Multiple Sclerosis: A New Hypothesis

MULTIPLE SCLEROSIS: A NEW HYPOTHESIS HUBERT S. MICKEL* Introduction "Despite a continuing advance in knowledge concerning many aspects of multiple sclerosis and the existence of several not entirely implausible aetiological theories, a number of experienced workers in this field have professed that they would not be too surprised if the final answer to the questions of causation and pathogenesis in multiple sclerosis involved entirely novel or hitherto unsuspected disease processes" [I]. Multiple sclerosis, as a clinical and pathological entity, was first described by Cruveilhier [2] and Carswell [3]. The term, "sclerose en plaques," appeared in the literature in 1866 in a report by Vulpian, in which two cases were described by Charcot [4]. Charcot called attention to mild cases andformes frustes, but further description of the disease —including the triad of nystagmus, scanning speech, and intention tremor—is also attributed to him [5-7]. Many different etiologies have been suggested for multiple sclerosis. A prominent consideration has been an infectious origin of the disease. In 1884, Marie stated that it might be a complication of a number of infectious illnesses [8]. Charcot suggested a relationship to an antecedent illness and cited cases that had followed cholera, smallpox, and typhoid fever. Bullock, in 1913 [9], and Gye, in 1921 [10], claimed to have transmitted multiple sclerosis from man to rabbits, using cerebrospinal fluid injections. In these and other such studies, the failure to identify a specific organism has been a stumbling block. Pette has pointed out the ?Departments of Neurology, Harvard Medical School and Children's Hospital Medical Center, 300 Longwood Avenue, Boston, Massachusetts 021 15. Supported by grants from the Office of Naval Research, Department ofthe Navy, NR 908-108; United Cerebral Palsy Research and Educational Foundation R224-69; National Institutes of Health Developmental Neurology grant NS-HD 09704; National Institutes of Health Children's Hospital Medical Center Mental Retardation and Human Development Research program HD-03773; and National Institutes of Health grant HE-10098. I express my gratitude to the following individuals for their comments and suggestions on reviewing the manuscript prior to its submission for publication: Dr. Charles Barlow, Children's Hospital Medical Center, Boston; Dr. Torben Fog, Kommunehospitalet, Copenhagen, Denmark; and Dr. Floyd Gilles, Children's Hospital Medical Center, Boston. I am also grateful to Lynn Gerrick for her assistance in typing the manuscript. Perspectives in Biology and Medicine · Spring 1975 I 363 absence of a preliminary phase in this disease, seen in most viral infections , as \vell as the predilection of most known neurotropic viral infections for gray matter [11-12]. The possibility of a latent viral infection causing multiple sclerosis is widely considered, as suggested by Gadjusek , Gibbs, and Alpers [13]. The hypothesis that the disease is associated with diffusion of a circulating myelinolytic toxin or enzyme was proposed by Marburg in 1906 [14], and again by Brickner in 1931 [15]. A vascular, thrombogenic etiology of multiple sclerosis was postulated by Putnam in 1933, by the observation of the close proximity of the plaques to small venules in both brain and spinal cord [16-17]. Torben Fog has elaborated on this hypothesis with extensive observations [18]. A dietary etiology of multiple sclerosis was proposed by Swank, who has claimed improvement by treating multiple sclerosis patients with low-fat diets, especially restricted in fats ofanimal origin [19-20]. Others have shown that there is a decrease in polyunsaturated fatty acids in plasma [21-24] and in brain [25-28] in patients with multiple sclerosis. These observations have been advanced as evidence for a dietary hypothesis for the disease. A diet relatively low in polyunsaturated fatty acids and high in saturated fatty acids is considered to predispose to the disease. The lack of confirmation of these decreases in linoleic acid in plasma and brain in cases of chronic multiple sclerosis has been advanced as evidence against the saturated fatty acid dietary hypothesis [29-30]. An autoimmune etiology is currently also considered possible. The accumulation oflymphocytes and plasma cells in areas ofdemyelination, as well as the deposition of gamma globulin in the same area, supports this view. However, there is no raised plasma gamma globulin level in multiple sclerosis. On the other hand, cerebrospinal fluid gamma globulin levels...