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THE INDIAN JOURNAL OF TUBERCULOSIS

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Tuberculous Meningitis and its Management* (A Preliminary Note)

By

P. KOSHY , Associate Professor of Medicine, V. BENJAMIN, Tutor, S. JANAKY Clinical Registrar,

Department of Medicine, Christian Medical College & Hospital, Vellore, South India. In this short paper, it is our purpose to discuss tuberculous meningitis and its management, dealing especially with some aspects of our own experience. The cases comprise those of adults (above the age of 12 years) admitted into one of the medical units of the Christian Medical College Hospital, Vellore, South India. Twelve cases were studied during the period 1953-54 (up to time of writing). Factors in the manifestations, diagnosis and treatment and complications will be discussed. We have, however, cited examples of cases studied at an earlier period, for purposes of comparison, or to mention some particular features of importance.

Type of Cases

For convenience we have accepted the classification and grading of cases of tuberculous meningitis made by the Medical Research Council of Great Britain (1948). On this basis, the present series could be distributed as follows :

1 Early Cases : Those with mainly non specific symptoms, with little or no classical signs of meningitis, with no paresis, in good general condition, and fully conscious diagnosis being established mainly on the findings of the cerebrospinal fluid (c.s.f.) .. Nil

2. Advanced Cases : Those who are obviously extremely ill, deeply stuperosed or comatosed or with gross paresis ............ ... 4 3. Medium Cases: Those in a condition between the above two types ... 8

Early cases of tuberculous meningitis rarely get to hospitals even while early ; they are often seen by private practitioners, for vague symptoms, headache, mild fever and so on, and get to hospitals only when they have more trouble. It will be noticed that none of our cases were early. Though a note of pessimism surrounds the talk of treatment of medium or advanced cases of tuberculous meningitis, our own experience tells us otherwise. Two of our patients are examples of people who came to us as extremely disorientated and disabled people, but who are now normal for all practical purposes, 11 months and 14 months after admission respectively (Case Nos. 1 and 2). Four cases have now been in hospital for a period of less than three months, and six cases now followed up for more than six months period, all show evidence of considerable improvement. Two cases died within the first three months period. The survival rate (10 out of 12) is thus quite good, considering the fact, that all the cases were either moderately, or far advanced.

*From the Department of Medicine (Firm II), Christian Medical College & Hospital, Vellore, South India.

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Diagnosis

The establishment of the diagnosis of tuberculous meningitis in any particular case may quite often be found to be difficult. In the series studied, the following conditions had to be thought of:

1. Pyrexia of unknown origin. 2. Typhoid. 3. Meningitis other than tuberculous. 4. Virus infection of central nervous system. 5. Hysteria.

One case, a boy of 14, was admitted as a case of pyrexia of unknown origin for investigation, and with no signs of meningitis. During his stay in hospital, he developed signs suggestive of congestive heart failure. An x-ray of the chest, taken at this time, revealed miliary tuberculosis. The cerebrospinal fluid (c.s.f.) was then studied, and it showed acid fast bacilli (A.F.B.) on the direct smear. Another case, studied in 1952, (not included in this series) sought admission for occasional attacks of difficulty in swallowing and because of negative physical findings, was almost being discharged from hospital as a case of hysteria, when he suddenly developed weakness of one arm. A lumbar puntcure and c.s.f. study, however, established the diagnosis. The establishment of the diagnosis of tuberculous meningitis, depended on the evaluation of many factors, the most important of which was a study of cerebrospinal fluid. A previous episode of an illness suggestive of pleurisy or cervical adenitis, should lead one to suspect tuberculous meningitis. A meticulous search for evidence of systemic tuberculosis is another step which is often fruitful. In all our 12 cases (Chart 1) evidence of tuberculosis was found in other organs of the body. The study of the c.s.f. is vital for a diagnosis. It has been our experience, that a careful and proper search for acid fast bacilli in the c.s.f. have yielded positive results in the majority of our cases (9 out of 12). This experience of ours is in sharp contrast to the common statement made in India that it is the exception to find A.F.B. in the direct smear of the c.s.f. Shah and Vakil (1954) from Bombay write as follows on the study of 61 cases of tuberculous meningitis : "Only in 6 cases out of 61 were the A.F.B. seen in the direct smear. It has been a problem with us, and many others working on the subject especially in India as to how to succeed in isolating T.B. from the c.s.f." Again, Patel (1953) could demonstrate A.F.B. in only one out of 21 cases. (In the children's ward of the Christian Medical College and Hospital a much larger number of cases of tuberculous meningitis is seen and treated. The majority of them have A.F.B. demonstrated in the direct smear). The probable reason for the difficulty that other workers have had in this respect is, we feel, faulty technique. The formation of the cobweb, though not specific for tuberculous meningitis, should always be looked for, because that is the most important and surest place, where A.F.B. may be found.

The c.s.f. Biochemistry and Cells

As medical students, we were taught that one of the most significant and diagnostic changes in the c.s.f. in tuberculous meningitis was the decrease in the chloride content. It needs to be now emphasised, that this view is no longer acceptable as a completely true statement. Recent literature (Doxiadis et al. 1954, Smith and

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Vollum, 1954, Lincoln et al. 1949) emphasises the fact that the chloride content is quite often quite normal in tuberculous meningitis. The more characteristic change is rather a decrease in the sugar content to less than 40 mgm%. Accompanying this change, is a rise in the protein content, and cells, mainly the lymphocytes. A decrease in sugar and increase in the protein and cells of the c.s.f. which is negative by direct smear and culture for organisms other than tubercle bacilli, is a combination of findings, which have remained our criterion for diagnosis. It is true that acute virus infections of the central nerves systems can give rise to c.s.f. findings, almost similar to those of tuberculous meningitis ; however, the c.s.f. sugar is practically never decreased in virus infections. If in addition to the above criteria, A.F.B. was demonstrated in the direct smear, there was no doubt of the diagnosis. Though the Medical Research Council of Britain have insisted on a positive culture, and a positive inoculation test for final diagnosis, we have have no hesitation in making a diagnosis, without waiting for such a positive result. It is significant also, that Rubie and Mahun (1949) followed up cases where A.F.B. was negative by direct smear, culture, and guinea pig inoculation, to necropsy, and found typical changes of tuberculous meningitis. We therefore, do not insist on or wait for a culture or guinea pig inoculation report for either diagnosis or initiating treatment. In our experience, we have taken the abovementioned characteristic biochemical and cell changes in the c.s.f. with the possibility of demonstrating A.F.B., sometimes after repeated examinations, as adequate for the diagnosis of tuberculous meningitis.

Treatment It must be remembered that there was a time, when no effective drug therapy was available for tuberculous meningitis till very recently. When Streptomycin became available cases were first put on intramascular (I.M.) injections alone. Since this was found inadequate, intrathecal Streptomycin was then advocated as an additional measure. The results were again poor, mainly because of severe drug resistance (Bruce Douglas 1953). The advent of Para-Amino-Salicylic Acid (P.A.S.) and later of Isonicotinic Acid Hydrazide (INAH) has helped to overcome this difficulty. Therefore, we now have a larger combination of drugs to use.

In our experience, during the years 1951-52, Streptomycin was relatively costly and so no cases were treated with it in those days, and obviously the results were very poor (Chart 1). In 1951, four cases were admitted and two of them were dead in a month, while two of them were discharged in a bad condition, and probably died soon after. In 1952, four cases were admitted ; only one of them was discharged as clinically cured, while the fate of the three others is not known. The figures for 1953 and 1954 are quite in contrast to what was obtained in 1951-52. Total number of cases studied was 12. Of these,

Number alive after one year Number alive for more than six months Number alive for more than four months Number dead within three months of admission ... ... ... ... 2 2 6 2

The above results are all the more significant if it is remembered that none of these were `early cases'. The mode of administration of Streptomycin has varied with time. In the early part of 1953, we adhered to the recommendation (M.R.C.I948) of prolonged intrathecal Streptomycin, but found that severe and sometimes alarming symptoms occurred and tended to persist if intrathecal Streptomycin was kept up (Figs. 1 and 2).

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TUBERCULOSIS MENINGITIS

Accordingly, we have tended to modify our methods, and have found good results, even without intrathecal medication. We have, however, found that it is essential to give all three drugs, namely Streptomycin, PAS and INAH for securing best results. Though the number of cases studied is very small, our results to date indicate that improvement is possible without intrathecal medication. Moreover, those cases, where intrathecal medication was given we have not adhered to the principle of going on with intrathecal medication for a set number of days (e.g. six weeks according to the M.R.C. recommendations) irrespective of effects ; rather, we have preferred to lessen the frequency of intrathecal injection or altogether stopping them, when a pleocytosis and an increase in proteins has occurred as a result of the treatment (Figs. 1 and 2). It is also being increasingly recognised now that these changes that occur with intrathecal administration of Streptomycin are characteristic "if not pathognomonic of tuberculous meningitis" (Smith and Vollum 1954). We have now eight cases in whom no intrathecal Streptomycin was ever given; and one of them (Case 3) was discharged in good condition five months after admission, and has remained well with normal c s.f. for now eight months. The others are still under observation. Only one of the cases, a lady, with pulmonary as well as renal tract tuberculosis has failed to show satisfactory improvement after 83 days of treatment under this regime. But we still hope that improvement will occur after some more time. All cases, however, had a lumbar tap done at least once a week, as long as they were in hospital. Total number of cases treated with I.M.S.M., P.A.S. and I.N.A.H. and no intrathecal Streptomycin ............... Of these,

Number of cases which died within 2 weeks of admission Number of cases alive for more than six months Number of cases alive for more than three months Number of cases observed for less than three months ... ... ... ... 2 2 2 2

8

Criteria for Discharge

Our criteria for discharge from hospital has been as follows : We have persuaded patients to stay in hospital, till the c.s.f. sugar has remained above 40 mgm % for a period of at least one month (4 weeks). Though it may have been ideal to keep patients till the c.s.f. protein and cells also came down to normal, we have found that they are slower to get to normal; and in the cases which have been followed up, they steadily came down after discharge. Figure 3 shows the results of the changes in the c.s.f. on admission, on discharge, and on follow-up in three typical cases. It will be seen from the figure, that so far we have continued to observe a steady improvement in the c.s.f., if cases are discharged only after they have had a c.s.f. sugar level remaining above 40 mgm % for about a month in hospital. We do not yet know, how long it will take for the c.s.f. to attain complete normality.

COMPLICATIONS 1. c.s.f. Changes

One of the complications of intrathecal medication is the production of a severe exacerbation of meningeal irritation. This has been interpreted at various times in different ways. It was thought to be a form of chemical meningitis. But the work of

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Swithinbank, Smith and Vollum has made it increasingly clear that this type of change is probably similar to the "intrathecal tuberculin reaction" (Swithinbank, Smith and Vollum, 1953). This type of reaction resulting from intrathecal Streptomycin medication has also been considered as being characteristic for tuberculous meningitis, as it does not occur if intrathecal Streptomycin is given to normal individuals or to people suffering from other forms of meningitis (Swithinbank et al. 1953). The patient becomes more uncomfortable, there is increasing headache and vomiting, and the c.s.f. shows a characteristic pleocytosis, with a relative increse in polymorpho-nuclear cells, and a marked increase in proteins and an increasing anthochromia. Spinal block may also be produced. The production of a state of internal hydrocephalous has also been thought to be due to intrathecal medication. Figures 1 and 2 show characteristic changes described. 2. Damage to the VIIIth Cranial Nerve

A dreaded complication of the prolonged use of Streptomycin is the damage to the 8th cranial nerve producing deafness and/or vestibular disfunction. In this series, we have probably had only one case (P-Fig. No. 3) in which both divisions have been grossly affected ; but we feel that this could have been partly avoided by using only pure Streptomycin sulphate, (and not dihydrostreptomycin) intrathecally. It is our practice to emphasize that no dihydrostreptomycin should be used intrathecally ; but due to an oversight, this patient was given a fair number of intrathecal injections of dihydrostreptomycin and she also had a total of 130 gms. of Streptomycin I.M. It is necessary to mention in this connection that all druggists now dispense dihydrostreptomycin on a prescription for streptomycin and unless it is specifically mentioned pure Streptomycin sulphate may not be dispensed. Unfortunately the market is flooded with dihydrostreptomycin and not Streptomycin sulphate. Ambystrin (a mixture of equal parts of Streptomycin and dihydrostreptomycin) is now becoming increasingly available, but even this may be unsuitable for intrathecal medication. 3. Arachnoiditis

We have had one case (1952-1954) who developed extensive arachnoiditis and paraplegia. It was difficult to determine whether the tuberculous process or the treatment was responsible for this. We feel that excessive intrathecal medication may very well be a contributory factor to such a complication. In this patient, a surgical removal of the adhesions resulted in a remarkable recovery of function of the lower limbs. She has been followed up for 740 days (2 years and 10 days) and her c.s.f. study at the end of this period was as follows : Sugar 56 mgm %, Proteins 25 mgm %, Chlorides 703 mgm %, cells 3/c.mm. 4. Hypothalamic Syndromes

The occurrence of hypothalamic syndromes characterised by some or all of the following symptoms were observed in one of the patients : The symptoms and signs are excessive perspiration, disorders of sleep rhythm, bullimia, and hyperglycemia, and occasionally hypertension, and sometimes diabetes insipidus. This patient had excessive perspiration and a marked disorder of sleep rhythm. They are usually due to pressure over/or arterial damage to the hypothalamic region, and the occurrence of an internal hydrocaphalous is the commonest cause. In as much as internal hydrocaphalous is often precipitated by too enthusiastic intrathecal medication, it is conceivable that this state of affairs can be reversed. In this particular patient, the symptoms cleared up to a large extent, when intrathecal medication, stopped,

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5. Phenomenon of Prolonging Life

One of the dreaded complications of treatment in the early years of Streptomycin therapy was the phenomenon of prolonging life, but leaving a patient with gross neurological defects, both psychologically and organically. Reports from other sources give examples of decerebrate rigidity, blindness and paraplegia or hemiplegia as common sequelae. In this respect our experience with treatment, using the combination of all three drugs has been very much more fortunate. Far from leaving behind gross neurological deficits, we have had the gratifying experience of seeing patients who came to us completely disorientated and mentally unsound, and others with defective vision and irresponsible sphincter mechanisms, all recovering beyond recognition. One patient, who was struck with the disease, while studying in college, came to us disorientated and unable to walk, and with loss of control of the sphincters. He is now completely normal, and keen to go back to college, 11 months after commencement of treatment (P.V.G., Fig. 3). Another patient who came to us delirious and partially blind has recovered completely and has remained so for 14 months (C., Fig. 3). A third patient who came to us with a Foster-Kenndy-Syndrome (optic atrophy of the right eye, and papilloedema of the left disc) and hemiparesis, is now after treatment for three months, almost normal as regards his vision, and is ambulant except for a slight spasticity of the left lower limb. The recovering of mental functions and organic neurological deficits, have been so striking in our experience, that we have no hesitation in strongly recommending a fair and adequate trial of chemotherapy in all advanced cases of tuberculous meningitis. TYPICAL CASE SUMMARIES

Case No. 1 (P.V.G.)

This young man of 25 years had been in Persia some years ago working in a firm, and while there, had pleurisy with effusion in 1950. He was asked to take rest, and the condition seemed to have cleared up on rest alone. No chemotherapy was given. He came back to India in 1952, and joined college to complete his education. In August 1953, he developed a low-grade fever and headache, and a month later developed vomiting. He came under our observation on 15-9-1953 in a gravely disorientated condition with neck rigidity, diplopia and incontinence of urine and faeces mild papilloedema, and exaggerated knee jerks (bilateral) and bilateral extensor plantar responses. The c.s.f was under tension (lumbar tap) and on analysis showed a clear fluid with 62 cells/c.mm., Protein 105 mgm%, Sugar 13 mgm%, and Chlorides 520 mgm% ; direct smear showed A.F.B. X-ray of the chest showed marked hilar adenitis. Treatment was started with all three drugs, and intrathecal medication was given till a marked reaction occurred. (Fig. 1). Figure 3 shows the c.s.f. changes with treatment. The interesting features of this case that we would like to point out are :

1. The inadequate treatment for pleural effusion--a potent cause for the occurrence of tuberculous meningitis later. 2. The remarkable improvement, in spite of the short course of intrathecal Streptomycin. 3. A case where a typical reaction to intrathecal therapy took place--now considered to be pathognomonic for tuberculous meningitis (Smith and Vollum, 1954).

Case No. 2. (C) This patient was admitted with a history of a fever of 21 months duration, which was treated as typhoid with chloramphenicol. She was also given terramycin

CSF CHANGE NAME CSF ON ADMN. S

mgm%

WITH TREATMENT CSF AT DISCH. S

p.c.mm

CSF- FOLLOW-UP CH S G CLS

Pcmm

p CH

mgrn%mgn%

G CLS P CH

P.cmm

G CLS P 7 25

P.V.G

105

52 O

13

+

162 45 738

42 +

728 61

3

225 D A Y S 36 + 150 45

+

DAYS AFTER ADMISSION : 331

C

130 495

7O7 47

161 DAYS

9

45 730 60

+ -

1 4

DAYS AFTER ADMISSION : 420

150 655 P.

28

+ 2O3 45 696

61

+

2

30 700 61

2

142 DAYS

DAYS AFTER ADMISSION : 176

Showing changes in c.s.f. on admission, at time of discharge, and at a later follow-up, of three typical cases.

Fig. 3.

Fig. 4.

X-ray-- chest of case No. 1 (P.V.G.) a month after admission. Shows marked hilar adeinitis and pleural thickening.

Fig. 5.

X-ray--chest of case No. 1 (P.V.G.) on followup study--331 days after admission--shows decrease in size of hilar shadows.

(To fact page 20)

X-ray chest of Case No. 3. (B.S.) showing miliary tuberculosis of lung.

Fig. 6.

(To face page 21)

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for the fever. One of her neighbours had pulmonary tuberculosis. On admission (4-6-1953), she had slight neck rigidity and had a constant stare, with only hand movements visible. All other cranial nerves were normal. Plantar responses--bilateral extensor response. Fundus showed papilloedema in both eyes. She had a lesion in left apex. She was given all three drugs and also some intrathecal medication. She showed a steady improvement and at the time of discharge she was normal except for a slight central scotoma. Her c.s.f. changes are shown in figures 2 and 3. Points of interest in this patient are: (1) the original mistaken diagnosis of tyspoid ; (2) the contact with neighbours having tuberculosis, and (3) a tuberculous focus in the lung, which was not discovered earlier because of insufficient symptoms.

Case No. 3 (B.S.)

This patient aged 14 years was admitted for bieathlessness on exertion, oedema of the legs, distension of the abdomen. No history of cough. On examination (183-1954) there was generalised anasarca, some clubbing of the fingers, distended neck veins, normal sized heart with normal sounds and plenty of crepitations and rales in both lung fields. He had a temperature of about 103 F to 104° F, and marked tachycardia, and the diagnosis was not made till an x-ray of the lungs was taken (Fig. b), A lumbar puncture was done at this stage, and the c.s.f. findings were as follows : Cells 350/c.mm. (92 lymphocytes), Proteins 130 mgm %, Sugar 15 mgm %, Chlorides 555 mgm.%. Direct smear showed large number of A.F.B. He was put on all three drugs, but no intrathecal medication was given. He was discharged in good condition on 30-7-54 (134 days after admission) with the following c.s.f. findings : Cells 2/c.mm ; Proteins 50 mgm %, Sugar 56 mgm%, Chlorides 700 mgm %, Globulin trace. He continued on chemotherapy with PAS and INAH at home and at a check up on 23-11-1954 (249 days after admission) was found to be completely normal on physical examination, and the c.s.f. study showed : Cells 5/c.mm, Proteins 15 mgm.%, Sugar 66 mgm%, Chlorides 750 mgm%, Globulin--nil. This case is a remarkable example of good results for eight-month period, on a regime where intrathecal medication was not given. COMMENTS This paper is not an attempt at a comprehensive study of all aspects of tuberculous meningitis. Some aspects have been emphasised however ; and some of these require some comment. The problem of early diagnosis of tuberculous meningitis cannot be underestimated. We have, however, emphasized the importance of a careful and diligent search for A.F.B. in the direct smear. In fact, the discovery of the organisms in the smear has often helped us to clear up a diagnosis which was in doubt from a biochemical study of the c.s.f. alone. The fallacy of depending too much oil a low c.s.f. chloride content, has been clearly brought out by the study of electrolyte balances in tuberculous meningitis (Doxiadis et al. 1954). An excellent appraisal of the problem has been recently published (Smith and Vollum, 1954), Of additional tests, the blood c.s.f. bromide barrier and ratio as an aid to early diagnosis, seems to be the most promising one worthy of further trial (Taylor et al. 1954). We gave up intrathecal medication with Streptomycin mainly because of alarming symptoms accompained by acute discomfort for the patient that occurred with the

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continued use of such a regime. Subsequently however, many reports of successful therapy without intrathecal medication have occurred (Fitzpatrick, 1954; Beguena Candela 1953). Significant, however, in all these reports was the fact that either all three drugs were used, or, if only two of them were used, INAH was always one of them. Though we have not yet tried it ourselves, the use of massive dose of INAH alone orally is being advocated with enthusiasm (Spies et al. 1954). A possible explanation for the good results obtained with the combined use of drugs, specially when INAH is included in the schedule, is to be found when the significant difference that is noted in the healing process of a tuberculous lesion when Streptomycin alone is used, is compared with that which occurs when Streptomycin and INAH are used in combination (Ritchie et al, 1953). They studied the histopathological changes in human tuberculosis and found more complete healing, when INAH was used in addition to Streptomycin and concluded that these effects were probably due to the capacity for greater diffusability that INAH has. We do recognise that the total number of cases what we present here are too small for generalisation, and the period of observation is far too inadequate. While recognising these limitations we wish to point out that we have been meeting with a larger number of cases of tuberculous meningitis in adults, while the chemotherapy of tuberculosis has been prevalent. We have in our series two cases where probably inadequate treatment of earlier tuberculosis was given, and the patients subsequently developed tuberculous meningitis. We cannot help drawing an analogy from inadequate treatment of early syphilis with the late manifestations of neuro-syphilis. Summary 1. The experience gained in the diagnosis and management of 12 cases of tuberculous meningitis in adults is described. 2. The criteria for diagnosis from the c.s.f. study is given, emphasising especially the possibility of getting a larger percentage of positive results for acid fast bacilli in the direct smear examination, by improvement of technique. 3. The possibility of getting good results with a negligible amount of intrathe cal medication, and even without any intrathecal medication whatever, but by the use of all three drugs (Streptomycin, PAS and INAH), is pointed out. The possible explanation for such a phenomenon is also mentioned. 4. It is suggested that the occurrence of tuberculous meningitis in consider able numbers even while the chemotherapy of tuberculosis in general has been quite prevalent, may be due to inadequate treatment, and that it may be analogous to the late manifestations of neuro-syphilis occuring after inadequate therapy for primary syphilis. Acknowledgements We express our thanks to a host of house-physicians who were largely responsible for the accurate and regular recording of data. Special mention must be made of the efforts of Dr. Ethel Pcreira, whose initiative made this study possible. REFERENCES 1. 2. BAGUENA CANDELA (in Med. Espan.), (1954) Tuberculosis Index ; 69 ; 370. DOUGLAS, BRUCE E. : (1953); Proc. Staff Meet., Mayo Clin. ; 28 ; 381.

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3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

D OXIADIS , S.A., G OLDFINCH , M.K., And P HILPOT , M.G., (1954). Brit. M.J, 1 : 1406. F ITZPATRIC , MJ.: (1954): Am. Rev. Tuberc. ; 69: 370, L INCOLN , E.M., & K IRMBE , T.W.; (1949); Lancet, 1: 767. Medical Research Council Report On Trials Of Streptomycin, (1948); Lancet, 1 : 582. P ATEL , B.D. : (1953); Indian J. Child Health; 2: 105. R ITCHIE , G.M., T AYLOR R.M. & D ICK , J.C.: (1953); Lancet; 2: 419. R UBIE , J., And M AHUN , A.F.: (1949) ; Brit M.J. ; 1 : 338. S HAH , M.J. And V AKIL , BJ.: (1954); Indian J.M.Sc. 8 : 77. S MITH , H.V., And V OLLUM , R.L. (1954); Brit. M. Bull. ; 10: 140. S PIES , H.W. Et Al. : (1954); Am. Rev. Tuberc.; 69: 192. S WITHINBANK , J., S MITH , H.V., 5; V OLLUM , R.L.: (1953); J. Path. & Bad. ; 65: 565. T AYLOR , L.M., S MITH , H.V., & H UNTER , G. : (1954); Lancet, 1: 700.

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