Anterior ischemic optic neuropathy is an important cause of vision loss in adults divided into arteritic (AAION) and non-arteritic (NAION) categories. Previously, the incidences per 100,000 individuals for NAION and AION, respectively, were reported as 2.30 and 0.36 . In terms of pathogenesis, AAION results from inflammatory changes and thrombosis of the short posterior ciliary arteries, which causes infarction of the optic nerve head [36, 37]. AAION is an ophthalmic emergency and treatment with systemic corticosteroids is standard . NAION is typically idiopathic , though there is an association with sleep apnea syndrome [38–40], medications including interferon alpha and sildenafil [41–43], and the presence of optic disc drusen [44–46]. It commonly presents with an altitudinal field defect. Post-vaccination NAION has also been previously reported following influenza vaccination [47, 48].
Previous studies have demonstrated a female predominance of incident optic neuritis, with one large study in the United Kingdom demonstrating that 69.4% of new cases over 22 years were in females . However, Lee et al. previously demonstrated in a cohort of diabetic patients that male gender increases the risk of developing AION by 32% .
Optic neuropathy has been reported rarely in the literature following vaccination against COVID-19. Only a total of 8 reports on 9 patients have been published to date, 8 (88.9%) of whom were females (Table 1). The currently reported case is the second case of post-COVID-19 vaccination optic neuropathy in a male, and the first case of post-BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) optic neuropathy in a male. In a relatively large multinational study of ocular inflammatory events following COVID-19 vaccination, 70 patients were reported to develop ocular inflammation within 14 days of COVID-19 vaccination, but only 2 (2.9%) patients were diagnosed with optic neuritis . This indicates that the incidence of optic neuropathy following COVID-19 vaccination could be low. The latter study, however, did not provide specific details on cases with optic nerve involvement. Elnahry et al. previously reported on a pair of patients, one of whom was a 69-year-old woman who developed CNS inflammatory syndrome with neuroretinitis and papillitis following vaccination with the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech), and the other of whom was a 32-year-old woman who developed retrobulbar optic neuritis following vaccination with the CoviShield COVID-19 vaccine (AstraZeneca/University of Oxford, Cambridge, UK) . Only the patient who developed retrobulbar optic neuritis demonstrated significant improvement with IV methylprednisolone. Elsewhere, Leber et al. , Pawar et al. , and Garcia-Estrada et al.  all reported cases of optic neuritis in women aged 32, 21, and 19, respectively. All three patients demonstrated improvement with IV methylprednisolone therapy.
The remaining cases reported in the literature were cases of AAION or NAION. Nachbor et al. reported on a 64-year-old woman who developed acute, unilateral vision loss 6 days after receiving her first dose of the BNT162b2 vaccine . Examination revealed superior sectoral optic disc edema at that time. While waiting for ophthalmologic follow-up, the patient received her second dose of the vaccine three weeks after her first dose. She awoke the next morning with painless, near-complete vision loss, with visual acuity on presentation being counting fingers at 2 feet. Examination revealed peripapillary splinter hemorrhages in the optic nerve OS and Humphrey visual field testing revealed dense constriction OS. OCT showed diffuse thickening of the retinal nerve fiber layer OS. All examination findings were normal OD. The patient was diagnosed with NAION and treated with one week of oral prednisone 1 mg/kg/day. At a six-week follow-up, visual acuity was 20/100 OS with resolved optic disc edema replaced by diffuse pallor, consistent with NAION.
Tsukii et al. reported on a 55-year-old woman who presented with visual field disturbance which developed three days after the first dose of the BNT162b2 vaccine . Although VA was 20/20 OD and OS at presentation, fundoscopy revealed diffuse optic disc swelling and Goldmann visual field testing revealed an inferior visual field defect. A diagnosis of NAION was made. The patient received no treatment. At follow-up, vision remained unchanged and there was only residual diffuse optic nerve pallor.
We have previously described that an autoimmune mechanism underlies the development of optic neuropathies following vaccination . Previously, Stübgen et al. reported that there is no long-term risk of developing optic neuropathy following vaccination, but that the presence of adjuvants contributes to the process . However, in the absence of adjuvants in several of the COVID-19 vaccines, this explanation is insufficient . Clinically, it is challenging to differentiate between AION and optic neuritis, and the diagnosis is usually based on both clinical impression and multimodal imaging findings [54–56]. Some differentiating features include an older age of onset, altitudinal visual field defect, and worse visual outcome in patients with AION which was also found in our study, however, these features cannot confidently distinguish between both conditions . Furthermore, the pathophysiology (and treatment) of both types of optic neuropathies is postulated to be different and it is not currently clear why some patients develop AION while others develop optic neuritis following vaccination. Documented risk factors for NAION include diabetes, small cup-to-disc ratio, hyperlipidemia, and hypertension and it is likely that the development of NAION is a multifactorial process which includes pre-existing structural compromise of the optic nerve [36, 57, 58].
Our patient had the risk factor of type 2 diabetes, and the transient pro-inflammatory and hypercoagulable state following vaccination may have led to the development of AION. Nachbor et al. also endorsed this hypothesis for their patient with NAION . Tsukii et al. also proposed that neutralizing antibodies directed against SARS-CoV-2 spike proteins after vaccination may cross-react with proteins in the retinal vasculature and retinal pigment epithelial cells, a mechanism also endorsed by Maleki et al [34, 52]. It is conceivable that both processes may have played a role in the development of AION in our patient. Another possible explanation for the development of post-vaccination optic neuropathy that could link the occurrence of inflammation and ischemia was recently elucidated by Francis and colleagues in patients developing optic neuropathy in association with immune checkpoint inhibitors used for cancer treatment . These immunotherapy agents, like vaccines, enhance the adaptive immune response which may result in a range of adverse inflammatory events including ophthalmic and neurologic phenomenon . Francis and colleagues indicated that this class of drugs may result in optic papillitis, a specific type of optic neuritis that involves inflammation of the optic nerve head, leading to ischemia of the optic nerve head and a picture similar to AION [59, 60].
In conclusion, several cases of optic neuropathy have been reported following the administration of COVID-19 vaccines. Nevertheless, the benefits of vaccination against SARS-CoV-2 have been substantial and probably outweigh the associated risks. Furthermore, most of the reported cases were self-limiting and had a good prognosis with available treatments. Future studies should aim to evaluate for risk factors, both ocular and systemic, which may contribute to the development of optic neuropathy after COVID-19 vaccination, and to elucidate the mechanisms underlying the development of these conditions in order to optimize their follow-up and treatment.