PEER REVIEWED

Proliferative Vitreoretinopathy

MARC J. SPIRN, MD • CARL REGILLO, MD

Proliferative vitreoretinopathy (PVR) is currently the biggest obstacle to successful retinal reattachment surgery, accounting for approximately 75% of all primary surgical failures. PVR is characterized by growth and migration of preretinal or subretinal membranes. Contraction of these membranes causes foreshortening of the retina, leading to stretch holes or traction, which redetaches the retina. As the proliferation matures, the once compliant retinal tissue becomes rigid and immobile, making repair more difficult. In addition, patients with PVR-associated detachments often have extensive levels of visual loss. As technological advances in vitreoretinal surgery continue to move forward, effective new treatments for PVR continue to lag behind. Although anatomic repair is possible in greater than 90% of detachments with associated PVR, primary prevention of PVR remains an obstacle.

RISK FACTORS

Proliferative vitreoretinopathy complicates approximately 5% to 10% of all retinal detachment repairs. Typically, PVR occurs after primary retinal detachment repair; however, it can occasionally occur with longstanding primary detachments. Multiple factors have been associated with the formation of PVR. In general, processes that increase vascular permeability are more likely to increase the probability of PVR formation. Specific risk factors 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 2 quadrants of the eye.^2-5

DEVELOPMENTAL STAGES

Ocular wound healing typically occurs in 3 stages: an inflammatory stage, a proliferative stage, and a modulatory stage.⁶ Proliferative vitreoretinopathy can be viewed in a similar fashion, with the wound being the retinal detachment. This "healing" response takes place over many weeks. Early on, preretinal PVR adopts an immature appearance and consistency. During this phase, the retina may still remain compliant, and the PVR may be difficult to remove due to its amorphous form. By 6 to 8 weeks, however, the membrane becomes more mature, taking on a white, fibrotic appearance. In this stage, the PVR is more easily identifiable, causes rigidity of the retina, and can be more identifiably removed.⁷

HISTOPATHOLOGY

The histopathologic components of PVR reflect the different aspects of wound healing. Histopathologic specimens suggest that pre- and subretinal proliferative membranes are composed of retinal pigmental epithelial cells, fibroblasts, glial cells, inflammatory cells, and type 4 collagen.⁸

CLASSIFICATION

The term "proliferative vitreoretinopathy" was coined in 1983 by the Retina Society Terminology Committee. In 1989, the classification was amended by the Silicone Study Group before being most recently modified in 1991 to its current classification. Currently, PVR is divided into grades A, B, and C. 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. Grade C is further delineated as being anterior to the equator (grade Ca) or posterior to the equator (grade Cp) and by the number of clock hours involved (1 to 12).

MANAGEMENT OF PVR

The current management of PVR primarily involves surgical remedy. Currently retinal detachments may be repaired using any of several techniques, including laser retinopexy, pneumatic retinopexy, encircling or segmental scleral buckling, or pars plana vitrectomy (PPV).

Laser retinopexy is a valuable technique that can be considered for limited detachments when there is no noticeable visual field loss. Benefits of laser retinopexy include patient convenience, no need for systemic anesthesia, and limited cost. Laser retinopexy may be effective treatment for retinal detachments with only grade A PVR, but is less likely to be successful when grade B or more PVR is present.

Pneumatic retinopexy likewise has the advantages of being an in-office procedure with less anesthesia-related morbidity. It can be utilized in patients with larger detachments and with visual field loss, but it is dependent on patient positioning and cooperation. Similarly, pneumatic retinopexy may be useful with detachments associated with grade A PVR, but it is less effective in the setting of grades B and C PVR.

Scleral buckling is frequently utilized when treating PVR detachments. Scleral buckles relieve both anteriorposterior traction and circumferential traction. This acts as an opposing force against which proliferative membranes must pull to redetach the retina. In the setting of PVR, encircling bands that support the entire vitreous base are more useful than segmental elements and are frequently used in conjunction with PPV. With milder degrees of grade C PVR, such as PVR limited to 1 quadrant, scleral buckling alone may be a viable option.⁹ This was similarly shown by Yao et al., who achieved high rates of anatomic success using scleral buckling alone in chronic detachments with PVR.¹⁰

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

ALL FIGURES APPEAR COURTESY OF THE AUTHORS.

Pars plana vitrectomy with or without scleral buckling remains the mainstay of surgical repair when PVR is present. One major advantage of vitrectomy over other surgical modalities is that it allows for removal of the inciting proliferative nidus. During surgical repair, vitreous cells can be removed, which may prevent these cells from progressing to further stages of PVR. Another obvious advantage of PPV over other treatment modalities is that PPV allows direct access to the proliferating membranes, which can be peeled during surgery. One disadvantage of PPV over other treatment modalities is that it may increase permeability of the blood retina/aqueous barrier more than other techniques.

SURGICAL TECHNIQUES

The goal of PVR detachment surgery is similar to traditional retinal detachment surgery: treat all tears and relieve all traction. Several surgical techniques may enable more permanent anatomic success. After performing a core vitrectomy and meticulous peripheral dissection with 360° of scleral depression, attention is directed to the proliferative membranes. Intravitreal triamcinolone acetonide suspension may highlight these membranes, especially when they are immature. When membranes are immature, using a diamond dusted silicone tip "scraper" in conjunction with forceps may facilitate identification and removal. When membranes are more mature, fixed folds are often present. Mature preretinal membranes can often be removed with forceps, a pick, or a combination of both. We typically remove posterior membranes before anterior membranes whenever possible, stripping from the posterior pole toward the periphery in order to avoid disinserting peripheral retina. After membrane stripping is performed, perfluorocarbon liquid (PFCL) can be used to flatten the retina and to help identify areas of residual traction.¹¹

Iatrogenic tears are more common when removing anterior PVR (near the vitreous base). When tears occur or when PVR is difficult to remove with peeling alone, a relaxing retinectomy may be needed. In fact, it has been observed that relaxing retinectomies may improve the chances of successful repair. A retinotomy or retinectomy may also be of value when subretinal membranes are present because they enable direct access to these membranes, which can then be removed with forceps. Many believe that in cases of severe PVR, meticulous vitreous base dissection, removal of membranes, and, when necessary, a retinectomy are critical. Quiram et al. reported functional and anatomic outcomes in patients with recurrent rhegmatogenous retinal detachments secondary to PVR.¹² In their series, patients who underwent radical anterior vitreous base dissection and lensectomy and patients who underwent inferior retinectomy had the highest success rates. Similarly, Tseng et al. evaluated the utility of relaxing retinectomies in PVR detachments. They found that retinectomies were most useful when used in conjunction with silicone oil tamponade but added little additional benefit when combined with gas tamponade.¹³

After performing a retinectomy or peeling membranes, instillation of PFCL may help identify any residual areas of traction. When areas of subretinal fluid persist under PFCL, either more membranes need to be peeled or the retinectomy needs to be enlarged.

Another surgical factor that may determine the likelihood of success is the type of tamponade. The Silicone Study compared silicone oil with either sulfur hexafluoride (SF6), or perfluoropropane (C3F8) in eyes with severe PVR.^14-16 The Silicone Study suggested that silicone oil was more effective than SF6 but approximately equivalent to C3F8 in cases of severe PVR. Conversely, Quiram et al. noted that patients who received silicone oil had better attachment rates than did patients who received gas tamponade.¹²

One major drawback of conventional tamponades, ie, SF6, C3F8, and silicone oil, is that they have limited exposure to the inferior retina over time. Because gravity causes most of the proliferative mediatiators to settle in the inferior retina, PVR is most common inferiorly (Figure 1). Ability to more effectively tamponade the inferior retina may prevent these recurrences. Recently some investigators have sought to more adequately tamponade the inferior retina using agents that are heavier than water. Berker et al. used a heavy silicone oil, Oxane HD (Bausch & Lomb, Rochester, NY), and they found that doing so increased their anatomic success with an acceptable complication profile.¹⁷ Rizzo et al. also found a heavy silicone oil, HWS 46-3000 (not yet produced commercially), to be effective and well tolerated in 32 consecutive patients with PVR, despite a 100% occurrence of posterior subcapsular cataracts.¹⁸ Other compounds such as Densiron (Medicel, Boston), a heavy silicone oil, are also currently under investigation, and retinal physicians hope they will decrease the rate of inferior redetachments.

ADJUNCTIVE TREATMENTS

With many of the surgical techniques noted above, surgical success approximates 90% in detachments complicated by PVR. Despite this high anatomic success rate, patients with PVR frequently have substantial visual loss. Because PVR most commonly occurs after primary retinal detachment repair, prevention would optimally take place during primary repair. In addition to meticulous removal of vitreous gel, pharmacologic therapies have been sought in an effort to prevent PVR.

Given the inflammatory nature of PVR, corticosteroids would seem a prime therapeutic candidate when trying to prevent PVR. In animal models of PVR, intravitreal or periocular corticosteroid injections have shown much promise. Studies in humans, however, have shown a more limited effect on PVR presentation. In addition, the benefits must be weighed against the potential side effects, including glaucoma and systemic manifestations.

Given the proliferative nature of PVR, antineoplastic drugs that target reproducing cells are another approach to limit the spread of PVR. Many agents have been studied in animal or cell culture models including 5-fluorouracil (5-FU), daunorubicin, mitomycin, vincristin, and bleomycin sulfate, among others. Among these agents, 5-FU and daunorubicin have been the most extensively evaluated with regard to PVR.

The antineoplastic 5-FU is readily available and is used in trabeculectomy surgery and for removal on conjunctival lesions. Garcia et al. evaluated combining 5-FU and lowmolecular- weight heparin with silicone oil in treating grade C PVR detachments (Figure 2).¹⁹ They concluded, however, that this combination did not improve the success in treating these complicated detachments.

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

The most extensive study of daunorubicin, an anthracycline antibiotic that acts as a topoisomerase inhibitor, was a prospective, multicenter, controlled clinical trial that evaluated eyes with equal to or worse than grade C (This is explained under the heading "Classification" above) PVR. Eyes were randomized to receive either silicone oil alone or silicone oil and a 10-minute intraoperative perfusion with daunorubicin. The rates of anatomic success were equal between the groups.

One major drawback of using antineoplastic drugs is their potential toxicity. Many antineoplastic therapies target cells that are most biologically active. If systemic absorption occurs, toxicity can result. Creten et al. showed that in 2 tested patients who received 5-FU in vitrectomy infusion, systemic absorption occurred and 5-FU levels could be found in urine up to 48 hours later.²⁰ The significance of this was unclear, but certainly it raises a cautionary flag when considering antineoplastic agents.

Other antiproliferative agents have also been analyzed, though with limited success. Schiff et al. evaluated VIT100 (Immunosol, San Diego), a ribozyme to proliferating cell nuclear antigen, in a randomized, controlled, multicenter clinical trial of 175 patients with grade C PVR. They concluded that VIT100 was not effective in preventing recurrent PVR.²¹

Other cytokines and growth factors have been implicated in the complex migration, proliferation, and contraction of PVR. Inhibitors of these agents are being studied extensively in animal models and cell cultures. Specific targets for inhibition include protein kinase C²², transforming growth factor-beta, epidermal growth factor, microtubules, and platelet-derived growth factor,²³ among others. Targeting these components either alone or in combination may prove useful in preventing PVR formation.

FUTURE DIRECTIONS

The last several years have produced some tremendous technological advances in vitreoretinal surgery. Surgical instruments have become smaller, enhancing patient postoperative comfort and enabling transconjunctival sutureless surgery. PVR continues, however, to hamper successful retinal detachment surgery. To improve our success rates after retinal detachment, we must find ways to limit the production and proliferation of PVR, either through pharmacologic means or enhanced surgical techniques. RP

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