LEPROSY REVIEW

The Quarterly Publication of

THE BRITISH LEPROSY RELIEF ASSOCIATION

VOL. xxx. No. 4 OCTOBER 1959

Principal Contents

Editorial Two Years' Experience of Ciba 1906 in the Treatment of Leprosy The Multipuncture Depot Lepromin Test with Different Antigens

Intramuscular Injection of Sulphones Circulation in the Feet of Leprosy Patients The Etiology of Plantar Ulcers A Tension Equaliser in the Operation for Claw Hands A Modified Technique for Staining Leprosy Bacilli Letters to the Editor

Abstracts Report Review

8 PORTMAN STREET, LONDON, W.l

Price: Three Shillings and Sixpence, plus postage Annual Subscription: Fifteen Shillings, including postage LEPROSY REVIEW

VOL. xxx, No. 4 OCTOBER, 1959

CONTENTS

PAGE EDITORIAL A Further Report on the Diphenylthiourea, Ciba 1906 208

Comparative Clinical Trial of I njection Therapy 208

The Multipuncture Type Lepromin Test 209

Two Years' Experience with Diphenylthiourea (OPT or Ciba 1906) in the Treatment of Leprosy, J. M. B. GARROD 210

The Multipuncture Depot Lepromin Test ; Investigations with Different Antigens, J. A. KINNEAR BROWN and M. M. STONE 215

Short and Long Acting Sulphones by Intramuscular Injection, G. CURRIE 220

Circulation in the Feet of Leprosy Patients, with and without Ulcers, B. B. GOKHALE, S. M. VABLE, and SUMAN MODAK 234

Studies in Plantar Ulcers in Leprosy : IV The Etiology of Plantar Ulcers, E. W. PRICE 242

Use of a Tension Equaliser in the Many Tailed Operation for Claw Hands, R. H. THANGARAJ . . 249

A Modified Technique for Staining Leprosy Bacilli in Sme-drs, R. RHODES- fuNB HI

Letter to the Editor on press report of 2nd WHO Expert Committee on Leprosy,H. W. WADE 252

Letter to the Editor on "blue-black macules", BASIL NICHOLSON 254

Abstracts 255

Report 268

Review 269

Edited by DR. J. Ross INNES, Medical Secretary of the British Leprosy Relief Association, 8 Portman Street, London, W.l, to whom all communications should be sent. The Association does not accept any responsibility for views expressed by writers.

Contributors of original articles will receive 25 loose reprints free, but more formal bound reprints must be ordered at time of submitting the article, and the cost reimbursed later. 208 LEPROSY REVIEW

EDITORIAL

A Further Report on the DiphenyIthiourea, Ciba J906 Dr. Garrod of the East African Lepros y Research Centre gives in this issue (p. 210) his experiences withCiba 1906, which follow up the earlier reports of Ross Innes et all from the same Centre, and the earliest and later reports by Davey and Currie2 and Davey). Garrod's results are a general confirmation of the previous work. He draws attention more to the great reduction in the incidence of reactions during administration of Ciba 1906 for long periods, and reports that this drug has been fo und to be useful in cases resistant to the stan­ dard treatment by DDS; also it has been free from toxic effects, and as regards the fa ll in bacterial index as compared with standard treatment, in the first 12 months the advantage lies with Ciba 1906. ft seems that the advantages of this drug are very solid ones, and either alone or in combination it is emerging as a valuable standard treatment of leprosy. Much is sometimes made of the somewhat greater cost of this drug, but fo rtunately for the patient most physicians find an irresistible attraction in using a drug which is the more efficient, in spite of greater price, as in that way lies true economy in the end.

Comparative Clinical Trial of Injection Therapy In this issue Dr. Gordon Currie gives a very useful and careful study of the important differences in behaviour of the various injections of DDS (p. 220). Against a control group on oral DDS he tried DDS suspended in ethyl esters of hydnocarpus oil, DDS in an aqueous suspension, and DDS in the form of a special soluble sul­ phone. He evaluated these by records of the improvement in bacillary index and the evidence of degenerative changes in the bacilli, and objective and subjective clinical improvement, as well as occurrence of the reaction ENL. He usefully distinguishes between side effects and true leprosy reactions, and it is important that he also made a note of the incidence of pain as a result of the injection, and investi­ gated the occurrence of anaemia in the different methods. While there was little to choose between the therapeutic effectiveness of the sulphones, whether given by mouth or injected, there were distinct differences in other directions� There was no significant lessening of the incidence of ENL by the parenteral methods, but there was a great diminution of unpleasant and depressive side effects. There was an increased incidence of ENL with the oily suspension group, and the cause of this remains obscure. The oily suspension was undoubtedly difficult to inject, and quite painful, whereas the aqueous suspension was easy and relatively painless. Dr. Currie discusses the psycpological factors in regard to the pain of the injection and the reverence of certain African peoples for the EDITORIAL 209

"healing power of the needle", andjnfers that this might be an advan­ tage. However, it might be safer to be more cautious about this and look to the long term effect of a painful injection which often has to be repeated at intervals of a fortnight or more, often over a long period of time. In spite of the reported reverence of the African for such things, we beg to express some doubt whether in the long term a painful injection will ensure a high attendance rate ; there is more to human nature than a reverence for magic. Though the soluble preparation apparently can only produce high peak levels at fortnightly intervals, Dr. Currie found no loss of efficiency. He found that the Avlosulfone aqueous suspension was the preparation of choice on the grounds of freedom from pain, absence of side effects, ease of injection, economy in the total quantity of suI phone needed, and efficiency.

The Multipuncture Type Lepromin Test Dr. Kinnear Brown reports on his further studies with this test (p. 215) and points out that any response to lepromin by this route can be independent of any normal tissue element it contains. He used antigen made from normal skin and from tuberculoid skin, and studied the effect of BCG vaccination on the depot lepromin. All the lepromin negatives became positive, and there was an enhance­ ment in the degree of positivity. His continued experience with the multipuncture test has convinced him of its simplicity, economy, and effectiveness. As regards the general use of multipuncture BCG vaccination, recently A. H. Griffith4has reported on his experiments to compare the multi puncture and intradermal routes. He found a falling off in conversion rate with the multipuncture route compared with the intradermal vaccination, and suggests that the general use of multi­ puncture should be delayed until the method has been improved and standardised. Kinnear Brown's work therefore has much practical importance, as supporting the efficiency of the multipuncture method.

References I. INNES, J. Ross et al. E. Afr. Med. J., 1957,34, p. 395. 2. DAVEY, T. F. and CURRIE, G. Lep. Rev., 1956,27, p. 94. 3. DAVEY, T. F. et al. Lep. Rev., 1958,29, p. 25. 4. GRIFFITH, A. H. Lancet, ], 7084, 6th June, 1959, pp. 1170- 1172. (See Abstract p. 264 or this issue.) 210 LEPROSY REVIEW

TWO YEARS EXPERiENCE WITH DIPHENYLTHIOUREA (DPT or CIBA 1906) IN THE TREATMENT OF LEPROSY

B.A.O., H. by J. M. B. GARROD, M. B. , B.ch., D.T.M. & Director, East African Leprosy Research Centre, A/upe, Kenya

Introduction One of the drawbacks to the use of the sui phones in leprosy is that reactions are increased in number and severity. At the best these are troublesome and interrupt treatment. They can cause serious constitutional disturbances and are hardly beneficial to the patient if the more severe types develop. Severe cases may only be kept in tolerable comfort by continuous administration of corticosteroids. Diphenylthiourea (OPT) was reported to be active in leprosy by Davey and Curriel ( 1956) and by Ross rnnes et af.2 (1957). A further report by Davey et a/.3 (l958) confirmed the earlier report, and drew attention to the lesser incidence of reactions among patients treated with DPT. Further experience here with some of the patients reported by Ross Innes and some additional patients up to April 1959 is recorded here.

Patients All were inpatients of whom four had had substantial previous treatment with DDS. All others denied previous treatment, or admitted to receiving only a few tablets of DDS beforehand at outpatient dispensaries and health centres where oral DDS is generally available. Forty patients were studied and their numbers and types are shewn in Table I. The distribution of cases bears no relation to the general incidence but is more an indication of the types seeking inpatient treatment. TABLE r Tuberculoid Lepromatous Borderline Indeterm. Male Adult 10 II 2 0 Female Adult 3 5 0 Male under 18 3 0 I Female under 18 0

17 18 2 3

Lepromin tests were done on all patients before starting treatment. The lepromin used was a crude Mitsuda-Hayashi type prepared here. The lepromatous cases except three had negative Mitsuda tests. The three had doubtful tests with reactions less than 3 mm. in diameter. Biopsies were taken before starting treatment. Histologic­ ally not all might have been accepted as lepromatous but they were Two YEARS' EXPERIENCE WITH OIPHENYLTHIOUREA 21 1 what is known as frank lepromatous cases in Africa. Nodules were generally present, and bacilli were found easily in globi and in masses. The tuberculoid cases had positive Mitsuda tests. Clinical photo­ graphs were taken at the start of treatment, and reference was made to them to refresh the memory. Twenty-three inpatients on standard treatment were followed as controls for the bacilliferous cases. One male lepromatous case has been on both treatments, 17 months on standard treatment, and 12 months on OPT. The numbers and types of those on standard treatment are shewn in Table 2. There were no tuberculoid cases in this group. TABLE 2 Lepromatous Borderline Indeterm. Male Adult II I ° Female Adult 8 I 0 Male under 18 °

20 2

Seventeen patients discharged themselves; six had no visible lesions; one was indeterminate, the other five were tuberculoid. The other 11 left for various personal reasons. All intended to get stan­ dard treatment at their homes.

Methods At first liver and kidney function tests were done frequently. Red and whjte cell counts, haemoglobin estimations, and weight records were done monthly. Later when the absence of toxic effects was apparent, only haemoglobin and weight were recorded monthly. Smears were taken in alternate months of the' bacterially positive cases. Smears of negative cases were taken every six months. Smears were taken from six sites, their positivity estimated as 0, ], 2, 3, or 4 and the average calculated as a BaciUary Index (B.J.) Absence of patients on home leave has interfered with J egular timing of the above, but has not affected the overall picture.

Results The average initial B.I. for those lepromatous patients on OPT was 3.2, after 12 months 2.0, and after 24 months 1.6. For those on standard treatment the figures are 2.7, 2.0, and 1.3. Expressed as percentages of the initial B.I. for comparison the figures are for OPT 100, 62.5, and 50; for standard treatment 100, 74, and 48. Figures for bacterial indices supplied by the M.O. in charge of the leprosarium and calculated on a comparable basis, show that for a111epromatous patients on standard treatment in the lepJOsarium the percentages 212 LEPROSY REVIEW are 100, 76, and 50. For the first twelve months the advantage lies with DPT. Clinical impressions support this. At first lesions resolve quicker on OPT than on standard treatment. Later progress slows. All patients on DPT have improved clinically. Tuberculoid and indeterminate cases have reacted to OPT in a manner similar to that expected on standard treatment. Nerve reactions have occurred but not tuberculoid reactions. One female tuberculoid patient has been discharged cured after 32 months treatment, having shewn no signs of activity fo r the previous year. Among the mOl e expensive and troublesome items of leprosy treatment is the necessity to provide ward accommodation for various reasons. The figures fo r the total treatment in months for those on OPT and on standard treatment were added up separately. The times spent in the wards, for whatever reasons, were also added up for each treatment, and the figures compared. Those on standard treatment total 400 months treatment with 926 days in the wards. Those on OPT, excluding tuberculoid cases, total 642 months treatment and 569 days in the wards. The time spent in the wards by those on DPT is considerably less than by those on standard treatment. For tuberculoid cases on DPT the treatment time is 368 months with 262 days in the ward, to which one patient alone contributed 129 days because of a foot ulcer. Part of the difference in favour of the OPT cases may be because reactions with DPT are milder and seldom require treatment. Seldom is there any need to interrupt treatment with DPT because of reactions. In only three cases was the dosage of DPT halved because reactions were difficult to control. Possibly this is the reason for the superiority of OPT in the firstyear, as it is then that patients are most in need of extra treatment for con­ corrutant illnesses, and appear most likely to react. DDS is known to have a prophylactic effect against malaria (Leiker4, 1956). DPT apparently has no such effect as patients' on it have been ill with malaria, and it is in spite of this that the ward time is better with DPT. Some of our patients here come from non-malarial areas and have no premunity.

Histology In lepromatous cases biopsies show improvement after six months. Areas of infiltration grow less and become discrete. Round cells increase and fibrocytes appear. Bacillary densities are not much reduced in the early stages, but the absolute numbers are reduced because only rarely does a decrease in the area of infiltration cause an increase in the bacillary density. Ridley'S Biological Index5 (1958) has been estimated for those patients on DPT and those on standard treatment. The average drop is 41 % for those on OPT and 45 % for those on standard treatment every six months. In tuberculoid cases Two YEAR'S EXPERIENCE WITH D,PHENYLTH,OUREA 213

the area of infiltration lessens, giant cells disappear, and fibrocytes appear in six to 12 months.

Dosage and Toxicity The daily dosage of DPT was based on a rate of 50 mgm.jkg. giving a dosage of 1.5 to 4 g. daily. A special group of 10 patients was put on double dosage. Seven have received this higher dosage for two years; the other three discharged themselves. There were no toxic effects. Mention must be made of the death of one patient from an acute anaemja of undiagnosed cause. The anaemia developed after he received 4 g. of DPT over seven days. Unless one accepts an acute sensitivity it seems unlikely that the drug was the cause of death. Fifteen patients had abnormal liver function as judged by thymol turbidity and bromsulphthalein tests at the start of treatment; seven of these became normal in one year. Four patients who had abnormal renal function tests became normal. There was no interference with the action of drugs commonly employed for treatment of the common local infections and infestations. Absorption and excretion studies here (to be published later) suggest dosage more than once a day would give best results.

Special Cases Certain cases justify individual mention. They illustrate how DPT can be given to cases liable to reaction; Case No.3. A male lepromatous patient who had been on standard treatment for several years became unstable and reacted easily. From December, 1956- April, 1958, that is after 17 months of standard treatment, his case card reads "on verge of reaction most of the time". Most of this time he had to be warded, and was on cortisone. His B.1. fell from 2.75 to 2 during this period. In May, 1958 he was put on DPT working up to a full dosage of 2.5 g. daily by mid-July. By the end of July his reaction had stopped and cortisone had been stopped. He had occasional reactions up till October, 1958, since when he has been free from E.N.L. His B.1. has dropped from 2.0 to 1.2 in 12 months. He states that he is now free of the former continuous pain. Case No.4. A male lepromatous patient had had sulphones for four years with frequent reactions, and spent much of his time in the ward. He was put on DPT. His reactions continued for II months but were mild, and he remained ambulant except for a total of 12 days. For various periods totalling six months the dosage of DPT was halved. His B.I. has fa llen from 1.7 and he achieves an occasional negative now. Case No.5. A tuberculoid male patient had reached that stage of no progress after 25 months on DDS. He improved during six months DPT then became stationary again. After 30 months OPT he has again started to improve. He has a persistent ulcer on his heel which may be the reason for his slow recovery.

Case No. 39. A lepromatous male patient had relapsed after insufficient standard treatment ending seven months previously. His progress on DPT has not been substantially different from what one would expect. Case No. 38. A lepromatous male discharged himself against advice after 26 months treatment with only two months in which reactions were noted. DDS at an outpatient dispensary keeps him in continuous reaction. Case No. ] 1. A female lepromatous patient was admitted in reaction. She was started on a full dose of DPT (3.0 g. daily) with no ill effects. 214 LEPROSY REVIEW

Summary DPT has shewn itself to have a curative effect in leprosy of an order similar to that of sulphones. Its cost is high and a daily dose is needed. Reactions are less, especially in cases which react easily. Reactions are generally mild and easily controlled and interruption of dosage because of reactions is generally unnecessary. This enables continuous effective treatment to be kept up. It has been free from toxic effects. DPT has been found to be useful in cases resistant to the standard treatment.

Acknowledgments Thanks are due to the following persons who have assisted : E. J. Bishop, G. Ellard, J. Obwa, J. Opio, R. Rhodes-Jones, M. Smith, and to the leprosarium staff for co-operation in the work, and also to the patients for willing submission to troublesome and at times painful procedures. Thanks are expressed to Messrs. Ciba Ltd. for generous supplies of tablets and helpful advice and assistance. Thanks are expressed to the Administrator, East Africa High Commission, for permission to publish and also to BELRA for financial assistance.

References I. DAVEY, T. F. and CURRIE, G. Leprosy Review, 27, 94, 1956. 2. INNES, J. Ross, et 01. East African Medical Journal, 34, 395, 1957. 3. DAVEY, T. F. et 01. Leprosy Review, 29, 25, 1958. 4. LEIKER, D. L. Leprosy Review, 27, 66, 1956. 5. RIDLEY, D. S. Leprosy Review, 29, 45 , 1958. MULTIPUNCTURE DEPOT LEPROMIN TEST 215

THE MU LTIPUNCTU RE DEPOT LEPROMIN TEST: INVESTIGATIONS WITH DIFFERENT ANTIGENS

J. A. KINNEAR BROWN, B.SC., M.D., M.R.C.S., D.T.M. Specialist Leprologist, Uganda and M. M. STONE, S.R.N., S.C.M. Kumi Ongino Leprosy Settlement

The work of de Farial (1950), Kooij and Gerritsen2 (1956), Floch) (1956) and Davey4 (1958) has shown that a local response can be elicited in some individuals by the intradermal injection of a saline suspension of normal skin taken from a non-leprous person. An early reaction at 24-48 hours or a late infiltration at three weeks is possible. This phenomenon might be taken to mean that the Fernandez and Mitsuda reactions to lepromin are only incidental and have little direct relationship to prognosis; alternatively, that an antigen prepared from normal skin might for practical purposes be substituted for that prepared from bact�riologically positive tissue. The response to normal skin, however, was generally much smaller, comparable with that to a very weak lepromin. It is allowed for in the standard method of calibrating the results of the usual lepromin test, by not regarding as positive any reaction that is less than a certain diameter. We have already reported the use of depot lepromin injection by the multipuncture route, the results of which are easily correlated with those obtained with the standard saline suspension by the usual intradermal method (Kinnear Brown and Stone5,6,7, 1958-9). The modified test has the advantages that the reaction is less violent, the method is economical, and the lepromin is retained in the skin sufficiently long to indicate if there is conversion from negative to positive within a fe w weeks. A number of children whose depot tests were negative at three, fo ur and five weeks showed °a change to positive within fo ur weeks of BeG vaccination, whilst others who were not BeG vaccinated showed no change whatever. Apart from the inference that BeG vaccination was the cause of the conversions, the investigations showed that this method eliminates the need for a second test and, therefore, the complicating effect of a second dose of antigen. We now decided to investigate by the multipuncture route the results of using various skin preparations suspended in the depot medium, and the subsequent effect of BeG vaccination. We first tested 25 patients who were known to be positive to lepromin, the majority strongly so, with a I :20 depot 'lepromin' made from the skin of an active tuberculoid lesion which was bacteriologically negative on staining by Ziehl Neelsen. Eight were 216 LEPROSY REVIEW positive at three weeks; of these seven were Grade I, and one was Grade II. The remaining 17 were negative. Three of the 17 negatives (Nos. 5, 7 and 13) gave a Grade I response which was just palpable at some point in the first or second week, but which rapidly sub­ sided ; seven (Nos. 1, 3, 6, 8, 9, 10 and 23) became temporarily visible during the same period but were never palpable, the remaining seven showed no change whatever. Of this group of 25 patients 1 9 were subsequently tested with a 1 :20 depot preparation made from normal skin, but none reacted positively at any time. The results are set out below in tabular form to make comparison easy. REACTIONS AT THREE WEEKS IN 25 PATIENTS Size 0/ Reaction in Serial Nos. mm. 0/ Original Grade- With Lepro- With Lepro- 0/ Patients Lepromin Test 0/ Reaction min made/rom mill made from and whether Tuberculoid Normal Skill Ulceratioll Skin Present 1 14.U 2 15.U 3 1I 4 Il. U 5 14.U 6 9 7 III 8 19 9 LJ 10 II 11 I 12 1 3 1 J 14 10. U 15 13.U 16 8 17 26.U 11 18 19 II 20 I 21 III 22 24.U 23 II 24 III 25 IT NOTES U Ulceration. • Grade according to response to previous multipuncture test with 1 ;20 lepromin. Nos. 5, 7 and 13 gave a transient Grade J response in the 1st or 2nd week. Nos. I, 3, 6, 8, 9, 10 and 23 gave a transient visible change which was never palpable. MULTIPUNCTURE DEPOT LEPROMIN TEST 217

What responses there were to the preparation made from tuber­ culoid skin were much less pronounced than those to normal lepromin and more transient, but they appeared to be related, e.g., those who were weakly positive at 21 days to a 'tuberculoid' lepromin were strongly positive with ulceration to ordinary lepromin or Grade III by the multipunc ture method. There was no reaction to the normal skin preparation in any patient. This was not expected, as the responses reported to 0.1 m\. by intradermal injection were proportionally weak (Floch3, Kooij et aU,8, and Davey4) and the quantity of antigen injection by the multi puncture route is very much less. or the 19 patients who had 'tuberculoid' lepromin and 'normal skin' antigen ten were tuberculin negative. They were vaccinated with BeG three weeks after their depot tests but none showed any sub­ sequent change at the sites of the tests. We now applied various suspensions by the multipuncture method to 56 non-leprous school children. Of these Group A comprised 37 who were tested simultaneously in the interscapular area with four different 1 :20 antigens made up with depot medium as follows : (i) normal skin from a healthy individual; ( ii) active tuberculoid tissue, using the same preparation as in the above 25 patients; (iii) bacteriologically negative skin from a lepromatous patient; (iv) normal lepromin from bacteriologically positive tissue. Group B included 19 children who were given antigens from the same sources but made up with saline. Neither group gave any responses to the preparations made from normal or tuberculoid skin. There were 28 of the 37 in Group A positive to normal lepromin, and three of those who had a Grade III reaction gave a Grade I to the lepromin from bacteriologically negative tissue. ]n Group B all 19 were positive to normal lepromin and five gave also a feeble positive to that from the bacteriologically negative tissue from a lepromatous patient. Of the 37 children in Group A 36 were now vaccinated with BeG; nine were weakly tuberculin positive (Grade I Heaf) and 27 negative. There was no untoward reaction in the nine who were weakly tuberculin positive. Of these, six were lepromin positive and three negative. After BeG vaccination the depots in the three negatives showed conversion and the other six showed an increase in positivity. Of the 27 tuberculin negatives 22 had been lepromin positive and five lepromin negative. After BeG the depots in the five negatives showed conversion and 16 of the 22 positives registered an increase in positivity. Th ere was no change in any of the other depots. 21R LEPROSY REVIEW

Summary and Discussion I. The injection of a normal skin preparation by the multi­ puncture route did not produce any reaction in either lepromin positive patients or uninfected children. rt would, therefore, appear that any response to lepromin by this route is independent of any normal tissue element it contains, which is another point in favour of this method of testing. 2. The response to antigen made from tuberculoid skin in the patients tested was less marked and more transient than that to normal lepromin. That one occurred at all may have been due to undetected bacilli or tuberculoid tissue elements in the antigen. As no reaction with this same ·antigen was obtained in the lepromin positive healthy children, it may well be that lepromin positivity in patients includes an individual element that may be stimulated or exaggerated by the disease. rn this connection one patient who had a large indolent ulcer in the site of the ordinary Mitsuda Test, a similar ul�er with weak lepromin, a Grade ITT response to the multipuncture method, and a Grade J to tuberculoid antigen, had also a violent contact dermatitis after applying an irritant herb to a large asym­ metrical and clinically tuberculoid patch on his forehead which persisted for almost a year (see photograph). Tn this case biopsies of symm,etrically distributed hypopigmented nodules elsewhere gave the picture of dimorphous leprosy. The response of a few individuals may, therefore, include two elements, one an allergic or foreign body reaction whi,ch is generally weak, and one which is stronger and more specific, owing to the presence of numbers of bacilli. 3. Of the 47 uninfected children in both groups who were lepro­ min posi!ive, eight gave companitively a much weaker response to antigen made from wha� was thought to be bacteriologically negative skin taken from a lepromatous patient. This patient had been con­ sistently negative to Ziehl Neelsen fo r some time. The skin from which the lepromin was prepared had been infiltrated originally, but at the time the tissue was taken for the antigen it had the wrinkled appear­ ance of resolution and a smear from it was negative. The weak response may theref

5. Continued experience with. the multipuncture depot test has convinced us of its simplicity, economy, and effectiveness. The response is less likely to include any factor due to normal tissue ; conversely, and from a practical point of view, it does not appear possible to lise any other skin preparation as a substitute, at least by this method .

Acknowledgements We are grateful to Dr. J. M. Lea of the Kumi Leprosarium for his continued assistance in providing patients for this work.

References I. DE FARIA, J. L. The Mitsuda Test as an Indicator of Normal Resistance; Late Reaction with Normal Skin. Reviewed Internat. J. of Lep., 18, 3; OCI. 1950, p. 443. . 2. KoolJ, R., and GERRITSEN, Th. Positive 'Lepromin' Reactions with Suspen­ sions of Normal Tissue Particles. Internal. J. of Lep., 24, 2: April, 1956, p. 171. 3. FLOCH, H. Sur la Reaction de Mitsuda: Intradermal Reaction a I'aide d'extrait phenique de Peau Normale. Internal. J. of Lep., 24,3; July, 1956, p. 292. 4. DAVEY, T. F. and DREWETT, S. E. Lepromin-like Activity of Normal Skin Tissue. Leprosy Review, 29,4: October, 1958, p. 197 . . 5. BROWN, J. A. KINNEAR. A Modification of the Lepromin Test, Leprosy Review, 29,4: October, 1958, p. 184. 6. BROWN, J. A. KINNEAR and STONE, M. M. The De pot Lepromin Test and­ BCG Vaccination, Leprosy Review, 30, 2: April, 1959, p. 110. 7. BROWN, J. A. KINNEAR; SHORT, G. M.; BLENSKA, W. Lepromin Reactions with Normal Tissue Preparations. Correspondence, Internal. J. of Lep., 25, 3: July, 1957, p. 27 1. 8. KoolJ, R., and GERRITSEN, Th. Lepromin Reactions with Normal Tissue Preparations. Correspondence, Internal. J. of Lep., 25,3: July, 1957, p. 273. 220 LEPROSY REVIEW

SHORT AND LONG ACTING SULPHONES BY INTRAM.U SCU LAR lN JECTION

G. CURRIE, M.B., eh.B., D.T.M. and H. Kochira Leprosarium, Nyasaland A preliminary report is presented of a clinical trial of dapsone (DDS) therapy by fortnightly intramuscular injection over a period of one year.

Material. We selected 60 patients with advanced lepromatous leprosy and divided them into fo ur groups of 15 patients each. Only fo ur patients failed to complete the course (two because of severity of reactions and two absconding) and it has been possible to compare 13 patients from each group. All of these had received oral dapsone therapy for fo ur to eight months prior to the experiment enabling each patient to make a personal comparison of the effects of the parenteral therapy later instituted. Great care was taken to exclude macular lepromatous cases or any showing tissue reactivity suggesting an inclination towards the borderline state. Restricting the sample to lepromatous cases has several advan­ tages. One avoids the varying levels of resistance encountered in tuberculoid cases and the immunological chaos of the borderline varieties. The clinical picture is not complicated by those factors of immunity which are evidenced by delayed (tuberculin type) sensi­ tivity, and the ability to respond to the bacillus with a tuberculoid granuloma, as all cases are reduced to a common denominator of complete anergy. The rate of bacteriological improvement in lepro­ matous leprosy on sui phone therapy is remarkably constant. RIDLEY] ( 1959) using serial biopsy technique demonstrated a standard rate of 25 % improvement in the bacillary count per six month in Europeans with lepromatous leprosy. Furthermore the variety of reactions encountered is considerably reduced and the reactions are easier to interpret.

Groups. The original intention was to compare the results of a fixed dose ( 1.2 g.) of dapsone per fortnight administered by differing routes and vehicles. This was modified as the experiment developed. The following preparations were compared : Group I Oral dapsone in dosage of 300 mg. twice a week, equivalent to 1.2 g. dapsone per fortnight.

Group II Dapsone (\.25 g.) suspended in ethyl esters of hydno­ carpus oil (5.0 ml.) administered once every two weeks by intramuscular injection. Group III 'Avlosulfon' Aqueous Suspension (ICI) administered by intramuscular injection in dosage of 3 ml. containing 0.6 g. of dapsone at intervals of two weeks. SHORT AND LONG ACTING SULPHONES 22 1

Croup IV 'Avlosulfon' Soluble (lC]) administered by intramuscular injection once every two weeks in dosage of6 ml. liberating in the tissues 1.2 g. of dapsone on decomposition.

Review of Literature. Deep subcutaneous injection was the route selected by COCHRANE2 (1949) when he pioneered the use of dapsone in human leprosy. In the fo llv.ving year LOWE3 (1950) published his work on oral dapsone therapy which established this route as the method of c�oice. Although the optimum blood level of dapsone cannot be precisely stated, LOWE4 ( 1952) considered that a safe blood level lay between 1.0 and 0.2 mg. %. The figure of 0. 1 mg. % appears to be generally accepted as the lowest satisfactory level for therapeutic benefit. Fearing the abuses which have occurred when mass oral therapy has been organised in primitive communities, several workers have continued to explore the possibilities of parenteral therapy. MOLESWORTH5 (1949) for example used subcutaneous injections of dapsone (0.3 g.) suspended in pure cocoanut oil (1.5 ml.) at weekly intervals. Blood levels varied between 0. 1 and 0. 15 mg. % and reactions were few. MUJR6 (1951) used arachis oil as the vehicle but there was a tendency to the occurrence of painful subcutaneous depots of unabsorbed dapsone and cocoanut oil was preferred. Neither method gave adequate blood levels for longer than one week. Interest in injection therapy increased when FLOCH7 (1951) produced evidence that parenteral dapsone may be less toxic than oral dapsone therapy. He showed that when dapsone is given by injec­ tion the drug is recovered unaltered from the blood and urine. When the same drug is given by mouth 20 % of the dapsone is changed into an unstable derivative. Among his patients the parenteral route was accompanied by 8 % of 'lepra' reactions whereas the oral route was accompanied by 47 % of 'lepra' reactions. It was suggested that the dapsone may have been altered by the action of intestinal secretions, by bacteria, or by passage through the liver. Several workers have repeated the claim that suI phones administered by injection give rise to fewer undesirable reactions than the same drug given by mouth, attributing reactions to toxic derivatives. This is discussed later. Because of the inconvenience of weekly injections, LAVIRON8 (1953) experimented with fortnightly injections of dapsone (1.25 g.) in oily suspension. When arachis oil was used blood levels rose to a peak 0 f 0.54 mg. % but fell to 0.06 mg. % before the end of the second week. The first figure was considered excessive, the second inadequate ; but, when hydnocarpus oil was used as the vehicle, a maximum blood level of 0.29 mg. % occurred and the blood level at the end of the second week was still 0. 13 mg. %. It was suggested that irritation by the fatty acids of hydnocarpus oil slowed the rate of absorption of . the dapsone. In practice a mixture of the oil and its ethyl esters 222 LEPROSY REVIEW

proved to be the most suitable vehicle, being less viscous than the oil alone and less irritant than the ethyl esters alone. Guaiacol 4 % was added as an antiseptic and for its anaesthetic action. LA VI RON (1954) reported a three year trial of this preparation on 1,225 patients in French West Africa. Excellent therapeutic results were claimed with very few reactions. His earlier claim of synergic action by the hydnocarpus oil was not repeated in this paper. His work was confirmed by MONTESTRUCIO (1955) who found that hydnocarpus oil suspensions gave more constant blood levels than those achieved with arachis oil. A depot effect was also achieved by FLOCH" (1954) who studied the influence of particle size on the rate of absorption. Using larger crystals (200 to 500 microns) a single injection of 1.8 g. dapsone suspended in 12 ml. of physiological saline containing 0.2 % agar given once a month produced satisfactory blood levels. In the first week the concentration averaged 0.194 mg. % and in the last ten days of the month 0.098 mg. %. Satisfactory clinical results and freedom from reactions were claimed. LAVlRONI2 (1955) combined large crystal size with an oily vehicle giving 2.5 g. of dapsone (crystal size 120 to 190 microns) suspended in 8.5 ml. of ethyl esters of hydno­ carpus oil at monthly intervals. The series involved 20 patients. Tn the ten patients tested blood levels were very variable and a peak as high as 1.95 mg. % occurred in one patient. In some cases the blood level fell below 0.1 mg. /� after the second week but two cases showed no peak and still had a blood level of 0.25 mg. % by the 20th day. In both experiments the bulk of the injection and the large-bore needle required were disadvantages. The internal diameter of a No. 3 (gauge 20) serum needle is 0.9 mm. and if three or more crystals of 200 microns or two crystals of 500 microns were to clump blockage would occur. MONTESTRUO o (1955) also used saline agar suspen­ sions giving 1.5 g. of dapsone (crystal size 150 to 180 microns) at fort­ nightly intervals. Blood levels varied between 0.25 and 0. 1 mg. �Iu and injections were well tolerated and less painful than hydnocarpus oil injections, but the comment was made that a larger bore needle was required. Attempts to produce a retard effect were not confined to the parent sulphone. FLOCHI3 (1954) extended the period of effective sulphonaemia obtained with 'Avlosulfon' Soluble ICI by giving it in a depot vehicle. 3 ml. of a 25 % solution of polyvinylpyrrolidone were added to 6 ml. of 'Avlosulfon' Soluble (equivalent to 1.2 g. of dapsone). The 9 ml. injection was given at weekly intervals producing a total sulphonaemia of 7.72 mg. % at the fourth hour falling to 0.06 mg. % on the seventh day. As dapsone can be given orally at weekly intervals in dosage up to 600 mg. little advantage was gained apart from the claim of reduced toxicity by the parenteral route. SHORT AND LONG ACTING SULPHONES 223

The Trial. Facilities for estimation of blood sulphone levels do not exist at Kochira Leprosarium. Fortunately these have been worked out for the various preparations used at other research centres.

Group I The Control Dapsone tablets were given in oral dosage of 300 mg. twice a week, equivalent to 1.2 g. per fortnight. Dapsone by mouth is moderately rapidly absorbed and slowly excreted and in this dosage the limits of safety and effectiveness suggested by LOWE4 (1952) namely 1.0 mg. % maximum and 0.1 mg. % minimum are not trans­ gressed. As already stated a proportion of the circulating sulphone is in the form of unstable derivatives of dapsone following oral dosage.

Group II Dapsone (1.25 g.) suspended in ethyl esters of hydnocarpus oil (5 ml.) with 4 % guaiacol administered by intramuscular injection at fortnightly intervals. In the preparations used 90 % of the particles were between 3-5 microns in diameter and 10% between 5-15 microns. Blood sui phone levels may be expected to lie between 0.29 and 0.13 mg. % (LAVIRON8 1953) and are thus well within the limits set by Lowe.

Group III 'Avlos ulfon' Aqueous Suspension (ICI Compound 20, 177) containing 20 % dapsone per 1 ml. was used in this group. In the development of this preparation, Imperial Chemical Industries, Ltd. have attempted to provide a relatively painless injection of small bulk achieving a sustained blood level by depot action. Because oil tends to produce pain and tissue damage at the injection site, water has been substituted as a vehicle. A small particle size varying from 1 to 15 microns with the majority of particles falling between 2.5 to 8 microns permits the use of fine needles and ensures that the suspension will 'stand up' well. The retard effect has been achieved by a novel agent which maintains dapsone in watery suspension. Our original intention was to give fortnightly injections contain­ ing 1.2 g. of dapsone in 6 ml. From experiments in monkeys (private communication, ICI Research Laboratories) using a single dose of 20 mg./kg. body weight it was estimated that an injection of 1.2 g. would be necessary to maintain a blood level greater than 0.05/0. 1 mg. % for 10 to 14 days. Shortly afterthe commencement of the trial DAVEY14 (1958) established that a single injection of 3 m!. intra­ muscularly gives a maximum blood level of 0.8 mg. % falling to 0.1 mg. % on day 13. Thus a dosage of 0.6 g. fortnightly, which is half the quantity required by oral dosage, gives a blood level which is within the conventionally accepted limits of safety and effective­ ness. In the experiment therefore 3 mI. of 'Avlosulfon' Aqueous Suspension containing 0.6 g. of dapsone were given by intramuscular injection at fortnightly intervals. 224 LEPROSY REVIEW

Group IV 'Avlosulfon' Soluble (ICl Compound M21916), being a 41 % aqueous solution of acetaldehyde sodium bisulphite complex of dapsone which breaks down rapidly in the body to release half its weight of dapsone. The dosage was 6 ml. by Intramuscular injection at fortnightly intervals which is equivalent to 1.2 g. of dapsone. The drug has been studied by TOUZINI5 (1953) and DAVEYl6 (1956) who drew attention to the similarity of its chemical structure and behaviour to that of Sulphetrone. Indeed the use of 'Avlosulfon' Soluble in this experiment was suggested by a misunderstanding in 1954 whereby sulphetrone injections were instituted in error at fortnightly intervals (3.0 g.) in the Mlanje district of Nyasaland instead of twice weekly in the treatment of leprosy out-patients. Records were not adequate for analysis but the medical staffof the Mlanje clinic formed a strong impression afterone year of treatment that the patients receiving sulphetrone had made better progress, had fewer reactions, and had attended more regularly than those on oral treatment with dapsone. The dosage selected is high. TOUZINI5 (1953) demonstrated that 5 ml. of 'Avlosulfon' Soluble equivalent to 1.0 g. of dapsone, by intramuscular injection gave peak blood suI phone levels up to 9.85 mg. % (average 7.53 mg. %) within one hour but that the level at 48 hours was less than 0.5 mg. %. DAVE YI6 (1956) using up to 4 mI. equivalent to 0.8 g. of dapsone, in general confirmed these figures. An extremely high level is attained within two hours declining to about 0.1 mg. % after 72 hours regardless whether the initial dose was I, 2, or 4 ml. The dosage in the present trial (6 mI., equivalent to 1.2 g. of dapsone) is higher still and may therefore be expected to produce a peak level exceeding Lowe's 'safe' maximum ten fold but sustaining his 'effective' blood level for only three days out of the fortnight. Grosser fluctuation to our knowledge has not been used in sulphone therapy. It must be stated however that most of the cir­ culating sulphone at the peak period is a water soluble form and there­ fore either 'Avlosulfon' Soluble itself or a metabolite other than dapsone. At 72 hours however the bulk of the suIphone circulating consists of the fraction extractable by benzene which is presumed to be the parent suiphone (dapsone).

Findings TABLE I Bacillary Index, Mean Values; Maximum Possible, 12. Avloslllion Control Oily Dapsone AvloslIllo n DrllK Aqueous Oral Dapsone Suspension Solllble Suspension

At commencement 7.8 9.4 9.4 8.5 Afterone year 6.7 7.6 8.4 7.5 Improvement 1.1 1.8 1.0 1.0 ( \ 4.1 %) (19.2 %) (10.6%) (11.8 %) I

PLA TE No. 1. (February, 1958) PLATE NO. 2. (February, 1959).

Clinical impro vement as a result of one year's treatmelll with fo rtnightly illjections of 'Avlosulfon' Soluble. Case No. 708 (K.H.) A gross nodular leproma of eleven years duration. Oral dapsone therapy was instituted in October, 1957 and clinical improvemellt was detectable ill Jalluary, 1958. After fo ur months of oral therapy, injections of 'Avlosulfo n' Soluble were substituted and a photograph (Plate No. I.) was taken. A second photograph (Plate No. 2.) taken a year later ill February, 1959 shows the strikillg improvemellt which has occurred. SHORT AND loNG ACTING SULPHONES 225

The improvement in bacillary index can be seen from Table 1. This index cannot be regarded as an accurate yard-stick for measuring progress as too many variable factors are involved in taking, making, and reporting smears. All that can be said is that improvement has occurred in all four groups with a bias of doubtful statistical signifi­ cance in favour of the oily suspension.

TABLE Jl Evidence of Degenerative Change in the Bacilli

Assessmelll of COfllrol Oily 'A vlosul/on' Bacterial Oral Dapsone Aqueous I A v/osul[on' Degeneration Dapsone Suspellsin/l Suspellsioll Soluble

Nil (-) Slight ( + ) 3 I 2 2 Marked ( + + ) 7 9 10 9 Gross (+++) 3 3 2

Definite evidence of degenerative change in the bacilli occurred in all patients in the series as can be seen from Table n. There was no significant bias in favour of any one group and the tendency is in agreement with that shown by the change in the bacillary index.

TABLE HI Objective Clinical Improvement-Examiner's Assessment

Control Oily • A vlosu/fon' Assessment of Oral Dapsone Aqueolls 'Avlosul/oll' Improvement Dapsone Suspension Suspension Soillble

Nil Slight 5 8 4 8 Marked 8 5 9 5

TABLE IV Subjective Clinical Improvement-Patient's Assessment

Assessment 0/ Control Oily • A vlosul/o n' , Avlosu/fon' Improvement Oral Dapsone Aqueous Dapsone SlispensiOtl Suspension Soluble

Nil Slight 3 3 3 4 Marked 10 10 10 9

It is necessary to state what is meant by 'clinical improvement' when assessing progress. In this paper it is taken to mean evidence that the body defences are gaining ascendancy over the bacillary invasion. It is seen mainly as subsidence of lepromatous infiltration a process which can generally be discerned even during episodes of erythema nodosum Jeprosum (ENL) or other reactions which might tempt the assessor to record that the leprosy is 'worse'. The majority of our patients undergoing such reactions of moderate severity could distinguish the two processes. By this conception increases of 226 LEPROSY REVIEW

paralysis and anaesthesia and the occurrence of reactional lesions may not indicate that the patient's leprosy is worse but may rather be scars of an otherwise successful battle. Tables J I I and TV indicate that no patient has become worse under treatment and that clinical progress has been well maintained in all groups. There is little to pick and choose between them on this score. Erythema Nodosum Leprosum (ENL) DAVISON17 (1957) regards ENL as a normal reaction in leproma­ tous leprosy receiving sulphones. It is universal experience that in susceptible subjects this reaction is provoked by high dosage or too rapid increase in dosage and lessened by reduction of dosage. This would suggest that the incidence of ENL in a given group of lepro­ matous patients might serve as an index of the therapeutic activity of the sulphone in use. The reaction is not confined to sulphone drugs, witness its occurrence perhaps in less degree with isoniazid and the thiosemicarbazones, nor is it merely an accompaniment of drug induced bacillary degeneration, witness the freedom from ENL of patients receiving the new potent drugs diphenylthiourea and diethyldithiol-isophthalate which produce a rapidity of destruction of the bacilli not previously experienced in the history of leprosy treatment. It can only be said that the significance of ENL is still obscure and that the question as to whether it is beneficial or harmful is still under debate. It does certainly interfere with therapy and lead to irreparable physical lesions. The incidence of ENL in the present series is set out in Tables V and VI.

TABLE V Incidence of Erythema Nodosum Leprosum (ENL)

COlltro/ Oily • A vlosul/o ll' Incidence of Ora/ Suspension Aqueous 'Avlosul/oll' ENL Reactioll Dapsolle 0/ Dapsolle Suspension Soillble

Nil 4 2 4 6 Mild 3 5 4 3 Severe 3 3 5 2 Very Severe 3 3 Nil 2 Total ENL 9 (69 %) 11 (84 %) 9 (69 %) 7 (54 %)

TABLE VI Reduction in dosage necessitated by ENL over a period of one year expressed as a percentage of the scheduled total dosage fo r the yea/'.

Cotllrol Oily 'AvloSIlI/OII' Oral Dapsolle Aqueous 'AvloSIII/olI' Dapsone Suspension Su.fpension SO/Ilb/e

Reduction in dosage 11.0 % 14.5% 6.0% 11.0%

A djstinct difference is seen in the incidence and pattern of ENL SHORT AND LONG ACTING SULPHONES 227

reactions in the four groups. The total incidence is high. However, about 15 % of the reactions were so mild that the patients did not consider them worth reporting and they were discovered only as a result of close routine surveillance and questioning. The hydno­ carpus oil vehicle produced beyond doubt the nighest incidence and the greatest severity of ENL reactions. fn addition two cases of erythema multi forme (papulate variety) occurred in this group which have not been included under ENL in Table V, and the two cases which were eliminated from the series as a result of gross reaction were in the oily suspension group. The 'Avlosulfon' Aqueous Suspension (ICI Compound 20, 177) provoked the same number of reactions as occurred in the oral dapsone group but the duration of reactions and their severity as reflected in dosage reduction which they caused was only half

(54. S %) of that encountered in the oral dapsone group. The 'Avlosulfon' Soluble (ICI Compound M 2196) gave rise to the least number of ENL reactions but these tended to be moderately brisk and the dosage reduction called for was equivalent to that in the control group where more reactions occurred. Dosage reduction was probably exaggerated by our greater caution, which seemed indi­ cated by the extreme fluctuation of blood levels produced by this suiphone. Thus, although the 'Avlosulfon' Soluble group received a dosage in terms of dapsone identical to that of the control group, the incidence of ENL was less.

Side Effects Before the trial began the 52 selected patients were questioned as to what side effects they experienced on standard oral dosage of 300 mg. of dapsone twice a week. There were 37 who admitted to various side effects occurring from 5 to 24 hours after swallowing the tablets and passing offgeneral ly by the 48th hour. The side effects, which were quite independent of episodes of ENL, were as follows : No. of Patients Nature of Side EfFect 7 General tiredness and physical depression interfering with performance of the task allotted for the day. 22 Various paraesthesiae including formication, biting, prickling and burning sensations in the skin and superficial tissues. II Deeper aches and neuralgic pains often described as being felt 'in the bones'. 17 Headaches, mostly frontal. 7 Abdominal colic. Sleep was commonly disturbed by such symptoms on the night following treatment but none of the patients admitted to troubled or excessive dreams. One patient obtained temporary relief from his burning sensation by taking a cold bath in the night. 228 LEPROSY REVIEW

TABLE VII ln cidence of side effects

Conlrol Oily 'A vlosulfo ll' Drug Oral Dapsone Aqueous I A vlosulfo n' Dapsone Suspension Suspension Soillble

No. of Patients 9 5

It will be seen from Table VII that side effects are virtually absent from parenteral suI phones with the exception of ' A vlosulfon' Soluble, and that despite the high blood concentration produced by this drug side effects were markedly fewer and milder than with oral dapsone. As might be expected, no clear relationship was found between the incidence of ENL and the above side effects. Of the 36 patients who had no ENL, 11 (68 %) had no side effects. It can there­ fore be assumed that the phenomena are separate. An attack of EN L may of course mask the occurrence of side effects.

TABLE VIII Incidence of Pain on In tramuscular Injection

'A vlosulfo n' Drug Oily Dapsone Aqueous • A vlosul[o ll' Suspension Suspension Soluble

No. complaining of mild pain 6 11 9 No. complaining 7 2 4 of severe pain Average duration of pain (days) 2.5 days 1.3 days 2.1 days

The incidence of pain following the administration of the paren­ teral sulphone preparations can be seen from Table VIII. The oily suspension proved to be the most painful. Several patients were unable to perform manual labour for one or two days following injection into the deltoid muscle and sweIIing was a feature in most patients of this group. Two sterile abscesses occurred which had to be opened. The 'abscesses' were found to be virtually depots of oil and resulted from inadequate massage and failing to change the site of the injection sufficientlyin subsequent injections. Pain and swelling with 'Avlosulfon' Aqueous Suspension were negligible. 'Avlosulfon' Soluble caused moderate pain on intramuscular injection but the local reaction was not incapacitating and was not associated with abscesses or significant local swelling. All patients were asked at the conclusion of one year of injections whether they wished to continue with injections or to resume oral dapsone. Only three patients, all in the oily suspension group and all timid souls, expressed a preference for tablets on account of the discomfort of the injections. The reasons given for preferring SHORT AND LONG ACTING SULPHONES 229

injections were the absence of side effects and of general physical depression which the patients associated with oral dapsone treatment.

Anaemia The causes of anaemia in sUlphone treated leprosy are complex. ft is common in untreated lepromatous leprosy as a result of depres­ sion of the haemopoietic system or actual involvement of the bone marrow. It also complicates suI phone treatment of dermatitis herpetiformis and other skin conditions occurring in patients who have no leprosy. Furthermore it is common experience that a fall in haemoglobin accompanies severe ENL reactions in treated leprosy. Gross anaemia was seen only in the hydnocarpus oil group and occurred in three out of the original 15 patients in the group, associated with ENL, and severe enough to give rise to some anxiety. It is of interest that the anaemia was haemolytic in type and accom­ panied by pre-hepatic jaundice with no evidence of hepatitis. Improve­ ment followed reduced sulphone dosage coupled with the admini­ stration of iron and liver extract in two patients, but the third patient was eliminated from the series because of the severity of the anaemia and slow response to treatment. Haemolysis accompanying ENL reactions would appear to be an allergic phenomenon. HARTl 8 (1955) draws attention to the fact that red blood cells, like the tubercle and leprosy bacilli, have a pre­ dominantly lipid outer layer the composition of which influences their sensitivity to haemolysis during thermal shock, and BOYDENl.9 (1955) points out that if red blood cells are treated with poly­ saccharides (from a variety of different bacteria) these cells can be rendered susceptible to specific anti-polysaccharide sera. The association of ENL with haemolytic anaemia would suggest a common basis. Presumably a polysaccharide derived from the M. leprae antigen complex is involved in both phenomena forming in the latter a lipo-polysaccharide complex on the surface membrane of the red blood cells and rendering them susceptible to circulating antibodies. If further experiment confirms that there is an increased incidence of both ENL and haemolytic anaemia when hydnocarpus oil is used as the vehicle it might be regarded as circumstantial evidence of adjuvant action by the oil. To quote HANKS20 (1958), "injection of oils and esters into leprosy lesions probably con­ stitutes the first clinical application of the adj uvant principle to an immunological problem". In this case the esters were not injected into the skin lesion and a meeting of esters and antigen in the regional lymph glands must be postulated, which is not improbable. Granulo­ matous reactions in regional lymph glands have been demonstrated by UNGAR21 (1948) following subcutaneous injections of synthetic fatty acids into sensitized guinea-pigs. The fact that leprosy bacilli also reach the regional lymph glands is neatly illustrated by the 230 LEPROSY REVIEW lymphadenitis which so often heralds an EN L reaction. It is of interest to note that the glands most prone to such inflammation are those situated in cold parts of the body such as the sub-mental, pre-auricular and epitrochlear glands whereas those lymph nodes which are maintained at body temperature appear to escape. The dosage of ethyl esters of hydnocarpus oil used in the present series is insufficient for therapeutic advantage (unless given by the intra­ cutaneolls route) and leprologists are now unwilling to claim that the vehicle can exert any appreciable synergistic therapeutic action in this dosage. It 'may well however predispose to the occurrence of ENL reactions.

Other Reactions The classical lepra reaction did not occur. No cases of dapsone psychosis, incipient psychosis, sensitization dermatitis, or hepatitis were seen and no other major reactions complicated therapy.

Discussion Therapeutic Action There is little to choose in therapeutic effectiveness between the many suI phones which have been used in leprosy and it was not expected that one drug in this trial would prove more potent than another. It was anticipated that 'Avlosulfon' Soluble in such widely spaced dosage might show some fa lling offof bacteriostatic action and it is of considerable interest that no such inferiority of thera­ peutic action was demonstrated. TOUZIN15 (1953) has doubted the necessity of maintaining a constant blood level and DA VEY16 (1956) has suggested that brief phases of high blood sulphone too transient to produce toxic signs may exert a good chemotherapeutic effect by periodic 'hammer like' action. Both authors were referring to their experience with 'Avlosulfon' Soluble injected twice a week. Their opinions are strongly supported by our experience with fortnightly spacing of the injections. A second year will be required to confirm initial impressions, but, to borrow a phrase from the cardiologists, 'regular irregularity' of blood level with a 'hammer blow' lasting a few hours and an 'effective concentration' maintained for only three out of fourteen days has produced clinical improvement comparable to that achieved by sustained blood concentrations.

Reactions The incidence of reactions in the fo ur groups is interesting and indicates the need for accurate definition of the term. The 'lepra' reactions which occurred were all of the erythema nodosum or erythema multiforme type. The use of the term lepra reaction by workers in other continents, especially India, suggests that reactions among other races may approximate more closely to the picture of SHORT AND LONG ACTING SULPHONES 23 1 classical lepra reaction as encountered in untreated or hydnocarpus treated leprosy. It has been claimed that lepra reactions and ENL are less frequent when suI phones are administered parenterally. This has not been our experience. Indeed the incidence and severity were markedly greater in the hydnocarpus oil suspension group. It has also been claimed that a fluctuating blood sulphone level predisposes to reactions. In the 'Avlosulfon' Soluble group exhibiting gross blood fluctuation the incidence of ENL was actually less than in the other groups nor was it related to the time of peak suI phon­ aemia. Reactions beginning in the second week after injection were as frequent as those occurring during the first week when blood concentrations were high. Lepra reactions and ENL must be distinguished from drug side effects. This may appear a statement of the obvious but may not be easy for leprosy workers contending with uneducated and primitive people and a language barr ier. Although no significant reduction of the incidence of ENL occurred when dapsone was given parenterally, unpleasant and depressive side effects common with oral dapsone were greatly diminished. It must be admitted that such side effects are less common when dapsone is given orally in daily dosage of 100mg. , as is our practice with outpatients at this lepro­ sarium, than with twice weekly dosage of 300 mg. In the case of 'Avlosulfon' Aqueous Suspension side effects appeared to be virtually eliminated. The relative well-being which results from freedom from such side effects may lead the patient to state that 'reactions' are less with injection therapy than with oral dosage. The significance of the increased incidence of ENL in the oily suspension group must remain obscure in the present state or our knowledge. Our findings agree with those of COCHRANE22 (1959) that the oily vehicle has a greater liability to precipitate reactions. ENL may be regarded as an allergic flare-up which is a concomitant of successful sulphone therapy but not necessarily part of the essential immune mechanism of the host. It only occurs and is therefore only a nuisance in lepromatous leprosy. Injection therapy however lends itself best to the outpatient treatment of tuberculoid leprosy in which ENL reactions do not occur. In such patients skin sensitiza­ tion (tuberculin type) is an essential factor in the immune reaction and adjuvant action of the oil, if proven, may be of advantage.

Psychological Factors The psychological appeal of injections varies from community to community. In Nyasaland the Bantu people have great faith in the healing power of the needle and (with the exception of timid individuals) a painful injection is deemed more potent than a painless one and may be more appreciated if not repeated too often. The immense popularity of neoarsphenamine as used in yaws campaigns 232 LEPROSY REVIEW

in the continent can be partly attributed to the bitter taste experienced during injections which impressed primitive patients. Injection therapy is therefore a useful device for popularising leprosy treatment in Africa. Therapeutic benefit and faith in the drug are established before injections begin to pall. rdeally the injection should be as painless as possible and in this respect 'Avlosulfon' Aqueous Suspen­ sion was the most satisfactory preparation.

Ease of Injection The viscosity of the suspension in ethyl esters of hydnocarpus oil calls for considerable muscular effort on the part of the injector particularly when a 20 ml. syringe is used. This difficulty was not encountered with 'Avlosulfon' Aqueous Suspension and the small volume of the injection (3 ml.) apart from reducing pain at the injec­ tion site is an advantage in mass treatment, saving time spent in charging syringes. Neither the oily nor the aqueous suspension showed any tendency to cake on standing for periods up to two years and needle blocking was not a nuisance with either preparation. The needle used in all injections was a gauge 20 serum needle with an internal diameter of 0.9 mm.

Summary and Conclusions A trial is described of one short acting sulphone ('Avlosulfon' Soluble) and two long acting sulphones (dapsone suspended in ethyl esters of hydnocaI:pus oil and 'Avlosulfon' Aqueous Suspen­ sion) given in roughly equivalent dosage by intramuscular injection at fortnightly interva.ls. The control group received dapsone 300 mg. twice a week by the oral route. Thirteen lepromatous patients in each group completed the first year of the proposed trial and pre­ liminary results are presented and discussed. No significant difference in therapeutic activity has been detected between the fo ur preparations. The effectiveness of 'Avlosulfon' Soluble administered at fortnightly intervals in dosage equivalent to 1.2 g. of dapsone supports the view that a sustained blood sulphone level is not essential and that briefly sustained high peak levels at fortnightly intervals are tq-erapeutically active. The claim that dapsone i}dministered parenterally gives rise to fe wer 'tepra' reactions and ENL than by the oral route was not confirmed, but side effects of the drug were markedly less when it was administered by injection. The grossly fluctuatingbloo d sulphone levels produced by 'Avlosulfon' Soluble did not provoke an excess of ENL reactions. On the grounds of freedom from pain, absence of side effects, convenience of injection and economy in the total quantity of sul­ phone used the 'Avlosulfon' Aqueous Suspension was considered to be the' preparation of choice. SHORT AND LONG ACTING SULPHONES 233

AcknowJedgements My thanks are due to the Director of Medical Services, Nyasaland, fo r permission to publish this paper. I am grateful to Imperial Chemical Industries, Ltd., Pharmaceuticals Division, Wilmslow, for generous supplies of 'A-vlosulfon' Soluble and 'Avlosulfon' Aqueous Suspension (lCI 20, 177), to Societe Parisienne d'Expansion Chimique (SPECIA) for supplies of 'Hyrgathione' and to Union Chimique Beige for supplies of 'Sulfone U.C.B.' The two latter preparations are 25 % suspensions of dapsone in ethyl esters of hydnocarpus oil. r wish to thank Dr. J. M. Mungavin, Medical Department, ICI Ltd., Pharmaceuticals Division, for his advice, for assistance in compiling a survey of the literature and for commenting upon the paper. I am grateful also to the patients and members of staffof Kochira Leprosarium for their co-operation in this trial.

References I. RIDLEY, D. S. (1959) Leprosy Review, 30, p. I I. 2. COCHRANE, R. G. (1949) Leprosy Review, 20, p. 4. 3. LoWE, J. (1950) LallceJ, I, p. 145. 4. LowE, J. (1952) Leprosy Review, 23, p. 4. 5. MOLESWORTH, B. D., and NARAYA'NASWAMI, P. S. (1949) Internat. J. Leprosy, ' 17, p. 197. 6. MUIR, E. (1951) Leprosy in India, 23, p. 1 25. 7. FLOCH, H., LECUILLER, A. and DESTOMBEs, P. (1951) Bull. Soc. Path. Exot., 44,p. 461. 8. LAVIRON, P., LAuRET, L., and JARDIN, C. (1953) Ylth Int. Leprol. Congr., Madrid. 9. LAVIRON, P., LAuRET, L., and JARDIN, C. (1954) Med. Trop., 14, 1'. 69. 10. MONTESTRUC, E., LE SAGET, M., and BERDONNEAU, R. (1955) Bull. Soc. Path. Exot., 48, p. 64. 11. FLOCH, H., and GELARD, A. M. (1954) Bull. Soc. Path. Exot., 47, p . 646. 12. LAVtRON, P., LAURET, L., KERBASTARD, M., and JARDIN, C. (1955) Bull. Soc. Path. Exot., 48, p. 126. 13. FLOCH, H., and GELARD, A. M. (1954) Bull. Acad. Nat. Med., 138, p. 523. 14. DAVEY, T. F., DREWETT, S. E., and CAP, J. (1958) Yllth Int. Leprol. Congr. Tokyo. 15. TOUZIN, R., and MERLAND, R. (1953) Med. Trop., 13, p. 1002. 16. bAVEY, T. F., (1956) Leprosy Review, 27, p. 6. 17. DAVISON, A. R. (1957) Leprosy Review, 28, p. 148. 18. HART, P. D'ARCY, and REES, R. J. W. (1955) Ciba Foundation Symposium on Experimental Tuberculosis, Churchill, p. 299. 19. BOYDEN, S. Y., and SORKIN, E. (1955) Ciba Foundation Symposium on Experimental Tuberculosis, Churchill, p. 144. 20. HANKS, J. H. (1958) Internat. J. Leprosy, 26, J). 9. 21. UNGAR, J., CoULTHARD, C. E., and DICKIN�, L. (1948) Brit. J. Exp. Path., 29, p. 312. 22. CocHRANE, R. G. (1959) Leprosy in Ttwory and Practice, Bristol, John Wright, p. 214. 234 LEPROSY REVIEW

C1RCULATION IN THE FEET OF LEPROSY PATI ENTS, WITH AND WITHOUT ULCERS

DR. B. B. GOKHALE Hon. Dermatologist and Venereologist, Sassoon Hospitals, Poona DR. S. M. V ABLE Dept. of Dermatology and Venereology, Sassoon Hospitals, Poona SUMAN MODAK Staff Nurse, Dept. of Dermatology and Venereology, Sassoon Hospitals, Poona

Introduction Trophic ulcers are quite a familiar sight in leprosy and are one of its most crippling complications. These lesions develop or continue to persist in spite of their local treatment along with the general treatment directed towards leprosy. A large number of factors are responsible for the causation and persistence of these lesions. While the importance of trauma and neurotrophic factors in their etiology has been well stressed, the impression of some of the workers is that an inadequate blood supply must also play an important role in their causation and in their persistence. Such circulatory disturbances could be due to abnormal impulses from the peripheral fibres of the autonomic nervous system, for this system is involved very early in leprosy (Khanolkarl 1955); as also due to the involvement of blood vessels by a leprous process (Faget2 1944). Observation of skin temperatures has been used from the earliest times in the estimations of blood flow through a part. Surface thermometry is a simple but important procedure in the evaluation of peripheral circulation. Though this method is not very suitable for the study of transitory changes in circulation, it gives quite valuable information when these changes persist fo r several minutes. The difference of temperature in the symmetrical areas is of clinical significance, but the difference of temperature in response to paralysis of vasomotor fibres is still more important. Such a paralysis can easily be achieved by a regional anaesthesia. This allows the dilatation of the muscular coat Yof the blood vessels when not damaged by a serious pathological condition. Thus by this method it is possible to differentiate organic disease of the artery from functional vasomotor spasm, and also to forecast the results of sympathectomy.

Material and Method During this study, fo ur comparable groups of adults were stl!died, mostly males, aged between 1 8 to 50 years. Group A Normal-Patients with normal healthy extremities and negative serological test for syphilis (S.T.S.) Most of these CIRCULATI ON IN THE FEET OF LEPROSY PATIENTS 235

patients were given spjnal anaesthesia for operations like hernia, hydrocele, etc. Group B Patients with positive S.T.S. with clinically normal extremities. This group was included because one of the predominent features of syphilis is the occurrence of periarteritis and endarteritis. Group C Leprosy patients with otherwise normal inferior extremities with normal muscular power, etc. (as judged by clinical examination). Group D Leprosy patients with non-healing chronic ulcer on one of the feet (without any gross mutilation of feet and involve­ ment of bones) with normal muscular power in both lower legs. These ulcers were usually existent for more than three months and did not yield to bed rest, aseptic dressings, and similar measures. The leprosy patients under study were classified, their smears made, and records made of general details and of their ulcers. The procedure adopted for the study of each patient was as follows. A patient was made to lie down in a quiet draughtless room with trousers and underclothes removed. The oral temperature was noted and the blood pi essure taken. After half an hour, the oral temperature was taken again and the temperatures of the lower third of the legs and dorsa of the feet were registered by the use of a thermocouple. Then 50 mg. of ephedrine were injected and five to ten miriutes later an injection of 1.5 ml. of a spinal anaesthetic containing 0.5 % nupercaine was given. The extremities were then tested for loss of sensation and power. After25 and 35 minutes the temperatures in the lower third of the legs and the dorsa of the feet were recorded. (By experience it has been established that any changes in temperatures stabilise completely within 35 minutes of the spinal anaesthesia.) The differences in temperature before and after the spinal anaesthesia have been recorded under the title 'Variation' in Tables No. I, II, III, and IV, as given in an Appendix to this paper.

Results It is evident from Table I that there is no significantdiff erence in the variations in temperatures in the normal feet and legs. Similarly, it is indicated by Table II (Group B) and Table III (Group C) that there is no significant variation of the temperatures in the cases with positive S.T.S., and in leprosy cases wirhout ulcer on the feet. But Table IV (Group D) clearly shows that there is a significant variation in the temperatures between the ulcerated and non­ ulcerated feet, without any significant variation in the legs. 236 LEPROSY REVIE'A

It is interesting, as demol)strated by Table V, that there is nu significant difference between variations in the temperature in the normal foot of a leprosy patient having an ulcer on the other foot and in feet of a patient suffering from leprosy with otherwise normal lower extremities. But there is a significant variation between the normal subjects and the normal foot of leprosy patients with an ulcerated other foot.

Discussion From the results recorded it seems that the variation in tem­ perature, after the spinal anaesthesia, in the ulcerated feet of the leprosy patients is less as compared with the normal subjects (Table I-Group A), leprosy patients with normal feet (Table III-Group C), the other non-ulcerated foot of leprosy patients with ulcerated feet (Table IV-Group D) and patients with positive serological test for syphilis (Table II-Group B). However, there is no significant variation in the lower third of the leg in any of these groups. This leads us to the conclusion that the arteries in the ulcerated feet of the leprosy patients are involved in the pathological process leading to deficiency in circulation. Table VI showing the range clearly brings out this point. Thus, the arterial system in leprosy patients with ulcers on the feet is not the same as in normal subjects. This may be due to the pathological involvement of blood vessels, or it may be due to an inherent defect in the arterial circulation of the patients. This is illustrated by Case No. 8 of Table I. The interesting point is that the variation in temperature afterthe spinal anaesthesia is very small, in comparison to Cases No. 2, 5, 6, etc., of Table I. Thus it is possible that leprosy subjects with a similar inherent defective circulation could be predisposed to ulceration of feet under the conditions of stress and strain. In the Cases Nos. 8 and 9 of Table IV, the variations are like those in normal subjects. These might be the cases which would improve after treatment directed towards vasodilatation, using sympatholytic vasodilators Hke Priscol (Ciba). But in Cases Nos. 2, 5, 6, etc., of Table IV, the results with such drugs may not be en­ couraging, as the arterial system in these cases is inadequate. How­ ever, Hydergine (Sandoz) may be of some use because in addition to its sympatholytic effect it also has a direct action on the musculature of the blood vessels. This explains the variation in results after the therapeutic use of vasodilators (Gokhale,3 1956; Wa tt Maney4, et al., 1958). Therefore it can be concluded that there are definite circulatory deficiencies in the feet of leprosy patients with ulcers, some due to the leprotic involvement of blood vessels and others due to the in­ herent inadeq uacies of the circulatory system. CIRCULATION IN THE FEET OF LEPROSY PATIENTS 237

Summary Four groups of patients; (a) normal healthy individuals, (b) normal individuals with positive serological test for syphilis, (c) leprosy patients without trophic ulcers on the feet and (d) leprosy patients with non-healing chronic ulcer on one of the feet; were examined for the difference in variations in temperature in the lower third of the legs and dorsa of the feet before and after the admini­ stration of spinal anaesthesia. This study indicates that the arterial circulation is defective in ulcerated feet in leprosy as judged by the significant difference in variation of temperatures before and after spinal anaesthesia. The arterial circulatory deficiencies in ulcerated feet in leprosy could be due in some cases to the pathological involvement of the arterial system and in others to the inherent inadequacies of this system.

APPENDIX TABLE No. I GROUP A-NORMALS Variation in temperature (Variation in temperature (in centigrade)

FOOT LEG Serial No. Right Left Right Left

1 3.6 2.0 1.6 1.9 2 2.0 1.6 1.9 1.5 3 3.2 3.0 1.0 2.0 4 2.0 0.3 \.7 0.7 5 3.0 3.4 1.6 2. 1 6 3.0 3.1 0.0 0.3 7 1.4 1.0 0.9 0.6 8 0.4 0.5 0.6 0.6 9 4.6 3.4 0. 1 0. 1 1 0 2.2 2.4 0.4 1.6 11 3.2 3.6 1.0 0.6 12 3.2 3.8 1.1 1.5 13 1.5 1.4 0.3 0.6 1 4 3.8 3.7 0.2 0.8 1 5 4.5 4.4 0.2 0.8 16 2.9 \.7 0.6 1.0

Mean 2.8 2.3 0.8 1.04

NORMALS

hEM LEG FOOT n -- Right Left Right Left n Mean 0.8 1.04 2.8 2.3 1 6

RXL RXL D,f. Value of 'I' 1.16 1.08 30 not significant not sign ificant

In the normal sample the differences of means of the right and left legs or right and left feet are not significant. 238 LEPROSY REVIEW

TA BLE No. II GROUP B-PATIENTS WITH POSITIVE S.T.S. Variatioll ill temperatllre (ill cellligrade)

FOOT LEG Serial No . Right Lej; Right Left

I 3.1 3.8 0.9 1.7 2 5.7 7.0 2.0 3.3 3 3.2 2.6 104 0.9 4 0.9 2.2 0.5 0.7 5 4.0 4.0 2.6 2.8 6 2.2 2.0 2.2 1.0 7 1.6 1.0 0.8 2.2 8 0.8 2.2 0.2 004 9 3.6 2.3 1.6 1.0 10 5.0 3.8 2.0 3.1 II 3.2 2.7 1.7 1.6

Meim 3.03 3.05 lAS 1.70

Patients with positive S.T.S.

ITEM LEG FOOT n

Right Left Right Left n Mean 1045 1.70 3.03 3.05 II

Value of 't' 0.65 0.3 for d.f.20 not significant not significant

In the sample with positive S.T.S. the differencesof means of the right and left foot and right and left leg are not sign ificant at all.

TABLE No. III GROUP C-LEPROSY PATIENTS WITHOUT ULCERS ON FEET Variatioll ill temperature (ill cellligrade)

FOOT LEG Serial No. Right Leji Right Left

I 3.3 4. 1 1.5 2.2 2 3.2 3.7 104 1.3 3 0.2 0.9 0.2 0.3 4 2.2 1.3 0. 1 0.9 5 1.3 1.8 1.4 2.5 6 0.8 2.0 0. 1 1.0 7 2.7 1.5 1.8 1.3 8 0.2 1.2 0.8 0.4 9 0.8 1.0 0.7 0.2 10 1.0 1.0 0.2 1.7 II 1.0 1.0 0.2 1.7 12 1.8 1.4 0.0 0.0 13 3.8 3.0 2.6 2.6 14 2.2 1.0 1.2 1.7 15 0.2 1.2 0.8 0.6 16 1.2 1.2 0.8 0.7

Mean . 1.68 1.66 0.89 1.16 CIRCULATION IN THE FEET OF LEPROSY PATIENTS 239

Leprosy patients without ulcer

ITEM LEG FOOT n - - Right Left Rig/II Left n Mean 0.89 1.16 1.68 1.66 I S 16

28 30 D.f. Value of ',' 0.304 O.OS I not significant not sigifican,

In the sample of leprosy patient without ulceration of feet, the difference in the means of the right and left leg or right and left foot are not significalll.

TABLE No. IV

GROUP D-LEPROSY PATIENTS WITH ULCER ON ONE OF THE FEET

Variation ill temperature ( in cellligrade)

FOOT LEG Serial No. Ulcerated Non-ulcerated Ulcerated Non-ulcerated

I 0.5 3 .2 0.0 0.0 2 0.0 O.S 0.0 0.2 3 0.0 1.0 0.2 1.2 4 0.0 2.0 0.2 1.6 5 0.4 0.2 0.0 O.S 6 0.4 0.4 0.0 0.2 7 1.2 0.6 1.7 1.6 8 2.2 1.8 1.9 1.9 9 1.6 2.0 2.4 1.6 10 0.4 0.7 1.8 0.3 It 1.0 0.7 1.I 0.4 1 2 0.2 2.8 0.0 2.8 13 0.4 1.0 0.4 0.6 14 1.2 3.2 1.2 2.2

Mean 0.68 1.44 0.71 1.09

Leprosy patients-Ulcer on one foot

ITEM LEG FOOT

Ulcerated Non-ulcerated Ulcerated Non-ulcerated

0.71 1.09 0.68 1.44

1.19 2.06 Value of 't' (d.f.26) (d.f.26) not significant Significant (not highly)

From the above values it seems that the value of 'I' in case of feet with ulcer and without ulcer is found to be significant but in the case of the leg the value of 'I' is not significant. 240 LEPROSY REVIEW

TABLE No. V A-Normal (Table I). C-Leprosy without ulcer (Table III). D-Leprosy with ulcer (Table IV). FOOT I. Comparison between non-ulcerated foot of D and a foot of C.

C D Mean 1.67 1.44

Value of 't' 0.59 (for d.f.28) not significant

The two samples non-ulcerated foot of Leprosy patielll with ulcer and a foot of Leprosy patient without ulcer are not significantly different. 2. Comparison between non-ulcerated foot of D (Leprosy with ulcer) and a foot of A (Normal).

A D Mean 2.56 1.44

2.78 (for d.f.28) Value of 't' Value significant

This means, that, two samples-non-ulcerated foot of leprosy patient with ulcer and a foot of normal person-are significantly different. (But not very highly significant as in case of ulcerated foot.) LEG

C D I. Mean 1.1 1.09

Value of 'I' 0.032 (for d.f.27) not significant at all

A D 2. Mean 0.93 1.09

Value of 't' 0.61 (for d.f.28) not significant at all.

From the above two results, it seems, in the case of the non-ulcerated leg, of leprosy patients with ulcer, there is no significant difference when compared with a leg of Leprosy patients without ulcer and Normal persons.

TABLE No. VI Variation in temperature after spinal anaesthesia for range 0.0 to 1.0.

Group Description Results

A Normals Only 6.3 % of values lie in the range 0.0 to 1.0 •

C Leprosy 43.8 % values lie in the without ulcers same range 0.0 to 1.0

D Leprosy 71.4 % values lie in the with ulcers same range 0.0 to 1.0

From the above it can be inferred that Group D always tends to have lower values than Groups A and C while Group A always tends to higher values. CIRCULATION IN THE FEET OF LEPROSY PATIENTS 24 1

Acknowledgements Our thanks are due to Superintendent, Kondhwa Leprosy Hospital, for permission to work in the hospital as also to Dr. S. v. Marathe and Mr. W. Jennings ofthe same hospital for their help and co-operation. Thanks are also due to Civil Surgeon, Sassoon Hospitals, Poona, and colleagues at these hospitals, for their co-operation and en­ couragement, and kind thanks to Mrs. S. S. Pande for her help in statistical representation of data.

References I. KHANOLKAR, V. R. Prospectives in Pathology of Leprosy. Indian J. of Med. Science, 9, 24 (Supplement). 2. FAGET, G. N. Bone Changes in Leprosy. Radiology, 42, I, 1944. 3. GOKHALE, B. B. Treatment of Trophic Ulcers of the Soles of the Feet in Leprosy with certain Hydrogenated Ergot Alkaloids. Dermatologica, 113, 1956, 142. 4. WATT MANEY, W. A., HAN-WEEFONG, Lo-HONG LING. Trophic Ulceration of the Foot Treated with Intra-arterial Hydergine. Internat. J. of Leprosy, 26, 1958, 115. 242 LEPROSY REVIEW

STUDIES IN PLANTA R ULCERS IN LEPROSY

IV. EnOLOGY OF PLANTAR ULCERS

E. W. PR ICE , F.R.C.S. Orthopaedic Surgeon to Leprosy Service, Eastern Nigeria

Introduction The problems of plantar ulcer in leprosy include why it occurs in the first place, why it resists simple treatment, and why it oftenrec urs after healing. At the moment we do not know the answer to any of these questions, though there have been several suggestions on which different types of treatment have been based. In this paper we summarise the known facts about plantar ulceration in leprosy and then discuss various theories of their causation, and finally suggest a modified etiology which corresponds to clinical observations and which will serve as a basis of treatment, and protection against relapse. Similar ulcers occur in the neuropathic foot of diabetes, though in this there is often a vascular disturbance which is absent in leprosy. OATLEY, et af. (1956)1 summarised current views on the etiology of these diabetic lesions of the feet, and gave clinical photographs of plantar ulcers which appear identical with those of leprosy.

Accepted Facts about Plantar Ulcers in Leprosy I. The ulcer occurs on an anaesthetic sole The skin on which a plantar ulcer occurs is always anaesthetic. The relation of ulceration to deep sensation is less clear. Deep ulcers may be either painful or painless, and surgical intervention can some­ times be undertaken in the deep tissues without the induction of anaesthesia. We studied a recent series of cases in an attempt to correlate the occurrence of plantar ulcers with the state of deep sensation, using the presence or absence of joint sensation as an indicator of the integrity of deep sensibility. The subject appreciates the position of a joint by means of sensation transmitted from the joint itself and from the skin, and sensory mechanisms from tendons and muscles play no part in it (HARRISON, 19582). Nevertheless, some of our patients obviously did estimate the position of the joint by contracting the flexorand extensor muscles in alternation, and calculating the position of the joint from the varying tensions. However this is not true joint sense. We used the big toe to test the first metatarso-phalangeal joint, because the toe is easy to handle, and plantar ulcers are common over this joint. We had also noted that normal barefooted villagers are aware of the position of the big toe when they are not always clear about the position of their lateral toes. STUDIES IN PLANTAR ULCERS IN LEPROSY 243

We tested 50 consecutive cases in this way, and fo und no correla­ tion between the presence of ulceration over the first metatarso­ phalangeal joint and the presence or absence of position-sense in the joint itself. However similar observations on a series of new ulcers might reveal significant facts. The present series included cases of varying duration, and it may well be that joint-sense was absent at the period when the ulcer occurred. It is also possible that deep sensation may be absent in soft tissues when joint-sense is intact, which is a relation difficultto establish clinically. We have fo und no references in the literature to observations of this sort, and it calls for investigation by those who deal with such cases. 2. Some anaesthetic soles never ulcerate at any period This fact is related to the previous one, and is stated separately because'study of deep sensation in non-ulcerated soles may help us to understand the problem, and will play a part in plans to provide suitable footwear for the protection of anaesthetic feet in leprosy patients. It would be a most helpful advance if we could know which feet are likely to ulcerate and which not. 3. Ulcers occur on the pressure-bearing areas of the sole This is true of the undeformed foot. In a foot mutilated by advanced infection or by surgical intervention, ulceration will occur wherever the pressures are maximal. Apart from these latter cases, all plantar ulcers can be plotted on a tracing of the walking footprint (see drawings in Fig. 2 of the Mechanics of the Foot in Relation to Plantar Ulcers, Lep. Rev. 30, 2: April, 1959, facing p. 101). This does not apply to the standing footprint, in which the pressure areas include only the heel and metatarsal pads. The tips of the toes may leave an imprint, but in the standing foot are not pressure-bearing areas, nor is the area under the interphalangeal joint of the big toe. Both these latter are common sites for plantar ulceration. 4. A Plantar ulcer will heal with bed rest, or ff immobilized in a walking plaster cast It has long been known that plantar ulcers will heal if the patient is kept offhis feet long enough, and periods of fo ur to six weeks are adequate in uncomplicated cases. It is also known that they will heal if the foot is encased in a walking plaster cast, taking a week or two longer but not requiring complete rest in bed. If plaster cast immobilization is kept up long enough, all ulcers will heal eventually without surgical intervention, though for feet grossly affected period up to one year may be needed. The earliest reference to treatment by plaster casts appears to be that of KHAN (1939)3, and repeated mention has been made of its success since then, (MILROY PAUL, 19474, FISHER, 19555, BOSE, 19566). There is a reluctance to adopt the method, which is undoubtedly due to the high proportion of relapses when natural walking is resumed. It has been suggested that the healing achieved in a plaster cast is due 244 LEPROSY REVIEW to the distribution of pressure over the full area of the sole by a closely-fitting cast. However, experience of such casts makes one doubtful whether they really do this for long, for most are quite loose at the end of a month and can hardly be distributing weight. In spite of this, the ulcer heals and it seems that some other process promotes it. 5. A plantar ulcer overlies a bony prominence Plantar ulcers are found over the following prominences in the unmutilated foot ; the metatarsal heads ; the tubercle on the base of the 5th metatarsal ; the· head of the proximal phalanx of the big toe ; the tubercles of the calcaneus; the heads of the distal phalanges of the toes. It should be noted that the tubercle on the base of the 5th metatarsal is a lateral projection in the normal foot, and only presents in the sole if there is weakness in the pronators which evert the foot. The head of the proximal phalanx of the big toe and the tips of the toes only become bony prominences in the walking foot. Study of the mechanics of the foot makes it more likely that the operative factor is not so much the presence of the bony prominence but the points of pressure-rotation during the walking roll (see Leprosy Review, 30, 2, April, 1959, p. 102.)

Theories of the Etiology of Plantar Ulcers The literature does not include careful studies into the etiology of plantar ulcers in leprosy, and etiological theories have to be deduced from the type of treatment suggested. These theories include the following: I. That plantar ulcers are specific lesions Though this has not been explicitly stated anywhere, the local use of specific drugs such as chaulmoogra oil or deratives of DDS implies a suspicion of it. In the earljer experiments of LOWE et al. (1936)7, hydnocarpus oil was injected weekly into the base of the ulcer by a series of punc­ tures, and photographs showed that the ulcer healed in six weeks. However, ulcers will heal spontaneously if weight-bearing is avoided for six weeks, and the beneficial effects may well have been due to the fact that walking on the ulcer was made difficult or impossible by this treatment. The report stated that all ulcers do not respond to injection treatment. In a later series by DHARMENDRA, et 01. (1955)8 a derivative of DDS was used locally in fifteen cases, with X-ray controls. Healing occurred in only nine of these cases after treatment from 1 to 12 months, with an average of nine months. Judging by the clinical descriptions, the time needed for healing is no less, and appears longer, than that associated with simple rest or immobilization in a walking- cast. STUDIES IN PLANTAR ULCERS IN LEPROSY 245

Thus there is little probability that plantar ulcers are specific lesions. 2. That the autonomic nervous system is in volved Some workers have wondered whether lesiQns of the autonomic nervous system contribute either to the occurrence of plantar ulcer or to its chronicity, with particulal reference to disturbance of the blood supply to the part. Treatment based on this surmise would take note of the effect of a damaged autonomic system, or seek to increase the blood supply to the ulcer-bearing area in a normal autonomic system. Tn the treatment of tropical ulcers in pre-antibiotic days there was some success from increasing the blood supply in this way (PRICE, ]945)9. There are few records of the use of this method in ulceration in leprosy. VrsHNEVSKY ( 1938)10 reported a series treated by novocaine blockade, but concluded that the results were indefi­ nite. LElTNER ( 1 938)11 prepared arteriograms of feet amputated for long-standing ulceration in leprosy and found an ample blood supply even afterlong -standing infection and advanced destruction. As in the strapping treatment for varicose ulcers the success of plaster casts might be due to support given to the peripheral circula­ tion. To test this we treated a few cases of plantar ulcers by giving them a plaster sandal to wear, which did not reach above the ankle. The sandal had to be strapped to the foot to prevent it coming off, and it was difficultto avoid rubbing the heel, but the ulcers healed in much the same time as those which had long casts. It seems as if disturbance of the autonomic system plays little part in the pathology of plantar ulceration. 3. Th at trauma is the prime cause Infected trauma can cause an ulcer on the sole, as on the hand or elsewhere on the body skin, but the lesion can be recognized as an infected cut or puncture in most cases, and we think it can be clearly distinguished from the chronic ulceration with which we are concerned here. However, COCHRANE (1947) states "We believe all trophic ulcers commence from injury; this may be so slight as hardly to be noticed." He gives the impression that the trauma concerned is damage to the skin by an external agent. BRAND (1950)12 concludes that "The two factors which produce ulceration are sustained pres­ sure and active injury. In general, people who wear shoes suffer from sustained pressure and people who walk barefoot from direct injury." In order to study the relation of external trauma to plantar ulcers the writer examined every week for six months the feet of 500 patients in a leprosarium, aided by a trained Nigerian assistant. We paid particular attention to the occurrence of trauma by cuts and pricks, etc., and to cases in whom plantar ulceration obviously impended. We confirmed CoCHRANE in his observation that the 246 LEPROSY REVIEW earliest lesions are frequently in the form of idiopathic blisters, but there seemed to be no connection between obvious trauma and subsequent plantar ulcer. The idea that the trauma may be so small as to escape careful regular examination also seemed wide of the mark, for the blisters were observed to arise from deep tissues and follow a sequence at a time when in very many cases the skin surface was perfectly intact. The relation of superficial trauma to plantar ulcer is not merely academic. Jf such trauma were really the initial lesion it would be logical to provide protective footwear for all leprosy patients who have anaesthetic soles. Those who have experience in providing and maintaining such footwear for even a limited number of patients in a leprosarium, will realise the amount of work and expense involved ; it would be even more difficult in rural clinics. On the other hand, if external trauma only plays a minor part, the provision of footwear can be limited to those patients who are passing through the phase when plantar ulcer is a danger. We believe that this period can be judged by the weekly palpation of the ulcer-bearing areas of anaesthetic soles. Only these cases are in need of protective footwear.

4. Th at plantar pressure is a cause of plantar ulcer That the pressure of the weight of the body is important in pro­ ducing plantar ulcers is clear, but it is not so clear how it acts. BRAND (1950)12 believes that prolonged standing is the dangerous factor, stating "It is fundamental that no patient be allowed to stand for more than five minutes at a time". In this connection we recall that pressure ulcers from the recumbency of sleep, where the weight of the limb rests on the posterior aspect of the heel or one on of the malleoli, are remarkably uncommon in leprosy. It is also significant that the pressure distribution during standing in patients with anaesthetic soles varies rapidly from one part of the sole to another as the patient maintains his balance without the help of the sensory mechanism of the sole. In this the muscles of the calf and front of the lower leg are in constant movement in order to maintain balance.

5. Th at clawing of the toes exposes the metatarsal heads It is an attractive theory that intrinsic muscle weakness is a factor in the production of plantar ulceration, even though perforating ulcers have been reported in tabes, where muscle weakness is not a fe ature. Because of the suggestion that the cocked toes of leprosy expose the metatarsal heads to pressure and.injury, and so predispose to ulceration, we kept a careful check on patients with clawed or cocked toes in relation to the incidence of ulcer on the corresponding metatarsal pad. We soon fo und that there was no obvious relation between the two. We also examined a group of healthy subjects in a training school and found a surprising number of normal feet which had toes which did not touch the ground on standing. STUDIES IN PLANTAR ULCERS IN LEPROSY 247

We think therefore that clawing of the toes has no relation to plantar ulcer insofar as it exposes the metatarsal head. Often a foot with no toes is remarkably free from ulcers. We hold strongly that the inability of weakened toes to perform their protective function at the moment of the walking roll is a potent factor in the production and chronicity of plantar ulceration in leprosy. Suggested Etiology as a Basis fo r the Treatment and Prevention of Plantar Ulcers Thus a critical examjnation of existing theories reveals several unsatisfying features, if only because treatment based on them has yielded no lasting results so far. No theory fits all the facts, when one carefully examines a series of anaesthetic feet. We suggest the follow­ ing etiology which incorporates the known facts, adds recent observations, and gives a plan of treatment and prophylaxis which can give good results. It also gives an indication of the type of foot­ wear likely to be of value, and the circumstances in which protective footwear should be provided. The factors involved in the production of plantar ulcer are : I. An anaesthetic fo ot: superficial anaesthesis is invariable, but deep anaesthesia appears to be variable and may be absent at the moment of ulceration : 2. A walking fo ot: patients who do not walk do not develop ulcers and they occur at points on the sole where there is pressure­ friction round points of rotation of the walking roll ; these include the point of contact at the heel, the points of dorsiflexion of the foot at the mid-lateral and the metatarso-phalangeal joints, and the points of push offat the tips of the toes : 3 . A fo ot with a damaged intrinsic musculature: weakness of this nature compromises the mechanism by which the points of rotation are protected from damage during walking. It follows from the above that plantar ulcers will heal and remain healed if the walking roll is interrupted. This is ensured if the patient is in bed, if he is wearing a plaster cast even if w.alking in it, and if he wears footwear with a rigid sole; such footwear also protects the points of contact at the heel and in push off at the toes. Later we hope to report the results of a series of cases treated for a year by this method.

Summary The accepted facts about plantar ulcers in leprosy are that they occur on an anaesthetic sole, though some anaesthetic soles never ulcerate at any time ; that ulcers develop on the pressure-bearing areas of the sole; that they will heal with bed rest, or if immobilized in a walking plaster cast ; that they overlie bony prominences. The theories of the etiology of plantar ulcers are unsatisfactory, and include the ideas that plantar ulcers are specificlesi ons, that the 248 LEPROSY REVIEW autonomic nervous system is involved, that trauma is the prime cause, that plantar pressure is a ca use, and that clawing of the toes exposes the metatarsal heads. From his experimental studies the author thinks that plantar pressure is the most valid of these, but finds that it is not so much standing pressure as the inability of weakened toes to perform their protective function at the moment of the walking roll. He gives a suggested etiology fo r plantar ulcers which can be used for prevention and treatment. The chief factors in the production of them are an anaesthetic foot, a walking foot, a foot with damaged musculature. Plantar ulcers will heal and remain healed if the walking roll is interrupted, either by bed rest, or by wearing a plaster cast, or by wearing footwear with a rigid sole. He hopes later to report the results of a series of cases treated for a year on these principles.

References I. OATLEY, W., CATERALL, R. c., and MARTIN, M. M. Brit. Med. J. 1956, 2, 953 2. HARRISON, R. J. Report of B.M.A. Meetings, Brit. Med. J., July, 1958, 26, 230. 3. KHAN, J. S. Leprosy in India, 1 939, JJ, 19. 4. MILROY PAUL, quoted by COCHRANE, Practical Textbook of Leprosy, Oxford Univ. Press, 1947. 5. FISHER, C. Leprosy Review, 1955, 26, 107. 6. BoSE, D. N. Leprosy in India, 1956, 28, 77. 7. LOWE, J. and CHATTERJl, S. N., Leprosy in India, 1936, 9, 115. 8. DHARMENDRA, CHATTERJl, S. N., and SEN, N. R. Leprosy in India, 1955, 27, J80. 9. PRICE, E. W. Transact. Roy. Soc. Trop. Med. and Hyg., 1945, 39, 83. 10. VISHNEVSKY, S. M. Internat. J. of Leprosy, 1938, 6, 477. 11. LEITNER, A. J. Internat. J. of Leprosy, 1938, 6, 47 1. 12. BRAND, P. W. Journ. Christian Med. Assoc. of India, 1950.

Acknowledgement I am indebted to the Director of Medical Services, Eastern Nigeria, for permission to publish. USE OF A TENSION EQUALISER 249

USE OF A TENSION EQUALISER IN THE MANY TATLED OPERATION FOR CLAW HANDS

R. H. THANGARAJ, M.B.B.S. Medical Officer, Purulia Leprosy Home and Hospital, Purulia, West Bengal

Sublimis transplantation is almost given up now in the repair of claw hands and is replaced by the "many tailed" operation devised by Brand at Veil ore. This operation, in which the extensor carpi radialis brevis is used as the motor tendon, does not produce the plus deformity which is so common in the sublimis transplantation. Every care should be taken to equalise the tensions in all the fingers otherwise the action of the motor tendon on the fingers will be un­ equal and a re-operation is necessary to correct it. A splint which I have called the "Thangaraj Tension Equaliser" is quite useful in this matter. The author has performed over two hundred operations on the claw hands over this splint and the assessment of these cases showed very good results. Brand and Fritschi have a metal variation of the same and they also found it very useful.

Description of the splint

The splint as shown in the Fig. A consists of (1) forearm piece

A _.- G which has four grooves B, C, D and E but only the first three are used ; (2) the palmar piece H is attached to the forearm piece by a hinge ; (3) the finger piece I is attached to the palmar piece in a similar way and the angle between the forearm and palmar pieces can be varied by placing the finger piece in the different grooves. When low tension is desired the finger piece is placed in the groove B and for higher tension in the �roove D. The splint is made of good wood which can stand sterilization. We sterilize it by putting the splint in boiling water for ten minutes. If good wood is not available this can be made with aluminium. 250 LEPROSY REVIEW

Measurements I. A-G 15 in. (35. 10 cm.) 2. B-E 2 in. (5.08 cm.) 3. B-F 6 in. (15.24 cm.) 4. F-G 7t in. (19.05 cm.) 5. G-J 3 in. ( 7.62 cm.) 6. H measured from the hinge 7 I-measured from the hinge F-3 in. (7.62 cm.) K-3 in. (7.62 cm.)

Application of the splint Brand's many tailed operation consists of three main incisions. (I) Midlateral incisions over the proximal phalanges of the fingers 10 expose the dorsal expansions. (2) A one and half inch (3.8 cm.) 1 ransverse incision over the base ofthe third metacarpal on the dorsum to cut the extensor brevis tendon from its insertion. (3) Another one and half inch (3.81 cm.) transverse incision, over the dorsum on the radial side 2 in. (5.08 cm.) proximal to the wrist crease, to withdraw the tendon cut in the second incision. The graft, either the palmaris or plantaris or both, is sutured to the motor tendon and this is then passed to the second incision. Here the graft is divided longitudinally into two or four slips according to the number of fingers involved .

-- --

These slips are passed to their respective finger incisions and at this stage the splint is applied as shown in the Figure B. A tape may be tied around the forearm and the splint, just proximal to the 3rd incision, in order to keep the splint in position. The author varied the tensions according to the intelligence of the patients thus using higher tensions in persons with low intelligence and lower tensions in intelligent patients. Dr. Brand in his personal communication also felt that higher tension makes for easier re-education. The slips of the graft are sutured to their respective dorsal expansions with "O'� tension. I wish to thank Mr. A. D. Askew for his excellent diagrams of the splint.

References BRAND, P. W. ; Personal communication. BRAND, P. W. ; Leprosy in Theory and Practice 1959, edited by R. G. Cochrane. STAINING LEPROSY BACILLI IN SMEARS 25 1

J A MODl FlED TECH NIQUE FOR ST AINJNG LEPROSY BACTLLl rN SMEARS

R. RHODES-JONES

(From the laboratories of the East African Leprosy Research Centre, P.O. Box 1044, Busia, To roro, Uganda)

The following method of acid fa st staining of M. leprae has the advantage of timed decolourising, and so gives consistent results. Method All staining is carried out in Coplin jars. (a) Flame fix. (b) Stain with Ziehl-Neelsen stain at room temperature for 20 minutes. (c) Wipe stain from the back of the slides and wash in tap water. (d) Decolourise in 5 % sulphuric acid for fiveminut es. (e) Wash well in running water. (f) Counterstain with 0. 1 % toluidin blue for one minute. Wipe offany excess stain from the back of the slide and blot dry. Methylene blue 0. 1 % may be used instead of toluidin blue. The author prefers the latter as it gives a clearer background. This method has now been in used in this Research Centre for the last ten months, with excellent and consistent results.

Acknowledgement I wish to thank the Administrator, East Africa High Commission, for permission to publish this paper. ,.. -

LEPROSY REVIEW

LETTERS TO THE EDITOR

From: Dr. H. W. Wade, President ILA, and CULION SANITARIUM, Editor, International J. of Leprosy. PHILIPPINES

THE EDITOR.

Dear Sir, On August 3, 1959, the World Health Organization convened, in Geneva, Switzerland, a meeting of leprologists-the Second Expert Committee on Leprosy-to consider advances in leprosy work in recent years and to make recommendations for the future. The agenda laid considerable emphasis on anti leprosy campaigns, especially those in countries of high endemicity where resources of men and money for the work are relatively limited. Mass campaigns are a relatively new development, made possible by the application of suI phone (DDS) treatment, and WHO is actively supporting such activities in several countries. On August to, after the Committee had adjourned, the Division of Public Information of WHO issued a press release intended to give certain high lights of the conclusions which it had reached, since its full report cannot be published for several months. One feature of that statement immediately became the subject of unfor­ tunate misinterpretation in the world press. The pertinent sections of the release are quoted: "The Members of the Committee recommended that leprosy campaigns now underway be followed up and extended, using ambulatory treatment with sulphones. Ambulatory care is, in fact, the only valid method of dealing with the problem since there are about 12,000,000 leprosy sufferers in the world ...and not more than 100,000 of them can be hospitalised in existing institutions." Special legislation requiring segregation of victims of the disease " . . . should be abolished in view of the relatively low infectivity of leprosy, which should be dealt with as an ordinary public health problem in the same manner as other communicable diseases." On August 11, The Times, of London, ran an otherwise impec­ cable dispatch from their own Geneva correspondent under the startling headline, "Lepers need not be isolated"; the story ended with the unrelieved statement that "Ambulatory care is the only valid method of dealing with the problem." In Paris, it has been learned, a radio broadcast reported that the Committee had recommended that leprosaria be abolished ; what appeared in the newspapers I do not know. A UPI dispatch from Geneva distributed to American newspapers began with the totally unj ustified statement that the Committee had recommended "the abolishment of all leper colonies" and the home treatment of all cases. LETTERS TO THE EDITOR 253

I t is readily understandable how such statements about lepro­ saria may be highly disturbing in various quarters, especially to government health services which employ such institutions as one element of their means of controlling leprosy, and to organizations such as the Mission to Lepers and the American Leprosy Missions, Inc., which support leprosaria of their own and give aid to others. Patients now in such institutions may very well become apprehensive about their future prospects. It should be noted that the press release in question made mention of the fact that some 100,000 patients are now hospitalized in existing institutions, but did not say that those institutions should be abolished. The intention would doubtless have been clearer if, after "dealing with the problem", the words "of extending anti­ leprosy campaigns" had been added. The day of the leprosarium as a mere asylum is of course long since past, and long experience has shown that segregation in lepro­ saria as the sole method of control is futile. The modern view of the matter is expressed in the fo llowing excerpt from the resolutions on Epidemiology and Control of the vn International Congress of Leprology, held in Tokyo last November: "(b) Hospitals, leprosaria and other fa cilities fo r inpatient care ... Although outpatient care is stressed, facilities for inpatient care are necessary for patients in reaction, and they can play an important part in the control of leprosy. In countries with adequate facilities, as many infectious patients as can be accommodated should be induced to enter leprosaria on a voluntary basis. The period of hospitalization, however, should be only sufficient to effect clinical regression. A prolonged series of negative smears should not be required. From the epidemiologic point of view it is more advan­ tageous to reduce infectiousness in many patients than to eliminate infectiousness in afew. The leprosarium may also be a centre for research education of professional personnel, special surgery and vocational training of patients." As for the view that leprosy should be dealt with as a public health problem on a par with other communicable diseases-which, if the qualifying term "chronic" is added, brings tuberculosis especially to mind-without special legislation but appropriate regulations established under the general public health legislation, that has been developing for some time. It was emphasized by the PASBjWHO seminar held in Bela Horizonte in 1958. The resolutions of the Tokyo Congress referred to include this statement: "Indiscriminate compulsory segregation is an anachronism and should be abolished. Discretionary authority should be given to the health authorities to require isolation in those instances in which the patient is discharging leprosy bacilli and in which suI phone 254 LEPROSY REVIEW

therapy is neglected or ineffective and young children are exposed in the home." Although it may be taking something of a liberty to do so, ] may say with assurance that the WHO Committee took no more radical a stand on either of the points here discussed than did the recent Congress. ] am confident that the Division of Public Information of WHO, if asked, will confirm this statement, although it cannot itself initiate any action to correct newspapermen's misconstructions of the necessarily brief statement which it issued. H. W. WADE, M.D. President, International Leprosy Association

Dr. Basil Nicholson, Senior Leprosy Officer, Western Region, Nigeria, writes from Ossiomo, Benin Province, as follows : "Dr. R. G. Cochrane refers on page 21 1 of his new work 'Leprosy in Theory and Practice' to a condition noted by Dr. S. G. Browne in the Belgian Congo, in which numerous hyperpigmented macules were seen on the skin of patients who were receiving DDS treatment. In Western Nigeria in the past two or three years we have seen a number of cases which correspond almost exactly to his descrip­ tion, and to the colour photograph shown on page 212. We call them blue-black macules, as they resemble stains with blue-black ink. They are flat, inert, and extremely persistent. However, the cases which we have seen almost all have been in persons who have not been taking sulphones, but have come to us afterthe appearance of these macules, in the belief that they may be caused by leprosy. Dr. S. J. Healy, Area Superintendent of Ossiomo Settlement, has observed that in all such cases seen by him the patient has been in the habit of taking one of the proprietary brands of choco­ late laxative which are sold widely in this area. A standard� textbook of dermatology (Sequeira's, 6th Edition) describes phenolphthalein eruptions as erythematous, with a violet tint as a rule, and there may be brownish discolouration. This textbook shows a colour illustra­ tion which, allowing fo r the difference in skin pigment, is very similar to the colour photograph on page 212 of Dr. Cochrane's book. We have observed many thousands of patients on sui phone treatment. I can only remember one or two who developed such macules while on treatment with DDS and in those cases there was some evidence that they had also been taking the laxatives. As this condition is by no means rare in the general community, in persons who have never taken any suI phone, I should be most reluctant to accept it as a newly discovered complication of DDS treatment." ABSTRACTS 255

ABSTRACTS

Fa ctors influencing the Transmission of Leprosy. J. A. KINNEAR BROWN, Trans. Royal Soc. of Trop. Med. and Hygiene, 53, 2; 1959, pp. 179- 1 89. F.rom his seven years of work in Uganda and more than 100 leprosy surveys the author studies the transmission of leprosy. He concludes that the influence of climate, density of population, and overcrowding have only a secondary importance, nor under natural conditions are the children the only ones to sustain the infection. The age of onset is determined by the opportunity for infection, and individual susceptibility decides the issue. The author thinks that lepromatous cases are not the only source of infection, nor always the most important. Susceptibility is a compound factor, and there is a genetic component. Susceptible individuals form a race within a race. The response of the host determines the fo rm of his disease, and the picture resulting is not always clear-cut, though there are cer­ tain predominating patterns. The Problem of Self-administration of Drugs, with Particular Refer­ ence to Pulmonary Tuberculosis. WALLACE Fox, Tubercle, 39, 5, Oct. 1958, pp. 269-274. Most of what this author says will be of interest and value to leprosy workers also. He studies the unreliability of long-term self­ administration of drugs by the patient. He finds that there is even failure of perfect short-term administration, and failure in prophy­ lactic administration of drugs. In the Tuberculosis Chemotherapy Centre, Madras, the author made check studies and fo und plenty of evidence of irregularity in dosage, or under-dosage. Apart from side­ effects from the medicine, many patients seem incapable of establish­ ing the new pattern of behaviour which is called for by the need to take a medicine regularly for a long period. Much research is needed to obviate the human obstacles to regular self-administration, if fu ll and continuous observation is not be be retained over the actual administration of drugs for chronic diseases. Th e Nodule in Onchocerciasis. M. S. ISRAEL. Trans. Royal Soc. of Trop. Med. and Hygiene, 53, 2; March, 1959, pp. 142- 147. This article contains eight informative illustrations and studies the subcutaneous nodules in which coiled-up adult worms may be demonstrated amid a mass of chronic inflammatory tissue, occurring as a feature of human infestation with Onchocerca volvulus. (This condition leads to confusion with leprosy in endemic areas of both diseases). The author examined 70 subcutaneous nodules obtained from Kaduna, North Nigeria. The tissue reaction round the worm is diverse and non-specific,in cluding some form of foamy cell and giant cell. There' is a great tendency to degeneration of the worms and 256 LEPROSY REVIEW

liquefaction Q[ the contents of the nodules. The basis of the nodules seems to be a gradual fibrou� encapsulation of worms which have become lodged at junctions of lymphatic vessels in the subcutaneous tissues. This non-abscessing fibrous tumour takes about a year to fo rm. The change which precipitates encapsulation seems to be one of degeneration and death of the worm : healthy worms lie fre�ly in the subcutaneous tissues and nodules are formed in response to products of autolysis of dying worms. The more numerous nodules are associated with the final stage of regression of onchocerciasis, when there is a decreased concentration of microfilariae in the skin and the cornea.

Clinical Evaluation Studies in Lepromatous Leprosy : Th ird Series : Nicotinamide and BCG as Supplements to DDS. J. A. DOULL, J. N. RODRIGUEZ, A. R. DAVISON, J. G. TOLENTINO, and J. V. FERNANDEZ. Internat. J. of Leprosy, 26, 3: July-Sept. 1958, pp. 219-235. This reports on a fu rther section of the results of the excellent co-operative effort carried out at two leprosaria in the Philippines and one in the Union of South Africa. Two major groups of patients at each leprosarium were treated respectively with DDS, and with DDS plus nicotinamide. Of each group the tuberculin-negative were ascertained and divided into two sub-groups, of which one was given BCG vaccination at least once. The other sub-group was left un­ vaccinated. No evidence was found that either supplementary therapy with nicotinamide or initial vaccination with BCG was advantageous. There was clinical and bacteriological improvement in alJ classes of patients, but those treated only with DDS showed about the same progress as the others. Only six out of 434 patients developed lepro­ min reactivity of the Mitsuda type. Erythema nodosum leprosum occurred equally frequently in the two chief groups ; it was not evoked by BCG vaccination, and was not associated with either clinical or bacteriological improvement, nor with reactivity to PPD. Consideraciones Patogenicas acerca de los Momentos de Origen de la Enfermedad de Hansen. (Pathogenesis of the Early Stages of Leprosy). G. TARABINI and J. TERENC IO. Revista de Leprologia, Fontilles, 4, 5, 1958, pp. 345-353. The authors point out the importance of the activity of the suprarenal glands before or during the initial stage of leprosy, which occurs more frequently among young children. In young children, the suprarenals are small, and at about 12 years of age they reach again their former size which they had at the sixth month of intra­ uteri ne life. The tendency to spontaneous healing of leprosy in children may have some relation to the physiological increase in activity of the suprarenals. At the other end of life, cases have been reported of middle aged persons who develop leprosy after extreme ABSTRACTS 257

psychological or physical suffering. This suggests that the appro­ priate hormonal treatment might be of value in checking the disease particularly in the early, but perhaps also in cases of late onset.

Ideas sobre la inmunoalergia Hanseniana (ideas on.Leprosy immunity and Allergy) G. TARABTNJ, Revista de Leprologia, Fontilles, 4, , 5; 1958, pp. 355-362. £' / The author suggests certain ideas for experimental and statistical study. The mesenchyme is the basis for the development of immuno­ allergy in the leprosy patient, which in itself gives rise to the individual diathesis of the patient in relation to leprosy. Among the mesenchyme components of particular interest are the following: (a) the reticulocyte which turns into foamy cell or epithe­ Iioid cell and (b) the basic tissue substance which may give more or , less resistance against the enzymes which modify its permeability. The antigens produced by M. leprae that act on this basic substance are (a) the proteic antigens which produce antiproteic antibodies in the serum, and the early lepromin reaction in the skin, and (b) the lipoid antigens producing anti-lipoid antibodies in the serum, and the late lepromin reaction in the skin. The positive skin tests indicate the capacity of tissues to check the spread of antigens, whereas the_ serum antibodies indicate the amount of antigens which exist in each individual as a whole. BCG vaccination probably favours the development of allergy, probably acting through the neuro-endocrine system, giving it a tendency to produce the epithe­ lioid rather than the foamy cell. The antiphagocytic power of the mesenchyme is expressed best in the late lepromin reaction, which has more importance than the early, because it expresses the power to limit the development of the bacillus by antagonism towards its lipoids.

La Triamcinolona en el Tratamiento de las Leprorreacciones (Triam­ cinolone in the Treatment of Lepra Reactions). G. T ARABINJ and V. HERNANDEZ. Revista de Lepr. olQgia, Fontilles, 4, 6; 1958, pp. 48 1 -488. The authors tried traimcinolone (Trialona) in lepra reactions in four female patients and found a marked action on the temperature and hepatic function disturbances, and a rapid improvement of the skin manifestations. There was a marked water depletion and a fa ll of arterial pressure without serious consequences, and a good gastric tolerance. The lack of gastric upsets was quite notable.

Symposium on Tuberculosis and Leprosy : On the Immunological Relations. S. W. A. KUPER. Transactions of NAPT Common­ wealth Chest Conference, London, 1958, pp. 67-71. He found in a study by meticulous techniques in patients in South Africa that there was no significant correlation between 258 LEPROSY REVIEW

lepromin and tuberculin sensitivity in healthy subjects nor in patients with leprosy of the two main types. But tuberculous subjects showed a strong positive correlation : high tuberculin sensitivity was freq uently associated with raised lepromin sensitivity. The experiment was later amplified to include many antigens. Again the leprosy subjects showed no correlation, but the wider results showed some relationship between lepromin and tuberculin sensitivity, but not a simple and direct one, so a study of the histology of the reactions was introduced in the hope of clarifying the picture. Firstly biopsies of the lepromin reaction at fo ur weeks were made in 150 leprosy patients. 1 n lepromatous leprosy the reaction �onsists of a widespread infiltration by active eosinophilic histiocytes, which accumulate round the sweat glands and permeate the neurovascular connective-tissue bundles and subpapillary plexus; there are no lymphOcytes. I n tuberculoid leprosy the cellular infiltration is largely lymphocytic; the histiocytes present tend to be vacuolated and to occur mainly .near the centre of the inflammatory reaction ; there­ may be tubercles and giant cells. Borderline leprosy shows a reaction intermediate between two extremes, usually with intensely vacuolated histiocytic accumulations, infiltrated by lymphocytes. Secondly , a study was made of the influence of BeG vaccine on the tuberculin. There were 30 lepromatous, eight tuberculoid, and 15 healthy sub­ jects. Pre- and post-BeG reactions to lepromin were excised from each. Nearly three-quarters of the lepromatous showed a definite increase in lymphocytes, often accompanied by vacuolation of the histiocytes, and sometimes even tubercles and giant cells were seen. The effect of BeG vaccination on the histological reaction to lepro­ min is to stimulate a lymphocytic respons e in many patients with lepromatous leprosy. It would be of value to conduct a trial to assess the value of BeG injected repeatedly at intervals, as an ancillary to chemotherapy of lepromatous leprosy.

Lepra Iilfanti/: Es tudio de un Caso Tuberculoide. (Child Leprosy : .,( Study oJ a Tuberculoid Case). A. SAUL. Dermatologia, Revista Mexicami, 2, 1-4: December, 1958, pp. 45-55. With twp clinical and two histological photographs the author reports the case of a girl of 3t years who acquired tuberculoid leprosy by livillg for over one year in the same house as an adult who was lepromatous. The child developed three reddish-violet infiltrated plaques on the right side of the face. The Mitsuda reaction was positive. Histologically there was a tuberculoid granuloma with giant cells, and epithelioid cells and lymphocytes. The case was con­ sidered to be spontaneously curable, and no treatment was given. The lesions slowly decreased, becoming more and more pale, especially in the centre, and at the end of six months could scarcely be distinguished, except for a yellowish pink colour in the site of the ABSTRACTS 259

lesions and some fine wrinkles. ("cigarette paper"). The author reflects on leprosy in childhood and points out its importance for study.

EI Problema Social en el Enfermo de Lepra. (The Social Problem in the Leprosy Patient). SOR CATALINA MONTOJO : Dermatologia ;

Revista Mexicana : 2, 1 -4 : December, 1958, pp. 73-77. Sister Catalina describes well the importance of the social problems of the leprosy patient, and the present humane and helpful approach in Mexico. The Social Service works well with the doctors, and time: is given to a new patient to listen to his troubles and to establish confidence and sympathy even -before he is subjected to the routine medical examination. After he is enrolled, methods of repressive institutional segregation are not applied, and he may be allowed to stay at home. His family and relations are also inter­ viewed. The author cites an illustrative case of a patient of 42 years, a man of middle class who was in a state of great depression by remarks made to him by the doctor about the "high contagiosity" of his disease and the danger to his fa mily. His alarm was dissipated at the first interview by the social worker, who gained his confidence by a sympathetic listening to his worries, and who explained the error in the idea of excessive contagion, and explained that he could ·even stay in his own home and be treated. The co-operation of this patient was thus assured by "a less scientific medicine but one very humane". Thi� patient will continue his normal life while progressing towards cure, and his contacts would be supervised in the same humane manner.

Th e Treatment of Leprosy with the Preparation Diphenylthiourea (Ciba 1906) : Interim Report. J. M. M. FERNANDEZ, et al. Leprologia, 3, I , Jan.-June, 1958, pp. 86-87. The authors report their experience in the treatment of leprosy using Ciba 1906, one of the derivatives of diphenylthiourea. They began the experiment in March, 1957, in two groups of patients, the first without any previous treatment, and the second with pre­ vious treatment with DDS or its derivatives. First of all a detailed study, was made of the patients clinically and in the laboratory. There were 20 cases altogether of whom eight had qot had previous treatment and 12 had received suIphones. Of the eight in the first group, seven were lepromatous and one reactional tuberculoid. The 12 patients who had had previous treatment with sulphones all belonged to the lepromatous type, and most of them intolerant to the sulphones. The dosage was based on the advice of Davey, and the treatment began with a dose of I gm. daily, increasing by t gm. every 15 days to as to reach in some cases the maximum daily dose of 3 gm. Tn general tolerance was very good. There were no important 260 LEPROSY REVIEW complications, except for two cases who had lepra reaction. There were no blood changes of any importance. The group of patients who had no previous treatment showed the most definitesigns of the therapeutic activity of the drug. The clinical improvement which took place comprised flattening and re-absorption of the lepromas, disinfiltration of the lepromatous plaques, and partial or total regression of the macules. Bacteriologically there were changes in the morphology of the bacilli, in the shape of a more or less marked granulation. Changes in staining and in number of the bacilli were small. The most fa vourable changes showed in the histopathology. There was a marked vacuolisation of the lepromatous lesions; fusion of the intracellular vacuoles with an increase in their size ; fusion of the vacuoles of several cells, with the appearance of giant vacuoles, giving the appearance of Gruyere cheese. In some cases there were giant cells. There was a decrease in the density of the infiltrate giving the appearance of an old leproma. Tn general the histological changes were much as one would expect, in the lesions of patients given sulphone therapy. The authors think that this new drug should be taken into account in the treatment of leprosy, because of the favourable results they have obtained, especially clinically, histopathologjcally, and because of its low toxicity. They are continuing with the study of nine cases.

Preliminary Report on DP T in the Treatment of Leprosy. N. MUKHERJEE and S. GHOSH. Bull. of the Calcutta Sch. of Trop. Med. 6, 4; October, 1958, p. 166. The authors divided 25 cases into two groups at random and treated 13 patients with DPT with a dose varying between 125 and 1,000 mgm. per day by mouth. The control group were given ten to 100 mgm. DDS per day. There was no toxic effect, but it was not superior to DDS in producing bacteriological improvement. (Ross JNNES and DAVEY used doses of DPT in the region of 2 or even 3 g. per day, and in divided doses throughout the day. In a personal communication, G. A. ELLARD, biochemist at the East Africa Leprosy Research Centre, has reported that it is important for the \ absorption and action of DPT that the total daily dose be given in . spaced intervals throughout the tlay, at least three times. EDITOR.)

A Further Inquiry into the Leprosy-Tuberculosis Relationship. G. MURRAY SHORT. East African Med. J. 36, 6: June, 1959, pp. 298-304. � The author discusses this relationship. Specific tuberculin &ensi­ tivity is produced by tuberculin infection and by BCG; non-specific sensitivity is produced by an agent as yet unknown, possibly leprosy infection; and is produced transiently by lepromin. Lepromin ABSTRACTS 26 1

sensitivity is produced by leprosy infection, but not consistently; it can be produced by tuberculous infection, either the natural infection or BCG ; and by lepromin. He considers it especially important that no future mass BCG campaign should be carried out without the active co-operation of the leprologists. The leprosy and tubercle bacilli are both antigenic and allergenic. The former is the weaker agent, producing an inconstant lepromin conversion and no specific tuberculin conversion. Lepromatous leprosy forms the reservoir of leprosy infection and it is precisely in this type that the persistently negative lepromin react(jrs occur. The tubercle bacillus is the stronger agent, producing both tuberculin and lepromin conversion and in greater number. It may be possible to utilize a benign tuber­ culous infection, fortified perhaps by other acid-fast bacilli to the same end. There would then be a strong argument fo r the wide use of BCG in tropical countries, as a weapon against both tuberculosis and leprosy.

Trends in Leprosy in the Pacific. D. A. LONIE. 1959 Technical lnforma­ tion Circular No. 32, South Pacific Commission, Noumea, New Caledonia. This account of the introduction and spread of leprosy in the Pacific represents a thesis presented by Dr. Lonie to the University of New Zealand. It gives a useful summary of the known history of the disease in the area and of its current prevalence. The areas dealt with are Polynesia, Micronesia, and Melanesia. The prevalence rate per 1000 population seems to run from I to 60. The history of the introduction of leprosy in many of the islands is comparatively recent. In Nauru it was in 1911 or 1912 and an epidemic followed. In the Solomons the survey of INNES in 1938 and RODRIGUEZ showed respectively a prevalence rate of 10.2 and II per 1000, and a lepro­ matous rate of 16.7% and l8.5�;';. In Netherlands New Guinea the prevalence rate varies greatly from area to area but seems to be generaIly high (46, 66, and 75 per 10(0). Introduction of leprosy into the Pacific islands is usually ascribed to the immigration of Chinese, and from island to island by indigenous carriers in some cases. The slow rise of prevalence is the usual course of the endemic, though there are instances of the endemic state with epidemic periods, as in two places in French Polynesia, where epidemic spread occurred a quarter of a century after firstintr oduction. Some high lepromatous rates are recorded, e.g., 64 % in Western' Samoa and 57 % in the Gilbert and Ellice Islands.

/J ' La Reaccion Leprosa. (The Lepra Reaction). A. J. MELAMED, Medi- cina Panamericana, 126, 3-4, February, 1959, Buenos Aires, pp. 55-73. The author was awarded the Prize of the Leprosy Association 262 LEPROSY REVIEW of the Argentine Republic for his work, as the best work on leprosy published in 1957-58. He reviews previous work by many authors and deduces a body of evidence for the existence in every case of leprotic reaction of acute and subacute inflammatory phenomena, and that it is possible to explain the reactive state as an acute inflammation of the leprotic focus. This is bound up with physio­ chemical alterations in arterioles and minor blood vessels. He thinks that neurological disturbances in leprosy set going the abnormal vascular reactions and changes in permeability. All elements of the local connective tissue also are affected. The inflammation may go on to necrosis and be the primitive and only manifestations in mild cases, whereas in severe cases they are only two steps in a long process of changes. The major factors which induce lepra reactions are neurogenic vascular ataxia, permeability disturbances in the connective tissue matrix (with capillary permeability, precipitation of colloid, and anoxia), auto-immune antibody variations, anti­ inflammatory hormone changes due to stress, dysproteinaemia and especially hypoalbuminaemia. Therapy needs to be directed along these lines.

Present Status of Sulonef Therapy at Nagashima Aiseien. S. TAKASHIMA. Nagashima Archives of Leprosy, 3, 7, 1959, p. I-I I. Most patients at Nagashima have been receiving sulphone therapy since 1949. The total number of patients admitted since 1930 is 1,753. On 367 patients reviewed in 1958, compared with 53 previously assessed by Doull in 1952, the author found that 75.2 were improved, compared with 24.5 % in the earlier group. The influence of sulphones on the cutaneous lesions was also good ; with remarkable results on mucous membrane lesions. A few cases failed to respond to the long term use of the suI phones, and for these it is proposed to use DPT which already has a good reputation, and the antibiotic Kanamycin. Between 1952 and 1958 the bacillary index has become five times less, but negative cases are few. Histology has shown a paral1el improvement in most cases. With the. lepromin tes t there was noted a paradoxical increase in negative cases over two years in one group but over a longer period there was a decrease in negative cases. Lepra reaction� were troublesome in many, but not enough to spoil the therapy by sulphones. Sulphones seem of little" effect in nerve symptoms and in secondary lesions.

Skin Reaction in Leprosy with Antigens Prepared from Kedrowsky and Takeuchi Strains of Acidfa st Bacjlli Isolated fr om Human Leproma by Chatterjee-Bose Method. S. SATO, M. FUKUDA and M. TAKEDA. Science Reports of the Research Institutes of Tohoku University·, 8, 4; March, 1959, pp. 379-387. The authors applied the new antigen of Chatterjee-Bose in skin ABSTRACTS 263

tests on 155 leprosy patients and compared the results with those obtained from the Mitsuda, Dharmendra and Takeuchi antigens. They found the new antigen very promisin-g.

A New Method of Detecting Leprosy Bacilli in the Circulating Blood: A. A. SRTEIN and L. M. TUTKEVICH. Abstracts of Soviet ":' Medicine, 2, 2; 1958, pp. 178 179, para. 409 : from Sovremennye Voprosy Dermatologii, Kiev, 1957, pp. 184-1 86. [n order to detect leprosy bacilli in the circulating blood the authors prepared a "large drop" from the blood of the patients, diluted with distilled water and stained by Poorman's method, without previous fixation. The preparations were stained for I minute with carbolfuchsin, washed with water, stained anew with I % alcohol solution of methylene blue fo r 20 secs., washed anew with water and dried in the air. In addition to "large drops", blood smears from a vein and also smea�s from the tissue fluid of the skin in the ulnar flexure were prepared as a contr91. Single bacilli were observed- in the smears; in the tissue fluid of the ulnar flexure, M. /eprae were not found. Working on the "large drop" method the authors detected lepra bacilli in II� out of 226 specimens prepared from the blood of 59 patients with lepromatous (nodular) type of leprosy (50.8 %). The results obtained testify, according to the authors, to the presence of bacillaemja in patients with leprosy.

Relapse of Leprosy in American Samoa. R. B. PRICE. Amer. 1. of Trop. Med. and Hygiene. 8, 3: May, 1959, pp. 358-363. The author has conducted a general survey of leprosy in American Samoa, which has a popUlation of 20, 154. The disease has been thought to have been introduced by Chinese coolies in the 19th century. The incidence of leprosy is 5.3 per thousand, with 24 open cases. He fo und that lepromatous Jeprosy shows a strong tendency to relapse (25 % of cases) when suIphon e therapy is discontinued, even after five years of such therapy. Tuberculoid leprosy tends to . undergo arrest of activity, even when the chemotherapy has been of brief duration and long since discontinued. The importance of follow­ up of patients is very great.

Caso impressionante da Ineficacia das Sulfonas na Lepra. (An Impres- sive Case of the Ineffectiveness of the Sulfones in Leprosy). ,.I • C. SOUZA-ARAUJO. I H. DE Revista Brasileira de Medicina, 15, 12, December, 1958, pp. 827-828. The author reports the history of a male patient first seen by him at 20 years of age who presented as a tuberculoid leprosy in 1942. In 1945 he became lepromatous. He was treated from the beginning with intravenous Promine, and was also given Lyosulphone. After II years of this he still. continues-.bacilLiferous in the skin and nasal 264 LEPROSY REVIEW

mucosa, after II litres of Promine and Lyosulphone and more than 4.5 kg. of DDS.

Effe ct of Roentgen Rays on M. Leprae. S. GHOSH, S. P. BASU and N. MUKERJEE, Leprosy in lndia, 30, 3; July, 1958, pp. 150- 1 53. Mukerjee in 1957 had observed beading or disintegration of leprosy bacilli when excised lepromatous tissue was subjected to prolonged irradiation with moderate doses (63r to 85r). The present authors extended the experiment to use different doses for varying periods, and also applied them to smears from the tissues. No detectable change was fo und in the morphology or staining character, nor decrease in the number of bacilli.

BCG Vaccination by MUltiple Puncture. A. H. GRIFFITH. Th e Lancet, 1, No. 7084, 6 June, 1959, pp. 1170- 1172. The author carried out two trials in Cardiffand Pembrokeshire to compare the allergenic effects of BCG by the multiple puncture method with BCG by the intradermal route. With the fo rmer the conversion rate was only 83 % after using BCG suspension 50 mg. per ml. and 20 needles penetrating 3 mm. into the skin, compared with 100% using intradermal vaccination with freeze-dried and liquid fresh vaccines. 1 n the trial at Cardiffth e conversion was 93 % by multipuncture of freeze-dried BCG 20 mg. per m!. with 20 needles? and a penetration of 2 mm. ; it was 93 % at the end of 8 to 12 weeks, 94 % at the end of a year, and 85 % at the end of two years . . The author therefore points out that the multi puncture method of BCG vaccination can be effective under some conditions and unsatisfactory under others. A significant difference existed between the multiple puncture methods used in these two trials, and the nature of this difference requires to be established in order to develop a reliable effe�tive method of BCG vaccination. The general use of multiple puncture BCG vaccination should be delayed until the method has been improved and standardized.

Clinical and Immunological Examination of the Staff and their Family Members fr om a Leprosy Hospital. S. SCHUlMAN, C. K. LI, C. T. LIANG, T. C. Hsu, Y. C. Ho, M. W. TSANG and C. L. CHENG, Chinese Medical Journal; 78, 1: January, 1 959, p. 18. The Sinchow Leprosy Hospital has lOOO patients. Staffmem bers and their fa milies live at 500 m. distance from the hospital. Clinical -examination was given to 130 out of 135 ·staff members and their families and no one had leprosy manifestations. The lepromin test was applied to all, and the Mitsuda was found positive in all, and in 62 % the Fernandez reaction was positive. The tuberculin test was found positive in .37 %. There was no important difference in the reactivity to lepromin between the medical and administrative ABSTRACTS 265 staffs, nor belween the staffas a whole and their families. Because most of them have been living there less than five years, this examina­ tion will be repeated periodically.

The Value of the Lepromin Test in the Classification of Leprosy. S. SCHUlMAN and colleagues, Chinese Medical J., 78, I: January, 1959, pp. 19-21. Schujman has apparently introduced the use of the lepromin test at the Sinchow Leprosy Hospital. On 81 patients there he demon­ strated the value of the lepromin test in classification of cases, particularly of "pure neural" leprosy, wherein their position on the lepromatous or tuberculoid side was made clear. Production of Immune Reactions by Electro-acupuncture and Simple Acup uncture. CH'EN K'O-CH'IN, National Medical J. of China, 44, 12, J958, p. 1173 (Abstract in Chinese Med. J., 78, 2; February, 1959, p. 183). The revival of acupuncture in present-day Chinese medicine, wherein "t'u" or native medical methods are increasingly being brought in to aid "yang" or foreign, and wherein many diseases are being treated by acupuncture, even leprosy, makes any explanation of the rationale of acupuncture of interest. This author state.s that acupuncture elicits reactions of excitation and inhibition, and enhances the phagocytosis by leucocytes, especially of neutrophils. He carried out experiments to try to produce immune reactions. In the first experiment 34 healthy rabbits were divided into three groups. The first group contained 16 rabbits which had two fine steel needles inserted into the nerve on the median side of each fore­ leg. In addition, pulsating electric current of 0.02 m.a. at 0. 15 to 0.3 v. with frequency of 50 cis. was passed through these needles. The second group of 11 rabbits had the needles inserted but electric current was not passed through. The third group of seven rabbits we.re kept as controls. The rabbits were aU immunized with B. pertussis in a preparation of 5 thDusand rruUion per mI., being given at five day intervals, 0.5 ml. subcutaneously and 1 and 2 ml. intravenously. After each injection, simple acupuncture of electro-acupuncture was applied for 30 minutes daily for three consecutive days. The author \ays "antibody responses were conspicuously increased by electro-acupuncture a�d simple acupun�ture stimulations, especially the former". In the second experiment 24 healthy dogs were used. The first group of ten dogs were given electro-acupuncture, the second group of seven dogs were given simple acupuncture, and the third group of seven dogs were kept as controls. The nerves used were the median nerve of the right foreleg and sciatic nerve of the left hind leg. The frequency was 150 to 1000 kc. "The results showed that the serum complement responses were increased in the stimu­ lated animals." 266 LEPROSY REVIEW

An Electron Microscope Study of the Disposition and Fine Structure of M. lepraemurium in Mouse Spleen. G. B. CHAPMAN, J. H. HANKS, and J. H. WALLACE, Journal of Bact., 77, 2: February, 1959, pp. 205-211: II illustrations, 16 references. These authors studied ultrathin sections of mouse spleen infected with M. lepraemurium, embedded in methacrylate. The bacteria were found separated from the cytoplasm of the host by a mejllbrane which enclosed a capsule or spa�e apparently deriving from the host cytoplasm. The space is occupied by a. finelygr anular material which may be bacterial product. The cell walls of the bacteria are about 150 A thick and may be closely apposed to the cytoplasmic mem­ brane or separated from it by a narrow shrinkage space. Low density areas have been noted in the bacteria. These sometimes show granular threads of denser material, and are thought to be the nuclear apparatus. Many sectioned bacteria showed inclusions containing numerous spherical particles. They are thought to be the mitochondria. Besides the low density areas thought to be nuclear, ·an occasional different low density inclusion was observed. Several bacteri,f! were noted which had just completed cellular division.

The Problem of Leprosy. KHUSHDEVA SINGH. The Licentiate, Ambala, [ndia, 8, II: Febraury, 1959, pp. 359-364. Dr. Singh gives a balanced description of leprosy as understood today and outlines the problem in India. The early work in leprosy in India was done by BElRA (now succeeded by Hind Kusht Nivaran Sangh) and the Mission to Lepers, and individual Mission, and in recent years their work has been augmented by the Gandhi Memorial Leprosy Foundation, WHO, The Belgian Leprosy Foundation, and the Government itself. The Government has launched the National Leprosy Control Programme and in its second Five-Year Plan proposes to spend Rupees 52,900,000 (£3,967,500) on pilot control projects, upgrading of leprosaria and clinics, training of doctors and ancillary workers, and mass treatment schemes including domiciliary treatment. It is estimated that there are at least 1,500,000 leprosy sufferers in India. There are 200 institutions, with a total accommo­ dation of 23,000 patients: There are 1,300 clinics dealing with 200,000 patients. Altogether, only about 10% of leprosy patients are receiving care, a little over I % as inpatients and the rest as out­ patients. Dr. Singh points out that the disease is preventable and nowadays is eradicable, and appeals for the co-operation of the people themselves and all men of good will. (On page 668 of the same journal, it is reported that Dr. Singh had collected funds for leprosy work in the streets of Patiala and obtained Rs. 6000 (£450) with which he proposes to begin a leprosy centre in Patiala.) ABSTRACTS 267

Prophylactic Value of BCG Vaccination against Leprosy: A Prelimin­ ary Report. K. R. CHAITERJEE, P. Soucou, and M. SAINTE-RoSE. Bull. of the Sch. of Trop. Med. Calcutta: 6, 4: October, 1958, pp. 164- 1 66. The authors tudied leprosy endemic areas in Pondicherry where BCG vaccinations had been given in 1953, comparing them with populations in the same region which had not received BCG. Childre"n were grouped comparably, as to social status and degree of contact. It was found tha.t the-incidence of leprosy in children who did not receive BCG was 20 'times greater than in the vaccinated. Not a single case of lepromatous leprosy developed among the vaccinated children. The authors conclude that the protective action of BCG against leprosy is considerable. This is the first report from India.

Reactivity ol a Lecithin-Free Cardiolipin Preparation (Cardchol) in Leprosy Sera. H. SCHMIDT. Bull. WId. Health Org. 1959, 20, pp. 1175-1 191. He had previously_ found that a mixture of cardiolipin and chplesterol in absolute ethanol, named "cardchol", is usabJ'e as an antigen in complement fixationtests. He cQmpared the activity of an ordina:ry cardiolipin antigen (CWRM) with cardchol and found that the reactivity of cardchol was especially pronounced in sera from false positive reactors . .Sera from leprosy patients were found to be highly reactive with cardchol but non-reactive or fa intly reactive with CWRM, and this was fully confirmed in a second and larger series. The highest reactivity occurred in lepromatous patients, particularly in those with leprosy of short duration. Electrophoretic studies showed that the substances reiCting with cardchol were in the gamma-globul}n or gama-and-beta-globulin serum fractions.

Isoniazid Neuropathies in Malnourished Tuberculous Patients. G. L. MONEY. J. of Trop. Med. and Hyg. : August, 1959, 62, 8, pp. 198-202. The author studied 84 tuberculosis patients in Ibadan, Western Nigeria, and found an incidence of polyneuropathy and burning f�et in 16 on an isoniazid dosage level- of 4 to 6 mg./kg. daily. The neuropathies found included a painful feet syndrome, pains and paraesthesiae in the feet and legs with patchy superficial sensory defects and a small amount of motor weakness. There was some evidence of myelopathy and encephalopathy, and there seems some relation to. a pre-existing malnutrition. He recommends the routine use of cheap Vitamin B supplements (yeast) in treatment and prophylaxis. 268 LEPROSY REVIEW

REPORT

The East African Leprosy Research Centre (John Lowe Memorial). Dr. J. M. B. Garrod, the Director, reports for 1957-58. A plaque has been fixed near the entrance of the laboratories showing the con­ nexion of the Research Centre with the late Dr. John Lowe through BELRA. Dr. Lowe was Medical Secretary of BELRA at his death, and generous funds from BELRA were provided for the founding of the Centre and continue to be provided for recurrent cost. At the end of 1958, BELRA has also sent a biochemist, Mr. Gordon Ellard, M.SC., on financial provision from Messrs. Ciba Ltd., Horsham, England. Mr. R. Rhodes-Jones has been the technologist at the Centre since January, 1958, and Mrs. Rhodes-Jones acts as secretary. The .site of the Centre was previously known as Itesio, but has been changed to Alupe, at the request of the Teso Location African District Council. Work has continued on the trial in leprosy of the drug diphenyl­ thiourea or DPT. "There has been no sign of drug resistance. No toxic effects have been noted in spite of continued high dosage in a specially selected group of cases. Unpleasant reactions appear to occur less frequently than with standard drugs and there appears to be a more uniform effect." Dr. Ralph Naylor of Makerere College, Uganda, continued his work on tetrazolium compounds in the staining of mycobacteria. Dr. D. S. Ridley of the Hospital for Tropical Diseases, London, spent three weeks at the Centre to demonstrate his serial biopsy method of assessing results in drug trials. The Director carried out supervision of three leprosy outpatient clinics in Kenya, and will include six more clinics in Uganda. REVIEW 269

REVJEW

Lepr% gia. Organ of the Argentine Society of Leprology, 3, I, January-June, 1958, Cassilla de Correos 2899, Buenos Aires. This number has 100 pages with II original articles, news of the proceedings of the Argentine Society of Leprology, and other news, and a section of Therapeutic Notes. The Editorial of G. Basombrio puts the case for an enlightened and humane form of leprosy control using all good methods, but turning away from hard-hearted and severe restrictive ones. Leprosy is not a disease apart, but belongs to the general problem of public health. Drs. N. O. Castro, P. B. Arcuri, and L. B. Toranzos contribute a paper on the lepromin reaction in house contacts of leprosy patients. They studied the lepromin reactions in 756 such contacts from the years 1942 to 1956 in S. Miguel de Tucumon. The reaction studied was that to the first injection of lepromin. They fo und that the frequency of positive reactions increases progressively with age. Of the total number of contacts, 41.4 % were positive to the Fernandez reaction, and 76 % to the Mitsuda. The authors think that the Fernandez is a significant index of sensitization and the Mitsuda of resistance. Drs. C. A. Consigli and R. Biagini report on the treatment of lepra reaction with prednisone in six cases. The immediate results are very good, and there is slower but satisfactory response in the cutaneous reactional features, and in the joints, glands, and nerves. Relapses on suspension of the treatment can be prevented by a moderate daily oral dose of I or 2 tablets. Oral BCG in a dose of 0.2 g. once a week had a beneficial adjuvant effect. J n almost alJ the cases the specificsui phone treatment could be reinstated. In no case were there complications. The maximum dose used was six tablets of prednisone daily, up to 200 tablets in five months (1000 mg.) The treatment is much easier to manage than with cortisone and hydrocortisone. Dr. M. Bergel has a paper on the biochemistry of the lepromatous granuloma and the yellow fat, when studied by methylene blue. He found that methylene blue strongly stains these tissues in vivo and in vitro but is negative in normal tissues. He thinks that lesions with an abundant content of acidfast bacilli and with yellow fat are selectively and persistently stained by methylene blue. In the case of the yellow fat it is the ceriod pigment which is acid-resistant. Drs. N. O. Castro and P. B. Arcuri report on their study of the results of the injection of normal skin suspension in subjects who have reacted to whole lepromin. They used proteinic extracts of normal skin and got negative results at 48 hours and 21 days. They think that this means that the reactivity to lepromin is specific and provoked by M. leprae itself. Drs. E. D. L. Jonquieres, H. J. Sanchez Caballero, E. T. Capurro, and F. F. Mercadante studied discharged dispensary patients and 270 LEPROSY REVIEW

fo und sulphone therapy had brought great amelioration to tuber­ culoid and indeterminate cases ; only two lepromatous were definitely discharged. There was an increase in the number of cases diagnosed early ; half of the cases were seen in the first year of the appearance of signs of leprosy. Dr. N. O. Castro discusses the concepts of hypersensitization and resistence in leprosy and their relations and asks fo r a uniform terminology. Dr. J. P. Whitelaw and M. Guadagnini draw attention to the value of surgery in the trophic and destructive and neuritic lesions and from the experience in Uruguay report good results. Dr. A. J. Melamed reports on a study of the use of phenyl­ butazone in the lepra reaction on six cases. He gave potassium thiocyanate, fo llowed by or in addition to phenylbutazone, and fo und the first was effective and the latter strengthened the action of it, and if the fi rst fa iled the second also fa iled. He thinks the action is mainly one of modification of collagens and on cellular. vascular. and interstitial permeability. Drs. E. A. Carboni, A. R. Mercau, and A. Serial report three cases of tuberculoid reaction in a single lesion on the fa ce in adults. The reactive features were the same as if there were multiple lesions, and there was no relapse. As they regressed the lesions went through a papular stage and then a macular stage with fa int staining. Drs. A. J. Melamed and A. Barcia studied the paper electro­ phoresis in two patients who had lepra reaction and were under treatment with corticosteroids (prednisone and ACTH). The most important changes were increase in albumin and diminution of alpha- 2-globulin, and a tendency 10 normalization during the corti­ costeroid therapy. They correlate this with similar changes in the nephrotic syndrome, and relate it to changes in the fu ndamental substance and the collagen. I n the report of proceedings of the Argentine Society of Leprology there is a note on the principles of leprosy control and other subjects. and in the First Sessions of 1958 Dr. M. Bergel gives several accounts of his biochemical approach to the action of leprosy drugs and to the transmission of M. leprae to rats on a special diet. Dr. J. M.M. Fernandez ef al. gave some account of the treatment of leprosy with OPT (Ciba 1906). They fi nd it non-toxic and definitely active clinically and histopathologically and think it is a drug to be reckoned with. Their study continues. Bergel pointed out that OPT fits into his theory. for it is an active drug against leprosy and is an anti­ oxidant. LEPROSY REVIEW VOLUME XXX (1959)

INDEX

The letters after the entry have the fo llowing significance : Original Art icles (0); Editorials (E); Letters to the Editor (L); Proceedings of VII International Congress (P).

PAGE A Absorption and ExcretiQn of Ciba 1906 (OPT), Experimental Investi­ gation of. K. SCHM ID and J. TR IPOD (0) .. 85

A BSTRACTS Progressive Experimental Infection with M. leprae in a Chimpanzee : Prelirpinary Report. A. E. GUNDERS 123 Haemagglutination and Haemolytic Reaction of Red Cells Sensitized with Extracts of Murine Leprosy Bacilli. N. YAMADA 123 Studies on Lepromin Test : Sensitization Experiments with Trypsin Isolated Bacilli. K.YANAGISAWA and N. ASAMJ 123 Sensitization of tre Dog with Lepromin and BCG, and Evidence of Cross Sensitization : Persistence of Sensitization and Cross Sensitization. N. O. CASTRO and P. A. ARCURI 124 Studies on fmmunology of Murine Leprosy. T. TANIMURA, S. NISHI ­ MURA Y . TANIMU RA .. 124 Chemotherapy of Murine Leprosy : Effect of Cycloserine (Seromycin) on Mouse Leprosy. Y. T. CHANG .. 125 Reactions in the Skin of Leprosy Patients to Intradermr l Injections of Fatty Acids from Tubercule Bacilli. N. P. Buu-Hol, and T. V. BANG 125 Treatment of Leprosy by Monthly Injections of DDS. P. LAVIRON, L. LAURET, D. KERBASTARD, and C. JARDIN 125 Treatment of Lepra Reaction. M. F. LECHAT .. 126 Thoughts on Chemotherapy of Leprosy. M. BERGEL .. 126 Familial Leprosy. N. MUKHERJEE and S. GHOSH 128 Acupuncture and Galvanic Current in Treatment of Lepra Reactions. KAo HUAI-AN and colleagues .. 128 Use of D-Cycloserine in Treatment of Leprosy : Preliminary Results. . E. DE ALMEIDA Nno and J. P. REVELLES . . 128 Our Observations on Diphenylthiourea in Treatment of Leprosy. A. M. ALOKso ...... 129 Experimental Study on Action Exerted by Certain Synthetic Anti­ malarial Drugs upon Endocrine System.. C. I. PARHON, V. SAH- LEANU, and L. IANcu . . 129 Local Treatment of Neurovascular Ulcers of Lower Limbs. O. RAMIREZ 130 Outstanding Achievements in Health Work in 1958. Chinese Medical Journill 130 On the Nature of Kveim Reaction and Pathogenesis of Sarcoidosis. R. KoolJ 198 Neural Leprosy Syndrome. F. BRESANT SILVA .. 199 Tuberculostiltics and Salts of Heavy Metals : Metallic Complexes of D-Cycloserine. E. NEUZIL ana J. C. BRETON 20 1 Very Active and Accelerated Multiplication of M. leprae Inoculated into Rats Subjected to Severe Conditions of Pro-oxidation. M. BERGEL 202 Contribution to Study of Lepromin Reaction. M. FuKUDA .. . . 202 Experimental Transmission of H"uman Leprosy Infection to Selected Laboratory-bred lfybrid Black Mouse : K. R. CHATTERJEE 202 Communicable Diseases in Africa : Leprosy. WHO Chronicle 203 Factors Influencing Transmission of Leprosy. J. A. KINNEAR BROWN 255 Problem of Self-Administration of Drugs, with Particular Reference to Pulmonary Tuberculosis. WALLACE Fox 255 Nodule in Onchocerciasis. M. S. ISRAEL .. 255 ...... ------

( ' Iinical Lv;i luation Studies in Leproillatous Leprosy. Third Series : Nicot inaillide ;lI1d BeG as Supplements to I)DS . .I . A. 1 )01 1 1.1. .I . N. R Ol)il l (;III· /.. A. R. DAVISON . .I . C. TOI I' N rt No and .1 . V. �I Il N A N - 1)1';: ...... 2 5 6 Pathogenesis of learl y Stages or Leprosy. G. TAIlAIlINI and .l . T I' RI NCIO 256 Ideas on Leprosy Immunity ;1Ilt! Alkrgy . G. TAIlAIlINI 257 Triamcinol one in Treatment of Lepra Reactions. G. TAIlAIlINI and V. H FIlNANDFZ ...... 257 Symposium on Tuberculosis and Leprosy : on Immunologica I Rela- tions. S. W. A. KIII'I Il .. .. 2 5 7 Child Leprosy : Study of a Tuhen:uloidCase . A. SAUL . . . . 258 Social Prohlem in the Leprosy Patient. SOil CA 1 AI.INA MONrllj( ) 259 Treatment of Leprosy with Preparation Diphenylthiourea (Ciba 1906 ): 259 Interim Report . .I . M . M. h· Il N A N D I· /. , I "I. . . PI'elilllinary Report on I)PT in Treatmcnt or Leprosy. N. M1I KIII IUI+ and S. CIIOSI I ...... 260 Furt her EnLluiry into Leprosy-Tuberculmis Relationship. (i. MlliUl AY SIIOR I ...... 26 1 Trends in Leprosy in Pacific. D. A. LONII 261 Lepra Reaction. A. J. MI· I.AMH) .. 26 1 Present Status of Sulfone Therapy at Naga shima Aisein. S. TA KASIl IMA 262 Skin Rcaet ion in Leprosy with Antigens Prepared from K ed rowsky and Ta keuchi Strains of Aeidfast Baci lli Isolated from Human Leproma by Chatterje;:- Bose Method. S. S A rno M. FUKIIDA and M. TAKI' D A 262 New Method of Detecting Leprosy Bacilli in Circulating Blood . A. A. S H I I ' I N and L. M. Tl I IKI'VICH 26.1 Relapse of Lcprosy in American Samoa. R. B. PIlICI' 263 Illlpressiw Case or Inefku iveness of Sulfoncs in Leprosy. H. C. Dlo SOlJ ZA- AIl A IiJO ...... 2 6 .1 Efreet of Rocntgen Rays on M. leproe. S. G I I OS I'I , S. P. BASU and N. M1J K UU H' . . . . 264 BCG Vaccination by Multiplc Puncture. A. H. GIU HITH 264 Clinical and Immunological Examination of Stair and Iheir Fam i l y Members from a Leprosy Hospital. S. S C H U M A N el al. 264 Value of Leproillin Test in Classil'ication of Lcprosy. S. SCHUJ MA N a n d co lleagues . . 265 Product ion of Immune Reactions by E lect ro-acupu ncture and S imple Acupuncture . CH'EN K 'O-CH'IN . . 265 E lectro n M icroscope Study of Disposition and Fine Structure of M. lepraelllllrilllll in Mouse Spleen. G. B. CHAPMA". J. H. HANKS and J. M. WALLACF 266 Problem of Leprosy. KI'IUSHDEVA SINGH . . 266 Prophylactic Value of BCG Vaccination aga inst Leprosy: Pre l i m i nary Report . K. R. CHA TTERJEI:, P. Soucou and M. SAINTE-RoSE 267 Reactivity of a Lecithin-Free Cardiolipin P re parati o n (Cardchol ) in Leprosy Sera. H. SC H M I D T .. . . 267 Isoniazid Neuropathies in M aln ourished Tuberculous Patients. G. L. MONl:Y ...... 267 Acute Psychosis in Lepromatous Leprosy : Management of. R. H. THAN- GARAJ and Mrs. SAf:OJ lNI THANGARAJ (0) 186 Aden. Notes on Leprosy in. A. L. FAWDRY (0) /14 AI Walid Leprosarium, Damascus, Report on a Visit to : A. E. H. VAN GORKUM (0) 188 Anti - l eprosy Therapy Today (E) 77

B

Bact eriological I ndex in Leprosy, Some Observations on. S. G. BROWNl: (0) 174 Bacleriolog.l · alld Parhology . . . . 7 Study of Rat Leprosy in Tissue Culture. R. J. W. R E I'S (P) 8 Evaluation of Physiological State of M. leprae by Cytology. J. H. HANKS (P) . . 8 Histiocytic Granulomatous Mycobacterial Lesions in G o lden H am - sters Inoculated with M. leprae: Negative Results in 10 Experi- ments in Other Animals. D. H. BINFORD (P) 9 Experimental Transmi ssion of Human Lcprosy to a Hybrid Strain of Black Mice. K. R. CHATTERJEE (P) . . 9 PAGE Observations of Prognosis of Different Classes of Leprosy in Different Races. D. S. RIDLEY (P) II Tissue Culture of Mycobacterial Pathogens. C. C. SHEPARD (Pl 12 Study of Action of Sulphones on the Metabolism of Mycobacteria. R. F. NAYLOR (P) 12 Attempt to Determine Morphology of Living and Dead Mycobacteria by Electron Microscopy. J. R. McFADZEAN and R. C. VAL ENTINE (P) 1 2 Electronmicroscopic Appearances of Mycobacteria. R. J. W. REfs, R. C. VALENTINE and P. C. WONG (P) 12 Murine Leprosy Bacilli in Electronmicroscopic Studies. S. OKADA (P) 13 Skin Reaction to Lepromin and Tuberculin: Effect of BCG on Histology. S. W. A. KUPER (P) J3 Phagocytosis of Leprosy Bacilli by Leucocytes of Leprosy Patients and Phagocytosis of other Acidfast Bacilli. Y. HAYASHI (P) .. 13 Electronmicroscopy of Lepromatous and Tuberculoid Lesions. T: YAMAMOTO, N. NISHIURA, N. HARADA and T. IMAEDA (P) .. J4 Disease Types of Leprosy Studied from the Basis of Experimental Pathology. T. OGATA (P) 14 Association between Damage from Leprosy and Temperature. P. BRAND (P) .. J4 Peripheral Nerve Involvement in Upper Limbs of Leprosy Patient (c1il)ical). J. MINATO ( P) 15 Classification of Disability. GAY PRIETO and F. CONTRERAS (P) 15 Arteriography of Feet in Mutilated Cases of Leprosy. J. CHARDOME, M. LECHAT (P) 15 Arterial Angiography in Perforating Ulcer. T. V. BANG, N. D. TEIP (P) J 5 Experimental Transmission of Human Leprosy to Monkey by Frequent Long-term Implantation. S. LAI ( P) 15 Enumeration of M. leprae for Standardization of Lepromin. J. H. HANKS (P) 16 BERGEL, M. Influence of Various Pro-oxidant Nutritional Conditions on Growth in vivo of M. leprae (0) J 53 BLENSKA, W. M. (see BROWN, J. A. KINNEAR) 108 "Blue-black Macules". BASIL NICHOLSON (L) 254 BROWN, J. A. KINNEAR on Dr. Worsfold's Survey in Northern Rhodesia (L) J J 9 BROWN, J. A. KINNEAR, and BLENSKA, W. M. Leprosy Control in Uganda : Duration of Treatment of Inpatients and Outpatients (0) 108 BROWN, J. A. KINNEAR, and STONE, M. M. Depot Lepromin Test and BCG Vaccination (0) 110 BROWN, J. A. KINNEAR, and STONE, M. M. Multipuncture Depot Lepromin Test : Investigations with Different Antigens (0) 215 BROWNE, S. G. Some Observations on the Bacteriological Index in Leprosy (0) .174

C

Camoquin in the Treatment of Acute Lepra Reaction. R. H. THANGARAJ � 1M Ciba 1906 : A Further Report on DPT (E) 208 Ciba J906 : Two Years' Experience with Diphenylthiourea (DPT or Ciba J906) in Treatment of Leprosy. J. M. B. GARROD (0) 2JO Circulation in Feet of Leprosy Patients, with and without Ulcers. B. B. GOKHALE, S. M. VABLE, SUMAN MODAK (0) 234 Classification 30 Japanese System of Classification. K. KlTAMURA (P) .. 30 Critical Appraisal of Classification of Leprosy. R. G. COCHRANE (P) 30 Classification of Leprosy in India. D HARMENDRA (P) .. 3J On Acute Infiltration of Lepromatous Type of Leprosy. 1. TOJ IRI (P) 32 COCHRANE, R. G. Reply to A. S. GARRETI' on Streptohydrazid (L) 193 Control : Epidemiology and 35 Corticosteroids in Management of Foot-drop in Lepromatous Leprosy : A Case Report. W. H. JOPLING (0) 171 CURRIE, G. Short and Long Acting Sulphones by Intramuscular Injection (0) 220 D 1 ) /\vI-Y, T. F. Diethyl Dithiolisophthalatc in Treatlll<:nt of Lcprosy (ETI!' or '"Eti�ul"): Progress Report (0) 61 OAVI 1', T. F. Diethyl Dithiolis/lphthalate (ETI!' or '"Etisul") in Trea tment of Lcprosy : Second Progress Rcport (0 I 141 DAVISON, A. R. Erythcma Nodosum Leprosum (0) II] DAVISON, A. R. Triple Trcatmclll of Tuberculoici Leprosy (0) 184 Depot Lepromin Test and BCG Vaccination. J. A. K I NNI- A R i:lROWN and M. M. STONE(0) 110 Depot Leproll1in Testing . .1 . P�PYS (L) 190 D� SouzA-ARAUJO, H. C. Morphology of Mycobacterium Leprae (0) 80 O� SouzA-ARAUJO, H. C. on Correct Dates of Early Leprosy Congresses (L) . . 193 Dicthyl Dithiolisophthalatc in Treatment of Leprosy (1:1'1 I' or .. Et isul"): Progress Report. T. F. D AV I Y (0) 61 Diethyl D i thio l i.w phthala�e in Trc;llillent or Lepro:iY (1'1'11' or "Etisul") : Second Progress Re port . T. F . D,\VI' \' (0) 141

E Early Lcprosy Congresses. Correct f)ates of. II. C. 01 S()\ l zA- ARAI'JO (Ll 193 EDr ! ORIALS : VII International Congress 4 Dr. Davey's Report on "Etisul" 6 Anti-Leprosy Therapy Today 77 New Book on Leprosy 7 9 Visit to South Africa 135 WHO Leprosy Conkrence at I3rauavi!le 135 Furt her News of Macrocyclon . . 136 Nature of Mitsuda React ion, with Contributions by R. K()ou and I. SAla11' R . . 137 Further Report on the Diplh;nylthiour'::I, Ciba 1906 208 Comparative Clinical Trial of Injcct ion Tilerapy 208 Multipuncture Type Lepromin Test . . .. 209 Effects of Outpatient DDS Administration in Katsina Province, Nort hern Nigeria. An Assessment of. D. G. J A M I SON (0) . . 159 ELDON, J. H. Mobile Anti-leprosy Treatment Centres in Ghana (0) 168 £pir/ellliolo/{ i ' alld COllfrol . . . _ . . 35 Suceess of Case Detection Campaign in Sulphonc Therapy. R. V. WARDEKAR (1') 36 BCG in Prophylaxis of Leprosy. E. MONTESTRUC (I') . . 36 New Programme of Leprosy Control in Brazil. O. DINIZ (1') 37 Epidemiological Study of Leprosy in Aichi Prefecture. A . SOllltE (1') 40 Epidemiological Studies of Leprosy in Kor ea . .I . LEW and CHUNG (P) 40 Anti-leprosy Campaign in Mexico. B ARBA RUBIO, G. Pml-LSUAREZ ( 1') .. . . 40 Leprosy in Mexico in 1958. N U N E Z ANDRAD!' (1') 41 Note Proposing Abolilion of Strict Segregation fo r White Hansen's Disease SulTerers. M. H. GAIlRII:L(1 ') _. .. 41 Anti- leprosy Ca mpaign i n Madagascar. P. BONNIOL (P) 41 Orientation for Ant i-leprosy Campaign in Portu guese Ove rseas Terr i - tories_ A. SA LAZA R LEIT E (p) 41 Epidemiology and Control of Leprosy in Brazil. E. AG R ICOLA (1') 42 Praetiral Application of Modern Methods to Leprosy Control. A. R. PIN TO (1') . _ . . 42 Dermatologist's Report on Leprosy in California. P. FASAL (1') 42 Leprosy Campaign in Indonesia. M _ A R I F (1') . . 43 Statement on Princip les of Work at Carville. G. L. FITE (1') 43 E rythe ma Nodosum Leprosum. A. R . DAVISON (0) 112 '"Etisul". Dr. D avey's Report on (E) 6

F FA W D R Y. A_ L. Notes on Leprosy in Aden (0) 114 Filial Plellart' Sessioll 55 C l os i n g Cereillony .. 58 Speech by J. H_ HANKS SUlllmarising Work of Congress 58 Speeeh by T. F. D A V E Y Sumillarising Work of Congress 59 PAG E

G GARRETT, A. S. on Streptohydrazid (L) J93 GARRETT, A. S. on Vadrine (L) ] 18 GARROD, l. M. B. Two Years' Experience with Diphenylthiourea (DPT or Ciba 1906) in Treatment of Leprosy (0) 210 GOKHALE, B. B., VABLE, S. M., MODAK, SUMAN. Circulation in Feet of Leprosy Patients, with and without Ulcers (0) 234

Iml1lunology 44 Criteria of Reading the Lepromin Reaction. K. YANAGISAWA (P) 44 Infl uence of Repeated Lepromin Tests. L. M. BECHELLI (P) .. 45 Nomenclature and Classification of Skin Test Antigens. H. W. WADE (� � Mitsuda Test after Mass BCG. J. ALEIXO, J. STANCIOLl, J. MARIANO, A. SALOMAO (P) 47 Correlation of Clinical and Histological Mitsuda Reaction. L. M. BECHELLI, RATH DE SOUZA, R. QUAGLI ATO (P) 47 Lepromin Test in Guinea-pigs after Previous BCG and Dead M. Tu berculosis Vaccinations. R. D. AZULAY (P) 47 Serial Dilutions of Lepromin in Normal Young Children. H. W. WADE, R. E. GUINTO (P) 47 Natural Reactivity to Lepromin : Association between Mitsuda and Tuberculin Reaction for Graded Doses of Tuberculin. J. A. DouLL, R. S. GUINTO, M. MABALAY (P) .. 48 Serological Agglutinations with Cardiolipin Lecithin Antigen in Leprosy Sera. T. OGATA, M. ABE (P) 48 Antigenicity of BCG Wax to Sera from Leprosy Tuberculosis. T. FUMINAMI, H. HONDA (P) 48 Defence Mechanism in Leprosy as Related to the Internal Lesion and Malnutrition. O. SKINSNES (P) 48 [nfluence of Factor of Tuberculosis on Lepromin Reaction. J. M. M. FERNANDEZ (P) 49 Injection Therapy. Comparative Clinical Trial of (E) 208 Tnternational Congress, Seventh (E) 4

J JAMISON, D. G. Assessment of Effects of Outpatient DDS Administration in Katsina Province, Northern Nigeria (0) 159 JOPLING, W. H. Corticosteroids in Management of Foot-drop in Lepro- matous Leprosy : A Case Report (0) ]'71 JOPLING, W. H., on Reactional Leprosy ( L) . . 194 JOPLING, W. H. and RIDLEY, D. S. on Vadrine (L) . . 119

K KOOIJ, R. Nature of the Mitsuda Reaction (E) 137

L Letters to the Editor: on Vadrine. A. S. G ARRETT J J 8 on Vadrine. W. H. JOPLING and D. S. R IDLEY . . I J9 on Dr. Worsfold's Survey in Northern Rhodesia. J. A. KINNEAR BROWN 119 on Correct Dates of Early Leprosy Congresses. H . C. DE SOUZA- ARAUJO 193 on Naming and Classification ofSkin Test Antigens. H. W. WADE .. 193 on Streptohydrazid. A. S. GARRETT with reply by R. G. COCHRANE .. J93 on Reactional Leprosy. W. H. JOPLING . . J94 on Depot Lepromin Testing. J. PEPYS J96 on Press Report of 2nd WHO Expert Committee on Leprosy. H. W. WADE .. 252 on "Blue-black Macules". B. NICHOLSON 254

M Macrocycion, Further News of (E) J 36 M itsuda Reaction, The Nature of (E) J 37 Mobile Anti-leprosy Treatment Centres in Ghana. J. ELDON (0) . . 168 PA GE

MODAK, SUMAN. (See GOKH ALE, B. B., VABLE, S. M.) 234 Morphology of Mycobacterium Leprac. H. C. DE SouzA-ARAUJO (0) 80 Multipuncture Depot Lepromin Test : Investigations with Different Antigens. J. A. KINNEAR BROWN and M. M. STONE (0) 215 Multipuncture Type Lepromin Test (E) 209

N New Book on Leprosy (E) 79 NICHOLSON, BASI L on "Blue-black Macules" (L) 254

o Obituaries Dr. A. FllIPEANU 121 Dr. CYR I L F. A. WA LLACE 121

p Pathology, Bacteriology and 7 PEPYS, J. on Depot Lepromin Testing (L) 196 Plantar Ulcers in Leprosy : J, General ; II, Mechanics of the Foot in Relation to Plantar Ulcers. E. W. PRICE (0) 98 Plantar Ulcers in Leprosy : nr, Natural History of Plantar Ulcers. E. W. Price (0) 180 Plantar Ulcers in Leprosy : IV, Etiology of Plantar Ulcers. E. W. PRICE (0) 242 PR ICE, E. W. Plantar Ulcers in Leprosy. I, General; n, Mechanics of the Foot in Relation to Plantar Ulcers (0) 98 PRICE, E. W. Plantar Ulcers in Leprosy. III, Natural History of Plantar Ulcers (0) .. 180 PRICE, E. W. Plantar Ulcers in Leprosy. IV, Etiology of Plantar Ulcers (0) 242 Proceedings of VII International Congress of Leprology-Preliminary Report 7-60 Pro-oxidant Nutritional Conditions on Growth in vivo of M. leprae, Influence of Various. M. BERGEL (0) 153

R Reactional Leprosy. W. H. JO PLI NG (L) 194 REPORT : East African Leprosy Research Centre 1957-1 958 268 R EVIEW : Leprologia, 3, 1, Jan.-June, 1958 269 RHODES-JONES, R. Modified Technique for Staining Leprosy Bacilli in Smears (0) .. 251 RIDLEY, D. S. (See JOPLING, W. H.) 119

S SAG HER , F. The Nature of the Mitsuda Reaction (E) 137 SCHMID, K. TRIPOD, J. Experimental Investigation of Absorption and Excretion of Ciba 1906 (DPT) (0) . . 85 Skin Test Antigen : Naming and Classification of. H. W. WADE (L) 193 Social Aspects 50 Social Aspects of Leprosy Problems. E. WEAVER (P) .. 50 Why I have Established the "World Leprosy Patients' Day". R. FOLLEREAU (P) 50 Social Assistance in Leprosy. F. CONTRERAS (P) 51 Pattern of Social Assistance in Countries of High Leprosy Prevalence. F. HEMERIJCKX (P) 52 Social Aspects of Leprosy in Mexico. M. C. ESTRADA (P) 53 Social Activities at the Leprosarium in Japan. R. OZAWA (P) 53 Staining Leprosy Bacilli in Smears, Modified Technique for. R. RHODES- JONES (0) 25 1 STONE, M. M. (See BROWN, J. A. KJNNEAR) . . 110 STONE, M. M. (See BROWN, J. A. KINNEAR) . . 215 Streptohydrazid. A. S. GARRETT with reply by R. G. COCHRANE (L) 193 Sui phones, Short and Long Acting by Intramuscular Injection. G. CURRIE (0) ...... 220 Survey in Northern Rhodesia by Dr. Worsfold. J. A. KrNNEAR BROWN (L) 119 PAGE

T, Tension Equaliser. Use of in Many Tailed Operation for Claw Hands. R. H. THANGARAJ (0) . . 249 THANGARAJ, R. H. Camoquin in the Treatment of Acute Lepra Reactions (0) 106 THANGARAJ, R. H. Use of a Tension Equaliser in Many Tailed Operation for Claw Hands (0) 249 THANGARAJ, R. H. and Mrs. SAROJINI THANGARAJ. Management of Acute Psychosis in Leprom:ltous Leprosy (0) .. 186 Th erapy 17 Relapses after Sulphone Therapy in Lepromatous Leprosy. J. M. RODRIGUEZ (P) J 7 Sulphone Therapy in Aisei-en. S. TAKASHIMA (P) 18 Progress with New Anti-leprosy Drugs. T. F. DAV EY ( P) 20 Treatment and Prevention of Deformity. P. BRAND (P) 21 Thiocarbanilides, a New Class of Chemical Compounds in Leprosy. K. SCHMID (P) 23 Antituberculous and Antileprosy Activity of Ciba J906. R. L. MAYER � n Thioethyl Compounds in Therapy of Leprosy. E. DEL PIANTO (P) .. 23 Treatment of Leprosy with Viomycin Pyrazinamide, Cycloserine, BACCAREDA Boy (P) .. 25 Treatment with Cycloserine. ROLLIER (P) 26 Physical Therapy in Hansen's Disease. S. V. KIBBY (P) 26 Reconstructive Surgery of Deformities in Leprosy. K. IKEDA (P) 26 Lepra Reactions in a Mass Treatment Centre and their Management. C. VELLUT (P) 27 Antigen Marianum in Treatment of Leprosy. G. FARRIS (P) . . 27 Kanamycin in Murine Leprosy. K. YANAGISAWA (P) .. 27 Use of Isonicotinylhydrazones in Chemotherapy of Leprosy. N. P. Buu-Hol (P) .. 27 Clinical Evaluation Studies of Leonard Wood Memorial. J. TOLEN- TI� (� � Triple Treatment of Tuberculoid Leprosy. A. R. DAVISON (0) J84 TRI POD, J. (See SCHMID, K.) 85'

U UGANDA : Leprosy Control in. Duration of Treatment of Inpatients and Outpatients. J. A. KINNEAR BROWN and W. M. BLENSKA (0) . . J 08

v B E V A L , S. M. (See GOKHALE, B. B. and MODAK, SUMAN) . . 234 Vadrine. A. S. GARRETT (L) 118 Vadrine. W. H. JOPLING and D. S. RIDLEY (L) 119 VAN GORK U M , A. E. H. Report on a Visit to AI Walid Leprosarium, Damascus (0) 188

W WADE, H. W. on Naming and Classification of Skin Test Antigens (L) 193 WADE, H. W. on Press Report of 2nd WHO Expert Committee on Leprosy (L) " " 252 World Health Organisation Leprosy Conference at Brazzaville (E) 135 World Health Organisation 2nd Expert Committee on Leprosy : on Press Report of. H. W. WADE (L) 252