Adjunctive Pharmacological Therapies in the Management of Proliferative Vitreoretinopathy

  • Pasha Anvari
  • Khalil Ghasemi Falavarjani


Proliferative vitreoretinopathy (PVR) is considered the major culprit of failed retinal detachment (RD) surgery, complicating 5–10% of RD repairs [1, 2]. PVR is an abnormal healing response, analogous to exaggerated scar formation [3]. It is characterized by membrane formation and contraction on both sides of the retinal surfaces or within the vitreous cavity, resulting in traction over the retina and recurrent RD.


  1. 1.
    Claes C, Lafetá AP, Williamson TH. Proliferative vitreoretinopathy. In: Developments in ophthalmology, vol. 54. Berlin: Karger Publishers; 2014. p. 188–95. Scholar
  2. 2.
    Pastor JC, Abrams G, Glazer L, et al. Proliferative vitreoretinopathy: an overview. Surv Ophthalmol. 1993;43(1):3–18. Scholar
  3. 3.
    Banerjee PJ, Charteris DG, Wong D, Iv F. Pharmacotherapy of proliferative vitreoretinopathy. In: Sebag J, editor. Vitreous. New York: Springer; 2014. p. 523–36. Scholar
  4. 4.
    Charteris DG. Proliferative vitreoretinopathy: pathobiology, surgical management, and adjunctive treatment. Br J Ophthalmol. 1995;79(10):953–60. Scholar
  5. 5.
    Patel NN, Bunce C, Asaria RH, Charteris DG. Resources involved in managing retinal detachment complicated by proliferative vitreoretinopathy. Retina. 2004;24(6):883–7.CrossRefGoogle Scholar
  6. 6.
    Williamson TH. Proliferative vitreoretinopathy. In: Vitreoretinal surgery. Berlin: Springer; 2013. p. 189–208. Scholar
  7. 7.
    Banerjee PJ, Bunce C, Charteris DG. Ozurdex(registered trademark) (a slow-release dexamethasone implant) in proliferative vitreoretinopathy: study protocol for a randomised controlled trial. Trials. 2013;14(1):1–8. Scholar
  8. 8.
    Banerjee PJ, Quartilho A, Bunce C, et al. Slow-release dexamethasone in proliferative vitreoretinopathy. Ophthalmology. 2017;124(6):757–67. Scholar
  9. 9.
    Wickham L, Bunce C, Wong D, McGurn D, Charteris DG. Randomized controlled trial of combined 5-fluorouracil and low-molecular-weight heparin in the management of unselected rhegmatogenous retinal detachments undergoing primary vitrectomy. Ophthalmology. 2007;114(4):698–704. Scholar
  10. 10.
    Barsam A, Sundaram V. Intravitreal low molecular weight heparin and 5-Fluorouracil for the prevention of proliferative vitreoretinopathy following retinal reattachment surgery. Cochrane Database Syst Rev. 2007;1:3–5. Scholar
  11. 11.
    Kumar A, Nainiwal S, Choudhary I, Tewari HK, Verma LK. Role of daunorubicin in inhibiting proliferative vitreoretinopathy after retinal detachment surgery. Clin Exp Ophthalmol. 2002;30(5):348–51. Scholar
  12. 12.
    Sadaka A, Giuliari GP, Press D. Proliferative vitreoretinopathy: current and emerging treatments. Clin Ophthalmol. 2012;6:1325–33. Scholar
  13. 13.
    Charteris DG. Prevention of proliferative vitreoretinopathy. In: Kirchhof B, Wong D, editors. Vitreo retinal surgery, Essentials in ophthalmology, vol. 1. Berlin: Springer; 2005. p. 135–45. Scholar
  14. 14.
    Khan MA, Brady CJ, Kaiser RS. Clinical management of proliferative vitreoretinopathy. Retina. 2015;35(2):165–75. Scholar
  15. 15.
    Tousi A, Hasanpour H, Soheilian M. Intravitreal injection of bevacizumab in primary vitrectomy to decrease the rate of retinal redetachment: a randomized pilot study. J Ophthalmic Vis Res. 2016;11(3):271. Scholar
  16. 16.
    Hsu J, Khan MA, Shieh WS, et al. Effect of serial intrasilicone oil bevacizumab injections in eyes with recurrent proliferative vitreoretinopathy retinal detachment. Am J Ophthalmol. 2016;161:65–70e2. Scholar
  17. 17.
    Pennock S, Kim D, Mukai S, et al. Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease. Am J Pathol. 2013;182(5):1659–70. Scholar
  18. 18.
    Pennock S, Kazlauskas A. Vascular endothelial growth factor A competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses. Mol Cell Biol. 2012;32(10):1955–66. Scholar
  19. 19.
    Cheema RA, Peyman GA, Fang T, Jones A, Lukaris AD, Lim K. Triamcinolone acetonide as an adjuvant in the surgical treatment of retinal detachment with proliferative vitreoretinopathy. Ophthalmic Surg Lasers Imaging. 2007;38(5):365–70.PubMedGoogle Scholar
  20. 20.
    Munir WM, Pulido JS, Sharma MC, Buerk BM. Intravitreal triamcinolone for treatment of complicated proliferative diabetic retinopathy and proliferative vitreoretinopathy. Can J Ophthalmol. 2005;40(5):598–604. Scholar
  21. 21.
    Rubsamen PE, Cousins SW. Therapeutic effect of periocular corticosteroids in experimental proliferative vitreoretinopathy. Retina. 1997;17(1):44–50. CrossRefGoogle Scholar
  22. 22.
    Koerner F, Merz A, Gloor B, Wagner E. Postoperative retinal fibrosis—a controlled clinical study of systemic steroid therapy. Graefes Arch Clin Exp Ophthalmol. 1982;219(6):268–71.CrossRefGoogle Scholar
  23. 23.
    Ahmadieh H, Feghhi M, Tabatabaei H, Shoeibi N, Ramezani A, Mohebbi MR. Triamcinolone acetonide in silicone-filled eyes as adjunctive treatment for proliferative vitreoretinopathy. A randomized clinical trial. Ophthalmology. 2008;115(11):1938–43. Scholar
  24. 24.
    Yamakiri K, Sakamoto T, Noda Y, et al. One-year results of a multicenter controlled clinical trial of triamcinolone in pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2008;246:959–66. Scholar
  25. 25.
    Dehghan MH, Ahmadieh H, Soheilian M, et al. Effect of oral prednisolone on visual outcomes and complications after scleral buckling. Eur J Ophthalmol. 2010;20(2):419–23.CrossRefGoogle Scholar
  26. 26.
    Koerner F, Koerner-Stiefbold U, Garweg JG. Systemic corticosteroids reduce the risk of cellophane membranes after retinal detachment surgery: a prospective randomized placebo-controlled double-blind clinical trial. Graefes Arch Clin Exp Ophthalmol. 2012;250(7):981–7. Scholar
  27. 27.
    Williams RG, Chang S, Comaratta MR, Simoni G. Does the presence of heparin and dexamethasone in the vitrectomy infusate reduce reproliferation in proliferative vitreoretinopathy? Graefes Arch Clin Exp Ophthalmol. 1996;234(8):496–503.CrossRefGoogle Scholar
  28. 28.
    Bali E, Feron EJ, Peperkamp E, Veckeneer M, Mulder PG, Van Meurs JC. The effect of a preoperative subconjunctival injection of dexamethasone on blood-retinal barrier breakdown following scleral buckling retinal detachment surgery: a prospective randomized placebo-controlled double blind clinical trial. Graefes Arch Clin Exp Ophthalmol. 2010;248(7):957–62. Scholar
  29. 29.
    Kuo HK, Chen YH, Wu PC, Kuo YH. The effects of Ozurdex® (dexamethasone intravitreal implant) on experimental proliferative vitreoretinopathy. Ophthalmologica. 2015;233:198–203. Scholar
  30. 30.
    Reibaldi M, Russo A, Longo A, et al. Rhegmatogenous retinal detachment with a high risk of proliferative vitreoretinopathy treated with episcleral surgery and an intravitreal dexamethasone 0.7-mg implant. Case Rep Ophthalmol. 2013;4(1):79–83. Scholar
  31. 31.
    Sherif M, Wolfensberger TJ. Intraocular dexamethasone implant as adjunct to silicone oil tamponade for proliferative vitreoretinopathy. Klin Monatsbl Augenheilkd. 2017. Scholar
  32. 32.
    Feller DB, Weinreb RN. Breakdown and reestablishment of blood-aqueous barrier with laser trabeculoplasty. Arch Ophthalmol. 1984;102(4):537–8. Scholar
  33. 33.
    Green E, Wilkins M, Bunce C, Wormald R. 5-Fluorouracil for glaucoma surgery. In: Wormald R, editor. Cochrane database of systematic reviews. Chichester, UK: Wiley; 2014. Scholar
  34. 34.
    Stern WH, Guerin CJ, Erickson PA, Lewis GP, Anderson DH, Fisher SK. Ocular toxicity of fluorouracil after vitrectomy. Am J Ophthalmol. 1983;96(1):43–51. Scholar
  35. 35.
    Blumenkranz MS, Ophir A, Claflin AJ, Hajek A. Fluorouracil for the treatment of massive periretinal proliferation. Am J Ophthalmol. 1982;94(4):458–67. Scholar
  36. 36.
    Kon CH, Occleston NL, Foss A, Sheridan C, Aylward GW, Khaw PT. Effects of single, short-term exposures of human retinal pigment epithelial cells to thiotepa or 5-fluorouracil: implications for the treatment of proliferative vitreoretinopathy. Br J Ophthalmol. 1998;82(5):554–60.CrossRefGoogle Scholar
  37. 37.
    Khaw PT, Sherwood MB, MacKay SL, Rossi MJ, Schultz G. Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon’s capsule fibroblasts. Arch Ophthalmol. 1992;110(8):1150–4. Scholar
  38. 38.
    Araie M, Nakano Y, Akahoshi T. Effects of subconjunctival 5-fluorouracil injections on the corneal endothelium and ciliary epithelium. Graefes Arch Clin Exp Ophthalmol. 1990;228(6):573–81.CrossRefGoogle Scholar
  39. 39.
    Levy J, Tessler Z, Rosenthal G, et al. Toxic effects of subconjunctival 5-fluorouracil and mitomycin C on ciliary body of rats. Int Ophthalmol. 2001;24(4):199–203. Scholar
  40. 40.
    Blankenship GW. Evaluation of a single intravitreal injection of 5-fluorouracil in vitrectomy cases. Graefes Arch Clin Exp Ophthalmol. 1989;227(6):565–8. CrossRefGoogle Scholar
  41. 41.
    Blumenkranz MS, Hartzer MK, Iverson D. An overview of potential applications of heparin in vitreoretinal surgery. Retina. 1992;12(3 Suppl):S71–4.CrossRefGoogle Scholar
  42. 42.
    Johnson RN, Blankenship G. A prospective, randomized, clinical trial of heparin therapy for postoperative intraocular fibrin. Ophthalmology. 1988;95(3):312–7. Scholar
  43. 43.
    Kondo H, Hayashi H, Oshima K. Fibrin prophylaxis with low molecular weight heparin during intraocular surgery. Jpn J Ophthalmic Surg. 1993;6:597.Google Scholar
  44. 44.
    Iverson DA, Katsura H, Hartzer MK, Blumenkranz MS. Inhibition of intraocular fibrin formation following infusion of low-molecular-weight heparin during vitrectomy. Arch Ophthalmol (Chicago, Ill 1960). 1991;109(3):405–9. Scholar
  45. 45.
    Yamashita Y, Mochizuki K, Sakai H, Torisaki M, Tanabe J. Retinal tolerance of intravitreal low-molecular-weight heparin, colchicine or interferon {β} determined by eye-cup ERG in albino rabbits. In: Ocular toxicology. Berlin: Springer; 1995. p. 85–91.CrossRefGoogle Scholar
  46. 46.
    Asaria RH. Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy. Ophthalmology. 2001;6420(1):1179–83.CrossRefGoogle Scholar
  47. 47.
    Shinohara K, Tanaka M, Sakuma T, Kobayashi Y. Efficacy of daunorubicin encapsulated in liposome for the treatment of proliferative vitreoretinopathy. Ophthal Surg Lasers Imaging. 2003;34(4):299–305.Google Scholar
  48. 48.
    Raczyńska K, Gebka A, Iwaszkiewicz-Bilikiewicz B, Ciechanowski C. Vitrectomy with daunorubicin. Klin Ocz. 2004;106(3 Suppl):481–4.Google Scholar
  49. 49.
    Wiedemann P, Hilgers RD, Bauer P, Heimann K. Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Am J Ophthalmol. 1998;126(4):550–9. Scholar
  50. 50.
    Moysidis SN, Thanos A, Vavvas DG. Mechanisms of inflammation in proliferative vitreoretinopathy: from bench to bedside. Mediat Inflamm. 2012. Scholar
  51. 51.
    Ghasemi Falavarjani K, Modarres M, Hadavandkhani A, Karimi Moghaddam A. Intra-silicone oil injection of methotrexate at the end of vitrectomy for advanced proliferative diabetic retinopathy. Eye. 2015;29(9):1199–203. Scholar
  52. 52.
    Hardwig PW, Pulido JS, Bakri SJ. The safety of intraocular methotrexate in silicone-filled eyes. Retina. 2008;28(8):1082–6. Scholar
  53. 53.
    Hardwig PW, Pulido JS, Erie JC, Baratz KH, Buettner H. Intraocular methotrexate in ocular diseases other than primary central nervous system lymphoma. Am J Ophthalmol. 2006;142(5):883–5.CrossRefGoogle Scholar
  54. 54.
    Sadaka A, Sisk R, Osher J, Toygar O, Duncan M, Riemann C. Intravitreal methotrexate infusion for proliferative vitreoretinopathy. Clin Ophthalmol. 2016;10(4):1811–7. Scholar
  55. 55.
    Ghasemi Falavarjani K, Modarres M, Parvaresh M, Hashemi M, Naseripour M, Hadavand Khani A. Intra-silicone oil injection of methotrexate at the end of retinal reattachment surgery for severe proliferative vitreoretinopathy. In: Euretina Oral Presentation. Blackrock, Co Dublin: EURETINA; 2014.Google Scholar
  56. 56.
    Lemor M, Yeo JH, Glaser BM. Oral colchicine for the treatment of experimental traction retinal detachment. Arch Ophthalmol. 1986;104(8):1226–9. Scholar
  57. 57.
    Berman DH, Gombos GM. Proliferative vitreoretinopathy: does oral low-dose colchicine have an inhibitory effect? A controlled study in humans. Ophthalmic Surg. 1989;20(4):268–72.PubMedGoogle Scholar
  58. 58.
    Ahmadieh H, Nourinia R, Ragati Haghi A, et al. Oral colchicine for prevention of proliferative vitreoretinopathy: a randomized clinical trial. Acta Ophthalmol. 2015;93(2):e171–2. Scholar
  59. 59.
    Araiz JJ, Refojo MF, Arroyo MH, Leong FL, Albert DM, Tolentino FI. Antiproliferative effect of retinoic acid in intravitreous silicone oil in an animal model of proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1993;34(3):522–30.PubMedGoogle Scholar
  60. 60.
    Takahashi M, Refojo MF, Nakagawa M, Veloso A, Leong FL. Antiproliferative effect of retinoic acid in 1% sodium hyaluronate in an animal model of PVR. Curr Eye Res. 1997;16(7):703–9.CrossRefGoogle Scholar
  61. 61.
    Veloso AA, Kadrmas EF, Larrosa JM, Sandberg MA, Tolentino FI, Refojo MF. 13-Cis-retinoic acid in silicone-fluorosilicone copolymer oil in a rabbit model of proliferative vitreoretinopathy. Exp Eye Res. 1997;65(3):425–34. Scholar
  62. 62.
    Fekrat S, de Juan E Jr, Campochiaro PA. The effect of oral 13-cis-retinoic acid on retinal redetachment after surgical repair in eyes with proliferative vitreoretinopathy. Ophthalmology. 1995;102(3):412–8. Scholar
  63. 63.
    Chang Y-C, Hu D-N, Wu W-C. Effect of oral 13-cis-retinoic acid treatment on postoperative clinical outcome of eyes with proliferative vitreoretinopathy. Am J Ophthalmol. 2008;146(3):440–6. Scholar
  64. 64.
    Brady CJ, Kaiser RS. PVR: an update on prevention & management. Rev Ophthalmol. 2015;22(10):64.Google Scholar
  65. 65.
    Khan A, Hsu J. Proliferative vitreoretinopathy: current evidence and clinical pearls. Retin Physician. 2016;13:22–6.Google Scholar
  66. 66.
    Su CY, Chen MT, Wu WS, Wu WC. Concentration of vascular endothelial growth factor in the subretinal fluid of retinal detachment. J Ocul Pharmacol Ther. 2000;16(5):463–9.CrossRefGoogle Scholar
  67. 67.
    Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Inverse levels of pigment epithelium-derived factor and vascular endothelial growth factor in the vitreous of eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy. Am J Ophthalmol. 2002;133(6):851–2. Scholar
  68. 68.
    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(6):505–9. Scholar
  69. 69.
    Ricker LJAG, Dieudonné SC, Kessels AGH, et al. Antiangiogenic isoforms of vascular endothelial growth factor predominate in subretinal fluid of patients with rhegmatogenous retinal detachment and proliferative vitreoretinopathy. Retina. 2012;32(1):54–9. Scholar
  70. 70.
    Citirik M, Kabatas EU, Batman C, Akin KO, Kabatas N. Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy. Ophthalmic Res. 2012;47(1):7–12. Scholar
  71. 71.
    Falavarjani KG, Hashemi M, Modarres M, Khani AH. Intrasilicone oil injection of bevacizumab at the end of retinal reattachment surgery for severe proliferative vitreoretinopathy. Eye. 2014;28(5):576–80. Scholar
  72. 72.
    Zhao X, Xia S, Wang E, Chen Y. Efficacy of intravitreal injection of bevacizumab in vitrectomy for patients with proliferative vitreoretinopathy retinal detachment: a meta-analysis of prospective studies. Retina. 2017;1. Scholar
  73. 73.
    Pastor JC, Rojas J, Pastor-Idoate S, Di Lauro S, Gonzalez-Buendia L, Delgado-Tirado S. Proliferative vitreoretinopathy: a new concept of disease pathogenesis and practical consequences. Prog Retin Eye Res. 2016;51:125–55. Scholar
  74. 74.
    Chiba C. The retinal pigment epithelium: an important player of retinal disorders and regeneration. Exp Eye Res. 2014;123:107–14. Scholar
  75. 75.
    Kon CH, Occleston NL, Charteris D, Daniels J, Aylward GW, Khaw PT. A prospective study of matrix metalloproteinases in proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1998;39(8):1524–9.PubMedGoogle Scholar
  76. 76.
    Ozerdem U, Mach-Hofacre B, Keefe K, et al. The effect of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinases, on posttraumatic proliferative vitreoretinopathy. Ophthalmic Res. 2000;33(1):20–3.CrossRefGoogle Scholar
  77. 77.
    Ozerdem U, Mach-Hofacre B, Cheng L, et al. The effect of prinomastat (AG3340), a potent inhibitor of matrix metalloproteinases, on a subacute model of proliferative vitreoretinopathy. Curr Eye Res. 2000;20(6):447–53. Scholar
  78. 78.
    Lei H, Velez G, Cui J, et al. N-Acetylcysteine suppresses retinal detachment in an experimental model of proliferative vitreoretinopathy. Am J Pathol. 2010;177(1):132–40. Scholar
  79. 79.
    Priglinger CS, Obermann J, Szober CM, et al. Epithelial-to-mesenchymal transition of RPE cells in vitro confers increased β1,6-N-glycosylation and increased susceptibility to galectin-3 binding. PLoS One. 2016;11(1):1–25. Scholar
  80. 80.
    Ishikawa K, He S, Terasaki H, et al. Resveratrol inhibits epithelial-mesenchymal transition of retinal pigment epithelium and development of proliferative vitreoretinopathy. Sci Rep. 2015;5:16386. Scholar
  81. 81.
    Li M, Li H, Liu X, Xu D, Wang F. MicroRNA-29b regulates TGF-β1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells by targeting AKT2. Exp Cell Res. 2016;345(2):115–24. Scholar
  82. 82.
    Nagasaka Y, Kaneko H, Ye F, et al. Role of caveolin-1 for blocking the epithelial-mesenchymal transition in proliferative vitreoretinopathy. Investig Opthalmol Vis Sci. 2017;58(1):221. Scholar
  83. 83.
    Tamiya S, Kaplan HJ. Role of epithelial-mesenchymal transition in proliferative vitreoretinopathy. Exp Eye Res. 2016;142:26–31. Scholar
  84. 84.
    Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem. 1997;30(2):91–113. Scholar
  85. 85.
    Frémont L. Biological effects of resveratrol. Life Sci. 2000;66(8):663–73. Scholar
  86. 86.
    Chen C-L, Chen Y-H, Tai M-C, Liang C-M, Lu D-W, Chen J-T. Resveratrol inhibits transforming growth factor-β2-induced epithelial-to-mesenchymal transition in human retinal pigment epithelial cells by suppressing the Smad pathway. Drug Des Devel Ther. 2017;11:163–73. Scholar
  87. 87.
    Khanum BNMK, Guha R, Sur VP, et al. Pirfenidone inhibits post-traumatic proliferative vitreoretinopathy. Eye. 2017. Scholar
  88. 88.
    Szczesniak A-M, Porter RF, Toguri JT, et al. Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy. Neuropharmacology. 2017;113(Pt B):627–38. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Pasha Anvari
    • 1
  • Khalil Ghasemi Falavarjani
    • 1
  1. 1.Eye Department, Eye Research Center, Rassoul Akram HospitalIran University of Medical SciencesTehranIran

Personalised recommendations