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The results of treatment of African trypanosomiasis in Europeans with tryparsamide and bayer 205
479 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYOIENE. Vol. X X V . No. 6. May, 1932.
T H E R E S U L T S OF T R E A T M E N T OF A F R I C A N T R Y P A N O S O M I A S I S I N EUROPEANS W I T H T R Y P A R S A M I D E AND BAYER 205. BY
PHILIP MANSON-BAHR, M.D., F.R.C.P.,* Physician to the Hospital for Tropical Diseases.
The recent paper by Dr. C. C. CHESTERMANon the results of tryparsamide and combined treatment of Gambian sleeping sickness has naturally aroused a considerable degree of interest, and has stimulated those who have had the opportunity of observing cases in Europeans to examine the final results they have obtained in the treatment of this disease. Since the publication by Dr. G. CARMICHAELLOW and myself~" in 1923 of cases of sleeping sickness treated by injection of Bayer 205, I have had the opportunity of observing eleven other cases of trypanosomiasis in Europeans over a considerable time, and of being able to examine the end results of treatment. In his paper CHESTERMANrecognises two stages of infection of the human body with trypanosomes, the first the invasion of the blood and lymph streams by these protozoa, and the second the penetration of the cerebrospinal axis and the cerebrospinal fluid. Out of the large series of 272 cases in Congo natives carefully observed over a number of years, only seventeen could be classified as belonging to the first stage, and all these were conclusively cured by tryparsamide. In the second stage cases he is able to record in his series only 26.43 per cent. of cures from tryparsamide in varying doses, although actually 50 per cent. of those who had received large doses were cured, about 30 per cent. responded to medium doses, whereas only about 12 per cent. were cured by small doses. His results with tryparsamide following Bayer 205 in second stage cases were better than with tryparsamide alone, but he confirms his previous experience that Bayer 205 alone in second stage ,cases fails to cure. He recognises clearly that, as in other prolonged h~emic infections (syphilis for example), the earlier in the course of the disease the infection is treated, the sooner a permanent cure is liable to result, but when the trypanosomes have invaded the tissues of the body, then their eradication, even by these highly * My best thanks are due to Drs. A. L. GREOa,W. E. COOKEand a succession of House Physicians at the Hospital for Tropical Diseases for their assistance in these various cases and especially to Dr. G. M. BALFOURfor his help in the compilation of this paper. I have: also to acknowledge my grateful thanks to Dr. N. HAMILTONFAIRLEYand his laboratory staff for their valuable assistance in some of the laboratory aspects of this paper. t Low, G. C., and MANSON-BAHR,P. H. (1923). Trans. Royal Soc. Trop. Med. and Hygiene xvi (7), 339-393.
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TREATMENTOF AFRICANTRYPANOSOMIASISIN EUROPEANS.
specific drugs, becomes a matter of great difficulty. Further he has shown that in the Congo native the danger of serious visual trouble, or optic atrophy, is to be expected in 30 per cent. of the cases after tryparsamide treatment. With a view of ascertaining what comparable results may be expected to be obtained in Europeans, I have summarised my experience in the treatment of eleven eases in adult European males who have come under my care during the last eight years, i.e., since 1924. Naturally, I acknowledge that this is a very small series, as compared with the material handled by CHESTERMANand other prominent workers in the same field in Central Africa, so that it seems probable that the results obtained in the treatment of Europeans living under the best conditions in the English climate, are not strictly comparable with those obtaining in Central Africa ; but there must be some explanation forthcoming for apparent discrepancies. I am able to report that these eleven eases are cured of their infection as far as can be ascertained. Some cases who relapsed clinically and parasitologically after intensive Bayer 205 treatment, have been cured by subsequent tryparsamide, and vice versa. Among these eleven cases I have to record three of Trypanosoma rhodesiense infection (Nos. 4, 5, and 10) ; the remainder were due to T.gambiense. Regarding the views I have formed on this subject, I published in 1927~, a short statement on the combined treatment of human trypanosomiasis and upon the principles on which this was based ; consequently I have noted with great interest that CHESTERMAN considers that subsequent treatment of tryparsamide-resistant cases with Bayer 205 has proved in his hands to be inefficacious, but per contra previous intravenous injection of Bayer 205 renders the trypanosomes more amenable to later tryparsamide. In the present series eight can be classified as being in the first hmmic stage, and three in the second stage with cerebrospinal fluid containing trypanosomes. Probably the best method of treating this subject is to give a short resume of each case and the main conclusions which may be drawn by the interpretation of the facts. Case 1. T. gambiense infection. First stage case. Failure of Bayer 205, subsequent success of tryparsamide. Total : Bayer 205, 5 grams ; tryparsamido 23 grams. An official, aged 49, contracted T. gambiense on the Gambia in 1923. He had been ill with fever and lassitude for one year. Diagnosed by the author by discovery of trypanosomes in blood on 23rd June, 1924. Typical rash, enlarged cervical axillary glands and splenomegaly. Marked auto-agglutination of red cells. No trypanosomes found in glands or in cerebrospinal fluid. Preliminary treatment with Bayer 205 was 5 grams. Relapse clinical and parasltological fourteen days later. Subsequent treatment, in the Hospital for Tropical Diseases, from 2nd August, 1924 to 24th September, 1924 with intraveneous tryparsamide--medium doses--2 grams three times weekly, i.e., 6 grams per week. Total 23 grams. No visual disturbances. Returned to duty in the Gambia. Has been observed at different periods during the last eight years and has since been treated for subterfian malaria. No recurrence of symptoms. * ~SON-BAHR, P.H. (1927). Proc. Roy. So¢. Mcd. Jan. 5,976-979.
PHILIP MANSON-BAHR.
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Case 2. T. gambiense infection. First stage case. Preliminary Bayer 205. Subsequent tryparsamide. Total : Bayer 205, 5 grams ; tryparsamide 12 grams. A trader, aged 24, from Fernando Po. Diagnosed as T. gambiense infection in 1924. Glandular enlargement, rash, splenomegaly. In the Hospital for Tropical Diseases from 20th July, 1925 to 28th September, 1925. Enlarged cervical and inguinal glands, splenomegaly. Treatment in Fernando Po with Bayer 205, 5 grams. Subsequently in the Hospital for Tropical Diseases, tryparsamide 12 grams, in medium doses. Maximum dose lk grams, i.e., 3 grams per week. Blood and cerebrospinal fluid normal. Relapse of B.T. Malaria after tryparsamide treatment. N o further symptoms. Case 3.
T. gambiense infection. F i r s t stage case. Bayer 205. Subsequent tryparsamide.
Total : Bayer 205, 6 grams ; tryparsamide, 2 grams.
Colonial official, aged 27 from N. Nigeria. Diagnosed at Jemaa, Nasarawa Province 9th July, 1925 by discovery of trypanosomes in blood. Temperature 104 ° F. Splenomegaly - - n o rash. Immediate injection of Bayer 205, 3 grams (1 gram on three successive days). Disappearance of symptoms. Admitted to Hospital for Tropical Diseases 28th August, 1925 to 22nd September, 1925. Further treatment Bayer 205, 3 grams, and tryparsamide 2 grams. Blood and C.S.F. normal. No further symptoms.
Case 4. ? T. rhodesiense infection. First stage case. Failure of preliminary tryparsamide. Subsequent success of Bayer 205. Planter, aged thirty, from Nyasaland. Contracted infection on Mozambique border on 1st July, 1926. Incubation period of disease definitely fourteen days. Initial remittent fever with delirium, resembling typhoid. Temperature 105 ° F. on three occasions. Enlarged axillary and cervical glands. Rash eight days after onset. Splenomegaly. Incontinence of urine. Numerous trypanosomes in blood. Tryparsamide 7 grams within ten days. Maximum dose 3 grams. F o u r days later return of symptoms with numerous trypanosomes. Injection of 2 gram Bayer 205 within five days followed by definite reaction. Admitted to HospitaI for Tropical Diseases 27th October, 1926, to 9th November, 1926. All
Case 4.
Trypanosomiasis (? T. rhodesiense). Initial fever. Incubation period fourteen days.
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TREATMENT OF AFRICAN TRYPANOSOMIASIS I N EUROPEANS.
investigation, blood and C.S.F. negative. No enlargement of spleen or glands. Considered cured. Animal inoculation (rats) negative. (Details of earlier treatment supplied by the late Dr. MILNE TOUCH). Has remained well since. Case 5. ? T. rhodesiense infection. First stage case. Early success of Bayer 205. Total : Bayer 205, 5 grams. Big game hunter, aged twenty-two, from Tanganyika. Infected in Tanganyika at Ikomo on 26th November, 1926. Temperature 104 °. Cervical adenitis, rash. T r y p a n o somes found in blood by Dr. J. F. CORSON on 30th November, 1926, confirmed by Prof. F. K. KLEINE. Immediate injections of Bayer 205, 3 grams within four days. Subsequently two further injections on 10th December, 1926 and 21st December, 1926. On arrival in England, 13th January, 1927, no enlargement of lymphatic gland or splenomegaly. C.S.F. normal. Examined one year later. Increase of weight six pounds. Has remained well since. Case 6. T. gambiense infection with mental disturbances. First stage case. Success of tryparsamide. Total : tryparsamide 23 grams. A trader, aged thirty, from the Gambia. Diagnosed there as trypanosomiasis in April, 1928. Headaches. Diurnal lethargy, nocturnal insomnia. Enlarged cervical glands, splenomegaly. No rash. Admitted to Hospital for Tropical Diseases 26th April, 1928 to 23rd May, 1928. Lethargic, splenomegaly, tremors, marked autoagglutination of blood. Some anzemia. T. gambiense found in blood. C.S.F. normal. Tryparsamide, large doses, twelve injections total 23 grams, average six grams per week in three injections of 2 grams each. No complications or visual disturbances. Optic discs normal. Re-examined irt September, 1928. Then no evidence of trypanosomiasis. Has remained well since. Case 7, T gambiense infection. Second stage case. Success of combined treatment. Total : Tryparsamide, 24 grams ; Bayer 205, 2 grams. Colonial official, aged thirty-seven, from Uganda. October, 1928, complained of febrile attacks with lethargy and loss of power, ataxia. June, 1929, trypanosomes found in blood and cerebrospinal fluid. Treatment. Tryparsamide 16 grams in eight weekly injections of 2 grams each. Subsequently two injections of Bayer 205 of 1 gram each and four further injections of tryparsamide of 2 grams each. Admitted to Hospital for Tropical Diseases 1st July, 1929 for investigation. Some. splenomegaly. Blood and C.S.F. normal. Reexamined by Dr. A. E. HORN, on 29th October, 1931 to whom I am indebted for details. T h e n in good health. No further evidence of trypanosomiasis. Case 8. T. gambiense infection. First stage case. Success of combined treatment. Total • Bayer 205, 9 grams ; tryparsamid% 18 grams. A diver, aged thirty-three, employed at Kinshasha on the Congo. Apparently first infected in April, 1928. In July, 1928 clinical symptoms--enlarged glands and splenomegaly. December, 1928, complaining of fatigue and insomnia. Trypanosomes found in blood. Preliminary. treatment, 9 grams Bayer 205 in doses of 1 gram each. Subsequently tryparsamide 18 grams. Maximum dose 2 grams. Further treatment discontinued on account of visual disturbances (tryparsamide)--impairment of vision. Concentric reduction of visual fields. Albuminuria. C.S.F. examined upon leaving Hospital at Kinshasha--normal. N o trypanosomes found in blood after triple centrifugation. Admitted to Hospital for Tropical Diseases 24th July, 1929 to 10th August, 1929. Loss of memory, headaches--neurasthenia marked. No fundus changes found. Loss of vision ascribed to errors of refraction. N o signs of trypanosomiasis found in Hospital for Tropical Diseases. Blood and C.S.F. normal. (For details I am indebted to the late Dr. HARALD SEIDELIN). Case 9. T. gambiense infection. Second stage case. Total : Preliminary Bayer 205, 2 grams ; tryparsamide, 23 grams. No visual disturbance. Success of combined treatment. Preliminary Bayer 205, later tryparsamide. A trader, aged forty, eighteen years service on the Gold Coast, chiefly in the Accra district. Some time in the Spring of 1929 bitten b y glossina. Local, painful swelling half an inch in diameter on left instep. Twenty-one days later erythematous rash followed, enlarged glands in left groin, pyrexia. Treated as enteric on 9th June, 1929. Returned to England in poor" health. Loss of weight, pyrexia, enlarged glands in axilla and neck,
PHILIP MANSON-BAHR.
483
erythematous rash gradually appeared. Nature of illness not suspected till more than a year later. Admitted to Hospital for Tropical Diseases on 3rd July, 1930. Marked case of trypanosomiasis. Trypanosomes in blood, gland juice and C.S.F. Marked autoagglutination of blood. C.S.F. under pressure, excess of globulin : cells 35 per c.mm. Rats repeatedly inoculated failed to contract infection. Preliminary injection Bayer 205, 2 grams within three days. Tryparsamide well tolerated, average 6 grams per week. Twenty-three grams given within a period of twenty-eight days. No visual disturbances. C.S.F. examined 15th August, 1930. Fluid and cells normal. Re-examined in February, 1932. C.S.F. and blood normal. No autoagglutination of red cells found. Optic discs normal. N o visual disturbances.
Case 10. T. rhodesiense infection. Second stage case. Failure of Bayer 205 and tryparsamide in initial fever and first relapse. Eventual success of combined treatment. Engineer, aged twenty-nine, infected in August, 1928 in Luangwa Valley, N. Rhodesia. N o record of bite of glossina. Pyrexia, lethargy, abdominal pain. Treated with Bayer 205 and tryparsamide (quantity unknown). Course of treatment said to have been repeated in March, 1929, but details are vague. Relapse in October, 1929. Treated by Dr. R. M. MORRIS, of Salisbury, Rhodesia (to whom I am indebted for details). Trypanosomes found in blood. Rat inoculation positive T. rhodesiense. Treatment for First Relapse. Bayer 205, 6 grams at three days interval. Subsequent tryparsamide 13 grams. Maximum dose 2 grams at weekly intervals. First relapse. Total : Bayer 205, 5 grams ; tryparsamide, 13 grams. Admitted to Hospital for Tropical Diseases 27th August, 1930 to 13th November, 1930. Second Relapse. Headaches, pyrexia, Temperature 103 ° restlessness, tremors, splenomegaly. T. rhodesiense in blood. Inoculation into rats (Dr. C. M. WENYON) posterior nucleated forms. C.S.F. under pressure. Ninety-two cells per c.mm. globulin -[-. trypanosomes present in numbers. Autoagglutlnation of red blood corpuscles. Treatment for Second Relapse. Tryparsamide 2 grams then Bayer 205, 2 grams followed by tryparsamide 11 grams, maximum dose 3 grams at three-day intervals. See0nd relapse. Total : Tryparsamide, 13 grams ; Bayer 205, 5 grams. Complained of dimness of vision and contraction of visual fields. Atrophic patches noted on temporal margin of each disc. Immediate injection of 10.8 gram thiostab intravenously with improvement in vision. Subsequently three more injections of Bayer 205 (3 grams) at weekly intervals. No alteration in state of discs noted. Re-examined 29th May, 1931 to 5th June, 1931. Improvement in visual powers, though still contraction of field. No extension of atrophy. No clinical evidence of trypanosomiasis. C.S.F. nineteen cells per c.mm. No trypanosomes. After being passed as probably cured of trypanosomiasis, returned to Rhodesia in August, 1931, managed estate of 15,000 acres with success. In September, 1931, and again in November, 1931, and January, 1932, suffered from intermittent febrile attacks with cerebral symptoms. No tests being locally available, was suspected of further relapse of trypanosomiasis, therefore admitted to Hospital in Northern Rhodesia for fifteen days in January, 1932. Treated with three injections of tryparsamide (3 grams); and two injections of Bayer 205 (2 grams) and quinine, the latter appeared to control the fever but further tryparsamide was withheld on account of danger to vision. Was sent home under suspicion o£ relapse of trypanosomiasis. Re-admitted to Hospital for Tropical Diseases on 20th March, 1932. Spleen now found definitely enlarged, subtertian parasites (crescents) in blood. Malarial flocculation test (Henry) positive, C.S.F. normal, no globulin, no cells, no trypanosomes, no autoagglutination of red blood corpuscles. No clinical signs of trypanosomiasis. Report on vision (Col. H. KIRKPATRICK),no material alteration, if anything, improvement in June, 1931. Result : all evidence points to cure of trypanosomiasis, cause of supposed relapse found to be subtertian malaria. Case 11. T. gambiense infection. First stage case. Successful treatment with Bayer 205. Total : Bayer 205, 3 grams ; tartar emetic 6 grams. Mining engineer, aged thirty-three, from Bauchi Plateau, Northern Nigeria. Bitten by glossina on 1st September, 1930. Site of infective bite became inflamed and cedematous.
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(T. gambiense).
Incubation period of disease accurately known as twenty-three days. Headaches, initial high pyrexia. Temperature 104 ° F. No palpable glands or enlarged spleen. ~During fourteen days, 27th September, 1930 to l l t h October, 1930, injected Bayer 205, 3 grams and tartar emetic 6 grams (for details I am indebted to Dr. N. A. DYCE SHARP). Admitted to Hospital for Tropical Diseases, 14 November to 4th December, 1930 for complete investigation. No physical signs whatever. Blood and C.S.F. negative. No symptoms since. This patient was therefore treated in initial fever with 3 grams Bayer 205 within one week and this apparently eradicated the infection.
DISCUSSION. I t m a y be a r g u e d t h a t it is n o t permissible to d r a w conclusions f r o m s u c h a c o m p a r a t i v e l y small n u m b e r of cases, b u t one c a n n o t avoid b e i n g influenced b y personal experiences gained over a n u m b e r of years a n d in E u r o p e a n s w h o have b e e n carefully w a t c h e d a n d w h o s e s u b s e q u e n t h i s t o r y can be traced. M y results a p p e a r to agree with CHESTERMAN'S in one r e s p e c t - - n a m e l y - - t h a t c o m b i n e d t r e a t m e n t in t r y p a n o s o m i a s i s is m o r e effective t h a n t h e p u s h i n g of one individual d r u g to t h e e x t r e m e s of tolerance after parasitical relapses have
PHILIP MANSON-BAHR.
485
taken place ; nor does success appear to depend upon the size of the dose or the length of the course of treatment, at any rate, in first stage cases, but rather upon the time that the infection has lasted and the spacing of the drug. In Cases 3, 5, 6, and 11 where the trypanosomiasis has been treated within three weeks from time of infection (where this can be accurately ascertained) or in the incubation stage of the disease, equally successful results have to be recorded whether tryparsamide or Bayer 205 has been employed whilst, in Case 11, I have to record a permanent cure after as small a dose as three grams of Bayer 205. In cases in which the trypanosome infection has become well established, I have to record, as in Case 1 the primary and undoubted failure of Bayer 205, and the subsequent success of tryparsamide, and in Case 9 the almost immediate success in a second stage case of a combination of the two. T. rhodesiense infections are naturally more difficult to cure. Case 4 was treated immediately on appearance of symptoms and showed no reaction to tryparsamide, but responded immediately to Bayer 205, and Case 10 whose infection appeared at first to be equally resistant to both remedies, but eventually recovered after suffering from serious disturbance of vision. It is doubtful whether he would ever have been cured unless a second course of tryparsamide had been pushed to the limit, for in this case Bayer 205 had little effect. If any conclusions can be drawn from the above records it is, I think, that Bayer 205 followed by tryparsamide, gives the most hopeful outlook, but, as originally advocated by KLEIN~,~ the former drug should be pushed in the first instance to three grams in the first week. Subsequent tryparsamide injections should be given in tolerated doses. Three of my cases received as much as six grams per week, but it is possible that this dose is too large for the average European male. There is only one record of optic neuritis due to tryparsamide treatment (Case 10) and in this instance the damage was not serious, but it appeared as if preliminary tryparsamide dosage ten months previously, had rendered him more liable to toxic disturbances from this drug. CHESTERMAN has pointed out the apparent non-success of Bayer 205 treatment following prolonged tryparsamide, when, apparently, the trypanosomes have become arsenic-resistant. M y own impressions of this subject are that in Europeans this is the method by which success is to be obtained. I would like to quote once more in support of this view the first case I reported in 1923 (S.B.J.)t This man who, after having suffered for two years (1920 and 19_291) from chronic trypanosomiasis and who obviously was in the second stage of the disease, was apparently cured after receiving three grams of Bayer 205 intravenously on three consecutive days, He has had no signs of recurrence since. * KLEINE, F. K., 1924, Trans. Roy. Soc. Trop. Med. ~ Hygiene, xvii (8), 462. J- Low, G. C. and MANSON-BAHR,P. H., 1923, Trans. Roy. Soc. Trop. M e d . & Hygiene, xvi (7), 356.
486
TREATMENT OF AFRICAN TRYPANOSOMIASIS I N EUROPEANS.
He had received over 179 grains of atoxyl and large quantities of liquor arsenicalis, so it may be assumed with some probability that in his case the trypanosomes had become what is called arsenic-fast. In the literature of recent years several workers have reached similar conclusions upon the rationale of the combined treatment. MACLEAN*has advocated in Rhodesian cases preliminary Bayer 205 followed by tryparsamide.
O MACLEAN, G.
(1929), Ann. Trop. Med. ~ Paras#, xxiii (3), 337-344.
T H E R E S U L T S OF T R E A T M E N T OF A F R I C A N T R Y P A N O S O M I A S I S I N EUROPEANS W I T H T R Y P A R S A M I D E AND BAYER 205. BY
PHILIP MANSON-BAHR, M.D., F.R.C.P.,* Physician to the Hospital for Tropical Diseases.
The recent paper by Dr. C. C. CHESTERMANon the results of tryparsamide and combined treatment of Gambian sleeping sickness has naturally aroused a considerable degree of interest, and has stimulated those who have had the opportunity of observing cases in Europeans to examine the final results they have obtained in the treatment of this disease. Since the publication by Dr. G. CARMICHAELLOW and myself~" in 1923 of cases of sleeping sickness treated by injection of Bayer 205, I have had the opportunity of observing eleven other cases of trypanosomiasis in Europeans over a considerable time, and of being able to examine the end results of treatment. In his paper CHESTERMANrecognises two stages of infection of the human body with trypanosomes, the first the invasion of the blood and lymph streams by these protozoa, and the second the penetration of the cerebrospinal axis and the cerebrospinal fluid. Out of the large series of 272 cases in Congo natives carefully observed over a number of years, only seventeen could be classified as belonging to the first stage, and all these were conclusively cured by tryparsamide. In the second stage cases he is able to record in his series only 26.43 per cent. of cures from tryparsamide in varying doses, although actually 50 per cent. of those who had received large doses were cured, about 30 per cent. responded to medium doses, whereas only about 12 per cent. were cured by small doses. His results with tryparsamide following Bayer 205 in second stage cases were better than with tryparsamide alone, but he confirms his previous experience that Bayer 205 alone in second stage ,cases fails to cure. He recognises clearly that, as in other prolonged h~emic infections (syphilis for example), the earlier in the course of the disease the infection is treated, the sooner a permanent cure is liable to result, but when the trypanosomes have invaded the tissues of the body, then their eradication, even by these highly * My best thanks are due to Drs. A. L. GREOa,W. E. COOKEand a succession of House Physicians at the Hospital for Tropical Diseases for their assistance in these various cases and especially to Dr. G. M. BALFOURfor his help in the compilation of this paper. I have: also to acknowledge my grateful thanks to Dr. N. HAMILTONFAIRLEYand his laboratory staff for their valuable assistance in some of the laboratory aspects of this paper. t Low, G. C., and MANSON-BAHR,P. H. (1923). Trans. Royal Soc. Trop. Med. and Hygiene xvi (7), 339-393.
480
TREATMENTOF AFRICANTRYPANOSOMIASISIN EUROPEANS.
specific drugs, becomes a matter of great difficulty. Further he has shown that in the Congo native the danger of serious visual trouble, or optic atrophy, is to be expected in 30 per cent. of the cases after tryparsamide treatment. With a view of ascertaining what comparable results may be expected to be obtained in Europeans, I have summarised my experience in the treatment of eleven eases in adult European males who have come under my care during the last eight years, i.e., since 1924. Naturally, I acknowledge that this is a very small series, as compared with the material handled by CHESTERMANand other prominent workers in the same field in Central Africa, so that it seems probable that the results obtained in the treatment of Europeans living under the best conditions in the English climate, are not strictly comparable with those obtaining in Central Africa ; but there must be some explanation forthcoming for apparent discrepancies. I am able to report that these eleven eases are cured of their infection as far as can be ascertained. Some cases who relapsed clinically and parasitologically after intensive Bayer 205 treatment, have been cured by subsequent tryparsamide, and vice versa. Among these eleven cases I have to record three of Trypanosoma rhodesiense infection (Nos. 4, 5, and 10) ; the remainder were due to T.gambiense. Regarding the views I have formed on this subject, I published in 1927~, a short statement on the combined treatment of human trypanosomiasis and upon the principles on which this was based ; consequently I have noted with great interest that CHESTERMAN considers that subsequent treatment of tryparsamide-resistant cases with Bayer 205 has proved in his hands to be inefficacious, but per contra previous intravenous injection of Bayer 205 renders the trypanosomes more amenable to later tryparsamide. In the present series eight can be classified as being in the first hmmic stage, and three in the second stage with cerebrospinal fluid containing trypanosomes. Probably the best method of treating this subject is to give a short resume of each case and the main conclusions which may be drawn by the interpretation of the facts. Case 1. T. gambiense infection. First stage case. Failure of Bayer 205, subsequent success of tryparsamide. Total : Bayer 205, 5 grams ; tryparsamido 23 grams. An official, aged 49, contracted T. gambiense on the Gambia in 1923. He had been ill with fever and lassitude for one year. Diagnosed by the author by discovery of trypanosomes in blood on 23rd June, 1924. Typical rash, enlarged cervical axillary glands and splenomegaly. Marked auto-agglutination of red cells. No trypanosomes found in glands or in cerebrospinal fluid. Preliminary treatment with Bayer 205 was 5 grams. Relapse clinical and parasltological fourteen days later. Subsequent treatment, in the Hospital for Tropical Diseases, from 2nd August, 1924 to 24th September, 1924 with intraveneous tryparsamide--medium doses--2 grams three times weekly, i.e., 6 grams per week. Total 23 grams. No visual disturbances. Returned to duty in the Gambia. Has been observed at different periods during the last eight years and has since been treated for subterfian malaria. No recurrence of symptoms. * ~SON-BAHR, P.H. (1927). Proc. Roy. So¢. Mcd. Jan. 5,976-979.
PHILIP MANSON-BAHR.
481
Case 2. T. gambiense infection. First stage case. Preliminary Bayer 205. Subsequent tryparsamide. Total : Bayer 205, 5 grams ; tryparsamide 12 grams. A trader, aged 24, from Fernando Po. Diagnosed as T. gambiense infection in 1924. Glandular enlargement, rash, splenomegaly. In the Hospital for Tropical Diseases from 20th July, 1925 to 28th September, 1925. Enlarged cervical and inguinal glands, splenomegaly. Treatment in Fernando Po with Bayer 205, 5 grams. Subsequently in the Hospital for Tropical Diseases, tryparsamide 12 grams, in medium doses. Maximum dose lk grams, i.e., 3 grams per week. Blood and cerebrospinal fluid normal. Relapse of B.T. Malaria after tryparsamide treatment. N o further symptoms. Case 3.
T. gambiense infection. F i r s t stage case. Bayer 205. Subsequent tryparsamide.
Total : Bayer 205, 6 grams ; tryparsamide, 2 grams.
Colonial official, aged 27 from N. Nigeria. Diagnosed at Jemaa, Nasarawa Province 9th July, 1925 by discovery of trypanosomes in blood. Temperature 104 ° F. Splenomegaly - - n o rash. Immediate injection of Bayer 205, 3 grams (1 gram on three successive days). Disappearance of symptoms. Admitted to Hospital for Tropical Diseases 28th August, 1925 to 22nd September, 1925. Further treatment Bayer 205, 3 grams, and tryparsamide 2 grams. Blood and C.S.F. normal. No further symptoms.
Case 4. ? T. rhodesiense infection. First stage case. Failure of preliminary tryparsamide. Subsequent success of Bayer 205. Planter, aged thirty, from Nyasaland. Contracted infection on Mozambique border on 1st July, 1926. Incubation period of disease definitely fourteen days. Initial remittent fever with delirium, resembling typhoid. Temperature 105 ° F. on three occasions. Enlarged axillary and cervical glands. Rash eight days after onset. Splenomegaly. Incontinence of urine. Numerous trypanosomes in blood. Tryparsamide 7 grams within ten days. Maximum dose 3 grams. F o u r days later return of symptoms with numerous trypanosomes. Injection of 2 gram Bayer 205 within five days followed by definite reaction. Admitted to HospitaI for Tropical Diseases 27th October, 1926, to 9th November, 1926. All
Case 4.
Trypanosomiasis (? T. rhodesiense). Initial fever. Incubation period fourteen days.
482
TREATMENT OF AFRICAN TRYPANOSOMIASIS I N EUROPEANS.
investigation, blood and C.S.F. negative. No enlargement of spleen or glands. Considered cured. Animal inoculation (rats) negative. (Details of earlier treatment supplied by the late Dr. MILNE TOUCH). Has remained well since. Case 5. ? T. rhodesiense infection. First stage case. Early success of Bayer 205. Total : Bayer 205, 5 grams. Big game hunter, aged twenty-two, from Tanganyika. Infected in Tanganyika at Ikomo on 26th November, 1926. Temperature 104 °. Cervical adenitis, rash. T r y p a n o somes found in blood by Dr. J. F. CORSON on 30th November, 1926, confirmed by Prof. F. K. KLEINE. Immediate injections of Bayer 205, 3 grams within four days. Subsequently two further injections on 10th December, 1926 and 21st December, 1926. On arrival in England, 13th January, 1927, no enlargement of lymphatic gland or splenomegaly. C.S.F. normal. Examined one year later. Increase of weight six pounds. Has remained well since. Case 6. T. gambiense infection with mental disturbances. First stage case. Success of tryparsamide. Total : tryparsamide 23 grams. A trader, aged thirty, from the Gambia. Diagnosed there as trypanosomiasis in April, 1928. Headaches. Diurnal lethargy, nocturnal insomnia. Enlarged cervical glands, splenomegaly. No rash. Admitted to Hospital for Tropical Diseases 26th April, 1928 to 23rd May, 1928. Lethargic, splenomegaly, tremors, marked autoagglutination of blood. Some anzemia. T. gambiense found in blood. C.S.F. normal. Tryparsamide, large doses, twelve injections total 23 grams, average six grams per week in three injections of 2 grams each. No complications or visual disturbances. Optic discs normal. Re-examined irt September, 1928. Then no evidence of trypanosomiasis. Has remained well since. Case 7, T gambiense infection. Second stage case. Success of combined treatment. Total : Tryparsamide, 24 grams ; Bayer 205, 2 grams. Colonial official, aged thirty-seven, from Uganda. October, 1928, complained of febrile attacks with lethargy and loss of power, ataxia. June, 1929, trypanosomes found in blood and cerebrospinal fluid. Treatment. Tryparsamide 16 grams in eight weekly injections of 2 grams each. Subsequently two injections of Bayer 205 of 1 gram each and four further injections of tryparsamide of 2 grams each. Admitted to Hospital for Tropical Diseases 1st July, 1929 for investigation. Some. splenomegaly. Blood and C.S.F. normal. Reexamined by Dr. A. E. HORN, on 29th October, 1931 to whom I am indebted for details. T h e n in good health. No further evidence of trypanosomiasis. Case 8. T. gambiense infection. First stage case. Success of combined treatment. Total • Bayer 205, 9 grams ; tryparsamid% 18 grams. A diver, aged thirty-three, employed at Kinshasha on the Congo. Apparently first infected in April, 1928. In July, 1928 clinical symptoms--enlarged glands and splenomegaly. December, 1928, complaining of fatigue and insomnia. Trypanosomes found in blood. Preliminary. treatment, 9 grams Bayer 205 in doses of 1 gram each. Subsequently tryparsamide 18 grams. Maximum dose 2 grams. Further treatment discontinued on account of visual disturbances (tryparsamide)--impairment of vision. Concentric reduction of visual fields. Albuminuria. C.S.F. examined upon leaving Hospital at Kinshasha--normal. N o trypanosomes found in blood after triple centrifugation. Admitted to Hospital for Tropical Diseases 24th July, 1929 to 10th August, 1929. Loss of memory, headaches--neurasthenia marked. No fundus changes found. Loss of vision ascribed to errors of refraction. N o signs of trypanosomiasis found in Hospital for Tropical Diseases. Blood and C.S.F. normal. (For details I am indebted to the late Dr. HARALD SEIDELIN). Case 9. T. gambiense infection. Second stage case. Total : Preliminary Bayer 205, 2 grams ; tryparsamide, 23 grams. No visual disturbance. Success of combined treatment. Preliminary Bayer 205, later tryparsamide. A trader, aged forty, eighteen years service on the Gold Coast, chiefly in the Accra district. Some time in the Spring of 1929 bitten b y glossina. Local, painful swelling half an inch in diameter on left instep. Twenty-one days later erythematous rash followed, enlarged glands in left groin, pyrexia. Treated as enteric on 9th June, 1929. Returned to England in poor" health. Loss of weight, pyrexia, enlarged glands in axilla and neck,
PHILIP MANSON-BAHR.
483
erythematous rash gradually appeared. Nature of illness not suspected till more than a year later. Admitted to Hospital for Tropical Diseases on 3rd July, 1930. Marked case of trypanosomiasis. Trypanosomes in blood, gland juice and C.S.F. Marked autoagglutination of blood. C.S.F. under pressure, excess of globulin : cells 35 per c.mm. Rats repeatedly inoculated failed to contract infection. Preliminary injection Bayer 205, 2 grams within three days. Tryparsamide well tolerated, average 6 grams per week. Twenty-three grams given within a period of twenty-eight days. No visual disturbances. C.S.F. examined 15th August, 1930. Fluid and cells normal. Re-examined in February, 1932. C.S.F. and blood normal. No autoagglutination of red cells found. Optic discs normal. N o visual disturbances.
Case 10. T. rhodesiense infection. Second stage case. Failure of Bayer 205 and tryparsamide in initial fever and first relapse. Eventual success of combined treatment. Engineer, aged twenty-nine, infected in August, 1928 in Luangwa Valley, N. Rhodesia. N o record of bite of glossina. Pyrexia, lethargy, abdominal pain. Treated with Bayer 205 and tryparsamide (quantity unknown). Course of treatment said to have been repeated in March, 1929, but details are vague. Relapse in October, 1929. Treated by Dr. R. M. MORRIS, of Salisbury, Rhodesia (to whom I am indebted for details). Trypanosomes found in blood. Rat inoculation positive T. rhodesiense. Treatment for First Relapse. Bayer 205, 6 grams at three days interval. Subsequent tryparsamide 13 grams. Maximum dose 2 grams at weekly intervals. First relapse. Total : Bayer 205, 5 grams ; tryparsamide, 13 grams. Admitted to Hospital for Tropical Diseases 27th August, 1930 to 13th November, 1930. Second Relapse. Headaches, pyrexia, Temperature 103 ° restlessness, tremors, splenomegaly. T. rhodesiense in blood. Inoculation into rats (Dr. C. M. WENYON) posterior nucleated forms. C.S.F. under pressure. Ninety-two cells per c.mm. globulin -[-. trypanosomes present in numbers. Autoagglutlnation of red blood corpuscles. Treatment for Second Relapse. Tryparsamide 2 grams then Bayer 205, 2 grams followed by tryparsamide 11 grams, maximum dose 3 grams at three-day intervals. See0nd relapse. Total : Tryparsamide, 13 grams ; Bayer 205, 5 grams. Complained of dimness of vision and contraction of visual fields. Atrophic patches noted on temporal margin of each disc. Immediate injection of 10.8 gram thiostab intravenously with improvement in vision. Subsequently three more injections of Bayer 205 (3 grams) at weekly intervals. No alteration in state of discs noted. Re-examined 29th May, 1931 to 5th June, 1931. Improvement in visual powers, though still contraction of field. No extension of atrophy. No clinical evidence of trypanosomiasis. C.S.F. nineteen cells per c.mm. No trypanosomes. After being passed as probably cured of trypanosomiasis, returned to Rhodesia in August, 1931, managed estate of 15,000 acres with success. In September, 1931, and again in November, 1931, and January, 1932, suffered from intermittent febrile attacks with cerebral symptoms. No tests being locally available, was suspected of further relapse of trypanosomiasis, therefore admitted to Hospital in Northern Rhodesia for fifteen days in January, 1932. Treated with three injections of tryparsamide (3 grams); and two injections of Bayer 205 (2 grams) and quinine, the latter appeared to control the fever but further tryparsamide was withheld on account of danger to vision. Was sent home under suspicion o£ relapse of trypanosomiasis. Re-admitted to Hospital for Tropical Diseases on 20th March, 1932. Spleen now found definitely enlarged, subtertian parasites (crescents) in blood. Malarial flocculation test (Henry) positive, C.S.F. normal, no globulin, no cells, no trypanosomes, no autoagglutination of red blood corpuscles. No clinical signs of trypanosomiasis. Report on vision (Col. H. KIRKPATRICK),no material alteration, if anything, improvement in June, 1931. Result : all evidence points to cure of trypanosomiasis, cause of supposed relapse found to be subtertian malaria. Case 11. T. gambiense infection. First stage case. Successful treatment with Bayer 205. Total : Bayer 205, 3 grams ; tartar emetic 6 grams. Mining engineer, aged thirty-three, from Bauchi Plateau, Northern Nigeria. Bitten by glossina on 1st September, 1930. Site of infective bite became inflamed and cedematous.
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Incubation period of disease accurately known as twenty-three days. Headaches, initial high pyrexia. Temperature 104 ° F. No palpable glands or enlarged spleen. ~During fourteen days, 27th September, 1930 to l l t h October, 1930, injected Bayer 205, 3 grams and tartar emetic 6 grams (for details I am indebted to Dr. N. A. DYCE SHARP). Admitted to Hospital for Tropical Diseases, 14 November to 4th December, 1930 for complete investigation. No physical signs whatever. Blood and C.S.F. negative. No symptoms since. This patient was therefore treated in initial fever with 3 grams Bayer 205 within one week and this apparently eradicated the infection.
DISCUSSION. I t m a y be a r g u e d t h a t it is n o t permissible to d r a w conclusions f r o m s u c h a c o m p a r a t i v e l y small n u m b e r of cases, b u t one c a n n o t avoid b e i n g influenced b y personal experiences gained over a n u m b e r of years a n d in E u r o p e a n s w h o have b e e n carefully w a t c h e d a n d w h o s e s u b s e q u e n t h i s t o r y can be traced. M y results a p p e a r to agree with CHESTERMAN'S in one r e s p e c t - - n a m e l y - - t h a t c o m b i n e d t r e a t m e n t in t r y p a n o s o m i a s i s is m o r e effective t h a n t h e p u s h i n g of one individual d r u g to t h e e x t r e m e s of tolerance after parasitical relapses have
PHILIP MANSON-BAHR.
485
taken place ; nor does success appear to depend upon the size of the dose or the length of the course of treatment, at any rate, in first stage cases, but rather upon the time that the infection has lasted and the spacing of the drug. In Cases 3, 5, 6, and 11 where the trypanosomiasis has been treated within three weeks from time of infection (where this can be accurately ascertained) or in the incubation stage of the disease, equally successful results have to be recorded whether tryparsamide or Bayer 205 has been employed whilst, in Case 11, I have to record a permanent cure after as small a dose as three grams of Bayer 205. In cases in which the trypanosome infection has become well established, I have to record, as in Case 1 the primary and undoubted failure of Bayer 205, and the subsequent success of tryparsamide, and in Case 9 the almost immediate success in a second stage case of a combination of the two. T. rhodesiense infections are naturally more difficult to cure. Case 4 was treated immediately on appearance of symptoms and showed no reaction to tryparsamide, but responded immediately to Bayer 205, and Case 10 whose infection appeared at first to be equally resistant to both remedies, but eventually recovered after suffering from serious disturbance of vision. It is doubtful whether he would ever have been cured unless a second course of tryparsamide had been pushed to the limit, for in this case Bayer 205 had little effect. If any conclusions can be drawn from the above records it is, I think, that Bayer 205 followed by tryparsamide, gives the most hopeful outlook, but, as originally advocated by KLEIN~,~ the former drug should be pushed in the first instance to three grams in the first week. Subsequent tryparsamide injections should be given in tolerated doses. Three of my cases received as much as six grams per week, but it is possible that this dose is too large for the average European male. There is only one record of optic neuritis due to tryparsamide treatment (Case 10) and in this instance the damage was not serious, but it appeared as if preliminary tryparsamide dosage ten months previously, had rendered him more liable to toxic disturbances from this drug. CHESTERMAN has pointed out the apparent non-success of Bayer 205 treatment following prolonged tryparsamide, when, apparently, the trypanosomes have become arsenic-resistant. M y own impressions of this subject are that in Europeans this is the method by which success is to be obtained. I would like to quote once more in support of this view the first case I reported in 1923 (S.B.J.)t This man who, after having suffered for two years (1920 and 19_291) from chronic trypanosomiasis and who obviously was in the second stage of the disease, was apparently cured after receiving three grams of Bayer 205 intravenously on three consecutive days, He has had no signs of recurrence since. * KLEINE, F. K., 1924, Trans. Roy. Soc. Trop. Med. ~ Hygiene, xvii (8), 462. J- Low, G. C. and MANSON-BAHR,P. H., 1923, Trans. Roy. Soc. Trop. M e d . & Hygiene, xvi (7), 356.
486
TREATMENT OF AFRICAN TRYPANOSOMIASIS I N EUROPEANS.
He had received over 179 grains of atoxyl and large quantities of liquor arsenicalis, so it may be assumed with some probability that in his case the trypanosomes had become what is called arsenic-fast. In the literature of recent years several workers have reached similar conclusions upon the rationale of the combined treatment. MACLEAN*has advocated in Rhodesian cases preliminary Bayer 205 followed by tryparsamide.
O MACLEAN, G.
(1929), Ann. Trop. Med. ~ Paras#, xxiii (3), 337-344.