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A 53-year-old man presented to the hospital after losing vision in his left eye. He explained that he had been given his second dose of Pfizer's COVID vaccine (Comirnaty) 10 days previously. He said that he had experienced similar symptoms 7 days after he received his first dose of the vaccine.

Clinicians learned that the man also had an altitudinal defect in his right eye, which he explained had improved on its own, so he had not seen his doctor. However, he added that his vision had not fully returned to normal.

He had no other symptoms, and no relevant past medical history. On examination, clinicians found that his left eye had a best-corrected visual acuity (BCVA, Snellen equivalent) of 20/40. They also noted a relative afferent pupillary defect. Fundoscopy revealed a large optic disc swelling with some hemorrhages. The patient's right eye had a BCVA of 20/20 along with a lazy pupil and mild papillary edema with two hemorrhages.

Clinicians performed optical coherence tomography (OCT) which confirmed the presence of bilateral papillary edema, and a minor loss of ganglion cells in his right eye only. Disturbance of the visual field was noted in both eyes: The left eye had constricted peripheral vision, and the right eye had an incomplete lower nasal scotoma.

Further work up included a SARS-CoV-2 PCR nasal swab test, which was negative. Based on their suspicion that the patient had bilateral anterior ischemic optic neuropathy, clinicians performed further evaluations. A neurological examination revealed nothing unusual.

Serological testing did not reveal any infectious diseases. The patient's blood cell count was suggestive of iron deficiency anemia; however, this diagnosis was ruled out when there was no evidence of active bleeding and the patient's platelet count was within normal values. Erythrocyte sedimentation rate and C-reactive protein were also found to be normal. Tests did not assess for antibodies against platelet factor 4 (PF4). There was no evidence of antineutrophil cytoplasmic antibody or antinuclear antibodies, and tumor markers Alfa 1 fetoprotein, carcinoembryonic antigen, cancer antigen 19, cancer antigen 125, cytokeratin fragment 21.1, and neuron-specific enolase were within normal values. An echo-Doppler of the supra-aortic vessels was also normal.

Clinicians performed an MRI of the brain and orbits, with and without gadolinium, to assess for potential optic neuritis, but findings were unremarkable. The patient underwent a lumbar puncture, which noted an opening pressure of 38 cm H2O. Cerebrospinal fluid (CSF) testing showed normal protein and glucose levels, and infection serology tests were negative. Findings of a full body CT scan were also unremarkable.

Based on a chance CSF finding suggestive of increased intracranial pressure, clinicians prescribed acetazolamide at 750 mg/day. However, the patient reported that his vision had not improved at that time, which was still the case 3 months later.

At 3-month follow-up, clinical assessment showed the patient's visual acuity to be 20/20 in his right eye and 20/40 in his left eye, with lazy pupils and normal eye movements. Fundoscopy revealed pallor disc in both eyes, without any hemorrhages. The OCT identified slight loss of ganglion cells bilaterally, and there was evidence of atrophy on retinal nerve fiber layer. The visual field had not changed in the right eye, and there was minor improvement in the left eye. Although there was no evidence of a typical altitudinal defect, based on test results and clinical changes, clinicians made the diagnosis of NA-AION.

Discussion

Clinicians presenting this (one of two originally published) of non-arteritic anterior ischemic optic neuropathy after receiving the Pfizer vaccine emphasized that the case "describes an association, not causation, between NA-AION and COVID-19 vaccination." However, they noted that "the timing between the vaccine and the development of the ischemic optic neuropathy," in addition to the patient's symptom onset "in one eye after the first dose and in the other eye after the second dose makes a potential role of the COVID-19 vaccines in the pathogenesis of this condition plausible in these two cases."

Vaccination with the Pfizer (BNT162b2 mRNA), Moderna (mRNA-1273), Johnson & Johnson (Ad26. COV2.S), and AstraZeneca (AZD1222) vaccines elicits an immune neutralizing response that helps prevent SARS-CoV-2 infection, but have also been associated with some rare but serious secondary effects, including thromboembolic events, case authors wrote.

The group explained that while this patient's elevated intracranial pressure may be associated with bilateral papilledema, his atypical presentation with only acute visual symptoms raised the possibility that the patient did have an ischemic optic neuropathy, "or that the vaccine may have precipitated an ischemic event in prone optic nerves, with crowded structure due to elevated intracranial pressure."

That NA-AION is the most common cause of acute optic neuropathy among individuals over age 50, with an annual incidence in the U.S. of 2.3 to 10.3 per 100,000 people overall, the team observed. While the cause of most cases is unexplained, they noted specific etiologies linked with it, including sleep apnea syndrome, medications such as interferons or sildenafil, and optic disc drusen. In addition, some data have suggested pathophysiological involvement of predisposing risk factors such as optic disc anatomy, nocturnal hypotension, or vasculopathic risk factors.

A recent large scale meta-analysis reported that in addition to a medical history of taking cardiovascular drugs, the following were significantly associated with NA-AION:

• Male gender (OR 1.67, 95% CI 1.50-1.85)
• Hypertension (RR 1.28, 95% CI 1.20-1.37)
• Hyperlipidemia (RR 1.43, 95% CI 1.26-1.62)
• Diabetes mellitus (RR 1.53, 95% CI 1.36-1.73)
• Coronary heart disease (RR 1.68, 95% CI 1.24-2.27)
• Sleep apnea (RR 3.28, 95% CI 2.08-5.17)
• Factor V Leiden heterozygous (RR 2.21, 95% CI 1.19-4.09)

Case authors said that the timing of the acute optic neuropathy shortly after vaccination leads them to suspect vaccination as the predisposing event that triggered the onset of NA-AION. Despite its rarity, they cited another that followed a COVID-19 vaccine and four cases reported to follow influenza vaccination.

As well, the group listed previous secondary ocular effects thought to be related to COVID-19 vaccination, although they noted that their etiology is not clearly understood and may be varied – these included episcleritis, scleritis, uveitis (both anterior and posterior), acute macular neuroretinopathy, paracentral acute medial maculopathy, corneal transplant rejection, central serous chorioretinopathy, and arteritic ischemic anterior optic neuropathy.

The group referred to the only published report of an arteritic anterior ischemic optic neuropathy case, which those authors suggested might be due to "cross-reactivity between the neutralizing antibodies against the SARS-CoV2 spike proteins and arterial antigens, resulting in a presumed autoimmune phenomenon." Case authors commented that the plausibility of this proposed mechanism was supported by that patient's presentation with fever, elevated C-reactive protein, an elevated erythrocyte sedimentation rate, and positive findings on a temporal artery biopsy, which led to his diagnosis with Horton disease.

They noted that in their two case patients, an autoimmune mechanism "seems unlikely" based on their lack of systemic manifestations and normal blood test findings, "although a local ophthalmic autoimmune event may still be considered."

Additionally, the authors noted a potential role of a thrombotic trigger, pointing to rare reports of cerebral venous sinus thrombosis (CVST) following SARS-CoV-2 vaccination as a result of immune thrombotic thrombocytopenia (VITT).

The group explained that "VITT is caused by antibodies that PF4, also called CXCL4, binds to platelets. These antibodies are immunoglobulin G (IgG) molecules that activate platelets via low-affinity platelet FcgIIa receptors (receptors on the platelet surface that bind the Fc portion of the IgG molecule)." This activation of platelets, potentially along with involvement of neutrophils and other cells, stimulates the coagulation system and can result in clinically significant thromboembolic complications, already well-known to be associated with both SARS-CoV-2 infection and COVID-19 vaccination. Indeed, ischemic optic neuropathy has also been reported in patients with COVID-19, they said, citing six previously reported cases.

"The occurrence and significance of autoimmune manifestations after the administration of viral vaccines remain controversial," case authors noted, citing a recent report considering whether serious ocular inflammatory adverse effects of COVID-19 recombinant mRNA vaccines are "." That analysis of cytokine secretions showed that levels of IFN-γ and IL-2 were increased after SARS-CoV-2 vaccination compared to controls, while there was no change in IL-4 and IL-13 levels, indicating a predominantly T-helper 1 response, those authors observed.

VITT characteristics with arterial thrombosis have been described in a report of three cases of ischemic stroke that followed COVID-19 vaccination, case authors wrote, noting that immune-mediated coagulopathy can also trigger arterial thrombosis, which often involves several arteries, "although small-artery stroke is less common." VITT has been observed more often with the adenovirus vector vaccine, authors noted, with only one reported case of a catastrophic thrombosis that followed a second dose of the Moderna mRNA vaccine.

Case authors acknowledged that because neither of their patients were assessed for antibodies against PF4, "this pathogenic mechanism cannot be completely ruled out." Further research will be needed to better understand the pathophysiologic process underlying the link between ischemic optic neuropathy and mRNA-based COVID-19 vaccination, they concluded.

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