Multiple Evanescent White Dot Syndrome (MEWDS)

Key points of this disease

• Multiple evanescent white dot syndrome (MEWDS) was first reported by Jampol et al. in 1984 ¹⁷⁾. It is an acute inflammatory disease that typically occurs unilaterally in young myopic women.
• The primary pathology is transient dysfunction of the outer retina and ellipsoid zone, with multiple gray-white spots appearing from the posterior pole to the equator of the fundus.
• The male-to-female ratio is 1:4, with a strong predominance in women, and it most commonly occurs in the 20s to 50s. The annual incidence is reported to be approximately 0.22 cases per 100,000 people ¹⁰⁾.
• Foveal granularity is an important diagnostic finding, observed in 74–96% of cases ^2,5).
• Fundus autofluorescence (FAF) is useful for detecting lesions even in cases where white dots are unclear on fundus photographs ²⁾.
• FA shows wreath-like hyperfluorescence, and ICGA shows a pattern of late hypofluorescence ^2,6).
• OCT can confirm disappearance or disruption of the ellipsoid zone in the active phase, and visual acuity improves with recovery ^2,3).
• Spontaneous recovery within a few weeks is common, and the basic approach is observation. Anti-VEGF therapy is considered in cases complicated by choroidal neovascularization (CNV) ¹⁾.
• Rarely, recurrence or bilateral involvement occurs, and cases following COVID-19 infection or vaccination have been reported ^11,14,15).

1. What is Multiple Evanescent White Dot Syndrome?

Multiple evanescent white dot syndrome (MEWDS) is an acute inflammatory disease first reported by Jampol et al. in 1984 ¹⁷⁾. It typically occurs unilaterally in young myopic women, presenting with numerous pale gray-white spots at the level of the deep retina to the retinal pigment epithelium (RPE) in the posterior pole to the equator. The white spots almost disappear over several weeks, and visual acuity improves; it is a self-limiting disease.

According to the Uveitis Clinical Practice Guidelines (Journal of Japanese Ophthalmological Society 2019;123(6):635-696), it is classified as non-infectious posterior uveitis predominantly involving fundus lesions, characterized by unilaterality, acute onset, and transient course ¹⁾.

MEWDS is considered part of the AZOOR complex (MEWDS, AZOOR, AMN, PIC, MFC, AIBSE, AAOR), and these diseases are regarded as a continuum (spectrum) of inflammatory disorders primarily affecting the outer retina, photoreceptors, and RPE ²⁾. Among the white dot syndromes, MEWDS is one of the diseases whose pathophysiology has been most elucidated through multimodal imaging ²⁾.

Epidemiology

• Age of onset: 20s to 50s
• Sex ratio: 1:4, overwhelmingly more common in women¹⁾
• Annual incidence: approximately 0.22 cases per 100,000 people¹⁰⁾
• Predilection for myopic eyes, often unilateral
• About half of cases have flu-like prodromal symptoms 1–2 weeks before onset¹⁾
• Precipitating factors include flu-like symptoms, oral contraceptive use, vaccination, and upper respiratory tract infection¹⁾
• Bilateral involvement is rare, often asymmetric, and the milder side may be asymptomatic¹⁸⁾
• Atypical ages have been reported; the youngest is a 9-year-old girl¹³⁾ and the oldest is a 75-year-old man¹⁰⁾

Q Does MEWDS recur?

A

Most cases resolve after a single episode, but recurrences are observed in about 10% (14% in a large retrospective cohort)¹¹⁾. Although some case reports show a temporal association with vaccination or infection, a causal trigger for recurrence has not been established.

2. Main symptoms and clinical findings

Papasavvas I, et al. Choroidal vasculitis as a biomarker of inflammation of the choroid. Indocyanine Green Angiography (ICGA) spearheading for diagnosis and follow-up, an imaging tutorial. J Ophthalmic Inflamm Infect. 2024. Figure 5. PMCID: PMC11618284. License: CC BY 4.0.

Fundus photographs show faint white dot lesions in the posterior pole. FA and ICGA reveal scattered dot lesions, and FAF also shows abnormal signals, providing a visual understanding of the clinical findings of MEWDS.

Subjective symptoms

• Acute unilateral vision loss, blurred vision, photopsia, floaters, visual field defects¹⁾
• Enlarged Mariotte blind spot, central scotoma, visual field constriction¹⁾
• Marked flattening of amplitude near the macula on ERG or multifocal ERG in the acute phase¹⁾

Fundus Findings

Multiple pale patchy lesions scattered in the deep retinal layer to RPE from the posterior pole to the equator of the fundus¹⁾. The white spots range in size from 100 to 200 μm, vary in size, and may coalesce. Mild optic disc hyperemia and mild vitreous cells may be observed¹⁾. Foveal granularity (orange to yellow granular appearance) is a diagnostic finding detectable on near-infrared FAF, seen in 74–96% of cases, and may be the only finding after the white spots resolve²⁾⁵⁾.

Other clinical findings include the following:

• Relative afferent pupillary defect (RAPD): rarely positive
• Optic disc edema: may be accompanied by peripapillary serous subretinal fluid
• Retinal venous sheathing and retinal hemorrhages: rare findings

Acute Phase Findings

Fundus white spots: Numerous pale gray-white spots scattered from the posterior pole to the equator. They are smaller and more widespread than the spots in APMPPE¹⁾.

Foveal granularity: A diagnostic finding confirmed by near-infrared FAF and slit-lamp biomicroscopy as foveal granularity. It appears in the active phase and resolves with recovery²⁾⁵⁾.

FAF (fundus autofluorescence): Shows hyperautofluorescence in the acute phase, with a mixture of hypofluorescence and hyperfluorescence¹⁾²⁾.

OCT: Marked disruption or loss of the ellipsoid zone and focal thickening of the RPE. Disruption of the IS/OS line in the active phase is useful for diagnosis²⁾³⁾.

Remission Phase Findings

Resolution of white spots: White spots disappear within a few weeks, and visual acuity improves¹⁾.

Recovery of the ellipsoid zone: The ellipsoid zone on OCT often recovers over time²⁾³⁾. This correlates with visual acuity improvement.

Preservation of choriocapillaris: On OCT-A, choriocapillaris blood flow is generally preserved, although transient flow voids have also been reported in some cases^4,8).

Q What is the "scintillation" (photopsia) felt in MEWDS?

A

Photopsia is thought to be related to changes in the outer retina and ellipsoid zone that are transiently impaired in MEWDS. It usually resolves with recovery from the disease²⁾.

3. Causes and Risk Factors

Pathophysiology

The primary site of MEWDS is the outer retina and ellipsoid zone (IS/OS), while the choriocapillaris is generally preserved²⁾. Late-phase hypofluorescence on ICGA is observed, but it has been suggested that this may result from abnormal pigment uptake due to RPE dysfunction rather than ischemia of the choriocapillaris²⁾. Choriocapillaris impairment (ICGA findings) is also observed around the optic disc where no white spots are seen, and may be more extensive than the clinically visible lesions¹⁾.

Triggers and Risk Factors

• Unknown cause. Hypotheses include autoimmune and viral infection triggers.
• Preceding factors: flu-like symptoms (influenza, mumps, etc.), oral contraceptive use, vaccination, upper respiratory tract infection¹⁾
• Myopia (especially moderate to high myopia)
• Temporal associations with flu-like symptoms, infection, vaccination, etc., have been reported, and immune mechanisms are being considered as hypotheses, but the established cause is unknown^2,7)
• Vaccination: Onset after hepatitis B, influenza, HPV, meningococcal, and COVID-19 vaccines has been reported^11,14,15). A review of 27 cases after COVID-19 vaccination found a mean time from vaccination to onset of 14.7 days (range 1–90 days)¹⁴⁾
• COVID-19 infection: Multiple cases of MEWDS onset after SARS-CoV-2 infection have been reported. A review of 7 reported cases found a mean time from infection to onset of 29.6 days (range 0–70 days)¹⁴⁾

Proposed mechanisms for post-vaccination onset include molecular mimicry, immune response to vaccine components, and complement activation, but these are not established causal mechanisms¹⁵⁾. A preliminary report also suggests that the frequency of the HLA-B51 haplotype is 3.5 times higher in MEWDS patients than in normal controls¹²⁾.

Prevention and Daily Care

If you experience sudden vision loss, visual field abnormalities, or photopsia after a cold or while cold-like symptoms persist, promptly consult an ophthalmologist, as differentiation from other types of posterior uveitis is necessary¹⁾.

4. Diagnosis and Examination Methods

The diagnosis of MEWDS is made based on characteristic fundus findings and multimodal imaging.

Imaging Tests

Test	Characteristic Findings
FA	Wreath-like hyperfluorescence of the white spots from the early phase, persisting into the late phase. Optic disc leakage present2)6)
ICGA	Late-phase hypofluorescence of the white spots. Extensive hypofluorescent areas beyond clinical findings. Peripapillary hypofluorescent spots also appear1)2)
FAF (Fundus Autofluorescence)	Hyperautofluorescence in the acute phase. Mixed hypofluorescence and hyperfluorescence. Useful for diagnosis1)2)
SD-OCT	Marked disruption or loss of the ellipsoid zone and focal thickening of the RPE in the active phase2)3)
OCT-A	Choriocapillaris blood flow is generally preserved (some reports of flow void 4)8))
Multifocal ERG	Macular amplitude flattening (acute phase). Normalizes with recovery 1)
Goldmann perimetry	Enlarged Mariotte blind spot, central scotoma 1)

Diagnostic points

A key feature of MEWDS is that FA shows hyperfluorescence from the early phase, which is an important distinction from APMPPE. APMPPE shows a reversal phenomenon (early hypofluorescence → late hyperfluorescence), whereas MEWDS shows persistent hyperfluorescence from the early phase ²⁾⁶⁾. In OCT, the ellipsoid zone (IS/OS line) becomes irregular during the active phase, and improvement of this irregularity correlates with visual recovery, which is an important finding for understanding the pathology ³⁾.

Differential diagnosis (from Uveitis Clinical Practice Guidelines “Table 3”) ¹⁾

Disease	Key differentiating features
APMPPE	Bilateral, large plaques, FA fluorescence reversal (early hypofluorescence → late hyperfluorescence)
AZOOR	Normal fundus, only ERG abnormalities
AIBSE	Peripapillary annular gray-white opacity, enlargement of Mariotte blind spot
AMN	Reddish-brown macular lesion
AAOR	Annular gray-white opacity in the deep retina
PIC	Moderate myopia in women, small yellow-white spots in the posterior pole, high rate of CNV (reported as 40–76% in English literature), often bilateral
Birdshot chorioretinopathy, multifocal choroiditis	Persistent inflammation, bilateral
Sarcoidosis, intraocular lymphoma	Systemic involvement, persistent inflammation

Q How do you differentiate MEWDS from PIC?

A

MEWDS tends to be unilateral, transient, and fully recover, whereas PIC is often bilateral, leaving atrophic scars or complicated by choroidal neovascularization (CNV). On FA, MEWDS shows hyperfluorescence from the early phase, while PIC shows leakage in the late phase. On OCT-A, the choriocapillaris is generally preserved in MEWDS, but PIC may show more pronounced changes¹⁾.

5. Standard Treatment

Basic Policy

Since spontaneous healing can be expected without special treatment, observation is the basic approach for mild cases¹⁾. White spots disappear spontaneously within weeks, and visual prognosis is good. Over time, the ERG becomes quiescent and normalizes¹⁾.

Indications for Anti-inflammatory Therapy

Because of the strong tendency for spontaneous improvement, most cases do not require treatment¹⁾. In cases with significant visual loss or papilledema, anti-inflammatory treatment may be considered on an individual basis, but standard drugs and dosages have not been established.

In a review of 7 cases of COVID-19-associated MEWDS, 5 cases (71%) received some form of treatment, suggesting that COVID-19-associated cases may be slightly more severe than viral MEWDS in general¹⁴⁾. Cases of incomplete visual recovery have also been reported, and careful follow-up is required for COVID-19-associated cases.

Chronic Recurrent Cases

Recurrent or persistent cases are rare. One recurrent case treated with cyclosporine has been reported, but this does not demonstrate efficacy as a standard treatment¹⁹⁾.

Cases Complicated by CNV

When choroidal neovascularization is present, intravitreal anti-VEGF agents (bevacizumab, ranibizumab, aflibercept) should be considered¹⁾. Although CNV is rare, it can cause poor visual prognosis and requires attention. OCT-A is useful for assessing CNV activity and aids in treatment decisions and efficacy evaluation of anti-VEGF therapy⁸⁾.

Treatment Precautions

Cases with CNV are at risk of irreversible visual loss. If there is rapid worsening of visual acuity or increased metamorphopsia, anti-VEGF therapy should be considered promptly. Treatment decisions should be made by the attending ophthalmologist.

Q Does steroid treatment lead to faster recovery?

A

Since this disease generally has a strong tendency for spontaneous improvement, treatment is unnecessary in most cases. The uveitis clinical guidelines also state that “spontaneous recovery without special treatment” is the basic policy¹⁾. Although steroids may be used in severe cases, there is no established evidence that they accelerate recovery compared to the natural course.

6. Pathophysiology and Detailed Pathogenesis

The main site of damage in MEWDS is the outer retina and ellipsoid zone (IS/OS junction), while the choriocapillaris is generally preserved²⁾. This is an important pathophysiological difference from APMPPE.

Outer retina / ellipsoid zone damage

On OCT, the ellipsoid zone (the junction between the inner and outer segments of photoreceptors) becomes irregular or absent during the active phase. It has been reported that visual acuity recovers as this disruption improves, indicating that transient and reversible outer retinal damage is the essence of MEWDS ³⁾. Recent en face swept-source OCT has also visualized the extent of lesions that were difficult to recognize on conventional tomographic images ³⁾.

ICGA and choriocapillaris

Although late-phase hypofluorescence is observed on ICGA, it has been suggested that this may result from abnormal pigment uptake due to RPE dysfunction rather than ischemia of the choriocapillaris ²⁾. On OCT-A, blood flow in the choriocapillaris is generally preserved, with transient flow voids reported only in some cases ⁴⁾⁸⁾. Studies using swept-source OCT-A have confirmed sparing of the choriocapillaris in MEWDS ⁴⁾.

Foveal granularity

Foveal granularity observed on near-infrared FAF is a characteristic finding reflecting damage to the foveal photoreceptor layer ²⁾⁵⁾. It can also be detected on multicolor imaging (near-infrared reflectance and blue reflectance) and is considered useful for diagnosis in the active phase.

Positioning as part of the AZOOR complex

A concept has been proposed that integrates MEWDS, AZOOR, PIC, and MFC as part of the AZOOR complex ^2,7). Jampol and Becker (2003) hypothesized that these diseases share a common genetic autoimmune and inflammatory mechanism, but specific genetic factors unique to MEWDS have not been established ⁷⁾.

7. Latest research and future perspectives

For patients: Please read this

The following content is currently at the research stage and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

• OCT-A assessment of choriocapillaris function: Transient detection of flow voids in the choriocapillaris using swept-source OCT-A has been reported, and reevaluation of the involvement of the choriocapillaris is ongoing⁴⁾⁸⁾. In some cases, decreased choriocapillaris blood flow is also observed, suggesting diversity in the pathophysiology⁸⁾.
• En face swept-source OCT: Reports are increasing on this new diagnostic method that three-dimensionally visualizes the shape, distribution, and inner layer boundaries of white dot lesions³⁾.
• Evolution of the AZOOR complex concept: Research is advancing toward an integrated understanding of MEWDS, AZOOR, PIC, AMN, AIBSE, and AASR as a single spectrum²⁾⁹⁾. Zicarelli et al. (2020) proposed a new interpretation of the pathophysiology of MEWDS⁹⁾.
• Multicolor imaging: Development of clinical diagnostic aids using near-infrared reflectance and blue reflectance. Noninvasive assessment of foveal granularity is now possible⁵⁾.
• MEWDS after COVID-19 infection and vaccination: Case reports after infection and after mRNA vaccination have accumulated, and the association with immune triggers is being investigated^14,15).
• Recurrence rate and long-term prognosis data: Accumulation of large-scale long-term follow-up studies is awaited.

Association between COVID-19 and MEWDS

Chen et al. (2024) reviewed 7 cases of MEWDS occurring after COVID-19 infection in the literature and reported a mean age of 38.4 years, 5 female patients, and a mean interval from infection to onset of 29.6 days¹⁴⁾. Two cases (29%) were bilateral, and 5 cases (71%) received treatment, suggesting that COVID-19-related cases may have a higher likelihood of incomplete visual recovery and need for therapeutic intervention than typical cases.

Regarding COVID-19 vaccine-associated MEWDS, a review summarizing 27 previously reported cases showed a mean age of 34.1 years, female predominance, and a mean interval from vaccination to onset of 14.7 days¹⁴⁾. The mRNA vaccine (Pfizer-BioNTech) was the most common.

Vaccination and recurrence

Ramirez Marquez et al. (2022) reported a 17-year-old female who developed MEWDS after simultaneous HPV and meningococcal vaccination, and subsequently experienced two recurrences in the contralateral eye following COVID-19 infection and BNT162b2 vaccination¹¹⁾.

Reports of Atypical Cases

Yasuda et al. (2022) reported a 67-year-old Japanese woman who developed MEWDS the day after receiving the second dose of the BNT162b2 mRNA vaccine¹⁵⁾. She had moderate vitreitis, and visual acuity decreased to 0.2 but recovered to 0.8 without treatment.

Wiley et al. (2022) reported a case of a 17-year-old female who developed bilateral optic disc edema and MEWDS-like white dot lesions two days after SARS-CoV-2 vaccination, with cerebrospinal fluid examination revealing an opening pressure of 55 cmH2O and a white blood cell count of 48 cells/μL, consistent with uveomeningeal syndrome¹⁶⁾. This was the first report of uveomeningeal syndrome associated with MEWDS.

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8. References

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