Ординатура / Офтальмология / Английские материалы / Current Aspects of Pathogenesis and Treatment in Diabetic Retinopathy_Kroll_2007

36 Bartz-Schmidt KU, Thumann G, Psichias A, Krieglstein GK, Heimann K: Pars plana vitrectomy, endolaser coagulation of the retina and the ciliary body combined with silicone oil endotamponade in the treatment of uncontrolled neovascular glaucoma. Graefes Arch Clin Exp Ophthalmol 1999;237:969– 975.

37 Helbig H, Kellner U, Bornfeld N, Foerster MH: Rubeosis iridis after vitrectomy for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 1998;236:730–733.

38 Dowler J, Hykin PG: Cataract surgery in diabetes. Curr Opin Ophthalmol 2001;12:175– 178.

39 Blankenship GW: The lens influence on diabetic vitrectomy results: report of a prospective randomized study. Arch Ophthalmol 1980;98:2196–2198.

40 Menchini U, Bandello F, Brancato R, Camesasca FL, Galdini M: Cystoid macular oedema after extracpasular cataract extraction and intraocular lens implantation in diabetic patients without retinopathy. Br J Ophthalmol 1993;77:208–211.

41 Benson GT, Flynn HW, Blankenship GW: Posterior chamber intraocular lens implantation during diabetic pars plana vitrectomy. Ophthalmology 1989;96:603–610.

42 Benson WE, Brown GC, Tasman W, McNamara JA, Vander JF: Extracapsular cataract extraction with placement of a posterior chamber lens in patients with diabetic retinopathy. Ophthalmology 1993; 100:730– 738.

43 Aiello LM, Wand M, Liang G: Neovascular glaucoma and vitreous hemorrhage following cataract surgery in patients with diabetes mellitus. Ophthalmology 1983;90:814–820.

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

45 Jonas JB, Sofker A, Degenring R: Intravitreal triamcinolone acetonide as an additional tool in pars plana vitrectomy for proliferative diabetic retinopathy. Eur J Ophthalmol 2003;13:468–473.

46 Sakamoto T, Miyazaki M, Hisatomi T, Nakamura T, Ueno A, Itaya K, Ishibashi T: Triam- cinolone-assisted pars plana vitrectomy improves the surgical procedures and decreases the postoperative blood-ocular barrier breakdown. Graefes Arch Clin Exp Ophthalmol 2002;240:423–429.

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

48 Helbig H, Kellner U, Bornfeld N, Foerster MH: Cataract surgery and YAG-laser capsulotomy following vitrectomy for diabetic retinopathy. Ger J Ophthalmol 1996;5:408– 414.

49 Honjo M, Ogura Y: Surgical results of pars plana vitrectomy combined with phacoemulsification and intraocular lens implantation for complications of proliferative diabetic retinopathy. Ophthalmic Surg Lasers 1998;29:99–105.

50 Shinoda K, O’Hira A, Ishida S, Hoshide M, Ogawa LS, Ozawa Y, Nagasaki K, Inoue M, Katsura H: Posterior synechia of the iris after combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation. Jpn J Ophthalmol 2001;45: 276–280.

51 Melberg NS, Thomas MA: Nuclear sclerotic cataract after vitrectomy in patients younger than 50 years of age. Ophthalmology 1995; 102:1466–1471.

52 Lahey JM, Francis RR, Kearney JJ: Combining phacoemulsification with pars plana vitrectomy in patients with proliferative diabetic retinopathy: a series of 223 cases. Ophthalmology 2003;110:1335–1339.

53 Senn P, Schipper I, Perren B: Combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation in the capsular bag: a comparison to vitrectomy and subsequent cataract surgery as a two-step procedure. Ophthalmic Surg Lasers 1995;26:420– 428.

54 Schachat AP, Oyakawa RT, Michels RG, Rice TA: Complications of vitreous surgery for diabetic retinopathy. II. Postoperative complications. Ophthalmology 1983;90:522– 530.

55 Virata SR, Kylstra JA: Postoperative complications following vitrectomy for proliferative diabetic retinopathy with sew-on and noncontact wide-angle viewing lenses. Ophthalmic Surg Lasers 2001;32:193–197.

56 Kroll P, Gerding H, Busse H: Occurrence of retinal complications by reproliferation following vitreoretinal silicone surgery. Klin Monatsbl Augenheilkd 1989;195:145–149.

57 Messmer E, Bornfeld N, Oehlschlager U, Heinrich T, Foerster MH, Wessing A: Epiretinal membrane formation after pars plana vitrectomy in proliferative diabetic retinopathy. Klin Monatsbl Augenheilkd 1992;200: 267–272.

58 Meredith TA, Kaplan HJ, Aaberg TM: Pars plana vitrectomy techniques for relief of epiretinal traction by membrane segmentation. Am J Ophthalmol 1980;89:408–413.

59 Meredith TA: Epiretinal membrane delamination with a diamond knife. Arch Ophthalmol 1997;115:1598–1599.

60 Meier P, Wiedemann P: Vitrectomy for traction macular detachment in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 1997;235:569–574.

61 Martin DF, McCuen BW 2nd: Efficacy of flu- id-air exchange for postvitrectomy diabetic vitreous hemorrhage. Am J Ophthalmol 1992;114:457–463.

62 Bopp S, Lucke K, Laqua H: Acute onset of rubeosis iridis after diabetic vitrectomy can indicate peripheral traction retinal detachment. Ger J Ophthalmol 1992;1:375–381.

Fig. 1. Pathomechanism and pharmacological treatment of diabetic retinopathy. Hyperglycemia results in the production of advanced glycation end products (AGE) and leads to increased diacylglycerol (DAG) levels. This activates protein kinase C (PKC- ), leading to an overexpression of VEGF. Therefore PCKactivation results in capillary leakage and neovascularization. The effects can be inhibited with the PKCinhibitor ruboxistaurin mesylate. Capillary occlusion leads to an increased expression of IGF-1, which is a strong permissive factor for the development of neovascularization. The somatostatin analogue octreotide can inhibit IGF-1 and therefore inhibit neovascularization.

Histological findings are early thickening of basement membranes and loss of intramural pericytes and vascular endothelial cells. Due to this cellular loss the vascular reactivity is reduced. Damage of the tight junctions of the retinal vascular endothelial cells results in a breakdown of the inner blood-retinal barrier, leading to the manifestation of a diabetic macular edema. All stages of DR are characterized by the overexpression of a number of different growth factors, leading to manifestation and progression of the disease [1].

The more advanced stages of DR show progressive occlusion of capillaries resulting in retinal hypoxia. The hypoxic retina produces angiogenic growth factors like vascular endothelial growth factor (VEGF) and Insulin-like growth factor 1 (IGF-1). The result is the development of preretinal and iris neovascularization [2–4] (fig. 1).

DR occurs after 20 years in 95% of all type 1 and 50– 80% of all type 2 diabetic patients. Proliferative DR is found after 20 years in 50% of the type 1 and 10–30% of the type 2 diabetic patients. Clinically significant macular edema occurs after 15 years in 15% of the type 1 and 25% of the type 2 patients.

Pharmacological Treatment of DR

Treatment with Somatostatin Analogue

Growth hormones (GH) and IGF-1 are important mediators of angiogenesis in the retina. Somatostatin analogues have 2 different mechanisms of action. First they

can stabilize the blood-retinal barrier in patients with diabetic macular edema. Second they inhibit the neoangiogenesis in patients with advanced stages of DR. The synthetic somatostatin analogue octreotide has proven to be effective in small series of patients and is at present under investigation in 2 phase 3 trials [4].

The Role of Somatostatin, GH and IGF-1

Somatostatin is a neuropeptide, which is produced in different human organs like hypothalamus, hypophysis and also in the retina. Somatostatin acts via 5 somatostatin receptors (Sstr1–5). It inhibits the release of different hormones and enzymes. After binding somatostatin, the Sstr generate a transmembrane signal. This results in a reduction of the calcium concentration and activation of tyrosine phosphatases. Somatostatin is a postreceptor antagonist of growth factors acting by inhibition of signal transduction [4]. Somatostatin also appears to have an effect on fluid transport from the retinal pigment epithelium to the choroid, a process that is important in the development of macular edema.

GH is produced in the anterior pituitary, resulting in the synthesis of IGF-1. IGF-1 increases the cellular uptake of glucose in the tissue and acts as surviving, growth and progression factor. It presumably acts as key signal for cells going into the mitotic cycle. IGF-1 stimulates somatostatin secretion and inhibits GH secretion [5].

Somatostatin and Sstr have been identified in human retina and are produced in the retina.

Role of Somatostatin, GH and IGF-1 in DR

Poulsen [6] found a relation of pituitary hormone and DR in a patient with proliferative DR, who suffered a postpartal pituitary insufficiency (Sheehan syndrome). Five years after the event retinopathy had regressed, indicating the important role of GH and IGF-1 in DR.

It is known that somatostatin, GH and IGF-1 play a role in the manifestation and progression of DR. In patients with DR a hypersecretion of GH was found. Retinal hypoxia leads to an increased expression of IGF-1. In eyes of diabetic patients increased IGF-1 levels were found. The highest levels of IGF-1 were found in patients with proliferative DR. In patients who had undergone vitrectomy after laser treatment the intravitreal VEGF levels were reduced but not the IGF levels [7].

Clinical Use of Octreotide

Octreotide is in clinical use for the treatment of tumors like GH producing pituitary adenoma. Octreotide inhibits the pituitary release of GH from the tumor and lowers IGF-1 plasma levels. As overproduction of GH and IGF-1 play an important role in the pathogenesis of DR, octreotide is under investigation for the treatment of DR.

Mechanism of Action of Octreotide in DR

DR develops as a result of imbalance of proand antiangiogenic factors. VEGF and IGF-1 are major players in the pathogenesis. However, DR only develops if at the same time there is a lack of natural angiogenesis inhibitors like transforming growth factor (TGF- ) and pigment epithelium derived factor [8].

Octreotide acts via paracrine and autocrine effects on retinal endothelial cells [5]. It binds to the Sstr and inhibits endothelial cell growth stimulated by growth factors like VEGF and IGF-1. In preclinical studies octreotide also directly inhibits endothelial cell proliferation, indicating additional mechanisms of antiangiogenic action, probably by direct Sstr-mediated inhibition [9, 10].

Treatment of DR with Octreotide

In vitro and in vivo studies have confirmed that somatostatin analogues are potent inhibitors of GH and IGF-1. Octreotide reduces elevated levels of GH and IGF-1. Octreotide showed a positive effect on DR in small controlled trials and case reports.

Böhm et al. [11] showed in a study on 18 patients with persistent proliferative DR with vitreous hemorrhage after laser treatment a significantly reduced incidence of vitreous hemorrhages and number of vitrectomies in the

group treated with octreotide. In the treated group of 9 patients 78% showed an improvement in contrast to the control group. In the octreotide group visual acuity was stable, whereas it significantly decreased in the control group. Neovascularizations decreased in 85% of the patients in the treated group and were stable in 15%, and in the control group neovascularizations increased in 42% and were unchanged in 58%.

Grant et al. [12] studied the effect of octreotide in type 1 and 2 diabetics with preproliferative and early proliferative DR. In the treated group significantly fewer patients developed high risk characteristics. In only 1 of the 22 eyes was laser treatment required in contrast to 9 of 24 eyes in the control group.

Somatostatin analogue treatment of DR is promising. Octreotide is under investigation in 2 large ongoing multicenter randomized controlled trials. Included were type 1 and 2 diabetic patients with Early Treatment Diabetic Retinopathy Study (ETDRS) stages 47–61. The patients are treated with the long acting octreotide (Sandostatin LAR, Novartis), which is injected intramuscularly once a month.

Side Effects

Octreotide results in a reduction of the blood glucose level in patients treated with insulin, requiring lower insulin doses. Therefore the insulin dosis has to be reduced by 25–50% in patients with octreotide treatment. Close daily monitoring of blood glucose levels is mandatory under octreotide treatment because of the risk of hypoglycemia [4].

Diarrhea and tenesmus are common at the beginning of octreotide treatment but rapidly improve. Nausea and vomiting are less common. Hypothyroidism and gallstones are rare side effects.

Treatment of DR with Protein Kinase C Inhibitors

Protein kinase C (PKC- ) inhibitors act via influencing the cellular signal transduction by inhibition of specific protein kinases. The balance of kinases and phosphatases is important for cellular processes like growth, differentiation and motility. PKC consists of a family of about 12 isoforms, which differ in structure, substrate requirements, location and function. The -isoform has been most closely linked to the development of DR [13].

The protein kinases can be divided into 4 classes according to the acceptor amino acids, serine-/threonine-, tyrosine-, histidineand aspartate-/glutamate-specific

protein kinases. Serine-/threonine-specific kinases, which are found in all tissues, are divided into 3 groups: a cAMP-dependent protein kinase A, a protein kinase B and a calcium-phospholipid activated PKC [14].

The PKC family was first isolated in 1977 as a proteolytic activated kinase in rat brain [15]. PKC is a single polypeptide with an N-terminal regulatory region and C-terminal catalytic regions. The conventional and novel isoforms are activated by diacylglycerol (DAG). The group of atypical PKCs are not activated by DAG [16].

Die PKC pathways are responsible for cell growth and cell death. They are regulated isoenzyme and cell specific [3]. PKC acts by catalyzing the transfer of a phosphate group from ATP to various substrate proteins.

PKC and Diabetes Mellitus

Several studies showed that the activation of PKC via hyperglycemia in diabetics is associated with increased DAG levels in vascular tissue. This was also proven for the retina. In recent studies it was shown that PKCis involved in vascular dysfunctions which are induced by hyperglycemia [3]. The intracellular release of DAG is the primary step for the activation of PKC.

PKC and DR

The activation of PKC via hyperglycemia plays a central role in the development and progression of DR [17]. Glucose gets into the cells and is further metabolized via glycolysis. This results in the synthesis of DAG. Increased DAG levels have been found in the retina of diabetics [18]. Hyperglycemia results in an increased DAG-PKC signal transduction in the retina [19]. Furthermore independently of DAG synthesis lipid acids play an important role in the modulation of PKC activation. However, the PKC isoenzymes in the various tissues are activated differently. PKCis the dominating isoenzyme in the retina. One reason for the privileged activation of PKCin diabetics is the high sensitivity against DAG [19]. The activation of the DAG-PKC metabolic pathway leads to long acting structural and functional changes, which are associated with different complications.

The vascular endothelial cells play a key role in the regulation of homeostasis, the vascular tonus, vessel permeability and thrombocyte activation. Endothelial dysfunction and cell activation lead to the development of microangiopathy. Biochemical or mechanic stimulation release a number of substances in endothelial cells, among others angiotensin 2, endothelin-1, TGF- , VEGF and prostaglandins. The PKC activation is an important biochemical step in the hyperglycemia-induced endothelial

dysfunction. PKC for example inhibits the NO-mediated vasodilation [20]. This is important because the inhibition of PKC can normalize the retinal microvascular hemodynamics.

The adhesion of monocytes on endothelial cells is increased in diabetes mellitus. The membrane-associated activity of PKC in monocytes is markedly increased in diabetics and leads to an increased adhesion of monocytes on endothelial vessel walls [21].

The activity of PKC plays an important role in the regulation of receptor density on the cell surfaces for hormones, in the intracellular signal response, the ion canal activity, the intracellular pH and the phosphorylation of proteins [22]. The increased reactive contractility of smooth muscles, which is observed in diabetic patients, is caused by hyperglycemia-induced PKC activation. Changes in the intracellular calcium concentration are associated with the PKC activation and modulate growth- factor-induced mitogenesis and contraction. Finally, apoptosis of smooth vascular muscle cells is dependent on PKC [23].

The loss of endothelial cell barrier function is an early pathophysiological phenomenon in DR. The PKC-medi- ated phosphorylation and relaxation of cytoskeletal and adhesion proteins like caldesmon, vimentin, talin and vinulin are responsible for increased vascular permeability caused by increased glucose levels.

VEGF is not only the primary mediator of disturbed vascular permeability but also of the neoangiogenesis. In eyes of diabetics high VEGF levels were found. When glucose levels are increased the VEGF gene expression is dependent on PKC. The VEGF-induced disturbed bloodretinal barrier, endothelial cell proliferation and neoangiogenesis can be blocked by -specific PKC inhibition [24].

The thickening of capillary basement membrane and the increase of extracellular matrix are the predominant vascular changes in the early phase of diabetes mellitus. The basement membrane plays an important role concerning vascular permeability, cellular adhesion, proliferation, differentiation and gene expression. The production of collagen type 4 and 6 as well as fibronectin are enhanced in diabetics. PKC inhibitors can prevent these effects.

A key role in the thickening of basement membrane and the synthesis of extracellular matrix is played especially by TGFand connective tissue growth factor. The expression of these growth factors can be blocked by PKC inhibition [25].

Treatment of DR with PKCInhibitors

Recently an isoenzyme selective PKC inhibitor was developed [26], ruboxistaurin mesylate (RBX), which is orally administered. RBX is the first of a new class of compounds and the most potent and selective PKCin- hibitor being investigated. The treatment of diabetic rats with RBX showed an improvement of the retinal blood flow and a reduction of the retinal PKC activity [27]. RBX reduces the VEGF-induced blood-retinal barrier breakdown and neovascularization [24].

In a multicenter, double-masked, randomized, place- bo-controlled study the safety and efficacy of the orally administered PKCinhibitor RBX was evaluated in subjects with moderately severe to very severe nonproliferative DR (ETDRS 47B to 53E). A total of 252 subjects received placebo or RBX (8, 16 or 32 mg/day) for 36–46 months. Compared with placebo, 32 mg/day RBX was associated with a delayed occurrence of moderate visual loss and sustained moderate visual loss. This was evident only in eyes with definite diabetic macular edema at baseline. In this clinical trial, RBX was well tolerated and reduced the risk of visual loss but did not prevent DR progression. Further multicenter trials investigate if RBX can reduce the progression of diabetic macular edema and DR. One of the phase 3 clinical trials finished recently and it was announced by Eli Lilly & Co. that RBX significantly reduced the occurrence of vision loss in pa-

tients with DR. RBX will be the first oral medication for the treatment of DR.

Side Effects

Ruboxistaurin is very well tolerated without significant adverse events over 52 months of treatment. Mild side effects like diarrhea, headache and cough are rare [28].

Conclusion

The most promising drugs for the treatment of DR are octreotide and the PKCinhibitor RBX.

The beneficial effect of octreotide on preproliferative and proliferative DR as well as diabetic macular edema has been shown in small studies and case reports. Two phase 3 octreotide studies ended in December 2005. Octreotide might be helpful in the treatment of advanced stages of nonproliferative and early proliferative DR as well as diabetic macular edema.

The PKCinhibitor RBX was shown to reduce the risk of visual loss in a concentration of 32 mg/day in comparison to placebo in patients with moderately severe to very severe nonproliferative DR [28]. The results of a second phase 3 trial with RBX have been announced by Eli Lilly & Co. to also significantly reduce the occurrence of visual loss in patients with nonproliferative DR.

References

1 Fauser S, Krohne T, Kirchhof B, Joussen AM: Die diabetische Makulopathie – Klinik und Therapie. Klin Monatsbl Augenheilkd 2003; 220:526–531.

2 Joussen AM, Fauser S, Krohne TU, Lemmen KD, Lang GE, Kirchhof B: Diabetische Retinopathie: Pathophysiologie und Therapie einer hypoxieinduzierten Entzündung. Ophthalmologe 2003;100:363–370.

3 Lang GE, Kampmeier J: Die Bedeutung der Proteinkinase C in der Pathophysiologie der diabetischen Retinopathie. Klin Monatsbl Augenheilkd 2002;219:769–776.

4 Lang GE: Therapie der diabetischen Retinopathie mit Somatostatinanaloga. Ophthalmologe 2004;101:290–293.

5Grant MB, Caballero S, Smith LEH: Somatostatin in diabetic eye diseases; in Lamberts SWJ, Ghigo E (eds): The Expanding Role of Octreotide. II. Advances in Endocrinology and Eye Diseases. Bristol, BioScientifica Ltd, 2002, pp165–184.

6 Poulsen JE: Diabetes and anterior pituitary insufficiency: final course and postpartum study of a diabetic patient with Sheehan’s syndrome. Diabetes 1966;15:73–77.

7 Spranger J, Mohlig M, Osterhoff M, Bühnen J, Blum WF, Pfeiffer AFH: Retinal photocoagulation does not influence intraocular levels of IGF-1, IGF-2 and IGF-BP3 in proliferative diabetic retinopathy – evidence for combined treatment of PDR with somatostatin analogues and retinal photocoagulation. Horm Metab Res 2001;33:312–316.

8 Böhm BO, Lang GE, Volpert O, Jehle PM, Kurkhaus A, Rosinger S, Lang GK, Bouck N: Low content of the natural ocular anti-an- giogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy. Diabetologia 2003;46:394–400.

9 Baldysiak-Figiel A, Lang GK, Kampmeier J, Lang GE: Octreotide prevents growth factorinduced proliferation of bovine retinal endothelial cells under hypoxia. J Endocrinol 2004;180:417–424.

10 Spraul CW, Baldysiak-Figiel A, Lang GK, Lang GE: Octreotide inhibits growth factorinduced bovine choriocapillary endothelial cells in vitro. Graefes Arch Clin Exp Ophthalmol 2002;240:227–231.

11 Böhm BO, Lang GK, Jehle PM, Feldmann B, Lang GE: Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm Metab Res 2001;33:300– 306.

12 Grant MB, Mames RN, Fitzgerald C, Hahariwala KM, Cooper-DeHoff R, Caballero S, Estes KS: The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy. Diabetes Care 2000;23:504–509.

13 Hayashi A, Seki N, Hattori A, et al: PKCnu, a new member of the protein kinase C family, composes a fourth subfamily with PKCmu. Biochem Biophys Acta 1999;1450;99– 106.

14 Idris I, Gray S, Donnelly R: Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia 2001;44:659–673.

15 Inoue M, Kishimoto A, Takai Y, Nishizuka Y: Studies on a cyclic nucleotide-indepen- dent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain. J Biol Chem 1977;252:7610– 7616.

16 Kishimoto A, Takai Y, Mori T, et al: Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J Biol Chem 1980;255:2273–2276.

17 Xia P, Inoguchi T, Kern TS, et al: Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 1994;43:1122–1129.

18 Craven PA, Davidson CM, DeRubertis FR: Increase in diacylglycerol mass in isolated glomeruli by glucose from de novo synthesis of glycerolipids. Diabetes 1990;39:667–674.

19 Nishizuka Y: The molecular heterogeneity of protein kinase C and its implication for cellular regulation. Nature 1988;334:661–665.

20 Chakravarthy U, Hayes R, Stitt A, et al: Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end-products. Diabetes 1998;47:945– 952.

21 Kreuzer J, Denger S, Schmidts A, et al: Fibrinogen promotes monocyte adhesion via a protein kinase C dependent mechanism. J Mol Med 1996;74:161–165.

22 Malhotra A, Reich D, Nakouzi A, et al: Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. Circ Res 1997;81:1027– 1033.

23 Li PF, Maasch C, Haller H, et al: Requirement for protein kinase C in reactive oxygen species-induced apoptosis of vascular smooth muscle cells. Circulation 1999;100: 967–973.

24 Aiello LP, Bursell SE, Clermont A, et al: Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997;46:1473–1480.

25Fumo P, Kuncio GS, Ziyadeh FN: PKC and high glucose stimulate collagen 1 transcriptional activity in a reporter mesangial cell

line. Am J Physiol 1994;267:632–638.

26 Liao DF, Monia B, Dean N, et al: Protein kinase C- mediates angiotensin II activation of ERK1/2 in vascular smooth muscle cells. J Biol Chem 1997;272:6146–6150.

27 Ishii H, Jirousek MR, Koya D, et al: Amelioration of vascular dysfunctions in diabetic rats by an oral PKCinhibitor. Science 1996;272:728–731.

28 The PKC-DRS Study Group: The effect of ruboxistaurin on visual loss in patients with moderately severe to severe nonproliferative diabetic retinopathy. Diabetes 2005;54: 2188–2197.

Fig. 1. Vitreous and subhyaloidal hemorrhage. Fibrovascular membranes were visible and tractional detachment of the retina was suspected. Vision was hand movement. Surgery was recommended.

Fig. 2. Long-standing tractional detachment of the macula. The retina was covered by extensive active fibrovascular membranes. The retina itself was barely visible. Vision was light perception. Vitrectomy was performed anatomically successfully, but vision did not improve.

Eyes with iris neovascularizations require immediate retinal coagulation therapy to avoid irreversible obstruction of the chamber angle by progressive growth of fibrovascular membranes. If media opacities make adequate coagulation therapy impossible, surgical removal of the hemorrhage and intense endolaser treatment become necessary.

It is therefore not possible to give general recommendations about how long to wait for surgery in diabetic vitreous hemorrhage. Vitreous hemorrhage is a dramatic event for the patient, but the prognosis for vision in the long term is often dependent on other factors.

Tractional Detachment of the Fovea

Eyes with tractional detachment of the fovea have very poor vision and if left untreated will not improve (fig. 2). Surgery is the only therapeutic option and it is generally assumed that there is little to lose even if surgery fails. The functional results of surgery are usually disappointing, even after anatomically successful surgery. The poor visual outcome is mostly due to advanced ischemia of macula and optic disc. Analysis of risk factors revealed extension of the retinal detachment, dura-

tion of macular detachment and iris neovascularizations being associated with poor visual outcome [17, 25]. In eyes with these risk factors, chances for significant visual improvement are so small that one has to consider not performing any surgery, especially if the fellow eye is good and general health is poor. Even if these eyes have little vision to lose, failed surgery with complications may even accelerate the loss of the remaining function and loss of the globe. If both eyes have reduced vision, surgical attempts will nevertheless have to be performed despite a poor prognosis.

Extrafoveal Tractional Detachment

Tractional retinal detachment usually does not start in the fovea. Fibrovascular membranes mostly grow along the vascular arcades and close to the optic disc, where traction and tractional detachment usually begin. Extrafoveal tractional retinal detachment is not an absolute indication for surgery. In many cases the situation may remain stable (fig. 3) and a detached retina may even spontaneously reattach [26]. It is important, however, that eyes with extrafoveal tractional detachment must be carefully watched, especially after laser treatment. Active