Classic Paper
Classic Papers
Help build MSDF's collection of classic papers. These studies broke new ground and changed the field's direction. Please send the MSDF editors your nominations. Let us know what the paper showed and how it altered people's thinking.
Classic Paper
Moxon W
Eight cases of insular sclerosis of the brain and spinal cord. Guy Hosp. Reports 1875; 20:437-478.
Suggested by Thomas Murray
William Moxon, a prominent London consultant at Guy’s Hospital, published a series of well-illustrated cases between 1873 and 1875, and summarized these in a further paper in 1875. The term “insular sclerosis” was used in the English-language publications over the next decades and then replaced by the term “disseminated sclerosis.” Moxon’s papers are sometimes said to be the first papers on MS in the English literature, but like Charcot’s famous lectures, they were not the first, but were the papers that made the disease known in the English-speaking world.
Classic Paper
Charcot JM
Lectures on the diseases of the nervous system. Volume II, Translated by George Sigerson, London, New Sydenham Society, 1881. http://www.archive.org/details/lecturesondiseas03char
Suggested By Thomas Murray
Although there were physicians who recognized the relapsing and progressive neurological disease in young adults earlier, the description of multiple sclerosis is usually credited to Jean-Martin Charcot, as he clarified the clinical picture and pathology of the disease remarkably well in three published lectures, and he gave the disease a name. Very little was added to Charcot’s description in the next 50 years. He published his description in 1868, and it was translated into English in 1881.
Classic Paper
Dawson JD
Transactions of the Royal Society of Edinburgh. 1916; 50: 517-740.
Suggested By Alastair Compston and Alasdair Coles
In this paper, James Dawson provides the greatest pathological account of multiple sclerosis in the English language. After summarizing the literature—and the debate, which went on then as now, about whether the disease is “inflammatory” or “developmental” (degenerative)—Dawson reviews the histology of nine personal cases. Illustrating the text with 22 colour and 434 black-and-white figures in 78 plates, Dawson describes the form, symmetry, distribution, and histological features of several types of lesions and provides an analysis of changes in each cellular element of the nervous system—nerve cells and their axons, neuroglia, blood vessels, and lymphatics. Dawson then attempts a clinicopathophysiological correlation. (Weakness in the legs is consistent with the extensive spinal cord gliosis, for example.) He also characterizes old and acute lesions. Dawson summarizes his ideas on plaque formation around brain inflammation to include a sequence of events that, although not disease-specific, produces recognizable clinical characteristics. Maybe he falls into the trap of believing that the pathologist can see the cause, effects, and evolution of disease merely by observing snapshots of its end state.
Suggested by Thomas Murray
James Walker Dawson in Edinburgh made a major contribution to the understanding of multiple sclerosis in 1916 with his detailed pathological descriptions of nine cases and in particular by concentrating on one case, LW, a 28-year-old kitchen maid. He showed the changes in lesions at various stages and described shadow plaques and the pattern we now call “Dawson’s Fingers” on MRI.
Classic Paper
Davenport CB
Association for Research in Nervous and Mental Diseases (ARNMD) vol 2. New York: Herber, 1921: 8–19.
Suggested By George Ebers
This was the first systematic study showing that the geography of MS had unexplained irregularity. Davenport became somewhat controversial later because of his interests and studies in eugenics (a scientific zeitgeist among his contemporaries in educated circles). He studied the occurrence of MS in U.S. World War I veterans and showed the high prevalence around the Great Lakes, something that was attributed to the Scandinavian origins of much of this population at the time. This continues to the present to a degree, c.f. the Swedes of Minnesota and the Finns around the northern lakeshores, e.g., Thunder Bay. Later, the migration of Norwegians to the U.S. Northwest, making up some 50% of the migrants in the mid-19th century, would show up in the geography of veterans with MS. The highest U.S. rates by state continue to be in Washington state. The U.S. VA records proved grist for John Kurtzke’s mill and his industry and determination was to be most productive, but the use of the veteran’s databases began here and with Beebe (Beebe et al., 1967).
Classic Paper
Brain WR
Critical Review: disseminated sclerosis. Quart. J. Med. 1930; 23:343-391.
Suggested By Thomas Murray
It is not often in the annals of medicine that a review has an important place in the history of progress, but Russell Brain, a young consultant at the London Hospital (later Lord Brain), clarified the confusing state of understanding and claims in 1930. He reviewed the extensive literature of MS and gave his clear view on all aspects, including his conclusion that all therapies available provided no more benefit than would have occurred spontaneously.
Classic Paper
Curtius F
Multiple Sklerose und Erbanlage. Leipzig: G. Thieme, 1933.
Suggested By Thomas Murray
Many authors in the late 19th and early 20th century noted more than one case of MS in a family but dismissed this repeatedly as coincidental. Curtius in Germany in 1933 provided convincing evidence of a familial relationship, probably a genetic factor, in 10% of families with MS, which was 42 times greater than expected risk calculated from studies at the time. He referred to 84 other observations of familial cases in the literature and reported a careful study of 3,129 relatives of 106 MS cases in Bonn and Heidelberg.
Classic Paper
Rivers TM, Sprunt DH, Berry GP
J Exp Med. 1933 Jun 30; 58(1):39-53. Epub 1969 Dec 31. PMID: 19870180. Abstract
Suggested by Ian T. Rossman and Jeffrey A. Cohen
The Pasteur rabies vaccine, developed in the late 19th century, was produced by intracranial inoculation of rabbits with rabies virus, then treating dried infected spinal cord with potassium hydroxide to kill the virus. Shortly after introduction of the vaccine, it was noted that some recipients developed an acute paralytic illness with a characteristic pathological picture of perivascular inflammation and demyelination in the central nervous system (CNS). This disorder, termed acute disseminated encephalomyelitis (ADEM), was recognized as having some pathologic similarities to multiple sclerosis (MS). Through studies in monkeys, Dr. Rivers and colleagues sought to determine whether ADEM was caused by rabies virus escaping inactivation or by exposure to normal brain constituents in the vaccine. In their 1933 paper, Rivers et al. reported that there was no evidence of transmission of rabies infection. Rather, after repeated intramuscular injection of rabbit CNS-derived extract alone, 2 of 8 monkeys developed clinical and pathologic manifestations similar to those described in humans with ADEM and MS.
This paper represents the first description of experimental autoimmune encephalitis (EAE), which has been extensively studied up to the present as an inducible animal model of MS. The voluminous literature on EAE includes studies of immunologic, pathologic, and physiologic assessments in a wide range of variations of the model in different animal species, strains, and genetic backgrounds; with a large number of different CNS-derived immunogens; and utilizing a variety of induction protocols. Concepts derived from studies of EAE have dominated thinking over the last century about the pathogenesis and therapy of MS as an autoimmune disease. Virtually every potential MS therapy has been tested in EAE. Nevertheless, it also has become evident that EAE is an inexact model of MS and that no individual EAE version fully recapitulates all the features of the human disease.
Classic Paper
KABAT EA, Moore DH, Landow H
J Clin Invest. 1942 Sep; 21(5):571-7. PMID: 16694947. Abstract
Suggested by Gavin Giovannoni
Elvin Kabat pioneered the study of proteins in the spinal fluid and serum using electrophoresis. He showed there was an increase in the proportion of gamma globulins in the spinal fluid from patients with multiple sclerosis. This was a key finding in establishing MS as an immunological disorder and has been a major focus of research ever since. Some think the intrathecal antibody response will be the key to discovering the cause of MS.
Classic Paper
ACHESON ED, BACHRACH CA, WRIGHT FM
Acta Psychiatr Scand Suppl. 1960; 35(147):132-47. PMID: 13681205. Abstract
suggested by George Ebers
This paper is often cited as the origin of the sunshine hypothesis and this is largely true, but it was temporally immediately after Dean and was undoubtedly derived from Dean’s observations in South Africa (Dean, 1949). However, Acheson was an adviser to Dean in this study as acknowledged at the end of the paper. Acheson, who subsequently became the chief medical officer for the U.K. and later dean of the Southampton Medical School, proposed at a Queen Square seminar that MS was related to sunshine deficiency. He was told by FMR Walshe, then the dean of the National Hospital, that it was “more likely to be moonshine,” the implication being that the young Acheson was under its influence.
Pathological Anatomy: Illustrations of the elementary forms of disease. London: Longman, Orme, Brown, Green, and Longman.
Suggested by Thomas Murray
A young Scottish physician with a talent for art created a great atlas of pathology from study in the dead houses of the Paris hospitals in 1838. One of the illustrations (Plate 4, Figure 4.4) was of a “peculiar disease state” showing the spinal cord and pons, with scattered softening, atrophy, and scarring, which we would now recognize as MS. This was the earliest illustration of MS. The original atlas resides at University College Hospital Archives in London.