Inflammatory choroidal neovascularization: an update on diagnosis and management

Introduction

Choroidal neovascularization (CNV) associated with ocular inflammatory disease, also known as inflammatory CNV (iCNV), is a rare complication that can lead to severe vision loss in patients with infectious and noninfectious uveitis (1-3). After pathologic myopia, ocular inflammatory disease is a frequently implicated cause of CNV in patients younger than 50 years old (4). The pathogenesis of iCNV consists of abnormal blood vessel growth across the retinal pigment epithelium (RPE)-Bruch’s membrane complex driven by uncontrolled inflammation, choriocapillaris ischemia, and mechanical damage to the outer retina, with genetic factors also playing a role (1). The drivers of iCNV are multifactorial and complex, and include inflammatory cytokines, vascular endothelial growth factor (VEGF), and the disruption of the outer blood-retinal barrier.

In cases of noninfectious uveitis, iCNV in anterior uveitis and intermediate uveitis is very rare, with a prevalence of less than 0.1%; whereas, in posterior uveitis and panuveitis, the prevalence of iCNV is 2%, and the incidence over two years is 2.7% (5). Etiologies that have been noted to have iCNV at presentation include multiple evanescent white dot syndrome, punctate inner choroidopathy, serpiginous choroidopathy, multifocal choroiditis with panuveitis, birdshot chorioretinopathy, and Vogt-Koyanagi-Harada syndrome. In particular, an increased risk of iCNV development has been noted for Vogt-Koyanagi-Harada syndrome and punctate inner choroidopathy. Risk factors that have been associated with the development of iCNV are: active inflammation (with 2+ anterior chamber cells or worse), preretinal neovascularization, or CNV in the other eye. In cases of infectious uveitis, data are more limited, but there are reports of iCNV associated with histoplasmosis, toxoplasmosis, toxocariasis, tuberculosis, congenital rubella, and West Nile virus (1-3).

Recent literature, including Servillo et al. (1), has provided a comprehensive evidence-based update on iCNV, focusing on diagnostic and therapeutic strategies across a variety of inflammatory conditions. However, further work is needed to elucidate practical clinical guidance on the use of multimodal imaging in the diagnosis and monitoring of iCNV. This review expands upon prior work by providing a focused, up-to-date synthesis of diagnostic features across imaging modalities while highlighting their complementary roles in the diagnosis of iCNV. Additionally, newer treatment combinations in the management of iCNV merit further contextualization. This review offers a critical appraisal of current treatment options—including intravitreal and systemic agents—with an emphasis on clinical decision-making in the absence of standardized guidelines to aid ophthalmologists in effectively approaching the complex diagnosis and management of iCNV.

Clinical presentation

Symptoms of iCNV include sudden decrease in vision, metamorphopsia, or scotoma, although some presentations can be asymptomatic (1-3,6). Active iCNV lesions appear grayish with possible hemorrhage or exudation present, while inactive ones appear as atrophic yellow-white scars, and mixed patterns may also be seen. Inflammatory CNV can be subfoveal, juxtafoveal, or extrafoveal, and may develop adjacent to active chorioretinal lesions or inactive chorioretinal scars. The diagnosis of iCNV can be challenging, and the use of multimodal imaging with optical coherence tomography (OCT), OCT angiography (OCTA), fluorescein angiography (FA), and indocyanine green angiography (ICGA) is necessary to guide management (7).

Multimodal imaging (Figure 1)

Figure 1 Multimodal imaging of iCNV in a patient with idiopathic multifocal choroiditis. Fundus photograph (A) depicting a yellow-white macular chorioretinal scar with a grayish lesion superiorly, as well as several scattered hypopigmented chorioretinal scars in the posterior pole. OCT (B) depicting subretinal hyperreflective material, retinal thickening, and intraretinal and subretinal fluid. Fluorescein angiography early (C) and late (D) frames depicting the iCNV lesion with early hyperfluorescence followed by late leakage. Indocyanine green angiography early (E) and late (F) frames depicting the iCNV lesion as hyperfluorescent and the inflammatory lesions as hypofluorescent. iCNV, inflammatory choroidal neovascularization; OCT, optical coherence tomography.

OCT and OCTA

On OCT, iCNV can be visualized as hyperreflective lesions between the RPE and neurosensory retina (1,2,6). Active lesions can demonstrate retinal thickening, intraretinal or subretinal fluid, intraretinal hyperreflective flecks, or subretinal hyperreflective material (SHRM). Other common OCT features of iCNV include ellipsoid zone disruption and choroidal hypertransmission (8). OCT can be used to identify iCNV via the “pitchfork sign” of hyperreflective finger-like projections from the CNV lesion into the outer retina, although this sign is no longer thought to be unique to iCNV (7,9). OCT may also demonstrate the “sponge sign” of increased choroidal thickness in iCNV that decreases with treatment, a finding which can help differentiate it from myopic CNV (10).

Additional data on iCNV can be obtained through OCTA by analyzing neovascular flow (11). Studies have demonstrated the usefulness of OCTA in identifying iCNV when other imaging modalities proved inconclusive (12). The presence of blood flow can help differentiate CNV from inflammatory lesions, as well as active from inactive iCNV. OCTA has been found to have 87–89% sensitivity and 89–98% specificity in identifying iCNV and its activity (13,14). Furthermore, parameters such as SHRM height, width, and flow can be used to monitor treatment response and guide therapy (15). While OCTA in age-related macular degeneration has been well studied, further data on OCTA use in ocular inflammatory disease and iCNV is needed (2). Nevertheless, both OCT and OCTA are particularly helpful because they are noninvasive studies with ease of repeatability.

FA and ICGA

On FA, iCNV can be visualized as a classic lesion with early isofluorescence or hyperfluorescence followed by late leakage (1,2,6,16,17). However, the use of FA alone in the diagnosis of iCNV can be challenging, as active and inactive inflammatory chorioretinal lesions may also demonstrate a similar FA pattern, with early isofluorescence and late leakage or staining. Also, the presence of exudation, hemorrhage, scarring, or pigmentation may affect the pattern of fluorescence on FA and make it difficult to detect iCNV.

Additional data on iCNV can be obtained from ICGA, especially with regard to assessing for associated choroidal abnormalities such as choroiditis, choroidal granulomas, and choroidal vasculitis (1,2,6,17,18). On ICGA, iCNV can be visualized as hyperfluorescent lesions, while active inflammatory lesions appear hypofluorescent, providing possible clues to help differentiate between the two (19). Another value of ICGA is that it can be used to evaluate and follow CNV size to gauge response to therapy, as shown in prior studies on idiopathic CNV (20). In these ways, FA and ICGA can be complementary studies providing unique ways of characterizing iCNV in ocular inflammatory disease.

Treatment

There are currently no established guidelines for the management of iCNV. In theory and as demonstrated by prior studies, treatment approaches for iCNV should be designed to control both the angiogenic and inflammatory aspects of the condition (1,2). Treatments include intravitreal anti-VEGF, local and systemic corticosteroids, systemic immunomodulatory therapy (IMT), laser photocoagulation, photodynamic therapy (PDT), and surgical removal (21). Older studies have demonstrated the regression of iCNV with PDT and surgical removal (22,23). However, laser and surgical treatment modalities have been used less frequently since the advent of intravitreal anti-VEGF therapy. Furthermore, a randomized controlled trial demonstrated better visual outcomes with intravitreal anti-VEGF therapy compared to PDT (24).

More recent studies have shown that treatment with intravitreal anti-VEGF (bevacizumab, ranibizumab, or aflibercept) alone or in combination with local or systemic corticosteroids or systemic IMT can be effective in iCNV associated with infectious and noninfectious ocular inflammatory diseases (25-28). In particular, significant improvement in visual outcomes has been noted with prompt intravitreal anti-VEGF treatment, and a lower risk of CNV recurrence has been noted with the addition of oral steroids (25,26). Further studies have demonstrated that early treatment with systemic IMT results in better visual outcomes (29). Compared to patients on corticosteroid regimens, those on systemic IMT were less likely to have iCNV recurrence or require repeat intravitreal anti-VEGF (30).

Given that iCNV is associated with multiple etiologies, close monitoring is recommended to assess response to therapy and make adjustments based on patient factors. Other treatment options include the use of intravitreal steroid implants, with case series demonstrating the efficacy of intravitreal dexamethasone implant, where intravitreal anti-VEGF therapy or other systemic therapy may not be preferred (such as in pregnancy) (31). Intravitreal IMT may also be beneficial in certain cases, with a case report demonstrating the efficacy of intravitreal methotrexate in recurrent iCNV previously treated with ranibizumab (32). Although there are several therapeutic options available for the treatment of iCNV, and combination therapy is often utilized, future randomized controlled clinical trials comparing the different treatment modalities are necessary to establish a standard of care in iCNV.

Conclusions

Inflammatory CNV is a rare vision-threatening complication in ocular inflammatory disease, especially in cases of posterior or panuveitis. The pathogenesis is multifactorial, with contributions from angiogenic and inflammatory factors. Approaching iCNV with multimodal imaging is necessary through the utilization of OCT, FA, and ICGA to diagnose and manage CNV and its associated inflammatory component. Treatment typically consists of intravitreal anti-VEGF therapy in combination with anti-inflammatory therapy of corticosteroids or IMT. Future studies are needed to reach a consensus on the best method of treatment for iCNV.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-16/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-16/coif). The authors have no conflicts of interest to declare.

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References

1. Servillo A, Scandale P, Oldoni G, et al. Inflammatory choroidal neovascularization: An evidence-based update. Surv Ophthalmol 2025;70:451-66. [Crossref] [PubMed]
2. Agarwal A, Invernizzi A, Singh RB, et al. An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management. J Ophthalmic Inflamm Infect 2018;8:13. [Crossref] [PubMed]
3. D'Ambrosio E, Tortorella P, Iannetti L. Management of uveitis-related choroidal neovascularization: from the pathogenesis to the therapy. J Ophthalmol 2014;2014:450428. [Crossref] [PubMed]
4. Cohen SY, Laroche A, Leguen Y, et al. Etiology of choroidal neovascularization in young patients. Ophthalmology 1996;103:1241-4. [Crossref] [PubMed]
5. Baxter SL, Pistilli M, Pujari SS, et al. Risk of choroidal neovascularization among the uveitides. Am J Ophthalmol 2013;156:468-477.e2. [Crossref] [PubMed]
6. Karska-Basta I, Pociej-Marciak W, Żuber-Łaskawiec K, et al. Diagnostic Challenges in Inflammatory Choroidal Neovascularization. Medicina (Kaunas) 2024;60:465. [Crossref] [PubMed]
7. Bou Ghanem G, Neri P, Dolz-Marco R, et al. Review for Diagnostics of the Year: Inflammatory Choroidal Neovascularization - Imaging Update. Ocul Immunol Inflamm 2023;31:819-25. [Crossref] [PubMed]
8. Kim M, Lee J, Park YG, et al. Long-Term Analysis of Clinical Features and Treatment Outcomes of Inflammatory Choroidal Neovascularization. Am J Ophthalmol 2022;233:18-29. [Crossref] [PubMed]
9. Hoang QV, Cunningham ET Jr, Sorenson JA, et al. The "pitchfork sign" a distinctive optical coherence tomography finding in inflammatory choroidal neovascularization. Retina 2013;33:1049-55. [Crossref] [PubMed]
10. Giuffrè C, Marchese A, Fogliato G, et al. The "Sponge sign": A novel feature of inflammatory choroidal neovascularization. Eur J Ophthalmol 2021;31:1240-7. [Crossref] [PubMed]
11. Kongwattananon W, Grasic D, Lin H, et al. Role of optical coherence tomography angiography in detecting and monitoring inflammatory choroidal neovascularization. Retina 2022;42:1047-56. [Crossref] [PubMed]
12. Levison AL, Baynes KM, Lowder CY, et al. Choroidal neovascularisation on optical coherence tomography angiography in punctate inner choroidopathy and multifocal choroiditis. Br J Ophthalmol 2017;101:616-22. [Crossref] [PubMed]
13. 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;169:145-61. [Crossref] [PubMed]
14. Agarwal A, Handa S, Marchese A, et al. Optical Coherence Tomography Findings of Underlying Choroidal Neovascularization in Punctate Inner Choroidopathy. Front Med (Lausanne) 2021;8:758370. [Crossref] [PubMed]
15. Arora A, Agarwal A, Bansal R, et al. Subretinal Hyperreflective Material (SHRM) as biomarker of activity in Exudative and Non- exudative inflammatory choroidal neovascularization. Ocul Immunol Inflamm 2023;31:48-55. [Crossref] [PubMed]
16. Kotsolis AI, Killian FA, Ladas ID, et al. Fluorescein angiography and optical coherence tomography concordance for choroidal neovascularisation in multifocal choroidtis. Br J Ophthalmol 2010;94:1506-8. [Crossref] [PubMed]
17. Spaide RF, Goldberg N, Freund KB. Redefining multifocal choroiditis and panuveitis and punctate inner choroidopathy through multimodal imaging. Retina 2013;33:1315-24. [Crossref] [PubMed]
18. Agrawal RV, Biswas J, Gunasekaran D. Indocyanine green angiography in posterior uveitis. Indian J Ophthalmol 2013;61:148-59. [Crossref] [PubMed]
19. Perentes Y, Van Tran T, Sickenberg M, et al. Subretinal neovascular membranes complicating uveitis: frequency, treatments, and visual outcome. Ocul Immunol Inflamm 2005;13:219-24. [Crossref] [PubMed]
20. Rush RB, Rush SW. Evaluation of Idiopathic Choroidal Neovascularization with Indocyanine Green Angiography in Patients Undergoing Bevacizumab Therapy. J Ophthalmol 2015;2015:642624. [Crossref] [PubMed]
21. O'Toole L, Tufail A, Pavesio C. Management of choroidal neovascularization in uveitis. Int Ophthalmol Clin 2005;45:157-77. [Crossref] [PubMed]
22. Parodi MB, Iacono P, Spasse S, et al. Photodynamic therapy for juxtafoveal choroidal neovascularization associated with multifocal choroiditis. Am J Ophthalmol 2006;141:123-8. [Crossref] [PubMed]
23. Benson MT, Callear A, Tsaloumas M, et al. Surgical excision of subfoveal neovascular membranes. Eye (Lond) 1998;12:768-74. [Crossref] [PubMed]
24. Parodi MB, Iacono P, Kontadakis DS, et al. Bevacizumab vs photodynamic therapy for choroidal neovascularization in multifocal choroiditis. Arch Ophthalmol 2010;128:1100-3. [Crossref] [PubMed]
25. Labriola LT, Vangipuram G, Zarnegar A, et al. Use of Adjunctive Corticosteroid With Antivascular Endothelial Growth Factor Agents in the Treatment of Choroidal Neovascular Membrane Associated With Presumed Ocular Histoplasmosis. J Vitreoretin Dis 2023;7:510-20. [Crossref] [PubMed]
26. Woronkowicz M, Niederer R, Lightman S, et al. Intravitreal Antivascular Endothelial Growth Factor Treatment for Inflammatory Choroidal Neovascularization in Noninfectious Uveitis. Am J Ophthalmol 2022;236:281-7. [Crossref] [PubMed]
27. Zina S, Khochtali S, Invernizzi A, et al. Results of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Inflammatory Choroidal Neovascularization. J Curr Ophthalmol 2021;33:68-74. [Crossref] [PubMed]
28. Invernizzi A, Pichi F, Symes R, et al. Twenty-four-month outcomes of inflammatory choroidal neovascularisation treated with intravitreal anti-vascular endothelial growth factors: a comparison between two treatment regimens. Br J Ophthalmol 2020;104:1052-6. [Crossref] [PubMed]
29. Neri P, Pichi F, Pirani V, et al. Systemic Immunosuppression Is Highly Effective in the Long-term Control of Inflammatory non-infectious Uveitic Choroidal Neovascularization: A Comparative Study. Ocul Immunol Inflamm 2021;29:1132-6. [Crossref] [PubMed]
30. Airaldi M, Monteduro D, Tondini G, et al. Immunomodulatory Treatment Versus Systemic Steroids in Inflammatory Choroidal Neovascularization Secondary to Idiopathic Multifocal Choroiditis. Am J Ophthalmol 2024;262:62-72. [Crossref] [PubMed]
31. Capuano V, Serra R, Oubraham H, et al. Dexamethasone intravitreal implant for choroidal neovascularization during pregnancy. Retin Cases Brief Rep 2019;13:300-7. [Crossref] [PubMed]
32. Mateo-Montoya A, Baglivo E, de Smet MD. Intravitreal methotrexate for the treatment of choroidal neovascularization in multifocal choroiditis. Eye (Lond) 2013;27:277-8. [Crossref] [PubMed]