3.5New Frontiers

Many ocular agents are under investigation for the treatment of DME. Bevasiranib (Cand5) is a synthetic small-interfering RNA (siRNA) engineered

against the RNA targeting to VEGF expression. Primary unpublished data showed some benefits in the management of wet age-related macular degeneration and DME [145], even if data from randomized double-masked study are still lacking [146].

Another siRNA molecule (PF-04523655), targeting the RTP801 gene, has been evaluated as a therapeutic option in DME compared to focal/grid laser photocoagulation in a multicenter, prospective, masked, randomized clinical trial (DEGAS study) [147]. In the three arms, evaluating different doses of PF-04523655, an improvement of BCVA was reported in a 12-month follow-up. The study drug was generally well tolerated. A further study evaluating the effectiveness of PF-04523655 alone and in combination with IVR versus IVR alone is currently ongoing (MATISSE Study) [148].

Rapamycin, also known as sirolimus, is an antifungal agent with immunosuppressive properties, which inactivates multiple steps in the angiogenic cascade and consequently blocks the VEGF production. Multiple preclinical researches have been conducted to test the more effective and safe route of sirolimus administration, including the intravitreal and subconjunctival ways. In a phase I clinical trial, the subconjunctival route of administration revealed to be safe and well tolerated in human participants with DME. In a later phase I/II prospective, open-label pilot study, five patients with center-involved DME underwent 440 μg of subconjunctival sirolimus every 2 months, unless there was resolution of retinal thickening evaluated either on OCT or on FA [149]. Thus, the results showed no consistent treatment effect due to sirolimus. In the following randomized, phase I study, 50 patients with DME received a single administration of intravitreal or subconjunctival injection of sirolimus at different doses, revealing some positive benefits and a good safety profile [150]. Thus, a phase II study is required.

Intravitreal tumor necrosis factor (TNF) inhibitors are currently under investigation for the treatment of DME [151, 152]. In a recent interventional, retrospective, multicenter study, a study population of 39 eyes has been injected with adalimumab or infliximab at different doses. The results showed no apparent benefits at 3 months. In the 1 mg infliximab group, a BCVA improvement from 1.49 to 1.38 logMAR was seen, while in the 2 mg group, BCVA worsened from 0.76 to 1.03 logMAR. In the adalimumab group, BCVA improved from 1.44 to 1.08. A decrease in CRT from 459 μm at baseline to 388 μm was noted in the 1-mg infliximab group, while CRT remained unchanged in the 2 mg infliximab and in the adalimumab groups. Nevertheless, in the infliximab group, 42 % of eyes developed severe uveitis, and three of these eyes required pars plana vitrectomy.

Etanercept (Enbrel, Amgen, Inc. Thousand Oaks, CA, USA and Wyeth, Madison, NJ, USA) is another intravitreal TNF inhibitor, which is currently approved by the

References

1.Green WR (1996) Retina. In: Spencer W (ed) Ophthalmic pathology. W.B. Saunders, Philadelphia

2. Ophir A, Martinez MR, Mosqueda P et al (2010) Vitreous traction and epiretinal membranes in diabetic macular oedema using spectral-domain optical coherence tomography. Eye 24:1545–1553

3. Apple DJ, Rabb M (1998) Fundus. In: Ocular pathology: clinical applications and self assessment. St. Louis, Mosby

4. Early Treatment Diabetic Retinopathy Study Research Group (1985) Photocoagulation for diabetic macular edema, ETDRS report no 1. Arch Ophthalmol 103:1796–1806

5. Wilkinson CP, Ferris FL III, Klein RE et al (2003) Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110: 1677–1682

6. Bandello F, Battaglia Parodi M, Tremolada G et al (2010) Steroids as part of combination treatment: the future for the management of macular edema? Ophthalmologica 224:41–45

7. Do Carmo A, Ramos P, Reis A et al (1998) Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. Exp Eye Res 67:569–575

8. Nishikiori N, Osanai M, Chiba H et al (2007) Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy. Diabetes 56:1333–1340

9. Cohen AI (1965) A possible cytological basis for the “R” membrane in the vertebrate eye. Nature 205:1222–1223

10. Early Treatment Diabetic Retinopathy Study Research Group (1987) Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 94:761–764

11. Aroca PR, Salvat M, Fernandez J, Mendez I (2004) Risk factors for diffuse and focal macular edema. J Diabetes Complications 18:211–215

12. Weinberger D, Fink-Cohen S, Gaton DD et al (1995) Non-retinovascular leakage in diabetic maculopathy. Br J Ophthalmol 79:728–731

13. Wessel MM, Nair N, Aaker GD (2012) Peripheral retinal ischaemia, as evaluated by ultrawidefield fluorescein angiography, is associated with diabetic macular oedema. Br J Ophthalmol 96:694–698

14. Horii T, Murakami T, Nishijima K et al (2012) Relationship between fluorescein pooling and optical coherence tomographic reflectivity of cystoid spaces in diabetic macular edema. Ophthalmology 119:1047–1055

15. Byeon SH, Chu YK, Hong YT et al (2012) New insights into the pathoanatomy of diabetic macular edema: angiographic patterns and optical coherence tomography. Retina 32: 1087–1099

16. Deák GG, Bolz M, Ritter M et al (2010) Diabetic Retinopathy Research Group Vienna. A systematic correlation between morphology and functional alterations in diabetic macular edema. Invest Ophthalmol Vis Sci 51:6710–6714

17. Framme C, Schweizer P, Imesch M et al (2012) Behavior of SD-OCT-detected hyperreflective foci in the retina of anti-VEGF treated patients with diabetic macular edema. Invest Ophthalmol Vis Sci 53:5814–5818

18. Uji A, Murakami T, Nishijima K et al (2012) Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol 153:710–717, 717.e1

19. Comyn O, Heng LZ, Ikeji F et al (2012) Repeatability of Spectralis OCT measurements of macular thickness and volume in diabetic macular edema. Invest Ophthalmol Vis Sci 53:7754–7759

20. Chan A, Duker JS (2005) A standardized method for reporting changes in macular thickening using optical coherence tomography. Arch Ophthalmol 123:939–943

21. Diabetic Retinopathy Clinical Research Network, Bressler NM, Miller KM, Beck RW et al (2012) Observational study of subclinical diabetic macular edema. Eye 26:833–840

22. Tremolada G, Pierro L, de Benedetto U et al (2011) Macular micropseudocysts in early stages of diabetic retinopathy. Retina 31:1352–1358

23. Murakami T, Nishijima K, Akagi T et al (2012) Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci 53:1506–1511

24. Lee DH, Kim JT, Jung DW et al (2013) The relationship between foveal ischemia and spec- tral-domain Optical Coherence Tomography Findings in ischemic diabetic macular edema. Invest Ophthalmol Vis Sci 54:1080–1085

25. Querques G, Lattanzio R, Querques L et al (2012) Enhanced depth imaging optical coherence tomography in type 2 diabetes. Invest Ophthalmol Vis Sci 53:6017–6024

26. Esmaeelpour M, Povazay B, Hermann B et al (2011) Mapping choroidal and retinal thickness variation in type 2 diabetes using three-dimensional 1060-nm optical coherence tomography. Invest Ophthalmol Vis Sci 52:5311–5316

27. Vujosevic S, Martini F, Cavarzeran F et al (2012) Macular and peripapillary choroidal thickness in diabetic patients. Retina 32:1781–1790

28. Wanek J, Zelkha R, Lim JI, Shahidi M (2012) Feasibility of a method for en face imaging of photoreceptor cell integrity. Am J Ophthalmol 152:807–14.e1

29. Somfai GM, Tátrai E, Ferencz M et al (2010) Retinal layer thickness changes in eyes with preserved visual acuity and diffuse diabetic macular edema on optical coherence tomography. Ophthalmic Surg Lasers Imaging 41:593–597

30. Hatef E, Colantuoni E, Wang J et al (2011) The relationship between macular sensitivity and retinal thickness in eyes with diabetic macular edema. Am J Ophthalmol 152:400–405.e2

31. Grenga P, Lupo S, Domanico D, Vingolo EM (2008) Efficacy of intravitreal triamcinolone acetonide in long standing diabetic macular edema: a microperimetry and optical coherence tomography study. Retina 28:1270–1275

32. Nakamura Y, Mitamura Y, Ogata K et al (2010) Functional and morphological changes of macula after subthreshold micropulse diode laser photocoagulation for diabetic macular oedema. Eye (Lond) 24:784–788

33. Vujosevic S, Bottega E, Casciano M (2010) Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina 30:908–916

34. Vujosevic S, Casciano M, Pilotto E et al (2011) Diabetic macular edema: fundus autofluorescence and functional correlations. Invest Ophthalmol Vis Sci 52:442–448

35. Lövestam-Adrian M, Holm K (2010) Multifocal electroretinography amplitudes increase after photocoagulation in areas with increased retinal thickness and hard exudates. Acta Ophthalmol 88:188–192

36. Terasaki H, Kojima T, Niwa H et al (2003) Changes in focal macular electroretinograms and foveal thickness after vitrectomy for diabetic macular edema. Invest Ophthalmol Vis Sci 44:4465–4472

37. Greenstein VC, Chen H, Hood DC et al (2000) Retinal function in diabetic macular edema after focal laser photocoagulation. Invest Ophthalmol Vis Sci 41:3655–3664

38. Waldstein SM, Hickey D, Mahmud I et al (2012) Two-wavelength fundus autofluorescence and macular pigment optical density imaging in diabetic macular oedema. Eye 26:1078–1085

39. Chung H, Park B, Shin HJ et al (2012) Correlation of fundus autofluorescence with spectraldomain optical coherence tomography and vision in diabetic macular edema. Ophthalmology 119:1056–1065

40. Vujosevic S, Trento B, Bottega E (2012) Scanning laser ophthalmoscopy in the retromode in diabetic macular edema. Acta Ophthalmol 90:e374–e380

41. Han DP, Croskrey JA, Dubis AM et al (2012) Adaptive optics and spectral-domain optical coherence tomography of human photoreceptor structure after short-duration [corrected] pascal macular grid and panretinal laser photocoagulation. Arch Ophthalmol 130:518–521

42. Early Treatment Diabetic Retinopathy Study Research Group (1987) Techniques for scatter and local photocoagulation treatment of diabetic retinopathy. ETDRS report number 3. Int Ophthalmol Clin 27:254–264

43. Early Treatment Diabetic Retinopathy Study Research Group (1987) Photocoagulation for diabetic macular edema. ETDRS report number 4. Int Ophthalmol Clin 27:265–272

44. Ferris F III, Davis MD (1999) Treating 20/20 eyes with diabetic macular edema. Arch Ophthalmol 117:675–676

45. Early Treatment Diabetic Retinopathy Study (Research) Group (1985) Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol 113:1144–1155

46. Wilson DJ, Finkelstein D, Quigley HA, Green WR (1988) Macular grid photocoagulation. An experimental study on the primate retina. Arch Ophthalmol 106:100–105

47. Arnarsson A, Stefansson E (2000) Laser treatment and the mechanism of edema reduction in branch retinal vein occlusion. Invest Ophthalmol Vis Sci 41:877–879

48. Ogata N, Tombran-Tink J, Jo N et al (2001) Upregulation of pigment epithelium-derived factor after laser photocoagulation. Am J Ophthalmol 132:427–429

49. Diabetic Retinopathy Clinical Research Network (2007) Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 125:469–480

50. Bandello F, Polito A, Del Borrello M et al (2005) ‘Light’ versus ‘classic’ laser treatment for clinically significant diabetic macular oedema. Br J Ophthalmol 89:864–870

51.Desmettre TJ, Mordon SR, Buzawa DM et al (2006) Micropulse and continuous wave diode retinal photocoagulation: visible and subvisible lesion parameters. Br J Ophthalmol 90:709–712

52. Kumar V, Ghosh B, Mehta DK et al (2010) Functional outcome of subthreshold versus threshold diode laser photocoagulation in diabetic macular oedema. Eye 24:1459–1465

53. Figueira J, Khan J, Nunes S et al (2008) Prospective randomized controlled trial comparing subthreshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol 93:1341–1344

54. Blumenkranz MS, Yellachich D, Andersen DE et al (2006) Semiautomated patterned scanning laser for retinal photocoagulation. Retina 26:370–376

55. Paulus YM, Jain A, Gariano RF et al (2008) Healing of retinal photocoagulation lesions. Invest Ophthalmol Vis Sci 49:5540–5545

56. Sheth S, Lanzetta P, Veritti D et al (2011) Experience with the Pascal® photocoagulator: an analysis of over 1,200 laser procedures with regard to parameter refinement. Indian J Ophthalmol 59:87–91

57. Jain A, Collen J, Kaines A et al (2010) Short-duration focal pattern grid macular photocoagulation for diabetic macular edema: four-month outcomes. Retina 30:1622–1626

58. Inagaki K, Ohkoshi K, Ohde S (2012) Spectral-domain optical coherence tomography imaging of retinal changes after conventional multicolor laser, subthreshold micropulse diode laser, or pattern scanning laser therapy in Japanese with macular edema. Retina 32:1592–1600

59. Kozak I, Oster SF, Cortes MA et al (2011) Clinical evaluation and treatment accuracy in diabetic macular edema using navigated laser photocoagulator NAVILAS. Ophthalmology 118:1119–1124

60. Kernt M, Cheuteu RE, Cserhati S et al (2012) Pain and accuracy of focal laser treatment for diabetic macular edema using a retinal navigated laser (Navilas). Clin Ophthalmol 6:289–296 61. Ober MD, Kernt M, Cortes MA, Kozak I (2013) Time required for navigated macular laser photocoagulation treatment with the Navilas®. Graefes Arch Clin Exp Ophthalmol

251:1049–1053

62. Bamforth SD, Lightman S, Greenwood J (1996) The effect of TNFalpha and IL-6 on the permeability of the rat blood-retinal barrier in vivo. Acta Neuropathol 91:624–632

63. Funatsu H, Yamashita H, Noma H et al (2002) Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol 133:70–77

64. Yilmaz T, Weaver CD, Gallagher MJ et al (2009) Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: a systematic review. Ophthalmology 116:902–911

65. Audren F, Erginay A, Haouchine B et al (2006) Intravitreal triamcinolone acetonide for diffuse diabetic macular oedema: 6-month results of a prospective controlled trial. Acta Ophthalmol Scand 84:624–630

66. Massin P, Audren F, Haouchine B et al (2004) Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 111:218–224

67. Avitabile T, Longo A, Reibaldi A (2005) Intravitreal triamcinolone compared with macular laser grid photocoagulation for the treatment of cystoid macular edema. Am J Ophthalmol 140:695–702

68. Jonas JB, Kampperter BA, Harder B et al (2006) Intravitreal triamcinolone acetonide for diabetic macular edema: a prospective, randomized study. J Ocul Pharmacol Ther 22:200–207

69. Gillies MC, Sutter FK, Simpson JM et al (2006) Intravitreal triamcinolone for refractory diabetic macular edema two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 113:1533–1538

70. Sutter FK, Simpson JM, Gillies MC (2004) Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment: three-month efficacy and safety results of a prospective, randomized, double-masked, placebo controlled clinical trial. Ophthalmology 111: 2044–2049

71. Gillies MC, Simpson JM, Gaston C et al (2009) Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology 116:2182–2187

72. Diabetic Retinopathy Clinical Research Network (2008) A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 115:1447–1449

73. Diabetic Retinopathy Clinical Research Network (2009) Three-year follow-up of a randomized clinical trial comparing focal/grid laser photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 127:245–251

74. Bressler NM, Edwards AR, Beck RW et al (2009) Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol 127:1566–1571

75. Campochiaro PA, Brown DM, Pearson A et al (2012) Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 119:2125–2132

76. Diabetic Retinopathy Clinical Research Network (2010) Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 117:1064–1077

77. Diabetic Retinopathy Clinical Research Network (2011) Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 118:609–614

78. Haller JA, Dugel P, Weinberg DV et al (2009) Evaluation of safety and performance of an applicator for a novel intravitreal dexamethasone drug delivery system for the treatment of macular edema. Retina 29:46–51

79. Kuppermann BD, Blumenkranz MS, Haller JA et al (2007) Dexamethasone DDS Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 125:309–317

80. Haller JA, Kuppermann BD, Blumenkranz MS et al (2010) Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 128:289–296

81. Boyer DS, Faber D, Gupta S et al (2011) Ozurdex Champlain Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 31:915–923

82. Zucchiatti I, Lattanzio R, Querques G et al (2012) Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica 228:117–122

83. A study of the safety and efficacy of a new treatment for diabetic macular edema [ClinicalTrials.gov identifier NCT00168337]. US National Institutes of Health, ClinicalTrials. gov [online]. Available from URL: http://www.clinicaltrials.gov

84.Jaffe GJ, Martin D, Callanan D et al (2006) Fluocinolone Acetonide Uveitis Study Group. Fluocinolone acetonide implant (Retisert) for non infectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 113:1020–1027

85. Pearson PA, Comstock TL, Ip M et al (2011) Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 118:1580–1587

86. Campochiaro PA, Hafiz G, Shah SM et al (2010) Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology 117:1393–1399

87. Campochiaro PA, Brown DM, Pearson A et al (2011) Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology 118:626–635

88. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

89. Nguyen QD, Tatlipinar S, Shah SM et al (2006) Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 142:961–969

90. Massin P, Bandello F, Garweg JG et al (2010) Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 33:2399–2405

91.Nguyen QD, Brown DM, Marcus DM et al (2012) Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 119:789–801

92. Do DV, Nguyen QD, Khwaja AA et al (2012) Ranibizumab for Edema of the Macula in Diabetes Study: 3-year outcomes and the need for prolonged frequent treatment. Arch Ophthalmol 8:1–7

93. Mitchell P, Bandello F, Schmidt-Erfurth U et al (2011) The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 118:615–625

94. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP et al (2012) Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology 119:2312–2318

95. Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, Beck RW et al (2007) A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 114:1860–1867

96. Rajendram R, Fraser-Bell S, Kaines A et al (2012) A 2-year prospective randomized controlled trial of Intravitreal Bevacizumab or Laser Therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol 130:972–979

97. Soheilian M, Ramezani A, Obudi A et al (2009) Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 116:1142–1150

98. Cunningham ET Jr, Adamis AP, Altaweel M et al (2005) Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 112:1747–1757

99. Sultan MB, Zhou D, Loftus J et al (2011) Macugen 1013 Study Group. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 118:1107–1118

100.Do DV, Nguyen QD, Boyer D et al (2012) One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 119:1658–1665

101.Nguyen QD, Shah SM, Heier JS et al (2009) Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) study. Ophthalmology 116:2175–81.e1

102.Nguyen QD, Shah SM, Khwaja AA et al (2010) Two-year outcomes of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) Study. Ophthalmology 117:2146–2151

103.A 12 month core study to assess the efficacy and safety of ranibizumab (intravitreal injections) in patients with visual impairment due to diabetic macular edema and a 24 month open-label extension study (RESTORE) [ClinicalTrials.gov identifier NCT00687804]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www. clinicaltrials.gov

104.Lam DS, Lai TY, Lee VY et al (2009) Efficacy of 1.25 mg versus 2.5 mg intravitreal bevacizumab for diabetic macular edema: six-month results of a randomized controlled trial. Retina 29:292–299

105.Arevalo JF, Sanchez JG, Wu L et al; Pan-American Collaborative Retina Study Group (2009) Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology 116:1488–1497

106.Kook D, Wolf A, Kreutzer T et al (2008) Long-term effect of intravitreal bevacizumab (avastin) in patients with chronic diffuse diabetic macular edema. Retina 28:1053–1060

107.Michaelides M, Kaines A, Hamilton RD et al (2010) A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 117:1078–1086.e2

108.Paccola L, Costa RA, Folgosa MS et al (2008) Intravitreal triamcinolone versus bevacizumab for treatment of refractory diabetic macular oedema (IBEME study) Br J Ophthalmol 92:76–80

109.Shimura M, Nakazawa T, Yasuda K et al (2008) Comparative therapy evaluation of intravitreal bevacizumab and triamcinolone acetonide on persistent diffuse diabetic macular edema. Am J Ophthalmol 145:854–861

110.Gragoudas ES, Adamis AP, Cunningham ET Jr et al (2004) VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805–2816

111.Loftus JV, Sultan MB, Pleil AM et al (2011) Macugen 1013 Study Group. Changes in visionand health-related quality of life in patients with diabetic macular edema treated with pegaptanib sodium or sham. Invest Ophthalmol Vis Sci 52:7498–7505

112.Do DV, Schmidt-Erfurth U, Gonzalez VH et al (2011) The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology 118:1819–1826

113.Ikeda T, Sato K, Katano T, Hayashi Y (2000) Improved visual acuity following pars plana vitrectomy for diabetic cystoid macular edema and detached posterior hyaloid. Retina 20:220–222

114.Lewis H, Abrams GW, Blumenkranz MS et al (1992) Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology 99:753–759

115.Harbour JW, Smiddy WE, Flynn HW Jr et al (1996) Vitrectomy for diabetic macular edema associated with a thickened and taut posterior hyaloid membrane. Am J Ophthalmol 121: 405–413

116.Hikichi T, Fujio N, Akiba J et al (1997) Association between the short-term natural history of diabetic macular edema and the vitreomacular relationship in type II diabetes mellitus. Ophthalmology 104:473–478

117.Hartley KL, Smiddy WE, Flynn HW Jr et al (2008) Pars plana vitrectomy with internal limiting membrane peeling for diabetic macular edema. Retina 28:410–419

118.Pendergast SD, Hassan TS, Williams GA et al (2000) Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid. Am J Ophthalmol 130:178–186

119.Stefánsson E, Novack RL, Hatchell DL (1990) Vitrectomy prevents hypoxia in branch retinal vein occlusion. Invest Ophthalmol Vis Sci 31:284–289

120.Stefánsson E (2001) Therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand 79:435–440

121.Gandorfer A, Messmer EM, Ulbig MW et al (2000) Resolution of diabetic macular edema after surgical removal of the posterior hyaloid and the inner limiting membrane. Retina 20:126–133

122.Bahadir M, Ertan A, Mertoglu O (2005) Visual acuity comparison of vitrectomy with and without internal limiting membrane removal in the treatment of diabetic macular edema. Int Ophthalmol 26:3–8

123.Recchia FM, Ruby AJ, Carvalho Recchia CA (2005) Pars plana vitrectomy with removal of the internal limiting membrane in the treatment of persistent diabetic macular edema. Am J Ophthalmol 139:447–454

124.Rosenblatt BJ, Shab GK, Sharma S, Bakal J (2005) Pars plana vitrectomy with internal limiting membranectomy for refractory diabetic macular edema without a taut posterior hyaloid. Graefes Arch Clin Exp Ophthalmol 243:20–25

125.Diabetic Retinopathy Clinical Research Network Writing Committee, Haller JA, Qin H, Apte RS et al (2010) Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology 117:1087–1093.e3

126.Gandorfer A (2008) Enzymatic vitreous disruption. Eye 22:1273–1277

127.Kuppermann BD, Thomas EL, De Smet MD et al (2005) Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 140:573–584

128.Kuppermann BD, De Smet MD, Grillone LR (2005) Safety results of two phase III trials of an intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol 140:585–597

129.Codenotti M, Maestranzi G, De Benedetto U et al (2013) Vitreomacular traction syndrome: a comparison of treatment with intravitreal plasmin enzyme vs spontaneous vitreous separation without treatment. Eye 27:22–27

130.Azzolini C, D’Angelo A, Maestranzi G et al (2004) Intrasurgical plasmin enzyme in diabetic macular edema. Am J Ophthalmol 138:560–566

131.Bandello F, Cunha-Vaz J, Chong NV et al (2012) New approaches for the treatment of diabetic macular oedema: recommendations by an expert panel. Eye (Lond) 26:485–493

132.Bressler SB, Qin H, Beck RW et al (2012) Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol 130:1153–1161

133.Chhablani JK, Kim JS, Cheng L et al (2012) External limiting membrane as a predictor of visual improvement in diabetic macular edema after pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol 250:1415–1420

134.Aiello LP, Edwards AR, Beck RW et al (2010) Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology 117:946–953

135.Mohamed S, Leung GM, Chan CK et al (2009) Factors associated with variability in response of diabetic macular oedema after intravitreal triamcinolone. Clin Experiment Ophthalmol 37:602–608

136.Yamada Y, Suzuma K, Kumagami T et al (2012) Systemic factors influence the prognosis of diabetic macular edema after pars plana vitrectomy with internal limiting membrane peeling. Ophthalmologica 229:142–6

137.Shin HJ, Lee SH, Chung H, Kim HC (2012) Association between photoreceptor integrity and visual outcome in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 250:61–70

138.Yanyali A, Bozkurt KT, Macin A et al (2011) Quantitative assessment of photoreceptor layer in eyes with resolved edema after pars plana vitrectomy with internal limiting membrane removal for diabetic macular edema. Ophthalmologica 226:57–63

139.Shimura M, Yasuda K, Yasuda M et al (2013) Visual outcome after intravitreal bevacizumab depends on the optical coherence tomographic patterns of patients with diffuse diabetic macular edema. Retina 33:740–747

140.Kim YM, Lee SY, Koh HJ (2010) Prediction of postoperative visual outcome after pars plana vitrectomy based on preoperative multifocal electroretinography in eyes with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 248:1387–1393

141.Manousaridis K, Talks J (2012) Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? Br J Ophthalmol 96:179–184

142.Goel N, Kumar V, Ghosh B (2011) Ischemic maculopathy following intravitreal bevacizumab for refractory diabetic macular edema. Int Ophthalmol 31:39–42

143.Nakamura Y, Takeda N, Tatsumi T (2012) [Macular ischemia following intravitreal bevacizumab therapy for diabetic macular edema]. Nihon Ganka Gakkai Zasshi 116:108–113

144.Battaglia Parodi M, Iacono P, Cascavilla ML et al (2010) Sequential anterior ischemic optic neuropathy and central retinal artery and vein occlusion after ranibizumab for diabetic macular edema. Eur J Ophthalmol 20:1076–8

145.Singerman LJ (2007) Intravitreal bevasiranib in exudative age-related macular degeneration or diabetic macular edema. In: 25th Annual Meeting of the American Society of Retina Specialists, Indian Wells

146.Safety and efficacy study of small interfering RNA molecule (Cand5) to treat diabetic macular edema [ClinicalTrials.gov identifier NCT00306904]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov

147.Nguyen QD, Schachar RA, Nduaka CI et al (2012) Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study). Invest Ophthalmol Vis Sci 53:7666–7674

148.PF-04523655 dose escalation study, and evaluation of PF-04523655 with/without ranibizumab in diabetic macular edema (DME) (MATISSE) [ClinicalTrials.gov identifier NCT01445899]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov

149.Krishnadev N, Forooghian F, Cukras C et al (2011) Subconjunctival sirolimus in the treatment of diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 249:1627–1633

150.Dugel PU, Blumenkranz MS, Haller JA et al (2012) A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema. Ophthalmology 119:124–131

151.Wu L, Hernandez-Bogantes E, Roca JA et al (2011) intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the PanAmerican Collaborative Retina Study Group. Retina 31:298–303

152.Owen ME, Beare NA, Pearce IA, Mewar D (2012) Intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema. Retina 32:2179–80

153.Tsilimbaris MK, Panagiotoglou TD, Charisis SK et al (2007) The use of intravitreal etanercept in diabetic macular oedema. Semin Ophthalmol 22:75–79

154.Hariprasad SM, Callanan D, Gainey S (2007) Cystoid and diabetic macular edema treated with nepafenac 0.1 %. J Ocul Pharmacol Ther 23:585–590

155.Callanan D, Williams P (2008) Topical nepafenac in the treatment of diabetic macular edema. Clin Ophthalmol 2:689–692

156.Singh R, Alpern L, Jaffe GJ et al (2012) Evaluation of nepafenac in prevention of macular edema following cataract surgery in patients with diabetic retinopathy. Clin Ophthalmol 6:1259–1269

157.Cable M (2012) Comparison of bromfenac 0.09% QD to nepafenac 0.1% TID after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. Clin Ophthalmol 6:997–1004

158.Elbendary AM, Shahin MM (2011) Intravitreal diclofenac versus intravitreal triamcinolone acetonide in the treatment of diabetic macular edema. Retina 31:2058–2064

159.Maldonado RM, Vianna RN, Cardoso GP (2011) Intravitreal injection of commercially available ketorolac tromethamine in eyes with diabetic macular edema refractory to laser photocoagulation. Curr Eye Res 36:768–773

160.Tanito M, Hara K, Takai Y (2011) Topical dexamethasone-cyclodextrin microparticle eye drops for diabetic macular edema. Invest Ophthalmol Vis Sci 52:7944–7948

161.Cukras CA, Petrou P, Chew EY et al (2012) Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study. Invest Ophthalmol Vis Sci 53:3865–3874

162.Thakur A, Scheinman RI, Rao VR, Kompella UB (2011) Pazopanib, a multitargeted tyrosine kinase inhibitor, reduces diabetic retinal vascular leukostasis and leakage. Microvasc Res 82:346–350