Proliferative vitreoretinopathy (PVR) represents a severe complication of rhegmatogenous retinal detachments, occurring in 5 to 10% of all retinal detachments and accounting for up to 75% of subsequent retinal redetachment surgeries.1 As the primary cause of surgical failure in retinal detachment repair, PVR presents a significant challenge in ophthalmologic surgery.
While the condition can develop pre- and post-operatively, it is predominantly diagnosed following retinal detachment surgery. The formal recognition of PVR dates back to 1983 when the Retina Society Terminology Committee established its terminology and classification system.2
Figure 1: Intra-operative image of macular PVR.
Figure 1: Courtesy of David RP Almeida MD, MBA, PhD.
Pathogenesis of PVR
The development of PVR follows a complex cascade of cellular events initiated by retinal detachment. The initial injury triggers the migration of inflammatory cells, particularly glial cells and retinal pigment epithelial (RPE) cells, to the injury site.
These cells subsequently proliferate and form membranes on both surfaces of the detached retina. Membrane maturation leads to contraction through extracellular collagen production, resulting in retinal folding that prevents successful reattachment.
Figure 2: Intra-operative image of a funnel-shaped retinal detachment (RD) due to PVR.
Figure 2: Courtesy of David RP Almeida MD, MBA, PhD.
Cellular proliferation represents the critical therapeutic target in PVR pathogenesis. This process can persist for 30 to 90 days after retinal reattachment, necessitating treatments that maintain activity throughout this extended timeframe.
Despite decades of research focused on controlling the proliferation of retinal and peri-retinal cells and extensive investigation into medical management strategies, therapeutic breakthroughs have remained elusive. Surgical intervention continues to be the cornerstone of PVR treatment.
Classification of proliferative vitreoretinopathy
The Retina Society Terminology Committee developed the classification of PVR at the time the disease was first classified:2
- A: Vitreous haze, pigment clumps, and pigment clusters on the inferior retina
- B: Wrinkling of the inner retinal surface, retinal stiffness, vessel tortuosity, rolled and irregular edge of a retinal break, and decreased mobility of vitreous
- CP (posterior): Full-thickness retinal folds or subretinal strands posterior to the equator (1 to 12 clock hours involvement)
- Focal: Starfolds posterior to the vitreous base
- Diffuse: Confluent starfolds posterior to vitreous base; optic disc that may not be visible
- Subretinal: Proliferation under the retina; annular strand near disc; linear strands; moth-eaten-appearing sheets
- CA (anterior): Full-thickness retinal folds or subretinal strands posterior to the equator (1 to 12 clock hours involvement), anterior displacement, and condensed vitreous strands
- Circumferential: Retina contraction inwards at the posterior edge of the vitreous base, with central displacement of the retina; peripheral retina stretched; posterior retina in radial folds
- Anterior: Anterior contraction on the retina at the vitreous base; ciliary body detachment and epiciliary membrane; iris retraction
Surgical management of rhegmatogenous retinal detachment
Rhegmatogenous retinal detachment (RRD) can be treated with surgical approaches, including scleral buckling, pars plana vitrectomy (PPV), or a combination of these procedures.
Pars plana vitrectomy
While scleral buckling alone may occasionally treat retinal detachment complicated by PVR, management most commonly includes PPV with membrane peeling.3 PPV represents the most common surgical technique for treating RRD. The procedure involves the removal of the vitreous fluid, resolution of vitreoretinal traction, identification, and repair of retinal tears, and insertion of an intraocular tamponade.
Figure 3: Intra-operative image of PPV.
Figure 3: Courtesy of David RP Almeida MD, MBA, PhD.
Managing PVR with PPV and scleral buckling
In cases complicated by PVR, scleral buckling is frequently employed alongside PPV and membrane peeling to provide additional management of retinal traction that may persist even after membrane removal. The technical process of membrane removal typically employs end-grabbing forceps with or without a scraper instrument (e.g., Tano diamond-dusted or Alcon flex-loop).
The surgical approach sometimes begins with using the scraper instrument to partially separate the membrane from the detached retina, followed by forceps to grasp and remove the membrane. The maturity of the membranes significantly influences the ease of removal—mature membranes typically separate in a continuous sheet, while immature membranes are more prone to tearing and splitting.
Video 1: David RP Almeida, MD, MBA, PhD, demonstrates peeling the scar tissue and membrane from the retina of an eye with PVR RD.
Video 1: Courtesy of David RP Almeida MD, MBA, PhD.
Combining PPV and scleral buckle for PVR
A significant 2014 study compared outcomes between PPV combined with scleral buckle versus primary vitrectomy alone in high-risk PVR patients.4 Among 678 patients studied, 65 were identified as high-risk based on criteria including retinal detachment in two or more quadrants, retinal tears greater than one clock hour, pre-operative PVR, or vitreous hemorrhage.
Results demonstrated that combination PPV-scleral buckle surgery achieved significantly higher single-surgery anatomical success than PPV alone. Notably, neither visual acuity outcomes nor risk of eventual PVR development differed between treatment groups. The study also found no significant difference in surgical outcomes between long-acting intraocular gas (SF6 or C3F8) and silicone oil tamponade.4
Using 23- and 25-gauge instruments during PPV
Drainage retinotomy sites represent another component of facilitating reattachment of the detached retina to the retinal pigment epithelial cells. When employed for PVR treatment, retinotomies allow for aspiration of subretinal fluid, especially when tears are pretty peripheral. Retinectomy, the act of cutting and relaxing the foreshortened retina, is sometimes also employed when circumferential or peripheral traction is severe.
Surgical advancements in the treatment of PVR have included surgeons incorporating the use of smaller instruments during PPV. While the procedure historically has been conducted using 20-gauge instruments, a move to smaller instruments (23- and 25-gauge) has taken place over the last two decades.
A study conducted in 2008 investigated the use of 25-gauge instruments during retinectomy to treat complicated retinal detachment. Results showed that this gauge of instruments was safe and comparable to the use of 20-gauge instruments.5
Another study conducted in 2009 looked at using 23-gauge instruments during vitrectomy.6 In total, 40 patients with tractional retinal detachment and PVR were included in the study. The authors found that using 23-gauge instruments was effective and safe for treating these complicated vitreoretinal diseases.
While 27-gauge instrumentation is also available, it has not gained widespread use partly due to the filmy nature of the forcep instruments and the limited variety of 27-gauge tools available (i.e., lighted endolaser and lighted picks are not readily available in 27-gauge).6
Extrascleral cryotherapy has also been investigated as a possible adjunctive treatment in the surgical management of PVR. A small study published in 2020 evaluated the effect of this technique during retinal detachment repair.
Patients with retinal detachment and associated peripheral grade C star-folds were included in the study.7 In each of the patients, PVR star-folds were treated with cryotherapy. Results showed that the procedure was safe and effective, achieving retinal reattachment in all six patients included in the study.
Medical management of PVR
Methotrexate
Methotrexate is a medication commonly used in the treatment of malignancies and autoimmune diseases. When used as a treatment for cancer, it works through the inhibition of dihydrofolate reductase, the enzyme responsible for converting dihydrofolate to tetrahydrofolate, the active form of folate.
This biochemical conversion is necessary in the synthesis of nucleotides of both DNA and RNA. Through inhibition of nucleotide formation, methotrexate prevents cellular proliferation. The mechanism garnered interest for its possible role in treating PVR, a disease whose pathogenesis heavily relies on cellular proliferation.8
Initial clinical investigation through a 2016 case series examined intravitreal methotrexate infusion during pars plana vitrectomy for retinal detachment. The study included patients with either tractional retinal detachment and recurrent PVR or a history of severe inflammation associated with high PVR risk.9
Results showed that best-corrected visual acuity (BCVA) in 83% of the eyes remained stable or improved compared with the initial presentation, and 90% of retinas remained attached at the last follow-up. Notably, no complications due to intravitreal methotrexate occurred during an average follow-up of 27 months.9
The molecular basis for these clinical findings was explored in a 2017 in-vitro study examining methotrexate's effect on PVR membranes.10 Using membrane fragments obtained from six patients with grade C PVR, researchers compared treatment with PVR media alone versus methotrexate at various concentrations (100μM, 200μM, and 400μM).
Results demonstrated that methotrexate significantly reduced C-PVR band formation, cell number, and proliferation. This effect was particularly notable compared to previous studies using dexamethasone and daunorubicin, which showed no significant reduction in proliferation.11,12,13
While methotrexate had no significant effect on cell migration, it induced regulated cell death through increased expression of caspase-3/7.
Figure 4: Intra-operative image of subretinal band removal.
Figure 4: Courtesy of: David RP Almeida MD, MBA, PhD.
Further studies on the efficacy of methotrexate for PVR
Further investigation in 2019 evaluated retinal reattachment rates in patients with grade C PVR using repeated intra-silicone oil methotrexate injections.14 Following PPV, patients received 250μg methotrexate injections into the silicone oil-filled vitreous cavity, repeated at weeks 3 and 6. All 11 eyes achieved retinal reattachment during the average 9-month follow-up period, with significantly improved mean post-operative BCVA and no observed ocular or systemic side effects.
A 2021 in-vitro study provided additional mechanistic insights by analyzing the cytotoxic and antiproliferative effects of methotrexate and 5-fluorouracil (5-FU) on fibroblasts and RPE cells and examining potential effects on photoreceptor cells.15 The study revealed that while 5-FU showed antiproliferative effects on fibroblasts and RPE cells, it also caused decreased viability and induced apoptosis in photoreceptor cells.
In contrast, methotrexate demonstrated selective efficacy, inhibiting RPE cell proliferation at concentrations as low as 8μg/mL while maintaining cell viability and avoiding increased apoptosis even at 266μg/mL concentrations.
The clinical investigation continued with another 2021 study examining methotrexate use following PPV in patients with grade C PVR, recurrent RD, and open globe trauma.16 The study reported that 80% of patients maintained retinal attachment at 4 months, with the remaining patients achieving reattachment after secondary surgery. Notably, no complications attributable to methotrexate were observed during the follow-up period.
The therapeutic applications were further expanded in a 2022 study investigating intravitreal methotrexate for PVR treatment in pediatric patients with retinal detachments.17 The study included three pediatric patients who received a combination surgery therapy and intra-operative methotrexate infusion, followed by at least one injection of 200μg methotrexate into the vitreous cavity.
Additionally, patients underwent 12 weeks of subcutaneous methotrexate injections for short-term systemic immunosuppression. All patients showed retinal reattachment and visual acuity improvement throughout follow-up, with no observed side effects from intraocular or systemic methotrexate administration. A similar case report using intraoperative intravitreal methotrexate published successful re-attachment in a patient with PVR requiring silicone oil tamponade.18
Clinical trials on intravitreal methotrexate for PVR prevention
Currently, the Phase 3 Guard Trial is investigating repeated intravitreal injections of 0.8% methotrexate versus the standard of care for PVR prevention in patients undergoing PPV due to recurrent retinal detachment or open globe injury.19
Initial results have shown the achievement of the primary endpoint in reducing retinal detachment over 6 months compared to historical controls, with demonstrated superiority over routine surgical care across multiple secondary endpoints. The medication has been well tolerated, with no observed safety concerns.
The extensive history of methotrexate use in treating other ocular conditions, particularly intraocular lymphoma, has provided valuable safety data. Corneal epithelial keratopathy is the most commonly observed side effect with intraocular administration, typically appearing after the third injection and improving with increased intervals between treatments.20
5-fluorouracil (5-FU)
5-fluorouracil represents another therapeutic approach derived from cancer treatment. Its mechanism of action centers on inhibiting thymidylate synthase, the enzyme responsible for producing deoxythymidine monophosphate, a crucial molecule in DNA replication and repair.
Additionally, 5-FU functions as a pyrimidine analog, misincorporating into RNA and DNA instead of uracil or thymine. These combined mechanisms result in double-stranded DNA breaks and, ultimately cell death in rapidly proliferating cells.21 Like methotrexate, 5-FU's ability to target cellular proliferation made it a candidate for PVR treatment.
Early investigation showed promise, with a 2004 study assessing the in-vitro use of sustained release naproxen and 5-FU in rabbit retinas.22 The research demonstrated significantly lower severity and percentage of moderate or worse tractional detachment in eyes treated with the codrug pellet than controls.
Clinical application of 5-FU has mainly focused on combination therapy with low molecular weight heparin (LMWH). A 2001 clinical trial studying this combination for PVR prevention after vitrectomy and retinal reattachment surgery showed encouraging results, with significantly lower PVR incidence in the treatment group (12.6%) compared to placebo (26.4%).23
However, more recent investigations have yielded conflicting results. A 2022 randomized clinical trial comparing 5-FU and LMWH with placebo in high-risk primary RRD patients found no significant difference in PVR rates between treatment and placebo groups.
A comprehensive 2021 meta-analysis evaluated the efficacy of combined 5-FU and LMWH therapy, analyzing six clinical trials encompassing 1,208 patients.24 Results indicated that the combination therapy neither improved primary vitrectomy success at 6 months nor affected the number of patients requiring vitreoretinal repair.
While the treatment showed no overall effect on post-operative PVR prevention, subgroup analysis revealed that pre-intervention grade C PVR showed significantly reduced PVR occurrence with treatment.24
Daunorubicin
Daunorubicin belongs to the anthracycline antibiotic class and, like methotrexate and 5-FU, was initially developed for cancer treatment. Its mechanism involves DNA intercalation between base pairs, leading to the uncoiling of the DNA double helix and subsequent single and double-stranded breaks. This process inhibits DNA and RNA synthesis, making it another candidate for PVR treatment through its antiproliferative properties.
Clinical investigation of daunorubicin began with a significant 1998 study examining 286 eyes with stage C2 or more advanced pre-operative PVR. The trial compared standardized surgery with daunorubicin to surgery alone.25 While 6-month outcomes showed no significant difference in complete retinal reattachment rates without additional vitreoretinal surgery, the treatment group demonstrated significantly fewer vitreoretinal reoperations within the first post-operative year.
Further investigation in 2002 focused on daunorubicin's role in PVR prevention following retinal detachment.26 This study of 30 patients evaluated retinal attachment, vitreous activity, and visual acuity changes 3 months post-surgery. Results demonstrated a statistically significant reduction in vitreous reaction during the post-operative period in patients receiving daunorubicin.
A notable advancement came in 2015 with the study of daunorubicin-loaded porous silicon particles.27 This novel delivery system, administered 8 to 9 weeks before PVR induction in rabbit eyes, demonstrated the ability to safely reside in the vitreous for at least 3 months, significantly extending daunorubicin's half-life from hours to 29 days.
The study revealed a clear dose-dependent relationship between daunorubicin and PVR severity. While the control group showed PVR with tractional retinal detachment in 88% of cases, this decreased to 63% in the low-dose group, 14% in the medium-dose group, and remarkably, 0% in the high-dose group.27
Anti-VEGF
Vascular endothelial growth factor (VEGF) serves as a regulator of angiogenesis through its promotion of vascular endothelial cell formation. Anti-VEGF molecules have established their therapeutic value in treating proliferative diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion.
The demonstrated ability of these agents to limit vascular proliferation in these conditions prompted an investigation into their potential role in managing PVR related to retinal detachment. However, clinical studies have yielded disappointing results.
A 2014 investigation examining bevacizumab injection into silicone oil after retinal reattachment surgery for severe PVR-complicated cases revealed concerning findings.28 Rather than showing benefit, the treatment group experienced higher rates of retinal redetachment and subretinal fibrous proliferation than controls.
These findings were further supported by a 2018 meta-analysis investigating bevacizumab in PVR-related retinal detachment treatment.29 Analyzing 120 patients, the study found no clinically or statistically significant differences in either BCVA or retinal redetachment rates between bevacizumab-treated and untreated patients. Additionally, bevacizumab showed no impact on the interval between vitrectomy and retinal redetachment.
Platelet-derived growth factor receptor kinase inhibitor
Platelet-derived growth factor (PDGF) plays a crucial role in cellular growth, survival, proliferation, and migration. It exerts these effects through binding to two receptor tyrosine kinases (RTKs): PDGFα and PDGFβ.
Early molecular investigation in 2000 explored the role of PDGF receptors through targeted mutations.30 Researchers generated point mutations in the human PDGF alpha receptor, creating single amino acid substitutions and a truncated protein form. The study demonstrated varying degrees of PVR prevention among the mutated receptors, with the truncated mutant showing the highest efficacy.
A 2003 study investigated tyrphostin AG1295, a selective PDGF RTK blocker, in rabbit PVR models.31 Following PVR induction and gas vitrectomy in 35 rabbits, the treatment group (n=18) received AG1295 injections titrated to 100μM concentration, with repeated administration on days 7, 14, and 21. Day 14 examinations revealed a statistically significant reduction in tractional retinal detachment development in treated eyes.
While treated eyes showed reduced tractional retinal detachment development on days 7, 21, and 28, these differences did not reach statistical significance. Notably, this study focused exclusively on fibroblast proliferation, excluding retinal epithelial cell proliferation from its analysis.
Subsequent research in 2010 provided crucial insight into the relative importance of PDGF versus PDGF receptors (PDGFRs) in PVR development.32 Using a rabbit model, researchers discovered that targeting PDGFRs offered superior protection against PVR compared to targeting PDGF itself. The researchers attributed this finding to PDGFRs' susceptibility to activation by factors beyond the PDGF family.
Further investigation by the same group focused on PDGFα's role in RPE cells, revealing that despite lower expression levels than fibroblasts, increased receptor expression significantly enhanced the PVR potential of RPE cells.33
Decorin
Transforming growth factor-beta (TGF-β) is a critical growth factor in cellular differentiation, epithelial-mesenchymal transition, and cell adhesion. Decorin, a naturally occurring TGF-β inhibitor, has emerged as a potential therapeutic agent for PVR prevention.
Research into decorin's therapeutic potential was advanced by a 2011 study examining its use in treating induced traumatic PVR in rabbits.34 When administered with vitrectomy, decorin demonstrated statistically significant reductions in both PVR score and fibrosis development.
Steroids
Steroids have been considered in PVR treatment due to their anti-inflammatory effects and ability to inhibit growth factor production and cellular proliferation. However, their use in PVR prevention following retinal detachment remains controversial due to mixed efficacy results in clinical studies.
A 2008 study evaluated intraocular triamcinolone acetonide in silicone-filled eyes for PVR prevention following vitreoretinal surgery.35 Results showed no significant difference in retinal reattachment rate, visual acuity, rate of recurrent PVR, or reoperation rate.
A 2010 study assessed oral prednisolone's effect on visual outcomes and complications of scleral buckling in phakic eyes following vitreoretinal surgery.36 Treatment consisted of 1mg/kg oral prednisolone for 10 days post-surgery, with results showing no significant improvement in visual outcomes or complications.
A 2012 study investigating systemic corticosteroids for preventing early PVR stages administered prednisone for 15 days, starting at 100mg with tapering to 12.5mg.37 While the study demonstrated a statistically significant reduction in cellophane membrane formation throughout follow-up, final visual outcomes showed no significant difference between treatment and control groups
A 2015 study examined slow-release dexamethasone implants for improving vitreoretinal surgery outcomes in established grade C PVR.38 While showing no significant improvement in anatomic success rates; the implant significantly reduced the incidence of cystoid macular edema and cases of foveal thickness exceeding 300μm.
A comprehensive 2023 meta-analysis reviewed the above randomized controlled trials with 478 total patients and found no significant difference in PVR recurrence between steroid-treated and control groups.39 While overall retinal reattachment rates and reoperation needs were similar, the analysis revealed reduced PVR incidence in grades A and B cases treated with steroids.
The study also demonstrated reduced post-surgical macular edema with steroid treatment. However, due to varied steroid types and administration routes in included studies, optimal steroid delivery methods could not be determined.39
A recent 2024 retrospective study examined oral prednisone's impact on visual acuity and PVR prevention in PPV patients with global injuries.40 These patients showed significant visual improvement despite the treatment group presenting with more severe initial conditions, including increased zone 3 involvement and worse initial visual acuity. The study found that oral prednisone did not predict PVR or retinal detachment development.
Retinoic acid
Retinoic acid has emerged as another potential therapeutic option for PVR treatment. A 2008 study investigated oral 13-cis-retinoic acid in improving vitreoretinal surgery outcomes for PVR management.41 The treatment protocol consisted of 10mg oral retinoic acid for 8 weeks post-surgery.
Results demonstrated statistically significant improvements in retinal attachment maintenance and visual acuity among treated patients. Additionally, the treatment group showed significantly lower rates of macular pucker formation.
Further investigation in 2019 examined low-dose oral isotretinoin for reducing PVR risk following retinal detachment repair. The treatment protocol involved 20mg daily oral isotretinoin for 12 weeks post-surgery, with outcomes compared against historical controls. The study demonstrated statistically significant improvement in single surgery success rates for recurrent PVR-related retinal and high-risk retinal detachment cases.42
Mitomycin C
Mitomycin functions as an alkylating agent in cancer treatment, cross-linking DNA and inhibiting its synthesis. Its cellular proliferation suppression properties have generated interest in its potential application for PVR treatment.
A 2019 study evaluated intraocular mitomycin for PVR prevention in open globe trauma cases.43 While the results did not reach statistical significance, the authors suggested a potential role for mitomycin C in reducing post-traumatic PVR rates.
A 2021 retrospective study investigated intraocular mitomycin C in treating traumatic retinal detachments with PVR.44 The treatment protocol involved injecting 10μg/ml concentrated mitomycin C above perfluorocarbon liquid in areas with PVR and potential PVR development.
Results showed a complete absence of PVR around retinal breaks or retinotomy sites, with nearly 100% retinal attachment maintained throughout follow-up. Importantly, patients receiving mitomycin C demonstrated statistically significant visual acuity improvement.
In conclusion
PVR remains a significant challenge in the management of retinal detachment. While surgical intervention with PPV and membrane peeling continues to be the primary modality of treatment, advances in medical therapy show promise in both the prevention and management of PVR.
Recent research has demonstrated particular promise in the use of methotrexate. Positive outcomes have been shown in both clinical and laboratory settings. The ongoing Phase 3 Guard Trial may provide definitive evidence of its PVR prevention role.
Despite some advances, challenges remain. Many treatments that showed initial promise in laboratory studies have failed to demonstrate a consistent clinical benefit. Furthermore, the optimal timing and combination of medical and surgical interventions remains unclear.
Future research should continue to focus on developing targeted therapies based on our increasing understanding of the pathogenesis of PVR. Special attention should be given to preventing disease progression in high-risk cases.
