Sent from Sydney Price James
11 Jan 1924
Description:

‘1. Dr. Bond in his memorandum of 21st June, 1923, on this file has described the present position with regard to the clinical trials which are being made in some mental hospitals in England and Scotland of the method initiated a few years ago in Austria of treating general paralysis of the insane by inducing attacks of inoculated malaria. The first trial in England was begun in July 1922 at the Whittingham Mental Hospital, Lancashire. Towards the end of the same year and in the spring of 1923 trials in several other mental hospitals were commenced and one or two articles stating the technique adopted, the clinical features of the induced malaria and some opinions of its effects on the mental and other symptoms of the original disease were published in leading medical journals of this country. From the beginning of the trials the Board of Control took steps to be kept closely informed of the procedure and progress in the hospitals concerned.

2. In July 1923 the public health aspects of the treatment came officially before the Ministry of Health on the questions whether the cases of induced malaria must be notified under the Malaria Regulations of 1919 and what steps might be necessary to guard against the accidental spread of the disease from inoculated cases. These questions are being dealt with in co-operation with the Board of Control and in consultation with the Ministry’s Legal Department and it is now under consideration whether the Ministry’s Malaria Regulations may have to be amended and what form of memorandum as to precautionary measures may have to be drawn up for issue to medical superintendents of mental hospitals and to the medical officers of health of districts in which the hospitals are situated.

3. At the request of the Board of Control and under our Ministry’s instructions I have visited some mental hospitals to obtain information and to give advice on the subject. I have also undertaken, in collaboration with Dr. Steen, Medical Superintendent of the City of London Mental Hospital at Dartford and of Dr. Eastwood at the Ministry’s Pathological Laboratory, a necessary experimental enquiry to ascertain whether the malaria-carrying mosquitoes of this country, in the actual conditions which pertain, become infected with malaria and capable of spreading the disease if they bite the inoculated patients.

4. The present report states the results of this enquiry and certain other observations which have a bearing on the administrative action which now may be considered necessary in connection with the new line of treatment. The suggestions and recommendations which appear to be justified by the observations recorded are also noted.

5. I think that I ought to note first that during a visit to Austria in May 1923 I learnt that for the purposes of the treatment in that country care was taken to use only a mild strain of benign tertian malaria which in the first event had been contracted in Europe not from an imported case but from a local case in an area where the disease is mildly endemic. The strain wa also particular in that it had never been subjected to the action of quinine. In England the benign tertian malaria which is being induced for the purposes of the trials is different in that it has been derived hitherto from patients who contracted the disease in the tropics and suffered from relapses in England; doubtless also these relapsing cases have been treated more or less vigorously with quinine.

6. Secondly I must say that particularly in two of the four hospitals which I have visited I have been surprised at the severity of the induced malaria in the inoculated cases. They were certainly more severe than the inoculated cases which I had previously seen in Austria, Holland and Denmark. The usual clinical symptoms of a severe attack of malaria in a normal person may be masked in patients suffering from general paralysis of the insane but microscopical examinations have shown a quite unusual abundance of parasites in the peripheral blood. Also, some of the temperature charts shown to me record hyperpyrexia during the malarial attacks and I have been informed that in one hospital three deaths from the induced malaria have occurred since the beginning of the trial phase.

7. In seeking an explanation of the severity of these infections one thinks first of the original source of the parasitic strain employed, an done wonders if it might not be desirable in future to endeavour to obtain and to employ exclusively a strain derived from the mild endemic disease of England or Holland. Next one thinks of the possibility that the strains which have been passed by direct inoculation of blood from person to person through many human hosts may have become increased in virulence. Dr. Grant of the Whittingham hospital has placed on record his opinion that the virulence of the strain used in that hospital is increasing [note: ‘British Med. Journal. Oct. 20. 1923; p. 698.’] and certainly it would appear from the microscopical examination of blood films at other hospitals that a parasite which has been “cultivated” by the procedure involved in the present method of treatment thrives and multiplies luxuriantly, and that infections subsequently induced by its use are of a severity seldom encountered in ordinary benign tertian malaria of the tropics. If this view of increased virulence is accepted it would be wise in future to discontinue to employ a strain after its passage through a few individuals. Next there is the possibility that the severity may be due to the injection of an unnecessarily large dose of parasites. The practice in Austria is to inject only 2 cubic centimetres of the donor’s blood, one cubic centimetre being injected subcutaneously, the other being scarified into the skin. In England at one hospital, where severe cases seemed to be the rule, 5 cubic centimetres of the donor’s blood was the amount usually injected. At another hospital intravenous instead of subcutaneous inoculation was practiced in some instances and a second injection was given if malaria symptoms did not appear within the expected incubation period. I think that at least 20 days should be allowed to elapse before deciding that an injection has “failed to take”.

8. I have mentioned the above points at some length not by way of criticism but in order to show that there are differences between the practice adopted in England and the practice which I understand is recommended by the initiators of this therapeutic measure in Austria and that there are differences of procedure even between the very small number of hospitals which I have visited in England. If it is the intention to endeavour to arrive at a considered decision on the merits of the measure in England it would seem very desirable to ensure uniformity of procedure and practice in all the hospitals where trials are being arranged.

9. Continuing on the subject of these differences I must note that in the different hospitals there are differences between the numbers of malarial rigors which are considered necessary before beginning quinine treatment and that the practice as to quinine dosage and as to the period of its continuance after clinical recovery is not uniform. Effective quinine treatment and “after-treatment” is important in the public health interest. It is necessary that the patients should be thoroughly treated with quinine both to ensure their speedy recovery from the induced malaria and to minimise as far as possible the likelihood that they will suffer subsequently from malarial relapses which in the case of patients who might be discharged to their homes in certain parts of England would provide a potential source of spread of malaria to their families and neighbours. In this connection I am aware of the opinion recorded in several articles that an entire absence of relapse is a particular feature of inoculated malaria. While this may be true as regards the cases hitherto observed in Austria (where the strain was of mild indigenous malaria and where thorough treatment and after-treatment with quinine in tropical doses is the rule) I am somewhat anxious lest it may not hold good for cases in England (where the strain is of tropical origin and where in some instances only very small doses of quinine are given). I think it probable that the opinion, as expressed in articles in the English medical journals, has reference to what are called technically “clinical relapses” as distinguished from “parasitic relapses”. I have already mentioned that it may be quite easy to fail to observe a “clinical relapse” in a patient suffering from general paralysis of the insane, and I am now able to record an instance in which such failure occurred at one of the hospitals which I visited. Examination of the blood of all patients who had been inoculated at this hospital showed that parasites were present in the blood of a patient who was said to have recovered from his malaria some weeks previously. His temperature chart showed no rise above the normal line. When parasites were found in his blood I asked for it to be arranged that his temperature should be taken every two hours. This procedure revealed the presence of mild attacks of tertian fever each lasting two or three hours. Moreover, during a careful examination of many parasites from the blood of inoculated patients I have been unable to detect any differences between them and the parasites of naturally contracted malaria which would justify the view that they lack relapsing characters, and I therefore think that if systematic blood examination of all patients hitherto inoculated in England can be made during the coming spring we shall find at least a few instances of relapse among them.

10. I now refer as briefly as possible to our enquiry to ascertain if the malaria-carrying mosquito of England becomes infected when it sucks blood from inoculated patients. In a previous note addressed to Dr. Bond I explained the reasons for this enquiry. The mosquito (Anopheles maculipennis) is distributed practically everywhere in England. It is active and to be found in all stages of its life history during the months of May to October but during the winter months only the adult female insects remain alive; they are to be found in a relatively inactive, sluggish condition (so-called hibernating condition) in stables, cowsheds, etc; and we so found them at the end of October (when arrangements for this enquiry were begun) in the stables of one of the hospitals visited. Our first collection of insects for the purposes of the enquiry was made on the 15th November when about 60 specimens of Anopheles maculipennis caught in cowsheds in Kent were brought to the laboratory and placed in a moist incubator at 23˚C. (71˚F.). In this changed environment the mortality of the insects was heavy but a sufficient number survived to justify a first feeding experiment and on the 20th they were taken to the mental hospital at Dartford and fed during the night on 3 patients whose blood contained suitable forms of the parasite. A second collection of about 100 insects from farms in the Sheerness district was made on 4th December and the first feeding experiment with those that survived of this batch was made on the 7th December and a second on the 11th. Subsequent feeding experiments were made at intervals. Between the different feeding experiments and after their conclusion the insects were kept in a moist atmosphere at 23˚C. and when attempts to get them to suck blood failed they were fed on bananas. There were many difficulties in carrying out this investigation during the winter at a distance from our laboratory and with insects whose vital functions and metabolism during the cold weather work at a very slow rate, but except to say that the difficulties were sufficiently overcome for the purpose of our enquiry I need not enter into details. We succeeded in keeping a few insects alive for nearly a month after they had fed on suitable cases. The insects which died during the course of the enquiry were examined for developmental stages of the malaria parasite. In the result we have specimens of four insects showing the infecting stage of the parasite (sporozoites) in the salivary glands and proboscis, and a number of specimens showing the cystic stage (zygotes) in the stomach wall. These specimens prove that at temperatures which ordinarily prevail during several months of the year in England the common malaria-carrying mosquito of the country when it bites inoculated patients before quinine treatment is begun will become infective and capable of conveying malaria to other persons. Under the particular conditions of our experiments from 17 to 20 days elapsed between the time of feeding on patients and the time when the finding of sporozoites in the salivary glands proved that the mosquitoes were infective to human beings. This somewhat long period is doubtless due to the low metabolic activity of the “wintering” mosquitoes which alone were available for the experiments and to the lowered temperature to which the insects were subjected during the journeys to and from the mental hospital and during the actual feeding operations. If the experiments are repeated with freshly reared insects during the summer months the period required for reaching infectivity will almost certainly be reduced to perhaps 12 days or less.

11. I endeavoured to “round off” these results by actually conveying malaria by Nature’s method to selected G.P.I. patients in the mental hospitals at Claybury and Hanwell. For this purpose five insects which had been fed on the 7th December and subsequent dates were available on 24th December. Sporozoites had been found in the salivary glands of an insect of the same batch two days previously. Unfortunately neither on Christmas eve nor again during long trials by both day and night up to 11 p.m. on the 27th and 28th could any of the five be induced to bite. [note: ‘I am greatly obliged to Dr. Lilley at Hanwell and to Dr. Rudolf at Claybury for their patient assistance in this endeavour.’] They had been subject to severe cold during a journey to Dartford on the 21st December and our efforts to revive their activity to a degree which would prompt them to seek a meal of blood were not successful. As this endeavour was not a necessary endeavour in the proof of infectivity (which had already been furnished) and as the failure to induce the mosquitoes to bite caused some disappointment to the patients and hospitals concerned I thought it best to await more favourable climatic conditions before renewing the attempt. The five mosquitoes were killed and dissected between the 29th December and 1st January and sporozoites were found in the salivary glands of three of them.

12. Before stating certain suggestions and recommendations based on the results of this enquiry and of other observations made at the hospitals visited I note a general conclusion which seems to emerge from them. It is that no essential difference appears to be detectable between the cases of induced malaria in England and somewhat severe cases of the naturally contracted disease as it occurs in the tropics and malarious areas of Eastern Europe. Before starting my enquiries I thought it possible that inoculated malaria might differ in important respects from the naturally contracted disease and that the difference might afford justification for modifying or perhaps dispensing with, the application of the Public Health Malaria Regulations of 1919 to them. In particular I thought it possible that the cases would be of very mild type, that no relapses would follow their treatment and that the parasites in the blood of the patients would be too scanty to cause infection of mosquitoes which might bite the patient before treatment was begun. It is clear, however, that, although in these cases infection is with the “benign tertian” parasite, some at least of them are of an unusually severe type with a tendency to fatality, that in all probability there is little or no justification the view that relapses do not occur, that parasites are numerous in the blood, and that mosquitoes that bite the readily become infected and infective.

13. Another conclusion at which I have arrived is that it is now advisable to take steps to limit trials of this new line of treatment to hospitals which are adequately equipped with laboratory facilities for regular and systematic blood examinations and at which the trials can be conducted with the assistance of a medical officer or pathologist who has had adequate previous training and experience of malaria as regards both its clinical aspect and laboratory technique. This is necessary in the interests of the patients. It is also desirable in connection with securing satisfactory records for estimating the merits of the treatment and in connection with preventing the accidental spread of malaria in the hospital or outside.

14. I make the following suggestions and recommendations:

(1) In the absence of definite rules limiting the localities and seasons of the year in which the procedure of inducing malaria may be carried out in England I am of opinion that it would not be justifiable to amend or modify the Malaria Regulations of 1919 with the object of excluding those cases from the application of the regulations. This implies that each case must be notified by name and address to the local medical officer of health and to the Ministry of Health, must be placed under efficient mosquito netting or other means of protection against the bites of mosquitoes, must receive necessary and proper quinine treatment and “after-treatment”, and in the case of discharge from hospital must receive proper advice as to the precautions to be taken to prevent the spread of infection.

(2) I think, however, that, as mentioned in paragraph 13 it is not justifiable to permit trials of the method to continue except under special rules and in selected hospitals where the arrangements and procedures comply with certain requirements and are carried out or supervised by an officer with knowledge of malaria. If the Mental Asylum Service does not already possess officers with that qualification there would be no difficulty, I think, in providing by Departmental agency a sufficient course of instruction which the selected officers could attend and I consider that this plan is to be preferred to the plan of appointing one or more specialists from outside the service.

(3) I do not think it is justifiable at present (having regard especially to the unknown strains of parasites which are being employed) to encourage hospitals where the treatment is now being tried to inoculate patients for other hospitals which desire to commence a trial.

(4) Having in view that the method is still in an experimental stage it is very desirable that there should be complete uniformity of procedure and of records in all the hospitals where the trials are made, that the strain of parasite and its dosage should be the same, that the patients should receive the same quinine treatment after they have passed through the same number of rigors and that in other respect the arrangements should comply with the requirements of a scientific experiment.

(5) If it is agreed that it is practicable and desirable to make arrangements for limiting the trials to selected hospitals and for otherwise exercising supervision and control by requiring definite rules of procedure to be followed it will not, of course, be necessary to require compliance with the official Malaria Regulations as all the matters with which they are designed to deal will have received attention.

(6) Until that point is decided no useful object would be served by entering into further detail but I shall, of course, be glad to have an opportunity of discussing any of the above suggestions in conference if that procedure commends itself.

S.P. James, 11/1/24’