Anti-Tubercular Treatment of Tuberculous Meningitis Cause Paradoxical Multiple Neurotuberculoma

Tuberculosis is the most common cause of infectious disease related mortality worldwide. Paradoxical reactions to antituberculous treatment have created difficulties in the management of extrapulmonary tuberculosis, particularly central nervous system tuberculosis. We report a three years baby with tuberculous meningitis, who was treated outside with anti-tuberculous drugs without steroid one month back and presented in our emergency as status epilepticus. This case emphasizes the importance of addition of steroid along with anti-tubercular drugs in the treatment of central nervous system tuberculosis.


Introduction
I ndia had an es mated 2.3 million (26% of global burden) Tuberculosis (TB) cases in 2010, and ranked 16 th in terms of incidence rate amongst 22 highest TB burden countries 1] .Tuberculosis is the most common cause of infec ous disease related mortality worldwide.Paradoxical reac ons to an -tuberculous therapy (ATT) have created diffi cul es in the management of extra pulmonary tuberculosis, par cularly central nervous system tuberculosis (CNS TB).We report a 3 years old baby with tuberculous meningi s, who was treated outside with an -tuberculous drugs without steroid one month back and presented in our emergency as status epilep cus.

The Case
Three years old baby presented to emergency department with repeated convulsive movement of the whole body for past six hours.Each convulsive episode persisted for 10 minutes, which was associated with uprolling of the eye ball and loss of consciousness.There was history of vomi ng one episode day before onset of seizure.There was no history of fever.Four weeks ago the pa ent was diagnosed as tuberculous meningi s in a private hospital on the basis of prolonged fever, vomi ng, convulsion, posi ve tuberculin test, history of tuberculous contact, posi ve meningeal signs and cerebrospinal fl uid analysis.Her ini al computed tomography (CT) Scan brain did not showed any ring enhancing lesion (Figure 1).She was started on 4 drugs ATT without steroid consis ng of isoniazid, rifampicin, pyrazinamide and ethambutol as intensive phase for two months, all taken once daily in morning empty stomach per orally.She was also given phenytoin@5mg/kg/day per orally.During fi rst four weeks of treatment, there was improvement in symptoms.On examina on she was tachycardic with heart rate of 102/ minute, and altered sensorium with Glasgow coma scale (GCS) of 12.Other vital parameter were within normal limits.On central nervous system examina on there were brisk deep tendon refl exes, Bibinski posi ve bilaterally and power and tone were normal.Complete blood count, rou ne biochemistry, serum electrolyte level were normal.Repeat CT Scan Brain revealed mul ple ring enhancing lesion (Infl ammatory granuloma) as shown in Figure 2.
In our Ins tute pa ent was managed with intra venous (IV) an -epilep cs Diazepam, followed by loading dose of Intra venous phenytoin as per protocol, seizure controlled and later changed to oral maintenance dose of phenytoin once daily, steroid was added (Ini ally IV Dexamethasone for seven days then shi ed to oral prednisone@ 2mg/kg/day in three divided dose for six weeks and tappered off over two weeks) and ATT were con nued as per earlier regimen.Pa ent gradually improved without any recurrence of seizure.

Discussion
Neurological deteriora on in pa ents with neuro-tuberculosis who are receiving ATT should alert clinicians to the possibility of paradoxical neurotuberculomas.A paradoxical response is defi ned as the clinical or radiological worsening of pre-exis ng tuberculous lesions or the development of new lesions not a ributable to the normal course of disease, in a pa ent who ini ally improved with ATT.Tuberculous involvement of the central nervous system in our case (clinical meningi s) was evident at the ini al presenta on.
The paradoxical response to ATT, which usually develops a er two weeks of treatment, is well known.Up to 10% pa ents with central nervous system TB report paradoxical response mostly if ATT not adjuncted with steroid during intensive phase, and this number may be as high as 30% in HIV-infected pa ents 2 .In our case, pa ent developed paradoxical result a er 4 weeks of ATT, and most likely due to non prescrip on of steroid during intensive phase ATT.Pa ents recently started on ATT should be monitored for the development of paradoxical response.Most authori es recommend that these pa ents con nue treatment with rou ne ATT.
The paradoxical response is a component of immune recons tu on infl ammatory syndrome or immune restora on syndrome, which results from an exuberant infl ammatory response toward incuba ng opportunis c pathogens 3 .T-cell suppression and anergy during ac ve tuberculosis have been well recognized.This phenomenon is related in part to the produc on of interlukin-10 by peripheral blood T-lymphocytes during ac ve tuberculosis.A er comple on of tuberculosis therapy, T-lymphocytes no longer produce interlukin-10.It is known that interlukin-10 down-regulates T-helper cell ac vity.Therefore, it is not surprising that successful treatment may reins tute T-cell ac vity.It means that, over the course of tuberculosis treatment, a heightened immune response may occur despite the vanishing pool of viable mycobacteria 4,5 .This reversal of anergy state can explain the paradox of development of mul ple neurotuberculomas despite ins tu on of eff ec ve an tuberculous drug therapy in our case.
Why does such phenomenon occur only in few pa ents with tuberculosis?This may be a ributed to the diff erences in the immune responses of pa ents.There is suffi cient evidence which showed that the host response to Mycobacterium tuberculosis plays a  There are many reports sugges ng resolu on of paradoxical response with steroids 7 .In our case we added adjuvant steroid to ATT and con nued ATT as per earlier regimen and pa ent symptoma cally improved without any recurrence of seizure.The ra onale behind the use of adjuvant steroids lies in reducing harmful eff ects of infl amma on as the ATT kill the mycobacterium 8 .

Conclusion
This case emphasizes the importance of addi on of steroid along with an -tubercular drugs in the treatment of central nervous system tuberculosis.There is a need for paediatrician caring children at primary level to be aware of the occurrence of paradoxical reac ons to ATT especially in CNS TB.

Fig 2 :
CT Brain a er 4 weeks of An -tubercular treatment without steroid in a case of TBM revealed mul ple neurotuberculoma with edema

Fig 1 :
Fig 1: CECT Brain at the me of diagnosis of TBM Showed basal exudates and mild ventriculomegaly