Brain Advance Access originally published online on June 21, 2008
Brain 2008 131(7):1677-1680; doi:10.1093/brain/awn130
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The problem of disseminated sclerosis (being the Presidential Address of the Neurological Section, Royal Society of Medicine, October 1946). By Douglas McAlpine. Brain 1946: 69; 233–250.
Cambridge
Quite when Douglas McAlpine (see Figure) became interested in the problem of disseminated sclerosis is unclear. He worked originally on encephalitis lethargica but published on demyelinating disease from 1931, first speculating that acute disseminated encephalomyelitis and disseminated sclerosis are caused by specifically different virus infections, the former being self-limited because immunity is conferred by the initial attack (Lancet 1931: 1; 846–52). In 1938, he wrote on concordance for neuromyelitis optica in a pair of identical twins (Brain 1938: 61; 430–48). The monograph on Multiple Sclerosis written with Charles Lumsden and Nigel Compston in 1955 has a concluding chapter on the problem of causation where ideas are developed on the aetiology and pathogenesis: ‘a study of the natural history suggests that more attention should be focused on the genetic and allergic backgrounds of the disease ... [and the role of] ... some so far unidentified factor with selective affinity for the oligodendroglia’. In an Annual Address to the Newcastle-upon-Tyne and Northern Counties Medical Society on December 6, 1956, entitled ‘Multiple sclerosis, a plea for a fresh outlook’, Dr McAlpine again sets out his views on the allergic nature of the disease: ‘the possibility that multiple sclerosis may be due to an antigen-antibody reaction within the nervous system is ... based on deduction from a number of widely different observations’. He attaches much importance to surveys of past experiences linked to onset and disease activity in his many patients (Quart J Medicine 1952: 21; 135–167). Given the paucity of secure experimental data, Douglas McAlpine necessarily uses his intellect and imagination to formulate a view on what happens in disseminated sclerosis.
Many of these speculations on the cause and mechanisms of disseminated sclerosis have their origins in the paper published in 1946 soon after he returned to civilian practice as a consultant neurologist at the Middlesex Hospital, London (UK), to which he had been appointed in 1924, after serving in the Middle East, India and South-East Asia during the Second World War. Douglas McAlpine takes the opportunity of a prestigious lecture, his Presidential Address to the Section of Neurology of the Royal Society of Medicine, to assemble his ideas: ‘the true nature of disseminated sclerosis eludes us’ ... but ... ‘the prospect of an early return to peacetime conditions in clinical and bacteriological research ... [allows us] ... to ‘hope that fresh interest may be aroused in a problem which, on humanitarian grounds alone, deserves the attention of those best qualified to take part in its investigation’. Dr McAlpine considers two lines of evidence: knowledge gained from pathology and experimental methods; and the lessons of clinical neurology.
Sifting the many available pathological descriptions, Dr McAlpine singles out the work of James Dawson for special praise. Neither the terms ‘disseminated sclerosis’ nor ‘sclérose en plaques’ convey the essential nature nor the origin of the disease but Dawson explains the distribution of lesions on a vascular basis. Only J.W. Williamson in a small book "On the relation of diseases of the spinal cord to the distribution and lesions of spinal blood vessels" (1895) has anticipated Dawson's view that ‘disseminated sclerosis is a form of acute or subacute encephalomyelitis due to a blood-borne infection’ in which the agent ‘acts so rapidly that it attacks not only the myelin sheath, but destroys the axis cylinder then the meshes of the glia’. Nor has Dr McAlpine ignored the emerging concept that disease mechanisms may be allergic reactions to bacterial or virus infections and that, after the initial lesion has been established, other factors may influence the course of the disease. But what is the nature of this infectious agent? With astonishing indifference, Dr McAlpine mentions, but does not offer an opinion on, the controversial work of Georg Schaltenbrand. In McAlpine's Multiple Sclerosis (2005) we wrote:
‘... Georg Schaltenbrand claimed to have transferred multiple sclerosis to monkeys using human cerebrospinal fluid and, in turn, infected verblodete Menschen (imbeciles) with material from these and other primates: one recipient, who had a glioblastoma multiforme, died after the second injection of monkey spinal fluid and was shown to have demyelinating lesions in the conus and peripheral nerves; later, Schaltenbrand claimed to have produced autopsy-proven demyelination in an individual by injecting cerebrospinal fluid from a patient with active multiple sclerosis. It seems that Schaltenbrand performed this procedure on up to 45 human subjects, including children with psychiatric disease or idiocy from an institute in Werneck.’At the discretion of Dr EA [Arnold] Carmichael, Douglas McAlpine has recently seen a paper to be published in the Journal of Neurology, Neurosurgery and Psychiatry and is impressed by these Russian observations claiming that a strain of virus (unidentified) recovered from two cases of acute disseminated encephalomyelitis can be transmitted experimentally. Moreover, it is neutralized by serum from 80% of patients with acute disseminated encephalomyelitis and from 50% of individuals with multiple sclerosis. But despite these tantalizing observations, the trail on infection and allergy seems to have gone cold and although ‘there are certain features of disseminated sclerosis ... that could be explained on the basis of allergy ... at the present time further speculation on this point would serve no useful purpose’.
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Disappointed by the elusive search for a causative infectious agent, proponents of the vascular doctrine have shifted attention to the veins—proposing that lesions develop in response to thrombosis, and later extending this concept to the occlusion of capillaries. By way of mechanistic interpretation, Weston Hurst has shown that demyelination and axonal degeneration can also be induced by exposing the nervous system to repeated doses of potassium cyanide or sodium azide suggesting that histotoxic anoxia affecting oxygen utilization, rather than vascular occlusion, is the primary defect. Presciently anticipating our current interest in hypoxia-like lesions (Marik et al., Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 2007; 130: 2800–2815), Douglas McAlpine has modified his view that the presence of lymphocytes around lesions necessarily implies an infective cause to a more general understanding that the histology of disseminated sclerosis may result from hypoxia or poisons.
Have clinical observations added to the general understanding of causation in disseminated sclerosis? The variable natural history, remissions that may last between a few months and several decades, unpredictable recovery from individual attacks, marked oscillation from florid to negligible disease activity, and the correlation between age at onset and the progressive course have all been interpreted as peculiarities of the disease rather than traits of the affected individual: ‘... since we have no precise knowledge of the character of the agent we may for the moment assume that the individual's reaction to the disease is the prime factor in modifying its course ...’. Trading on his belief that there may be a dividend for understanding the nature of the disease by studying large and representative groups of affected individuals, Dr McAlpine reports the results of a prospective survey started in 1937 but interrupted by the Second World War. Now resumed he can report on 142 cases, excluding 18 in whom the period of follow-up is too short from which to draw any meaningful conclusions. Females are preferentially affected irrespective of age at onset (1.7F : M). There is no social (class) or occupational discrimination, nor an effect of urban or rural domicile. Onset does not show seasonal variation. Although not studied as part of his survey, Dr McAlpine considers that disseminated sclerosis is common in northern Europeans but less so in Australia than the United Kingdom, and rare in Africa, India and the Far East. Having worked in Asia during the war and seen not a single case amongst the indigenous people, and struck by the rarity of disseminated sclerosis in British troops posted to those parts, he senses that the geography of the disease must reflect distribution of the causative infection.
Noting that Curtius reported familial clustering in 6 of 56 families, and realising the danger of confusing familial disseminated sclerosis with hereditary cerebello-pyramidal disorders (specifically, the Drew family of Walworth described by Ferguson and Critchley in 1929), Dr McAlpine draws attention to familial recurrence, affecting both siblings (six examples) and parents (one mother and one father) in 8 of 142 cases (5%): ‘the familial incidence would seem to indicate an occasional hereditary predisposition’. Neither body build nor colouring mark that tendency but obesity may be protective against the development of disseminated sclerosis. Psychic trauma can unmask the disease. Mrs C, a nurse with a history of allergy in childhood, had four episodes of optic neuritis each coinciding with periods of stress, the last precipitated by the return of her husband from the war. N.W.J. had a lucky escape whilst riding his motorcycle and 1 week later experienced a first episode of demyelination; a second attack developed after he fell downstairs. Six percent of respondents provide a history of allergy, and 25% report migraine; but, although Dr McAlpine does not deal specifically with the need for controls, ‘the frequency of this condition amongst the present-day population [makes it] doubtful whether any significance can be attached to this finding’. Although there is evidence for weight loss and irregular meals in some patients, in no case can malnutrition be invoked as a precipitant cause of disseminated sclerosis and therefore ‘a food deficiency is not important in this disease’. McAlpine sets running a hare that is not altogether yet caught by suggesting that trauma within a month preceding the onset of disseminated sclerosis occurs in 8 of 142 (5%) cases: in two, this followed within a few hours of a bomb exploding in their vicinity; and in two others optic neuritis was preceded by minor trauma to the same eye. He concludes: ‘after excluding those case in which the disease itself was responsible for the alleged trauma, there remain a few cases of disseminated sclerosis in which there can be little doubt of the close relationship between peripheral trauma and the appearance of signs’.
Dr McAlpine's main interest is the allergic reaction to infection. R.J.M. has a history of recurrent abscess on the left side of his neck with pain in that shoulder; 3 years later he presents with symptoms and signs sufficient to establish the diagnosis of disseminated sclerosis and, within another 5 years, he is severely disabled—still with enlargement of the cervical lymph nodes. R.V.W. develops traumatic cellulitis of the left hand and a year later has symptoms and signs indicating spinal cord and brainstem disease that lead to the diagnosis of disseminated sclerosis from which eventually he becomes severely disabled. We share Dr McAlpine's own conclusion that, with an interval of 18 and 12 months between infection and the emergence of neurological symptoms, ‘the evidence that ... a peripheral focus of infection and disseminated sclerosis were related is purely circumstantial’. The contemporary reader may also have reservations about accepting these examples as evidence that the infectious agent enters via the skin and, after a latent interval, sensitizes the central nervous system. Disappointingly, in view of his preferred hypothesis that disseminated sclerosis results from the allergic reaction to a toxi-infection, in only 18 of 142 (13%) cases can a history of peripheral sepsis within 1 year of onset be obtained, and in only 12 cases is there circumstantial evidence to suggest systemic infection. If an infectious agent is involved, he argues, why did not more cases occur during and following the Great War? Again, somewhat lamely, the conclusion is that ‘since much that I have said on the possible role of the skin as a portal of entry in certain cases of disseminated sclerosis is speculative, no good purpose would be served by pursuing the subject further’.
What then does Douglas McAlpine conclude from his synthesis of experimental and clinical observations? The histology suggests a viral infection; the clinical course is consistent with an immune reaction to that infection, the nature and extent of which vary between individuals; hereditary factors condition that susceptibility; pregnancy (not otherwise mentioned), trauma and mental stress trigger expression of the disease process; since disease onset is rarely accompanied by evidence for infection, there must be an interval between invasion of the nervous system and expression of the disease process, as in syphilis; although the likelihood is that entry is via the skin, his researches have not established at what point in the patient's life sensitization occurs. ‘I hope that the controversial nature of this Address may be justified ... by drawing attention to the increasing evidence in support of the infective nature of disseminated sclerosis and to the urgent need of carefully planned research work based on the close cooperation of clinician and bacteriologist’; and he acknowledges help in preparation of his Address provided by James McIntosh (1882–1948: Professor of Pathology and Director of the Bland-Sutton Institute at the Middlesex Hospital from 1920).
The first day's proceedings of the 1st International Congress of Neuropathology held in Rome on September 8–13, 1952 were devoted to demyelinating disease. Georg Schaltenbrand was a discussant: ‘by injecting spinal fluid from polysclerotics into monkeys, we could produce a demyelination together with inflammatory changes in the c.s. fluid and degeneration of the optic nerve and spinal roots’. There is no mention of verblodete Menschen. Douglas McAlpine marked his copy of the proceedings only to correct one of Schaltenbrand's statistics but his more extensive pencil jottings in the volume reveal enthusiasm for the idea that disseminated sclerosis depends on an ‘immunological response to brain tissue ... and antibody production ... lymphocytes and plasma cells are prominent in the lesions ... neural tissue contains a series of antigenic substances, only one of which may be the offending agent ... autoimmunisation as a possible mechanism in the production of lesions must be considered ...’. Douglas McAlpine remained in touch with progress in understanding the aetiology and mechanisms of tissue injury in multiple sclerosis until his death in 1981 (aged 91). He was intellectually energetic and his 1946 synthesis is remarkable for the accuracy of the speculations based, it must be said, on rather flimsy evidence. He would surely have responded imaginatively and with enthusiasm to the rich seam of contemporary knowledge on the immunology and neurobiology of demyelinating disease now available and added to by the cluster of articles in the present issue.
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