Bilateral neovascular age-related macular degeneration: unilateral regression following endophthalmitis with persistent activity in the fellow eye

Abstract

A woman in her 70s who was being followed up for neovascular age-related macular degeneration (nAMD) in both eyes for 2 years with recalcitrant choroidal neovascularisation (CNV) and had an episode of acute endophthalmitis in one eye was identified. After treatment of postinjection culture-negative right eye (RE) endophthalmitis with intravitreal vancomycin and tazobactam, the patient had complete regression of treatment-resistant CNV in RE to date with postinfection follow-up of 2 years. In contrast, the fellow eye continued showing activity in the choroidal neovascular membrane that required antivascular endothelial growth factor injections on a pro re nata basis to date. Prolonged regression of nAMD for 3 years in the affected eye and continued activity in the fellow eye support the hypothesis that inflammation accompanying endophthalmitis or the drugs used for the treatment can have a role in the regression of nAMD.

Background

Neovascular age-related macular degeneration (nAMD) is described by the growth of abnormal new blood vessels (choroidal neovascularisation (CNV)). In current literature, the prevalent mode of treatment in these cases is intravitreal antivascular endothelial growth factor (VEGF) injections, repeatedly given in monthly or extended regimen. Strategy for injection interval varies, depending on the clinical course of individual patients, but current evidence clearly says that treat-and-extend regimen is non-inferior to the monthly regimen.¹ In a study done by the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) group, among 555 eyes, 83% had fluid (61% intraretinal, 38% subretinal and 36% subretinal pigment epithelium) in spite of monthly or pro re nata (PRN) anti-VEGF injections at the end of 5 years.² This emphasises the long-term need for anti-VEGF treatment; however, a significant percentage of patients still have recurrent or persistent CNV. Endophthalmitis is a known complication of intravitreal injections (IVIs) with the reported incidence in literature as 0.06% or 1 per 1700 in the CATT trial²; 0.8% in the HAWK trial (Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for nAMD) and 0.3% in the brolucizumab group, and 0.6% in aflibercept group in the HARRIER trial.³ Eyes recovered from endophthalmitis may have some structural changes that are understood less clearly.⁴ Few studies in the literature have reported regression of nAMD following an episode of endophthalmitis managed with IVIs^{5 6} or vitrectomy,^{7 8} citing the role of vitrectomy or inflammation or intravitreal antibiotics or dexamethasone in inducing this regression; however, the exact pathogenesis remains unclear.

In this case report, we observed a case of neovascular AMD having recurrent subretinal fluid in both eyes for at least 2 years and complete regression of CNV in the right eye (RE) after an episode of presumed endophthalmitis, while the left eye (LE) followed the natural course of neovascular AMD requiring multiple injections in next 3 years. We discuss 3 years of follow-up of this patient and a possible link between endophthalmitis and regression of nAMD. The patient was retrospectively reviewed, and all data, including visual acuity, clinical examination findings, treatment protocols and monitoring of treatment response using retinal imaging, were recorded. Fundus photography and optical coherence tomography (OCT) sequentially done in follow-ups for disease activity were also reviewed.

Case presentation

A woman in her 70 s with a history of hypertension presented to our retina clinic with complaints of reduced vision in RE for 2 weeks. Her best-corrected visual acuity (BCVA) was 20/40 in RE and 20/20 in LE. Anterior segment examination was unremarkable with pseudophakia and posterior vitreous detachment and drusen in both eyes. OCT scans revealed nAMD in RE with shallow irregular pigment epithelial detachment and subretinal fluid (SRF) (figure 1A). LE OCT scan showed no evidence of choroidal neovascular membrane (CNVM) (figure 1B) at this time. Intravitreal ranibizumab (IVR) was given for RE and monthly follow-up was suggested. However, she was lost to follow-up and returned after 6 months with BCVA in RE recorded as 20/60 and OCT showing SRF, subretinal hyper-reflective material (SHRM) and few intraretinal cystoids (IRCs). She was restarted on IVR injections on a PRN basis with monthly monitoring. At 20 months following initial presentation, the patient was diagnosed with nAMD with type I CNV in LE with SRF seen on OCT scans. She was injected with three loading doses of IVR in the LE and continued monthly monitoring with injections on a PRN basis. She had received a total of seven IVR injections in the RE and two IVR in the LE when she received the eighth injection in the RE. Figure 2A shows the spectral domain OCT scans with active CNV with SHRM and SRF after seven anti-VEGF injections and just before the eighth injection. On the first postoperative day after the eighth injection, the patient came rushing to us with complaints of a sudden decrease in vision in the RE along with mild pain associated with redness. On examination, BCVA was finger-counting at 1 m in RE with 1+ cells and flare with a clear cornea. Fundus evaluation with indirect ophthalmoscopy revealed signs of vitritis with membranes with optic disc barely visible. A diagnosis of RE postinjection acute endophthalmitis was made, and the RE received intravitreal vancomycin (1 mg/0.1 mL) and tazobactam (225 μg/0.1 mL) with all aseptic precautions on the same day. The vitreous tap came out to be culture negative. The following day, the patient had BCVA 20/120 in RE and 20/40 in LE. Signs of endophthalmitis resolved over the next week, with BCVA improving to 20/30 in the RE. Follow-up examination at weeks after she developed endophthalmitis, the patient had BCVA of 20/30 in RE and 20/60 in LE. OCT scan revealed regressed nAMD in RE and active nAMD with SRF in LE. Figure 2B shows OCT scan of RE 1 month after endophthalmitis, demonstrating SHRM and no SRF. LE had received anti-VEGF injections on a PRN basis with regular monitoring by serial OCT scans.

Figure 1.

(A) OD (oculus dexter) SD-OCT image suggestive of irregular flat PEDs with SRF; digital fundus image on the right side corresponding to the OCT picture (2016). (B) OS (oculus sinister) OCT suggestive of multiple small drusen with no PED or SRF; corresponding digital fundus picture shown on the right side (2016).OS, OCT, optical coherence tomography; PED, pigment epithelial detachment; OD; SD-OCT, spectral domain optical coherence tomography; SRF, subretinal fluid.

Figure 2.

(A) RE SD-OCT picture showing active CNV with SHRM and SRF after seven antivascular endothelial growth factor injections; (B) RE OCT picture suggestive of regressed CNV with SHRM but no SRF after 1 month of endophthalmitis; (C) RE OCT with regressed CNV; (D) RE OCT with regressed CNV with fibrovascular PED and SHRM; at 17 months of follow-up after endophthalmitis. (E) RE OCT showing regression of CNV with no scarring/atrophy, at 30 months of follow-up picture; (F) RE OCT showing regression of CNV with no scarring/atrophy, Last follow-up picture at 37 months following endophthalmitis (November 2021). CNV, choroidal neovascularisation; OCT, optical coherence tomography; PED, pigment epithelial detachment; RE, right eye; SD-OCT, spectral domain optical coherence tomography; SHRM, subretinal hyper-reflective material; SRF, subretinal fluid.

Outcome and follow-up

At 37 months of follow-up since it developed endophthalmitis, the RE has not shown any OCT signs of recurrence of nAMD, with BCVA remaining stable at 20/30 with no colour vision defects and stable visual fields. Figure 2C–F shows OCT scans of RE demonstrating no SRF or IRC. LE has received seven IVIs (five ranibizumab and two aflibercept) during this period on PRN basis (figure 3A–E shows CNVM activity in LE on OCT scans done in 2018, 2019, 2020 and 2021). Figure 3F shows OCT scan on the last follow-up visit.

Figure 3.

(A) LE SD-OCT picture showing flat irregular PEDs highly suggestive of CNVM with SRF at 20 months of follow-up after initial presentation. (B) LE OCT suggestive of SRF after 1 month of endophthalmitis (OCT 2018). (C, D) Continued SRF and CNV activity in LE, being managed on pro re nata anti-VEGFs; 12 months of follow-up since RE endophthalmitis (C) and 17 months of follow-up (D). (E) LE OCT showing no activity after 1 month of anti-VEGF injection (30 months of follow-up since RE endophthalmitis). (F) LE OCT scan showing SRF with continued CNV activity at 37 months of follow-up following endophthalmitis in RE. CNV, choroidal neovascularisation; CNVM, choroidal neovascular membrane; LE, left eye; PED, pigment epithelial detachment; RE, right eye; SD-OCT, spectral domain optical coherence tomography; SRF, subretinal fluid; VEGF, vascular endothelial growth factor.

Discussion

We report a case with bilateral nAMD where we observed prolonged regression and CNVM inactivity for a period of 37 months following an episode of endophthalmitis in RE, while the fellow eye continues to demonstrate CNVM activity and is receiving anti-VEGF injections. Complete regression of recalcitrant CNV secondary to neovascular AMD for the past 3 years was seen following an episode of presumed endophthalmitis. Few studies in the literature have reported the similar inactivation or long-term remission of CNVM from nAMD either after endophthalmitis^{5 6} or after pars plana vitrectomy^{7 8} for the same. In 2016, Kally et al⁶ first reported a similar case of regression of nAMD after endophthalmitis, which was culture-positive and managed with intravitreal vancomycin (1 mg), ceftazidime (2.25 mg) and dexamethasone (0.4 mg). They inferred a role of complement factor H, which is upregulated in inflammatory conditions like endophthalmitis and inhibits the alternate complement pathway. Current literature strongly believes that complement factor H has a protective effect in the pathogenesis of AMD.⁹ Other alternative hypotheses suggest that antibiotics to treat endophthalmitis itself may have a role in the resolution of nAMD.⁶ Since we did not use any systemic or intravitreal steroid in our patient, it rules out any steroid effect as described by Kally et al.⁶ The other possible mechanisms for nAMD regression as described by Kokame et al⁸ are the antiangiogenic effects of guanylate binding protein-1 secreted by endothelial cells in response to proinflammatory cytokines such as interferon alpha/gamma, tumour necrosis factor alpha and interleukin (IL)-1a/b. There are reports of similar regression of nAMD following vitrectomy for endophthalmitis, possibly due to reduced load of intravitreal VEGF levels by removal of posterior cortical vitreous and improved oxygenation of the macula, along with the removal of traction,⁷ but a similar phenomenon has been noted in non-vitrectomised eyes also.⁵ Deshmukh et al¹⁰ reported high levels of IL-10 in vitreous postendophthalmitis, which has been found to show antiangiogenic properties in vitro. It is evident that CNVM activity is influenced by an interplay between more than one inflammatory mediators besides VEGF.

Since this patient presented with acute inflammation on the first day following injection and vitreous tap was negative and also because this patient responded favourably with excellent visual outcome, the possibility of sterile intraocular inflammation (IOI) following IVR injection cannot be rule out. Robbins et al, who have reported similar quiescence of CNVM in six eyes following both culture-negative (four eyes) and culture-proven (two eyes) endophthalmitis, have proposed that a sharp rise in intraocular cytokines and tissue damage accompanying endophthalmitis might lead to vascular emodelling or reduced oxygen demand, which can be responsible for this phenomenon.⁵

Our case adds to the literature on this under-reported phenomenon, and lack of vitrectomy or intravitreal dexamethasone makes inflammation-related mechanisms more likely to be the factor that induced regression of CNVM in the affected eye. Although current literature lacks information on comparison of CNVM activity and treatment response in both eyes of a patient with bilateral nAMD, the genetic predisposition, environmental influences and ocular features like Retinal Pigment Epithelium (RPE) pigmentation, choroidal thickness that influence CNVM are expected to be similar. The observation that RE maintained good BCVA despite showing SHRM on OCT scans can be explained by the lack of disruption of external limiting membrane and likelihood that SHRM in this eye was avascular as suggested by good reference to anti-VEGF therapy.¹¹ Right showing regression with good BCVA (20/30) in the absence of significant scarring or atrophy and LE showing continued CNVM activity even at 37 months of follow-up, strongly support the role of acute inflammation in CNVM regression in this case.

Prompt and long-term regression of CNVMs associated with inflammatory scars following anti-VEGF treatment has also been reported widely, as reported by the CATT group; 14% developed fibrotic scar at 1 year, and 54% developed atrophy at 5 years out of 474 subjects.¹² Recently, IOIs following four intravitreal anti-VEGF injections have been analysed with the highest incidence (4.6%) reported with brolucizumab showing more anatomical on CNVM as evident by more drying effect and longer treatment intervals.¹³ Another recent multicentric retrospective case series has reported reduced frequency of IVIs in eyes with nAMD following endophthalmitis with up to 13% eyes requiring no injection.¹⁴

This phenomenon invites for further research on role of proinflammatory mediators in nAMD.

Patient’s perspective.

It was 6 years back that I noticed a blurring of vision in RE. It was progressing gradually, but there was no pain and redness associated with it. I first thought that it was just a transient phenomenon and I might need a change of glass. One year later, blurring in RE increased further and then I panicked. I consulted an eye doctor, and he told me that I have age related degenerative disease related to the retina, which affects people at my age. He also informed me that my other eye has also got affected; although there is no symptom at present, it can also progress later with time. I decided to follow the doctor’s instructions. He told me to go for some eye tests, following which he suggested me that I need an injection in RE within some days. I asked him that how many injections will be given in my RE. He explained that maybe I need it for quite a few in first year but frequency is expected go down after first year. I got an injection in RE after five days, and I followed up with my doctor. I had to undergo a knee transplant so missed follow ups for six months after first injection but revisited my doctors after I recovered,. He prescribed me more injections for RE for around year later. Then in LE, I felt a similar problem after 20 months of initial diagnosis in RE, and the doctor informed me that I needed regular injections for LE also. I was little apprehensive, but I trusted him because till now, my RE was stable with his treatment, and I did not want to take any further risks. However I noticed that on first day after my 8th injection in RE there was a sharp decline in vision. It never so anxious before; in fact, my RE always felt better after injections. I rushed to the hospital immediately, and my doctor told me that I had developed some infection in RE for which I needed immediate treatment. I was little insecure about future of my RE at that time but I agreed for treatment. He gave me some antibiotic injection in RE on the same day as he told me it was an emergency. After three days, I felt improvement in vision in RE. I continuously followed up and noticed that my RE was stable, and my vision was also getting better, and most of all, I never needed an injection in RE after that incident. However, my LE is still getting periodic injections as before. Till now, after more than three years of that incident, I have a stable vision in RE without any further injections, and LE gets injections whenever my doctor tells me that I need it based on OCT test. I still get very anxious when I recall that incident in right eye. Anyways, all is well, that ends well, and I am happy that my right eyes could recover it’s vision finally.

Learning points.

• Acute inflammation accompanying endophthalmitis or the medicines used for its treatment (less likely) may be associated with long-term regression of neovascular age-related macular degeneration (nAMD).

• This case also calls for more studies comparing the choroidal neovascular membrane activity and treatment response between both eyes of all patients having bilateral nAMD.

• Future research is warranted to establish the role of proinflammatory mediators on the activity of neovascular AMD, which may pave the way for novel treatment modalities.

Ethics statements

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