Update on Proliferative Vitreoretinopathy

MARC J. SPIRN, MD

Proliferative vitreoretinopathy (PVR) is the major obstacle to successful rhegmatogenous retinal detachment repair, causing 5% to 10% of surgical failures. In many instances, when PVR occurs, redetachment of the retina follows. Even when anatomic success is later achieved, final visual outcomes are often poor. As a result, efforts continue to find ways to prevent and treat PVR.

In January 2008, Dr. Carl Regillo and I published a review of proliferative vitreoretinopathy in Retinal Physician.¹ In that article, we described the classification, treatment methods, and latest research on ways to treat PVR. In this article, I will provide an update on the current state of PVR research and newer advances in surgical techniques and preventive measures.

DIAGNOSIS: STAGES OF DISEASE

Proliferative vitreoretinopathy has been divided into multiple stages. Grade A is limited to the presence of vitreous cells or haze. Grade B is defined by the presence of rolled or irregular edges of a tear or inner retinal surface wrinkling, denoting subclinical contraction. Grade C is recognized by the presence of preretinal or subretinal membranes, which makes the retina stiff, immobile, and resistant to straight-forward repair. As vitreoretinal specialists, grade C PVR presents the greatest challenge, while grades A and B offer opportune times for prevention.

INTERVENTION: A BASIC SCIENCE APPROACH

Much is known about the underlying pathogenesis of PVR. Histopathologic specimens suggest that pre- and subretinal proliferative membranes are composed of RPE cells, fibroblasts, glial cells, inflammatory cells, and type 4 collagen.² Proliferation and signaling of these components occurs as a result of multiple factors, which include platelet-derived growth factor (PDGF), tumor necrosis factor, transforming growth factor, and calcium independent phospolipase A2, among others. The basic science literature continues to define how these different factors influence the production of PVR.

Among these various factors, PDGF continues to stand out as an important mediator of PVR. PDGF has been localized in the vitreous in both clinical and experimental PVR. PDGF receptors have been found on the surface of epiretinal membranes and are thought to be instrumental in the attachment, migration and proliferation of RPE cells, and therefore they are thought to be essential for the formation of PVR. As a result, inhibiting PDGF or its receptors would seem to be a logical mechanism to prevent proliferative vitreoretinopathy.

He et al. found that blocking the EphB4 receptor with soluble EphB4 inhibits PDGF-induced RPE activity. Lei et al. have attempted to neutralize PDGF in several ways. They observed that blocking plasmin — a major PDGF-C protease — with a plasmin inhibitor eliminated most PDGF-C activity.⁴ Later, they attempted to block vitreal PDGF using a neutralizing PDGF antibody and a PDGF trap, which bound to and blocked the PDGF alpha receptor. Despite their attempted blockage, the PDGF alpha receptor was still activated at a non-PDGF binding site by other non-PDGF vitreal growth factors. This research suggested that blocking the PDGF-alpha receptor at all its sites may be more effective than blocking PDGF alone, since blocking PDGF alone may still allow for PDGF-alpha receptor activation.⁵

Figure 1. Inferior PVR with fixed folds in a patient who previously underwent retinal detachment repair with silicone-oil placement.

CLINICAL INTERVENTION

Although there are many factors that contribute to PVR, the final common pathway is RPE proliferation and migration. It would follow, therefore, that blocking RPE migration and activity could prevent PVR. Based on this basic science research, multiple pharmacologic agents aimed at inhibiting PVR have been studied.^6-12 Unfortunately, few targets thus far have made an impact in a clinically meaningful way. One exciting pharmacotherapy recently investigated involved the use of isotretinoin or 13-cis retinoic acid (Accutane), an oral form of vitamin A that is FDA-approved for the treatment of severe nodular acne. Accutane may be most well known for its risk of causing severe, life-threatening birth defects when used during pregnancy.

In 1991, it was first reported that retinoic acid (RA) could inhibit the growth of human RPE cells in vitro.¹³ Wu et al. later found that 13-cis-RA, an isoform of alltrans RA, could inhibit human RPE cell proliferation from excised membranes of PVR. The isoform 13-cis-RA appeared to inhibit RPE proliferation in a dose-dependent manner and did so without any cytotoxic effects.¹⁴ In animal studies, intravitreal injection of RA inhibited the occurrence of PVR in experimental animal models.^15-19

One previous clinical study addressed the role of Accutane in the prevention of PVR and found it worthy of further investigation.²⁰ In that study, patients received a dose of 80 mg per day for four weeks. Although side effects from Accutane were uncom mon, adverse effects can range from mild (such as dry mouth) to severe (elevated lipids) and may be dose-dependent. Chang and associates recently evaluated the effects of lower-dose Accutane on postoperative clinical outcomes.²¹ In their study, patients who underwent complex retinal-detachment repair with silicone-oil placement were treated with 20 mg per day of Accutane for eight weeks. Retinal reattachment was achieved at a statistically higher rate in the Accutane-treated group compared to the untreated control group (94% vs 63%). Furthermore, fewer RA-treated patients developed macular pucker compared to the control group (19% vs 79%). Importantly, the Accutane was well tolerated with few adverse effects. This study suggests that Accutane may be an important pharmacologic strategy in the tertiary prevention of PVR and theoretically could be used in primary or secondary prevention strategies.

Figure 2. Grade C PVR in a patient with a primary detachment secondary to cytomegalovirus retinitis (cytomegalovirus still present along the superior temporal arcade).

SURGICAL REPAIR

Over the last several years, there have been multiple technological advances in vitreoretinal surgery. One major area of change has been the shift from 20-g vitrectomy to 25- and 23-g vitrectomy. Because of their increasing popularity, the instrumentation for these smaller techniques continues to grow. This is especially important for the treatment of PVR, where peeling membranes, performing relaxing retinectomies, and placing silicone oil are frequently employed. Until recently, most complicated retinal detachments have been repaired using 20-g instrumentation. As a result, instrumentation for 20-g surgery is the most varied. Transconjunctival sutureless vitrectomy using either 25- or 23-g instrumentation, however, does offer certain advantages to the patient and surgeon over traditional 20-g techniques.

The advantages of 25- and 23-g vitrectomy include improved patient comfort, decreased operative times, and decreased postoperative astigmatism.^22-25 For complex retinal detachments with PVR, my preference — after placing an encircling scleral buckle to relieve anterioposterior and circumferential traction — is to perform 23-g pars plana vitrectomy. The major advantage of 23-g over 25-g is that the instruments are stiffer, which facilitates peripheral membrane peeling and eases peripheral anterior laser. The basic tenets of PVR repair are highlighted in our January 2008 Retinal Physician article. ILM forceps, end-grasping forceps, and serrated forceps are all now available in disposable 23-g forms and can be useful for membrane peeling.

Erakgun et al. recently showed that 23-g pars plana trectomy with silicone oil injection is a feasible, safe, and effective technique for repairing both tractional retinal detachments as well as retinal detachments complicated by proliferative vitreoretinopathy. In their retrospective study of 40 eyes that underwent 23-g PPV with silicone oil placement, only one eye redetached. Postoperative complications were rare and included subconjunctival silicone oil migration (n=3) and hypotony (n=1).²⁶ Similarly, Riemann et al. found that 25-g vitrectomy with silicone oil placement was safe and effective, including in cases of proliferative vitreo-retinopathy.²⁷ In their series, two patients also had subcon-junctival silicone oil postoperatively. Because of the potential for subconjunctival silicone oil egress and postoperative hypotony, it may be beneficial to suture the sclerotomies.

Once PVR has formed, it is often necessary to dissect membranes and perform a peripheral relaxing retinectomy. Recent evidence continues to support the use of relaxing retinectomies. Tsui and Schubert recently described a series of patients with complicated rhegmatogenous retinal detachments that required greater than 180 degrees of retinectomy and silicone-oil tamponade. They noted that a large inferior retinectomy effectively treated proliferative vitreoretinopathy and that silicone oil tamponade was beneficial.²⁸ Similarly, in cases of severe anterior proliferative vitreoretinopathy and anterior hyaloidal fibrovascular proliferation, Banaee et al. found that a 360° retinectomy was an effective procedure for flattening the retina.²⁹

TAMPONADES

One continued area of interest is the use of heavy silicone oils. The premise behind their use is that most PVR occurs inferiorly, because gravity causes most inflammatory mediators to settle inferiorly. The inferior vitreous cavity is also the least likely area to be sufficiently tamponaded with gas or oil. Heavy silicone oils have a specific gravity that is greater than water; thus the oil sinks rather than floats on water. This enables the inferior retina to be well tamponaded, thereby offering a theoretical advantage over conventional silicone oils and long-acting gases when prolonged inferior tamponade is necessary.

Early clinical experience with first- and second-generation heavy tamponades — which include fluorinated silicone, perfluorocarbon liquids, and partially fluorinated alkanes — were tempered by complications including emulsification, intraocular inflammation, and increased intraocular pressure.³⁰ However, newer heavy silicone oils, which include oxane HD, Densiron 68, and HWS46-3000, appear to be better tolerated with a side-effect profile similar to conventional silicone oils.

Several recent series have evaluated the safety and efficacy of Densiron. Auriol et al. evaluated 68 patients with complicated retinal detachments with severe posterior and anterior PVR. They found Densiron to be an effective tamponade in conjunction with a large inferior retinectomy (mean follow-up was 57.5 weeks and mean Densiron removal was at 14 weeks).³¹ The Densiron restricted fluid accumulation under the inferior retina and limited the rate of reopening of the inferior retinectomy. Similarly, Lim et al. utilized Densiron in eyes that had failed initial retinal detachment surgery.³² Using Densiron, the overall reattachment rate was 70%.

Boscia et al. conducted a small study comparing the use of PPV with oxane HD to scleral buckle, PPV, and 1300-centistoke silicone oil.³³ In that study, reattachment rates were similar (80% in the oxane group vs 90% in the silicone oil group). The authors found that oxane without scleral buckling significantly reduced operative times.

As with the first-generation heavy oils, the major concern with the newer heavy oils is the rate of complications. Auriol et al. observed an inflammatory response with fibrin in the anterior chamber in 40% of their patients.³¹ Li et al. reported high rates of posterior capsule opacification (25.9%), intraocular inflammation (22.2%), and emulsifica-tion with raised intraocular pressure (18.5%).³⁴ Despite these seemingly high complication rates, most studies suggest that the newer heavy oils are safe.

CONCLUSION

Proliferative vitreoretinopathy continues to be the major impediment to sustained retinal detachment repair. As a result, efforts continue to identify factors that may contribute to PVR and help prevent its formation. Surgical techniques are now focusing on smaller-gauge surgery with 23- and 25-g vitrectomy, which in retrospective studies appear to be safe and effective. Other areas of continued interest include the use of heavy silicone oils, which may mitigate inferior complications associated with conventional tamponading agents. Preliminary evidence on these newer heavy oils seems to suggest that they are safe and effective, but their use may still be limited by postoperative side effects such as inflammation, cataract formation, and emulsification with high intraocular pressure. RP

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