Classic Papers

Suggested by George Ebers

This was the first conclusive demonstration that MS was largely a disease of place, as Dean showed that the rate of MS was markedly reduced in migrants to South Africa (Dean, 1949). This paper followed up his original observation in 1949 based on smaller numbers. The cognitive fallacy, which remains difficult to extinguish, was that diseases were either environmental or genetic. It was only recently that it has become clear that both genes and environment interact to produce susceptibility. Dean’s observation was seminal, and it is indeed a shame he received little recognition for this before his recent death.

Looking back over this paper, it is striking how little has been made of the difference in risk for native Afrikaaners vs. English-speaking residents born in South Africa. This can in retrospect be seen to provide the first clue to the transgenerational effects now apparent.

Suggested By Alastair Compston and alasdair coles

In this study, researchers in the lab of Paul Terasaki at the University of California, Los Angeles, identified the primary genetic association for multiple sclerosis. In 1970, Terasaki organized a workshop that identified 11 official HL-A specificities (HL-A1, 2, 3, 5, 7, 8, 9, 10, 11, 12 and 13), and perhaps eight other specificities. In this study, his group concluded, from 94 patients and 871 controls, that HL-A3 was overrepresented in patients with multiple sclerosis. Furthermore, the team demonstrated that the geographical variation in prevalence of multiple sclerosis paralleled the prevalence of HL-A3. They summarised some of the epidemiology that suggested an environmental cause for multiple sclerosis and concluded that “the evidence to date on MS, however, is still consistent with the idea that a genetic difference in susceptibility underlies some environmental influence.” Terasaki and others later discovered the association with what would come to be called the class II allele HLA-DR15, which is within the HL-A3 region and which remains the best characterized candidate susceptibility gene for multiple sclerosis. Only in the last few years has sufficient power emerged in the techniques and cohorts, forged through large collaborations (especially the International MS Genetics Consortium), to uncover the much smaller individual genetic contributions of a host of other alleles. The finding that multiple sclerosis is associated with the HLA system implicates the immune system in its pathogenesis; explains some of the geographical variation of the disease; provides a molecular substrate for the interaction of genetics and environment; and suggests treatment directed at the T-lymphocyte, the T cell receptor, and the class II molecule.

Suggested By Alastair Compston and alasdair coles

Today’s hope of remyelinating therapies depends on the demonstrations that remyelination is possible in the central nervous system, that this process is mediated by the oligodendrocyte precursor, and that it is accompanied by functional improvement. This paper definitively demonstrated remyelination in the adult mammalian central nervous system, and—perhaps most importantly—showed how to identify demyelinated fibres. The investigators compressed the spinal cords of three adult cats, which causes early demyelination with retained axons; remyelination starts 3 weeks later. Their main discovery, using electron microscopy, was that the remyelinated sheath is abnormally thin and has an intermodal distance reduced by 50% compared to control fibres of the same diameter. Under the light microscope, no evidence emerged for the presence of Schwann cells, so the team concluded that oligodendrocytes had been responsible for the remyelination. These ultrastructural characteristics—reduced internode distance and inappropriately thin myelin—have become the defining features used to recognise remyelinated axons (as opposed to the partially demyelinated axons) in experimental and human pathological studies. The next important step was the demonstration that such remyelinated axons could restore function (Smith, Blakemore, and McDonald, 1979; Smith, Blakemore, and McDonald, 1981).

Suggested By Alastair Compston and alasdair coles

In this paper, which is partly a review and partly based on original data, John Kurtzke lays out the big picture of multiple sclerosis epidemiology. He points out that the assertion of the day, that latitude determines multiple sclerosis prevalence, is incorrect. He notes that Scandinavia stands out as having a high prevalence of MS, which he interprets to suggest that it is “intrinsically related to geography” and thus “an acquired, exogenous, environmental disease.” To determine when the disease might be acquired, Kurtzke compares the age at which migration alters the risk of acquiring multiple sclerosis. He then presents new data on the risk of multiple sclerosis in veterans—by race and gender—and shows that it is greatest in white women. Kurtzke argues that if multiple sclerosis is due to an infectious agent rather than a toxin, transmissibility should be evident. He is keen to discuss possible “epidemics” of multiple sclerosis, based on his travels to the Faroe Islands, where a cluster of new cases seemed to follow the stationing of British troops. Kurtzke’s interpretation of the Faroese epidemic of multiple sclerosis has been the most controversial aspect of his work. But that should not detract from the enormous service he has performed in marshalling the huge and complex multiple sclerosis epidemiological data set into digestible synopses, of which this paper is a prime example.