Banerjee, Philip James; (2017) Proliferative Vitreoretinopathy; strategies to improve anatomical and visual outcomes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Proliferative vitreoretinopathy (PVR) is the most common cause of late anatomical failure of retinal detachment surgery. Efforts to modify this vitreoretinal scarring response have so far proved clinically unsuccessful, with surgical and visual outcomes remaining poor. This work is aimed at identifying strategies to improve outcomes in eyes at high risk of PVR development following open globe trauma (OGT), and those with established PVR disease. Two prospective clinical trials investigating the benefit of adjunctive corticosteroids in these two populations were conducted in a total of one hundred and eighty patients. Clinical and imaging data were collected over the course of approximately 3500 hospital attendances. The Adjunct in Ocular Trauma (AOT) Trial was a two year, pilot, single-centre prospective, participant and surgeon-masked randomized-controlled-clinical trial (RCT). Forty patients requiring vitrectomy surgery following OGT were randomized to either standard (control) or study treatment (adjuncts) in a 1:1 allocation ratio. Perioperatively, the adjunct group received intravitreal and subtenons triamcinolone acetonide, oral flurbiprofen and guttae prednisolone acetate 1%. The control group received standard care. Primary outcome was anatomical success at 6 months and showed similar results in anatomical success with 50% (10/20) in the adjunct group, compared to 47% (9/19) in the standard group (Odds Ratio 1.11, 95% Confidence Interval 0.316-3.904). Secondary outcomes included final visual acuity, occurrence of PVR, intraocular pressure (IOP) rise, number of operations and recruitment rate. Final median visual acuity was 31 ETDRS letters in the adjunct group compared to 25 ETDRS letters in the standard group. Other secondary outcomes were similar between the two groups. The hypothesis that an adjunctive slow-release dexamethasone implant (Ozurdex ®) could improve the outcomes of vitreoretinal surgery for established PVR was tested in the Ozurdex® in PVR Study. In this two year, single-centre prospective, participant and surgeon-masked RCT, 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR (Grade C) were randomized to either standard (control) or study treatment (adjunct) in a 1:1 allocation ratio. Intraoperatively, the adjunct group received an injection of 0.7mg of slow-release dexamethasone (Ozurdex) at the time of (a) vitrectomy surgery and (b) at silicone oil removal. The control group received standard care. Primary outcome measure was the proportion of patients with a stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. Secondary outcomes included i) final visual acuity (median and ETDRS of 55 letters or better), ii) cystoid macular edema (CMO), foveal thickness and macular volume iii) development of overt PVR recurrence, iv) complete and posterior retinal reattachment, vi) tractional retinal detachment, vii) hypotony/raised IOP, viii) macula pucker/epiretinal membrane, ix) cataract, x) quality of life All 140 patients were recruited within 25 months of study commencement; 138 patients had primary outcome data. Primary outcome assessment showed similar results in anatomical success between the two groups (49.3% vs 46.3%, adjunct vs control, (Odds Ratio 0.89, 95% Confidence interval 0.46 – 1.74, p= 0.733). Mean visual acuity at 6 months was 38.3 ETDRS letters and 40.2 letters in the adjunct and control group respectively. Secondary anatomical outcomes (complete/posterior reattachment rates and PVR recurrence) were comparable between the two groups. Exploratory analysis suggested that the proportion of patients with cystoid macular oedema (CMO) or a foveal thickness of >300µm was lower in steroid-treated eyes compared to controls (42.7% and 47.6% vs 67.2% and 67.7%, respectively p= 0.004, p= 0.023). Cystoid macular oedema is a secondary cause of visual loss. At 6 months following successful surgery for PVR, eyes with evidence of external limiting membrane (ELM) disruption on Spectral Domain-Optical Coherence Tomography achieve a worse visual outcome than eyes where the ELM appears preserved (p=0.006). Provisional work using retinectomy specimens retrieved at the time of surgery in sixteen patients were studied aiming to isolate a population of Müller glia with stem cell characteristics (hMSC). This suggested that it is feasible to isolate a cell population of appropriate morphology of hMSCs, from eyes with advanced PVR. These cells survived up to ten weeks in culture but eventually terminally differentiate. The work in this thesis has shown that corticosteroids do not modify the vitreoretinal scarring response sufficiently to improve anatomical outcomes at 6 months. Further work is required to improve the outcome in eyes with PVR. Adopting visual acuity as a primary outcome, may be a plausible design in future vitreoretinal trials.

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