https://orcid.org/0000-0002-2884-0736
ABSTRACT
Considering the widespread use of COVID-19 vaccines as a preventive measure against the spread of the virus, it’s necessary to direct attention to the adverse effects associated with vaccines in a limited group of populations. Multiple evanescent white dot syndrome (MEWDS) following COVID-19 vaccination is a rare adverse reaction associated with COVID-19 vaccines. In this systematic review, we collected 19 articles with 27 patients up to November 1, 2023, summarizing the basic information, clinical manifestations, examinations, treatments, and recoveries of the 27 patients. The 27 enrolled patients (6 males, 21 females) had a median age of 34.1 years (15–71 years old) and were mainly from 5 regions: Asia (8), the Mediterranean region (8), North America (7), Oceania (3) and Brazil (1). Symptoms occurred post-first dose in 9 patients, post-second dose in 14 (1 with symptoms after both), post-third dose in 1, and both post-second and booster doses in 1, while details on 2 cases were not disclosed. Treatments included tapered oral steroids (6), topical steroids (3), tapered prednisone with antiviral drugs and vitamins (1), and valacyclovir and acetazolamide (1), while 16 received no treatment. All patients experienced symptom improvement, and nearly all patients ultimately recovered. Moreover, we summarized possible hypotheses concerning the mechanism of COVID-19 vaccine-associated MEWDS. The findings provide insights into the clinical aspects of COVID-19 vaccine-associated MEWDS. More attention should be given to patients with vaccine-associated MEWDS, and necessary treatment should be provided to patients experiencing a substantial decline in visual acuity to improve their quality of life.
Introduction
Various vaccines have been developed during the global SARS-CoV-2 pandemic to protect individuals from COVID-19 infection and control the spread of the virus. According to the WHO COVID-19 dashboard, as of December 26, 2023, a total of approximately 13.59 billion doses of COVID-19 vaccines have been administered globally, 67% of the total population has received a complete primary series of COVID-19 vaccines, and 32% of the population has received at least one booster dose of a COVID-19 vaccine.Citation1 These vaccines include mRNA, viral vector, inactivated, and recombinant protein types. COVID-19 vaccines play a significant role in mitigating the transmission of the virus, but there are reports of severe adverse reactions, notably ocular complications.Citation2
Multiple evanescent white dot syndrome (MEWDS) is a rare, acute form of posterior uveitis identified by multiple, pale whitish dots visible in the midperiphery and posterior pole.Citation3 Patients primarily experience unilateral vision impairment, photopsia, and blind spot enlargement. A previous study conducted in the United States revealed that the annual incidence rate of MEWDS was 0.22/100,000 persons (95% CI, 0.04–0.39), based on a study in the Minnesota community population from 1998 to 2008.Citation4 Unfortunately, we were unable to find additional data regarding the global incidence of MEWDS. Nevertheless, the existing data indicate that the occurrence of MEWDS is rare in the natural population.
MEWDS occurs in young healthy adults, predominantly in women and myopic patients.Citation5 It usually takes several weeks for vision to return to normal or nearly normal, and vision rarely recurs. The number of patients that develop MEWDS following COVID-19 vaccination is so small that we have only identified 27 cases so far, but the number of cases has gradually increased over time and additional attention needs to be given to patients with vaccine-associated MEWDS.
Since the onset of the COVID-19 pandemic, several studies have reported MEWDS following COVID-19 vaccination. Additionally, similar occurrences of MEWDS have been observed after vaccination for other diseases, such as human papillomavirus (HPV), Meningococcus, hepatitis A, and influenza,Citation6–8 Owing to the widespread use of COVID-19 vaccines, this infrequent adverse reaction warrants our careful consideration.
This article summarized the similarities of different patients experiencing MEWDS after COVID-19 vaccination with the purpose of illustrating the possible pathogenesis of this type of MEWDS, which will contribute to future research on the precise pathogenesis of MEWDS.
Methods
Search strategy
The studies included in this research were obtained from the PubMed and Web of Science databases up to November 1, 2023. We searched the Web of Science using the following search format: TS = (“COVID-19 vaccine” OR “Coronavirus vaccine” OR “COVID-19 vaccination” OR “Coronavirus vaccination” OR “COVID-19 vaccinate” OR “Coronavirus vaccinate” OR “COVID-19 injection” OR “Coronavirus injection” OR “SARS-CoV-2 vaccine” OR “SARS-CoV-2 vaccination” OR “SARS-CoV-2 vaccinate” OR “SARS-CoV-2 injection”) AND (“Multiple evanescent white dot syndrome” OR “MEWDS” OR “Multiple Evanescent White-Dot Syndrome”) and searched PubMed with the same keywords listed above and without any restriction.
Study selection
As shown in , we retrieved a total of 42 articles (23 from PubMed and 19 from the Web of Science), which included 4 duplications. After reading the titles and/or abstracts to filter the unrelated records and records without complete clinical information, we finally collected 19 articles with 27 patients.
Figure 1. PRISMA flow diagram for study selection.
Results
Basic information
The basic information of the 27 patients is summarized in . Twenty-seven patients (six males, twenty-one females) had an average age of 34.1 years (15–71 years). These patients were mainly from 5 regions, with 8 from Asia (including 4 from China, 2 from Japan, 1 from India, 1 from Korea), 8 from the Mediterranean region (including 3 from France, 3 from Italy, 2 from Israel) 7 from North America (including 4 from the USA and 3 from Canada), 3 from Oceania (including 2 from Australia and 1 from New Zealand) and 1 from Brazil. Before the onset of symptoms, 3 patients had a history of MEWDS, 1 had myopia, 1 had myopia combined with a retinal tear, 1 had been infected with SARS-CoV-2, 1 had been diagnosed with central scotoma, and the other 19 had no special medical history. All 27 patients were vaccinated with COVID-19 vaccines, including 18 with the BNT162B2 vaccine, 3 with the (mRNA-1273) Moderna vaccine, 2 with the inactivated vaccine (Sinovac), 2 with the Oxford AstraZeneca COVID-19 (AZ) vaccine, 1 with the adenovirus vector-based COVID-19 vaccine (Covishield), and 1 with the Medigen Vaccine Biologics Corporation (MVC) COVID-19 vaccine. Symptoms occurred after the first dose in 9 patients, after the second dose in 14 patients(1 with symptoms after both), after the third dose in 1 patients, and after both the second and booster doses in 1 patient, while the details on 2 patients were not disclosed.
Table 1. Basic information of 26 patients.
Clinical manifestations
summarizes the main clinical features of the 27 patients. The time from vaccination to the onset of clinical symptoms ranged from 1 day to 3 months, with an average of 14.7 days. Nineteen patients involved had visual impairment (blurred vision or blurriness). Fifteen patients involved had photopsia. Six patients had scotomas. Visual field defects occurred in 4 patients. Symptoms were present in only one eye in 25 patients, 13 of whom had symptoms involving the right eye and 11 of whom had symptoms involving the left eye. Interestingly, 1 patient primarily had symptoms in the right eye, but symptoms recurred in the left eye after recovery of the right eye. Only 2 patients had symptoms in both eyes. Other ocular symptoms included eye metamorphopsia in 1 patient, an eye dark spot in 1 patient, and an eyebright spot in 1 patient. There are many other symptoms including flu-like symptoms in 3 patients, fever in 3 patients, myalgia in 2 patients, headache in 3 patients, soreness in 1 patient, and pain in 1 patient.
Table 2. Summary of clinical manifestation and examination of 26 cases of COVID-19 vaccine-associated MEWDS.
Examinations
Examinations including best corrected visual acuity (BCVA), ophthalmic specialty examination (including fundus autofluorescence (FAF), optical coherence tomography (OCT), fluorescein angiography (FA), indocyanine green angiography (ICGA), and visual field examination (VF), etc.) and other examinations (including general, serological, etc.), are summarized in . However, ocular examinations were not performed for 6 of the 27 patients. Hyperautofluorescent lesions detected by FAF were observed in 17 patients, disruption at the ellipsoid zone detected by OCT was detected in 13 patients, early hyperfluorescence detected by FA was observed in 11 patients, both early and late hyperfluorescence of the lesions were detected in 1 patient, hypocyanescent spots detected by ICGA were observed in 5 patients, multiple white lesions were detected in 8 patients, multiple small subretinal hyperreflective lesions were detected in 5 patients, cells in the vitreous were detected in 5 patients, multiple gray-white lesions were detected in 4 patients, an enlarged blind spot was detected in 4 patients, an altered macular reflex was detected in 3 patients, multiple yellowish-white lesions were detected in 2 patients, vitreous haze was detected in 2 patients, optic disc edema was detected in 2 patients, vitritis was detected in 2 patients, foveal granularity was detected in 2 patients, thickening of the retina’s outermost layers was detected in 1 patient, generalized reduction and paracentral islands of sensitivity loss were detected in 1 patient, irregularities of the outer retinal and retinal pigment epithelium were detected in 1 patient, posterior vitreous detachments were detected in 1 patient, increase in the flashing in both eyes was detected in 1 patient, retinal pigment epithelium atrophy in 1 patient, grayish lesions in 1 patient, anterior chamber inflammatory reaction in 1 patient, bilateral myopic degeneration in 1 patient, laser scars in 1 patient, and bilateral mild cataract in 1 patient. Most of the other examinations were normal but elevated equivalent series resistance was observed in 2 patients, hypertension was observed in 1 patient, and elevated cerebrospinal fluid pressure with elevated white blood cells was observed in another patient.
Treatment and recovery
The treatment and outcomes of the 27 patients included are summarized in . Among them, 6 patients were treated with tapered oral steroids, 3 patients were treated with topical steroids, 1 patient was treated with tapered prednisone combined with the antiviral agent acyclovir and vitamin B2 and C, 1 patient was treated with valacyclovir and acetazolamide, and 16 patients were not treated. There were 23 patients whose BCVA improved after treatment; among them, the BCVA of 18 patients returned to 20/20. However, the BCVA decreased in 1 patient after treatment. The final BCVA of 2 patients was unknown. Twenty-two patients recovered well, and the recovery time ranged from two weeks to nine months, with an average recovery time of approximately two months. Four patients experienced symptom improvement and 1 patient had an unknown outcome.
Table 3. Treatment and recovery of 26 patients.
Discussion
MEWDS is a type of primary inflammatory choriocapillopathy that is usually unilateral with characteristic multiple, small, white spots in the posterior pole or RPE, and was first reported in 1984.Citation27 The disease, which occurs more frequently in young women, involves multifocal retinopathy of the retinal pigment epithelium as well as the outer retina and usually presents with acute loss of vision but without systemic disease.Citation26 Because MEWDS is a benign lesion of inflammatory choriocapillopathy, it does not require treatment in most cases.Citation28 It usually takes several weeks for vision to return to normal or nearly normal with the resolution of white lesions, and the disease rarely recurs. The specific effects of steroids on MEWDS are not currently known, but it is certain that patients who use steroids seem to improve faster than those who do not based on the patients we reported.
We have summarized 27 cases of COVID-19 vaccine-associated MEWDS. Numerous studies have indicated that women, especially those between the ages of 20 and 40 are more likely to suffer from MEWDS than men are.Citation3 In this retrospective study, the average age of the patients was 34.1 years, and 77.8% were women, which was consistent with previous non-vaccine-associated studies. In addition, the clinical features are not significantly different between classic MEWDS and vaccine-associated MEWDS.Citation29,Citation30 Notably, among the 27 cases analyzed, three patients manifested a recurrence of MEWDS – an occurrence traditionally deemed uncommon in the context of MEWDS. Furthermore, the inclusion of older patients within our patient cohort constitutes an atypical feature, deviating from the usual age profile associated with MEWDS occurrence (71 years old, 67 years old, and 59 years old).
The typically used ocular examinations include: (1) enlarged blind spots on visual field examination (VF examination), (2) early patchy hyperfluorescence on FA, (3) patchy hypocyanescent spots in the posterior pole on ICGA, (4) disruption of the ellipsoid zone on OCT and (5) hyperautofluorescent spots on FAF.Citation1 The combination of FAF and OCT is appropriate for the diagnosis of MEWDS because they are complementary to each other and the hyperautofluorescence on FAF colocalizes with disruptions of the ellipsoid zone on OCT.Citation31
In our cohort, 16 patients received no treatment, while 11 patients underwent medical intervention. Given the self-limiting nature of MEWDS, the majority of patients will recover without requiring treatment. However, in certain instances, patients may experience a significant decrease in visual acuity, even to 20/400, necessitating medical intervention to enhance the patient’s quality of life.Citation11 The exact pathophysiology of this disease still lacks a unified consensus and there is a long-standing and wide-ranging debate about the precise location of the lesions. This debate derives from different pathophysiology explanations of the multimodal imaging of MEWDS. MEWDS is traditionally considered a primary inflammatory choriocapillaritis disease, as evidenced by the characteristic hypo-fluorescent lesions observed in ICGA, which are interpreted as hypoperfusion of the choriocapillaris.Citation28 However, this hypothesis contradicts the findings of several other researchers.Citation32,Citation33 With the widespread adoption of optical coherence tomography angiography (OCTA), some scholars have posited MEWDS as a primary photoreceptoritis disease, suggesting that OCTA reveals no discernible alterations in the choriocapillaris. In 2016, Pichi et al. asserted that MEWDS is indeed a primary photoreceptoritis disease, attributed to inflammation at the outer photoreceptor level, resulting in the loss of both the inner and outer segments.Citation33 Notably, in the late phase, ICGA revealed hypofluorescent lesions throughout all of the eyes examined in their study. In contrast, comparable retinal and choroidal circulation patterns in the eyes of patients with MEWDS and healthy eyes were observed via OCTA. En face OCT revealed that the hyporeflective lesions in the ellipsoid zone, which were converging in the central foveal area, matched the hypofluorescence on ICGA. With a combination of these multimodal imaging methods, the researcher claimed that MEWDS lesions may be located in the outer retina, challenging the previous assumption of their location in the choroid. However, dissenting opinions have been voiced by other researchers.Citation3,Citation28 Given the limitations of OCTA, which fails to visualize end-capillary circulation evident in ICGA, these researchers argue that the hypothesis of primary photoreceptoritis is a misinterpretation of OCTA and ICGA imaging.Citation3,Citation28 Zicarelli et al. confirmed the absence of alterations in the choriocapillaris on OCTA, and characterized MEWDS as a disease that primarily damages the RPE layer and consequently leads to secondary damage to the outer segments of the photoreceptor layer.Citation34 Furthermore, the activation of Müller cells may also represent a plausible pathophysiological mechanism. The hyperreflective dots observed on the fovea of the retina on en face OCT are thought to be linked to Müller cells, which govern retinal blood flow and modulate the immune response.
In summary, three primary hypotheses have been posited to elucidate the pathophysiology of MEWDS. First, MEWDS is classified as a primary inflammatory choriocapillaritis disease, and the hypofluorescence of the choriocapillaris and the photoreceptor layer are subsequently damaged. Secondly, it is proposed to be a primary inflammatory photoreceptoritis disease, causing a loss in both the inner and outer segments. Third, MEWDS is delineated as a primary RPE disease, resulting in secondary damage to the outer segments of the photoreceptor layer. In addition, recent research has indicated an association between MEWDS and Müller cell activation, which plays a regulatory role in immune and inflammatory responses.Citation35
The relationship between COVID-19 vaccines and MEWDS remains unclear, and we summarize the potential mechanisms of COVID-19 vaccine-associated MEWDS in . Molecular mimicry is the most likely mechanism involved. The structural similarities between pathogens and self-proteins prompt the activation of autoreactive T cells or B cells among genetically predisposed individuals upon vaccination, a phenomenon known as molecular mimicry. Previous studies have indicated the presence of autoantibodies targeting both human epitopes and infectious agents in individuals infected with COVID-19, and cross-reactivity has been observed in prepandemic acutely infected patients,Citation39 suggesting that molecular mimicry may constitute a plausible mechanism for this form of MEWDS. In addition, hypersensitivity reactions to COVID-19 vaccination have been reported,Citation40 which may serve as another proposed mechanism of this type of MEWDS. Vaccine-induced hypersensitivity reactions are recognized as IgE-dependent and manifest through either a G protein signaling pathway or the activation of the complement system. Moreover, vaccine adjuvants integrated into vaccine formulations to augment efficacy may contribute to ASIA among genetically predisposed individuals. Adjuvants are considered to primarily target dendritic cells (DCs) and monocytes, granulocytes, B cells, and lymph node-resident macrophages may also be essential for adjuvanticity.Citation41 Last but not least, live vaccines may infect ocular tissue directly.Citation13
Figure 2. The potential mechanisms of COVID-19 vaccine-associated MEWDS. Including (1) molecular mimicry,Citation36 (2) hypersensitivity reactions,Citation37 (3) adjuvant-induced autoimmunity,Citation38 and (4) direct infection with attenuated, live vaccines.Citation13
MEWDS has also been observed after other various vaccinations, including influenza, rabies and human papillomavirus, which are summarized in . Therefore, it is worth noting that vaccine-associated MEWDS is not limited to COVID-19 vaccines, and more attention should be given to patients following the occurrence of MEWDS. Active treatment foe MEWDS should be provided during vaccination.COVID-19 vaccines are also associated with many other categories of ocular diseases, including Vogt – Koyanagi – Harada,Citation48 nonarteritic anterior ischemic optic neuropathy,Citation49 retinal vasculitis,Citation50 and optic neuropathies,Citation51 but most cases of uveitis and other ocular complications associated with COVID-19 vaccines have a good prognosis, as shown by 34 patients with various ocular complications caused by COVID-19 vaccines.Citation25
Table 4. Summary of MEDWS caused by different vaccines.
In summary, we reviewed 27 cases of MEWDS, a rare posterior uveitis, following COVID-19 vaccination. However, COVID-19 vaccine-associated MEWDS has not been identified and need to be further explored. Our study has several limitations. The occurrence of MEWDS in some areas has not been reported, and we may also have missed some cases. The number of MEWDS cases caused by COVID-19 vaccines is still small, which may be due to chance. In the postpandemic era, various adverse reactions following COVID-19 vaccines such as MEWDS need to receive more attention to ensure that humans can overcome COVID-19 and reduce damage. In addition, paying attention to adverse reactions to vaccines can provide a reference for preventive medicine and help maintain the health of people around the world. Nevertheless, various COVID-19 vaccines play a significant role in mitigating the rates of infections, hospitalization/severity and mortality.Citation52 Notably, the benefits of COVID-19 vaccines outweigh the risk of the adverse reactions.
Conclusion
In addition to common uveitis, clinicians need to be aware of MEWDS following COVID-19 vaccines and distinguish this disease by FAF, OCT, and other examination methods to reassure patients. The findings provide insights into the clinical aspects of COVID-19 vaccine-associated MEWDS. More attention should be given to patients with vaccine-associated MEWDS and necessary treatment should be provided to patients experiencing a substantial decline in visual acuity to improve their quality of life. Although COVID-19 vaccines may be associated with these unavoidable adverse reactions, we highly recommend the COVID-19 vaccines because of their indispensable role during the COVID-19 pandemic.
Author contribution
Yuqin Zeng and Ziye Du contributed equally as first authors. Mingyi Zhao contributed as correspondence author. Mingyi Zhao, Ziye Du, and Yuqin Zeng designed the study, Ziye Du and Yuqin Zeng carried out the manuscript searches, extracted the data; Chuhan Shao contributed to polishing articles; Ziye Du, Yuqin Zeng, Mingyi Zhao, and Chuhan Shao revised the manuscript. All authors agree to be accountable for all aspects of the work.
Acknowledgments
Thanks to Teacher Li Dan for her contribution to drawing .
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All data generated in this article are included in the paper and supplementary materials.
Additional information
Funding
References
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