Pathologic Classification Systems in MS: What is their Significance?

Despite extensive clinical and experimental investigations on the genetics, immunology, imaging and clinical investigations of the disease, fundamental questions still remain over the etiopathogenesis of multiple sclerosis. There are many reasons for attempting pathological classifications of multiple sclerosis. First is the need to try to predict and control clinical behavior in patients by trying to determine cases that are similar or different in order to differentiate etiopathogenic comparisons one from the other. In the absence of a definitive etiology, much has to be inferred from the study of the extensive body of experimental literature which has produced similar conditions in laboratory situations. This approach has both practical and conceptual limitations, but does yield some information as to what could be happening in multiple sclerosis. Secondly, modern diagnostic imaging techniques have transformed both the clinical management of MS (9), and the potential to carry these etiopathogenic inferences to a new level. The revival of the suggestion that MS is not a single homogeneous process has led to an attempt to develop a classification of type and stage, which will be recognizable by noninvasive imaging techniques, and will enable tailoring therapy to the individual patient. Classifications and staging systems also depend on delineating the state of progression of the disease. Classically the disease has been delineated into acute, sub-acute (acute on chronic) or chronic (10), but it is important to recognize that the definitions which govern the designation of each of these stages may vary. In this regard experimental evidence as to the progression of similar inflammatory diseases has been extremely useful (10). Recent work from the laboratory of Prineas and Barnett have raised the suggestion that the progression of the disease may not show classical inflammatory parameters early. This has led not only to questions as to etiopathogenesis, but as to the ability to stage lesions. Nonetheless, MS is a disease with common neuropathological processes including edema, inflammation, axonal damage, demyelination, remyelination and gliosis. Each of these plays a role in both the development and the resolution of the lesions, and each will have a role in determining the clinical and radiological presentation. It becomes critical to incorporate these elements in any common classification. Although most classifications of the disease has traditionally relied on determining the temporal nature of the process, with the report by Luchinetti et al. (6,7), an attempt was made to determine the pathogenetic basis for the disease by examining the various components of lesions seen at surgical biopsy and relating them to experimental processes. While this approach has not been uniformly used, and may not be operant in all cases, an enormous amount of information has been generated (8), and has led to the delineation of various forms, with suggestions as to etiopathogenesis. One of these includes the suggestion that many of the changes are related to local changes in tissue blood flow. This idea has been picked up by Prineas and Barnett in their recent study of what they postulate is the earlier stage of inflammation where the predominant lesion appears to be ischemic rather than inflammatory (1). Most of the current classifications and staging systems have not incorporated two very important features of the disease that are increasingly recognized to have enormous clinical and diagnostic significance. The first of these is the status of a normal appearing white matter (NAWM), which is increasingly found to play a significant role both clinically, and also potentially in the development of new lesions. The second is the realization that many of the clinical and prognostic parameters of MS depend on the degree and severity of axonal (2,4,5), as well as cortical (3) pathology. Both these features need to be incorporated into common classifications and staging systems. Reliance on older concepts that cover only demyelination, remyelination and inflammation, exclude the utility of this most important aspect of the disease. At the moment however, pathological classification, with attendant in vivo diagnostic imaging, remains of PATHOLOGIC CLASSIFICATION SYSTEMS IN MS: WHAT IS THEIR SIGNIFICANCE?