Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an acquired inflammatory disorder affecting the retina, the retinal pigment epithelium (RPE), and the choroid, characterized by bilateral multiple yellow-white placoid lesions, mostly affecting the posterior pole. Often bilateral, it involves young adults and typically resolves in weeks to months, sometimes with severe sequelae.1,2 APMPPE may occur in association with a number of systemic conditions, including cerebral vasculitis,3 bacterial infections,4 thyroiditis,5 and cancer.6
The pathogenesis is still controversial. Gass et al. suggested a primary pathophysiology affecting the RPE.7 In 1983, when studying fluorescein angiography (FA), Deutman identified obstruction of the precapillary choroidal arterioles as the primary cause of nonperfused choriocapillaris lobules and focal swelling of the RPE; therefore, he considered “acute multifocal ischemic choroidopathy” (AMIC) a more appropriate term.8 Dhaliwal et al.9 have demonstrated widespread choroidal flow abnormalities in APMPPE using indocyanine green angiography (ICGA); these abnormalities improved with functional visual recovery.
Optical coherence tomographic angiography (OCTA) is a noninvasive and depth-resolved imaging technique that studies the retinal and choroid vascular networks, layer by layer, using flowing blood cells to distinguish blood vessels from static tissue.10
In our study, we used OCTA to describe retinal and choroidal findings in different stages of APMPPE.
Patients and Methods
Six eyes of three young patients diagnosed with APMPPE were studied retrospectively. The study was conducted in agreement with the Declaration of Helsinki for research involving human subjects and was approved by the local institutional review board.
All patients underwent a clinical history collection and a complete ophthalmologic examination, including measurement of best-corrected visual acuity (BCVA) expressed in Snellen, fundus biomicroscopy, short-wavelength (488 nm) fundus autofluorescence (FAF), FA, ICGA, spectral-domain OCT (SD-OCT) (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany), and swept-source OCTA (DRI OCT Triton Plus; Topcon, Tokyo, Japan) or AngioVue OCTA (Optovue, Fremont, CA).
The patients underwent extensive uveitis work-up, including complete blood count, renal and liver function, purified protein derivative skin test for tuberculosis screening, rapid plasma regain, and treponema pallidum particle agglutination assay for syphilis assessment. Infective antibody panels for Borreliosis, Bartonella, viral hepatitis, and herpetic viruses, as well as Western blots for anti-Human Immunodeficiency Virus, were done.
Autoimmune diseases were investigated though antinuclear antibody, antineutrophil cytoplasmic antibodies, and rheumatoid factor, and chest X-ray, thoracic computed tomography, and angiotensin-converting enzyme were performed to exclude sarcoidosis.
Overall, six eyes of three Caucasian males with the diagnosis of bilaterally APMPPE were included. The presenting BCVA ranged between 20/200 and 20/12. Patient No. 1 was a 21-year-old male presenting with BCVA of 20/25 in the right eye (OD) and 20/250 in the left eye (OS). Patient No. 2 was a 27-year-old male whose BCVA was 20/200 OD and 20/32 OS. Patient No. 3 was a 26-year-old male with a bilateral BCVA of 20/12.
Physical and neurological examinations were unremarkable; the patients were afebrile with no signs of muscle weakness, limb rigidity, joint swelling, or oral or genital ulcers. They denied recent head trauma, skin rash, or blood transfusion. Patient No. 3 presented with a viral infection few weeks before symptoms onset.
A 21-year-old male presented to our clinic after 20 days of headache, bilateral floaters, and visual impairment, mainly OS. He had already been assessed by a private ophthalmologist 15 days before the visit to our clinic, who diagnosed chorioretinitis and prescribed systemic methylprednisolone (16 mg per day) and trimethoprim plus sulfamethoxazole. BCVA was 20/25 OD and 20/250 OS; spherical equivalent was −4.25 diopters in both eyes. FAF (Figures 1A and 1B) showed multifocal, branched patches of hyperautofluorescence with areas of hypoautofluorescence, mainly in the posterior pole but also beyond the vascular arcades. FA disclosed early hypofluorescence, with late-phase hyperfluorescence (Figures 1C and 1D) corresponding to the fundus biomicroscopy, whereas ICGA showed both early and late-phase hypofluorescence in the same areas at the posterior pole and the mid-periphery (Figures 1E and 1F). No vessel wall staining or papillary leakage was noted. Bilateral SD-OCT imaging (Figures 1G and 1H) centered on the fovea revealed bilateral retinal thinning, external limiting membrane (ELM) disruption, and severe alteration of the photoreceptor-RPE complex in the juxtafoveal area OD and foveal and perifoveal areas OS. These findings were compatible with the diagnosis of APMPPE.
Multimodal imaging of patient No. 1; both right and left eyes are shown. (A, B) Fundus autofluorescence. (C, D) Fluorescein angiography. (E, F) Indocyanine green angiography confirming the diagnosis of acute posterior multifocal placoid pigment epitheliopathy. (G, H) Spectral-domain optical coherence tomography revealing retinal thinning, alteration of photoreceptors, and external limiting membrane.
Prednisolone was reduced to 25 mg per day and then tapered and stopped at 4 weeks. Two weeks after discharge, the patient returned for a follow-up visit, and BCVA was 20/20 OD and 20/100 OS.
At 3 months, BCVA was unchanged in both eyes and at this stage we performed SS-OCTA (Figure 2). In both eyes, the superficial retinal capillary networks was unremarkable and was comparable to normal capillary networks reported in healthy eyes (Figures 2A and 2E), whereas the outer retinal plexus and the choriocapillaris showed widespread multiple dark spots, which corresponded to lack of flow signal and corresponded well to the yellowish-grey placoid lesion in the fundus biomicroscopy (Figures 2B, 2C, 2F, and 2G). In the left eye, the dark spots were wider and more confluent than in the right eye and involved the area below the foveal avascular zone, explaining the difference in BCVA between the two eyes. The hypoperfused areas observed by OCTA corresponded to hypofluorescent areas in the early and late phases of ICGA. Bilateral SD-OCT imaging (Figures 2D, and 2H) centered on the fovea revealed bilateral retinal thinning with outer retina damage, consisting in ELM-photoreceptor-RPE complex disruption.
Optical coherence tomography angiography (OCTA) of patient No. 1. Swept-source OCTA. (A) Normal superficial plexus. (B) Deep retinal vascular plexus with some voids of vessels. (C) Choriocapillaris with large area of reduced perfusion (white dotted area).
A 27-year-old male presented with bilateral scotoma, visual impairment, and dyschromatopsia that developed 1 month before coming to our service. The ophthalmological and medical history were unremarkable. BCVA was 20/200 OD and 20/32 OS. The anterior segment was normal bilaterally. Tyndall phenomenon was evident in the slit-lamp examination of the vitreous. Fundus examination showed grey-white lesions at the level of the RPE with RPE mottling. FAF demonstrated multiple small areas of hyperautofluorescence in the posterior pole and in mid-retinal periphery (Figures 3A and 3B). FA showed wide hypofluorescence in the macula area with no change during the exam surrounded by a small patch of hypofluorescence in the early phase with late hyperfluorescence staining (Figures 3C and 3D). ICGA showed both early and late-phase diffuse hypofluorescence areas in posterior pole and midperiphery (Figures 3E and 3F). Bilateral SD-OCT imaging centered on the macula revealed diffuse retinal thinning and severe alteration of the photoreceptor-RPE complex with backscattering areas (Figures 3G and 3H). These findings were compatible with the diagnosis of APMPPE.
Multimodal imaging of patient No. 2; both right and left eyes are shown. (A, B) Fundus autofluorescence. (C, D) Fluorescein angiography. (E, F) Indocyanine green angiography showing bilateral acute posterior multifocal placoid pigment epitheliopathy features. (G, H) Spectral-domain optical coherence tomography revealing diffuse defects of external limiting membrane, photoreceptors, and retinal pigment epithelium with back scattering.
After 2 weeks, we repeated FAF and SD-OCT that showed the same lesions. Therefore, the patient was treated with 25 mg prednisolone that was tapered and stopped at 4 weeks.
At 9-month follow-up, BCVA improved to 20/32 OD and to 20/25 OS, and OCTA was performed in both eyes showing that the superficial capillary networks was normal (Figures 4A and 4E), whereas the outer retina plexus and the choriocapillaris showed widespread multiple dark areas due to flow voids, a sign of vascular rarefaction (Figures 4B, 4C, 4F, and 4G). The hypoperfused areas observed by OCTA corresponded to the hypofluorescent areas in the early and late phases of ICGA. Bilateral SD-OCT imaging (Figures 4D and 4H) centered on the fovea revealed bilateral retinal thinning with outer retina damage, consisting in ELM-photoreceptor-RPE complex disruption.
Optical coherence tomography angiography (OCTA) of patient No. 2. Swept-source OCTA. (A) Normal superficial plexus. (B) Deep retinal vascular plexus with some voids of vessels. (C) Choriocapillaris with large area of reduced perfusion (white dotted area).
At 12 months after symptom onset, BCVA, FAF, OCTA, and SS-OCT were substantially unchanged.
A 26-year-old male presented with a 5-day history of bilateral paracentral scotomata. He was in good general health but had a viral upper respiratory tract infection 2 weeks before. Visual acuity (VA) was 20/12 in both eyes. Both fundi showed creamy white subretinal lesions in the posterior pole. On OCT, these lesions showed a typical “block early and stain late” appearance. ICGA was not carried out due to patient allergy.
Enhanced depth imaging OCT (EDI OCT) showed focal loss of the ELM, interdigitation zone, and ellipsoid layer, with hyperreflectivity of the RPE, together with thickening and loss of white dots in the underlying choriocapillaris (Figures 5 and 6).
Multimodal imaging of patient No. 3: Right eye follow-up. (A–C) The images in the first line are the baseline. (A) Choriocapillaris on optical coherence tomography angiography (OCTA) with small area of reduced perfusion. (B) Infrared. (C) Spectral-domain OCT showed hyperreflectivity from the outer plexiform layer to retinal pigment epithelium. (D–F) Lesions increased in size 1 week later. (G–I) After 6 weeks, the voids of the vessel were smaller. (J–L) At 3 months, the lesion persisted but was minimized.
Multimodal imaging of patient No. 3: Left eye follow-up. (A–C) At baseline, the lesion showed a dark area crossed by superficial vessels, as well as external limiting membrane disruption and photoreceptor loss. (D–F) After 3 months, the same lesion was smaller, with partial recovery of anatomy.
OCTA was normal for cuts through the superficial and deep retina. Imaging through the choriocapillaris showed focal marked flow voids at baseline, and some lesions increased in size at review 1 week later. The patient was hence started on a tapering regimen of 70 mg oral prednisolone.
At review 6 weeks after symptom onset, OCTA revealed significant normalization of choriocapillaris perfusion, which returned to near normal levels at 3 months. EDI OCT showed gradual recovery of the outer retinal layers, beginning with the ELM at 6 weeks and ellipsoid layer at 3 months. At 6 months, the RPE was intact but showed irregular thickening and high signal.
The patient was on a tapering course of oral steroids for 3 months. Review at 6 months showed VA of 20/16 both eyes, although the patient continued to describe some persistent paracentral scotomata.
APMPPE was first described by Gass in 19687 and has been included into the bigger nosologic group of the white dot syndromes, all characterized by multiple whitish-yellow inflammatory retinal lesions, which also include Birdshot chorioretinopathy, diffuse unilateral subacute neuroretinitis, multiple evanescent white dot syndrome, multifocal choroiditis with panuveitis, and serpiginous choroiditis.11
Patients with APMPPE tend to be young, with no gender preference, and all races are equally affected. Its natural history has been described as benign in the majority of cases, with a dramatic bilateral drop of VA at the beginning and a spontaneous recovery within few months; however, permanent visual loss can occur. Placoid subretinal lesions fade within few days and can be replaced by depigmentation, pigment clumping, or atrophic changes in the retina and in the choroid. Recurrences can occur, with severe visual loss experienced in cases of diffuse chorioretinal atrophy.7–9 Our patients presented with all the typical aspects of APMPPE, and the diagnosis was based on clinical findings.12–13
The pathophysiology of APMPPE is uncertain; it is believed to be an immune small vessel occlusive vasculitis, mediated by a type IV hypersensitivity reaction, of the terminal choroidal capillaries, resulting in secondary ischemic injury of the overlying retina and RPE. In fact, there have been several reports of APMPPE associated with other systemic disorders with a proven delayed-type inflammatory pathogenesis, including thyroiditis,14 erythema nodosum,15 systemic lupus erythematosus,16 and vaccine hypersensitivity.17,18
The diagnosis of APMPPE is typically based on clinical presentation and FA, with the characteristic “block early, stain late.”19 This early hypofluorescence is usually related to choroidal nonperfusion or malperfusion and blocking defect due to swelling of RPE cells. ICGA improved the knowledge of APMPPE pathogenesis, because of profound delayed choroidal filling in addition to extensive areas of choroidal vessel nonperfusion.9 However, the lesions shown in the FAF suggested an involvement of the RPE, as described by Gass originally in 1968.7
For the first time, OCTA shows the choriocapillaris network: in traditional dye-based angiography, retinal, choroidal, and abnormal circulations are all flattened into one two-dimensional image, whereas OCTA allows laminar evaluations of multiple slabs in the Z axis. Klufas et al. reviewed cross-sectional OCT B-scan, en face OCT, and OCTA in patients with longitudinal follow-up and described an acute decreased choriocapillaris flow on OCTA associated with concurrent outer retinal opacification and ellipsoid disruption.20 This suggests the inner choroidal origin of disease. Moreover, OCTA provides a better distinction between choriocapillaris atrophy and hypoperfusion than ICGA, as Mandadi et al. demonstrated in inflammatory choroiditis.21
We present cases of patients with APMPPE in different stages of the disease. In both eyes of Case 1 and 2, the disease had a large involvement of the posterior pole, and on fundus photograph, there was evidence of RPE mottling compatible with advanced stage. In these two cases, we performed OCTA in the advanced stage of the disease (at 3 months and 9 months from the enrollment, respectively) because baseline OCTA images were not available. In these cases, diffuse voids in vessel structure were found in the deep retinal plexus and in the choriocapillary net without any change during time, as reported in Case 2. These flow voids could be due to choroidal ischemia as in Case 1, or to transient choroidal hypoperfusion, in which the flow became too slow to be detected by instruments, as in Case 2. On ICGA, the hypofluorescent areas approximately correlated with apparent areas of flow void on OCTA, but ICGA was useless to differentiate atrophy from hypoperfusion areas, and the borders of hypofluorescent lesions were less discrete compared with OCTA. In Case 3, we had a complete OCTA follow-up (baseline, 1 week, 6 weeks, 3 months); therefore, we were able to study the disease changes during time, observing a near-complete recovery in vascular net, as demonstrated previously,22–25 which was probably due to the smaller chorioretinal extension of the disease. Flow in choroidal vessels was completely absent, and the dark areas were crossed by projection of superficial vessels. This caused secondary alterations, such as mottles in RPE seen in FAF and vascular rarefaction on outer retina in OCTA. Our findings support the theory26 that hypoperfusion of choriocapillaris is the primary process in the disease, despite Heiferman et al.'s proposed primary retinal and RPE involvement.27 Therefore, we agree with Deutman, who suggested the condition be renamed AMIC.8
Different clinical courses for our patients can be explained by two pieces of evidence: in Cases 1 and 2, the lesions were much more extensive and numerous and also involved the macular region, whereas in Case 3, the lesions were isolated, of smaller diameter, and did not involve the central fovea. Therefore, number, size, and location are predictive factors of visual prognosis.
Therapy management was also different. Case 1 received immediate high-dose oral steroid therapy, but the functional recovery was incomplete. Case 2 presented to us 2 months after the onset of symptoms and steroid therapy was initiated later and at a lower dose; nevertheless, the VA was significantly improved, especially in left eye, where the central fovea was preserved. Case 3 was initially treated with topical steroids for anterior uveitis and reviewed after 1 week; the extra macular lesions were extended, and the patients received high-dose oral steroid therapy. In this case, functional recovery was complete and the voids in vessel structure were smaller but persistent. These data suggest that steroid therapy may be helpful in stopping the progression of the disease, but it does not seem to be able to produce recovery of preexisting lesions.
In conclusion, OCTA suggested the retinal vascular deep plexus and choriocapillaris as the primary origin of the APMPPE and enabled us to localize exactly the placoid lesions and to monitor the areas of fluid signal absence. OCTA does not require dye, so it is noninvasive, and therefore, pregnancy, kidney failure, and allergy are not contraindications. Therefore, OCTA is safe and sensible for the diagnosis and follow-up of APMPPE. Studies with larger sample sizes are needed to improve our understanding of pathophysiology of this rare disease.
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