2
580 ÆTIOLOGY OF DISSEMINATED SCLEROSIS. professorial chairs are fairly numerous. These are certainly defections from the point of view of breeding whole-time clinical researchers, though for obvious reasons we should hesitate to deplore them if the succession were assured. A tendency at some of the great hospitals for the medical and surgical units to be regarded as recruiting grounds for the staff has been apparent ; and this is certainly a useful way of gradually widening the scientific horizon of the honorary staff, a group whose outlook on medical problems has an incalculable influence on generations of students and therefore on British medicine. It is obvious, though, that if clinical research is to absorb a due amount of the annual grant of £150,000 placed in the hands of the Council for distribution, more men must be found who are permanently willing to devote their lives to this end. The conclusion reached by the Council is that " there can never be a successful and maintained recruitment of young men of ability for clinical research until there are at least a few stable positions in sight, the occupation of which at middle age will provide reasonable remuneration and adequate power of educating a family. It was hoped originally that the directorships of the University clinics in London, with others that might be established elsewhere in the provinces, would provide posts sufficiently numerous and attractive to keep the abler men at the work of investigation with the ambition of succeeding to them. But a young man able enough to advance knowledge is not likely to be attracted by a post to which he might be appointed in the future if his occupation of it is to bring such burdens of teaching and administration as would greatly debar him from the very research work that it is his ambition to pursue." The Medical Research Council are trying to meet the situation by a statement of their intention to encourage still further the scientific and direct study of disease in man. They wish to recruit for this purpose young workers of ability, to help them during a preliminary period of training and probationary work, and, when they are able, to select candidates whose training is adequate and whose efforts show promise to increase the number of clinical workers on their permanent staff. we are impressed WItl1 tne arguments in this care- fully worded section of the Council’s introduction to a masterly Report. No hint is given of the type of training to be offered, but doubtless this will follow the time- honoured lines of apprenticeship to one with knowledge of the difficulties involved, or association with a team of workers. Whatever form the discipline takes, it is to be hoped that an elementary grounding of statistics as applied to medicine will be imperative. Where the material available for study is so precious, and sometimes so difficult to come by, it is unjustifiable to waste it by planning work which, examined statistically, is of little value compared with the controlled observations that might have been made. Criticisms offered, and legitimately offered, on the outcome of laborious work which has extended over years are sometimes resented. It is pardonable to be dis- heartened if figures honestly collected are found to be meaningless, but not to condemn statisticians for exposing fallacies due to ignorance of proper methods. Where many unknown factors can be eliminated, as in a well-constructed laboratory experiment, the need is perhaps not so great; but the assessment of clinical research, to be economical, requires either great experience, natural ability, or some knowledge of the laws of probability and averages. A significant sentence in the section on Statistics (p. 123 of the Report) reads, " Much time and energy have again been used in giving statistical help to research workers in other departments." It is unlikely that a brief training in applied mathematics would make it possible to dispense with the assistance available from Prof. MAJOR GREENwOOD and his staff, but it might at least enable them to economise some of the "time and energy’’ so generously offered to other workers. ÆTIOLOGY OF DISSEMINATED SCLEROSIS. DISSEMINATED sclerosis is one of the commonest chronic diseases of the nervous system. In England it ranks second only to neurosyphilis in frequency; in Switzerland it holds the foremost place. But in spite of its prevalence its cause has hitherto remained in doubt. Until the present century even its patho- logical nature was much disputed. Histological study, however, tracing the " sclerotic plaque " to its earliest stages, has there discovered all the manifestations of inflammation in the nervous system, and increasing knowledge of neuroglia has led to the recognition of the glial " sclerosis " as an inflammatory reaction rather than a neoplastic hyperplasia. Hence disseminated sclerosis is now almost universally regarded as an encephalomyelitis characterised histologically by neuronal demyelination and clinically by its relapsing tendency. This conception has naturally led to the search for a causal organism, and to many conflicting observations. Some workers have claimed to have transmitted a neurotropic virus of unknown nature from cases of disseminated sclerosis to animals. Others have impugned a spirochæte. Many completely negative experimental observations have been recorded, and no positive claim has gained general acceptance. To-day ’we publish a paper by Miss KATHLEEN CHEVASSUT, bringing forward evidence in favour of the view that the cause of disseminated sclerosis is a filtrable virus which she claims to have isolated from the cerebro- spinal fluid of a large number of patients. This discovery, if it is substantiated, will certainly rank among the foremost achievements of bacteriology. Other bacteriologists will doubtless avail themselves of the opportunity of repeating Miss CHEVASSUT’S experiments. This, however, must take time. In the meantime it is desirable that her claim should be subjected to all possible well-informed and fair- minded criticism, and that hasty acceptance and rejection should equally be avoided. Miss CHEVASSUT first describes some original observations upon the colloidal gold reaction in the cerebro-spinal fluid and blood-serum in disseminated sclerosis which she interprets as indicating that this reaction " is related in some way to the causal factor." She then brings forward evidence that " in a high percentage of cases of disseminated sclerosis there is deficiency in the antitoxic and metabolic functions of the liver." Both of these conclusions are open to criticism, but they have no direct bearing upon her main thesis. She reports that in a special medium, Hartley’s broth to which human blood-serum has been added, she has succeeded in growing an organism which, when examined microscopically by a special technique, appears as spherical bodies, some of which have granules attached to them. She has cultivated this organism from the cerebro-spinal fluid of 176 out of 188 cases of disseminated sclerosis, and has found it present in all stages of the disease. She describes the conditions affecting its growth and has observed that it ferments glucose, lævulose, and mannito

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580 ÆTIOLOGY OF DISSEMINATED SCLEROSIS.

professorial chairs are fairly numerous. These arecertainly defections from the point of view of breedingwhole-time clinical researchers, though for obviousreasons we should hesitate to deplore them if thesuccession were assured. A tendency at some of thegreat hospitals for the medical and surgical units tobe regarded as recruiting grounds for the staff has beenapparent ; and this is certainly a useful way ofgradually widening the scientific horizon of thehonorary staff, a group whose outlook on medicalproblems has an incalculable influence on generationsof students and therefore on British medicine. It isobvious, though, that if clinical research is to absorb adue amount of the annual grant of £150,000 placedin the hands of the Council for distribution, moremen must be found who are permanently willingto devote their lives to this end. The conclusionreached by the Council is that" there can never be a successful and maintainedrecruitment of young men of ability for clinicalresearch until there are at least a few stable positions insight, the occupation of which at middle age willprovide reasonable remuneration and adequate powerof educating a family. It was hoped originally thatthe directorships of the University clinics in London,with others that might be established elsewhere inthe provinces, would provide posts sufficientlynumerous and attractive to keep the abler men at thework of investigation with the ambition of succeedingto them. But a young man able enough to advanceknowledge is not likely to be attracted by a post towhich he might be appointed in the future if hisoccupation of it is to bring such burdens of teachingand administration as would greatly debar him fromthe very research work that it is his ambition topursue."The Medical Research Council are trying to meet thesituation by a statement of their intention to encouragestill further the scientific and direct study of disease inman. They wish to recruit for this purpose youngworkers of ability, to help them during a preliminaryperiod of training and probationary work, and, whenthey are able, to select candidates whose training isadequate and whose efforts show promise to increasethe number of clinical workers on their permanentstaff.we are impressed WItl1 tne arguments in this care-

fully worded section of the Council’s introduction to amasterly Report. No hint is given of the type of trainingto be offered, but doubtless this will follow the time-honoured lines of apprenticeship to one with knowledgeof the difficulties involved, or association with a teamof workers. Whatever form the discipline takes, it isto be hoped that an elementary grounding of statisticsas applied to medicine will be imperative. Where thematerial available for study is so precious, andsometimes so difficult to come by, it is unjustifiable towaste it by planning work which, examined statistically,is of little value compared with the controlledobservations that might have been made. Criticismsoffered, and legitimately offered, on the outcome oflaborious work which has extended over years aresometimes resented. It is pardonable to be dis-heartened if figures honestly collected are found to bemeaningless, but not to condemn statisticians for

exposing fallacies due to ignorance of proper methods.Where many unknown factors can be eliminated, as ina well-constructed laboratory experiment, the needis perhaps not so great; but the assessment ofclinical research, to be economical, requires either

great experience, natural ability, or some knowledgeof the laws of probability and averages. A significantsentence in the section on Statistics (p. 123 of the

Report) reads, " Much time and energy have again been

used in giving statistical help to research workers inother departments." It is unlikely that a brieftraining in applied mathematics would make it possibleto dispense with the assistance available from Prof.MAJOR GREENwOOD and his staff, but it might at leastenable them to economise some of the "time andenergy’’ so generously offered to other workers.

ÆTIOLOGY OF DISSEMINATED

SCLEROSIS.DISSEMINATED sclerosis is one of the commonest

chronic diseases of the nervous system. In Englandit ranks second only to neurosyphilis in frequency;in Switzerland it holds the foremost place. Butin spite of its prevalence its cause has hitherto remainedin doubt. Until the present century even its patho-logical nature was much disputed. Histologicalstudy, however, tracing the " sclerotic plaque

"

to its earliest stages, has there discovered all themanifestations of inflammation in the nervous system,and increasing knowledge of neuroglia has led to therecognition of the glial

" sclerosis " as an inflammatoryreaction rather than a neoplastic hyperplasia. Hencedisseminated sclerosis is now almost universallyregarded as an encephalomyelitis characterisedhistologically by neuronal demyelination and clinicallyby its relapsing tendency. This conception hasnaturally led to the search for a causal organism, andto many conflicting observations. Some workershave claimed to have transmitted a neurotropicvirus of unknown nature from cases of disseminatedsclerosis to animals. Others have impugned a

spirochæte. Many completely negative experimentalobservations have been recorded, and no positiveclaim has gained general acceptance. To-day ’wepublish a paper by Miss KATHLEEN CHEVASSUT,bringing forward evidence in favour of the view thatthe cause of disseminated sclerosis is a filtrable viruswhich she claims to have isolated from the cerebro-spinal fluid of a large number of patients. Thisdiscovery, if it is substantiated, will certainly rankamong the foremost achievements of bacteriology.Other bacteriologists will doubtless avail themselvesof the opportunity of repeating Miss CHEVASSUT’Sexperiments. This, however, must take time. Inthe meantime it is desirable that her claim should besubjected to all possible well-informed and fair-minded criticism, and that hasty acceptance andrejection should equally be avoided.

Miss CHEVASSUT first describes some originalobservations upon the colloidal gold reaction in thecerebro-spinal fluid and blood-serum in disseminatedsclerosis which she interprets as indicating that thisreaction " is related in some way to the causal factor."She then brings forward evidence that " in a highpercentage of cases of disseminated sclerosis there isdeficiency in the antitoxic and metabolic functionsof the liver." Both of these conclusions are opento criticism, but they have no direct bearing upon hermain thesis. She reports that in a special medium,Hartley’s broth to which human blood-serum has beenadded, she has succeeded in growing an organismwhich, when examined microscopically by a specialtechnique, appears as spherical bodies, some of whichhave granules attached to them. She has cultivatedthis organism from the cerebro-spinal fluid of 176 outof 188 cases of disseminated sclerosis, and has foundit present in all stages of the disease. She describesthe conditions affecting its growth and has observedthat it ferments glucose, lævulose, and mannito

581HEALTH AND EMPIRE.

The granules have been shown to pass throughcollodion membranes. These positive observationshave been controlled by culturing the cerebro-spinalfluid from 269 persons suffering from other conditions,always with negative results. Miss CHEVASSUT,then, appears to have demonstrated the presence ofcertain bodies in cultures made from the cerebro-

spinal fluid of patients with disseminated sclerosis.Is she entitled to conclude that these bodies constitutethe causal organism of the disease ? We must nowconsider how this conclusion might be criticised, notnecessarily as incorrect, but as requiring furtherevidence before it can be regarded as proved. Thebodies have never been demonstrated in the cerebro-

spinal fluid itself. There may be good technicalreasons for this, as Miss CHEVASSUT suggests, but ifthese difficulties could be overcome it would go farto remove the possibility that the supposed organismsmay be products of the interaction of the fluid and theculture medium. It may be strange to regard theuniformity of the success of an experiment as evidenceagainst its validity, but workers with the filtrableviruses may be inclined to regard the demonstrationof the virus in 93 per cent. of the specimens examinedas almost too good to be true, especially when thematerial is derived from quiescent as well as fromactive cases. It may be suggested that some bio-chemical change in the fluid is more likely to be thusconstant than the presence of the organism. It seemsdesirable, too, that some attempt should be made toascertain whether the virus is obtainable from nervoustissue as well as from cerebro-spinal fluid. It is

naturally the aim of all who claim to have isolatedan organism to transmit it to animals, to show thatin inoculated animals it produces the symptoms andhistological changes of the disease in man, and thatit can be recovered and cultivated from animalsthus infected. The evidence that these tests havebeen successfully carried out with Miss CHEVASSUT’sorganism is at present inconclusive.Sir JAMES PURVES-STEWART, in the paper on p. 560,

summarises expeiiments which he has carried out inconjunction with Dr. BRAXTON HiCKS and Dr. F. D. M.HOCKING, and which will be fully reported in our nextissue. It is disappointing that more striking resultswere not obtained from such drastic inoculations as theintravenous and intracisternal injections of culturesof the virus into monkeys. Possibly the monkeyis not a susceptible animal, though G. STEINERhas described the successful inoculation of a monkeywith the disease. Perhaps intracerebral inoculationwould yield better results. There is nothing inMiss CHEVASSUT’S observations inconsistent withher view that she has isolated the organism ofdisseminated sclerosis, but the proof of her contentioncan hardly as yet be regarded as complete. Wesincerely hope that further investigations will prove herright, and neither she nor Sir JAMES has spared painsin their admirable work.We turn now to the practical applications of the

observations we have been discussing. An exceed-ingly important one is entirely independent of theirinterpretation and, curiously, has not been mentionedeither by Miss CHEVASSUT or by Sir JAMES PURVES-STEWART. Whether or not the Spherula insularisis the cause of the disease, if the existence of thesebodies is confirmed their diagnostic value is clearlyvery great. A test applicable to the cerebro-spinalfluid which yields a positive result in 93 per cent.of cases and is pathognomonic of disseminated sclerosis,will be an even more valuable aid to the diagnosisof this disease than is the Wassermann reaction inneurosyphilis. It will be of great use in early cases,

and also may be expected to throw light upon therelationship between disseminated sclerosis, neuror

myelitis optica, and other forms of demyelinatingencephalitis. The isolation of a causative organismsuggests the therapeutic employment of an autogenousvaccine, and Sir JAMES PuRVES-STEWART contributesa weighty paper setting forth the results achieved bymeans of killed cultures of Miss CHEVASSUT’S organism.He wisely emphasises the need of caution in drawingconclusions as to the effects of any therapeutic measurein disseminated sclerosis. His patients have

apparently only been under treatment for one or twoyears, a time too short to permit one to speak withconfidence of clinical arrest. The clinical improve-ment which occurred in the four cases fully reportedis not greater than may occur spontaneously. SirJAMES PuRVES-STEWART lays stress upon improve-ment in the colloidal gold and globulin reactions inthe cerebro-spinal fluid. The significance of these

changes could have been better appreciated if controlshad been investigated. J. D. AYER and H. E.FOSTER have observed spontaneous variations in thecolloidal gold-curve corresponding to progressive andstationary phases of the disease, and ADAMS, BLACK-LOCK, DUNLOP, and SCOTT have found a diminutionin the curve following treatment with salvarsan. The

disappointing feature of the vaccine treatment is thefact that after treatment the organism was stillobtainable from the fluid in 62 out of 70 cases. Thisfact, of course, has no direct bearing upon the questionof the specificity of the organism. The discovery ofthe tubercle bacillus and the Treponema pallidumhas not led to the cure of tuberculosis and syphilisby means of vaccines. Disseminated sclerosis, anotherrelapsing disease, seems to offer a rather unpromisingfield for such treatment, for natural immunity, atleast, appears to be short-lived.

Miss CHEVASSUT, Sir JAMES PURVES-STEwART, andtheir collaborators have laid before the medicalprofession observations of great interest, involvingmatters of technical difficulty in more than one depart-ment of science. The work required for theirconfirmation must necessarily take many months.In the meantime, the wise (among whom we mayinclude the lay press) will suspend judgment.

HEALTH AND EMPIRE.THE Hastings Lecture delivered by Sir ANDREW

BALFOUR in the Hall of the British Medical Associationlast Wednesday, a brief abstract of which will befound in our front pages to-day, is an eloquent pleafor the development of medical research, with thedevelopment of the British Empire as the source ofthe information given and of the arguments set out.He paints a picture of a great battle between manand disease as witnessed in the various phases of theexpansion of British rule. The story of tropicaldisease to-day is sufficiently tragic, but the ravagesof endemic, epidemic, and incidental disease whichoccur within our borders in the twentieth centuryrepresent but a small fraction of the horrors whichin the previous epochs decided the fates of armies andnavies, and slew, or harassed to the point of death,the pioneers of colonial expansion. And when wespeak of previous epochs it should be recalled thatmany of the diseases, now labelled tropical, until themiddle of the nineteenth century flourished in ourmidst. Sir ANDREW BALFOUR reminded his hearersthat as late as 1866 cholera was present in Englandand that three years later relapsing fever was claiming