Optic Neuritis Following COVID-19 Vaccination: Real-World Ophthalmic Presentation

Abstract

After being plagued by COVID-19 for nearly 2 years, the whole world wishes for little more than the complete eradication of the disease. Our country, India commenced the much-awaited vaccination drive in Jan 2021. Ophthalmic manifestations have appeared in many forms post-COVID, amongst which neuro-ophthalmic manifestations are infrequent. This is a short series of three cases that presented with optic neuritis (ON). On further inquiry, all had received the Covishield vaccine within 5–12 days before the presentation, with no history of COVID-positive RT-PCR. All patients improved after pulse steroid therapy and are still under follow-up. Nevertheless, it’s hard to determine whether post-COVD vaccine ON is a coincidence or cause. This series highlights the importance of taking the history of recent vaccination, especially in patients presenting with ON in the COVID 19 pandemic era.

1. Introduction

Optic neuritis, a predominantly clinical entity that is typically characterized by a diminution of vision, loss of color vision, and painful eye movement, is an uncommon but serious consequence following vaccination. Vaccinations contributed to the eradication of many infectious diseases like smallpox, poliomyelitis, and measles in world history. Neurological events following vaccination such as seizures, encephalopathy, or GBS [1, 2], are not unheard of, with the earliest reports dating back to the late 19th century, following the development of neuroparalytic syndrome after Pasteur’s rabies immunization [3]. The rapid development and availability of vaccination, ahead of an anticipated timetable, for relief from the COVID-19 pandemic, was an unprecedented and monumental accomplishment, which, consequently left the prospect and question of long-term safety open and ambiguous. A meta-analysis of five randomized, double-blind, placebo-controlled trials of COVID-19 vaccine candidates noted that local and systemic adverse events reported were all mild to moderate and transient in nature [4]. Therefore, reporting an untoward outcome following vaccination is paramount to establishing a safety threshold for widespread public usage. From January 2021 onwards, India commenced the much-awaited vaccination drive. Ophthalmic manifestations have appeared in many forms post-COVID, amongst which neuro-ophthalmic manifestations are infrequent. This review article presents a short series of three cases from the real-world scenario that presented with optic neuritis (ON), post-vaccination. On further inquiry, all had received the Covishield vaccine within 5–12 days just before the presentation, with no history of RT-PCR positive COVID infection. An improvement was noted in all the patients after the pulsed intravenous methylprednisolone therapy, as per the ONTT (Optic Neuritis Treatment Trial) study, and the patients are currently under follow-up. Although it’s hard to determine whether post-COVID vaccine ON is a coincidence or cause, this series highlights the importance of taking the history of recent vaccination, especially in patients presenting with ON in the COVID 19 pandemic era. Reporting cases of adverse reactions that manifest after the vaccination is a challenging yet imperative task to allow for the sustained development and research of vaccines, which are safe and effective for public usage.

2. Case descriptions

A 27-year-old lady presented with an acute onset decrease in vision, which was progressive in nature and associated with mild peri-ocular pain, in the left eye (LE) for 5 days. She did not give a history of diabetes or hypertension. On examination, the best-corrected visual acuity (BCVA) was found to be 20/20 in the right eye (RE) and 20/200 in the LE, along with RAPD and color desaturation (3 out of 21 plates on the Ishihara chart) in the LE. Fundoscopy of the LE revealed a diffusely swollen optic nerve head (Figure 1a). Visual field examination with automated perimetry (AP) showed an enlarged blind spot (Figure 1b). On further probing, it was revealed that 9 days before the presentation, she had received her first dose of the Covishield vaccine. MRI of the brain and orbits (T2) revealed an enhancement of the left optic nerve head just behind the disc (Figure 1c). VEP showed a flat wave in the LE compared to the RE (Figure 1d) which led to a diagnosis of optic neuritis (ON) in the LE, for which a neurologist’s opinion was sought. Hematological examination showed normal limits of ESR and CRP, and antibody titer (Ab): ANA, ANCA, MOG, NMO (Aquaporin4) was negative. The patient was administered intravenous methylprednisolone pulse therapy for 3 days, followed by an oral steroid, following which, there was an improvement in BCVA to 20/40 in LE and the fundus revealed a reduction in the swelling of the optic nerve head (Figure 1e).

Figure 1.

(a) Fundus showing swollen optic disc with blurred margins in LE. (b) AP showing enlarged blind spot. (c) MRI brain and orbit showing enhancement of the left optic nerve. (d) VEP showing flat waves in LE. (e) Fundus picture showing reduced swelling of the disc on follow-up.

A 48-year-old Indian woman came to the hospital with gradual and painless diminution of vision in the LE, for 3 days. Examination revealed a BCVA of 20/30 in the RE and 20/80 in LE, along with RAPD. On dilated fundoscopy, a swollen optic disc with blurred margins was discovered (Figure 2a). An OCT was done, which revealed peri-papillary swelling of the retina (Figure 2b). Examination of the visual fields showed an inferior arcuate defect (Figure 2c) and VEP showed delayed latency and decreased amplitude in LE (Figure 2d). On probing, it was revealed that 5 days before presentation, she had received the second dose of the Covishield vaccine. She did not have any systemic illness or history of preceding fever. A diagnosis of ON was made in LE, with indices such as ESR, CRP, MRI brain, and orbit found to be within normal limits. A neurologist’s consultation was sought and intravenous methylprednisolone pulse therapy was started. On follow-up, it was found that the BCVA had improved to 20/30 in LE and AP also showed a marked improvement (Figure 2e).

Figure 2.

(a) Fundus showing swollen optic disc with blurred margin in LE. (b) OCT showing peripapillary swelling of the retina. (c) AP revealing an arcuate defect in the inferior hemifield. (d) VEP showing delayed latency and decreased amplitude. (e) Follow-up AP showing improvement.

A 40-year-old Indian gentleman presented with a diminution of vision in both eyes (BE) which was acute in onset and was accompanied by peri-ocular pain for 7 days. Further inquiry revealed that 12 days before presentation, he had received the first dose of the Covishield vaccine. Ocular examination showed that the BCVA was 20/200 in BE. Anterior segment examination was unremarkable except for a sluggishly reacting pupil in both eyes (BE). On dilated fundoscopy, BE showed indistinct and swollen optic disc margins (Figure 3a and b). Visual field examination revealed generalized depression of the visual fields in BE (Figure 3d and e). VEP showed flat waves in BE (Figure 3c). A diagnosis of bilateral ON was made. Hematological examination revealed that ESR and CRP were within normal limits. He was started on intravenous methylprednisolone pulse therapy for 3 days followed by oral steroids in a tapering fashion after a neurologist consultation. After treatment with steroids, the visual acuity improved to 20/30 in RE and 20/40 in LE. Serial AP revealed an improvement of the fields with an inferior arcuate defect (Figure 3d and e). MRI brain and orbit was requested on follow-up.

Figure 3.

(a and b) Fundus photo showing swollen optic disc with blurred margin in both eyes. (c) VEP showing bilateral flat waves. (d and e) AP showing bilateral generalized depression of field on presentation, with improvement on follow-up.

3. Discussion

We are living amid a pandemic, where along with various systems, COVID-19 also involves the eye, including both the anterior segment, in the form of conjunctivitis, episcleritis, and the posterior segment, in the form of vascular occlusion, and maculopathy. Additionally, reports have been made of neuro-ophthalmic involvement in the form of ON, tonic pupil, and orbital involvement. COVID-19 is reported to involve nearly all systems from mild to life-threatening severe respiratory distress to even death [5]. They say necessity is the mother of all inventions, and true to the word, the COVID-19 pandemic has prompted a worldwide effort toward employing futuristic technology in the development of vaccinations at an expedited rate. COVID vaccines form a crucial step in controlling the pandemic, with over a hundred million vaccines administered since the commencement of the mass vaccination program in early December 2020. Studies and trials do not report any major safety concerns in phase 3 randomized trials [6] nor in prospective studies [7] with a reportedly minuscule number of serious neurological side effects of these novel vaccines [8, 9]. The COVID vaccine, like any other, can cause side effects including mostly low-grade fever or muscle aches, and rarely neurological events [10]. Ocular side-effects caused by vaccinations are widely studied in existing literature [11, 12, 13, 14, 15], and occurrence of facial nerve palsies [16], abducens nerve palsy [17], acute macular neuropathy [18, 19, 20], central serous retinopathy [21], thrombosis [22], uveitis [23, 24], multiple evanescent white dot syndrome (MEWDS) [25], Vogt-Koyanagi-Harada (VKH) reactivation [26] and Grave’s disease [27] has been documented after administration of the COVID-19 vaccination. As early as 2 weeks following administration of the inactivated COVID-19 vaccination, 12 eyes of 9 patients suffered from various ocular conditions such as choroiditis, uveitis, keratitis, scleritis, acute retinal necrosis, and iridocyclitis as reported by Kunpeng et al. [28] Predominantly retinal adverse events, namely paracentral acute middle maculopathy (PAMM), acute macular neuropathy (AMN), and subretinal fluid were reported by Pichi et al., after Sinopharm COVID-19 vaccination in 7 patients [29]. In this case series, all patients presented with ON, which developed within 5–12 days (mean 8.6 days) of COVID-19 vaccination. ON following vaccination, though rare, is not unheard of. There is a certain level of ambiguity when it comes to the exact mechanism which causes ON, but an activation of the host’s immune system, leading to widespread damage of the myelin sheath of the optic nerve by the host T cells, is a popularly accepted theory [30]. Any side effects after vaccination are reported to VAERS (Vaccine Adverse Event Reporting System), a passive surveillance system, by health care professionals, patients who are affected, and by the vaccine manufacturers directly. A majority of patients who suffered from ON after vaccination (229 of the reported 537 cases) were reportedly isolated events [31, 32, 33]. Predominantly reported post-vaccine ON was due to the influenza vaccine, followed by ON post HPV, HBV vaccine [34]. ON developing as early as 24 hours post MMR vaccination, had also been reported [35]. Sawalha et al. [36] reported a case of bilateral ON which occurred within a week of COVID-19 symptoms. Similarly, Zhou et al. reported another case within a few days of COVID-19 [37]. Although ON following vaccination is an uncommon side effect, safety concerns are required. Recently, following the COVID-19 mRNA vaccination, two cases of bilateral arteritic anterior ischemic optic neuropathy (AAION) and acute zonal occult outer retinopathy (AZOOR) were reported [38]. Another study reported an acute diminution of visual acuity and visual fields following the 2nd dose of Pfizer- BioNTech vaccine [39]. Following the first dose of the ChAdO_1 COVID-19 vaccine, a 40-year-old lady with a history of remitting-relapsing MS complained of blurred vision which quickly deteriorated to complete blindness, as reported by Helmchen et al., which on further investigation was diagnosed as optic neuritis with AQP4-antibody-negative neuromyelitis optica spectrum disorders-like syndrome [40].

To date, Alvarez et al. provide the largest multi-national report after vaccination against SARS-CoV-2, where 38 out of 55 cases of ON were associated with the AstraZeneca vaccine, mostly with a negative history of neuro-inflammation [41]. There was also a recent case report of the development of acute thyroiditis and bilateral ON following the CoronaVac vaccine [42]. Most of the reviewed literature includes case reports and series (Table 1), and there are certain limitations with regards to ophthalmic assessment, the treatment that was initiated, the visual outcome, and a general underreporting of cases.

Study	Type	Number of cases	Presentation	Duration between development of ON and vaccination	Vaccine	Age
Alvarez et al. (pre-print) [41]	Observational study, Cohort	55	27 papillitis 14- MOG +	Median – 18 days (range: 1–69)	38/55- AstraZeneca 13- Pfizer-BioNTech 4 - Sinovac	Median − 45 years (range: 18–75)
Helmchen et al. [40]		1	Optic neuritiswith AQP4-antibody negative neuromyelitis optica spectrum disorders-like syndrome		ChAdO_1 COVID-19 vaccine	40 years, female, history of relapsing-remittent multiple sclerosis (MS)
Pawar et al., 2021 [43]	Case report	1	Unilateral ON	21 days	Unspecified	28 years, female
Elnahry et al., 2021 [44]	Case report	1	CNS inflammatory syndrome with neuroretinitis	16 days	BNT162b2, #2	69 years, female
	Case report	1	Unilateral ON	4 days	AZD1222,#1	32 years, female

Table 1.

Review of literature of development of Optic neuritis following COVID-19 vaccination.

As per the existing literature, this is very likely the first reported series of ON from India, following COVID-19 vaccination, with no evidence of an active infection. The approved Covishield vaccination was administered to all three patients, following which, two of the patients developed ON after the first dose and one after the 2nd dose. None of the patients had a previous history of RT-PCR-positive COVID-19 infection. As per the current information, Covishield is a recombinant vaccine in which, the SARS-CoV-2 spike glycoprotein is encoded by a replication-deficient chimpanzee adenoviral vector, which initiates an immunological response upon administration. A majority of the side effects occur on the day of vaccination, within 6–8 hours, but they are mostly self-limiting and resolve within 2–3 days. ON has been shown to occur due to a dysimmunological process caused by B cells targeting the adenoviral vector [45]. Although a review of safety has shown that the vaccine is generally well-tolerated, the possibility of ON should be kept in mind. A way forward can be to ask to report any new visual symptoms early, following vaccination. In our series, all three patients responded well to steroids, as per the proposed ONTT trial. Although it’s hard to determine whether post-COVID vaccine ON is a coincidence or cause, this series highlights the importance of taking the history of recent vaccination, especially in patients presenting with ON in the COVID-19 pandemic era.

4. Conclusion

This case series from real-world evidence, although small, can serve as a precedent for the reporting of any further cases, to secure a foothold and build a foundation for a greater understanding of whether post-COVID-19 vaccine ON is consequential or coincidental. It is prudent to ask for a thorough history of not just SARS-CoV infection but also vaccination, in a patient presenting with ON, as per the established connection. A close follow-up should be maintained to detect demyelinating disease early, in such patients.

Key summary points

1. Further, more research on pharmacovigilance and a dedicated international body for compiling any rare side effects following COVID-19 vaccination would allow for better understanding and tailored guidelines.

2. It is imperative to keep in mind, the relatively low level of side effects that have occurred compared to the vast majority of the world population who have been vaccinated.

3. Tracking of potentially harmful side effects of the vaccine can be considerably improved if ophthalmologists and physicians reported cases using VAERS.

4. The benefits of vaccination abundantly outweigh the risks and no existing literature advises against vaccination, from an ophthalmic viewpoint.