Management of paradoxical response in pediatric tubercular meningitis with methylprednisolone.

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 five 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.

INTRODUCTION

The incidence of tuberculosis is quite high in India.1 Tuberculous meningitis (TBM) is the most devastating form of extrapulmonary tuberculosis in children,23 especially males.45 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 leptomeninges6 seen on magnetic resonance imaging (MRI) as basal exudates, which are most prominent around the optic chiasm.78 It may occur during the course of neurotuberculosis or as a paradoxical response to anti-tubercular treatment (ATT).69 OCA leads to profound visual impairment and, without timely diagnosis and effective treatment, it may cause irreversible blindness.610

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 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].

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

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 4

Optic discs of right (a) and left (b) eyes showing pallor

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.23 There is preponderance of the disease in male children.45

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.69 OCA is the leading cause of visual impairment in TBM.610 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.1213 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 thalidomide16 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.