The advent of optical coherence tomography angiography (OCTA) has enabled high-resolution, noninvasive, three-dimensional imaging of the retinal vasculature and has led to novel insights into the role of vascular pathology in numerous diseases, including macular telangiectasia, polypoidal choroidopathy, and central serous retinopathy, among others.1–3 One notable advantage of OCTA over traditional fluorescein angiography (FA) is the ability to segment the retina and resolve retinal vasculature as a function of depth. Importantly, OCTA can also noninvasively provide high-resolution images of choroidal blood flow, which was not readily attainable with prior imaging modalities. This is particularly relevant for the study of the choriocapillaris, as the ability to properly image this microvascular layer might give relevant insights to elucidate pathogenesis of chorioretinal diseases, as well as contribute to improved diagnosis, management, and treatment.
Among chorioretinal diseases, the understanding and differentiation of white dot syndromes (WDS) might benefit from the additional insight of OCTA. Many of the WDS, including acute posterior multifocal placoid pigment epitheliopathy (APMPPE), birdshot chorioretinopathy (BCR), presumed ocular histoplasmosis syndrome (POHS), and multiple evanescent white dot syndrome (MEWDS) are thought to involve the choroid, but their pathophysiology remains only partially understood. Better understanding of these diseases is particularly important in APMPPE, which can be accompanied by the potentially fatal association of cerebral vasculitis, thought to be an extension of choroidal vasculitis.4
To date, much has been discussed at scientific meetings, but little has been published about OCTA in WDS. To the best of our knowledge, there are no prior reports of OCTA in POHS. In APMPPE, there is one prior report of using OCTA that identified areas of choroidal hypoperfusion on both OCTA and indocyanine green angiography (ICG).5 There has previously been one case series of OCTA in patients with BCR showing hypoperfusion of the choriocapillaris and choroid corresponding to fundus lesions,7 and another case report on the development of a choroidal neovascular membrane, a late sequela of the disease.8 There exists only one published case of OCTA in a patient with MEWDS, but only showing late choroidal neovascularization.6
Herein, we compare and contrast the OCTA findings of WDS, identifying different patterns of choroidal and choriocapillaris hypoperfusion. OCTA offers an additional diagnostic, yet noninvasive tool for the clinician in narrowing the differential of WDS. Additional work is needed to further explore these patterns of hypoperfusion using OCTA.
Patients and Methods
We identified consecutive patients with a diagnosis of posterior uveitis imaged at the Massachusetts Eye and Ear (MEE) with either the Zeiss AngioPlex OCT Angiography (Carl Zeiss AG, Oberkochen, Germany) or the AngioVue OCT Angiography (Optovue, Fremont, CA) from February to November 2016. The OCTA images were reviewed and after exclusion of patients with an active infectious cause of posterior uveitis as well as patients with a diagnosis of idiopathic posterior uveitis, four patients with a diagnosis of APMPPE, BCR, POHS, and MEWDS were included in this study. Their demographic and clinical characteristics were collected, including age, gender, diagnosis, and presenting visual acuity, as well as imaging from ancillary studies such as OCT, FA, and fundus autofluorescence (FAF). OCTA images were analyzed by three investigators (JW, IL, JBM) using the built-in review software of Zeiss AngioPlex and Optovue AngioVue.
This study was approved by the institutional review board at MEE (Protocol #16-038H) and conformed to the provisions of the Declaration of Helsinki. All subjects provided written informed consent.
Case 1 (APMPPE): A 21-year-old man with no significant past medical or ocular history presented to the eye emergency department with a complaint of seeing white spots in his vision in both eyes for the past 24 hours. His visual acuity was 20/20 in both eyes, with normal intraocular pressures (IOPs). Complete ophthalmologic examination revealed bilateral 1+ cells in the anterior chamber and a single peripheral chorioretinal scar in the right eye. Of note, there was no vitritis, nor any lesions within the posterior pole of either eye. Topical prednisolone acetate 1% three times daily was started in both eyes for the anterior uveitis. Three days later, the patient's vision was 20/20 in the right eye and 20/25-1 in the left eye. On fundus exam, he was noted to have diffuse hypopigmented lesions in the posterior pole in both eyes (Figures 1A and 1B). FA revealed that these hypopigmented lesions blocked early and stained late, consistent with a diagnosis of APMPPE (Figures 1B–1F). Structural OCT showed focal disruption of the ellipsoid zone in the areas of the lesions (Figures 2A and 2B).
Color fundus photographs showing multiple round, creamy plaques (white arrowheads) concentrated mostly in the posterior pole in both eyes (A, B). Fluorescein angiography shows early blockage and late staining of these lesions (C–F).
Optical coherence tomography (OCT) showing disruption of the ellipsoid zone (white arrowheads) with preserved foveal contour in both eyes centrally with multiple punctate hyperreflective foci in the outer retina (A, B). OCT angiography at the level of the choriocapillaris (C, D) and deep choroid (E, F) demonstrating multiple areas of hypoperfusion in a placoid distribution (yellow arrowheads) but becoming confluent centrally generally corresponding to, but greater in extent than, the lesions seen on fundus photography.
The OCTA showed choriocapillaris hypoperfusion in a placoid pattern corresponding to the areas of hypopigmented retinal lesions (Figures 2C–2F). The plaques appeared larger and denser centrally, and became confluent in the posterior pole. Importantly, the abnormalities in the choriocapillaris seen on OCTA appeared to be of greater extent than the white placoid lesions seen on fundus examination (Figures 2C and 2D). We also observed some areas of hypoperfusion in the deep choroid, but to a lesser extent when compared with the ones seen in the choriocapillaris (Figures 2E and 2F). The superficial and deep vascular networks of the retina appeared normal.
Case 2 (BCR): A 58-year-old man with HLA-A29-positive BCR presented with a flare of his disease, complaining of increasing floaters and blurry vision in both eyes. BCR had been diagnosed 2 years prior, and the patient was on mycophenolate mofetil (CellCept; Genentech, South San Francisco, CA) 1.5 mg twice a day, adalimumab (Humira; AbbVie, North Chicago, IL) 40 mg every 2 weeks, and prednisone 5 mg daily. His visual acuity was 20/20 in the right eye and 20/25 in the left eye, with normal IOPs bilaterally. Fundus examination revealed trace vitreous cell in both eyes and multiple hypopigmented lesions in the posterior pole and mid periphery (Figures 3A and 3B). Autofluorescence demonstrated hypoautofluorescence centrally with some small areas of hyperautofluorescence corresponding to the fundus lesions, especially in the left eye (Figures 3C and 3D). OCT showed areas of focal loss of definition of the outer retinal layers in the left eye from the external limiting membrane to the retinal pigment epithelium (RPE) in the same locations (Figures 4A and 4B).
Color fundus photographs showing multiple scattered yellow hypopigmented lesions (white arrowheads) throughout the retina of both eyes, left more than right (A, B). Autofluorescence shows generalized hypoautofluorescence of the posterior pole with focal areas of hyper and hypoautofluorescence (yellow arrowheads) corresponding to the hypopigmented lesions (C, D).
Optical coherence tomography (OCT) shows a normal foveal contour in the right eye but segmental loss of definition of outer retinal layers in the left eye (white arrowheads) from the retinal pigment epithelium to the external limiting membrane (A, B). OCT angiography (OCTA) at the level of the choriocapillaris (C, D) and deep choroid (E, F) demonstrates many distinct small areas of nonperfusion scattered throughout the retina that are more evident in the left than right eye. Posterior pole autofluorescence (G) and fundus photograph of the left eye (H) for purposes of correlation with OCTA (red arrowheads show corresponding lesions, yellow arrowheads show areas of choroidal hypoperfusion without corresponding fundus lesions).
OCTA demonstrated multifocal hypoperfusion of the choriocapillaris (Figures 4C and 4D) that was mostly evident in the left eye. Deeper within the choroid, OCTA showed larger areas of hypoperfusion when compared with the choriocapillaris (Figures 4E and 4F). Some areas of hypoperfusion observed in the choriocapillaris and choroid did not appear to correspond directly to fundus lesions (Figures 4E–4H). However, there were shine-through artifacts of the more anterior retinal capillary plexuses corresponding to the areas of attenuation seen in the choriocapillaris (best seen in the righthand lower corner of Figure 4F).
Case 3 (Presumed ocular histoplasmosis syndrome): A 24-year-old asymptomatic man was referred from an outside optometrist for evaluation of chorioretinal scars in both eyes. His visual acuity was 20/20 in both eyes with normal IOPs. Fundus exam revealed no vitritis and many small spots of chorioretinal atrophy with RPE clumping in the posterior pole, especially along the inferotemporal arcades, as well as peripapillary atrophy (Figure 5A–B). There was no evidence of active lesions or choroidal neovascularization. Conventional OCT showed atrophy of the RPE and inner retina overlying the areas of chorioretinal scarring (Figure 6A–B).
Color fundus photographs demonstrating peripapillary atrophy and discrete pigmented “punched out” scars (white arrowheads) along the inferotemporal arcades (A, B). Optical coherence tomography angiography at the level of the choriocapillaris (C, D) and deep choroid (E, F) demonstrates sharply demarcated areas of hypoperfusion corresponding to the scars (yellow arrowheads).
Optical coherence tomography shows loss of definition of the inner retina and retinal pigment epithelium (white arrowheads), and decreased choroidal thickness in the areas corresponding to the pigmented scars (A, B).
OCTA showed well-demarcated loss in both the choriocapillaris and deeper choroidal layers (Figure 5C–F). These areas corresponded very well to the “punched out” lesions seen in the fundus (Figure 5A–B). Like the previous case, there again is hypertransmission of the overlying retinal capillary networks into the choriocapillaris and choroidal OCTA scans in the areas of the atrophic pigmented scars.
Case 4 (MEWDS): A 56-year old woman with a past ocular history of herpes zoster optic neuritis and keratitis of the left eye in the context of mononucleosis presented with 5 days of “grey spots” in her inferior visual field of her right eye. She denied any redness, eye pain, light sensitivity, flashes, or floaters. She had a mild respiratory infection 3 weeks prior to presentation. Her visual acuity was counting fingers at 1 foot in the right eye and 20/60 in the left eye. There was no anterior segment inflammation or vitritis. The fundus examination was significant for multiple small white dots in the posterior pole with three larger white subretinal lesions, one superotemporal to the fovea, and the other two nasally (Figure 7A). There was also pallor of the left optic nerve consistent with prior optic neuropathy.
Color fundus photograph of the right eye showing multiple small white dots (small white arrowheads) with three larger lesions (yellow arrowheads), one superotemporal to the fovea, and the other two nasally (A). Fundus autofluorescence showing hyperautofluorescence in a punctate pattern and hypoautofluorescence of the three larger lesions (yellow arrowheads) (B). Fluorescein angiography showing a “wreath-like” hyperfluorescence around white dot lesions (small white arrowheads) with especially intense hyperfluorescence of the three larger lesions (yellow arrowheads) (C). Indocyanine green angiography showing hypocyanesecence in the regions corresponding to the large white lesions (yellow arrowheads) (D). Optical coherence tomography (OCT) showing focal disruptions in the outer segments of the photoreceptors and retinal pigment epithelium (white arrows) with subretinal hyperreflectivity through the larger lesions (white arrowhead). The dotted line on (B) shows cross-section of OCT (E). OCT angiography showing hypoperfusion of the choriocapillaris and choroid in the regions corresponding to the larger white lesions (yellow arrowheads) (F, G).
FAF revealed hypoautofluorescence of the three larger lesions and hyperautofluorescence elsewhere in a punctate pattern in the posterior pole (Figure 7B). FA showed hyperfluorescence in a punctate “wreath-like” pattern along with leakage of the three larger lesions (Figure 7C). ICG revealed hypocyanescence in the area corresponding to the overlying white lesions (Figure 7D). OCT demonstrated segmental disruption of the inner segment-outer segment junction and dome-shaped subretinal hyperreflectivity at the level of the larger white lesions (Figure 7E).
OCTA showed punctate regions of nonperfusion in the choriocapillaris and deeper choroid in the areas corresponding to the large white lesions (Figures 7F and 7G). The superficial and deep vascular networks of the retina appeared normal.
We present the OCTA findings of four cases within the differential of WDS: APMPPE, BCR, POHS, and MEWDS. These cases demonstrate different patterns of choriocapillaris and choroid hypoperfusion on OCTA that may help differentiate these conditions while also offering insight into their pathogenesis and disease activity.
Correlating abnormalities in the choriocapillaris and deep choroid revealed by OCTA with overlying RPE and retinal changes can help elucidate disease mechanisms. For instance, loss of choriocapillaris networks in age-related macular degeneration closely correspond to regions of geographic atrophy, suggesting that the loss of choriocapillaris vasculature might precede the development of geographic atrophy.9,10 In contrast, in some inherited retinal degenerations, the loss of choriocapillaris vasculature seems to be smaller than overlying RPE and photoreceptor changes, suggesting that loss of choriocapillaris probably represents a secondary change.11
APMPPE, BCR, POHS, and MEWDS all have characteristic lesions in the retina and RPE that can usually be appreciated on clinical exam, but not always. Hypoperfusion of the choriocapillaris and choroid on OCTA was a shared feature among these conditions, but the differences in the distribution, depth, and extend of these OCTA changes may aid in diagnosis.
The RPE abnormalities in APMPPE are proposed to be secondary to choroidal vasculitis and decreased choroidal perfusion.12 A prior report on OCTA findings in APMPPE showed nonperfusion in the choriocapillaris corresponding to the placoid fundus lesions.5 We similarly observed areas of hypoperfusion that were more pronounced in the choriocapillaris than the deeper choroid. These areas were also more widespread than the retinal lesions seen on exam. Both examples support the idea that the choriocapillaris is the primary site of inflammation in APMPPE. Interestingly, a recent case report described that the areas of choriocapillaris nonperfusion actually reperfuse as the lesions clinically resolved.13 Improvement in choroidal blood flow has also been noted upon clinical resolution.14
Though the pathogenesis is not completely understood, the primary site of inflammation in BCR is thought to be the choroid. In our case, we observed abnormalities in perfusion that were more pronounced in the choroid than the choriocapillaris, in a fashion similar to previous reports.7 Although there was some spatial correlation with the hypopigmented fundus lesions, smaller areas of choroidal hypoperfusion did not have corresponding fundus lesions (Figures 4E–4H). A previous study also found that hyporeflective choroidal lesions on enhanced depth imaging OCTdid not always have corresponding fundus lesions.15 This suggests that subtle changes in the choroid detected by OCTA may precede the development of clinically apparent hypopigmented lesions on fundus examination, and may be a more sensitive indicator of disease.
We observed a robust correlation between the “punched out” lesions of POHS and the areas of choriocapillaris and choroid hypoperfusion on OCTA. This is consistent with the theory that choroidal seeding of Histoplasma capsulatum spores is responsible for the focal destruction of blood vessels in the choroid.16 The resultant inflammatory response may eventually lead to atrophic scarring and loss of choriocapillaris architecture, as demonstrated by OCTA. Focal injury appears to occur in POHS as opposed to more widespread immune response in BCR, APMPPE, and MEWDS.
In MEWDS, well-demarcated focal areas of hypoperfusion in the choriocapillaris corresponded well to the white dots seen in the condition, though slightly larger than typically seen. The absence of choroidal vasculature on OCTA suggests either that the choroidal vasculature is structurally absent, or that the vasculature is present but the blood flow is below the threshold of the OCTA. We theorize that these larger lesions are more active inflammatory infiltrates that have destroyed the underlying choroidal vasculature given the intense leakage on FA and hypoautofluorescence resulting from destruction of the underlying RPE. There exists disagreement regarding whether the primary insult in this condition is located in the choroid or outer retina; structural changes in the RPE and outer segments of the photoreceptors have been consistently observed on OCT,17,18 but choroidal hypoperfusion has also been demonstrated on indocyanine green angiography.19,20 Our finding that notable choriocapillaris hypoperfusion is present, but only in the context of larger white dots, lends support to the hypothesis that the location of primary pathology is in the outer retina, and only begins to affect the choroid when the inflammatory lesions become more significant.
In summary, we compared OCTA findings in APMPPE, BCR, POHS, and MEWDS, identifying focal loss of the choriocapillaris as a potential common feature of these WDS. Each condition may have different patterns of choriocapillaris hypoperfusion that could help with further subclassification and understanding of pathogenesis. Furthermore, comparing these OCTA abnormalities in the choriocapillaris over time may help us better understand the evolution of microvascular changes through our various treatments. Larger longitudinal studies are needed to confirm and further characterize our findings. Nevertheless, OCTA is a powerful tool that enables noninvasive visualization of the choroidal vasculature. The distribution and pattern of choroidal lesions may be instructive in diagnosis especially when characteristic fundus lesions may not be present.
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- Srour M, Querques G, Souied EH. Optical coherence tomography angiography of idiopathic polypoidal choroidal vasculopathy. Dev Ophthalmol. 2016;56:71–76. doi:10.1159/000442781 [CrossRef]
- Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers in macular telangiectasia type 2 imaged by optical coherence tomographic angiography. JAMA Ophthalmol. 2015;133(1):66–73. doi:10.1001/jamaophthalmol.2014.3950 [CrossRef]
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- Nozaki M, Hamada S, Kimura M, Yoshida M, Ogura Y. Value of OCT angiography in the diagnosis of choroidal neovascularization complicating multiple evanescence white dot syndrome. Ophthalmic Surg Lasers Imaging Retina. 2016;47(6):580–584. doi:10.3928/23258160-20160601-11 [CrossRef]
- de Carlo TE, Bonini Filho MA, Adhi M, Duker JS. Retinal and choroidal vasculature in birdshot chorioretinopathy analyzed using spectral domain optical coherence tomography angiography. Retina. 2015;35(11):2392–2399. doi:10.1097/IAE.0000000000000744 [CrossRef]
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- Choi W, Moult EM, Waheed NK, et al. Ultrahigh-speed, swept-source optical coherence tomography angiography in nonexudative age-related macular degeneration with geographic atrophy. Ophthalmology. 2015;122(12):2532–2544. doi:10.1016/j.ophtha.2015.08.029 [CrossRef]
- Waheed NK, Moult EM, Fujimoto JG, Rosenfeld PJ. Optical coherence tomography angiography of dry age-related macular degeneration. Dev Ophthalmol. 2016;56:91–100. doi:10.1159/000442784 [CrossRef]
- de Carlo TE, Adhi M, Salz DA, et al. Analysis of choroidal and retinal vasculature in inherited retinal degenerations using optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina. 2016;47(2):120–127. doi:10.3928/23258160-20160126-04 [CrossRef]
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