White Dot Syndrome Series Part 2: Acute Posterior Multifocal Placoid Pigment Epitheliopathy

Slideshow

  • Figure 1A. These OCT, color fundus, and fluorescein angiography images show the 18-year-old male patient from our first case with unilateral acute posterior multifocal placoid pigment epitheliopathy in his left eye.

  • Figure 1B. The patient’s OCT and color fundus images show his left eye with significant thickening of the outer retinal layers with mild subretinal fluid.

  • Figure 1C. After treatment the patient’s fundus and OCT images show significant improvements, although they’re not completely normalized.

  • Figure 2A. These color fundus and fundus autofluorescence (FAF) scans show the pigmented and creamy-colored placoid lesions in the macula and posterior pole of the 18-year-old patient from the second case. He reported sudden loss of vision in his right eye and blurring in his left.

  • Figure 2B. A fundus examination from his 10-day follow up visit shows further pigmentation of the creamy colored lesions. The OCT images, although yet not normal, reveal the effect of the treatments — partial remodeling of the RPE and ellipsoid zone.

  • Figure 2C. A month after beginning steroid treatments, his fundus and FAF images show further pigmentation of the inflammatory lesion primarily seen outside of the fovea. On OCT, further improvement of the RPE and outer retinal morphology can be seen.

  • Figure 2D. At 3 months, FAF shows only a few subtle pigmented lesions remained, and that they were shrinking. The OCT image shows further remodeling and improved macular anatomy.

  • Figures 3A. A 16-year-old girl’s fundus exam shows multiple creamy placoid lesions in the macula and involvement in the posterior pole. Fluorescein angiography revealed an early block and late staining of the lesions. The widefield fluorescein angiography image (in the lower middle) shows that the lesions extended beyond the posterior retina.

  • Figure 3B. The patient in case 3 — who had originally reported seeing a “curtain-like shadow” in the nasal field of both her eyes — was evaluated using indocyanine green angiography, which revealed the extent of choroidal involvement. She was also evaluated with OCT, which found diffuse inflammatory changes of the RPE and outer retina, and an abnormally thickened choroid.

  • Figure 3C. After being treated, she returned for a 1-week follow-up visit. An FAF exam shows pigmentary changes of the creamy lesions and the OCT shows improvements to the outer retinal and choroidal anatomy.

  • Figure 3D. This follow-up FAF shows the foveal area being spared from the damage that caused the original visual defect. OCT also shows improvements.

  • Figure 3E. At 3 months, the patient’s foveae have recovered remarkably, despite areas of altered RPE and outer retina.

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), was first described as rapid central vision changes in 3 healthy, young women with multiple yellow-white, placoid, subretinal lesions at the level of the pigment epithelium and choroid with subsequent resolution of these lesions and visual improvement.1 

The estimated incidence of APMPPE is 0.15 per 100,000 people per year.2 APMPPE affects both men and women, with a reported prevalence in men ranging from 54.5% to 61%.3,4 The median age of onset typically occurs in one’s mid-twenties, but could range from twenties to forties.3,4 A total of 77% of reported patients are White, with only a small minority of patients reporting as Black, Hispanic, or Asian.4 Bilateral eye involvement has been reported in 89% to 91% of cases.3,4 Most cases have a monophasic course, with only a minority having a recurrent or chronic disease course.4

The etiology of APMPPE is not fully understood, although preceding flu-like illness has been reported, suggesting an inflammatory or post-infectious inflammatory response as the pathophysiologic mechanism.5-9 

A review of 14 patients (26 eyes) from the Massachusetts Eye and Ear Infirmary and 187 patients (349 eyes) collected from a review of the literature reported visual acuity at time of presentation was 20/40 or worse in 58.3% of cases. Final visual acuity was 20/40 or worse in 23.7% of cases. The presence or absence of foveal involvement was associated with visual outcomes. Among eyes without foveal involvement at presentation, 87.5% had vision equal to or better than 20/25, while 39.2% of the eyes with foveal involvement at presentation had vision equal to or better than 20/25.3

 APMPPE Signs

Clinical features of APMPPE include multiple geographic, deep yellow lesions on fundus examination.3 These lesions, which are placoid in shape and located in the posterior pole, rarely involve the mid periphery or periphery.4 They are larger in size, with 55% being larger than 500 microns in size, and 37% in the 250 µm to 500 µm range.4 Most patients have a quiet anterior chamber without cell, flare, or evidence of keratic precipitates.4 However, if anterior chamber inflammation is present, it is usually less than 2+ cell.5 There is typically no vitreous haze.4 The placoid lesions fade over weeks, followed by varying degrees of hyperpigmentation or retinal pigment epithelium (RPE) atrophy.1,5,6,8-10 

Typical features on fluorescein angiography are the presence of lesions with early hypofluorescence and diffuse late staining.1,3,8 

Optical coherence tomography (OCT) of acute lesions shows hyperreflectivity in the outer retinal layers with normal retinal thickness.10 The presence of subretinal fluid has been reported in some cases.5,10 In the resolution phase, alterations of the ellipsoid zone with hyperreflectivity of the outer nuclear layer has been reported.5

Indocyanine green (ICG) of APMPPE lesions shows dark areas of hypoperfusion in early and late phases, corresponding to lesions seen on fluorescein angiography (FA) and fundus exam.10,11

Fundus autofluorescence (FAF) demonstrates hypoautofluorescence in areas of the placoid lesions.10 A 2015 study reported that lesions were hypoautofluorescent with hyperfluorescent borders and partially hypofluorescent halos.11

Systemic diseases that can present with a similar clinical phenotype include syphilis and sarcoidosis.4 

Symptoms

Neurologic symptoms have been reported in patients with APMPPE including headache, paresthesias, psychosis, vertigo, cerebral vasculitis, stroke, peripheral neuropathies, cranial neuropathies, meningoencephalitis, cavernous sinus thrombosis, and viral meningitis.12,13 It is uncertain whether cerebral complication is a complication of APMPPE, or if this is a unique disease process with ocular manifestations that mimic APMPPE.4

Systemic steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunomodulatory drugs, and local steroids have been used, but it unclear whether these therapies change the course of disease.3 Cerebral vasculitis and stroke have been treated with high dose steroids and antiplatelets.13

Many patients with APMPPE who do not have neurologic complications experience spontaneous visual recovery with favorable visual prognosis, even without treatment.1,3,5,8,9 However, persistent vision or visual field abnormalities have been reported.1,3,5,6,8,12 

Relentless placoid chorioretinitis (RPC), also known as ampiginous choroiditis, is a rare bilateral entity with overlapping features of both APMPPE and serpiginous choroiditis. It is, perhaps, a variation of these 2 white dot syndromes.14,15 Clinically, the lesions associated with it are similar to those of APMPPE, but more numerous and wider, extending across the central and mid peripheral retina.16 Systemic steroids and other immunomodulators have been used in treatment of the disease.17

Case 1. Unilateral APMPPE

An 18-year-old White male patient presented with “missing areas of central vision” in his left eye for 5 days. He reported no significant past medical or ocular history, and occasionally used ibuprofen. His visual acuities were 20/30 OD, 20/200 OS, IOPs 13 mm Hg OD, 15 mm Hg OS, pupils were normal with no APD, slit lamp examination were remarkable for mild anterior chamber cell in both eyes. His fundus exam (Figure 1A), as illustrated by color photographs, demonstrated mild vascular tortuosity in his right eye, with normal disc and macula. The left eye was remarkable for the creamy color placoid lesions seen in the macula and posterior pole. 

A fluorescein angiography of his right eye was normal, while his left demonstrated early hypofluorescence and late staining of the lesions, a finding typical of APMPPE. An OCT exam of his right eye was normal, while his left eye showed significant thickening of the outer retinal layers with mild subretinal fluid (Figure 1B). Due to the extent of foveal involvement, the patient was prescribed prednisolone, 20 mg by mouth, twice daily, and omeprazole 20.6 mg (OTC), once daily. 

On a return appointment 10 days later, the patient was tolerating the oral steroid and his symptoms had improved. His right eye was 20/20 and his left eye improved to 20/60. He was asked to taper off the prednisone and return in 1 month. At the 1 month follow-up, his symptoms had significantly resolved. His VA had improved to 20/40 and IOPs were stable. Although his fundus examination and OCT had not completely normalized, they showed significant improvement (Figure 1C). The patient returned in 6 months, for a delayed follow-up at which time his left eye was 20/30. He reported only occasional visual symptoms, and his fundus exam and OCT had also improved. While his fundus exam showed persistent retinal pigment epithelium (RPE) mottling, his OCT images demonstrated a disruption of the inner segment/outer segment (IS/OS) junction with abnormalities of the RPE. No subretinal fluid was present. 

Although the patient was given a 1 year follow-up appointment, he has not yet returned to our clinic.

Case 2. Bilateral Asymmetric APMPPE

An 18-year-old White male patient complained of sudden loss of vision in his right eye for several days. He also said his left eye had been somewhat blurry for several days. He reported no remarkable medical or ocular history. Visual acuities were 20/80 OD, and 20/20-2 OS. His IOPs were 13 mm Hg OD, and 13 mm Hg OS. All other findings were normal except for retinal findings. Fundus photography (Figure 2A) showed pigmented and creamy color placoid lesions in the macula and posterior pole. The right eye had a foveal lesion, explaining the patient’s complaint and the acuities. Fundus autofluorescence (FAF) demonstrated areas of hypofluorescence with a surrounding rim of hyperfluorescence delineating the areas of disease activity. FA had the typical early phase hypofluorescence and late phase staining (hyperfluorescence). 

His OCT exam was remarkable for disruption of the RPE and outer retina. His right eye had a foveal lesion with mild subretinal fluid. Due to the foveal involvement, this patient was also prescribed oral prednisolone starting with 20 mg orally 3 times daily. At 10 day follow-up, the patient felt like his vision in the OD had worsened, although his visual acuity had improved to 20/60. The fundus examination (Figure 2B) showed further pigmentation of the creamy color lesions, and OCT, although not normal, was revealing partial remodeling of the RPE and ellipsoid zone. The patient was given instructions for a slow steroid taper for the following 3 weeks, and was asked to follow up in 1 month. 

At the 1 month visit, his vision had improved to 20/25 and he had noticed a reduction of his symptoms. He was no longer using oral steroids. Fundus examination and FAF (Figure 2C) showed further pigmentation of the inflammatory lesion primarily seen outside of the fovea. The OCT also showed further improvement of the RPE and outer retinal morphology. 

When the patient returned 3 months later, he had visual acuities of 20/20 OU. At this visit, his fundus exam (Figure 2D) showed a few subtle pigmented lesions. FAF delineated these lesions, which remained hypofluorescent, but were smaller. Using OCT, examination demonstrated further remodeling and improved macular anatomy. 

Following this visit, the patient did not adhere to any further follow up. 

Case 3. Ampiginous Choroiditis (Relentless Placoid Chorioretinitis)

A 16-year-old White female patient presented with a complaint of seeing a curtain-like shadow in the nasal field of both her eyes for 10 days. Her medical history was remarkable for periodic migraine headaches, which had increased recently after she hit her head with a car door. Her visual acuities were 20/20 OU. Her IOPs were 12 mm Hg OD and16 mm Hg OS. All other findings were normal except for her fundus exam, which showed multiple creamy placoid lesions in the macula and involvement in the posterior pole (Figure 3A). Her FA findings also demonstrated the typical early block and late staining of the lesions. In this case, the lesions extended beyond the typical posterior retina, as seen in widefield FA (Figure 3A, middle bottom image). 

Indocyanine green (ICG) angiography (Figure 3B) shows the extent of choroidal involvement, which appears much more extensive than could be seen clinically. An OCT evaluation (Figure 3B) also showed the diffuse inflammatory changes of the RPE/outer retina, and an abnormally thickened choroid. The patient was prescribed oral prednisone 20 mg, 3 times daily and scheduled for 1 week follow up. An MRI of the brain was also ordered, which ruled out any cranial pathology. Her VA and IOP remained stable throughout follow-up. 

At the 1 week follow up, the patient’s symptoms had subsided, but she was having on-and-off blurred vision. Typical pigmentary changes of the creamy lesions were noted. This can be seen in the FAF (Figure 3C) and OCT showed improvements to the outer retinal and choroidal anatomy. The patient was given a taper-off regimen and scheduled for a 1 month follow up. Significant pigmentary changes can be seen in both eyes (Figure 3D), FAF shows the foveal area being spared from this damage explaining the visual acuity. OCT also shows further improvement. After 3 months, the foveae have recovered remarkably, despite areas of altered RPE and outer retina (Figure 3E). 

The patient now only has mild symptoms with near vision tasks. Her symptoms and examination findings remained stable throughout a 4-year follow-up. 

Mohammad Rafieetary, OD, is a consultative optometric physician at the Charles Retina Institute and has served on the board of the American Diabetes Association. Salar Rafieetary, MD, is a vitreoretinal surgery fellow at the Charles Retina Institute.

References

1. Gass JD. Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1968;80(2):177-85. doi:10.1001/archopht.1968.00980050179005

2. Abu-Yaghi NE, Hartono SP, Hodge DO, Pulido JS, Bakri SJ. White dot syndromes: a 20-year study of incidence, clinical features, and outcomes. Ocul Immunol Inflamm.  2011;19(6):426-30. doi:10.3109/09273948.2011.624287

3. Fiore T, Iaccheri B, Androudi S, et al. Acute posterior multifocal placoid pigment epitheliopathy: outcome and visual prognosis. Retina. 2009;29(7):994-1001. doi:10.1097/IAE.0b013e3181a0bd15

4. The Standardization of Uveitis Nomenclature (SUN) Working Group. Classification criteria for acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol. 2021;228(8):174-181. doi:10.1016/j.ajo.2021.03.056

5. Xerri O, Salah S, Monnet D, Brézin AP. Untreated acute posterior multifocal placoid pigment epitheliopathy (APMPPE): a case series. BMC Ophthalmol. 2018;18(1):76. doi:10.1186/s12886-018-0744-z

6. Roberts TV, Mitchell P. Acute posterior multifocal placoid pigment epitheliopathy: a long-term study. Aust N Z J Ophthalmol. 1997;25(4):277-81. doi:10.1111/j.1442-9071.1997.tb01515.x

7. Holt WS, Regan CD, Trempe C. Acute posterior multifocal placoid pigment epitheliopathy. Am J Ophthalmol. 1976;81(4):403-12. doi:10.1016/0002-9394(76)90294-4

8. Wolf MD, Alward WL, Folk JC. Long-term visual function in acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1991;109(6):800-3. doi:10.1001/archopht.1991.01080060064025

9. Williams DF, Mieler WF. Long-term follow-up of acute multifocal posterior placoid pigment epitheliopathy. Br J Ophthalmol. 1989;73(12):985-90. doi:10.1136/bjo.73.12.985

10. Steiner S, Goldstein DA. Imaging in the diagnosis and management of APMPPE. Int Ophthalmol Clin. 2012;52(4):211-9. doi:10.1097/IIO.0b013e318265d45a

11. Malamos P, Masaoutis P, Georgalas I, et al. The role of fundus autofluorescence imaging in the study of the course of posterior uveitis disorders. Biomed Res Int. 2015;2015:247469. doi:10.1155/2015/247469

12. Thomas BC, Jacobi C, Korporal M, Becker MD, Wildemann B, Mackensen F. Ocular outcome and frequency of neurological manifestations in patients with acute posterior multifocal placoid pigment epitheliopathy (APMPPE). J Ophthalmic Inflamm Infect. 2012;2(3):125-31. doi:10.1007/s12348-012-0077-7

13. Algahtani H, Alkhotani A, Shirah B. Neurological manifestations of acute posterior multifocal placoid pigment epitheliopathy. J Clin Neurol. 2016;12(4):460-467. doi:10.3988/jcn.2016.12.4.460

14. Jones BE, Jampol LM, Yannuzzi LA, et al. Relentless placoid chorioretinitis: A new entity or an unusual variant of serpiginous chorioretinitis? JAMA Ophthalmol. 2000;118(7):931-8. 

15. Lambrecht P, Claeys M, De Schryver I. A case of ampiginous choroiditis. Case Rep Ophthalmol. 2015;6(3):453-7. doi:10.1159/000442742

16. Raven ML, Ringeisen AL, Yonekawa Y, Stem MS, Faia LJ, Gottlieb JL. Multi-modal imaging and anatomic classification of the white dot syndromes. Int J Retina Vitreous. 2017;3:12. doi:10.1186/s40942-017-0069-8

17. Asano S, Tanaka R, Kawashima H, Kaburaki T. Relentless placoid chorioretinitis: a case series of successful tapering of systemic immunosuppressants achieved with adalimumab. Case Rep Ophthalmol. 2019;10(1):145-152. doi:10.1159/000500077

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