Acute Exudative Polymorphous Vitelliform Maculopathy (AEPVM)

Key Points at a Glance

Highlights of this disease

• Acute exudative polymorphous vitelliform maculopathy (AEPVM) is an extremely rare retinal disease characterized by bilateral multiple vitelliform subretinal lesions.
• It is classified into two types: idiopathic and paraneoplastic (associated with malignancy or immune checkpoint inhibitors).
• Fundus autofluorescence (FAF) is a key diagnostic test, characterized by high autofluorescence of the vitelliform material. ¹⁾
• Genetic testing (next-generation sequencing) is important for differentiating from similar diseases such as Best vitelliform macular dystrophy. ¹⁾
• Idiopathic cases are self-limiting, and vision recovers spontaneously in most cases.
• In paraneoplastic cases, ocular symptoms may precede the discovery of the primary tumor.
• Only about 20 idiopathic cases have been reported in the literature, making it an extremely rare disease. ¹⁾

1. What is Acute Exudative Polymorphous Vitelliform Maculopathy?

Acute Exudative Polymorphous Vitelliform Maculopathy (AEPVM) is a rare retinal disease characterized by bilateral, multiple yellowish-white subretinal lesions corresponding to serous retinal detachment. It was first reported by Gass et al. in 1988 (Trans Am Ophthalmol Soc 1988).

Age of onset ranges from 13 to 69 years, with no gender predilection. ¹⁾ It occurs mainly in Caucasians but has also been reported in other races. Only about 20 idiopathic cases have been reported in the literature. ¹⁾

AEPVM is classified into the following two types based on etiology:

• Idiopathic: thought to involve viral infection or autoimmune mechanisms
• Paraneoplastic: caused by malignant tumors or immune checkpoint inhibitors

This disease is classified under ICD-10 code H35.89 (Other specified retinal disorders).

Q How rare is AEPVM?

A

Only about 20 idiopathic AEPVM cases have been reported in the literature, making it an extremely rare disease. ¹⁾ Including paraneoplastic cases, the number of reports is increasing, but both types have few cases worldwide.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Bilateral visual acuity loss: Subacute onset, progressing over several weeks. ¹⁾
• Blurred vision: Often occurs in both eyes.
• Metamorphopsia: Appears with macular lesions.
• Headache: May be present in the acute phase of idiopathic AEPVM.

Clinical Findings

The main fundus finding is bilateral, symmetric, multiple yellowish-white subretinal lesions. The morphology of the lesions is diverse, taking various forms such as round, oval, or curvilinear. They are mainly located in the macula, but bleb-like lesions may also be observed along the vascular arcades. ¹⁾

The yolk-like material within the lesions may settle downward due to gravity, forming a meniscus-like fluid level (pseudohypopyon). ¹⁾ There is no vitreous inflammation or vasculitis, and no optic disc abnormalities. ¹⁾

Fundus findings differ between the acute and recovery phases. The findings for the two stages are shown below.

A comparison between the acute and recovery phases is shown below.

Stage	Fundus Findings	Visual Acuity
Acute phase	Multiple yolk-like lesions + serous retinal detachment	Decreased
Convalescent stage	Serous fluid disappears → downward sedimentation of egg yolk-like material	Tendency to improve

3. Causes and Risk Factors

AEPVM is classified into two types: idiopathic and paraneoplastic, each with different causes and pathogenesis.

Idiopathic

Prior infection history: Viral prodromes (HCV, Coxsackie B, EBV, HIV, COVID-19), syphilis, Lyme disease, and other infections may precede onset.

Ocular trauma: Ocular trauma before onset has been reported as a trigger in some cases.

Autoimmune hypothesis: Anti-peroxiredoxin 3 (PRDX3) antibodies are detected in the acute phase and disappear after remission. Autoantibodies against RPE and photoreceptor proteins are thought to be involved in the pathogenesis.

Idiopathic cases: There are also purely idiopathic cases where systemic and genetic tests are all negative. ¹⁾

Paraneoplastic

Melanoma: Cutaneous melanoma and choroidal melanoma are the most common causative malignancies.

Other malignancies: Associations with lung cancer, breast cancer, colon cancer, etc., have been reported.

Immune checkpoint inhibitors: May occur in association with the use of BRAF inhibitors (vemurafenib, dabrafenib) and PD-1 inhibitors (pembrolizumab, nivolumab).

Pathogenesis: It is thought that cross-reactivity (molecular mimicry) between tumor antigens and retinal antigens triggers an autoimmune response against RPE and photoreceptors.

Guidance on Consultation and Follow-up

If you experience unexplained bilateral vision loss or blurred vision, please consult an ophthalmologist promptly. Systemic examination (to rule out malignancy) is essential for diagnosing AEPVM, and collaboration with internal medicine or oncology may be important. If you are already being treated for a malignancy and using immune checkpoint inhibitors, be sure to inform your doctor of any vision changes.

4. Diagnosis and Examination Methods

Fundus photograph and OCT findings of AEPVM

Mohamed Osman; Omar Mehana; Mahmoud Eissa; et al. Coronavirus Disease 2019-induced Acute Exudative Polymorphous Vitelliform Maculopathy. Middle East African Journal of Ophthalmology. 2023 Sep 29. Figure 1. PMCID: PMC10754108. License: CC BY.

A side-by-side view of fundus photographs and OCT of both eyes. The distribution of macular lesions and subretinal changes are summarized for easy understanding.

The diagnosis of AEPVM is one of exclusion, requiring a systematic process to rule out similar diseases. A combination of multimodal imaging is key to diagnosis. ¹⁾

Imaging Tests

OCT (Optical Coherence Tomography): Detects dome-shaped neurosensory retinal detachment and hyperreflective or isoreflective subretinal deposits. During the recovery phase, resolution of subretinal fluid and reattachment of the RPE can be observed. Thickening of the ellipsoid zone is also noted. ¹⁾

FAF (Fundus Autofluorescence): The vitelliform material shows hyperautofluorescence. This is the most important test for diagnosis. ¹⁾ It reflects accumulation of lipofuscin and fluorescent pigments.

FA (Fluorescein Angiography): The vitelliform material appears hypofluorescent or non-fluorescent. It characteristically shows a pattern inverted from FAF. No leakage is observed.

Functional and Genetic Tests

EOG (Electrooculography): A decreased Arden ratio is observed, reflecting RPE dysfunction.

ERG (Electroretinography): Amplitude reduction may be observed.

Genetic Testing: Searching for BEST1 and PRPH2 mutations using next-generation sequencing panels is important. Negative results for these mutations can rule out Best vitelliform macular dystrophy. ¹⁾

Systemic Examination: A thorough systemic workup to rule out malignancy is mandatory. ¹⁾

The reversal pattern of FA and fundus autofluorescence (FAF) is a characteristic finding of this disease.

Finding	FA	FAF
Yolk-like material	Hypofluorescence	Hyperautofluorescence
Serous portion	Mild hyperfluorescence	No fluorescence

Differential Diagnosis

AEPVM must be differentiated from the following diseases.

• Best vitelliform macular dystrophy (BVMD): Differentiated by genetic testing (BEST1 mutation). AEPVM does not have BEST1 mutations. ¹⁾
• Adult-onset foveomacular vitelliform dystrophy (AVMD): Differentiated by the presence or absence of PRPH2 mutations.
• Vogt-Koyanagi-Harada disease (VKH): FA shows marked hyperfluorescence of the optic disc and pin-point leakage. AEPVM can be differentiated by the absence of leakage.
• Primary vitreoretinal lymphoma: Tends to be more asymmetric than AEPVM and often accompanied by vitreous opacity.

Q How to differentiate from Best disease (Best vitelliform macular dystrophy)?

A

Best disease is a hereditary disorder caused by mutations in the BEST1 gene and can be differentiated by genetic testing. In AEPVM, next-generation sequencing genetic testing shows negative for BEST1 and PRPH2 mutations. ¹⁾ The onset pattern (acute vs. gradual) and family history also aid in differentiation.

5. Standard Treatment

There is no established drug therapy for AEPVM. Idiopathic AEPVM is a self-limiting disease, and spontaneous recovery can be expected.

• Observation is the mainstay: Regular fundus examination and OCT monitoring are performed. In the report by Fernandes et al., complete remission was achieved after 6 months. ¹⁾
• Steroid therapy: Its efficacy for idiopathic AEPVM has not been confirmed and is not recommended as standard treatment at present.
• Cases with choroidal neovascularization (CNV): If CNV occurs, intravitreal injection of anti-VEGF agents is indicated.
• Paraneoplastic AEPVM: If association with immune checkpoint inhibitors (BRAF inhibitors, PD-1 inhibitors) is suspected, the appropriateness of drug discontinuation should be determined in collaboration with oncology, considering the treatment status of the primary tumor. Switching to alternative immunotherapy may also be considered.

Points to Note in Diagnosis and Treatment

• AEPVM is a diagnosis of exclusion. It is essential to exclude other diseases through systemic examination (malignancy workup) and genetic testing. ¹⁾
• In paraneoplastic AEPVM, ocular symptoms may appear before the primary tumor is detected. If bilateral vitelliform lesions are observed, systemic evaluation for possible malignancy is important.
• If visual changes occur in patients using immune checkpoint inhibitors, retinal complications including this disease should be suspected early.

Q What is the visual prognosis for idiopathic AEPVM?

A

Idiopathic AEPVM is a self-limiting disease, and spontaneous visual recovery is expected in many cases. In the case by Fernandes et al., best-corrected visual acuity improved to 20/25 in both eyes after 6 months, and OCT confirmed complete resolution of subretinal fluid. ¹⁾ However, the degree of recovery varies by case.

6. Pathophysiology and Detailed Pathogenesis

The exact pathogenesis of AEPVM remains largely unknown. The main hypotheses currently proposed are as follows.

RPE Dysfunction Hypothesis

Dysfunction of the retinal pigment epithelium (RPE) leads to lipofuscin accumulation and serous retinal detachment. Physical separation of the neurosensory retina and RPE impairs normal phagocytosis of photoreceptor outer segments. Shed photoreceptor outer segments are thought to accumulate in the outer retina and subretinal space (Spaide hypothesis). The hyperautofluorescence observed on FAF reflects this accumulation of lipofuscin and fluorescent pigments.

Autoimmune Hypothesis

Autoantibodies against RPE and photoreceptor proteins are thought to be involved in the pathogenesis. The following have been reported as putative target antigens of autoantibodies:

• Recoverin
• Transducin-α
• Peroxiredoxin 3 (PRDX3): Anti-PRDX3 antibodies have been detected in the acute phase of idiopathic AEPVM and disappeared after remission in reported cases.
• Carbonic anhydrase 2
• 120 kDa photoreceptor protein
• 145 kDa interphotoreceptor retinoid-binding protein

In paraneoplastic cases, cross-immune reactions (molecular mimicry) between tumor antigens and common antigens of the retina and RPE are speculated to cause the formation of vitelliform lesions.

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7. Latest Research and Future Perspectives (Reports at Research Stage)

For patients: Please read this

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

Establishment of diagnosis using multimodal imaging

The combination of color fundus photography, SD-OCT, and FAF is making it possible to clinically diagnose AEPVM without invasive testing. ¹⁾ Each modality provides complementary information, and the inversion pattern of FAF and FA is key to diagnosis.

Standardization of genetic testing

The use of next-generation sequencing panels allows comprehensive detection of genetic mutations such as BEST1 and PRPH2. Standardization of genetic testing contributes to improved accuracy of exclusion diagnosis. ¹⁾

New challenges in the era of immune checkpoint inhibitors

With the widespread use of BRAF inhibitors (vemurafenib, dabrafenib) and PD-1 inhibitors (pembrolizumab, nivolumab), the association between these drugs and paraneoplastic AEPVM has emerged as a new clinical challenge. As immunotherapy becomes more common, the number of reported cases of paraneoplastic AEPVM may increase.

Need for case accumulation and large-scale studies

Only about 20 cases of idiopathic AEPVM have been reported in the literature. ¹⁾ To elucidate the etiology and develop treatments, multicenter case accumulation and large-scale prospective studies are necessary.

Fernandes et al. (2023) reported a case of idiopathic AEPVM in a man in his 60s, in which systemic examination and genetic testing using a next-generation sequencing panel were both negative. After 6 months, best-corrected visual acuity improved to 20/25 in both eyes, and SD-OCT confirmed complete resolution of subretinal fluid. ¹⁾

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8. References

1. Fernandes JS, Gomes PP, Neves P, et al. Idiopathic acute exudative polymorphous vitelliform maculopathy: the importance of multimodal imaging, systemic workup and genetic testing. BMJ Case Rep. 2023;16:e253969.
2. Osman M, Mehana O, Eissa M, Zeineldin S, Sinha A. Coronavirus Disease 2019-induced Acute Exudative Polymorphous Vitelliform Maculopathy. Middle East Afr J Ophthalmol. 2022;29(4):235-237. PMID: 38162565.
3. Lentzsch AM, Dooling V, Wegner I, Di Cristanziano V, Sadda SR, Freund KB, et al. ACUTE EXUDATIVE POLYMORPHOUS VITELLIFORM MACULOPATHY ASSOCIATED WITH PRIMARY EPSTEIN-BARR VIRUS INFECTION. Retin Cases Brief Rep. 2022;16(6):740-746. PMID: 33031214.