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Show Vision Loss Caused by Retinal and Lateral Geniculate Nucleus Infarction in H1N1 Influenza Dane A. Breker, MD, Andrew W. Stacey, MS, MD, Ashok Srinivasan, MBBS, MD, Lulu L. C. D. Bursztyn, MSc, MD, Jonathan D. Trobe, MD, Mark W. Johnson, MD Abstract: A 13-year-old girl developed encephalopathy and severe bilateral vision loss to the level of light perception within 24 hours of having fever and myalgias heralding H1N1 influenza A. Ophthalmoscopy demonstrated findings of con-fluent ischemic retinopathy. Brain MRI disclosed lateral geniculate body signal abnormalities indicative of hemor-rhagic infarction. Despite aggressive treatment with intrave-nous corticosteroids, intravenous immunoglobulin, and plasmapheresis, vision did not substantially improve. This case demonstrates that H1N1 can cause simultaneous retinal and lateral geniculate body infarctions, a combination of findings not previously described in any condition. We postulate an immunologic response to the virus marked by occlusive damage to arteriolar endothelium. Journal of Neuro-Ophthalmology 2015;35:265-269 doi: 10.1097/WNO.0000000000000247 © 2015 by North American Neuro-Ophthalmology Society Influenza virus has been reported to cause a variety of neurologic and ophthalmologic problems (1, 2). We report a unique case of bilateral, irreversible, severe vision loss resulting from combined retinal and lateral geniculate nucleus (LGN) infarctions, believed to be an immunologic response to the virus. CASE REPORT A previously healthy 13-year-old girl was admitted to hospital with fever and myalgia, followed 1 day later by lethargy and vision loss. Medical history was significant for acne, for which she had been treated with doxycycline 40 mg/d intermittently starting 2 months before symptom onset. She had not received H1N1 vaccination. In the emergency department, the patient was difficult to arouse. Within 24 hours of onset, arousal level spontaneously returned to normal, but ophthalmologic examination disclosed light perception vision in both eyes and bilateral retinal ischemic whitening. Polymerase chain reaction testing was positive for influenza A H1N1 on secretions from a nasal swab. She was treated with oseltamivir, intravenous methylprednis-olone 1000 mg, and intravenous immunoglobulin 2 g/kg for a diagnosis of presumed influenza-related encephalitis. On transfer to our hospital 6 days later, she still had light perception vision in both eyes. Pupils measured 7 mm in dim illumination and constricted to light stimuli. The rest of the ophthalmic examination was normal except that ophthalmoscopy in both eyes revealed nearly confluent and sharp-bordered ischemic retinal white patches (Fig. 1). Optical coherence tomography demonstrated inner retinal thickening and hyperreflectivity in both eyes. The outer retinal layers were relatively spared (Fig. 2). Fluores-cein angiography showed multifocal arteriolar occlusions posteriorly with minimal late leakage and no retinal vascular abnormalities in the periphery (Fig. 3). The retinal abnormalities did not account for the severity of vision loss. Brain magnetic resonance imaging (MRI), performed 2 days after the complaint of vision loss, demonstrated symmetric T2 hyperintensities on fluid attenuated inversion recovery (FLAIR) images in the region of both LGNs and in the cerebellar vermis and dorsal midbrain. On a follow-up study performed 7 days after symptom onset, T2 gradient echo images showed hypointensities with blooming in the LGNs, indicative of hemorrhage. These lesions showed restricted diffusion, Department of Ophthalmology and Visual Sciences (DAB, AWS, LLCDB, JDT, MWJ), University of Michigan Kellogg Eye Center, Ann Arbor, Michigan; Division of (Neuroradiology), Department of Radiology (AS), University of Michigan, Ann Arbor, Michigan; and Department of Neurology (JDT), University of Michigan, Ann Arbor, Michigan. The authors report no conflicts of interest. Address correspondence to Jonathan D. Trobe, MD, University of Michigan Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, 1000 Wall Street, Ann Arbor, MI 48105; E-mail: jdtrobe@med.umich.edu Breker et al: J Neuro-Ophthalmol 2015; 35: 265-269 265 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. confirming ischemia. None showed contrast enhance-ment (Fig. 4). The patient was diagnosed with bilateral retinal and LGN infarctions attributed to an immune response to the H1N1 influenza virus. After 5 plasmapheresis treatments administered over 10 days, retinal whitening began to fade and the inner retinal thickening diminished. On ex-amination 60 days after onset, visual acuity had improved minimally to finger counting in a small sliver of inferior visual field in each eye. Pupillary constriction to light remained brisk bilaterally. The optic discs were pale, and the retinal whitening disappeared. Repeat MRI 75 days from symptom onset showed resolution of FLAIR signal changes and the expected evolution of the LGN hemorrhages. DISCUSSION Our patient manifested confluent ischemic retinal whiten-ing with discrete margins in the posterior retina of both eyes resembling Purtscher retinopathy (3). But as dramatic as these retinal findings were, they did not account for the profound vision loss, which likely resulted from bilateral LGN infarctions. The brisk pupillary responses were the key finding that the cause of vision loss was more posterior in the visual pathways. Furthermore, the peripheral retinal perfusion was intact, which should have permitted at least count fingers vision. This extent of retinal and LGB infarction has not been previously reported in H1N1 disease (4-6) or in any other condition. Two previous cases (7, 8) of nonconfluent cotton FIG. 1. There is near-confluent ischemic retinal whitening with several small retinal hemorrhages in the right (A) and left (B) eyes. FIG. 2. Optical coherence tomography. The right eye (A) and left eye (B) demonstrate inner retinal hyperreflectivity and inner greater than outer retinal thickening. There also are small pockets of subfoveal fluid. 266 Breker et al: J Neuro-Ophthalmol 2015; 35: 265-269 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. wool spots in H1N1 may have represented milder versions of ischemic retinopathy. In the first patient, visual acuity normalized over several months (7); in the second patient, bilateral peripapillary cotton wool spots resolved over 3 weeks (8). Although isolated LGN infarction has not been reported in H1N1 influenza, bilateral panthalamic lesions have been described in 9 patients (1, 4, 6, 9-14). However, in none of those cases was the LGN infarcted without involving the rest of the thalamus, and in no case was vision loss or retinal infarction described. Rather, thalamic infarction was usually associated with infarction of the brainstem, cerebellum, and cerebral white matter. When LGN infarction has occurred selectively, the setting has been systemic hypotension, extrap-ontine myelinolysis, preeclampsia/eclampsia, posterior revers-ible encephalopathy syndrome, microangiopathy, diarrheal illness, and syphilitic vasculitis (15, 16). Why should the retina and LGN have been selectively targeted for infarction? In acute necrotizing encephalopathy (ANE), an influenza-related condition in which hemor-rhages can be seen in the deep gray matter, the pathogenesis is based on breakdown of the blood-brain barrier through cytokine storm in response to virus exposure, akin to the mechanism proposed for Purtscher retinopathy (9, 10, 17). The excessive cytokine response may be mediated by the patient's genotype, as patients with point mutations of the nuclear pore gene RANBP2 (Ran-binding protein 2) are predisposed to the development of ANE (17, 18). RANBP2 is highly expressed in metabolically neural tissue, including the photoreceptors (17). A shared autoantibody target could also explain the exclusive involvement of the retina and LGB in our patient. A patient with ANE showed antibodies directed against Ephrin type B receptor 2 (EphB2), a protein found in neurons and vascular endothelium, which has various functions including angiogenesis, neural develop-ment, and neuroplasticity (19). EphB2 is also expressed in the retina, where it helps guide the developing retinal gan-glion cell axons to form the optic nerve (20). In 2013, the H1N1 virus was included in the United States' quadrivalent influenza vaccine, which our patient had not received. A Japanese study suggested that mass immunization decreases pediatric mortality rates from influ-enza infection with central nervous system signs including influenza A encephalopathy (21), but there are no studies regarding the value of vaccination in prevention of central nervous system morbidity. A novel example of severe FIG. 3. Retinal fluorescein angiogram shows occlusion of multiple small posterior arterioles in both eyes with minimal late vascular leakage. A. arterial phase, left eye; (B) arteriovenous phase of the left eye; (C) late phase, left eye; (D) late phase, right eye. Breker et al: J Neuro-Ophthalmol 2015; 35: 265-269 267 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. H1N1-related morbidity, our case should entice physicians to encourage vaccination of their patients. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: D. A. Breker, A. W. Stacey, A. Srinivasan, L. L. C. D. Bursztyn, J. D. Trobe, and M. W. Johnson; b. Acquisition of data: D. A. Breker, A. W. Stacey, A. Srinivasan, L. L. C. D. Bursztyn, J. D. Trobe, and M. W. Johnson; c. Analysis and interpretation of data: D. A. Breker, A. W. Stacey, A. Srinivasan, L. L. C. D. Bursztyn, J. D. Trobe, and M. W. Johnson. Category 2: a. Drafting the manuscript: D. A. Breker, A. W. Stacey, A. Srinivasan, L. L. C. D. Bursztyn, J. D. Trobe, and M. W. Johnson; b. Revising it for intellectual content: D. A. Breker, L. L. C. D. Bursztyn, and J. D. Trobe. Category 3: a. Final approval of the completed manuscript: D. A. Breker, A. W. Stacey, A. Srinivasan, L. L. C. D. Bursztyn, J. D. Trobe, and M. W. Johnson. REFERENCES 1. Ekstrand JJ. Neurologic complications of influenza. Semin Pediatr Neurol. 2012;19:96-100. 2. Khairallah M, Kahloun R. Ocular manifestations of emerging infectious diseases. Curr Opin Ophthalmol. 2013;24:574- 580. 3. Miguel AI, Henriques F, Azevedo LF, Loureiro AJ, Maberley DA. Systematic review of Purtscher's and Purtscher-like retinopathies. Eye (Lond). 2013;27:1-13. 4. Zhao C, Gan Y, Sun J. Radiographic study of severe Influenza-A (H1N1) disease in children. Eur J Radiol. 2011;79:447-451. 5. Haktanir A. MR imaging in novel influenza A(H1N1)-associated meningoencephalitis. 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