Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

244 Diabetes and Ocular Disease

sham group, and 0 of 4 fellow eyes showed either regression of neovascularization on fundus photographs or regression or absence of fluorescein leakage from neovascularization (or both) at 36 weeks. In 3 of 8 with regression, neovascularization progressed at week 52 after cessation of pegaptanib at week 30. Although a retrospective analysis, these findings implied an effect of pegaptanib upon retinal neovascularization in patients with diabetic retinopathy.

Bevacizumab (Avastin, Genentech, San Francisco, CA) is a full-length monoclonal antibody against VEGF. It is FDA approved for intravenous administration with intravenous 5-fluorouracil (5-FU)-based chemotherapy for the treatment of metastatic colorectal cancer. It has been shown to be nontoxic to the retina, retinal pigment epithelium, and optic nerve when injected intravitreally [54,55], and has been shown to penetrate the retina [56]. After the first report of the off-label use of intravitreal bevacizumab in treating choroidal neovascularization [57], its use has rapidly gained popularity among ophthalmologists and is now widespread.

It is used off-label, intravitreally, for the treatment of VEGF-mediated ocular diseases, such as choroidal neovascularization [55,58], central retinal vein occlusion [59,60], and PDR [61–63]. It has been shown to reduce leakage and cause regression of retinal and iris neovascularization in eyes with PDR [60,61]. Intravitreal bevacizumab is useful in eyes that have vitreous hemorrhage with actively bleeding neovascularization, where the view is inadequate to perform PRP. Injection of bevacizumab may promote faster reabsorption of the vitreous hemorrhage, by stopping active leakage, and may allow the view to clear enough for PRP to be performed. It is also useful to inject in eyes with PDR that have active neovascularization and require vitrectomy, as it makes for much less bleeding during delamination of fibrovascular tissue. Intravitreal bevacizumab is also beneficial in the treatment of neovascular glaucoma, by reducing iris neovascularization [64]. However, the half-life of intravitreal avastin in the vitreous is short: approximately 4.3 days in a rabbit model [65], and 5.6 days in a monkey model. It is therefore a temporary treatment for PDR, and must be followed up by proven long-term therapy such as PRP or pars plana vitrectomy.

In one prospective study, 28 eyes of 14 patients with bilateral DME participated. In each patient, one eye received an intravitreal injection of 4 mg triamcinolone acetonide and the other eye received 1.25 mg bevacizumab. The triamcinoloneinjected eye showed significantly better improvement in central retinal thickness than the bevacizumab-injected eye, and the improvement lasted longer than the bevacizumab-injected eye. Triamcinolone (410.4 ± 82.4 microns and 0.47 ± 0.25 microns) kept better results than bevacizumab (501.6 ± 92.5 microns and 0.61 ± 0.17 microns). This suggests that DME benefits not only from VEGF-suppression but also from other mechanisms of action of corticosteroids.

In another study [66], 126 patients with chronic diffuse diabetic macular edema were treated with repeated intravitreal injections of bevacizumab (1.25 mg). Patients were observed in intervals of 4 to 12 weeks for a period of up to 6 to 12 months. Within this period, 48% received at least three intravitreal injections of bevacizumab. Visual acuity changes were significant with ±5.1 ETDRS letters improvement from baseline after 12 months. Moreover, the mean central retinal

thickness on OCT decreased to 374 microns after 6 months (P < 0.001) and to 357 microns after 12 months (P < 0.001).

The most commonly used dose for intravitreal bevacizumab injection is currently 1.25 mg (0.05 cc) in the USA, although up to 2.50 mg (0.1 cc) may be used. Since such a small amount of drug from a large vial is required to treat ocular disease, ophthalmologists have been obtaining the drug from compounding pharmacies that fractionate the vial into smaller amounts, at a lower cost. The anti-VEGF activity has been shown to degrade minimally over 6 months when bevacizumab is withdrawn into a syringe and refrigerated or frozen [67]. Current reports of the use of intravitreal bevacizumab are limited to small series and anecdotal reports, and the optimum dose for each disease has not been established.

SUMMARY

Data concerning the effectiveness of intravitreal triamcinolone acetonide in macular edema for retinal diseases has come from small, interventional case series and the recent DRCR.net trial. Certainly, a dramatic response on OCT has been noted with cases demonstrating resolution of macular edema with large cystoid spaces and return of normal retinal contours after intravitreal triamcinolone injections. However, the visual results are commonly less impressive. Whether this is due to permanent photoreceptor damage by the time of injection in these refractory cases or a lack of efficacy still needs to be determined. In patients with long-standing macular edema unresponsive to conventional treatments such as focal or grid laser, or posterior subtenon triamcinolone, intravitreal triamcinolone acetonide injection can be considered. We also await the results of the ongoing trials of ranibizumab for diabetic macular edema.

REFERENCES

1.Machemer R, Sugita G, Tano Y. Treatment of intraocular proliferations with intravitreal corticosteroids. Trans Am Ophthalmol Soc. 1979;77:171–180.

2.Graham RO, Peyman GA. Intravitreal injection of dexamethasone. Treatment of experimentally induced endophthalmitis. Arch Ophthalmol. August 1974;92(2):149–154.

3.McCuen BW 2nd, Bessler M, Tano Y, Chandler D, Machemer R. The lack of toxicity of intravitreally administered triamcinolone acetonide. Am J Ophthalmol. June 1981;91(6):785–788.

4.Tano Y, Chandler D, Machemer R. Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. December 1980;90(6): 810–816.

5.Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB 3rd, Miller M. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology. April 2003;110(4):681–686.

6.Hida T, Chandler D, Arena JE, Machemer R. Experimental and clinical observations of the intraocular toxicity of commercial corticosteroid preparations. Am J Ophthalmol. February 15, 1986;101(2):190–195.

246 Diabetes and Ocular Disease

7.Antcliff RJ, Spalton DJ, Stanford MR, Graham EM, ffytche TJ, Marshall J. Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology. April 2001;108(4):765–772.

8.Young S, Larkin G, Branley M, Lightman S. Safety and efficacy of intravitreal triamcinolone for cystoid macular oedema in uveitis. Clin Experiment Ophthalmol. February 2001;29(1):2–6.

9.Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920–927.

10.Jonas JB, Hayler JK, Sofker A, Panda-Jonas S. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol. April 2001;131(4):468–471.

11.Jonas JB, Hayler JK, Panda-Jonas S. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative vitreoretinopathy. Br J Ophthalmol. September 2000;84(9):1064–1067.

12.Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina. 2000;20(3):244–250.

13.Challa JK, Gillies MC, Penfold PL, Gyory JF, Hunyor AB, Billson FA. Exudative macular degeneration and intravitreal triamcinolone: 18 month follow up. Aust N Z J Ophthalmol. 1998;26(4):277–281.

14.Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. December 1, 1994;331(22):1480–1487.

15.Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003;110(9):1690–1696.

16.Kang BS, Chung EY, Yun YP, et al. Inhibitory effects of antiinflammatory drugs on interleukin-6 bioactivity. Biol Pharm Bull. 2001;24(6):701–703.

17.Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active

glucocorticoids on IL-4, IL-5, and interferon-gamma production by cultured primary CD4± T cells. J Allergy Clin Immunol. 1997;100:511–519.

18.Floman N, Zor U. Mechanism of steroid action in ocular inflammation: inhibition of prostaglandin production. Invest Ophthalmol. 1977;16:69–73.

19.Bandi N, Kompella UB. Budesonide reduces vascular endothelial growth factor secretion and expression in airway (Calu-1) and alveolar (A549) epithelial cells. Eur J Pharmacol. 2001;425:109–116.

20.Fischer S, Renz D, Schaper W, Karliczek GF. In vitro effects of dexamethasone on hypoxia-induced hyperpermeability and expression of vascular endothelial growth factor. Eur J Pharmacol. January 12, 2001;411(3):231–243.

21.Wilson CA, Berkowitz BA, Sato Y, et al. Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol. 1992;110:1155–1159.

22.Naveh N, Weissman C. Prolonged corticosteroid treatment exerts transient inhibitory effect on prostaglandin E2 release from rabbits’ eyes. Prostaglandins Leukot Essent Fatty Acids. February 1991;42(2):101–105.

23.Lewis GD, Campbell WB, Johnson AR. Inhibition of prostaglandin synthesis by glucocorticoids in human endothelial cells. Endocrinology. July 1986;119(1):62–69.

24.Heffernan JT, Futterman S, Kalina RE. Dexamethasone inhibition of experimental endothelial cell proliferation in retinal venules. Invest Ophthalmol Vis Sci. June 1978;17(6):565–568.

25.Bhattacherjee P, Williams RN, Eakins KE. A comparison of the ocular anti-inflamma- tory activity of steroidal and nonsteroidal compounds in the rat. Invest Ophthalmol Vis Sci. August 1983;24(8):1143–1146.

26.Wang YS, Friedrichs U, Eichler W, Hoffmann S, Wiedemann P. Inhibitory effects of triamcinolone acetonide on bFGF-induced migration and tube formation in choroidal microvascular endothelial cells. Graefes Arch Clin Exp Ophthalmol. 2002; 240(1): 42–48.

27.Penfold PL, Wen L, Madigan MC, Gillies MC, King NJ, Provis JM. Triamcinolone acetonide modulates permeability and intercellular adhesion molecule-1 (ICAM-1) expression of the ECV304 cell line: implications for macular degeneration. Clin Exp Immunol. September 2000;121(3):458–465.

28.Penfold PL, Wong JG, Gyory J, Billson FA. Effects of triamcinolone acetonide on microglial morphology and quantitative expression of MHC-II in exudative age-related macular degeneration. Clin Experiment Ophthalmol. June 2001;29(3):188–192.

29.Leibowitz HM, Berrospi AR, Kupferman A, Restropo GV, Galvis V, Alvarez JA. Penetration of topically administered prednisolone acetate into the human aqueous humor. Am J Ophthalmol. March 1977;83(3):402–406.

30.Bakri SJ, Kaiser PK. Posterior subtenon triamcinolone acetonide for refractory diabetic macular edema. Am J Ophthalmol. February 2005;139(2):290–294.

31.Bakri SJ, Shah A, Falk NS, Beer PM. Intravitreal preservative-free triamcinolone acetonide for the treatment of macular oedema. Eye. June 2005;19(6):686–688.

32.Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. May 2002;109(5):920–927.

33.Jonas JB, Kreissig I, Sofker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol. January 2003;121(1):57–61.

34.Kim JE, Pollack JS, Miller DG, Mittra RA, Spaide RF, Isis Study Group. ISIS-DME: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema. Retina. May 2008;28(5):735–740.

35.Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology. February 2004;111(2):218–224; discussion 224–225.

36.Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24:S3–S19.

37.Wingate RJ, Beaumont PE. Intravitreal triamcinolone and elevated intraocular pressure. Aust N Z J Ophthalmol. 1999;27:431–432.

38.Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol. January 2003;87(1):24–27.

39.Bakri SJ, Beer PM. The effect of intravitreal triamcinolone acetonide on intraocular pressure. Ophthalmic Surg Lasers Imaging. September–October 2003;34(5):386–390.

40.Kaushik S, Gupta V, Gupta A, Dogra MR, Singh R. Intractable glaucoma following intravitreal triamcinolone in central retinal vein occlusion. Am J Ophthalmol. April 2004;137(4):758–760.

41.Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol. November 2003;136(5):791–796.

42.Benz MS, Murray TG, Dubovy SR, Katz RS, Eifrig CW. Endophthalmitis caused by Mycobacterium chelonae abscessus after intravitreal injection of triamcinolone. Arch Ophthalmol. February 2003;121(2):271–273.

43.Roth DB, Chieh J, Spirn MJ, Green SN, Yarian DL, Chaudhry NA. Noninfectious endophthalmitis associated with intravitreal triamcinolone injection. ArchOphthalmol. September 2003;121(9):1279–1282.

248 Diabetes and Ocular Disease

44.Nelson ML, Tennant MT, Sivalingam A, Regillo CD, Belmont JB, Martidis A. Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina. October 2003;23(5):686–691.

45.Moshfeghi DM, Kaiser PK, Bakri SJ, et al. Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide injection. Ophthalmic Surg Lasers Imaging. January–February 2005;36(1):24–29.

46.Moshfeghi AA, Scott IU, Flynn HW Jr, Puliafito CA. Pseudohypopyon after intravitreal triamcinolone acetonide injection for cystoid macular edema. Am J Ophthalmol. September 2004;138(3):489–492.

47.Sharma MC, Lai WW, Shapiro MJ. Pseudohypopyon following intravitreal triamcinolone acetonide injection. Cornea. May 2004;23(4):398–399.

48.Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina. October 2004;24(5):676–698.

49.Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol. September–October 1999;27(5):536–544.

50.Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology. October 2006;113(10):1706–1712.

51.Eyetech Study Group. Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina. April 2002;22(2):143–152.

52.Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized doublemasked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. October 2005;112(10):1747–1757.

53.Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. January 2006;113(1):23–28.

54.Bakri SJ, Cameron J D, McCannel CA, Pulido JS, Marler RJ. Absence of histologic retinal toxicity of intravitreal bevacizumab in a rabbit model. Am J Ophthalmol. July 2006;142(1):162–164.

55.Manzano RP, Peyman GA, Khan P, Kivilcim M. Testing intravitreal toxicity of bevacizumab (Avastin). Retina. March 2006;26(3):257–261.

56.Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina. March 2006;26(3):262–269.

57.Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331–335.

58.Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. April 2006;26(4):383–390.

59.Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. July–August 2005;36(4):336–339.

60.Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina. March 2006;26(3):279–284.

61.Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina. March 2006;26(3):275–278.

62.Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina. March 2006;26(3):352–354.

63.Bakri SJ, Donaldson MJ, Link TP. Rapid regression of disc neovascularization in a patient with proliferative diabetic retinopathy following adjunctive intravitreal bevacizumab. Eye. December 2006;20(12):1474–1475.

64.Kahook MY, Schuman JS, Noecker RJ. Intravitreal bevacizumab in a patient with neovascular glaucoma. Ophthalmic Surg Lasers Imaging. March–April 2006;37(2):144–146.

65.Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. May 2007;114(5):855–859.

66.Kook D, Wolf A, Kreutzer T, et al. Long-term effect of intravitreal bevacizumab (avastin) in patients with chronic diffuse diabetic macular edema. Retina. October 2008;28(8):1053–1060.

67.Bakri SJ, Snyder M, Pulido JS, McCannel CA, Weiss WT, Singh RJ. Six-month stability of bevacizumab (avastin) after withdrawal into a syringe and refrigeration or freezing. Retina. May–June 2006;26(5):519–522.

This page intentionally left blank

252Diabetes and Ocular Disease

3.Exclusion of other treatable causes of macular edema

4.Early Treatment Diabetic Retinopathy Study (ETDRS) laser photocoagulation

5.Careful follow-up and reassessment

6.Further treatment if indicated: either additional laser photocoagulation, use of adjuvant pharmacological therapy, combined photocoagulation and pharmacological intervention, vitrectomy, or referral of the patient to a clinical trial.

STEP 1: COMPLETE OCULAR EVALUATION

Emphasis on a complete and careful ocular evaluation is important because many factors other than the presence of thickening in the macula alone impact on the clinician’s decision-making when treating DME. To pick just a few examples, the patient’s visual acuity affects numerous decisions including the recommendation for treatment and discussion of the relative risks, side effects, and benefits of various management strategies. A small, mobile anterior chamber intraocular lens could be responsible for iris irritation and inflammation, which, in turn, may exacerbate edema. Iris neovascularization, if present, signals the presence of more emergent issues than edema alone. The lens examination impacts on the consideration of corticosteroid therapies or vitrectomy surgery, both of which cause cataract progression. Evaluation of intraocular pressure (IOP) and optic nerve cupping also factors into consideration of corticosteroid use with its attendant glaucoma risk. And retinal examination is important not only from the standpoint of assessing presence or absence of macular edema but also in terms of grading the level of retinopathy. Patients with more severe levels of retinopathy have a less favorable response to laser therapy and worse visual prognosis than those with milder levels. The patient deserves a complete overview of his or her ocular condition at the time of initial evaluation.

STEP 2: OPTIMIZE METABOLIC CONTROL

As important as the ocular evaluation in the ophthalmologist’s care of the diabetic patient, is the discussion about metabolic control and its impact on the eye. The ophthalmologist has a crucial role here as a communicator with the patient and also with the patient’s medical care team, including endocrinologist, primary care physician, internist and/or other personnel. The ophthalmologist needs to make it clear that optimization of metabolic control will impact significantly on the patient’s DME. This “tuning up” is the fi rst important step in the management of DME, and has occasionally been sufficient to result in edema resolution (Fig. 13.1A and B) [2]. Although these cases are the exception, certainly levels of glycemia, hypertension, and blood lipid abnormalities are crucial to assess and at least begin to control before committing patients to invasive treatment regimens.

Glycemia. The first step to reduce the progression of diabetic retinopathy is glycemic control. The Diabetes Control and Complications Trial (DCCT) [3] provided

C D

Figure 13.1. (A and B) Fundus photograph from a patient with type 2 diabetes and bilateral diabetic macular edema with severe hard exudates. Initial laboratory examination revealed a total cholesterol of 421 mg/dL and triglyceride of 1272 mg/dL. One session of focal laser photocoagulation was performed in each eye and medical treatment for his elevated serum lipids was initiated. (Source: Reprinted from Ophthalmology, Cusick M, Chew EY, Chan CC, et al. Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels, 110:2126–2133 © 2003 with permission from the American Academy of Ophthalmology.) (C and D) Twelve months after presentation, serum lipids normalized and fundus examination revealed regression of hard exudates and resolving diabetic macular edema. (Source: Reprinted from Ophthalmology, Cusick M, Chew EY, Chan CC, et al. Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels, 110:2126–2133 © 2003 with permission from the American Academy of Ophthalmology.)

incontrovertible evidence that intensive management of hyperglycemia, as demonstrated by a reduction in the HbA1c to 7.0%, is associated with decreased rates of development and progression of retinopathy in type 1 diabetic persons. In addition, the United Kingdom Prospective Diabetes Study (UKPDS) [4] showed that intensive control of blood glucose (reducing the HbA1C to 7.0%) in type 2 diabetics resulted in a 25% risk reduction in microvascular endpoints, such as the need for retinal laser photocoagulation. Data from these landmark studies have resulted in the recommendation for achieving intense glycemic control with HbA1C level