Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) is an inflammatory chorioretinopathy that produces multiple placoid lesions at the level of the retinal pigment epithelium (RPE) in the posterior pole. It was first reported by J. Donald Gass in 1968. It is classified as one of the white dot syndromes (WDS). 11)
The incidence is estimated at 0.15/100,000. 3) It commonly occurs in the 20s to 40s (mean age 25) with no gender predilection. It is often bilateral; even when unilateral at onset, lesions often appear in the fellow eye within days to weeks. 3)
It is a self-limiting disease that resolves spontaneously within 4 to 8 weeks. Visual prognosis is generally good, but some reports indicate visual acuity of 20/25 or worse when the fovea is involved. 7) After resolution, RPE atrophy or pigmentation may remain. Recurrence is rare; if it persists or recurs beyond 6 months, consider transition to Relentless Placoid Chorioretinitis (RPC). 7)
Most cases heal spontaneously, with final visual acuity of 20/25 or better. However, prognosis may be poor if the fovea is involved or if cerebral vasculitis occurs. Rarely, choroidal neovascularization (CNV) may develop and cause vision loss. 11)
Symptoms are usually bilateral but asymmetric, appearing a few days apart. About 33% of cases have influenza-like viral prodrome.
Multiple cream-colored to gray-white scaly lesions appear at the level of the posterior pole RPE. Lesion size ranges from 1/4 to 2 disc diameters, with relatively distinct borders.
Active Lesions
Scaly lesions: Multiple cream-colored to gray-white scaly lesions at the posterior pole RPE level, 1–2 disc diameters in size. 11)
Mild vitritis: About 50% of cases have mild vitreous opacities. Anterior uveitis may also be present.
Optic neuritis: 14 cases of optic neuritis have been reported in the literature. 1)
Resolution and Atypical Findings
RPE atrophy and pigment clumping: Lesions resolve within 1–2 weeks, transitioning to RPE atrophy and pigment clumping.
Serous retinal detachment: Rare but reported. Bilateral involvement is considered atypical. 2)
Vasculitis and CNV: Rarely associated with retinal vasculitis, venous occlusion, or choroidal neovascularization.
New lesions may appear in the periphery up to 3 weeks after onset. There may be a period where old lesions transition to RPE atrophy and pigment clumping while fresh scaly lesions coexist. Vitreous reaction is usually minimal or absent. 1) Cystoid macular edema (CME) is rare.
The cause of APMPPE is not established. About 33% of cases have preceding viral symptoms, suggesting viral infection as a trigger.
Associated with erythema nodosum, sarcoidosis, granulomatosis with polyangiitis, polyarteritis nodosa, scleritis, thyroiditis, nephritis, ulcerative colitis, and CNS vasculitis.
Associations with HLA-B7 and HLA-DR2 have been reported. 6) New associations with HLA-B15 and HLA-B35 have also been reported. 5)
Cases have been reported after various vaccinations, including COVID-19 vaccines. 1)7) It has been suggested that immune activation may trigger choroidal inflammation, but a causal relationship has not been established. If you notice vision changes after vaccination, it is advisable to see an ophthalmologist.
Diagnosis is based on clinical symptoms and fundus findings. Multimodal imaging is useful for understanding the pathology and monitoring the course.
Findings in the active and resolution phases for each modality are shown below.
| Examination | Active Phase Findings | Resolution Phase Findings |
|---|---|---|
| FA | Early hypofluorescence → late hyperfluorescence | Window defect |
| ICG | Persistent hypofluorescence | Signal normalization |
| OCT | Outer retinal hyperreflectivity, EZ loss | EZ recovery, RPE atrophy |
| OCTA | Choriocapillaris flow deficit | Partial flow recovery |
| FAF | Hyperfluorescence (RPE damage) | Hypofluorescence (scar) |
Fluorescein angiography (FA): In the active phase, early hypofluorescence (due to choriocapillaris hypoperfusion or blockage) is seen, which later transforms into irregular hyperfluorescence, a phenomenon known as “fluorescence reversal,” characteristic of APMPPE. 11) In the resolution phase, it remains as a window defect (depigmentation window defect).
Indocyanine green angiography (ICGA): Shows persistent hypofluorescence from early to late phases. This contrasts with FA and reflects impaired perfusion at the choriocapillaris level. 11)
Optical coherence tomography (OCT): In the active phase, hyperreflective lesions extending from the outer plexiform layer to the RPE are observed. Loss of the ellipsoid zone (EZ) suggests foveal involvement and visual decline. 11) Choroidal thickening is also noted. 5) Goldenberg’s OCT classification includes four stages (Stage 1: dome-shaped elevation + EZ disruption, Stage 2: separation of EZ and RPE, Stage 3: RPE hyperreflectivity + EZ/RPE fusion, Stage 4: resolution phase). 2)
Optical coherence tomography angiography (OCTA): Can detect blood flow deficits in the choriocapillaris. 11) Recovery of vascular density with treatment has been reported. 5)
Fundus autofluorescence (FAF): In the active phase, hyperautofluorescence reflecting RPE dysfunction is seen, which transitions to hypoautofluorescence due to RPE cell loss after scar formation. The change from hyper- to hypoautofluorescence is an indicator of scar formation. 8) Hyperautofluorescent lesions in the macula may indicate the need for intensive treatment. 8) FAF is considered superior to ICGA and OCT in differentiating new from old lesions. 8)
Electroretinography (ERG): Shows reduced amplitudes in the active phase, which improve with treatment. 5)
Differentiation from related diseases is important.
| Disease | Features | Differences from APMPPE |
|---|---|---|
| RPC | More than 50 lesions, around the equator | Chronic persistence/recurrence |
| Serpiginous choroidopathy | Centrifugal from the optic disc | Chronic progressive/recurrent |
| Vogt-Koyanagi-Harada disease | Exudative retinal detachment | Systemic symptoms, multifocal leakage |
Other differential diagnoses include multiple evanescent white dot syndrome (MEWDS). MEWDS is more common in young women, with white spots distributed extensively to the equator, and shows early hyperfluorescence on FA, differing from APMPPE. Serpiginous choroidopathy is more common in the 40s, is unilateral, and shows progressive enlargement and confluence. 11)
Clinical symptoms and fundus examination are fundamental. FA (reversal phenomenon of fluorescence) is a characteristic finding and useful for diagnosis. Combining multimodal imaging such as OCT, OCTA, FAF, and ICG improves understanding of the pathology and accuracy of follow-up. At initial diagnosis, exclusion of CNS vasculitis by MRI/MRA is also important. 4)
APMPPE is a self-limited disease, and consensus on the indications and methods of treatment has not been established. In cases with good visual acuity and no foveal involvement, observation without treatment is an option. 10) Steroid therapy is recommended for cases with foveal involvement, severe cases, and those complicated by cerebral vasculitis.
Oral steroids
Prednisolone: Taper from 0.5 mg/kg/day. Recommended for cases with foveal involvement. Start at 30 mg/day of Predonine tablets (5 mg) and taper over 2 weeks to 1 month.
Methylprednisolone: A protocol of 0.8 mg/kg/day tapered over 7 weeks has been reported. 5)
Steroid pulse therapy
Methylprednisolone infusion: 1,000 mg/day for 3 days of intravenous pulse therapy, followed by a taper of oral prednisolone 60 mg. Used in severe cases and those with cerebral vasculitis. 2)7)
Retrobulbar and sub-Tenon injection: Reports include retrobulbar triamcinolone 20 mg plus dexamethasone 6 mg and sub-Tenon triamcinolone 40 mg. 1)8)
Immunosuppressive therapy
Cases with cerebral vasculitis: Reports of rituximab 375 mg/m² (once weekly for 4 weeks) and mycophenolate mofetil 1,000 mg twice daily. 4)
Long-term immunosuppression: Azathioprine or steroid maintenance for 4 months or longer is recommended for cases with cerebral vasculitis. 6)
Acyclovir 5 mg/kg three times daily (for 5 days) has been reported, but it is not a standard treatment. 5)
Most patients achieve a final visual acuity of 20/25 or better. Many recover within 4 weeks, but up to 6 months of follow-up may be necessary. Foveal involvement is an important predictor of poor prognosis. Permanent scotomas or color vision changes may persist after treatment. 5) There is also a possibility of vision loss due to choroidal neovascularization. 11)
APMPPE is a self-limiting disease, and no treatment consensus has been established. In cases with good visual acuity and no foveal involvement, spontaneous recovery is common without treatment. 10) Steroid therapy is recommended for cases with foveal involvement or cerebral vasculitis. Treatment decisions should be made on a case-by-case basis.
Several hypotheses have been proposed for the pathogenesis of APMPPE.
The most widely supported theory is occlusive vasculitis due to a delayed-type hypersensitivity reaction (type IV allergy) occurring in the afferent arterioles of the choriocapillaris. Primary involvement of the choriocapillaris is thought to occur, with secondary damage to the RPE and outer retina. 11) OCTA has confirmed that outer retinal changes colocalize with blood flow deficits in the choriocapillaris, supporting this hypothesis. 11)
This mechanism is understood as a stepwise pathological process: occlusive vasculitis → choriocapillaris ischemia → hypoperfusion of RPE/photoreceptors. In the past, primary inflammation of the RPE and outer retina was assumed, but it is now considered secondary damage.
As a mechanism for APMPPE onset after COVID-19 infection, it has been proposed that ACE-2 receptors are expressed in the retinal ganglion cell layer, inner plexiform layer, inner nuclear layer, and photoreceptor outer segments, and SARS-CoV-2 RNA has been detected in retinal biopsies of deceased patients. This suggests a pathway of direct infection or molecular mimicry → vascular hyperinflammation → thromboembolism → decreased choroidal perfusion. 9)
EBV may directly infect RPE cells as a reservoir or induce autoimmune inflammation. Involvement of T-lymphocyte activation and type IV hypersensitivity has also been suggested. 10)
In some cases, it has been proposed that direct neurotropic infection causes RNFL changes that precede outer retinal changes. However, this is not currently the mainstream theory.
Not confirmed. Occlusive vasculitis of the choriocapillaris is currently the mainstream theory, and the RPE is thought to be secondarily damaged. 11) It is presumed that viral infection or immune activation triggers a delayed-type hypersensitivity reaction (type IV allergy). Research on the mechanism of association with COVID-19 infection and vaccination is also progressing. 9)
OCTA can non-invasively quantify blood flow deficits in the choriocapillaris and is becoming the gold standard for diagnosis. 5) It may allow monitoring of changes in vascular density during treatment (at admission vs. 5 weeks later).
Sarna et al. (2025) performed serial evaluations with OCTA and FAF in long-term follow-up cases and reported a correlation between recovery of choriocapillaris blood flow density and improvement in visual function. 5)
Hyperfluorescent lesions on FAF are attracting attention as new indicators of treatment efficacy and risk of scarring. 8)
Yokoi et al. (2022) showed that FAF is superior to ICGA and OCT in distinguishing new and old lesions, and reported its usefulness for treatment monitoring. 8)
New associations with HLA-B15 and HLA-B35 have been reported, and the elucidation of genetic predisposition is progressing. 5) Identification of risk genotypes other than the known HLA-B7 and HLA-DR2 may contribute to prediction of onset and understanding of pathology. 6)
Case reports of APMPPE after COVID-19 infection and mRNA vaccination are increasing, and research is progressing on mechanisms involving molecular mimicry and immune complexes. 2)7)9)
The efficacy of immunomodulatory drugs such as rituximab and mycophenolate mofetil for severe cerebral vasculitis has been accumulating at the case report level. 4) Further research is needed to establish evidence.
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Ogino Y, Namba K, Iwata D, et al. A case of APMPPE-like panuveitis presenting with extensive outer retinal layer impairment following COVID-19 vaccination. BMC Ophthalmol. 2023;23(1):233.
Mordechaev E, Shakarov G, Parikh D. Unilateral acute posterior multifocal placoid pigment epitheliopathy (APMPPE) with delayed contralateral eye involvement. BMC Ophthalmol. 2024;24(1):17.
Ayala Rodriguez SC, Ramirez Marquez E, Torres-Rosa AG, et al. Cerebral vasculitis presenting as acute posterior multifocal placoid pigment epitheliopathy in a 16-year-old male. Am J Ophthalmol Case Rep. 2024;36:102106.
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Tokuc EO, Yumuk Z, Karabas VL. Acute posterior multifocal placoid pigment epitheliopathy associated with infectious mononucleosis: A rare presentation. Saudi J Ophthalmol. 2022;36(4):387-389.
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