SARS-CoV-2 Impairs Vision

Disease of the Year: COVID-19 Section Editors: Bart Chwalisz, MD Marc J. Dinkin, MD SARS-CoV-2 Impairs Vision Josef Finsterer, MD, PhD, Fulvio A. Scorza, MD, Carla A. Scorza, MD, Ana C. Fiorini, MD Objectives: Affection of the central nervous system and the eyes is increasingly recognized as manifestations of a SARS-CoV-2 infection (COVID-19). This review aims at summarizing and discussing recent advances concerning causes and locations of impaired vision because of an infection with SARS-CoV-2. Methods: On a literature search through PubMed and ScholarOne, all available publications about COVID-19 patients with impaired vision were retrieved. Results: Visual impairment in SARS-CoV-2–infected patients may be due to infection of lacrimal glands (dacryoadenitis), conjunctivitis, tonic pupils, vitritis, central retinal artery/venous occlusion, retinitis, retinal bleeding, panuveitis, anterior ischemic optic neuropathy, optic nerve stroke, optic neuritis, optic perineuritis, or occipital ischemic stroke. Visual impairment may be the initial manifestation of SARS-CoV-2. Conclusions: This mini review shows that impaired vision may be the initial manifestation of COVID-19, that all sections of the visual tract may be affected and causative for visual impairment in COVID-19 patients, and that SARS-CoV2 manifests along the visual tract with ischemia, focal infection, and immunological reactions. Journal of Neuro-Ophthalmology 2021;41:166–169 doi: 10.1097/WNO.0000000000001273 © 2021 by North American Neuro-Ophthalmology Society W ith ongoing duration of the SARS-CoV-2 pandemic, increasing evidence accumulated that infected patients not only manifest in the lungs but also in other organs, either already as onset manifestation (Finsterer, sub- Klinik Landstrasse (JF), Messerli Institute, Vienna, Austria; Disciplina de Neurociência (FAS, CASC), Universidade Federal de São Paulo/ Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, Brazil; Programa de Estudos Pós-Graduado em Fonoaudiologia (ACF), Pontifícia Universidade Católica de São Paulo (PUC-SP), São Paulo, Brazil; and Departamento de Fonoaudiologia (ACF), Escola Paulista de Medicina/Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil. The authors report no conflicts of interest. Informed consent was obtained. Ethics approval: The study was approved by the institutional review board. Address correspondence to Josef Finsterer, MD, PhD, Neurological Department, Postfach 20, 1180 Vienna, Austria; E-mail: fifi[e-mail] 166 mitted) or later during the disease course (1). Extrapulmonary manifestations in the central nervous system (CNS) or the eyes (including the extraocular muscles) may lead to transient or permanent impaired vision in 1 or both eyes (2). This review aims at summarizing and discussing recent advances in the clinical presentation, pathophysiology, diagnosis, treatment, and outcome of SARS-CoV-2–associated impaired vision. METHODS A literature review in the databases PubMed and Google Scholar using the search terms “optic nerve,” “optic tract,” “chiasm,” “visual radiation,” “visual cortex,” “visual field,” “double vision,” and “occipital lobe,” together with “SARSCoV-2,” “COVID-19,” and “coronavirus” was conducted. In addition, reference lists were checked for further articles meeting the search criteria. Excluded were articles in languages other than English, French, Spanish, Italian, or German. RESULTS Current data provide evidence that vision in SARS-CoV-2– infected patient can be impaired at several levels (Table 1) (3–23). Ocular causes of impaired vision were more frequent than CNS causes (Table 1). However, if the retina and the optic nerve were regarded as part of the CNS, CNS abnormalities were more frequently responsible for impaired vision in COVID-19 patients. Neuroophthalmologic causes of visual impairment detected included dacryoadenitis, conjunctivitis, tonic pupils, myasthenia, vitritis, central retinal artery occlusion/central retinal venous occlusion (CRAO/CRVO), retinitis, retinal ganglion cell dysfunction, retinal bleeding, panuveitis, anterior, ischemic optic neuropathy (AION), optic nerve stroke, optic neuritis, optic perineuritis, ischemic stroke, sinus venous thrombosis (SVT), and posterior reversible encephalopathy syndrome (3–23). Thus, impaired vision due to SARS-CoV-2 is multicausal and multilocular. Dacryoadenitis has been only reported in a single patient (3). Conjunctivitis, on the contrary, has been much more Finsterer et al: J Neuro-Ophthalmol 2021; 41: 166-169 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: COVID-19 TABLE 1. Causes of visual impairment in COVID-19 patients Disorder Dacryoadenitis Follicular conjunctivitis Tonic pupil Myasthenia Vitritis CRAO Retinitis RGC and IPL lesion Retinal bleeding CRVO Panuveitis AION Optic nerve stroke Optic neuritis Optic perineuritis Blurring Balint–Holmes syndrome Occipital stroke SVT Palinopsia Structure Lat Pathophysiology Imaging Reference Lacrimal gland Conjunctiva Pupils EOM Vitreous body Retina Retina Retina Retina Retina Uvea Optic nerve Optic nerve Optic nerve Optic nerve nr Parieto-occipital Occipital lobe Cerebral veins Brain ul ul ul? ul, bl ul ul ul ul bl ul ul ul ul uk/bl ul bl bl bl bl bl Viral infection and IR Viral infection IR Autoantibodies Viral infection ED and HCG Retinal ischemia Capillary ischemia HCG Coagulopathy Endothelial damage HCG and ED Coagulopathy CKS nr nr Cerebral vasculopathy HCG Increased ICP Hypertension Clinical examination nr nr Normal nr OCT and retinal thinning Funduscopy Hyperreflexia on SS-OCT Fluorescein angiography Funduscopy and OCT Optic disc swelling Thickened RNFL MRI Optic nerve enhancement nr nr Ischemic stroke on MRI Ischemic stroke on CCT SVT PRES 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 AION, anterior ischemic optic neuropathy; bl, bilateral; CCT, cerebral computed tomography; CKS, cytokine storm; CRAO, central retinal artery occlusion; CRVO, central retinal vein occlusion; ED, endothelial damage; EOM, extraocular muscles; HCG, hypercoagulability; ICP, intracranial pressure; IPL, inner plexiform layer; IR, immune reaction; Lat, laterality; PRES, posterior reversible encephalopathy syndrome; RGC, retinal ganglion cell; RNFL, retinal nerve fiber layer; SVT, sinus venous thrombosis, ul: unilateral. frequently reported as a complication of COVID-19 and is probably the most frequent ophthalmologic complication of COVID-19 (4). Since myasthenia exacerbates in about half of the patients with a SARS-CoV-2 infection, it is comprehensible that double vision or blurred vision may evolve (6). Vitritis as a complication of COVID-19 has been reported in only 2 patients so far (7,23). Retinal abnormalities such as retinitis, CRAO/CRVO, or retinal bleeding are also rare complications of COVID19 (Table 1) (8,12). CRAO/CRVO is attributed to hypercoagulability frequently complicating COVID-19. Retinal bleeding may be due to hypertension, overanticoagulation, or hypocoagulability (11). Affection of the optic nerve is increasingly recognized as a complication of COVID-19. Most prevalent among the optic nerve affections is optic neuritis. Optic neuritis may occur unilaterally (13) or bilaterally (16). The optic nerve may be the only cranial nerve affected (16), or it may be damaged together with other cranial nerves (24). Although single or multiple cranial nerve involvement is frequent in Guillain–Barre syndrome (GBS) (Finsterer, submitted), affection of the optic nerve has not been reported in patients with SARS-CoV-2–associated GBS (Finsterer, submitted). Rarely, AION or ischemic stroke of the optic nerve has been reported as complications of COVID-19 (Table 1). Cerebral disease is increasingly recognized as a complication of COVID-19 and may occasionally impair vision in the form of double vision, hemianopia, or visual loss. Cyr Finsterer et al: J Neuro-Ophthalmol 2021; 41: 166-169 et al (20) described a 61yo SARS-CoV-2–infected man with diabetes, who presented with bilateral visual loss 7 days after onset of the viral infection. Since ophthalmologic investigations did not explain visual dysfunction, cerebral computed tomography was performed revealing bilateral occipital ischemic stroke (20). A 34yo SARS-CoV-2– infected woman with lupus erythematosus, hypertension, and renal insufficiency requiring hemodialysis experienced sudden painless bilateral visual loss 10 days after admission (20). Cerebral MRI revealed acute ischemic stroke in the right middle and left posterior cerebral artery territories and chronic stroke in the right posterior cerebral artery territory (20). Visual impairment in SVT is due to papilledema secondary to raised intracranial pressure, direct ischemic injury of intracranial visual pathways, or direct injury to cranial nerves responsible for ocular motility and pupillary function (21). Papilledema is found in 28%, visual loss in 13%, and diplopia in 13% of the patients with SARS-CoV2–associated SVT (21). Although conceivable, a recent study failed to demonstrate impaired perfusion of the radial peripapillary capillary plexus (25). In a case series of 4 HIV-positive patients who got superinfected with SARS-CoV-2, 1 experienced retinal detachment 1 month after discharge from hospital (26). Since a causal relation between COVID-19 and the retinal detachment could not unequivocally documented, this patient was not included in the current evaluation (26). 167 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: COVID-19 Visual impairment may not only develop after onset of pulmonary or extrapulmonary COVID-19 but may be the initial manifestation of the infection. Visual impairment as the initial manifestation of the infection has been reported in patients with conjunctivitis (27), panuveitis (13), and optic neuritis (13). Whether anti-COVID drugs applied to handle the infection may impair vision is so far unknown. DISCUSSION This review shows that visual impairment in SARS-CoV-2– infected patients is multicausal and multilocular. Visual impairment may be due to infection of lacrimal glands (dacryoadenitis) (3), tonic pupils (5), vitritis (7), CRAO (8), retinitis (9), retinal capillary ischemia (10), retinal bleeding (11), panuveitis (13), anterior ischemic optic neuropathy (14), optic nerve stroke (15), optic neuritis (16), optic perineuritis (17), or occipital ischemic stroke (20). Thus, visual impairment may originate from all possible locations of the optic tract but particularly from affection of the retina and the optic nerve. Pathophysiologically, visual impairment may be due to infection, ischemia, or immunological response. Visual impairment may occur even in the absence of classical pulmonary manifestations of a SARS-CoV-2 infection (13,27). Thus, patients complaining about impaired vision should be taken serious and investigated also for SARS-CoV-2. The pathophysiology of optic nerve involvement remains elusive, but it can be speculated that it results from intracellular uptake of the virus into neurons at a distal location with consecutive retrograde transport of the virus particles to the brain. An argument for this hypothesis is that in an autopsy study of 43 patients deceased from COVID-19, SARS-CoV-2 viral proteins were detected in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem (28). Furthermore, virus particles have been repeatedly found in neurons but also axons of cranial nerves in other autopsy studies (29). Experimental studies indicate that SARS-CoV-2 indeed migrates retrogradually within axons of cranial nerves to the CNS (30). In conclusion, this review shows that impaired vision may be the initial manifestation of COVID-19, that all sections of the visual tract may be affected, and that SARSCoV-2 manifests along the visual tract with ischemia, infection, and immunological reactions. Author Contributions: J. Finsterer: design, literature search, discussion, first draft, and critical comments. F. A. Scorza, C. A. S. CA, and A. C. Fiorini: literature search, discussion, critical comments, and final approval. REFERENCES 1. Javed A. Neurological associations of SARS-CoV-2 infection: a systematic review. CNS Neurol Disord Drug Targets. 2021. doi: 10.2174/1871527320666210216121211. 168 2. Luís ME, Hipólito-Fernandes D, Mota C, Maleita D, Xavier C, Maio T, Cunha JP, Tavares Ferreira J. A review of neuroophthalmological manifestations of human coronavirus infection. Eye Brain. 2020;12:129–137. 3. Martínez Díaz M, Copete Piqueras S, Blanco Marchite C, Vahdani K. Acute dacryoadenitis in a patient with SARS-CoV-2 infection. Orbit. 2021:1–4. doi: 10.1080/ 01676830.2020.1867193. 4. Lim LW, Tan GS, Yong V, Anderson DE, Lye DC, Young B, Agrawal R. Acute onset of bilateral follicular conjunctivitis in two patients with confirmed SARS-CoV-2 infections. Ocul Immunol Inflamm. 2020;28:1280–1284. 5. Gopal M, Ambika S, Padmalakshmi K. Tonic pupil following COVID 19. J Neuroophthalmol. 2021. doi: 10.1097/ WNO.0000000000001221. 6. Martin Paez Y, Bennett JL, Subramanian PS, Pelak VS. Considerations for the treatment of inflammatory neuroophthalmologic disorders during the COVID-19 pandemic. J Neuroophthalmol. 2020;40:305–314. 7. Gupta A, Dixit B, Stamoulas K, Akshikar R. Atypical bilateral acute retinal necrosis in a coronavirus disease 2019 positive immunosuppressed patient. Eur J Ophthalmol. 2020. 8. Montesel A, Bucolo C, Mouvet V, Moret E, Eandi CM. Case report: central retinal artery occlusion in a COVID-19 patient. Front Pharmacol. 2020;11:588384. 9. Liu L, Cai D, Huang X, Shen Y. COVID-2019 associated with acquired monocular blindness. Curr Eye Res. 2021:1–4. doi: 10.1080/02713683.2021.1874027. 10. Ortiz-Egea JM, Ruiz-Medrano J, Ruiz-Moreno JM. Retinal imaging study diagnoses in COVID-19: a case report. J Med Case Rep. 2021;15:15. 11. Monferrer-Adsuara C, Castro-Navarro V, González-Girón N, Remolí-Sargues L, Ortiz-Salvador M, Montero-Hernández J, Cervera-Taulet E. A case of bilateral unusual retinal hemorrhages in a COVID-19 patient. Eur J Ophthalmol. 2020:1120672120984381. doi: 10.1177/ 1120672120984381. 12. Walinjkar JA, Makhija SC, Sharma HR, Morekar SR, Natarajan S. Central retinal vein occlusion with COVID-19 infection as the presumptive etiology. Indian J Ophthalmol. 2020;68:2572– 2574. 13. Benito-Pascual B, Gegúndez JA, Díaz-Valle D, Arriola-Villalobos P, Carreño E, Culebras E, Rodríguez-Avial I, Benitez-Del-Castillo JM. Panuveitis and optic neuritis as a possible initial presentation of the novel coronavirus disease 2019 (COVID19). Ocul Immunol Inflamm. 2020;28:922–925. 14. Rho J, Dryden SC, McGuffey CD, Fowler BT, Fleming J. A case of non-arteritic anterior ischemic optic neuropathy with COVID19. Cureus. 2020;12:e11950. 15. Tavakoli M, Sotoudeh H, Rezaei A, Saadatpour Z, Vaphides MS, Kline LB. Optic nerve infarction in a patient with coronavirus disease 2019. J Neuroophthalmol. 2021. doi: 10.1097/WNO.0000000000001232. 16. Sawalha K, Adeodokun S, Kamoga GR. COVID-19-Induced acute bilateral optic neuritis. J Investig Med High Impact Case Rep. 2020;8:2324709620976018. 17. Dinkin M, Feinberg E, Oliveira C, Tsai J. Orbital inflammation with optic perineuritis in association with COVID-19. J Neuroophthalmol. 2021. doi: 10.1097/ WNO.0000000000001229. 18. Avener C, Gomez R, Williams T. Case report: need for vigilance in recognizing neurologic presentations of COVID-19. Am Fam Physician. 2020;102:645. 19. Panico F, Arini A, Cantone P, Crisci C, Trojano L. BalintHolmes syndrome due to stroke following SARS-CoV-2 infection: a single-case report. Neurol Sci. 2020;41:3487– 3489. 20. Cyr DG, Vicidomini CM, Siu NY, Elmann SE. Severe bilateral vision loss in 2 patients with coronavirus disease 2019. J Neuroophthalmol. 2020;40:403–405. 21. Medicherla CB, Pauley RA, de Havenon A, Yaghi S, Ishida K, Torres JL. Cerebral venous sinus thrombosis in the COVID-19 pandemic. J Neuroophthalmol. 2020;40:457–462. Finsterer et al: J Neuro-Ophthalmol 2021; 41: 166-169 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: COVID-19 22. Ghosh R, Lahiri D, Dubey S, Ray BK, Benito-León J. Hallucinatory palinopsia in COVID-19-induced posterior reversible encephalopathy syndrome. J Neuroophthalmol. 2020;40:523–526. 23. Zago Filho LA, Lima LH, Melo GB, Zett C, Farah ME. Vitritis and outer retinal abnormalities in a patient with COVID-19. Ocul Immunol Inflamm. 2020;28:1298–1300. 24. Raharimanantsoa OL, Razakarivony FA, Andriamiadanalisoa AO, Rajaona RA, Rakotoarisoa R, Randrianarimanana SER, Raobela L. Multinévrite oculaire dans le cadre d’une infection COVID-19 [Multiple infectious cranial nerve palsies in COVID19] [In French]. J Fr Ophtalmol. 2020;43:e351–e353. 25. Savastano A, Crincoli E, Savastano MC, Younis S, Gambini G, De Vico U, Cozzupoli GM, Culiersi C, Rizzo S. Gemelli against covid-postacute care study group. Peripapillary retinal vascular involvement in early post-COVID-19 patients. J Clin Med. 2020;9:2895. 26. Turken M, Altan H, Atalay S, Kose S. The course of COVID-19 in four patients with HIV during the pandemic. Curr HIV Res. 2020. doi: 10.2174/1570162X18666201201093540. Finsterer et al: J Neuro-Ophthalmol 2021; 41: 166-169 27. Ozturker ZK. Conjunctivitis as sole symptom of COVID-19: a case report and review of literature. Eur J Ophthalmol. 2020:1120672120946287. doi: 10.1177/ 1120672120946287. 28. Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, Fitzek A, Allweiss L, Dandri M, Dottermusch M, Heinemann A, Pfefferle S, Schwabenland M, Sumner Magruder D, Bonn S, Prinz M, Gerloff C, Püschel K, Krasemann S, Aepfelbacher M, Glatzel M. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19:919–929. 29. Bulfamante G, Chiumello D, Canevini MP, Priori A, Mazzanti M, Centanni S, Felisati G. First ultrastructural autoptic findings of SARS -Cov-2 in olfactory pathways and brainstem. Minerva Anestesiol. 2020;86:678–679. 30. Baig AM. Covert pathways to the cranial cavity: could these Be potential routes of SARS-CoV-2 to the brain? ACS Chem Neurosci. 2020;11:3185–3187. 169 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.