is also important in MS. The role of sensitized lymphocytes as mediators of this reaction was recognized only later, however. For some time research was focussed on the chemical composition of brain/spinal cord tissue and adjuvants, and the attempt to establish the chemical nature of the decisive pathogenic substance in EAE. The work on the encephalitogenic protein evolving from this approach is briefly reviewed. In relation to this, the necessity of more detailed studies on the nature of white matter, especially the myelin proteins in normal and pathological tissue of human origin, is pointed out.

The passive transfer of EAE by lymphocytes, electron microscopic studies on the morphology involved, differences in resistance of various animal species established the importance of cellular reactions in EAE. On the other hand, the role of humoral antibodies, found in similar patterns in EAE and in MS, as well as the possibility of protective antibodies, require closer study. The two main lines of investigation in this area are the cytotoxic factor in serum and cerebrospinal fluid and the elevated content of immunoglobulins, especially of the IgG group, in cerebrospinal fluid and brain/spinal cord tissue. In this connection the role of complement has also been studied. In the discussion of the results and the significance of investigations on these problems, the work on immunoglobulins is given more detailed consideration. Reference is made to the methodic possibilities of morphological and chemical studies of the immunoglobulins in brain and spinal cord tissue.

The progress in virological techniques and the advent of systematic epidemiological investigations reactivated the search for an exogenic, possibly infectious agent as the cause of MS. An important step in this direction was also the finding, that myelin lamellae are spirally arranged membranes derived from oligodendrocytes in the white matter of central nervous system, and thus components of cells which may be the site of virus infection.

In addition to the relation of MS-prevalence to climate, bourne out by earlier studies, epidemiological research on MS received an important new impetus from investigations on population groups transferred from areas of high MS-frequency to regions in which MS was a rare disease. Studies in South Africa and especially in Israel have shown, that differences are significant only in the immigrant generation, and that MS occurs less frequently in groups with a low standard of hygiene. These observations point to an exogenic factor. The majority of the newer epidemiological studies appear to converge on the concept of a childhood infection followed by a clinical latency period before manifestation of the demyelinating disease. Here the slow virus concept is introduced as a central hypothesis for the etiology and pathogenesis of MS, and the necessity of particular virological studies becomes evident. Kuru, the Icelandic slow virus infections and especially scrapie are receiving intensive study. The epidemiological and virological investigations bearing on these problems are reviewed. Another concept based on slow virus action and clinically light or inapperent childhood infection as the essential prerequisite for MS later in life deals with myxoviruses, especially measles. This work is alo summarized. Strong encouragement was given to the myxovirus hypothesis by the discovery, that subacute slerosing panencephalitis (SSPE) is a slow virus infection caused by the measles virus. A lot of work has been done and is under way on measles and MS; in none of the cases of MS have titre elevations been found even distantly approaching those seen in SSPE, however, and the transfer of MS to primates or other animals has thus far been unsuccessful. The question is thus still open, whether the weak elevations of myxovirus titres found in MS are pathogenetically related phenomena or non-related booster effects.

The study of these virological problems calls for a third type of epidemiological investigation: the intensive systematic and prospective survey of small areas with high MS- incidence and -prevalence. Results of investigations of this kind, which thus far have been based chiefly on retrospective data, are cited.

A number of publications exist on ultrastructural morphology. For valid conclusions bioptic studies are necessary. Obviously, the difficult decision to perform biopsy in the human limits the availability of such material. In MS, stereotactic operation in cases with severe ataxia represents a legitimate indication for biopsy. Reference is made to the development of microbioptic procedures for this purpose.

The orientation of research towards an exogenic cause of MS has not invalidated the autoimmune hypothesis for this disease. The probability, that a special immunological situation, perhaps in connection with the action of unspecific stress factors, is prerequisite for the clinical manifestation of MS. makes immunology an important line of future research.

A discussion of present therapeutic approaches, based predominantly on the idea of immunosuppressive action, is included in this survey, with particular reference to initial results with antilymphocytic globulin.

Therapy of diseases such as MS, in which etiology and pathogenesis are still unclear, generally — and often prematurely — reflects the dominant trends of basic and clinical research. Present therapy obviously is a child of the neuroallergic or autoimmunological era of MS-research. A more effective treatment of MS will hardly be possible before empiric schemes and procedures relying on hypotheses are replaced by methods based on well-founded knowledge concerning the cause of the disease. To achieve this end, not only greater facilities for research on MS, but also a more detailed exchange of information and comparable methods of documentation are important. In conclusion, the important contributions, which lay organizations have made to activate and promote research on the cause of MS, are acknowledged.