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Show Optic Chiasm Involvement on MRI With Ethambutol-Induced Bitemporal Hemianopia Vivian B. Osaguona, BSc, MBCHB, FWACS, James A. Sharpe, MD, FRCPC, Samira A. Awaji, MD, Richard I. Farb, MD, FRCPC, Arun N.E. Sundaram, MD, MSc, FRCPC Abstract: While ethambutol optic neuropathy usually causes central or cecocentral scotomas, bitemporal visual field defects also have been reported. The pathogenesis of the bitemporal hemianopia has not been established. This article describes magnetic resonance imaging abnormali-ties involving the optic chiasm in a patient with bitemporal visual field loss. To our knowledge, these neuroimaging findings have not been previously described in association with ethambutol therapy. Journal of Neuro-Ophthalmology 2014;34:155-158 doi: 10.1097/WNO.0000000000000095 © 2014 by North American Neuro-Ophthalmology Society Ethambutol is a bacteriostatic antimicrobial agent used in the treatment of mycobacterial infections. Ethambutol optic neuropathy is a complication arising from its use; it is dose dependent and usually reversible (1). Optic neuropathy commencing as early as 3 days after ethambutol therapy has been documented (2,3). Visual field changes in ethambutol optic neuropathy vary from central, cecocentral, bitemporal field defects and peripheral constriction. In previous reports of 26 patients with ethambutol-induced bitemporal visual field defects, neuroimaging had been normal (2,4-7). We present optic chiasm involvement on magnetic resonance imaging (MRI) in a patient with ethambutol-induced bitemporal hemianopia. CASE REPORT A 72-year-old woman weighing 70 kg reported progressive blurring of vision in both eyes 4 months after commencing medications for atypical mycobacterial infection. She had been evaluated for multiple pulmonary nodules. Percuta-neous biopsy of a lung lesion showed granulomatous inflammation containing multiple acid-fast organisms. Amplified Mycobacterium tuberculosis direct test was nega-tive as was examination of hypertonic saline-induced spu-tum smear and culture for tuberculosis. Mantoux test also was negative. Atypical mycobacterial infection, especially Mycobacterium avium complex, was considered likely by her infectious diseases specialist. The patient was concur-rently worked up for a renal mass, which potentially would require chemotherapy. Since chemotherapy is contraindi-cated in active pulmonary tuberculosis, there was urgency to initiate treatment for her pulmonary condition. The patient was aggressively treated for pulmonary atypical mycobacterial infection and empirically for possible pulmonary tuberculosis. She was prescribed 1600 mg of ethambutol daily (23 mg/kg) for 2 months followed by 1300 mg daily (19 mg/kg/d), 300 mg of isoniazid, 600 mg of rifampin, 250 mg of azithromycin, and 25 mg of vitamin B6 (pyridoxine). All anti-tubercular medications were stopped immediately after she reported blurred vision. Additional medications included aspirin, amlodipine, atorvastatin, ramipril, metoprolol, hydrocholorothiazide, and inhalers of tiotropium bromide, budesonide and formeterol, and albuterol. Comorbidities included chronic obstructive pulmonary disease, hypertension, and hypercholesterolemia. On examination, visual acuity was 20/200 bilaterally and the patient could identify only 1 of 17 Ishihara color plates with each eye. Pupils were equal and sluggishly reactive to light, with no relative afferent pupillary defect. Ocular motility and funduscopy were normal. Auto-mated perimetry revealed bitemporal visual field defects (Fig. 1A). Neuro-Ophthalmology Section, Division of Neurology, Departments of Medicine, Ophthalmology and Vision Sciences (VBO, JAS, SAA, ANES) and Medical Imaging (RIF), University Health Network, University of Toronto, Toronto, Ontario, Canada. The authors report no conflicts of interest. Address correspondence to Arun N.E. Sundaram, MD, MSc, FRCPC, Neuro-Ophthalmology Section, Division of Neurology, Department of Medicine, Ophthalmology and Vision Sciences, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8; E-mail: dr_arun72@ yahoo.com Osaguona et al: J Neuro-Ophthalmol 2014; 34: 155-158 155 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Brain MRI showed increased signal within the optic chiasm (Fig. 2A, B), and diffusion-weighted imaging showed no evidence of restricted diffusion (Fig. 2C). Complete blood count, erythrocyte sedimentation rate, antinuclear antibody, anti-neutrophil cytoplasmic antibodies, and serum vitamin B12 were normal. Screening for syphilis, human immunodeficiency virus, varicella zoster, and herpes simplex virus antibodies was negative. Cerebrospi-nal fluid analysis was normal. Renal function tests were normal with creatinine and urea values of 56 mmol/L FIG. 1. Automated visual fields (24-2 Humphrey). A. Bitemporal hemianopia is present 4 months after commencing eth-ambutol. B. Improvement in visual fields 16 weeks after discontinuing ethambutol. FIG. 2. Brain magnetic resonance imaging. A. Coronal T2 image shows hyperintense signal within the optic chiasm. B. Axial T2 image demonstrates a small amount of hyperintensity within the optic chiasm anterior to the infundibulum, while the more posterior hyperintensity is likely volume averaging artifact associated with cerebrospinal fluid (CSF). C. Axial diffusion-weighted image shows no evidence of restricted diffusion. D. Sixteen weeks after ethambutol was stopped, axial T2 scan reveals normalization of the signal intensity within the optic chiasm. The subtle hyperintensity in the superior aspect of the optic chiasm may represent gliosis or volume averaging from adjacent CSF signal. 156 Osaguona et al: J Neuro-Ophthalmol 2014; 34: 155-158 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (normal: 50-98 mmol/L) and 4.9 mmol/L (normal: 3.0- 7.0 mmol/L), respectively. Sixteen weeks after discontinuing ethambutol, visual acuity was 20/200, right eye, and 20/50, left eye. Dyschro-matopsia persisted, pupils and optic discs remained unchanged, and there was some improvement in the visual fields (Fig. 1B). Eight weeks after the initial MRI, repeat imaging demonstrated normal signal within the optic chiasm (Fig. 2D). DISCUSSION Bitemporal hemianopic visual field defects in ethambutol toxicity implicate a lesion in the optic chiasm, but neuro-imaging abnormalities of the chiasm have not been reported previously among 26 patients with this pattern of field loss (2-6). Our patient had bitemporal hemianopia with a T2 hyperintense signal in the optic chiasm on MRI. Ethambutol-treated animals have shown pathologic changes within the central nervous system with susceptibil-ity of the optic nerves, chiasm, and tracts (7-9). In the rat model, bilateral involvement of the optic chiasm (affecting both crossed and uncrossed fibers) and the intracranial por-tions of the optic nerves with axonal swelling and thinning of the myelin sheaths without demyelination have been reported (7). In this study, the optic nerve head as well as the intraorbital optic nerve and the retina were reported to be spared. Kinoshita et al (9) observed microglial prolifera-tion and demyelination within the optic nerves, chiasm, and tracts in ethambutol-treated monkeys. In 1 of the 3 monkeys, demyelination was seen at the center of the optic chiasm. Schmidt (8), in a study of rhesus monkeys treated with high doses of ethambutol, noted degenerative changes, including glial reaction, vacuolation, and demyelination at the center of the optic chiasm as well as in the proximal optic tracts and distal optic nerves. These degenerative changes occurred at doses of ethambutol much higher than therapeutic doses in man. It may follow that at lower doses in humans, the path-ologic changes, if detected early, may be reversible or not progressive. There is also evidence that ethambutol is toxic to the retina, particularly retinal ganglion cells (10). Necrosis of retinal ganglion cells and a decrease in their numbers in the parafoveal area (especially nasally) have been docu-mented. Glial reaction may occur in the retinal nerve fiber layer, with sparing of other portions of the retina. In humans, electrophysiologic studies, including the electro-oculography and multifocal electroretinography (mfERG), have demonstrated dysfunction of other layers of the retina apart from the retinal ganglion cells, including the retinal pigment epithelium, photoreceptors, and bipolar cells in the macula (4,11-14). Liu et al (4) studied 2 patients treated with ethambutol with bitemporal visual field defects and found the area of abnormal mfERG corresponded with the areas of bitemporal visual field loss. Orbital and brain MRI were normal, and it was concluded that ethambutol-induced bitemporal field may result, at least in part, from retinal toxicity. Various cellular mechanisms have been hypothesized in ethambutol-induced cytotoxicity. One study reported that ethambutol may cause death of retinal ganglion cells by acting as a chelating agent that depletes copper and zinc (15). Heng et al (10) concluded that ethambutol can cause mitochondrial dysfunction in the retinal ganglion cells via glutamate excitotoxicity. Contrary to these theories, Yoon et al (16) proposed that retinal ganglion cell damage caused by ethambutol is neither due to the depletion of zinc nor glutamate excitotoxicity, but through another mechanism that requires intracellular zinc. Our patient was treated with 2 other medications that may have affected her vision, azithromycin and isoniazid. Unlike most other macrolides, azithromycin generally does not interact with other medications causing adverse effects. This may be due to the fact that this antibiotic does not induce and bind to hepatic cytochrome P450 IIIA iso-enzyme system (17). Optic neuropathy has been described in patients treated with ethambutol in combination with isoniazid (18,19). In one report, there was minimal change in visual function after discontinuing ethambutol, but significant improvement after stopping isoniazid (18). There may be an additive toxic effect when isoniazid is used in com-bination with ethambutol and it is recommended to stop both medications as soon as the patient develops visual impairment (19). Our case illustrates clinical-neuroimaging correlation of optic chiasmal involvement from ethambutol toxicity. We await additional studies using high-resolution MRI of the anterior visual pathways to confirm our findings. REFERENCES 1. Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y Acad Sci. 1966;135:904-909. 2. Karnik AM, Al-Shamali MA, Fenech FF. A case of ocular toxicity to ethambutol-an idiosyncratic reaction? Postgrad Med J. 1985;61:811-813. 3. Chawla JPS, Crisan E, Jay WM. Ethambutol chiasmal toxicity with bitemporal hemianopia. Semin Ophthalmol. 2009;24: 221-224. 4. 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