Choroidal neovascularization (CNV) is a known sight-threatening complication of choroiditis with a reported incidence of 6.7% to 76.9% in multifocal choroiditis and punctate inner choroidopathy.1–3 However, its association with choroidal granulomas has been rarely reported.4 Conventionally, the detection of inflammatory CNV using clinical examination and dye-based fluorescein/indocyanine green angiography has posed considerable challenges in view of confounding findings in the presence of concomitant retinal scarring from healed lesions or due to the presence of active choroiditis lesions itself.5
In the recent past, optical coherence tomography angiography (OCTA) emerged as a very useful, noninvasive technique that can help in the detection of these inflammatory CNVs without subjecting the patient to the risks inherent to the dye-based techniques.6–8 We report a case of type 2 inflammatory CNV developing in a case of presumed tubercular choroidal granuloma detected using swept-source OCTA.
A 27-year-old Asian Indian male presented with diminution of vision in the right eye (OD) for the past 3 to 4 days. He had history of loss of central vision in the left eye (OS) a few years back, for which he had not received any treatment. His presenting visual acuity (VA) was counting fingers at 1 meter in both eyes (OU). On examination, the anterior segment was quiescent in OU. Posterior segment examination revealed the presence of vitritis 2+ and a yellowish, raised subretinal mass lesion in the macula, just inferior to the fovea with overlying retinal hemorrhages and surrounding exudative fluid OD. There was a yellowish pigmented scar nasal to the optic disc OD, which appeared healed. A healed pigmented chorioretinal scar was seen involving the macula OS (Figure 1).
(A) Fundus photograph of the right eye shows presence of vitritis with a large, yellowish, raised subretinal lesion with overlying retinal hemorrhages and surrounding exudative retinal detachment suggestive of a vascularized choroidal granuloma. (B) Fundus photograph of the nasal field shows the presence of a healed chorioretinal lesion with well-defined margins and no overlying fluid. (C) Fundus photograph of the left eye shows a healed pigmented chorioretinal scar involving the macula. (D) Optical coherence tomography line scan passing through the subretinal lesion in the right eye shows dome-shaped elevations of the retinal pigment epithelium with presence of subretinal fluid and hyperreflective deposits suggestive of fibrin. There is hyporeflectivity of the underlying choroid.
Combined fluorescein angiography (FA) and indocyanine green angiography (ICGA) was performed. FA showed early stippled hyperfluorescence corresponding to the raised subretinal lesion, which became progressively hyperfluorescent with pooling of dye in the late phase OD, suggestive of a vascularized choroidal granuloma with exudative retinal detachment (Figure 2). On ICGA, there was hypocyanescence in the early phase that persisted in the late phase, suggestive of a full-thickness choroidal granuloma (Figure 2). OCT revealed dome-shaped elevation of the retinal pigment epithelium with diffuse hyporeflectivity of the underlying choroid and presence of subretinal fluid and hyperreflective deposits, suggestive of fibrin in the subretinal space (Figure 1). There was transmission hyperfluorescence corresponding to the chorioretinal scar OS.
Combined fluorescein angiography (FA) and indocyanine green angiography (ICGA) of the right eye at presentation. (A) Early phase of FA shows stippled hyperfluorescence just inferior to the fovea and transmission hyperfluorescence corresponding to the chorioretinal scar nasal to the optic disc, whereas the ICGA shows a round hypocyanescent lesion inferior to the fovea and nasal to optic disc. (B) Late phase of FA shows progressive hyperfluorescence with pooling of dye and staining of the healed scar nasal to the optic disc, whereas the ICGA shows persistent hypocyanescence with a faint isocyanescence in the center of the macular lesion and persistent hypocyanescence in the area of the healed chorioretinal scar. These findings suggest that the lesion in posterior pole was active with a relatively full-thickness choroidal granuloma and presence of a healed choroidal lesion with choriocapillaris atrophy nasally. Pooling of the dye in the posterior pole is suggestive of surrounding exudative retinal detachment.
Laboratory evaluation revealed a positive Mantoux test (18 mm × 19 mm) and a positive QuantiFERON TB Gold test (Qiagen, Hilden, Germany). Treponema pallidum hemagglutination assay was negative and contrast-enhanced computerized tomography of the chest was normal. All other laboratory results were within normal limits. A diagnosis of possible tubercular choroidal granuloma was made,9 and treatment was initiated with oral corticosteroids (1 mg/kg body weight) along with two injections of intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA). This was followed by the addition of standard four-drug anti-tubercular therapy (ATT). ATT consisted of isoniazid (5 mg/kg/day), rifampicin (10 mg/kg/day) (Rifadin; Sanofi-Aventis, Paris, France), ethambutol (15mg/kg/day) (Myambutol; X-Gen Pharmaceuticals, Horseheads, NY), and pyrazinamide (20mg/kg/day) for the first 2 months, followed by continuation of isoniazid and rifampicin for another 7 months.
The lesion showed a good healing response and resolved completely within 3 months. The best-corrected VA improved to 20/60 OD. At the 7-month follow-up, a retinal hemorrhage was noticed at the edge of the healed choroidal granuloma, although the patient was asymptomatic and VA was maintained at 20/60. SS-OCT line scan showed presence of outer retinal hyperreflectivity nasal to the fovea without any intraretinal or subretinal fluid. OCTA imaging was performed using Optovue RTVue XR 100 Avanti (Optovue, Fremont, CA). OCTA (3 mm × 3 mm) en face scan revealed the presence of a type 2 CNV at the edge of the healed chorioretinal scar OD for which the patient received one injection of intravitreal ranibizumab (Lucentis; Genentech, South San Francisco, CA) OD (Figure 3). Since there was no improvement in vision, the patient refused any further injections and was lost to follow-up.
(A) Fundus photograph of the right eye at 7-month follow-up shows a healed pigmented chorioretinal scar at the site of the choroidal granuloma with the presence of a retinal hemorrhage at the edge of the scar (white arrow). Optical coherence tomography angiography (OCTA) en face image (obtained by adjusting the automatic segmentation slab at the choriocapillaris level so that the upper retinal pigment epithelium [RPE] reference offset was −9 μm and the lower RPE reference offset was 19 μm) reveals a network of vessels that stands out from the rest of the projection artefacts, suggestive of choroidal neovascularization (CNV). (C) The corresponding structural en face OCT image does not show any signal transmission defects. (D) OCT line scan passing through this area shows the disruption of the outer retinal layers, including the external limiting membrane and ellipsoid zone in the subfoveal region, with adjacent outer retinal hyperreflectivity suggestive of a type 2 CNV.
Thirteen months after initial presentation, he reported with complaints of recent-onset blurring of vision OD. On examination, there was presence of a grayish lesion juxtaposing the healed chorioretinal scar associated with a retinal hemorrhage (Figure 4). SS-OCT revealed outer retinal hyperreflectivity at the edge of the healed lesion on both sides of the fovea suggestive of a type 2 CNV with microcystic spaces in the outer retinal layers. OCTA (3 mm × 3 mm) en face image at this stage confirmed the presence of a network of thick anastomotic vessels (in the outer retinal and choriocapillaris layers), which had shown significant progression from the initial visit when the CNV was first diagnosed. The patient was advised to repeat injection of intravitreal ranibizumab but was again lost to follow-up.
(A) Fundus photograph of the right eye at 13-month follow-up shows a crescent-shaped, greyish lesion along the superior edge of the healed chorioretinal scar associated with retinal hemorrhages (white arrow). (B) Fundus autofluorescence shows hypoautofluorescence in the area of the healed choroidal granuloma and faint hyperautofluorescence with a hypoautofluorescent rim corresponding to the greyish lesion. (C) Optical coherence tomography angiography (OCTA) en face image shows a well-defined neovascular complex with hairpin loop configuration of anastamotic vessels and significant increase in size from the previous follow-up. (D) Structural en face scan does not show any signal transmission defects in the area of the neovascularization. (E) OCT line scan performed at this stage reveals outer retinal hyperreflectivity on either side of the foveal notch with breach in the retinal pigment epithelium suggestive of a type 2 inflammatory CNV, which has shown significant increase in size from the previous visit.
The introduction of cutting-edge technologies such as SS-OCT and OCTA have revolutionized the diagnostic capabilities of retina and uveitis specialists and greatly aided in improving our understanding of pathological basis of disease. In the index case, detailed evaluation using multimodal imaging helped in managing the case even after the primary pathology of choroidal granuloma had healed. As noted during the initial presentation, our patient had a large full-thickness choroidal granuloma that showed early and late hypofluorescence on ICGA and surrounding exudation and fluid. The initial therapy of this patient was with intravitreal bevacizumab, the addition of which has been shown to be of great benefit as an adjunct in vascularized choroidal granulomas along with oral corticosteroids and ATT.10,11 At this stage, therapy with bevacizumab was not targeted at any CNV lesion. With this regimen, the choroidal granuloma demonstrated successful resolution at 3 months and the patient had subjective improvement in VA.
However, a careful examination at the 7-month follow-up showed the presence of a small retinal hemorrhage. OCTA showed the presence of a distinct network of vessels with hairpin loop configuration in the outer retina extending from the choriocapillaris suggestive of type 2 CNV. On automated segmentation, although these vessels were seen in the outer retinal and choriocapillaris slab, clear demarcation was possible after manually moving the segmentation slabs. Manual segmentation can help in adjusting the thickness of the slab and differentiating projection artefacts from true neovascular lesions. At this time, the SS-OCT did not show presence of any intraretinal or subretinal fluid and the patient was asymptomatic. Subsequently, OCTA analysis at 13 months shows a remarkable growth in the CNV, and on SS-OCT, the neovascular complex had involved the subfoveal region with appearance of microcystic spaces in the outer retina. At this stage, the patient experienced diminuition of vision. Thus, it is imperative to note that such large, mature-looking loopy vessels (observed at 7 months) with no apparent exudation (ie, absence of fluid on OCT) can rapidly grow into large neovascular networks, resulting in permanent visual loss. These CNV lesions merit early diagnosis and close follow-up for any change in the size/appearance of fluid on OCT. Currently, there are no definite recommended guidelines for the treatment of inflammatory CNV with anti-vascular endothelial growth factor (VEGF) agents. However, since there was a documented increase in the size of the CNV on OCTA, it provided us with an objective evidence of the activity of CNV, and thus, the patient may have benefitted from anti-VEGF therapy.
Large choroidal granulomas may be associated with the development of local ischemia due to mass effect leading to increased levels of vascular endothelial growth factor (VEGF).12 Increased levels of VEGF, along with heightened inflammatory stimuli, may lead to the development of CNV in these cases.13 Although anti-VEGF agents such as ranibizumab (Lucentis; Genentech, South San Francisco, CA) are efficacious, the key in the management of these CNV lesions is early detection, prior to development of symptoms. A number of authors have demonstrated the utility of multimodal imaging in the detection and management of inflammatory CNV. In a study by Cheng et al., active type 2 CNV networks were detected in patients with multifocal choroiditis using FA and OCTA.14 Similarly, in a recent series by Zahid et al.,15 neovascular flow signals were evaluated in patients with multifocal choroiditis. OCTA has also been used in the detection of CNV in other inflammatory conditions such as punctate inner choroidopathy,3 serpiginous choroiditis,16 as well as TB-associated choroiditis.17 As illustrated in the index case, SS-OCT and OCTA were very useful in the early recognition of abnormal vascular plexuses in our patient with healed choroidal granuloma, before the new vessels started leaking and forming intra- or subretinal fluid spaces. Thus, OCTA may be an invaluable tool in the follow-up and serial imaging of posterior uveitic entities such as choroidal granulomas.
In summary, early detection of CNV on OCTA in healed choroidal granulomas is desirable as these lesions may benefit from early treatment before appearance of cystoid spaces in the retina. If left untreated, such type 2 CNV networks are likely to progress rapidly leading to suboptimal visual outcomes.
- Baxter SL, Pistilli M, Pujari SS, et al. Risk of choroidal neovascularization among the uveitides. Am J Ophthalmol. 2013;156(3):468–477.e2. doi:10.1016/j.ajo.2013.04.040 [CrossRef]
- Kedhar SR, Thorne JE, Wittenberg S, Dunn JP, Jabs DA. Multifocal choroiditis with panuveitis and punctate inner choroidopathy: comparison of clinical characteristics at presentation. Retina. 2007;27(9):1174–1179. doi:10.1097/IAE.0b013e318068de72 [CrossRef]
- Levison AL, Baynes KM, Lowder CY, Kaiser PK, Srivastava SK. Choroidal neovascularisation on optical coherence tomography angiography in punctate inner choroidopathy and multifocal choroiditis. Br J Ophthalmol. 2017;101(5):616–622. doi:10.1136/bjophthalmol-2016-308806 [CrossRef]
- Khatib T, Hughes PW, Burton BJ. Unilateral choroidal granulomas complicated by choroidal neovascular membrane treated successfully with intravitreal triamcinolone in a patient with sarcoidosis. 2014Aug28;2014. pii: bcr2014204794. doi:10.1136/bcr-2014-204794 [CrossRef].
- Bansal R, Bansal P, Gupta A, et al. Diagnostic challenges in inflammatory choroidal neovascular membranes. Ocul Immunol Inflamm. 2017;25(4):554–562. doi:10.3109/09273948.2016.1160128 [CrossRef]
- Agrawal R, Xin W, Keane PA, Chhablani J, Agarwal A. Optical coherence tomography angiography: A non-invasive tool to image end-arterial system. Expert Rev Med Devices. 2016;13(6):519–521. doi:10.1080/17434440.2016.1186540 [CrossRef]
- Park MM, Rebhun CB, Cole ED, et al. Diagnosing choroidal neovascularization in asymptomatic individuals using optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina. 2017;48(7):596–598. doi:10.3928/23258160-20170630-13 [CrossRef]
- Souedan V, Souied EH, Caillaux V, Miere A, Ameen AE, Blanco-Garavito R. Sensitivity and specificity of optical coherence tomography angiography (OCT-A) for detection of choroidal neovascularization in real-life practice and varying retinal expertise level. Int Ophthalmol. 2018;38(3):1051–1060. doi:10.1007/s10792-017-0559-6 [CrossRef]
- Gupta A, Sharma A, Bansal R, Sharma K. Classification of intraocular tuberculosis. Ocul Immunol Inflamm. 2015;23(1):7–13. doi:10.3109/09273948.2014.967358 [CrossRef]
- Bansal R, Beke N, Sharma A, Gupta A. Intravitreal bevacizumab as an adjunct in the management of a vascular choroidal granuloma. BMJ Case Rep. 2013Sep6;2013. pii: bcr2013200255. doi:10.1136/bcr-2013-200255 [CrossRef].
- Invernizzi A, Franzetti F, Viola F, Meroni L, Staurenghi G. Optic nerve head tubercular granuloma successfully treated with anti-VEGF intravitreal injections in addition to systemic therapy. Eur J Ophthalmol. 2015;25(3):270–272. doi:10.5301/ejo.5000528 [CrossRef]
- Wolfensberger TJ, Piguet B, Herbort CP. Indocyanine green angiographic features in tuberculous chorioretinitis. Am J Ophthalmol. 1999;127(3):350–353. doi:10.1016/S0002-9394(98)00325-0 [CrossRef]
- Grossniklaus HE, Ling JX, Wallace TM, et al. Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis. 2002;8:119–126.
- Cheng L, Chen X, Weng S, et al. Spectral-domain optical coherence tomography angiography findings in multifocal choroiditis with active lesions. Am J Ophthalmol. 2016;169:145–161. doi:10.1016/j.ajo.2016.06.029 [CrossRef]
- Zahid S, Chen KC, Jung JJ, et al. Optical coherence tomography angiography of chorioretinal lesions due to idiopathic multifocal choroiditis. Retina. 2017;37(8):1451–1463. doi:10.1097/IAE.0000000000001381 [CrossRef]
- Parodi MB, Iacono P, La Spina C, et al. Intravitreal bevacizumab for choroidal neovascularisation in serpiginous choroiditis. Br J Ophthalmol. 2014;98(4):519–522. doi:10.1136/bjophthalmol-2013-304237 [CrossRef]
- Yee HY, Keane PA, Ho SL, Agrawal R. Optical coherence tomography angiography of choroidal neovascularization associated with tuberculous serpiginous-like choroiditis. Ocul Immunol Inflamm. 2016;24(6):699–701. doi:10.3109/09273948.2015.1109669 [CrossRef]