SARS-CoV-2 Infection, Vaccination, and Neuro-Ophthalmic Complications

One microscopic agent, SARS-CoV-2, a novel single-stranded RNA beta coronavirus caused COVID-19-a novel illness for which humanity was not ready. Although the main challenge was to our immune systems, it also challenged our knowledge of immunology as well as humans' patterns of thinking and decision making in the face of new information and regulations. Although the; antivaccination movement had been gaining popularity since the work of the British ex-physician Andrew Whitfield, the MMR vaccine (measles, mumps, and rubella) had an acceptance rate of 90.8% in 2019 (1). By contrast, as of August 15, 2022, COVID-19 full vaccination rate is still 71.5% for people older than 5 years (2).

Editorial SARS-CoV-2 Infection, Vaccination, and NeuroOphthalmic Complications Pareena Chaitanuwong, MD, Heather E. Moss, MD, PhD, Mays A. El Dairi, MD O ne microscopic agent, SARS-CoV-2, a novel single-stranded RNA beta coronavirus caused COVID-19—a novel illness for which humanity was not ready. Although the main challenge was to our immune systems, it also challenged our knowledge of immunology as well as humans’ patterns of thinking and decision making in the face of new information and regulations. Although the antivaccination movement had been gaining popularity since the work of the British ex-physician Andrew Whitfield, the MMR vaccine (measles, mumps, and rubella) had an acceptance rate of 90.8% in 2019 (1). By contrast, as of August 15, 2022, COVID-19 full vaccination rate is still 71.5% for people older than 5 years (2). Causes for vaccine hesitancy include misinformation, distrust in published efficacy, fear of side effects, and lack of concern from the virus itself. The media also contributes to this hesitancy by highlighting the side effects of the vaccine. Our literature is becoming richer in case reports and case series of both different presentations of COVID-19 infection and different presentations with complaints postvaccination. To date, there has not been a good comparison of the outcomes of each manifestation to determine whether it was caused by the infection or the vaccine. Both COVID-19 infection and vaccination (virtually all available formulations) have been associated with different ocular manifestations. Below is a summary of what has been reported. ANTERIOR SEGMENT Conjunctivitis is the most common ocular manifestation of COVID-19 infection. It has been reported to cause follicular conjunctivitis (with or without systemic symptoms), hemorrhagic conjunctivitis, pseudo membrane formation, as well as nonremitting conjunctivitis and Kawasaki disease in children (3). Other anterior segment manifestations include pseudo-dendrite formation, anterior scleritis (4) (including a case of necrotizing scleritis has been described with one case necessitating systemic treatment with cyclophosphamide), and anterior uveitis including reactivation of an old quiescent uveitis. Postvaccine, there are reports of isolated eye redness and pain (5), anterior uveitis, and scleritis. These were more likely to occur after the first vaccine dose and in patients who had a history of similar prior event (6). In patients after partial or full-thickness corneal, limbal cell, or conjunctival transplant, graft vs host disease has been reported, some with severe complications of corneal melting and perforation after vaccination (7). The duration of treatment, time for recovery, and final visual outcomes are not well summarized for cases with infection nor with vaccines. RETINA AND CHOROID There have been reports of both retinal vein and/or retinal artery occlusions in patients without classic systemic vascular risk factors (8–11). Ophthalmology Department (PC), Rajavithi Hospital, Ministry of Public Health, Bangkok, Thailand; Department of Ophthalmology (PC), Faculty of Medicine, Rangsit University, Bangkok, Thailand; Department of Ophthalmology (HM) and Neurology and Neurological Sciences (HM), Stanford University School of Medicine, Palo Alto, California; and Department of Ophthalmology (MED), Duke University, Durham, North Carolina. Supported by NIH P30 026877, unrestricted grant from research to prevent blindness. The authors report no conflicts of interest. Address correspondence to Heather Moss, MD, Spencer Center for Vision Research, 2370 Watson Court, Palo Alto, CA 94303; E-mail: hemoss@ stanford.edu Chaitanuwong et al: J Neuro-Ophthalmol 2023; 43: 1-4 1 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Editorial Other retinal pathologies reported include acute macular neuroretinopathy and paracentral acute middle maculopathy (12), Purtscher-like retinopathy, posterior uveitis (including multifocal, serpiginous, and ampiginous choroiditis), retinal vessels tortuosity, microhemorrhages, cotton wool spots, and acute retinal necrosis (13,14). Again, the duration of treatment, time for recovery, and final visual outcomes are not well summarized for cases with infection nor with vaccines. OPTIC NERVE Optic neuritis has been reported after both infection and vaccine including cases presenting with neuromyelitis optica spectrum disorder and seropositivity to antiaquaporin 4 or antimyelin oligodendrocyte glycoprotein antibodies (15,16), or multiple sclerosis (17,18). Papilledema has been described in the setting of elevated intracranial pressure (ICP) secondary to widespread inflammatory, aseptic meningitis, or dural venous sinus thrombosis (19–21). Multisystem inflammatory syndrome in children (MIS-C) due to COVID-19 can have manifestations similar to Kawasaki disease and can cause papilledema and optic neuropathy as well. MIS-C has also been reported postvaccination albeit more rarely (22). EYE MOVEMENTS Both COVID-19 infection and COVID-19 vaccine have been associated with diplopia with ophthalmoplegia with or without ptosis. Some reports described an ocular motor cranial nerve palsy with or without cranial nerve enhancement on MRI, as well as in association with Miller Fisher/ Guillain–Barré syndromes and myasthenia gravis with and without seropositivity. Brown syndrome (23), ocular inflammatory syndrome, and Tolosa–Hunt syndrome have also been reported (24–29). A good number of the cases described (including the myasthenia) have been transient; however, no head-to-head comparison of symptom duration or final outcomes are available. Nystagmus and vertigo caused by vestibular neuritis, or central vestibular nystagmus have also been described in both COVID-19 infection and postvaccination (30,31). Parainfectious opsoclonus myoclonus syndrome has been reported post–COVID-19 (32) but not postvaccine. Internal Ophthalmoplegia Both tonic pupils with mydriasis and accommodation deficiency were reported post–COVID-19. Poor pupillary light responses have been described in patients with long-haul COVID-19 (33). This has not been described postvaccination. 2 VISUAL CORTEX Acute strokes affecting the posterior visual pathways have been reported extensively post–COVID-19 infection, occurring in a population that is younger with less risk factors, including in pediatric patients (34). There have been case reports describing ischemic strokes post–COVID19 vaccination in the setting of vaccine-induced immune thrombotic thrombocytopenia (35); however, without the immune complication, the rate of ischemic strokes in vaccinated patients is similar to those who were not vaccinated (36). LACRIMAL SYSTEM/ORBITS Dacryoadenitis has been reported after both COVID-19 infection (37) and the vaccine (38). Similarly, orbital myositis has been reported in both (28,39). An increased rate of infectious orbital cellulitis including mucormycosis has been reported to occur at a higher rate post–COVID-19 infection (3), which is believed to be due to increased respiratory congestion and/or the thriving of opportunistic infections in the hypoxic environment induced by COVID-19 infection. This is not reported postvaccination. ESTABLISHING CAUSALITY As reviewed, most of the literature on the neuro-ophthalmic complications associated with COVID-19 infection and vaccination consists of case series or case reports. Although these study designs are hypothesis generating, they cannot establish a causal relationship between COVID-19 infection or vaccination and a neuro-ophthalmic consequence. Further support of possible causal relationship is provided by plausibility of underlying pathophysiology. For example, COVID-19 infection was reported as a cause of vascular complications (40). The proposed mechanism is production of proinflammatory cytokines, which are powerful inducers of a procoagulant or prothrombotic response, resulting in intravascular coagulopathies and endothelial damage. Based on this, a relationship between COVID-19 infection and ischemic neuro-ophthalmic events is plausible. In some cases, a temporal association can be extremely compelling (essentially invoking a historical control) as is the case for immune thrombotic thrombocytopenia after COVID-19 vaccination (41). More rigorous study designs offer the opportunity to provide additional insight into the nature of the relationship. However, there are many challenges to implementation. Randomized controlled trials offer Level I evidence for causality but are unethical for infectious agents, and the sample size used for vaccine efficacy trials is underpowered to identify rare adverse outcomes. Cohort studies where subjects are classified by exposure can be instructive, providing there is a suitable control group. Chaitanuwong et al: J Neuro-Ophthalmol 2023; 43: 1-4 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Editorial A notable example of a risk interval study is the surveillance for adverse events after COVID-19 mRNA vaccination, which includes a large number of vaccination cases from several health care institutions to increase sample size (42). Another example of informative prospective cohort studies reported correlation between COVID-19 infection and conjunctivitis in a meta-analysis of 1,167 COVID-19 infected individuals and noninfected controls (43). Retrospective designs have the challenge of establishing exposure (or lack of exposure for controls), which is straightforward for vaccine, but less so for infection. There is also a challenge in establishing an outcome, identification of which may be confounded by where care was sought and what expertise was involved. These issues were overcome by using records of a closed medical system to study the temporal association between COVID-19 infection or immunization and retinal vascular occlusion (8,44). For rare outcomes, such as many neuro-ophthalmic diseases, case– control designs are attractive because cases can be identified. The challenge is to identify appropriate controls and to accurately identify the exposure. A case–control design was used to assess the risk of having a previous COVID-19 infection in patients with multiple sclerosis (45). Both COVID-19 and COVID-19 vaccination have been reported to be temporally associated with various neuroophthalmic complications. There are no good meta-analyses evaluating the neuro-ophthalmic complications of the infection or the vaccine, but it seems that the most severe complications, namely ischemic strokes, MIS-C, and orbital infections are features of COVID-19 infection and not the vaccine. For all other complications, particularly those with an autoimmune etiology, the literature is lacking data with accurate prevalence, symptom course, and final outcomes. Opportunities in neuro-ophthalmology include multiinstitution studies with careful assessment of exposure and outcome. On a local level, we would encourage reporting suspected vaccine-associated findings to registries such as the US Vaccine Adverse Events Reporting System and to rigorously apply and report complications in validated adverse drug reaction criteria such as the Naranjo scale (46). REFERENCES 1. Statistics NCfH. Vaccination Coverage for Selected Diseases by Age 24 Months, by Race and Hispanic Origin, Poverty Level, and Location of Residence: United States, Birth Years 2010-2015. United states, 2019. Available at: https://www. cdc.gov/nchs/data/hus/2019/031-508.pdf. Accessed December 22, 2022. 2. National Center for Immunization and Respiratory Diseases (NCIRD) DoVD. COVID-19 Vaccination Data in the United States, 2022. Available at: https://covid.cdc.gov/covid-datatracker/#vaccinations_vacc-people-additional-dose-totalpop. Accessed December 22, 2022. 3. 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