COVID-19 as a Potential Risk Factor for Acute Macular Neuroretinopathy

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and affects multiple systems throughout the body. It can lead to inflammatory storms, blood hypercoagulation, and other physiological changes.1 Inflammation is the main pathological mechanism of COVID-19–associated tissue damage. Elevations of D-dimer and fibrin degradation products in patients with COVID-19, resulting in blood hypercoagulability, contributes to the formation of blood clots, in turn inducing thromboembolic diseases such as arteriovenous thrombosis. COVID-19 mainly invades the human respiratory system, but it can also affect the heart, kidneys, brain, and eyes. Acute macular neuroretinopathy (AMN) is a rare macular disease involving localized nonperfusion of the deep retinal capillary plexus resulting in destruction of the outer peripheral layer, outer nuclear layer (ONL), and ellipsoid zone (EZ). The prevalence of AMN is less than one per million members of the population, and it is more common in young and middle-aged White women2. Onset is typically acute, with monocular or binocular involvement. The main symptom is the sudden appearance of central or paracentral scotomas with or without decreased vision. Factors associated with the pathogenesis of AMN include taking contraceptive drugs, viral infection, and trauma. However, the specific mechanism of pathogenesis has not been fully elucidated. It is currently believed that it may be related to inflammation and vascular ischemia. In this study, we report the clinical manifestations, imaging features, and prognoses of typical cases of AMN after COVID fevers. We also discuss a potential causative link between AMN and COVID-19. Finally, multiple ophthalmic manifestations after COVID-19 are reviewed with the aim of enhancing awareness and understanding of COVID-19 eye disease among ophthalmologists. Patient 1 was a 42-year-old male who complained about a vision decline and scotomas in the right eye 1 day after the COVID-19 fever. He tested positive for COVID-19 antigen. His best-corrected visual acuity (BCVA) of right eye was 12/20, and intraocular pressure (IOP) was normal. The slitlamp examination result of anterior segment had no abnormal changes. Multicolor fundus scanning (Heidelberg Engineering, Germany) examination indicated multiple small flaky brownish-red lesions around the fovea and a punctate retinal hemorrhage supratemporal the macula (Fig. 1A). Optical coherence tomography (OCT) (Heidelberg Engineering, Germany) revealed multiple dark lesions on en face, which were consistent with the morphology presented in fundus photograph (Fig. 1B). OCT B-scanning revealed that the multiple short and strong reflective strips in the outer nuclear layer and photoreceptor layer scattered around the macula (Fig. 1C, D). The patient was diagnosed with AMN, and no medication was prescribed. During follow-up, his visual acuity gradually improved to normal and the lesions gradually faded.FIG. 1.: In Patient 1, (A and B) muticolor fundus photograph and en face optical coherence tomography (OCT) showed multiple small flaky lesions around the fovea. C–D. OCT B-scanning revealed that the multiple short and strong reflective strips in the outer nuclear layer and photoreceptor layer. In Patient 2, (E–H) OCT images of right eye at the first visit, 2-week, 6-week, and 10-week follow-up timepoints. Hyperreflective bands in the outer nuclear layer and photoreceptor layer gradually vanished, and the discontinuous area of the ellipsoid zone (EZ) became narrowed.Patient 2 was a 16-year-old girl complained about a sharp decline in vision and accompanying scotomas in both eyes for 5 days. She had a fever 1 day before the onset of ocular symptoms. Her COVID-19 antigen test presented positive. At the first visit, her BCVA was 6/20, and IOP was normal in both eyes. Ophthalmoscopy revealed a normal optic disc, juvenile reflexes of the macula, and reddish-brown leafy lesions. OCT revealed that both eyes had obvious low-reflection wedge-shaped lesions pointing to the fovea in en face imaging. OCT B-scanning depicted strong reflective bands in the outer nuclear layer and photoreceptor layer, where the EZ is discontinuous with retinal pigment epithelium (RPE) sparing. The patient was diagnosed with AMN, and 20 mg prednisone was prescribed for 1 week. During follow-up, her visual acuity gradually improved. The structural alterations of the outer retina appeared to be regressive (Fig. 1E–H). Patient 3 was a 13-year-old boy, with a visual field defect in both eyes after a COVID-19–associated fever 3 days prior. Patient 4 was a 29-year-old woman who experienced vision loss in both eyes the day she developed COVID-19. These 2 patients were confirmed with COVID-19 infection using antigen tests. The visual acuity and slitlamp examination results of anterior segment in both were normal. OCT depicted a hyperreflective blurred outer nuclear layer between the RPE and ONL in the macular in these 2 patients. ELM, EZ, and IZ layers could not be differentiated. They were diagnosed with AMN. Both of them did not use any medication, and the hyperreflective lesions were gradually absorbed over a period of 2 months. Reports of AMN coinciding with COVID-19 are increasing in number. We collected and analyzed 14 reported studies which clearly pointed out the age of patients and the time correlation between AMN onset and COVID-19 infection (see detail in supplementary digital content). Compared with other cases, 2 of our 4 cases were pediatric patients younger than 16 years. Few pediatric cases with AMN after COVID-19 have been reported so far. The onset of our cases were sudden (1–3 days after fevers), and ocular symptoms as well as the lesions in OCT were obvious. Our cases, together with cases in PubMed, revealed that the age span of patients with AMN after COVID-19 infection is wider than typically reported, and a high overlap in time between AMN onset and COVID-19 as Jalink et al3 reported. Azar4 also reported that during the peak period of the COVID-19 pandemic, the number of patients with AMN increased from 0.66/100 000 to 8.97/10 0000. Meanwhile, COVID-19 can cause inflammation reactions and vasculopathy due to hypercoagulable blood state, both of which are main components of AMN pathogenesis. It was speculated that the inflammatory response and thromboembolic events–related COVID-19 resulted in ischemia of the deep capillary plexus in the retina, which led to the destruction of photoreceptors and the outer nuclear layer, and the development of AMN.5 COVID-19 infection caused a series of ocular diseases including conjunctivitis, keratitis, scleritis, optic neuritis, orbital neuropathy, and retinopathies. It was reported that during hospitalization, nearly a third of COVID-19 patients had conjunctival symptoms. Nearly 10% patients had retinopathy, which were suspected to be related to endothelial cell infiltration or a blood hypercoagulable state. Beside these, cases of optic neuritis after COVID-19 have been reported. It is supposed the COVID-19–activated T cells to damage the myelin sheath causing optic neuritis. STATEMENT OF AUTHORSHIP Conception and design: Y. Hu, Y. Deng, X. Yin; Acquisition of data: Y. Hu, Y. Wang, C. Peng, H. Li, C. Yi, G. Li; Analysis and interpretation of data: Y. Hu. Drafting the manuscript: Y. Hu, Y. Wang, C. Peng, H. Li, C. Yi, G. Li; Revising the manuscript for intellectual content: Y. Hu. Final approval of the completed manuscript: Y. Hu, Y. Deng, X. Yin.