How do we treat inflammatory CNVM ?

Dr. Krinjeela Bazgain, MS
Dr Nitin Kumar. MS FMRF
Dr. Reema Bansal, MS, PhD
Published Online: April 1st, 2021 | Read Time: 16 minutes, 24 seconds

Inflammatory choroidal neovascular membranes (CNVM) cause an acute and significant visual loss 1,2. Mostly affecting eyes with posterior or panuveitis, the chronic recurrent nature of inflammation further worsens the visual prognosis in these eyes, such as serpiginous like choroiditis, punctuate inner choroidopathy (PIC), multifocal choroiditis, Vogt-Koyanagi-Harada (VKH) disease, presumed ocular histoplasmosis syndrome, toxoplasma retinochoroiditis, etc,.3,4 . The angiogenic stimulus in inflammatory CNVM is driven by local inflammation and/or a degenerative breach in retinal pigment epithelium (RPE)-Bruch’s membrane complex4. An active intraocular inflammation induces the release of several inflammatory mediators including cytokines, chemokines, vascular endothelial growth factor (VEGF) and complement activation, which in turn promote retinal and choroidal neovascularization. Majority of inflammatory CNVM are classic (on fundus fluorescein angiography), and type 2 on spectral domain optical coherence tomography (SD-OCT) 5-8. While most of the studies report sub-foveal location as the commonest5-7, peripapillary CNVMs were the most common in our series (45.2%)8, and in a study by D’Souza et al (53.3%)9.

Treatment options for inflammatory CNVM

Both the diagnosis and treatment of inflammatory CNVM are challenging. Various treatment options for inflammatory CNVM include corticosteroids (local and systemic), laser photocoagulation, anti-VEGF agents, immunosuppressive agents, photodynamic therapy (PDT), and surgical removal of the membrane. There is no consensus on treatment algorithm due to the lack of randomized trials, and the first line of treatment depends upon the clinicians’ discretion based on their experiences.

Corticosteroids: In the pre-anti-VEGF era, corticosteroids were the first and only conservative therapeutic option available for inflammatory CNVMs10. They not only stabilized the visual acuity, but also controlled the inflammation-causing posterior uveitis. They act by inhibiting pro-inflammatory factors and also induce transcription and suppression of prostaglandin and interleukin synthesis11-13. Corticosteroids also interfere with the effects of VEGF11-13. Steroids (systemic or intravitreal injections) have been used as monotherapy, or combined with PDT, or with anti-VEGF therapy, or immunosuppressive agents for treating inflammatory CNVM14. Some practitioners continue to use them as the first line of treatment for inflammatory CNVM in non-infectious uveitis owing to their rapid and strong anti-inflammatory properties.

Photodynamic therapy: Though effective for sub-foveal CNVM, PDT offers only visual stabilization (and not an improvement) and has a high recurrence rate of CNVM due to PDT-induced local inflammation15. Though it has been found more effective for CNVM associated with uveitis than CNVM in age-related macular degeneration (AMD), the use of PDT as a monotherapy for inflammatory CNVM has largely decreased with the growing literature on the safety and efficacy of anti-VEGF therapy.

Immunosuppressive therapy: Immunosuppressants can limit angiogenesis owing to their anti-inflammatory property, and have been shown effective in the treatment of extrafoveal, juxtafoveal and subfoveal CNVMs16-18. Resolution or stabilization of the CNVM lesions have been reported with cyclosporine and mycophenolate mofetil. Combination therapy of systemic immunosuppression with PDT or with anti-VEGF agents is also a useful treatment option19. Successful use of intravitreal methotrexate (single injection) has been reported in a case of multifocal choroiditis with inflammatory CNVM unresponsive to previous three anti-VEGF injections20.

Surgical excision: This was considered several decades ago for large CNVMs or when laser photocoagulation was the only therapeutic option available. This treatment is not considered in the current practice.

With a high rate of complications and recurrence rates with the majority of these treatment modalities, anti-VEGF therapy is emerging as the popular and primary treatment for inflammatory CNVM. Further, the demonstration of VEGF expression in the excised CNVMs in eyes with uveitis justifies its use for treating these membranes by directly targeting their pathogenetic pathway21.

Figure 1: A case of bilateral healed choroiditis (a,b) with inflammatory CNVM in left eye (b). Fundus fluorescein angiography showed mixed fluorescence corresponding to scars in early (c) and late frames (d) with a subtle hyperfluorescence in the fovea in late frame (d) corresponding to the CNVM. SD-OCT scan showed type 2 CNVM with subretinal fluid (e), and OCTA showed the abnormal vascular network (f).

Anti-VEGF therapy for inflammatory CNVM

D’Souza et al reported the long-term successful outcome of inflammatory CNVM with anti-VEGF therapy in terms of visual and anatomical improvement, and low recurrence and complication rates9. Irrespective of the status of uveitis (active or inactive) and the cause of intraocular inflammation, anti-VEGF therapy was highly effective as a therapeutic approach for inflammatory CNVMs. Roy et al reported the outcome of inflammatory CNVM to anti-VEGF therapy in Indian eyes22.

When compared with laser photocoagulation or PDT, prompt response to intravitreal injections, safety, efficacy, and lack of collateral tissue damage to retina and choroid are the major advantages of anti-VEGF therapy6. Both bevacizumab and ranibizumab have been individually (or in combination) effective. The mean number of injections is much less as compared to CNVM in AMD, as reported by Adan et al (mean 1.3 injections)23, D’Souza et al (mean injections 2.6 + 1.2)9, and Fine et al (mean 2.3 injections, range 1-6)24. With no randomized comparative trial, there is no consensus on injection protocol, and the intravitreal injections have been widely used for inflammatory CNVM on PRN basis.

Complications following anti-VEGF therapy are very few and may include submacular fibrosis or hemorrhage, subfoveal RPE rip, ocular hypertension, choroidal detachment, reactivation of intraocular inflammation, or spread of chorioretinal atrophy9,25,26. Recurrence is uncommon and responds favorably to a repeat anti-VEGF agent.

Figure 2: A case of healed serpiginous like choroiditis with extensive scarring (a,b), presented with right eye blurred vision. Fundus fluorescein angiography showed areas of mixed fluorescence in early frames due to scars in both eyes (c,d). The late frames showed a small area of hyperfluorescence in the fovea in the right eye (e), suggesting a CNVM, while the left eye showed a brightly hyperfluorescent lesion near the disc, corresponding to the scar (f). SD-OCT showed a subretinal CNVM complex with intra-retinal and subretinal fluid (g). OCTA showed the abnormal CNVM complex (h).

Challenges in inflammatory CNVM

An inflammatory CNVM can develop in the presence or absence of concurrent active intraocular inflammation. In an eye with active uveitis, the clinical symptoms and signs of active intraocular inflammation take precedence over the signs of inflammatory CNVM, hence, leading to its missed or a delayed diagnosis. In eyes with chronic inflammation, the pre-existing fundus pigmentary changes complicate the presenting manifestations of inflammatory CNVM. However, the advances in ocular imaging tools have largely overcome the clinical challenges in their diagnosis.

Figure 3: Fundus photograph showing multifocal choroiditis with panuveitis in both eyes (a, b), with a peripapillary choroidal neovascular membrane in the right eye (white arrow) and a subretinal hemorrhage in macula (black arrow). Fluorescein angiography shows hyperfluorescence corresponding to active lesions in both eyes with cystoid macular edema (c, d).

Figure 4: Fundus photograph at four years follow up of a case of serpiginouslike choroiditis (SLC) treated with oral corticosteroids and anti-tuberculous therapy, showing healed lesions (A). Fundus photograph when patient presented with blurring of vision (vision decreased from 6/36 to counting fingers at two meters) (B), fluorescein angiography was inconclusive showing mixed fluorescence (C), SD-OCT showed few pockets of intraretinal fluid (D), and OCTA showed an abnormal vascular network suggestive of inflammatory CNVM (E). Following a single intravitreal injection of ranibizumab, the vision improved to 6/36. Fundus photograph (F) showed scars of SLC, SD-OCT (G) showed resolution of intra-retinal fluid, and OCTA (H) showed decreasing CNVM complex.

How do we treat inflammatory CNVM?

In our previously published report of inflammatory CNVM, we treated the majority of the eyes (78%) with intravitreal bevacizumab (1.25 mg in 0.05 ml), followed by oral corticosteroids (9.6%), and transpupillary thermotherapy (1.4%). We kept 10.9% eyes under close observation and added immunosuppressive agents in 6.8% eyes8. But these treatment modalities were administered to patients seen between 1998 and 20138. In the current era of anti-VEGF therapy, intravitreal injections (ranibizumab) are our first choice of treatment, both in infectious and non-infectious uveitis. Ancillary testing with relevant ocular imaging is performed, which often includes color fundus photography, fluorescein angiography, SD-OCT and OCT angiography (figures 1-3). If the eye has concomitant active uveitis (non-infectious), we also start (or escalate) systemic corticosteroids (usually oral prednisolone 1mg/kg/day)25. The immunosuppressive agents are usually continued in the maintenance dose. For active infectious uveitis with inflammatory CNVM, such as toxoplasmic retinochoroiditis, an anti-VEGF agent may be combined with intravitreal clindamycin plus dexamethasone. For inflammatory CNVM in tubercular uveitis, the anti-tubercular therapy is continued till its complete regimen. For eyes developing inflammatory CNVM without any active uveitis, an anti-VEGF agent is usually injected as monotherapy on PRN basis (figure 4). Recurrences are treated with repeat anti-VEGF agents.


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Dr. Krinjeela Bazgain, MS
Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Dr. Krinjeela Bazgain is currently pursuing her MCh in Vitreoretinal surgery in the Postgraduate Institute of Medical education and research (PGIMER), Chandigarh, India. She did her Ophthalmology residency from PGIMER, Chandigarh, India.
Dr Nitin Kumar. MS FMRF
Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Dr Nitin Kumar is currently working as a senior resident in the Retina and Uveitis services, department of Ophthalmology, PGIMER, Chandigarh. He did his, medical school, MBBS from SKIMS, medical college, Srinagar. He has completed his postgraduate training in ophthalmology from Advanced Eye Center, PGIMER, Chandigarh. He has done his fellowship in Uveitis from Sankara Nethralaya, Chennai. He has received best poster awards in Uveitis society of India and All Indian Ophthalmological society meetings for the year 2019. He has publications in various national and international peer-reviewed journals. He has special interest in management of Uveitis entities and diabetic retinopathy.
Dr. Reema Bansal, MS, PhD
Additional Professor,Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India-160012
Dr Reema Bansal MBBS, MS (Ophthalmology), PhD is currently Additional Professor Advanced Eye Centre PGIMER, Chandigarh India. She Has given multiple Invited Guest Lectures in various International and National meetings. She has multiple publications in Scientific Journals 127 (Total), She also authored many Chapters in Books. She has been reviewing editor for Ocular Immunology and Inflammations and assistant editor for (Medical Retina Section) Indian Journal of Ophthalmology. She is presently the reviewer for multiple journals like Ocular Immunology and Inflammation,Journal of Ophthalmic Inflammations and Infections, JAMA Ophthalmology , Eye ,Journal of Ophthalmology, Indian Journal of Ophthalmology. She has received multiple awards like Gold Medal in essay writing competition in the 27th Annual Gujarat Ophthalmology conference at MOUNT ABU 1999. Carl P Herbort award at the National conference of Uveitis Society of India at PGIMER, Chandigarh, 2010. Best poster award at VRSI Conference at Hyderabad 2011. Best E-Poster award EYECON 2012.J M Pahwa Best Paper award XXIst Annual meeting of Vitreoretina society of India, Guwahati 2012. AIOS Rema Mohan Award for Best Paper 72nd AIOC, Agra, 2014. Certificate of Merit for the year 2019 by Indian Journal of Ophthalmology .
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