Inflammatory Choroidal Neovascularization

Inflammatory choroidal neovascularization (iCNV) is an uncommon complication of uveitis resulting from direct involvement of the retinal pigment epithelium (RPE)-Bruch’s membrane complex by inflammation or infection.^1–5 The most frequently identified cause of iCNV is multifocal choroiditis/punctate inner choroiditis (MFC/PIC) – a well-described, idiopathic condition characterized by the occurrence of multiple circumscribed areas of inflammation at the level of the outer retina and inner choroid.^6–8 Seen most typically in young myopic woman, MFC/PIC lesions tend to occur in the posterior pole and peripapillary area, but can also develop in the mid- and far-periphery where they often arrange into curvilinear clusters or streaks known as Schlegel lines.⁹ Well over half of patients with MFC/PIC will develop CNV,^6,7,10 the majority of which are both well-defined (“classic”) in appearance on fluorescein angiography (FA) and both hyperreflective and type 2, or subretinal, in location on optical coherence tomography (OCT). Such subretinal hyperreflective material (SHRM) can contain inflammatory fibrin, hemorrhage and/or fibrosis in addition to the type 2 neovessels (NV).¹¹ Subretinal or intraretinal fluid may also be present and can serve as a useful biomarker of both activity and treatment response, especially in extrafoveal lesions where central visual acuity may se preserved. Finger-like extensions of hyperreflectivity on OCT can also occur over MFC/PIC lesions and may be a sign of early, active CNV formation.¹² Acute inflammatory lesions with or without CNV can otherwise appear as localized pigment epithelial detachments (PED) of medium hyperreflectivity. Such active MFC/PIC lesions are frequently associated with localized thickening of the underlying choroid.¹³ Choroidal hypertransmission can be seen when the RPE and overlying photoreceptors are disrupted. Less commonly, localized outer retinal hyperreflectivity over a flat and intact RPE may represent MFC/PIC activity.^14,15 Rarely, patients with MFC/PIC can develop focal or geographic areas of photoreceptor dysfunction producing visual field defects. These areas of involvement show outer retinal disruption on OCT and hyperautofluorescence on fundus autofluorescence (FAF) imaging.¹⁶ As most patients with MFC/PIC tend to be myopic and to lack active anterior chamber or vitreous inflammation, it can be difficult to differentiate myopic CNV from iCNV in such eyes. The presence of small, medium reflectivity PEDs, focal or geographic photoreceptor dysfunction, focal choroidal thickening, and/or atrophic punched-out lesions may point to a diagnosis of MFC/PIC – particularly in low to moderate myopes where non-inflammatory CNV is less common.¹⁷ Of note, it is important to distinguish MFC/PIC from multifocal choroiditis with panuveitis (MFCPU), a distinct condition characterized by the presence of active inflammation involving the vitreous – often with papillitis and cystoid macular edema (CME); an increased likelihood of an underlying systemic disorder – most typically sarcoidosis; and a tendency toward more peripheral focal, chorioretinal involvement and, consequently, less frequent development of CNV.^8,18–20 Other less common causes of iCNV^21–26 include Vogt-Koyanagi-Harada (VKH) disease, birdshot chorioretinopathy (BSCR), toxoplasmic retinochoroiditis, and the broad spectrum of serpiginous or serpiginous-like choriodities.²⁷

Although FA has been used traditionally to identify and monitor CNV in eyes with uveitis, OCT-angiography (OCTA) appears to be more reliable as eyes with uveitis tend to show both leakage and staining of involved areas even in the absence of CNV.^1,2,28–37 Most patients with iCNV respond well to a series of intravitreal anti-VEGF injections, commonly in conjunction with regional or short-term systemic corticosteroids. Longer-term systemic immunosuppression has been employed successfully in eyes with frequent recurrences.^1,2,38,39 Anti-microbial therapy should be added in eyes with CNV in the setting of active toxoplasmic or tuberculous retinochoroiditis. Four Original Articles^40–43 and two Letters^44,45 in this issue of Ocular Immunology & Inflammation (OII) describe the occurrence, clinical and multimodal imaging features, and management of CNV in the setting of uveitis.

Agrawal et al⁴⁰ studied the effect of the anti-Vascular Endothelial Growth Factor (VEGF) agent aflibercept administered as an intravitreal injection four days following laser on various markers of activity in a laser-induced CNV model in three C57BL/6 mice. Three mice administered intravitreal phosphate buffered saline (PBS) served as controls. All mice were given intravenous autologous leukocytes labeled with 1% sodium fluorescein on days 4, 7, 15, and 19 following laser injury. Study animals were monitored by serial imaging with color fundus photography, FA, OCT, and scanning laser ophthalmoscopy (SLO). While the amount of intraretinal/subretinal fluid and leukocyte infiltration were all similar at day 4 prior to treatment, these parameters were each markedly decreased at all subsequent time points in the eyes that received intravitreal aflibercept as compared to eyes treated with PBS. The authors concluded that quantitative measurement of infiltration of 1% sodium fluorescein labeled autologous leukocytes into inflammatory CNV lesions using SLO might serve as a valuable approach to the study CNV activity in various disease models. They cited numerous previous reports of an inhibitory effect of anti-VEGF agents on retinal leukostasis as well as leukocyte and fluid infiltration.⁴⁰

Ganesh and Ahmed⁴¹ described the occurrence of CNV in 10 eyes of seven pediatric patients seen in a uveitis referral center in Chennai, India, between January, 2000, and December, 2012. The CNV was subfoveal in five eyes; extrafoveal in three eyes; and both juxtafoveal and peripapillary in one eye. Seven of the ten eyes with CNV had active uveitis at the time CNV developed. Identified causes included serpiginous choroiditis (n = 2); presumed ocular histoplasmosis syndrome (POHS; n = 2); toxoplasmic chorioretinitis (n = 2); and VKH disease (n = 1). One eye each had intermediate uveitis and panuveitis with no identified underlying cause. Active iCNV lesions were treated in each instance with combined oral corticosteroids and immunosuppressive agents, including methotrexate and azathioprine. An intravitreal anti-VEGF agent was given in six eyes; an anti-VEGF agent plus photodynamic therapy (PDT) in one eye; and PDT without an anti-VEGF agent in three eyes. Anti-infective therapy was added in the two patients with toxoplasmic retinochoroidal scars and in one patient with evidence of Mycoplasma tuberculosis exposure by both tuberculin skin and interferon-gamma release assay (IFGA) testing. Follow-up ranged from five months to 15 years, with a mean of 7.5 years. Subjects generally responded to treatment, with eight of 10 lesions resolving with scar formation and only two eyes showing recurrence of the CNV. While follow up varied and two eyes had active CNV at last visit, vision tended to improve from baseline (mean = 0.69 logMAR ~ Snellen 20/100) to last visit (mean = 0.43 logMAR ~ Snellen 20/50). The authors concluded that CNV, although uncommon in children, can occur in the setting of various forms of uveitis, and that extended follow-up is required in such patients to identify recurrences. Management was intensive and involved a combination of oral corticosteroids, systemic immunosuppression, and an intravitreal anti-VEGF agent and/or PDT for all active lesions.

Lee et al⁴² retrospectively analyzed 40 eyes of 26 Korean patients with PIC seen at a referral center in Seoul, Korea, between 2004 and 2015. Twenty-five patients in the cohort (96.2%) were women. The mean age was 34.7 years (range 21–63 years). The mean follow-up was 36.7 months (range 2–114 months). Thirteen eyes (32.5%) had CNV at first visit, whereas four eyes developed CNV during follow up, and eyes with CNV tended to have worse vision at both presentation and last visit. Eyes with CNV tended to be more myopic (−5.4 mean diopters vs −2.3 mean diopters; p = .019) and were more likely to have lesions confined to the posterior pole. In five of 16 affected eyes (31.3%) the CNV was either sub- or juxta-foveal, whereas it was extrafoveal in the remaining 11 eyes (68.7%). Focal choroidal excavation (FCE) was observed in five eyes with CNV (31.3%) verses 10 eyes without CNV (41.7%; p = .44). Subretinal fibrosis was noted in four eyes with CNV (25.0%) verses no eyes without CNV (0.0%; p = .02). Treatment of active iCNV included both multiple intravitreal bevacizumab injections (75.0%) and PDT (12.5%). Two eyes with CNV were observed without treatment. Best-corrected vision at last visit was better than 20/50 in 82.5% of affected eyes. The authors acknowledged the limitations inherent to their study, most notably its retrospective nature, the potential for both referral and treatment bias, and variable follow-up, but concluded that the features and outcomes of PIC and PIC-associated CNV in Korean patients appeared to be similar to the reports on non-Koreans. While their criteria for treatment selection were not described, the authors further concluded that patients tended to do well when treated with serial intravitreal bevacizumab injections.

Haas et al.⁴⁴ retrospectively described multimodal imaging (MMI)-based findings from a 27-year-old myopic woman with PIC with FCE who then developed CNV at the site of excavation. The findings on MMI were similar to those previously reported and included hypoautofluorescence on FAF, late staining hyperfluorescence on FA, hypofluorescence on indocyanine green angiography (ICGA) in the area of FCE, late hyperfluorescence on both FA and ICGA, subretinal hyperreflective material and fluid on OCT, and the presence of CNV on OCTA. The authors cited similar, recently reported patients with PIC and FCE who developed secondary CNV in the area of excavation and noted that both their patient and others tended to respond well to a limited number of intravitreal anti-VEGF agent injections.⁴⁴

Chen et al⁴³ retrospectively evaluated the clinical features, treatment and outcome of 23 eyes in 22 consecutive patients with MFC/PIC that developed active CNV treated with anti-VEGF agents (all eyes) and systemic corticosteroids (21 eyes), 0.5 mg/kg tapered over 1–3 months, at a tertiary referral center in Taipei, Taiwan, between January, 2006, and April, 2018. Twenty-one of the subjects (95.5%) were female, with a mean age of 33.2 years (range 14–66 years). The mean spherical equivalent was −8.2 diopters (range −3 to −20 diopters). The mean duration of follow-up was 6.5 years (range 4–12 years). The mean number of anti-VEGF injections was 2.8 (range 1–12). Recurrent iCNV developed in seven eyes and eyes with recurrences required more intravitreal anti-VEGF agent injections (5.0 vs 1.9; p = .015) and had lower best-corrected vision at last visit (0.5 vs 0.1; p = .015). Worse vision at one, six, and 12 months also predicted lower best-corrected visual acuity at final visit. Best-corrected visual acuity at last visit was better than 20/40 in 19 eyes (82.6%). The authors acknowledged the limited size, variable follow-up, and retrospective, referral-center nature of the study, but concluded that most patients with MFC/PIC and CNV who are treated with sequential intravitreal anti-VEGF agents do well. Whether or not the systemic corticosteroids and/or non-corticosteroid immunosuppressive agents used in the study provided benefit above and beyond anti-VEGF agents was not tested directly.

Zonnevylle and Stanescu-Segall⁴⁵ described an 83-year-old man who develop Candida albicans chorioretinitis in the setting of post-surgical candidemia complicated by the formation of bilateral type 2 CNV. The active infection and CNV were treated with systemic fluconazole and a combination of intravitreal amphotericin B followed by a series of 11 monthly injections of bevacizumab in the right eye and 12 monthly injections in the left eye. The authors acknowledged a previously reported case of post-C. albicans chorioretinitis CNV treated successfully with intravitreal anti-VEGF agents, and described similar post-infectious CNV in the setting of ocular toxocariasis and ocular toxoplasmosis.⁴¹

Taken together, these studies highlight the occurrence, features, and treatment of CNV in eyes with uveitis. While CNV has been reported in setting of several forms of posterior uveitis, by far the most common cause is MFC/PIC, an uncommon condition characterized by the occurrence of multiple circumscribed areas of inflammation at the level of the outer retina and inner choroid.^6–8 Many studies, including several in this issue of OII, support the utility of OCTA in the diagnosis and monitoring of iCNV, and of intravitreal anti-VEGF agents in the treatment of active lesions – although the optimal anti-VEGF dosing schedule has yet to be defined.³⁶ The role and benefit of adjunctive short-term corticosteroids and longer-term non-corticosteroid immunosuppressive agents is less well studied, but both are recommended routinely.^38,39 While we typically use serial anti-VEGF injections and often use regional or systemic corticosteroids in the short term for eyes with MFC/PIC and CNV, we tend to reserve longer-term immunosuppression for eyes with documented, vision-threatening recurrences.

DECLARATION OF INTEREST

KBF is a consultant to Genentech, Optovue, Zeiss, Novartis, Bayer and Heidelberg Engineering, he receives research support from Genentech/Roche. RDM is consultant to Heidelberg Engineering, Novartis and Allergan; she receives research support from Genentech, Roche and Thrombogenics. The other authors have no relevant financial conflicts.

Additional information

Funding

The authors received no financial support for this study.