Long‐term follow‐up of a young male who developed acute macular neuroretinopathy following COVID‐19 vaccination

Key Clinical Message This report presents the clinical findings and prognosis of a healthy male patient who developed acute macular neuroretinopathy after COVID‐19 vaccination. Abnormal findings improved about 1 month after the onset and disappeared 3 months later. The subjective symptoms disappeared in 3 months, and no recurrence was observed for 1 year.


| BACKGROUND
Several cases of patients who developed various ocular complications following coronavirus disease 2019 (COVID-19) infection and vaccination have been reported.Specifically, cases of patients who developed herpes zoster ophthalmicus, [1][2][3] uveitis in Vogt-Koyanagi-Harada disease, [4][5][6][7][8] multifocal choroiditis, 9 scleritis, 10 multiple evanescent white dot syndrome, 11,12 acute posterior multifocal placoid pigment epitheliopathy, 4 acute zonal occult outer retinopathy, 4,13 optic neuritis, [14][15][16][17][18] ischemic optic neuropathy/optic nerve infarction, 13,19,20 corneal graft rejection, 21 and Bell's palsy 22 after COVID-19 have been reported.Development of other retinal disorders after COVID-19 infection and vaccination have also been reported, with acute macular neuroretinopathy (AMN) and paracentral acute middle maculopathy (PAMM) being particularly common.AMN is believed to be caused by disruption of the deep retinal capillary plexus owing to an ischemic event and is suggested to be associated with nonspecific flu-like illness or fever and the use of contraceptives. 23,24Most patients with AMN (>80%) are female. 23,24nly a few cases of male patients who developed AMN after COVID-19 have been reported.To our knowledge, no long-term clinical course of a male patient who developed AMN after COVID-19 vaccination has been reported to date.In this report, we present the findings of the longterm follow-up of a male patient who developed AMN following COVID-19 vaccination.

COVID-19 vaccination
A 19-year-old Asian male was referred to our department for ophthalmologic examination because of sudden onset of blurred vision in his left eye 2 days after receiving the second dose of the Moderna SARS-CoV-2 mRNA vaccine.The day after the vaccination, he developed a fever of 39.7°C and a headache.Three days after the vaccination, he visited a doctor who observed macular discoloration and disruption of the macular ellipsoid zone (EZ) on optical coherence tomography (OCT); therefore, he was referred to our hospital.He visited our hospital 9 days after the vaccination.He did not receive any treatment from the previous physician.He reported no history of systemic and ocular disease.
Laboratory investigations showed that his complete blood count and serum alanine transaminase, aspartate transaminase, alkaline phosphatase, creatinine, blood urea nitrogen, and C-reactive protein levels were within normal limits.Initial ophthalmological examination showed that his best-corrected visual acuity (BCVA) was 20/16 in both eyes.The intraocular pressure of his right eye and left eye was 12 mmHg and 10 mmHg, respectively.His pupillary light reflex was normal, and no relative afferent pupillary defect was detected in either eye.Slit-lamp examination of the anterior segments and lenses of both eyes revealed normal findings.However, bilateral fundoscopy revealed a clear vitreous and a small yellowish-white patchy discoloration of the fovea in the left eye.(Figure 1B).OCT revealed a discontinuity in the fovea and temporal ellipsoid zone of the left eye.The choroidal thickness of the eye was within normal limits (Figure 1D).Near-infrared reflectance (NIR) imaging of the left eye revealed multiple patchy hyporeflective lesions that involved the fovea and extended temporally (Figure 1F).Fundus autofluorescence (FAF) showed hyperfluorescence in the area corresponding to the hyporeflective lesions on NIR (Figure 1H).Visual field analysis performed using the Humphrey field analyzer (HFA) 10-2 program showed loss of sensitivity in the center of the left eye (Figure 1J).All the examination findings for the right eye were normal (Figure 1A, C,  E, G, I).Based on these findings, this patient was diagnosed with AMN of the left eye.improved (Figure 2A).In addition, the hyporeflective lesions and hyperfluorescence observed on NIR and FAF, respectively, had improved (Figure 2B,C).The loss of central field sensitivity in the left eye improved as well (Figure 2D).

| Clinical findings 86 days after the vaccination
Improvement of blurred vision in the left eye, which was a subjective symptom, was confirmed.The patient's BCVA was 20/16 in both eyes.The abnormal OCT, NIR, and FAF findings had almost disappeared (Figure 3A-C).HFA 10-2 visual field testing did not reveal any abnormalities (Figure 3D).

| Clinical findings 183 days after the vaccination
The patient reported that he was infected with COVID-19183 days after vaccination.He had a fever for 2 days and a sore throat for 7 days but had no ocular symptoms.He did not visit our hospital during this period.(Figure 4A-C).In addition, 10-2 visual field testing did not reveal any visual field abnormality (Figure 4D).The patient did not receive any additional COVID-19 vaccine during course of the AMN.

CONCLUSIONS
Acute macular neuroretinopathy was first reported by Bos and Deutman in 1975. 25AMN is a rare retinal disease that commonly occurs in young women, who often report being aware of a sudden paracentral scotoma.Although the etiology of AMN is not clear, it is believed to be caused by circulatory dysregulation 26 and disturbance of the deep capillary plexus in the outer layer of the retina due to ischemic events. 27n a review of 156 eyes of 101 patients with AMN, the onset of AMN was associated with nonspecific influenza-like illnesses or fever (47.5%), contraceptive use (35.6%), trauma, and dehydration.Most of the patients included in the review were female (84.2%), with mean age of 29.5 years. 23Other than infections, intravitreal anti-vascular endothelial growth factor injections, oral contraceptive pills, hypotension, intravenous contrast, intravenous ephedrine/epinephrine, caffeine, prothrombin-associated antiphospholipid antibodies, and preeclampsia are reported to be risk factors for AMN.However, none of these risk factors are applicable in the present case.The characteristic findings of AMN are the presence of reddish-brown petaloid perifoveal lesions, with the tips of the petals pointing toward the fovea; however, this symptom was not clearly observed in the present case.
Retinal vascular abnormalities caused by COVID-19 have been reported.COVID-19 causes hypercoagulability due to various other pathological events, leading to proinflammatory and antifibrinolytic conditions, such as the development of antiphospholipid antibodies and elevated D-dimer levels.These are believed to induce thrombus formation, leading to local embolism in small and microvessels in target organs. 28,29In a previous study, abnormal retinal vascular findings (microhemorrhage, retinal vascular tortuosity, and cotton wool spots) were observed in 25 of 216 eyes (11.6%) of patients with COVID-19.These signs were observed even in systemically asymptomatic patients. 30These previous reports suggest that a relatively large number of patients with COVID-19 may have hypercoagulable retinal microvascular impairments, including AMN, even in the absence of ophthalmological symptoms.
A systolic blood pressure of 140 mmHg and/or a diastolic blood pressure of 90 mmHg are reported to be strongly associated with retinal vasculopathy in patients with COVID-19. 30However, hypertension was not observed in the present case.
Retinal vascular disease can occur not only in patients with COVID-19 but in those who have received COVID-19 vaccines as well.The mechanism underlying this complication is believed to be the promotion of thrombus formation by oral contraceptives in the postinoculation inflammatory state and decrease in blood flow in the deep retinal capillary plexus due to the decrease in circulating plasma volume associated with the inflammatory reaction caused by inoculation. 31In a previous study, OCT angiography confirmed a decrease in deep retinal capillary plexus blood flow after COVID-19 vaccination. 32n a previous review, the mean age at onset of retinopathy, including AMN and PAMM, after vaccination was 24.8 ± 4.8 years, whereas the mean duration from vaccination to onset of ocular symptoms was 3.1 ± 2.4 days.In addition, five patients (35.7%) showed bilateral lesions. 33he young age at onset and the duration from vaccination to disease onset in the abovementioned review are similar to those in this case.
The patients in most reported cases of AMN after COVID-19 vaccination were female.To our knowledge, there are only two reports of AMN in males after COVID-19.The patients in these reports were aged 35 34 and 54 35 years old.The 35-year-old man developed bilateral AMN complicated by PAMM after receiving the Oxford-AstraZeneca COVID-19 vaccine.
In the present case, the patient was infected with COVID-19183 days after the second vaccination.However, he did not experience any subjective ocular symptoms at the time, and his subsequent ophthalmological examination findings were normal.Although some ocular diseases developed after COVID-19 spontaneously improved, the patient in the present case reported that he did not experience any subjective ocular symptoms after he got infected.Since his antibody titer was not measured during the course of the disease, the amounts of antibodies were produced after the first and second vaccinations, and COVID-19 infection is unknown.Therefore, why COVID-19 vaccination caused AMN, but the subsequent COVID-19 infection did not remains unclear.
In conclusion, this long-term report describes a case of a young, healthy, male patient who developed unilateral AMN after COVID-19 vaccination.After the onset of ANM, the patient was followed up without any treatment, and his subjective ophthalmological symptoms persisted for approximately 3 months.However, his abnormal ocular examination findings improved approximately 1 month after the onset ANM and almost disappeared 3 months after onset.The patient was infected with COVID-19 6 months after the onset of AMN; however, he did not experience any subjective symptoms and showed no abnormal findings in subsequent ophthalmological examinations.COVID-19 vaccination can cause AMN in healthy young men.Therefore, a review of vaccination history is important for diagnosis.

2. 2 |
Clinical findings 30 days after the vaccination The patient's BCVA was 20/16 in both eyes.The blurred vision in his left eye did not improve even 1 month after the vaccination.However, OCT showed that the discontinuity in the fovea and temporal ellipsoid zone of the left eye had F I G U R E 1 Fundus photographs (A, B) and optic coherence tomography (C, D), near-infrared reflectance (E, F), fundus autofluorescence (G, H), and 10-2 visual field test (Humphrey field analyzer) (I, J) findings at 3 days after the vaccination.

2. 5 |
Clinical findings 366 days after the vaccination The patient's subjective ocular symptoms had disappeared.His BCVA was 20/16 in both eyes.OCT, NIR, and FAF imaging did not reveal any abnormalities F I G U R E 2 Optic coherence tomography (A), near-infrared reflectance (B), fundus autofluorescence (C), and 10-2 visual field test (Humphrey field analyzer) (D) findings of the left eye at 30 days after the vaccination.

F I G U R E 3
Optic coherence tomography (A), near-infrared reflectance (B), fundus autofluorescence (C), and 10-2 visual field test (Humphrey field analyzer) (D) findings of the left eye at 86 days after the vaccination.

F I G U R E 4
Optic coherence tomography (A), near-infrared reflectance (B), fundus autofluorescence (C), and 10-2 visual field test (Humphrey field analyzer) (D) findings of the left eye at 336 days after the vaccination.