Optic Neuritis After SARS-CoV-2 Vaccination

The unprecedented outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a drastic impact on the world and global health care systems.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Optic Neuritis After SARS-CoV-2 Vaccination Asaf Shemer, MD, Assaf Greenbaum, MD, Amit Toledano, MD, Roy Biron, MD, Biana Dubinsky-Pertzov, MD, MPH, Lior Or, MD Background: To describe recent cases of optic neuritis in patients who received a vaccine for COVID-19. Methods: Retrospective case series of patients diagnosed with optic neuritis after a recent COVID-19 vaccination with BNT162b2 (Pfizer-BioNTech), in one university-affiliated tertiary hospital, from January 2021 to June 2021. Data were obtained from medical charts. Results: We describe 7 patients who developed optic neuritis after immunization with the BNT162b2 vaccine. Conclusions: A causal relationship cannot be deduced, and the importance of COVID-19 vaccination is not challenged. However, the authors encourage a prospective monitoring and reporting system for all patients receiving COVID-19 vaccines, to further assess the spectrum of adverse events in large databases. Journal of Neuro-Ophthalmology 2023;43:29–33 doi: 10.1097/WNO.0000000000001811 © 2022 by North American Neuro-Ophthalmology Society T he unprecedented outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a drastic impact on the world and global health care systems. The World Health Organization (WHO) declared COVID-19 a global pandemic on March 11, 2020, initiating extensive public health measures to combat spread of the virus (1). Overtime, the treatment methods for the COVID-19 progressed, and the turning point was with the introduction of a vaccine in December 2020. The first vaccine that received the Food and Drug Administration (FDA) emergency authorization was BNT162b2 (Pfizer/BioNTech, New York, NY) m-RNA vaccine (2). After massive provaccination campaigns around the world, millions of people were immunized. Studies have shown that the BNT162b2 vaccine is highly effective in preventing COVID-19, reducing hospitalization rates and death (3). However, despite a high safety profile, rare adverse events have been reported such as Guillain–Barré syndrome (GBS), myocarditis, lymphadenopathy, and others (4,5). Furthermore, ocular adverse events have also been reported recently after the vaccine including facial nerve palsy, anterior uveitis, retinal vein occlusions, and multifocal choroiditis (6,7). Optic neuritis (ON) is an inflammation of the optic nerve and is frequently associated with demyelinating, infectious, or inflammatory disorders. Evaluating and treating these patients as soon as possible is necessary to prevent nerve damage, future neurological dysfunction, and visual loss (8). Previously, a link was reported between ON and vaccinations, such as the measles–mumps–rubella (MMR) vaccine, seasonal influenza vaccine, and more (9). In this article, we report a series of 7 patients who developed optic neuritis after the second dose of the BNT162b2 vaccine. METHODS Department of Ophthalmology (AS, AG, AT, RB, BD-P, LO), Shamir Medical Center (formerly Assaf-Harofeh), Tzrifin, Israel; and Sackler Faculty of Medicine (AS, AG, AT, RB, BD-P, LO), Tel Aviv University, Tel Aviv, Israel. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). This study was approved by the institutional research committee and was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. Address correspondence to Asaf Shemer, MD, Department of Ophthalmology, Shamir Medical Center, Be’er Ya’akov 70300, Israel; E-mail: [e-mail] Shemer et al: J Neuro-Ophthalmol 2023; 43: 29-33 Setting This study was conducted at Shamir Medical Center (previously known as Assaf Harofe), which is an academic, tertiary medical center in central Israel, affiliated with TelAviv University. This study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of the Shamir Medical Center. Patient Population The study group included patients admitted to the emergency department of the Shamir Medical Center during January 1, 29 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 2021, to July 1, 2021, and were diagnosed with optic neuritis. In our center, we hospitalize all patients with optic neuritis to the ophthalmology department. Outcome The main outcome of this study is to describe all cases of optic neuritis in patients who were previously vaccinated with the BNT162b2 (Pfizer-BioNTech) m-RNA vaccine during the mentioned timeline. This is a retrospective case series and by nature does not aim to assess a causal relationship between COVID-19 vaccines and optic neuritis. Case Presentation Case 1 A 38-year-old man was referred to the department of ophthalmology because of reduced vision and eye pain for one day on the left side. He completed 2 doses of the BNT162b2 vaccination four and a half months before presentation. His medical history (PMH) included a previous retrobulbar ON in 2014. At presentation, there was pain with eye movements, positive relative afferent pupillary defect (RAPD), and color desaturation in the left eye. Visual acuity (VA) was 6/6 on the right eye and 6/7.5 on the left eye. The posterior segment showed no swollen or hyperemic optic discs bilaterally. Automated perimetry (AP) showed a peripheral impairment in the left eye. MRI of the brain and orbits revealed a prechiasmatic hyperintense lesion on T2, enhancing with gadolinium of the left optic nerve. Left retrobulbar ON was diagnosed, and the patient was admitted. Laboratory test were within normal limits including erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA), antiaquaporin4 (anti-AQP4), and antimyelin oligodendrocyte glycoprotein (MOG). Methylprednisolone intravenous (IV) therapy was initiated for 3 days followed by oral steroids. Last follow-up examination performed 3 months after discharge, revealed an improvement in both VA and perimetry in the left eye. Case 2 A 29-year-old healthy woman presented with visual loss in her right eye followed by appearance of gray spots in the lower visual fields as well as headaches. Symptoms started on the morning of her arrival. The patient was immunized with the BNT162b2 mRNA vaccine 6 months before presentation. VA was 6/12 and 6/6 in the right and left eyes, respectively. RAPD was positive (+2), and color desaturation was observed in the right eye. Eye movements did not produce pain. Fundus examination showed sharp disc margins bilaterally. She was admitted to the ophthalmology department where she was started on IV methylprednisolone therapy followed by additional laboratory workup. Inflammation markers were negative as well as antibody titers for ANA, ANCA, antiAQP4, anti-Ro, anti-La and anti-MOG. Stimulus V perimetry showed an altitudinal lower field defect. Brain and orbits 30 MRI demonstrated diffuse abnormal signal from the right optic nerve without enhancement and abnormal signal foci in the white matter and corpus callosum, compatible with multiple sclerosis (MS). Owing to the lack of improvement in her vision after 3 days of IV methylprednisolone regimen, an additional 5-day course of plasmapheresis was initiated. On follow-up examination a month after discharge, there was mild improvement in the VA with residual positive RAPD and color desaturation in the right eye. Case 3 A 54-year-old otherwise healthy man, presented to the emergency department (ED) with right eye visual loss that had evolved during the previous week. Symptoms started 6 months after the administration of his second dose of the BNT162b2 vaccine. At presentation, VA was counting fingers (CF) in the right eye and 6/6 in the left eye. There were pain with eye movement, positive (+2) RAPD, and color desaturation in the right eye. Funduscopic examination revealed a blurred upper-nasal margin at the optic disc in his right eye. Examination was normal in the left eye. Brain and orbits MRI showed abnormal signal in a short segment of the right optic nerve. All laboratory workup was within normal limits, and the patient was admitted to our department and treated with IV methylprednisolone 1 g/d for 3 days followed by oral prednisone. Five days later, on the day of discharge, the patient VA improved in his right eye. Three months later, a significant improvement was noted in all optic nerve functions. Case 4 A 38-year-old otherwise healthy woman, presented with pain in the left eye that started 3 weeks prior followed by headache. Two months before her presentation, she was immunized with the second dose of the BNT162b2 vaccine. At presentation, there was pain induced by eye movements and trace RAPD in the left eye and diffuse conjunctival injection bilaterally. VA was 6/6- in the right eye and 6/7.5- in the left eye. There were no abnormal findings in fundus examination. Brain and orbits MRI showed a thickening of the left optic nerve. She was hospitalized for suspected ON, and methylprednisolone IV treatment was initiated for 5 days followed by oral prednisone. She experienced clinical and subjective improvement and was pain free at discharge. An orbit MRI few weeks later demonstrated an abnormal and enhanced signal from the central and distal left optic nerve. On her final follow-up few months later, an excellent functional recovery was found. Case 5 A 42-year-old healthy woman presented with visual loss in her left eye followed by pain induced by eye movement that had evolved during the previous week. The family history revealed a sibling diagnosed with MS. The patient was immunized with the second dose of the Pfizer-BioNTech vaccine 3 weeks before presentation. At presentation, there was pain induced by eye movements in the left eye and Shemer et al: J Neuro-Ophthalmol 2023; 43: 29-33 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution positive RAPD on examination. VA was 6/6 on the right eye and 6/6- on the left eye. There were no abnormal findings in fundus examination. An MRI showed enhancement in the prechiasmatic optic nerve segment in the left eye, without cerebral lesions. The patient was admitted and treated with IV methylprednisolone 1 g/d for 5 days followed by oral prednisone. On the day of discharge, the patient reported significant improvement in the pain with eye movements. One week later, VA, RAPD, and color vision remained impaired in the left eye, while a mild improvement was noted in the left eye automated perimetry. The patient was lost to further follow-up. Case 6 A 45-year-old woman presented with blurred vision in the right eye lasting 4 days, followed by discomfort with eye movement. Her medical history (PMH) disclosed MS with 2 episodes of ON in the past. She presented to the ED 6 weeks after receiving the second dose of the BNT162b2 vaccine. BCVA was 6/9- in the right eye and 6/7.5 in the left eye. RAPD was positive (+1), and color desaturation was observed in the right eye. Eye movements produced a moderate pain. Fundus examination showed sharp disc margins bilaterally. AP showed a concentric reduction in the right visual field and a left normal field. The patient was treated with IV methylprednisolone for 5 days followed by oral prednisone. An MRI scan found abnormal signals in the white matter characteristic of active MS. Follow-up examination performed 3 weeks after discharge found a significant improvement in the VA and in the visual field and a negative RAPD. The patient was lost to follow-up. Case 7 A 14-year-old healthy man presented to the ED with occipital and frontal headaches for about a week accompanied by blurred vision and photophobia. The patient was immunized with the second dose of the BNT162b2 mRNA vaccine 9 weeks before presentation. Examination found positive RAPD +2 and color desaturation in the left eye. VA was 6/21 in the right eye and 6/6 in the left eye. Dilated fundus revealed swollen optic disc with vascular lining in the right eye. Diagnosis of atypical ON was made, and the boy was admitted for IV methylprednisolone course. An MRI test performed during his hospitalization found an abnormal signal in the left intraorbital optic nerve with enhancement. Antibody titers were negative for ANA, ANCA, APLA, anti-AQP4, anti-Ro, antiLa, anti-MOG. However, a positive Epstein–Barr nuclear antigen (EBNA) was found, which may suggest a postinfectious etiology. After treatment, there was a subjective and objective clinical and radiological improvement. At 3 months follow-up, a good visual function recovery was noted. Clinical data of all cases are summarized in Table 1 and Supplemental Digital Content (see Figure, http://links.lww.com/WNO/A673). RESULTS AND DISCUSSION During the pandemic caused by SARS-CoV-2, we all learned the harmful potential of COVID-19. In addition to high mortality, it can affect different organs and systems including the ocular system. Luckily, vaccines were developed and authorized quickly and thus saved millions of TABLE 1. Characteristics of patients with new-onset optic neuritis after vaccination with the BNT162b2 (PfizerBioNTech) vaccine Age, Serum AQP4- Serum MOG- Oligoclonal bands, Case years Gender IgG Abs IgG, Abs lumbar puncture Brain MRI 1 38 Male Negative Negative N/A 2 30 Female Negative Negative Negative 3 54 Male Negative N/A 4 38 Female Negative Positive Not performed 5 43 Female Negative Negative Not performed 6 46 Female N/A N/A N/A 7 14 Male Negative Negative Negative Negative Intraorbital optic nerve contrast enhancement Brain lesions correlate with MS Intraorbital optic nerve contrast enhancement Optic nerve contrast enhancement Optic nerve contrast enhancement Brain lesions correlate with MS Intraorbital optic nerve contrast enhancement Spine MRI Diagnosis Within normal Isolated ON limits Within normal MS-associated limits ON Within normal Isolated ON limits Within normal anti-MOG ON limits N/A MS-associated ON N/A MS-associated ON Within normal Isolated ON limits Ab, antibodies, AQP-4, aquaporin 4; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; MS, multiple sclerosis; N/A, not available; ON, optic neuritis. Shemer et al: J Neuro-Ophthalmol 2023; 43: 29-33 31 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution lives. However, the link between a new vaccine and potential adverse events must be monitored in the postvaccination period. Recently, Elnahry et al reported a 69-year-old Caucasian woman who noted sudden onset of blurry vision, 16 days after the immunization with the second dose of the PfizerBioNTech vaccine. She had bilateral optic nerve disc edema, and MRI was within normal limits. She was diagnosed with postvaccination central nervous system inflammatory syndrome and treated with IV methylprednisolone. Later, Pirani et al described 2 patients who developed atypical ON after BNT162b2 vaccination. Interestingly, those 2 patients had a history of autoimmune diseases. The authors conclude that individuals suffering from immune-mediated diseases may be predisposed of inflammatory conditions such as ON (10). In addition, cases have also been reported with other COVID-19 vaccines. Tugizova et al reported 2 cases of patients who developed atypical ON shortly after receiving the vaccine. In their article, one patient was immunized with the Pfizer vaccine and the second with Spikevax mRNA-1273 (Moderna) vaccine. Both patients were in their 60s and developed optic neuritis in the absence of MOG or AQP-4 antibodies, within a week from vaccination (11). Additional reports described 3 cases of patients who received the ChAdOx1 nCoV-19 (Vaxzevria, Cambridge, AstraZeneca, UK) vaccine and presented with optic neuritis, one case report of a 19-year-old woman diagnosed with ON 3 weeks after the Ad26.COV2.S recombinant vaccine (Janssen Biotech, Inc, Janssen Pharmaceutical Company of Johnson & Johnson, Horsham, PA) and a 32-yearold Caucasian woman presented with vision loss after the administration of the second dose of the CoronaVac (Sinovac Life Sciences vaccine, Sinovac Biotech, Beijing, China) (12–14). Furthermore, anti-MOG ON was also reported after COVID-19 vaccination. One case report was of a 54-yearold man who was diagnosed with anti-MOG ON 3 weeks after vaccination with COVISHIELD was recently reported (15). Another case of positive titer (1:1,000) of MOG antibodies was described in a 38-year-old man, 3 days after administration of the Moderna vaccine (16). Four cases of MOG positive ON were described in patients after the first dose of the ChAdOx1 vaccine, and one case was diagnosed in a 67-year-old Caucasian man immunized with 2 shots of the ChAdOx1 vaccine (210 and 154 days earlier) and later with the third dose of BNT162b2 vaccine (17,18). Optic neuritis is the most frequent vaccine-related demyelinating clinical manifestation. Although not common, previous immunization may trigger optic neuritis. Among the common pathogens whose vaccines have been linked to ON are hepatitis virus Type A and B (HAV, HBV), pneumococcal vaccine, influenza, measles, rabies, and more (9). 32 The precise pathophysiologic mechanism of optic neuritis after vaccination is not fully understood. It is hypothesized that the immune system is triggered by a common factor, such as an adjuvant used in vaccines. The latter is used to boost the immune response but may induce an accelerated molecular response in the immunized tissue (19). However, the BNT162b2 is a m-RNA vaccine, which induce a robust humoral response. Apart from neutralizing the virus, these antibodies are able to recruit the immune system using Fc receptors and complement. In particular, there is a concern for vaccine-induced autoimmunity through a cross-reactivity mechanism, and indeed reaction of anti–SARS-CoV-2 spike protein monoclonal antibody with human tissue antigens was documented recently (20). It is widely established in the literature that other factors may trigger for the recurrent of optic neuritis apart from vaccines. Most commonly ON is associated with demyelinating diseases, such as MS, NMOSD, or MOG (21). In Case 6, we refer to a 45 year-old woman who was diagnosed with MS and experienced 2 previous episodes of ON. Although vaccines in general can not only precipitate isolated ON, it should be highlighted that this relapse could have been triggered by the MS, which is the underlying disorder of the patient. Yet, a definitive etiology could not be concluded. Our case series has few limitations. First, this is a retrospective case series in its nature, and as so, it does not aim to assess causality between the COVID-19 vaccinations and the incidence optic neuritis. Second, we cannot definitely state these cases as vaccination-related, as MS-related cases could surely occur without a previous history of vaccination. Third, in our series, there is a wide span of time between the immunization and the diagnosis of optic neuritis, which may challenge the link between the vaccine and the neuritis. However, this inconsistency may imply both acute and late onset potential vaccine-associated optic neuritis. This case series reports 7 patients who developed optic neuritis after the COVID-19 vaccination. All patients received the BNT162b2 (Pfizer-BioNTech) m-RNA vaccine, and they all developed ON after the second dose. In our series, patients responded well to conventional treatment. Although studies have shown that the vaccine has a high safety profile and the vaccine is typically well tolerated, we think that this subject should be monitored and assessed in further real-world studies. STATEMENT OF AUTHORSHIP Conception and design: A. Shemer, L. Or; Acquisition of data: A. Shemer, A. Greenbaum, A. Toledano; Analysis and interpretation of data: A. Shemer, B. Dubinsky-Pertzov, L. Or. Drafting the manuscript: A. Shemer, A. Greenbaum, A. Toledano; Revising the manuscript for intellectual content: R. Biron, B. Dubinsky-Pertzov, L. Or. Final approval of the completed manuscript: A. Shemer, R. Biron, B. Dubinsky-Pertzov, L. Or. Shemer et al: J Neuro-Ophthalmol 2023; 43: 29-33 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution REFERENCES 1. Anon. WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19, 2020. 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