Randomized controlled trial of dexamethasone in tuberculous meningitis

T~~h~r~lea,rdLun~D1srase,lYY4~11.203-207 0 1994 Longman

GroupLtd

Randomized controlled trial of dexamethasone in tuberculous meningitis S. Kumarvelu”,

K. Prasad”, A. Khosla+, M. Behari”, G. K. Ahuja*

*Departments of Neurology New Delhi, India

andfNeuroradiology,

Neurosciences

Centre, All India Institute of Medical Sciences,

S U M M A R Y. Setting: The patients admitted to the Neurology ward of the All India Institute of Medical Sciences Hospital. Objective: To assess the role of dexamethasone as an adjunct to antimicrobial therapy in the treatment of tuberculous meningitis. Design: A randomised controlled trial of 47 patients was conducted over a 13-month period. 41 patients completed the trial. Patients were stratified into mild, moderate and severe groups and randomly allocated to steroid and non-steroid groups. All patients received a standardized antituberculosis drug regime. The end point was 3 months, or death if earlier. The evaluation at the end point included survival, resolution of symptoms, sequelae and activities of daily living. Results were analysed using the Wilcoxon rank sum test. Results: The patients in the dexamethasone group fared better. 75% of this group had mild sequelae as opposed to 62% of the control group. Amongst the survivors, those who received dexamethasone sensorium improved earlier, and there was greater improvement in mental function and daily activities. The difference, however, did not reach statistical significance. Conclusions: Dexamethasone appears useful as an adjunct in the treatment of tuberculous meningitis especiallq in patients who have severe disease. The results need confirmation by a larger trial. Objet: Evaluer le role de la dexamethasone comme appoint therapeutique au traitement antimicrobien de la meningite tuberculeuse. Cadre: Patients admis a la section de neurologie de 1’Hopital du All India Institute of Medical Sciences. Schkma: Un essai aleatoire controle de 47 patients a ete realise au tours d’une periode de 13 mois. 41 patients ont complete I’essai. 11sont ete stratifies en groupes de condition, respectivement, peu grave, moderee, severe et ont ete repartis au hasard dans des groupes ‘steroide’ et ‘non-sterdide’. Tous ont recu un traitement antituberculeux standardise. Le terme etait a 3 mois, ou a celui du d&es si celui-ci survenait plus tot. L’evaluation finale a pris en compte la survie, la resolution des symptomes, les sequelles et les activites quotidiennes. Les resultats ont CtCanalyses en utilisant le test de la somme des rangs de Wilcoxon. Rk&zts: Les patients qui ont recu de la dexamethasone ont eu de meilleurs resultats. 75% de ce groupe, compare a 62% du groupe temoin, ont eu des sequelles peu graves. Parmi les survivants ceux qui avaient recu de la dexamethasone sensorium ont montre une amelioration plus precoce, et il y a eu une plus grande recuperation des fonctions mentales et des activites quotidiennes. Neanmoins cette difference n’avait pas de signification statistique. Conclusions: La dexamethasone semble utile comme appoint therapeutique dans le traitement de la meningite tuberculeuse, surtout chez des patients qui sont severement atteints. Ces resultats demandent confirmation sur un essai plus Ctendu.

R ,6 S U M k.

R E S U M EN. Objetivo: Evaluar el papel de la dexametasona coma adyuvante de la terapia antimicrobiana en

el tratamiento de la meniningitis tuberculosa. Marco de referencia: Los pacientes hospitalizados en el servicio de Neurologia de1 Hospital All India Institute of Medical Sciences.

Correspondence to: Prof. G. K. Ahuja, FRCP(Edin), Professor of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi-l 10029, India. Paper received 22 September September 1993.

1992. Final version accepted

14

203

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Tubercle and Lung Disease

Mbtodo: Estudio controlado aleatorio de 47 pacientes llevado a cabo en un period0 de 13 meses. Un total de 41 pacientes terminaron el estudio. Los pacientes fueron estratificados en tres grupos (afeccih ligera, moderada y severa) y asignados de manera aleatoria a 10s grupos con o sin tratamiento con corticoides. Todos 10s pacientes recibieron un esquema estandarizado de quimioterapia antituberculosa. La evaluacih final se bizo a 10s 3 meses o al moment0 de1 fallecimiento, si Cste se producia antes de este plazo. Esta evaluacih incluia la sobrevida, la resolucih de 10s sintomas, las secuelas y las actividades de la vida cotidiana. Los resultados fueron analizados utilizando el test de la suma de rangos de Wilcoxon. Resultados: Los pacientes tratados con dexametasona evolucionaron mejor. El 75 % de este grupo tuvo secuelas ligeras, comparado con 62% en el grupo control. Entre 10s sobrevivientes, el grupo tratado con dexametasona present6 una mejoria sensorial mhs temprana y present6 una mejoria mhs importante de la funcih mental y de las actividades cotidianas. Sin embargo, la diferencia no fue estadisticamente significativa. Conclusiones: La dexametasona parece ser 6til coma adyuvante en el tratamiento de la meningitis tuberculosa, especialmente en pacientes con enfermedad severa. Los resultados necesitan confirmacih en un estudio mhs amplio.

INTRODUCTION Tuberculous meningitis (TBM) is the most common form of neurotuberculosis and an important health problem in developing countries.’ The results of therapy are unsatisfactory, especially in those who receive delayed treatment. It is imperative that diagnosis be made early and that treatment be initiated, often before laboratory confirmation can be obtained.2 The treatment of tuberculosis has undergone significant changes in the past decade.3,4 Glucocorticoids have been used in the treatment of TBM, but only a few controlled trials are available.5 Differences in the severity of illness, the stage at which the treatment is initiated and the drug regimens used add to the difficulty in assessing the role of steroids.“‘O Lincoln and Swell” felt that glucocortjcoids are useful and should be used in every patient with TBM, while Hockaday and Smith’* did not recommend their use in the routine management of TBM. We conducted a randomized controlled trial of steroids in patients of TBM as an adjunct to antituberculosis treatment to test the hypothesis that the use of dexamethasone decreases the mortality and major sequelae of TBM.

and tuberculoma; (4) Clinical, radiological or histological evidence of extracranial tuberculous. Treatment taken prior to hospitalization was documented. CSF examination was performed on admission and at 7 and 14 days, and later if required. Patients below 10 years of age and those who received antituberculosis therapy (ATT) for more than 4 weeks or glucocorticoids before admission were excluded from the study. Patients were evaluated at the time of admission for severity as per a severity scale used at our centre (Table 1). Patients were stratified into two groups, severe (score of 8 or more) and mild to moderate (score less than 8). The antimicrobial drugs were given once a day in the following dosages in adults: rifampicin 450 mg, isoniazid 300 mg and pyrazinamide 1500 mg, and in children 15 mg, 10 mg and 30 mg per kg body weight, respectively. Pyridoxine supplements were given routinely. Patients were randomized using the random numbers obtained from the Fisher’s table to steroid and non-steroid groups. Glucocorticoids were given as per the following

Table 1. severity

Tuberculous

S. No.

METHODS

scoring system for assessment

Parameter

Weightage

-

1 2 3 4 5

1.

Sensorium

2.

Associated pulmonary tuberculosis Associated extensive tuberculous/non-tuberculous disease Age less than 10 years or more than 50 years CSF protein more than 3 g/l CT scan evidence of (a) Exudates: Grade I Grade II Grade III (b) Hydrocephalus: mild moderate severe (c) Mid-line shift 1 Leucopenia/Leucocytosis Systolic hypotension

47 consecutive

patients with clinical diagnosis of probable TBM admitted to the neurology services of the All India Institute of Medical Sciences during the period March 1991 to March 1992 were included in the study protocol. The diagnosis of probable TBM was made if at least 3 of the following criteria were present: (1) Clinical: fever more than 38°C headache, neck stiffness with or without seizures or altered sensorium for two weeks or more; (2) Characteristic cerebrospinal fluid (CSF) picture: leucocytes more than 20 /mm3 with lymphocytic predominance, proteins more than 1 g/l, sugar less than two-thirds of corresponding blood sugar, cultures negative for pyogenic organisms and fungi, and negative cytology for malignant cells; (3) Contrast enhanced computerized tomography (CT) of the head showing basal exudates or hydrocephalus with or without infarcts

meningitis:

3. 4. 5. 6.

I. 8.

normal delirium drowsy semi-coma coma

Minimum score 1; Maximum

score 15.5.

0.5 0.5

0.5 0.5 1 2 3 1 2 3 0.5

1

(points)

of

Randomized

schedule: injection dexamethasone 16 mg intravenously in 4 divided doses per day for 7 days, followed by tablet dexamethasone 8 mg per day as a single dose after food for 21 days. In children, the doses were 0.6 mg per kg per day for 7 days and 0.3 mg per kg per day for 21 days. The dose was tapered off over the next 14 days. Liver function tests were performed as and when required. ATT was modified if a patient developed hepatitis, defined as a 4-fold increase in serum aspartate and alanine aminotransferase. The end point of the study was 3 months after the initiation of treatment, or death if earlier. At the end point, in addition to neurological examination, intellectual impairment was assessed by mini-mental score.13 Briefly, the mini-mental score tests orientation, registration, calculation, recall and language functions. The score ranges from O-30, 0 being worst performance and 30 as normal. Activity of daily living (ADL) was assessed by the Barthel index which includes bowel and bladder control, grooming, toilet use, feeding, transfer, mobility, dressing, walking up stairs and bathing.14 A score of 0 indicates a totally dependent patient, whereas a score of 20 means an independent existence. Auditory function was assessed by brainstem auditory evoked potentials or audiogram. The outcome was categorized as follows: (a) Died (b) Major sequelae: persistent vegetative state, blindness, symptomatic hydrocephalus, moderate to severe intellectual impairment, severe functional disability (totally dependent), uncontrolled seizures; (c) minor sequelae: mild intellectual impairment, mild to moderate functional disability (ADL with no/minimal assistance) and (d) no sequelae. Patients were divided into two groups: poor outcome (death and survival with major sequelae) and good outcome (survival with minor or no sequelae), for statistical analysis. Statistical methods used were the x2 test with Yates continuity correction for comparison of proportions and non-parametric methods of comparison (Wilcoxon rank sum test for two groups) for comparison of means. A probability value of less than 0.05 was taken as significant.

RESULTS Of 47 patients, 25 (53%) were men and 22 (47%) were women. The mean age was 26.9 years (range 12-78). 4 patients (8.5%) had been treated for extra-meningeal tuberculosis in the past, three had history of contact with known cases of tuberculosis. Headache was the presenting complaint in all patients. All patients except one had fever. 34 patients (83%) had altered sensorium with a mean duration of 49.86 + 71.85 and 30.67 + 33.65 days in patients who survived and died respectively. 21 of the survivors (72.4%) and all the patients who died (100%) had altered sensorium. 16 patients (34%) had seizures, and 39 patients (95%) had meningeal signs. 16 patients (34%) had papilloedema, 3 had third nerve, 7 had sixth nerve, 10 had seventh nerve and 1 had hypoglossal paresis. 17 patients (41.5%) had limb paresis. Abnormal CSF

controlled

trial of dexamethasone

in tuberculoua

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205

findings were present in 39 and an equal number had abnormal findings on CT scan. 24 patients (51%) received dexamethasone and 23 were controls. Both groups had comparable clinical features, CSF findings and CT morphology (Table 2). 6 patients were lost to follow-up. The analysis of outcome was carried out on 41 patients, of whom 20 (49%) received dexamethasone. Poor outcome was seen in 13 patients of whom 8 were controls. I2 patients died and 1 had persistent vegetative state (Table 3). The difference in the outcome between the steroid and the control groups was statistically insignificant, although there was a trend towards higher incidence of survival and mild sequelae in patients who received dexamethasone. There was no statistically significant difference between the steroid and the control groups as regards the duration of fever, headache, vomiting and recovery of altered sensorium amongst survivors. Of the severely affected patients, those who received steroids showed a trend towards early recovery of sensorium, subsidence of headache and improvement of ADL as compared to the score at entry into the trial. Of the 2 severely affected patients in le control group, one patient did not recover sensorium at the end point, suggesting a poor outcome in untreated patients (Table 4). 5 patients had hepatitis requiring modification of ATT. One of these died due to TBM. The other 4 were given INH and rifampicin later with no recurrence of hepatitis. One patient had a steroid-related side-effect in the form of mooning of facies.

Table 2. Tuberculous meningitis: groups at time of’ randomisation SI. No.

comparison

Parameter

Clinical I. 2. 3. 4. 5. 6. 7. 8.

features Hypotension Meningeal signs Altered Sensorium Seizures Papilloedema Cerebrovascular event Spinal arachnoiditis Extra meningeal tuberculosis CSF parameters 9. Abnormal cell count 10. Lymphocyte predominance 1I. Raised proteins Low glucose levels 12. CT parameters 13. Exudates 14. Hydrocephalus 15. Infarct 16. Tuberculoma

Table 3.

Tuberculous

meningitis

of steroid and control

Steroid group n = 24

Control group n = 23

7 22 22 II

3 23 17 7 5 x

(29%) (92%) (92%) (46%)

I2 (50%) 7 (29%) 4 (17%,

I

(13%) (100%) (74%,) (30%) (22%) (35%) (4%)

11 (46%)

12 (52%)

20 15 18 22

(83%) (63%‘) (75%) (91%)

23 (loo%) I4 (61%) 19 (X3%) ?I (88%)

19 14 3 s

(79%) (58%) (13%) (21%)

?I (91%) I2 (52%) 5 (22%)

outcome at 3 months

Outcome Group

Good

Poor

Steroid Control

I5 13

5 8

2 (c)c/)

206

Tubercle and Lung Disease

Table 4. survivors S. No.

Tuberculous

meningitis:

Parameter

1. Recovery time (days) Sensorium Fever Headache 2. Improvement in Mini-mental score ADL score 3. Full/partial recovery (patients) 4. Unchanged (patients)

comparision

of recovery

among

Steroid group Severe Mildmoderate (n = 4) (n = 11)

Control group Severe Mildmoderate (n = 2) (n = 12)

19 13 20

13 13 18

25 18 12

9 9 11

9 12 4

8 6 11

10 4 1

4 2 12

1

0

0

0

*One patient remained in persistent vegetative state at the end point, hence evaluation of recovery of sensorium, headache and minimental scale could not be done. ADL - activities of daily living.

DISCUSSION The use of steroids in the treatment of TBM, despite being in vogue for over 3 decades, remains a controversial subject. The rationale for the use of steroids in TBM included: (a) reduction in cerebral and spinal cord oedema; (b) reduction in the formation of exudate in the subarachnoid space and promoting its resorption, thus reducing the liklihood of development of hydrocephalus, cranial nerve and nerve root damage and spinal block,‘5,‘6 (c) prevention of vasculitis and d) treating associated adrenal failure. Attempts have been made to resolve the controversy by organising trials in which otherwise comparable groups of patients were treated with and without steroids. However, diversity in methodology, antituberculosis chemotherapy, statistical methods used and duration of the follow-up period make this task formidable. Using sequential analysis of matched pairs in 97 patients, steroids were shown to significantly reduce mortality without affecting morbidity.‘O There was no apparent stratification of patients according to severity and the results were assessed at a very early stage, i.e. around 4 weeks. Most of the trials so far show a reduction in mortality. “m2’ There is no significant reduction in the number of seriously disabled survivors. Several trials suggest that while preserving lives, the use of steroids somehow increases the amount of serious disability.6,7J7 In the present study the controls were well matched as regards age, sex, clinical features, CSF and CT parameters. All the patients received the same and effective ATT. The patients in the steroid group showed a trend towards better outcome with mild sequelae as compared to controls, which did not reach statistical significance. Amongst the survivors, patients treated with steroids regained their sensorium faster and had better recovery of higher mental functions and ADL in the severe group. These parameters again did not reach statistical significance, probably because of the small number of patients. There was no significant difference between the patients who survived and those who died in relation to dura-

tion of illness prior to therapy, contradictory to earlier observations.20,2’ There are a number of theoretical objections to the use of steroids.5 Steroids affect the inflammatory meningeal reaction, resulting in decreased penetration of the blood CSF barrier by certain antituberculosis drugs, especially streptomycin, suppress immune response and may result in failure to contain tuberculous infection. These agents cause spurious improvement in the patient’s condition by reducing fever and inducing a sense of well-being, and alter the usual CSF response to ATT, making the assessment of treatment difficult. A recent study has shown that concomitant administration of steroids with ATT did not alter the CSF concentration of streptomycin, INH, rifampicin and pyrazinamide.22 Spread of tuberculous infection was not a problem in many studies as steroids were being given along with effective ATT. As regards earlier improvement, most patients of TBM become asymptomatic after 4-6 weeks of treatment with or without steroids. None of our patients developed any serious complications of steroids. To conclude, our results demonstrate better outcome in patients of TBM treated with dexamethasone as compared to controls, especially in the severe group. The number of patients in this study is too small to reach any statistically meaningful conclusions. Larger randomized controlled studies are needed to confirm the trend shown in the present study.

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