Can PVR be Prevented?

A surgeon suggests three levels of prophylaxis.

Marc J. Spirn, MD

Proliferative vitreoretinopathy (PVR) is the major obstacle to successful retinal detachment repair, accounting for 75% of surgical failures. Since the inception of pars plana vitrectomy (PPV), several advances have resulted in improved PVR surgical outcomes. These advances include the use of relaxing retinectomies, perfluorocarbon liquids, illuminated endolasers and silicone oils. Over the last several years, there have been several major shifts in how vitreoretinal surgery is performed, including the surge in microincisional vitrectomy systems, improved illumination, wide-field, noncontact viewing systems and enhanced instrumentation, among others. Despite major advances in vitreoretinal surgical techniques, PVR rates are still high, causing 5% to 10% of all retinal detachment repairs to fail. If PVR continues to limit our surgical success nearly 40 years after Machemer introduced pars plana vitrectomy, can we ever hope to entirely prevent PVR?

PRIMARY PREVENTION

Primary prevention means preventing a disease before it ever occurs. With any medical problem, primary prevention is ideal because it avoids morbidity; therefore, it should be the objective with PVR. In order to prevent PVR primarily, all patients with new-onset posterior vitreous detachments (PVDs), trauma, lattice degeneration or tears would need to be examined and all high-risk pathology would need to be treated. Unfortunately, many patients seek treatment only after their symptoms have escalated to the point of retinal detachment. In some cases, the detachments are chronic and PVR has already set in (see Figure 1). Obviously, in these cases, pretreating high-risk pathology is logistically impossible, but it highlights the fact that, whenever possible, high-risk pathology should be treated.

Figure 1. Chronic retinal detachments can cause proliferative vitreoretinopathy to set in.

SECONDARY PREVENTION

Secondary prevention involves the prevention of the recurrence or exacerbation of a disease that has already occurred. In many of our patients, when primary prevention has failed and the PVD has progressed from a retinal tear to a retinal detachment, secondary prevention is paramount. Oftentimes, patients present with a macula-sparing retinal detachment, and if recurrence can be prevented, long-term vision can be preserved. Because the vast majority of surgical failures are the result of PVR, secondary prevention is dependent upon preventing PVR.

It is known from histological studies that PVR is composed primarily of RPE cells, fibroblasts, glial cells, inflammatory cells and type 4 collagen.¹ Any intervention that secondarily prevents PVR needs to prevent the signaling and congregation of these elements. In January 2008 and October 2009, I wrote in Retinal Physician about the pathogenesis and management of PVR. In the latter article, I wrote about some of the important factors in the signaling and proliferation of PVR including platelet-derived growth factor, tumor necrosis factor, transforming growth factor and calcium-independent phospholipase A2. Although these components likely play major roles in the signaling and development of PVR, there are probably other players in this process.

Over the last year and a half, several other factors have been further elucidated. Rasier et al. evaluated 22 vitreous samples after pars plana vitrectomy for retinal detachment and compared them to 12 eyes that underwent PPV for macular hole or epiretinal membrane repair. They observed that patients in the retinal detachment group had higher levels of interleukin 8 and vascular endothelial growth factor.² Similarly, Symeonidis et al. found increased levels of IL 6, matrix metalloproteinase (MMP)-1, MMP-3 and tissue inhibitor of MMP-1 in the vitreous of patients with RRD complicated by PVR.³

PHARMACOTHERAPY

While it is important to elucidate the many factors that cause PVR, the real value in understanding the underlying etiology is that it enables us to target therapies to inhibit PVR. Pharmacotherapeutic agents that can prevent PVR are the holy grail of PVR management. In previous editions of Retinal Physician, I have written about some of the merits of oral Accutane and intravitreal triamcinolone acetonide, therapies that may hold promise but are still unproven.

Recent publications have shed some light on other potential therapeutic agents and targets. As mentioned above, Rasier et al. noted increased levels of VEGF in eyes with retinal detachments compared to macular holes and pucker, suggesting that VEGF may have a role in the development of PVR. This conclusion raises the question of whether anti-VEGF therapy, for example with ranibizumab, bevacizumab or pegaptanib sodium, could inhibit PVR development.

Other pharmacologic agents that have been recently suggested for possible preventive effect include N-acetyl-cysteine (NAC) and glucosamine. NAC is a pharmacologic agent known for its potent antioxidant properties. It is most often prescribed to combat acetaminophen overdose or as a mucolytic. Because reactive oxygen species likely play a role in the development of PVR and because NAC has strong antioxidant properties, Lei et al. examined whether NAC could prevent PVR.⁴ In an experimental model in rabbits, an intravitreal injection of NAC protected against the development of PVR.⁴

If inhibiting reactive oxygen species is, in fact, critical in preventing PVR, then there may be many other candidate therapies. As retinal specialists, we are familiar with other antioxidants that are commercially available, especially for patients with dry age-related macular degeneration. These antioxidants include beta carotene, vitamin C, vitamin E, lutein, zeaxanthin and omega-3 fatty acids. While these supplements have been studied extensively for AMD patients, the work by Lei and colleagues raises the question of whether some of these commercially available antioxidants may be worthwhile in patients at risk for PVR.

Glucosamine is a naturally occurring monosaccharide that is a popular dietary supplement. Currently, it is marketed largely as a treatment for osteoarthritis. One manner in which glucosamine is thought to work is by inhibiting transforming growth factor beta (TGF-B), which is thought to be another important factor in PVR development. Liang et al. studied the effects of glucosamine on TGF-B signaling and found that glucosamine inhibited the effects of TGF-B.⁵ In this manner, in a mouse model, glucosamine was able to reduce the morphologic appearance of PVR.

While glucosamine and NAC are both already commercially available and may hold promise, other noncommercially available therapies are also being studied. These substances include genistin, geldanamycin and fasudil.

Genistin is an isoflavone found in dietary plants, such as soy and kudzu. Genistin was recently studied in a rabbit PVR model. In that model, You and Jiang found that eyes that underwent an intravitreal injection of genistin developed significantly lower levels of PVR than controls.⁶ Geldanamycin, is a benzoquinone ansamycin that was originally isolated as a natural product with antifungal activity. Wu et al. showed that geldanamycin and its analog 17-allylamino-demethoxy geldanamycin inhibit proliferation of cultured human RPE cells, suggesting it may be another potential therapy in PVR.⁷ Similarly, Kita observed that fasudil, a potent and selective rho-kinase inhibitor, could block collagen-gel contraction in vitreous samples obtained from PDR and PVR patients.⁸

SURGERY AND SECONDARY PREVENTION

While these factors are certainly relevant to the production of PVR, no pharmacologic intervention has yet truly prevented PVR. Therefore, optimizing surgical techniques and paying meticulous attention to detail are still the best current defenses against PVR. For example, we know that PVR is more likely in certain situations that increase permeability of the blood-retina barrier. Minimizing circumstances that increase vascular permeability may therefore limit PVR. For example, laser therapy causes less inflammation than cryotherapy. Whenever possible, therefore, laser therapy should be used. When cryotherapy is necessary, it should be used judiciously to limit the likelihood of breakdown of the blood-ocular barrier. Similarly, avoiding hypotony and associated choroidal hemorrhaging can also reduce breakdown of the blood-ocular barrier. Additionally, if a retinectomy is necessary, meticulous hemostasis should be achieved to avoid excessive pooling of blood from incised vessels.

Another surgical technique that may limit PVR formation involves removing residual cortical gel from the surface of the retina. When cortical gel remains on the surface of the retina even after a PVD has been induced, care should be taken to remove the excess gel to prevent it from acting as a scaffold for PVR. This cortical gel is best visualized with triamcinolone. Once visualized, it can then be removed using a Tano diamond-dusted scraper or ILM forceps. Aside from helping to visualize membrane removal, triamcinolone also has the added advantage of being anti-inflammatory. It has been well documented that inflammatory mediators, such as interleukins, play a critical role in PVR development. Blocking these mediators, therefore, may help to mitigate PVR.

Some recent studies have reconfirmed the multiple potential roles for corticosteroids. Acar et al. showed that triamcinolone-assisted visualization resulted in fewer redetachments than PPV without triamcinolone.⁹ Chen et al. observed that an intravitreal triamcinolone injection at the end of surgery, along with silicone oil for grade C and D detachments, resulted in a 97.3% reattached rate.¹⁰ Bali et al. observed that preoperative administration of subconjunctival dexamethasone in patients undergoing primary scleral buckle for retinal detachment resulted in a statistically significant decrease in postoperative flare one week after surgery.¹¹

TERTIARY PREVENTION

Tertiary prevention is the reduction in disability caused by a disease that has already occurred, thereby maximizing a patient's function. Oftentimes when PVR occurs, visual outcomes are poor. Visual loss can occur because of recurrent macular redetachments, as well as from complications from silicone oil, such as optic neuropathy or corneal edema.

Because gravity causes PVR mediators to settle inferiorly, the majority of PVR redetachments tend to occur inferiorly. Over the last several years, efforts have been made to improve inferior tamponade using heavy silicone oils, such as oxane D or Densiron 68. Several recent publications have expanded on the use of these heavy oils. Li et al. evaluated Densiron 68 in 20 patients with PVR. After one surgery, the success rate was 85.7%.¹²

Similarly, using Densiron, Ozdek et al. had an anatomical success rate of approximately 87.8% in patients with retinal detachment and inferior PVR.¹³ In their study, however, several oil-related complications were noted, including increased intraocular pressure, hypotony, cataract, corneal edema, band keratopathy and significant inflammation. These complications confirm findings from many earlier studies that suggested that, although heavy silicone oils may be effective inferior tamponades, their value is tempered by the risk of complications.

CONCLUSION

Although the treatment of PVR has evolved since vitrectomy surgery was first introduced, the majority of redetachments still occur as a result of PVR. Over the years, we have made many advances in PVR management, including improved visualization techniques with triamcinolone, the use of relaxing retinectomies and improved tamponades with conventional and heavy silicone oils. In addition to our improved surgical techniques, our knowledge of the factors that promote PVR continues to increase. Elucidating these factors will ultimately enable us to develop pharmacotherapies to prevent PVR. Recent studies suggest there may be a role for antioxidants such as NAC or transforming growth factor inhibitors such as glucosamine. However, despite the bright future pharmacotherapies hold for the prevention of PVR, present-day management of PVR is still primarily surgical in nature. RP

REFERENCES

1. Schwartz D, de la Cruz ZC, Green WR, Michels RG. Proliferative vitreoretinopathy. Ultrastructural study of 20 retroretinal membranes removed by vitreous surgery. Retina. 1988;8:275-281.
2. Rasier R, Gormus U, Artunay O, Yuzbasioglu E, Oncel M, Bahcecioglu H. Vitreous levels of VEGF, IL-8, and TNF-alpha in retinal detachment. Curr Eye Res. 2010;35:505-509.
3. Symeonidis C, Papakonstaintinou E, Androudi S, et al. Interleukin-6 and the matrix metalloproteinase response in the vitreous during proliferative vitreo-retinopathy. Cytokine. 2011;54:212-217.
4. Lei H, Velez G, Cui J, Samad A, Maberley D, Matsubara J, Kazlauskas A. Nacetylcysteine suppresses retinal detachment in an experimental model of proliferative vitreoretinopathy. Am J Pathol. 2010;177:132-140.
5. Liang CM, Tai MC, Chang YH, et al. Glucosamine inhibits epithelial-to-mesenchymal transition and migration of retinal pigment epithelium cells in culture and morphologic changes in a mouse model of proliferative vitreoretinopathy. Acta Ophthalmol. 2011 April 1. [Epub ahead of print]
6. You J, Jiang D. Effect of genistin on proliferative vitreoretinopathy. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010;35:749-753.
7. Wu WC, Wu MH, Chang YC, et al. Geldanamycin and its analog induce cytotoxicity in cultured human retinal pigment epithelial cells. Exp Eye Res. 2010;91:211-219.
8. Kita T. Molecular mechanisms of preretinal membrane contraction in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Nippon Ganka Gakkai Zasshi. 2010;114:927-934.
9. Acar N, Kapran Z, Altan T, Unver YB, Pasaoglu E. Pars plana vitrectomy with and without triamcinolone acetonide assistance in pseudophakic retinal detachment complicated with proliferative vitreoretinopathy. Jpn J Ophthalmol. 2010;54:331-337.
10. Chen W, Chen H, Hou P, Fok A, Hu Y, Lam DS. Midterm results of low-dose intravitreal triamcinolone as adjunctive treatment for proliferative vitreoretinopathy. Retina. 2011 Feb 11. [Epub ahead of print]
11. Bali E, Feron EJ, Peperkamp E, Veckeneer M, Mulder PG, van Meurs JC. The effect of a preoperative subconjuntival injection of dexamethasone on bloodretinal barrier breakdown following scleral buckling retinal detachment surgery: a prospective randomized placebo-controlled double blind clinical trial. Graefes Arch Clin Exp Ophthalmol. 2010;248:957-962.
12. Li W, Zheng Q, Wang X, Xu M, Wu R. Clinical results of Densiron 68 intraocular tamponade for complicated retinal detachment. Ophthalmologica. 2010;224:354-360.
13. Ozdek S, Yuksel N, Gurelik G, Hasanreisoglu B. High-density silicone oil as an intraocular tamponade in complex retinal detachments. Can J Ophthalmol. 2011;46:51-55.