Management of paradoxical response in pediatric tubercular meningitis with methylprednisolone.pdf

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  Middle East African Journal of Ophthalmology, Volume 21, Number 2, April - June 2014 189 Departments of Ophthalmology, 1 Pediatrics, Sri Aurobindo Institute of Medical Sciences, Indore, Madhya Pradesh, India Corresponding Author:  Dr. Nitin Nema, Department of Ophthalmology, SAIMS, 55 Shri Nagar Main, Indore - 452 018, Madhya Pradesh, India. E-mail: INTRODUCTION T he incidence of tuberculosis is quite high in India. 1  Tuberculous meningitis (TBM) is the most devastating form of extrapulmonary tuberculosis in children, 2,3  especially males. 4,5  Therefore, TBM is an important cause of optochiasmatic arachnoiditis (OCA) in the Indian subcontinent. 6 OCA is an inflammation around the optic chiasm and optic nerves. This inflammatory involvement of anterior visual pathway results in marked exudation in the leptomeninges 6  seen on magnetic resonance imaging (MRI) as basal exudates,  which are most prominent around the optic chiasm. 7,8  It may occur during the course of neurotuberculosis or as a paradoxical response to anti-tubercular treatment (ATT). 6,9  OCA leads to profound visual impairment and, without timely diagnosis and effective treatment, it may cause irreversible blindness. 6,10 Reports of OCA are rare in the literature particularly in pediatric patients. We report two cases of OCA who developed blindness due to a paradoxical response to ATT and the successful management of these cases. CASE REPORTS Case 1  A six-year-old male, who was fully immunized and his  vaccinations were current, was treated for stage II TBM for one month, with good response, developed profound diminution of vision. He was on oral 4-drug ATT, that comprised of isoniazid (5 mg/kg/day), rifampicin (10 mg/kg/day), pyrazinamide (25 mg/kg/day) and ethambutol (15 mg/kg/day), and systemic steroids (1 mg/kg/day) on a tapering dose. The visual acuity was no light perception in both eyes. The anterior segment examination was unremarkable except for semi-dilated pupils, which were not reactive to light. The fundus examination showed slight disc hyperemia with  well-defined margins bilaterally. Brain magnetic resonance imaging (MRI) showed extensive enhancing basal exudates along with dilatation of lateral and third ventricles and obstruction at the aqueductal level [Figure 1]. A diagnosis of  ABSTRACT Paradoxical response to anti-tubercular drugs remains a diagnostic dilemma. In India where tuberculosis is quite prevalent, paradoxical response to anti-tubercular treatment (ATT) is either misdiagnosed or under-diagnosed. We report two cases of optochiasmatic arachnoiditis due to paradoxical response in children suffering from tuberculous meningitis. Visual acuity was recorded as no light perception in all eyes of both patients while they were taking 4-drug  ATT (isoniazid, rifampicin, pyrazinamide and ethambutol). However their systemic conditions did not worsen. They were treated with intravenous methylprednisolone for ve days followed by systemic corticosteroids on a tapering dose for four weeks along with ATT. This case report highlights the importance of early recognition of this sight-threatening complication and timely, effective treatment to prevent permanent blindness.Key words: Anti-Tubercular Treatment, Intravenous Methylprednisolone, Optochiasmatic  Arachnoiditis, Paradoxical Response, Tubercular Meningitis Management of Paradoxical Response in Pediatric Tubercular Meningitis with Methylprednisolone Nitin Nema, Abha Verma, Kuldeep Singh 1 , Virendra Mehar 1 Case Report Access this article onlineWebsite: DOI:  10.4103/0974-9233.129775 Quick Response Code: [Downloaded free from on Wednesday, January 9, 2019, IP:]  Nema, et al. : Management of Paradoxical Response with Methylprednisolone 190 Middle East African Journal of Ophthalmology, Volume 21, Number 2, April - June 2014 paradoxical tuberculous OCA was made on the basis of MRI findings, cerebrospinal fluid (CSF) analysis (cells 910/cu mm, protein 230 mg/dL, glucose 30 mg/dL, Pandy test positive), and clinical findings. Under cover of ATT, intravenous methylprednisolone (IVMP), 30 mg/kg body weight/day, was administered. After three doses the visual acuity increased to light perception in both eyes. IVMP was continued for two more days and then the medication was changed to oral prednisolone tablets (2 mg/kg body weight/day in single dose) on a tapering schedule for a month. The vision slowly improved over a period of 12 weeks. Seven months after the visual loss, brain MRI showed decreased inflammation of the meningeal sheaths around the optic nerves and mild hydrocephalus [Figure 2]. ATT was stopped after 12 months.  At the 18 months follow-up visit, the best corrected vision  was 6/18 in right eye and 6/12 in the left. The pupils in both eyes were approximately 4 mm in diameter round and briskly reactive to torch light. Fundus examination showed optic disc pallor bilaterally [Figure 3]. Case 2  A four-year-old male child, fully immunized and his vaccinations  were current, had stage I TBM with hydrocephalus, was on oral ATT for three weeks. He underwent surgery for  ventriculoperitoneal shunt (VP shunt) under general anesthesia after his systemic condition stabilized. Preoperative ophthalmoscopic examination showed a normal fundus. Six days postoperatively, the child was referred back to us by the pediatric surgeon with complaints of bilateral loss of vision. The child was on 4-drug ATT (isoniazid 5 mg/kg/day, rifampicin 10 mg/kg/day, pyrazinamide 25 mg/kg/day and ethambutol 15 mg/kg/day) but not on systemic steroids. The visual acuity at this visit was no fixation or following of light. There was no light perception in both eyes with absence of pupillary reaction to light. Fundus examination by indirect ophthalmoscope and 78 D slit-lamp ophthalmoscopy showed normal fundi bilaterally. Brain MRI showed enhancing lesions at the level of optic chiasm involving both the optic nerves. A diagnosis of paradoxical OCA was made on the basis of the clinical picture, CSF analysis (cells 120/cu mm, 90% lymphocytes, protein 20 mg/dL) and neuroimaging findings. The child was started on 30 mg/kg body weight IVMP for five days and then placed on systemic prednisolone (2 mg/kg body weight/day) on tapering dose along with systemic ATT. Two weeks after starting systemic corticosteroids, the child started to perceive light on vision testing. ATT was stopped after a year and the best corrected visual acuity at that time was 6/18 in both eyes. The pupils were round, semi-dilated with brisk reaction to light. Fundus examination showed prominent temporal pallor of the optic nerve head in both eyes [Figure 4]. Magnetic resonance imaging of the brain showed VP shunt  in situ  with no evidence of exudate in the optochiasmatic region. Figure 1:  Contrast-enhanced MRI brain showing enhancing basal exudates in the perichiasmal region (arrow) with moderate dilatation of lateral and third ventricles and aqueductal obstruction Figure 2:  Contrast-enhanced MRI brain seven months after initiation of treatment showing decreased exudates around the optochiasmatic region (arrow) Figure 3: a   and b. Diffuse bilateral optic disc pallor ba Figure 4:  Optic discs of right (a) and left (b) eyes showing pallor ba [Downloaded free from on Wednesday, January 9, 2019, IP:]  Nema, et al. : Management of Paradoxical Response with Methylprednisolone Middle East African Journal of Ophthalmology, Volume 21, Number 2, April - June 2014 191 DISCUSSION Tuberculosis is a common cause of morbidity and mortality in developing countries such as India. TBM is the most serious form of TB in children below five years of age. 2,3  There is preponderance of the disease in male children. 4,5 OCA refers to inflammatory changes with exudates in the leptomeninges around the optic chiasm and the optic nerve. 6  Tuberculosis is endemic in India, hence, OCA can occur during the course of treatment for TBM or following withdrawal of systemic steroids. 6,9  OCA is the leading cause of visual impairment in TBM. 6,10  Early recognition of this condition and appropriate treatment can prevent further visual loss and, at least, salvage some functional vision. 6  A reliable method of establishing the diagnosis of OCA includes  visual complaints, abnormal pupillary reactions to light, dilated fundus examination with special attention on the examination of optic nerve head and contrast-enhanced MRI. Dense plaque-like basal exudates especially around the optic chiasm are seen on MRI that show enhancement and hypertrophy of the chiasm and proximal optic nerves. 11  These features may be associated  with hydrocephalus. 6 Paradoxical reaction is defined as appearance of fresh symptoms, physical and radiological signs in a patient who had shown improvement with ATT. 9  It may present while the patient is on  ATT and steroids. 6  It can occur as early as 2 weeks and as late as 18 months after the initiation of ATT. 12  Paradoxical response must be differentiated from drug-resistant tuberculosis where there is a worsening of the patient symptoms. In the absence of specific CSF findings and negative culture report, the diagnosis of paradoxical deterioration depends mainly on close clinical monitoring. 12 The paradoxical response to ATT is an exaggerated host-organism interaction resulting in massive inflammation. 12,13  Effective treatment with ATT leads to revival of the host’s immune system.  Additionally, the death of  M. tuberculosis  causes activation and accumulation of lymphocytes and macrophages at the site of bacterial deposition or toxin production. 12  This is predominantly seen in the basal region of the brain implicating the optic chiasm and optic nerves.The management of OCA remains a challenge and prognosis in most of the cases remains poor. 14  Systemic oral corticosteroids, IVMP, 6  intrathecal hyaluronidase, 15  thalidomide 16  and microsurgical scraping of exudates have been used to treat OCA with variable results.The treatment of OCA due to paradoxical reaction includes high-dose systemic corticosteroids along with continuation of  ATT. The rationale behind the use of adjuvant steroids lies in reducing the harmful effects of inflammation as anti-tubercular drugs kill the organisms. 9  Treatment with corticosteroids decreases the basal exudates and stabilizes vision, and in some cases improves vision. 6 In this case report, the two children were responding well to  ATT when they noticed profound vision loss. The first child was receiving systemic steroid on a tapering dose while the second child was on ATT only. Both cases were small male children with high protein content and cell count in the CSF who developed paradoxical OCA. They responded well to intensive high-dose intravenous methylprednisolone and systemic corticosteroids  with reasonably good final visual acuity. CONCLUSION Ophthalmologists and pediatricians should be aware of the paradoxical response to ATT. One must predict OCA in children suffering from TBM who present with severe visual loss without systemic deterioration and with high CSF protein and pleocytosis and perichiasmal exudates on MRI. Prompt treatment with IVMP followed by oral steroid may salvage vision in these children. REFERENCES 1. Chakraborty AK. Epidemiology of tuberculosis: Current status in India. Indian J Med Res 2004;120:248-76.2. Maltezou HC, Spyridis P, Kafetzis DA. Extra-pulmonary tuberculosis in children. Arch Dis Child 2000;83:342-6.3. Weir MR, Thorton GF. Extra-pulmonary tuberculosis. Experience of a community hospital and review of the literature. Am J Med 1985;79:467-78.4. Udani PM, Parekh UC, Shah PM, Naik PA. B.C.G. test in tuberculosis. Indian Pediatr 1971;8:143-50.5. Benkappa DG, Chandrashekhar SK, Chandrashekhar P, Kakkur M, Bhargava Krishna M. Tuberculous meningitis: Review of 50 cases. Indian Pediatr 1975;12:1161-7.6. Anupriya A, Sunithi M, Maya T, Goel M, Alexander M, Aaron S, et al  . Tuberculous optochiasmatic arachnoiditis. Neurol India 2010;58:732-5.7. Dastur DK, Lalitha VS, Udani PM, Parekh U. The brain and meninges in tuberculous meningitis-Gross pathology in 100 cases and pathogenesis. Neurol India 1970;18:86-100.8. Garg RK, Paliwal V, Malhotra HS. Tuberculous optochiasmatic arachnoiditis: A devastating form of tuberculous meningitis. Expert Rev Anti Infect Ther 2011;9:719-29.9. Monga PK, Dhaliwal U. Paradoxical reaction in tuberculous meningitis resulting in involvement of optic radiation. India J Ophthalmol 2009;57:139-41.10. Sinha MK, Garg RK, Anuradha HK, Agarwal A, Singh MK, Verma R, et al  . Vision impairment in tuberculous meningitis: Predictors and prognosis. J Neurol Sci 2010;290:27-32.11. Silverman IE, Liu GT, Bilaniuk LT, Volpe NJ, Galetta SL. Tuberculous meningitis with blindness and perichiasmal involvement on MRI. Pediatr Neurol 1995;12:65-7.12. Gupta M, Bajaj BK, Khwaja G. Paradoxical response in [Downloaded free from on Wednesday, January 9, 2019, IP:]  Nema, et al. : Management of Paradoxical Response with Methylprednisolone 192 Middle East African Journal of Ophthalmology, Volume 21, Number 2, April - June 2014 patients with CNS tuberculosis. J Assoc Physicians India 2003;51:257-60.13. Zaki SA, Shenoy P. Paradoxical response to anti-tubercular treatment. Indian J Pharmacol 2011;43:212-3.14. Gourie-Devi M. Optochiasmatic arachnoiditis and neurotuberculosis. Prognostic indicators and therapeutic strategies. Neurol India 2010;58:714-5.15. Gourie-Devi M, Satish P. Hyaluronidase as an adjuvant in the treatment of cranial arachnoiditis (Hydrocephalus and optochiasmatic arachnoiditis) complicating tuberculous Cite this article as:  Nema N, Verma A, Singh K, Mehar V. Management of paradoxical response in pediatric tubercular meningitis with methylprednisolone. Middle East Afr J Ophthalmol 2014;21:189-92. Source of Support:  Nil, Conict of Interest:  None declared. meningitis. Acta Neurol Scand 1980;62:368-81.16. Schoeman JF, Andronikou S, Stefan DC, Freeman N, van Toom R. Tuberculous meningitis-related optic neuritis: Recovery of vision with thalidomide in 4 consecutive cases. J Child Neurol 2010;25:822-8. [Downloaded free from on Wednesday, January 9, 2019, IP:]
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