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Bios Mr. Huang is a medical student at the University of Toronto. Dr. Felfeli is an ophthalmology resident at the University of Toronto. Dr. Mandelcorn is an associate professor of ophthalmology at the University of Toronto. DISCLOSURES: The authors have no relevant financial disclosures. |
Proliferative vitreoretinopathy continues to be a concern in retinal detachment surgery, presenting significant challenges in achieving optimal surgical outcomes. Despite advancements in surgical methods and a deeper comprehension of PVR’s pathophysiology, postoperative anatomical and visual results remain suboptimal.1 This has prompted the exploration of various adjunctive pharmacological therapies in conjunction with surgical intervention.
Current mainstay
PVR is predominantly implicated in postoperative RD complications, arising from the proliferation and contraction of cellular membranes within the vitreous, leading to tractional RD and persistent retinal folds.2 The Retina Society Terminology Committee’s classification (A-D) delineates PVR severity, ranging from minimal to massive, based on retinal changes. Subsequent revisions have enhanced this classification, incorporating the anatomic location and contraction type to better guide treatment strategies.3
The cornerstone of PVR treatment involves surgical intervention, primarily via pars plana vitrectomy accompanied by membrane peeling.4
The operative strategy for addressing PVR closely mirrors that of standard primary RDs, with the key distinction being the greater degree of retinal traction in PVR due to the presence of membranes and bands as opposed to vitreous gel. Consequently, surgeons may adapt their techniques to meticulously separate these membranes to facilitate retinal reattachment. In instances where a scleral buckle wasn’t placed during the initial repair of a primary RD, its insertion might be beneficial in the subsequent vitrectomy for PVR. Nonetheless, the necessity for a scleral buckle may be obviated if an extensive inferior retinectomy is anticipated.
The overarching aim of PVR surgery is the meticulous removal of epiretinal and subretinal membranes, which often necessitates bimanual surgical maneuvers to delicately handle the retina and its adherent membranes. In most cases, silicone oil is preferred for long-term internal tamponade, although perfluoropropane (C3F8) gas can be an alternative for less severe presentations.5
Despite surgical advances, the prevalence of PVR post-RD repair hasn’t significantly diminished, with most cases manifesting within three months postoperatively.6 In addition, postoperative outcomes following pars plana vitrectomy remain suboptimal, amplified by the recurrence of RD due to PVR.7 Considering these challenges, the investigation of new pharmacological agents aims to enhance both anatomical and functional results in PVR treatment.
In the ongoing search for effective management of PVR, no pharmacological agents have yet received approval for use as adjuncts to surgical treatment. The pathogenesis of PVR, characterized by inflammation, cellular proliferation and fibrosis has guided the investigation of various drugs, including corticosteroids, methotrexate and other antiproliferative agents, with promising results in preclinical studies that are now advancing to clinical trials (Table 1).
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Corticosteroids
Corticosteroids were among the first pharmacological interventions investigated, primarily due to their extensive anti-inflammatory and antiproliferative properties, diverse administration routes and minimal evidence of retinal toxicity.8 Preclinical studies have illustrated the potential of corticosteroids in mitigating PVR. Notably, one group of researchers conducted research on a rabbit model, observing that a 2-mg dose of triamcinolone acetonide significantly reduced the occurrence of PVR-associated RD from 90 percent to 56 percent.9
Despite these encouraging preclinical outcomes, clinical trials have yielded inconsistent results. A particular trial evaluating the adjunctive use of triamcinolone in 75 eyes with RD and advanced PVR undergoing vitrectomy with silicone oil tamponade found no significant difference between treated patients and controls.10 Emerging evidence from sustained-release systems suggests they can maintain therapeutic drug concentrations for extended periods, although a two-year randomized trial found no significant difference in anatomical success or visual acuity when comparing dexamethasone implants to placebo in PVR patients.11 While preclinical data on corticosteroids for PVR management are promising, clinical application has produced mixed results, emphasizing the need for further research to define their role in PVR therapy.
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Figure 1. Preoperative view shows temporal retinal detachment with marked peripheral chorioretinal scarring, proliferative vitreoretinopathy, subretinal bands in the macula and a star fold with adjacent retinal break. Corresponding optical coherence tomography shows disorganized retinal laminations with tractional elevation. Figure 2. Postop, the scleral buckle appears to support the area of inferior traction. Previous areas of macular |
Antiproliferative and antineoplastic agents
Methotrexate (MTX), a folate antagonist with antiproliferative and anti-inflammatory effects, has been under investigation for its potential in managing PVR.
Laboratory studies have indicated that MTX can inhibit the proliferation and migration of retinal pigment epithelium cells and induce apoptosis without the photoreceptor toxicity associated with other agents like 5-fluorouracil (5-FU).12
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| Figure 3. When dealing with proliferative vitreoretinopathy, Perfluoro-n-octane can stretch out or loosen up the retina. Also, it lets the surgeon judge the possibility to reattach the retina using a direct PFO-to-oil exchange. (John Kitchens, MD) |
Clinically, MTX has been tested in various dosages and delivery methods, including intraoperative and postoperative intravitreal applications. However, the benefits of MTX haven’t always been statistically significant. For example, a randomized study found a lower but not statistically significant rate of retinal redetachment in patients receiving intravitreal MTX compared to controls.13 Despite this, a study involving high-risk eyes demonstrated a considerable reduction in PVR incidence with MTX treatment during surgery, suggesting a potential prophylactic effect.14
Daunomycin, an anthracycline known for its role in inhibiting cell proliferation and migration, has been evaluated for its effectiveness in PVR management through animal studies.15,16 Its use as an adjunct to vitrectomy in patients with advanced PVR was assessed in a recent study showing a higher rate of retinal reattachment compared to controls, albeit with non-significant differences in visual acuity and requiring fewer additional surgeries.17 Research has also delved into the potential of low-molecular-weight heparin (LMWH) and 5-FU in PVR prevention, with a notable randomized trial demonstrating a decreased incidence of postoperative PVR and fewer reoperations in the treatment group, although no change in visual acuity was observed.18 Another trial, however, didn’t replicate these significant findings, indicating variability in treatment outcomes.19
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Retinoic acid, an inhibitor of RPE cell growth, has been shown in a study to significantly improve retinal attachment and ambulatory vision, and decrease macular pucker formation, compared to a placebo.20 In addition, mitomycin C and a host of other antiproliferative compounds have displayed promising results in preclinical studies, though their clinical efficacy and safety remain to be confirmed in human trials.21,22 Presently, topotecan is under Phase II clinical investigation for its antifibrotic and antiproliferative effects in PVR-related RD.
Anti-VEGF agents
Recent research has underscored the influence of growth factors in the development of PVR, particularly noting the role of vascular endothelial growth factor A (VEGF-A) in activating the platelet-derived growth factor receptor α, a key player in PVR’s etiology.23
Preclinical studies have assessed ranibizumab, an anti-VEGF medication that targets all VEGF-A isoforms, demonstrating its efficacy in reducing vitreous bioactivity and preventing PVR in animal models.24
However, the transition from animal to clinical studies hasn’t met with similar success. Prospective studies, including one that evaluated the effects of repeated bevacizumab injections within a silicone oil medium on both the anatomical success and best-corrected visual acuity, haven’t shown significant improvements in patients with PVR-induced RD.25
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These findings align with a meta-analysis of 133 studies, which concluded that bevacizumab does not effectively reduce rates of retinal redetachment nor enhance visual outcomes in patients undergoing vitrectomy for PVR. This gap between promising animal research and less conclusive clinical results highlights the complexities of PVR treatment and the need for further investigation into effective therapies.26
Bottom line
Collectively, these findings highlight a landscape of potential, yet unapproved, adjunctive pharmacotherapies for PVR. The journey from promising preclinical results to clinical application remains fraught with variability, necessitating further rigorous research to establish efficacy and safety profiles before these therapies can be recommended as part of PVR management protocols. RS
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