Neurological Worsening in a Child of Miliary Tuberculosis with Neuro-Tuberculosis on Anti Tubercular Treatment

A seven and half year old male child presenting with pyrexia of unknown origin was diagnosed to be a case of miliary tuberculosis. Neuroimaging revealed multiple discrete ring as well as nodular enhancing lesions indicative of tuberculomas. After the initial response to ATT along with systemic steroids the child again presented with severe headache along with vomiting towards the end of intensive phase. Repeat neuroimaging showed appearance of new lesions with perilesional edema. Child was started again on systemic steroids and Streptomycin was added to the anti tubercular regimen, to which the child responded well.


Introduction
C NS tuberculosis remains an important cause of mortality and morbidity in developing countries with resurgence in developed countries due to appearance of AIDS.Many of the symptoms, signs and sequelae of neurotuberculosis are the result of an immunologically directed infl ammatory reac on to the infec on 1 .Bacilli implanted on the meninges or brain parenchyma, result in the forma on of small lesions (Rich foci).The loca on of the expanding Rich focus determines the type of involvement.Tubercles rupturing into the subarachnoid space cause meningi s.Those deeper in the brain parenchyma cause tuberculomas.Arachnoidi s and infarcts are other features of neurotuberclosis 2,3 .While these lesions usually resolve following an tubercular therapy (ATT),rarely clinical deteriora on may occur in spite of good ini al recovery.This worsening in neuro-tuberculosis has been a ributed to a paradoxical response and may occur within days and even one year a er star ng standard an tubercular chemotherapy 4,5 .Paradoxical response is defi ned as recurrence or appearance of fresh symptoms, physical and radiological signs in a pa ent who had previously shown improvement with appropriate anitubercular treatment.The present case presented with features of raised intracranial pressure with appearance of new lesions in brain towards end of intensive phase of an tubercular treatment.

The Case
A seven and a half year old male child presented to us with complaints of high grade fever for six weeks followed by frontal headache and non projec le non bilious vomi ng off and on with decreased appe te since past seven days.There was no history of cough, urinary complaints, rigor and chills, altered sensorium, neurological defi cit or seizures during the course of illness.He had received treatment for enteric fever and Malaria by private prac oners but without any response.History of pulmonary tuberculosis was elicited in grandfather 5 years back.On examina on child was conscious, well oriented to me, place and person.Vital parameters were within normal range.Child had mild hepato splenomeagly with no signifi cant lymphadenopathy.Chest examina on was also normal.Meningeal signs were absent.Rest of the neurological examina on was normal.Fundus examina on showed mul ple choroid tubercles.CBC, Urine analysis, blood culture and Widal agglu na on test were non contributory.Tuberculin test was non reac ve.ESR was raised (60 mm 1 st hour).HIV status was nega ve.CSF examina on was not done.CXR showed miliary tuberculosis (Figure 1).MRI Brain revealed mul ple predominantly discrete ring as well nodular enhancing intra axial lesions sugges ve of tuberculomas (Figure 2).Diagnosis of Miliary TB with neurotuberculosis was made.He was started on 2HRZE+10HR along with systemic steroids for six weeks.Child improved clinically and remained well for about 6-7 weeks.Towards the end of intensive phase there was recurrence of severe headache along with vomi ng for 4-5 days.His vitals were within normal limits and neurological examina on was normal.Repeat MRI brain showed appearance of new ring enhancing lesions with perilesional edema (Figure 3).Fundus examina on was normal.Diagnosis of paradoxical immune response to ATT was made and child was restarted on systemic steroids.The intensive phase for ATT was extended for another two months and injec on Streptomycin was added to the regimen.In addi on child was also given intravenous Mannitol injec on for two days to relieve cerebral oedema.The child showed improvement a er 72 hours and remained well therea er.CXR also revealed resolu on of military tuberculosis.MRI repeated at six months revealed complete resolu on except few calcifi ed lesions in cerebellum.

Discussion
Paradoxical response is now increasingly being recognized as a cause of subsequent deteriora on in cases of CNS tuberculosis despite adequate and appropriate therapy.This phenomenon complicates the decision about the therapy of CNS tuberculosis.It is not possible to clearly diff eren ate between paradoxical deteriora on and development of secondary resistance in the absence of posi ve tests of culture and sensi vity for Mycobacterium tuberculosis.Expansion of a tuberculoma or development of mul ple new brain lesions during treatment of TBM, though uncommon, has been reported in the literature and is called a paradoxical response 6,7,8,9,10 .Meena Gupta et al described that the dura on of me between ini a on of therapy and worsening of pa ent was from one to seven months.Nine out of ten pa ents developed fresh intracranial tuberculoma while one case otherwise showing improvement developed expansion of tuberculoma and other one of tubercular empyema developed tuberculoma while on therapy.All these cases responded to addi on of second line drug or increase in dose of drugs previously prescribed and introduc on or increased dose of steroid 8 .Ajay SK et al described the occurrence of this condi on, though previously reported only in the developing world, is now frequently reported in human immunodefi ciency virus posi ve migrants in the western world.The exact pathogenesis of this condi on is s ll incompletely understood, and the mainstay of treatment is chemotherapeu c regimes along with systemic steroids.Neurosurgical interven on is rarely necessary, and is confi ned to cases of hydrocephalus a er tubercular meningi s and to large tubeculomas with space-occupying eff ects 12 .
The explana on for paradoxical response to treatment remains unclear.Various hypotheses have been put forward to explain this unusual phenomenon.One possibility is that this occurs because of decreased penetra on of an tubercular drugs into brain 12 .Restora on of blood brain barrier with appropriate treatment is proposed to result in reac va on of latent foci.However, this hypothesis cannot explain the development or enlargement of intracranial tuberculoma who are treated with isoniazid and pyrazinamide, both of which freely cross the blood brain barrier in the absence of infl amed meninges.This does not explain the improvement observed in pa ents in whom signifi cant change is made in an tubercular therapy.Enlargement of lymph nodes (which do not have the barrier like blood brain barrier) in pa ents on an -tubercular therapy further goes against the hypothesis.Paradoxical response is possibly due to a Type IV hypersensi vity reac on developing within the ini al lesion and resul ng in cerebral vasculi s, infarc on, and edema 11,12,13 .Paradoxical reac ons occur due to complex interplay between host's immune response and the direct eff ect of mycobacterial an gens 14,15,16 .Ac ve tuberculosis leads to depression of type IV hypersensi vity reac on and immunosuppression due to ac va on of monocytes by protein deriva ves of mycobacteria.Increased interleukin levels resul ng from this can lead to immunosuppression.Specifi c an gens lead to produc on of immunosuppressive concentra on of prostaglandin-E2 8 .Once ac ve tuberculosis is under control a er star ng ATT, immunosuppression resolves.It also leads to enhanced delayed-type hypersensi vity and ac va on and accumula on of lymphocytes and macrophages at the site of bacterial deposi on or toxin produc on occurs when bacilli die.The reason for occurrence of this response in only some cases and not all suggests that it depends on host immune responses, virulence of tubercle bacilli, an gen load and eff ec ve an tubercular therapy.The yield of AFB culture from CSF can be increased by centrifuging the CSF, preparing thick smears from cobweb and increasing the examina on me.The solu on to this dilemma of paradoxical response with nega ve laboratory support, lies in close monitoring of pa ent with con nua on of drugs already in use with addi on of steroid, increasing the dose of drugs already in use and/or addi on of second line ATT 17,18,19,20 .

Conclusion
In the fi nal analysis, clinical judgement, regular follow up, guarded reassurance of pa ent and recogni on of the possibility of paradoxical response is the only prac cal answer.There is also a need to report their occurrence so as to chronicle the en re spectrum.

Fig 1 :Fig 2 :
Fig 1: X ray chest PA view showing military mo ling

Fig 3 :
Fig 3: New ring enhancing lesions with perilesional oedema (a er 2 months of intensive phase of ATT).