Proliferative vitreoretinopathy (PVR) remains the most significant obstacle to successful retinal reattachment surgery, accounting for ∼75% of all primary surgical failures with a cumulative risk of 5% to 10% of all retinal detachment repairs.1 Proliferative vitreoretinopathy is characterized by proliferation of cells on either retinal surface or in the vitreous cavity, multiplication of which can lead to contraction and foreshortening of the retina, resulting in traction and recurrent detachment of the retina.
Specific risk factors for PVR that have been identified include uveitis; large, giant, or multiple tears; vitreous hemorrhage; preoperative or postoperative choroidal detachments; aphakia; multiple previous surgeries; and large detachments involving greater than two quadrants of the eye.1,2 In 1983, the Retina Society Terminology Committee devised a classification system, based on clinical findings, to grade PVR as minimal, moderate, marked, or massive (Grades A–D).3 The Silicone Study Group later proposed a revised grading system differentiating between the anterior and posterior forms of PVR.4 A further revision by Machemer et al5 was made in 1991, which offered more information regarding the location, extent, and severity (including distinction between anterior and posterior PVR) in an individual eye.
The PVR process is not completely understood but is thought to be analogous to the anomalous wound healing that leads to skin keloid formation.6 The most important cell types in PVR pathogenesis are the retinal pigment epithelial cells, which are believed to dedifferentiate and migrate through a retinal break and proliferate on the retinal surface. Retinal glial cells and macrophages may also play an important role, perhaps by providing the scaffold for membrane formation or by releasing trophic factors.6,7 This process is driven by and modulated by numerous growth factors (e.g., platelet-derived growth factor,8 vascular endothelial growth factor,9 transforming growth factor beta [TGF-β], epidermal growth factor, tumor necrosis factor alpha [TNF-α], TNF-β, and fibroblast growth factor10) and cytokines (e.g., interleukin-1 [IL-1], IL-6, IL-8, IL-10, and interferon gamma [INF-γ]11), which have been and continue to be explored as potential targets for pharmacologic prevention and treatment.12 However, despite these advances, the primary prevention of PVR remains elusive.
In this report, the authors review the recent literature (January 1, 2000–August 1, 2014) regarding available surgical and randomized controlled trials of medical treatments for PVR and the evidence supporting their use.
Despite our increasing knowledge about the pathogenesis of PVR and possible targets for prevention, the mainstay of PVR management remains surgical.
Twenty-three–Gauge and 25-Gauge Vitrectomy
Advancements in vitreoretinal surgery technology and instrumentation have led to the adoption of 23- and 25-gauge pars plana vitrectomy (PPV), including in patients with PVR-related detachments.
Erakgun and Egrilmez13 retrospectively reviewed outcomes of 40 eyes undergoing repair of tractional and PVR-related retinal detachments with 23-gauge vitrectomy and silicone oil tamponade. Single surgery anatomical success was achieved in 97.5% of patients at a mean follow-up of 6.5 months. Complications were rare, including silicone oil migration in three eyes and hypotony in one eye.
Shah et al14 retrospectively reported outcomes of sutureless 25-gauge vitrectomy and silicone oil tamponade in 18 patients with complex retinal detachment, including 7 patients with PVR. Of the 7 patients with PVR, single surgery anatomical success after 25-guage PPV was achieved in 5 patients (71.4%) at mean 5 months of follow-up. Visual acuity, however, was poor—ranging from 20/400 to light perception at final follow-up. Riemann et al15 similarly reported outcomes with 25-gauge vitrectomy. In a retrospective review of 35 patients undergoing 25-gauge vitrectomy and silicone oil tamponade for complex retinal detachment, 6 patients reviewed had PVR. At a mean follow-up of 7 months, no patient with PVR had recurrent detachment and final visual acuity ranged from 20/80 to counting fingers.
Although available studies are retrospective and do not exclusively include PVR-related detachments, they suggest that the use of 23- and 25-gauge vitrectomy technology in PVR-related detachments yields anatomical outcomes and safety profiles comparable with previous 20-gauge controls. Larger randomized studies would be required to identify unique complications or surgical considerations with the use of this technology in the PVR population.
Multiple individual trials and meta-analyses have compared outcomes of patients undergoing vitrectomy, scleral buckle, or combined vitrectomy and scleral buckle surgeries for uncomplicated retinal detachments.16–24 Studies comparing surgical techniques in patients with PVR-related detachments, however, are less common.
Yao et al20 retrospectively reviewed the outcomes of 40 eyes with longstanding retinal detachment treated with scleral buckle. Mean duration of retinal detachment was 13.8 months, and 4 patients had documented PVR Grade C at the time of treatment. Single-surgery success rate was 90% at a mean follow-up of 6.9 months, with the authors arguing that scleral buckle alone may be an effective treatment in patients with preexisting mild PVR and those at risk for PVR development because of chronic detachment.
For the Scleral Buckle versus Primary Vitrectomy for Rhegmatogenous Retinal Detachment Study Group, Heimann et al18 sought to compare anatomical and visual outcomes in patients undergoing vitrectomy with or without scleral buckle versus scleral buckle alone in patients with retinal detachments of “medium complexity.” Patients with PVR Grade B or C were excluded; however, patients with large breaks (1–2 clock hours), multiple breaks, noted vitreous traction, superior detachments, or those with high suspicion for unseen breaks were included. In pseudophakic patients, although final reattachment rates were similar, single-surgery success rate was 72% in patients undergoing PPV versus 53.4% in patients with scleral buckle alone (P = 0.0020). Also statistically significant, mean additional surgeries required for anatomical success was 0.43 for the PPV group and 0.77 for the scleral buckle group (P = 0.0032). These differences, however, were not observed in phakic patients.
In the European Vitreoretinal Retinal Detachment Study Report 2, Adelman et al25 reported the outcomes of patients who underwent PPV with or without scleral buckling for PVR Grade B and C retinal detachments. Follow-up intervals ranged from 3 months to 1 year. For PVR Grade C detachments (637 patients), primary reattachment rates for vitrectomy with scleral buckle versus vitrectomy alone were directly compared. Although not reaching statistical significance, patients treated with scleral buckle as a part of their surgery were associated with higher failure rates (8.9%) compared with those who did not (3.0%). In patients with PVR Grade B retinal detachments (917 patients), initial surgery failure rate was 0.8% in patients undergoing PPV with or without scleral buckle compared with 4.0% in those treated with scleral buckle alone, a statistically significant difference. Broad conclusions are limited by the surgeon's self-reported retrospective nature of the data, and a possible bias that the use of scleral buckle may have been reserved for patients with more severe complicated detachments. However, results suggest benefit to the use of PPV in surgical repair.
More recently, Storey et al26 compared single-surgery anatomical success rates in patients with retinal detachments deemed to be at high risk for PVR development and underwent combined PPV and scleral buckle versus PPV alone. Sixty-five patients were identified to be at high risk based on the following criteria: the presence of preoperative PVR, vitreous hemorrhage, retinal tears >1 clock hour, or retinal detachment in two or more quadrants. Single-surgery attachment rate was 75.0% in the PPV and scleral buckle group (27 of n = 36 patients) versus 48.3% (14 of n = 29) in the PPV alone group at a follow-up of at least 3 months, a statistically significant difference (P = 0.029). Of note, lens status and choice of tamponade agent (gas versus silicone oil) were not independently associated with single-surgery anatomical success rate. Age younger than 65 years, however, was associated with a significantly higher single-surgery success rate (84.6 vs. 46.2% for PPV–scleral buckle vs. PPV alone respectively; P = 0.017), whereas age older than 65 years was associated with no difference in single-surgery success rate between groups (50.0% for PPV–scleral buckle vs. 50.0% for PPV alone; P = 1.0). Mean visual acuity and rate of development of PVR did not differ significantly between groups at final follow-up, regardless of age or lens status.
Given the available evidence, conclusions regarding the utility of scleral buckle alone or in addition to vitrectomy remain limited. Retrospective studies comparing surgical techniques may lead to selection bias. Prospective studies would be needed to establish benefit or harm.
Multiple studies report favorable outcomes with the use of inferior retinectomy. Quiram et al27 retrospectively reviewed outcomes of 56 patients treated with PPV and inferior retinectomy for recurrent, PVR-related retinal detachment. Complete retinal reattachment was observed in 93% of eyes at a mean 25 months of follow-up, with anterior base dissection, lensectomy, and silicone oil tamponade associated with improved, single-surgery anatomical outcomes. Similarly, Tsui and Schubert28 reported a 90% anatomical success rate at final follow-up in 41 patients who underwent PPV, >180° retinotomy, and anterior retinectomy for treatment of severe PVR.
The use of retinectomy was evaluated in patients with anterior PVR in particular. Tan et al29 retrospectively reviewed 123 patients undergoing retinectomy without scleral buckling for anterior PVR. Ninety-six patients (77.2%) required no additional surgeries, 21 patients (17.1%) required 1 additional operation, and 4 patients (3.8%) required 2 additional operations. Visual acuity improved in a statistically significant fashion (P = 0.001), from 2.10 logMAR to 1.44 logMAR units amongst all patients. Banaee et al30 similarly report success, with a 70% anatomical success rate at final follow-up in 19 patients undergoing PPV and 360° retinectomy for anterior PVR-related retinal detachment.
Heavy silicone oils
The Silicone Study Group established the superiority of longer acting tamponade agents, namely silicone oil and perfluoropropane (C3F8), over sulfur hexafluoride (SF6) in patients with Grade C or worse PVR.31 Since these pivotal studies, efforts to improve tamponade to the inferior retina, given concerns regarding inferior displacement of pro-inflammatory mediators and subsequent recurrent PVR, led to the development of heavy silicone oils. At the present time, heavy silicone oil tamponade agents are not approved by the US Food and Drug Administration but have been evaluated overseas.
Multiple studies report excellent anatomical outcomes with the use of heavy silicone oils. Rizzo et al32 evaluated outcomes in 32 consecutive patients with inferior PVR treated with PPV, membrane peel, and tamponade with the heavy silicone oil HWS 46 to 3,000. Single-surgery success rate was 84.6%, overall anatomical success rate of 100% at 6 months, and improvement in logMAR visual acuity was observed. Of note, posterior subcapsular cataract formation occurred in 100% of patients. Two studies evaluated outcomes of Densiron 68, a heavy silicone oil mixture of 30.5% perfluorohexyloctane (F6H8) and 69.5% silicone oil. Auriol et al33 retrospectively evaluated outcomes of Densiron 68 for tamponade in 27 patients undergoing inferior retinectomy for repair of PVR Grade C retinal detachments. Anatomical success was achieved in 92.5% of eyes. Li et al34 similarly evaluated the use of Densiron 68 for PVR-related detachments, also noting a favorable anatomical success rate of 92.5%. Notable side effects include cataract development in up to 25.9%33 and intraocular inflammation in up to 40%34 of patients studied but patients were generally considered safe and well tolerated.
In comparative trials, however, no direct benefit of heavy silicone oils versus standard silicone oil has been observed. In the randomized controlled Heavy Silicone Oil Study, Joussen et al35 compared visual acuity and anatomical success rates in patients with inferior PVR treated with standard 5,000-centistoke (cSt) silicone oil versus heavy silicone oil (25:75% mixture of F6H8 and 5,000 cSt silicone oil). At 1 year, no statistically significant difference in visual acuity or reattachment rates was observed. Boscia et al36 randomized 20 consecutive patients with inferior PVR-related retinal detachment to repair with PPV, scleral buckle, and 1,300-cSt silicone oil tamponade versus PPV with Oxane HD tamponade, a heavy silicone oil mixture of 5,700-cSt silicone oil and hydrocarbonated olefin (RMN3). In similar fashion, no statistically significant difference in reattachment rate was observed at 6 months of follow-up.
Silicone oil containing aspirin
In a randomized controlled trial, Kralinger et al37 compared patients undergoing vitrectomy with standard silicone oil tamponade versus silicone oil containing 0.2 mg/mL aspirin (AS SiO). Given the known antiinflammatory effect of aspirin, it was postulated that such a suspension could prevent PVR development and recurrent detachment. Twenty-nine patients were randomized, but no statistically significant difference between groups was observed in redetachment rates or visual acuity at 6 months. No adverse effects of AS SiO were observed.
Conclusions Based on the Literature
Studies related to the surgical management of PVR are predominantly retrospective trials with significant heterogeneity in surgical technique and study population, precluding subgroup analysis and meta-analysis. This is partly due to the heterogeneity inherent in PVR-related detachments. Evidence supporting the use of scleral buckling procedures remains conflicting, whereas the use of retinectomy, particularly in cases of anterior PVR, has yielded favorable outcomes. Heavy silicone oils, although found effective, have not been shown to be superior to typical silicone oil in anatomical success rate for PVR-related detachments.
Medical Prevention and Treatment
Interventions aimed at curbing inflammation have long been the focus of PVR treatment strategies. Inflammatory changes such as anterior chamber flare are evident clinically and, more recently, proteomic analysis has confirmed up-regulation of inflammatory markers in the vitreous samples of PVR patients.38 Studies have evaluated the use of intravitreal triamcinolone (IVTA), oral predisone, and subconjunctival dexamethasone on anatomical outcomes and prevention of PVR as outlined in Table 1.
Jonas et al43 first reported the use of IVTA in combination with PPV and silicone oil tamponade. From this initial report, multiple retrospective studies44–46 have investigated the effect of IVTA in combination with PPV and silicone oil on anatomical success rates and prevention of PVR, with conflicting results.
Attempts to better evaluate the role of IVTA in randomized controlled trials have not demonstrated a clear beneficial effect. Ahmadieh et al39 randomized 75 patients with at least PVR Grade C to PPV and silicone oil tamponade with or without a single injection of 4-mg IVTA at the conclusion of surgery. At 6 months, no statistically significant difference in anatomical success rate, visual acuity, or prevention of PVR was observed. In a multicenter trial, Yamakiri et al40 randomized 774 eyes to primary PPV or triamcinolone-assisted PPV for repair of retinal detachment. In this study, 40 mg of triamcinolone in 5 mL of balanced salt solution was used for visualization of the posterior hyaloid and the peripheral vitreous during vitrectomy. At 1 year, no statistically significant differences in visual acuity, adverse events, or need for additional surgery were observed between groups.
Further information in a larger prospective trial would be particularly helpful, including subgroup analysis regarding race, dosage of triamcinolone, PVR grade, and efficacy in primary repairs versus reoperations.
Two randomized, double-blinded placebo-controlled trials have evaluated the efficacy of oral steroids for prevention of PVR, with mixed results.
Dehghan et al41 evaluated the outcomes of primary scleral buckling surgery in phakic patients who received a 10-day course of oral prednisone (1 mg/kg dose) versus placebo postoperatively. With a sample size of 52 eyes, no statistically significant difference in PVR formation between groups was observed.
Later, Koerner et al42 evaluated the utility of oral corticosteroids for prevention of early-stage PVR. Patients with previous retinal surgery or PVR Grade C were excluded. In this study, 220 patients with primary retinal detachments were randomized to treatment with an initial dose of 100 mg of oral prednisone, tapered over 15 days, or placebo after retinal detachment repair. Twenty-nine patients in the steroid group required reoperation for anatomical success versus 39 patients in the control group. In these patients requiring reoperation, PVR Grade B was present in 21% of eyes in the steroid group versus 54% in the placebo group at the time of the second surgery.
Applicability of these results is limited, as neither study included patients with previous history of vitreoretinal surgery or those with preoperative PVR Grade C or higher. Further studies, seeking to evaluate a minimal effective dose of prednisone and outcomes in patients with more advanced PVR at the time of intervention would be of particular interest.
Recent case reports have suggested that Ozurdex (0.7 mg intravitreal dexamethasone implant) may be helpful in the prevention of PVR after retinal detachment surgery.47 Clinical trials are planned to better characterize the use of the dexamethasone implant on the outcomes of patients with preexisting PVR undergoing retinal detachment surgery.48
Low Molecular Weight Heparin and 5-Fluorouracil
Low molecular weight heparin (LMWH) and 5-fluorouracil (5-FU) have been used in combination to mitigate the risk of postoperative PVR. Previous retrospective and preclinical data have demonstrated a potential benefit of both agents, leading to investigation in randomized clinical trials.49,50
Two studies sought to evaluate the benefit of LMWH and 5-FU in patients at risk for PVR or those with existing PVR at the time of surgery. Asaria et al51 found benefit in LMWH and 5-FU in preventing postoperative PVR in patients deemed to be at high risk for PVR development because of the presence of aphakia, preoperative PVR, large detachment size, previous cryotherapy, uveitis, or vitreous hemorrhage. One hundred and seventy-four patients were randomized to undergo vitrectomy with or without infusion of LMWH (200 μg/mL) and 5-FU (5 IU/mL). Normal saline was infused in the placebo arm. A statistically significant reduction in postoperative PVR was observed in the treatment arm (12.6 vs. 26.4% in the placebo arm, P = 0.02) at 6 months. Single-surgery success rates were similar in both groups; however, in those requiring reoperation, 10.3% were due to PVR in the treatment arm versus 18.4% in the placebo arm. Based on these favorable results, Charteris et al52 randomized 157 patients with Grade C PVR to perioperative infusion of 5-FU and LMWH versus placebo. In this study, there was no statistical difference in the primary outcome measure, defined as retinal reattachment without reoperation at 6 months, between the 2 groups.
Low molecular weight heparin and 5-FU have also been evaluated in unselected patients. Wickham et al53 randomized 641 patients undergoing primary vitrectomy with gas tamponade for retinal detachment to infusion of LMWH and 5-FU or placebo, regardless of risk factors for PVR. Notable exclusion criteria were patients with giant retinal tear formation or those in whom silicone oil was intended. No statistically significant difference between groups was noted for the primary outcome of retinal reattachment rate without reoperation at 6 months. In those who failed anatomical reattachment, PVR was not deemed a significant factor. Of note, in patients presenting with macula-sparing detachments, visual acuity was found to be worse in the treatment arm versus placebo (P = 0.0091).
The Asaria et al51 and Wickham et al53 studies were reviewed in a 2010 Cochrane Review by Sundaram et al.54 Given the differences in study design and differing conclusions, a meta-analysis was unable to be performed and the authors concluded a recommendation for guiding clinical care could not be drawn based on the evidence provided.
Additional smaller studies have also been completed in patients with preexisting PVR. Kumar et al55 randomized 30 patients with Grade D PVR to vitrectomy with or without infusion of LMWH, with follow-up to 3 months. Anatomical attachment was observed in 14 of 15 patients (93%) in the study group versus 11 of 15 patients (73%) in the control group at final follow-up. Media clarity as determined by the Nussenblatt classification was judged to be significantly better in the LMWH group, but visual acuity and anatomical success rates were not statistically different amongst groups. Scheer et al56 randomized 60 patients with Grade C PVR to infusion of LMWH and 5-FU versus placebo, with no statistically significant difference in reattachment rate, reoperation rates because of PVR, or visual acuity. Small number and follow-up interval limit conclusions.
Summarized in Table 2, the available evidence for LMWH and 5-FU is conflicting. Their use in patients at high risk for PVR may be of benefit, but larger studies are needed to clarify efficacy. Neither LMWH nor 5-FU was associated with significant adverse effects; however, the observation in one study that LMWH and 5-FU in patients with macula-sparing detachments resulted in worse visual outcomes deserves caution.
Isotretinoin (13-cis-Retinoic Acid)
Numerous preclinical studies have demonstrated benefit of isotretinoin (13-cis-retinoic acid) in preventing or mitigating experimental PVR,57–60 leading to evaluation in human studies. Fekrat et al,61 in a retrospective study published in 1995, first reported isotretinoin may be of benefit in increasing the rate of retinal reattachment.
In a randomized controlled trial, Chang et al62 randomized 35 patients to receive oral isotretinoin (10 mg orally twice daily for 8 weeks) postoperatively or no treatment after surgery for PVR-related detachments. The study was not masked or blinded. For the treatment group, results revealed a higher rate of retinal attachment (93.8 vs. 63.2%, P = 0.047), lower rate of macular pucker formation (18.8 vs. 78.9%, P = 0.001), and a higher rate of ambulatory vision (56.3 vs. 10.5%, P = 0.009) at a minimum follow-up interval of 1 year. All study outcomes achieved statistical significance.
Given the suggestion of benefit by both the Fekrat et al and Chang et al studies, a prospective, randomized placebo-controlled trial is currently planned and undergoing recruitment at Wills Eye Hospital to better evaluate the benefit of isotretinoin in PVR.
Daunorubicin and Other Agents
The antimetabolite daunorubicin has shown a beneficial effect in experimental models of PVR,63–65 resulting in two human trials to date.
Wiedemann et al66 randomized 286 eyes with Grade C2 or worse PVR to receive treatment with daunorubicin (10 minutes infusion of 7.5 μg/mL daunorubicin in balanced salt solution) or no additional treatment. All patients received silicone oil, with retinal attachment rate at 6 months as the primary study outcome. No statistically significant difference in reattachment rate was observed between groups at 6 months. However, significantly fewer reoperations (P = 0.05) were required in the treatment group to achieve the same 1-year anatomical success rate as the control group (80.2 and 81.8%, respectively), suggesting a possible benefit.
Kumar et al67 randomized 30 patients with Stage D1 or worse PVR to receive an intravitreal injection of dauorubicin (5 μg) or no additional treatment at the conclusion of retinal surgery. No significant difference in attachment rate was observed at 3 months. Media/vitreous clarity was improved in the treatment group (P = 0.0044), but the clinical significance of this difference is uncertain.
In these two randomized studies, no statistically significant advantage of daunorubicin on primary study outcomes was found. Additional randomized trials with longer-term follow-up are needed to clarify the role of daunorubicin as an adjunctive treatment.
VIT100 is a chimeric ribozyme previously shown to be effective in mitigating PVR in experimental models.68 The ribozyme binds to and cleaves proliferating cell nuclear antigen, a factor in the cell division cycle, and is hypothesized to prevent PVR by inhibiting proliferation of a broad range of cells (Table 3).
Schiff et al69 randomized 175 patients with Grade C or worse PVR to receive intravitreal injection of low-dose VIT100 (0.15 mg), high-dose VIT100 (0.75 mg), or placebo at the conclusion of retinal surgery. At 24 weeks, the drug was not found clinically effective, with no statistically significant difference in PVR-related detachment rates observed between groups.
Conclusions Based on the Literature
Randomized trials investigating a variety of medical agents for the prevention and treatment of PVR are not yet able to guide clinical care. The only agent that has yielded possible benefit in recent studies, isotretinoin, is in need of larger follow-up trials to confirm efficacy and better determine effective dosing. As with studies regarding surgical management, the heterogeneity in study design, outcomes, and patient population preclude meta-analysis and broader application of data.
Proliferative vitreoretinopathy remains a significant challenge for vitreoretinal surgeons. Preclinical studies continue to add insights into the complex molecular events leading to PVR development, helping to identify new targets for potential prophylactic or therapeutic agents as reviewed above. Ongoing advances in surgical technology, also reviewed, have allowed surgeons more options. However, although we have indeed learned a great deal about the pathogenesis of PVR over the past decades, no proven prophylactic or therapeutic options exist. Certainly, more work needs to be done to address this visually devastating disease process.
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