Corticosteroids in Tuberculous Meningitis

Nurdjaman Nurimaba
Dept. of Neurology Hasan Sadikin Hospital Faculty of Medicine, University of Padjadjaran

INTRODUCTION
Tuberculous Meningitis (TBM) is an inflammation of the Meninges. Covering the brain and spinal cord Caused by infection Mycobacterium tuberculosis Condition usually present headache, fever, convulsion Confirmation by microscopic and culture of the spinal fluids

 Each year around 80.000 people contact TBM

28.000 of those die and a further 12.000 are left with severe disability TBM is a global problem, it is particularly prevalent in developing world

 Monotherapy with Streptomicyn reduce the case fatality rate to 63% (Parson 1988) Combination (Isoniazid, Rifampicin and Pyrazinamide) fatality rate varying from 20% to 32% with permanent neurological deficit 5% to 40% (Jacob, 1990; Alarcon, 1990; Ramchandran, 1986) Doctors have used corticosteroids for TBM since the 1950s but their role remains controversial

 The corticosteroids used in different study were :

Dexamethasone (OToole 1969, Girgis 1991, Kumarvelu 1994, Lardizabal 1998, Thwaites GE et al 2004) Prednisolone (Chotmongkol 1996, Schoeman

1997)

 Steroids may :
Decreased inflammation, especially in arachnoid space Reduced cerebral and spinal cord oedema (Parson 1988, Feldman 1958) Reduced inflammation of small blood vessels and therefore reduce damage from blood flow slowing to the underlying brain tissue

 On the other hand, it is possible that steroids may harm for patients :
Suppress the immune response to Mycobacteria, making the systemic effect worse Reduced inflammation of the meningen, reducing drug penetration into the subarachnoid space In study reported Gastrointestinal hemorrhage (5 episodes), Glycosuria (1 episodes), infection (2 episodes) and hypothermia ( 5 episodes ) in 11 patients receiving dexamethasone (OToole 1969)

 Reaction to steroid use among 25 patients were (Lardizabal 1998) :

Cushingoid features (20)
Increased appetite (15)

Dermatoses (6)
Psychoses (1)

Gastrointestinal bleeding (1)

 Adverse Events (Thwaites GE et al, 2004) :

Significantly were reported in placebo group than in dexamethasone group (214 of 271 vs 186 of 274) p < 0,05 8 severe cases of hepatitis (1 fatal) occurred in placebo group and non occurred in dexamethasone group Stop the study in 12 patients (5 in dexamethasone group and 7 in placebo group) : gastrointestinal bleeding 6 (3 in each group), bacterial sepsis in 4 (3 in placebo group), and hypertension in 2 (1 in each group)

Dose of corticosteroids
Chotmongkol 1996 (in Thailand) :
Prednisolone oral on tapering daily dose for 5 weeks (wk I : 60 mg, wk II : 45 mg, wk III : 30 mg, wk IV : 20 mg, wk V : 10 mg)

Girgis 1991 (in Egypt):

Dexamethasone was given intramuscular (12 mg/day to adults and 8 mg/day to children weighing less than 25 kg) for three weeks and then tapered during the next three weeks

 Kumarvelu 1994 (in India):

Dexamethasone was given intravena 16 mg/day in four devided doses for seven days, then oral tablet 8 mg/day for 21 doses

Lardizabal 1998 (in Philipines) :

Dexamethasone was given at a dose of 16 mg/day for 3 weeks (first 5 days intravenous thereafter orally or via nasogastric tube). After 3 weeks steroid was tapered by 4 mg decrements every 5 days

 Schoeman 1997 (in South Africa) :

Prednisolone was given to the first 16 patients in a dose of 2 mg/kg/day and to the remaining 54 patients in a dose of 4 mg/kg/day (once in the morning). The decision to double the dose after the first 16 patients rifampicine decreased the bioavailability of prednisolone by 66% and increased the plasma clearence of the drug by 45%.

 JA Escobar et al 1975 :
Result further suggest that low dosages of steroids (1mg/kg of prednisone daily for r 30 days) are equally effective in treating the

disease as high dosages (10 mg/kg of prednisone at the start of treatment, gradually reduced over a 30 day period)

 Thwaites GE et al 2004 :
Grade I two weeks of intravenous therapy (0,3 mg/kg/day for wk I and wk II) and then four weeks of oral therapy (0,1 mg/kg/day for wk III, then a total of 3 mg/day, decreasing by 1 mg each week)

Grade II or III four weeks (0,4 mg/kg/day for wk I; 0,3mg/kg/day for wk II; 0,2 mg/kg/day for wk III; 0,1 mg/kg/day for wk IV) and then oral treatment for four weeks, starting at a total of 4 mg per day and decreasing by 1 mg each week

Results
Chotmongkol 1996 :
The result revealed that prednisolone not beneficial in patient with severe brain lesions, increased intracranial pressure and cranial nerve palsy

 Girgis 1991 :
The fatality rate was significantly lower in the group receiving dexamethasone (43% vs 59%, p less than 0,05), particularly in the drowsy patients (15 % vs 40%, p less than 0,04)

Development of neurologic complication after initiation of therapy (4 vs 10) and permanent sequele (6 vs 13) were significantly lower in the dexamethasone-treated group (p less than 0,02)

 Kumarvelu 1994 :
The patient in dexamethasone group fared better 75% of this group had mild sequele as opposed to 62 % of the control group Among the survivor, those who receive dexamethasone sensorium improve earlier and there was greater improvement in mental function and daily activities

 Thwaites GE et al :
Treatment with dexamethasone was associated reduced risk of death (relative risk, 0,69 : 95% CI 0,52 to 0,92 : p = 0,01)

It was not associated with a significant reduction in the proportion of severely of the disable patients (34 of 187 patients(18,2%) among survivor in dexamethasone group vs 22 of 159 patients (13,8 % in placebo group, p = 0,27)

Conclusion
Adjunctive treatment with dexamethasone improve survival in patients over 14 years of age with TBM but probably does not prevent severe disability