The COVID-19 pandemic has ushered in a “new normal,” significantly altering daily life and establishing new standards worldwide. The pandemic has also affected the incidence and course of certain diseases. Aydin et al. 15 demonstrated increased frequency and altered clinical features of pediatric uveitis during the pandemic period, compared with the pre-pandemic period. Azar et al. 16 demonstrated a significant increase in the incidence of acute macular neuroretinopathy from 0.66 per 100,000 people in 2019 to 8.97 per 100,000 people in 2020, which may be attributed to the COVID-19 pandemic. The present study was performed upon recognition of the increased number of hospital visits by patients with MEWDS during the pandemic period, compared with the pre-pandemic period. The annual visit rate of patients with MEWDS at our hospital also significantly increased from 2017 to 2022. Finally, the sex distribution differed between the pandemic and pre-pandemic periods.
In COVID-19, SARS-CoV-2 targets endothelial cells through the angiotensin-converting enzyme 2 receptor, causing disruption of intercellular junctions, cell swelling, and impaired barrier function. 17,18 When these abnormalities occur in the peripapillary circulation of the retina, inflammation may involve the outer retinal layer. Ocular inflammation after COVID-19 vaccination is caused by molecular mimicry between uveal peptides and vaccine peptide fragments, antigen-specific cell and antibody-mediated hypersensitivity reactions, and adjuvant-induced inflammatory damage. 9,19–21 The pathogenesis of MEWDS, described as “common cold of the retina” by Tavallali and Yannuzzi, 22 involves the entry of viral agents into retinal photoreceptor cells located at the border of the optic nerve and ora serrata, triggering an autoimmune response. 2,23 Therefore, episodes of COVID-19 and vaccination against the disease can increase the risk of MEWDS. Bosello et al. 24 demonstrated that the incidence of MEWDS was significantly higher in autumn, which may be due to the higher incidence of common influenza-like viral illnesses. We believe that increased viral transmission and vaccine use during the pandemic were associated with the increased frequency and altered clinical features of MEWDS.
In Group 2, two patients developed MEWDS after COVID-19, including Cases 5 and Case 11. Case 5 was a 13-year-old boy who presented with a 5-day history of blurred vision in the right eye. Because he exhibited cough and chills for 10 days, he was tested by COVID-19 polymerase chain reaction; the result was positive. He had not undergone COVID-19 vaccination because of his young age. Case 11, a 36-year-old man, developed a scotoma 10 days after diagnosis with COVID-19. Despite receiving a second booster vaccination approximately 1 year prior, this was his first episode of COVID-19. Jain et al. 25 reported the case of a 17-year-old boy who developed MEWDS after COVID-19; Zecevic et al. 11 described MEWDS in a patient with concurrent COVID-19. Smeller et al. 12 documented the case of a patient with COVID-19 who developed bilateral MEWDS. Also there was a case after COVID-19 vaccination. Case 7, a 78-year-old man, was the oldest patient in Group 2; he developed blurred vision for 7 days. This patient had received the fourth booster vaccination 2 weeks prior during admission to a nursing hospital. Soifer et al. 13 summarized 13 cases with COVID-19 vaccine-associated MEWDS and found that these patients had clinical features similar to the findings in patients who developed MEWDS after other vaccinations. All three cases of MEWDS associated with COVID-19 and vaccination against the disease occurred in male patients, indicating a significant difference in sex distribution among the groups. Despite the small sample size in the present study, the proportion of female patients was lower (58%) than in previous reports (80–90%).24,26,27 Cases 5 and 7 had outlier ages, which contributed to the wider age range in Group 2 compared with Group 1; furthermore, Group 2 included the oldest and youngest participants.
Two patients with MEWDS developed complications during the pandemic period. Case 2 (Fig. 2), a 40-year-old woman, developed complicated MNV 9 months after diagnosis with MEWDS. OCT demonstrated exudates and OCT angiography revealed MNV. FA showed well-defined hyperfluorescent leakage. This exudative lesion was resolved after anti-VEGF injection and appeared quiescent at the final follow-up. MNV is a rare complication of MEWDS, and few cases have been reported. Parodi et al. 28 performed a prospective study of four patients with MEWDS-related MNV, all of whom were successfully treated with anti-VEGF agents. Chen et al. 29 described four cases of MEWDS accompanied by type 2 MNV. Although the incidence of MNV in patients with MEWDS is unknown, this inflammation driven MNV is rare.
Case 9
(Fig. 3), a 23-year-old woman, complained of scotoma and blurred vision in the left eye, along with flu-like symptoms. Fundoscopy revealed juxtapapillary white lesions and OCT exhibited fluid accumulation as bacillary layer detachment (BALAD) with serous retinal datachment in corresponding lesion. Three days later, it was spreaded to the peripheral retina as white dot lesion in the manner characteristic of MEWDS. After 40 days, the left eye lesion had resolved but the patient developed similar symptoms in the right eye. Fundoscopy of the right eye revealed white dot-like lesions. Because the patient exhibited persistent fever and chills, she was evaluated for systemic diseases and diagnosed with Crohn’s disease. Fuganti et al. 30 reported two cases of BALAD associated with acute central serous chorioretinopathy in patients after COVID-19. They described development of BALAD may be related to the systemic inflammatory condition observed in patients with COVID-19. In addition, several cases of Vogt–Koyanagi–Harada disease, in which BALAD is most frequently observed, 31 after COVID-19 and vaccination against the disease have been reported. 32,33 This bilateral, sequentially developed MEWDS accompained with BALAD, was never reported before and we speculated that the underlying Crohn’s disease and the COVID-19 pandemic led to a more severe disease course and variable clinical findings.
Two female patients developed disease recurrence and were included in both groups. Case 10 experienced MEWDS before the pandemic, followed by disease recurrence in the right eye during the pandemic. Case 14 experienced the first episode of MEWDS before the pandemic and two disease recurrences during the pandemic. Ramakrishnan et al. 27 reported that 10 of the 73 patients with MEWDS (14%) in their study experienced disease recurrence; this proportion was similar to the present study, in which 2 of the 18 patients in both groups experienced recurrence (11%). Soifer et al. 13 described a case of recurrent MEWDS after COVID-19 vaccination, and they summarized two similar cases that were previously reported. These findings suggest that repeated exposure to viruses and vaccines during the pandemic can predispose an individual to MEWDS recurrence.
It is challenging to prove a causal relationship between MEWDS and episodes of COVID-19 or vaccination against the disease. However, previous studies have demonstrated an increased risk of uveitis after COVID-19 vaccination. Testis et al. 9 described 70 patients who exhibited ocular inflammation within 14 days of COVID-19 vaccination, among whom 12.9% had posterior uveitis. Rabinovitch et al. 14 reported 21 cases with uveitis after COVID-19 vaccination: 19 with anterior uveitis and 2 with MEWDS. The investigators suggested that a causal relationship between these conditions was likely based on the short time interval (< 30 days) between vaccination and uveitis; however, according to the WHO classification of adverse drug reactions, all patients had probable or possible causality. In South Korea, more than 87% of individuals have received COVID-19 vaccines and numerous people have experienced COVID-19. Moreover, it is challenging to determine the number of asymptomatic COVID-19 cases. Our results suggest that the complex changes associated with the pandemic, including multiple infections and immunological responses, contributed to the increased incidence of MEWDS and associated variable clinical findings.
This study had several limitations. First, the sample size was small due to the low incidence of MEWDS. To overcome this limitation, we acquired data over a long period of time (i.e., 6 years). Second, this was a retrospective study. To minimize variability across data, we applied the recent SUN classification criteria for MEWDS. Third, some cases had missing information related to COVID-19 or vaccination against the disease, making it challenging to determine a causal relationship. Fourth, data were collected from a single center, limiting the generalizability of our results to other populations. Nevertheless, our study is clinically valuable because we demonstrated an increased incidence of MEWDS during the pandemic period, compared with the pre-pandemic period. Future multicenter studies with a larger sample size are needed to clearly characterize the relationship between COVID-19 and MEWDS.
In conclusion, we observed a significantly greater number of patients with MEWDS presenting to our hospital during the COVID-19 pandemic period, compared with the pre-pandemic period. Furthermore, the annual visit rate of patients with MEWDS significantly increased over the 6-year study period. Considering the increased exposure to viruses and vaccines during the COVID-19 pandemic, the demographic and clinical features of MEWDS are likely to become more diverse.