(P. Kroll) Diabetic Retinopathy

Current Aspects of Pathogenesis and Treatment in Diabetic Retinopathy
Guest Editor
Peter Kroll, Marburg
30 gures, 13 in color, and 8 tables, 2007
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Vol. 221, No. 2, 2007
Contents
Laudatio
75 Laudatio for Professor Peter Kroll Bchele Rodrigues, E. (So Paulo) 77 Editorial Kroll, P. (Marburg) 78 Pathogenesis and Classification of Proliferative Diabetic
Vitreoretinopathy
Kroll, P.; Bchele Rodrigues, E.; Hoerle, S. (Marburg)
95 Laser Treatment in Diabetic Retinopathy Neubauer, A.S.; Ulbig, M.W. (Munich) 103 Surgery for Diabetic Retinopathy Helbig, H. (Zurich) 112 Pharmacological Treatment of Diabetic Retinopathy Lang, G.E. (Ulm) 118 Current Treatment Approaches in Diabetic Macular Edema Meyer, C.H. (Marburg) 132 Evidence Based Therapy of Diabetic Retinopathy Hoerle, S.; Kroll, P. (Marburg) 142 Author and Subject Index
2007 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/oph_issues
Laudatio
Ophthalmologica 2007;221:7576 DOI: 10.1159/000098478
Laudatio for Professor Peter Kroll
Peter Kroll was born in Bratislava in the Slovak Republic on 16 May 1943. He graduated from medical school in 1971 and wrote his postgraduation thesis in 1973 at the University of Bonn. Peter Kroll also completed a residency in Ophthalmology in 1978 at the University Eye Hospital in Bonn. Dr. Kroll joined the University Eye Clinic in Mnster in 1978 as faculty ophthalmologist, where he obtained his professorship in 1983. In 1989 Professor Peter Kroll was elected chairman and head Professor in the Ophthalmology Department of the Philipps-Universitt Marburg. Professor Kroll made the Department of Ophthalmology in small historic Marburg achieve international recognition as a major center in vitreoretinal diseases and surgery. With his great friend and fellow Dr. Jrg Schmidt, Professor Kroll developed one of the most outstanding and highest-quality vitreoretinal surgeries in the world. Throughout the years the reference eye clinic in Marburg has attracted patients and professional visitors from all over the world including Mexico, Russia, USA, France, Spain, Brazil and China. Professor Krolls personal goal has been to train a few fellows very well and enable them to perform high-standard vitrectomy to
Dr. Eduardo Bchele Rodrigues studied and learned vitreoretinal diseases/surgery under Professor Peter Krolls guidance as a German Academic Exchange Service (DAAD) scholar fellow during the years 20012004.
work in the interest of their patients. Professor Krolls productive career comprises over 250 publications in internationally recognized scientific journals and 1 book of ophthalmology. Through his career he has been recognized as a permanent member of several important retina societies including the Club Jules Gonin and the former Vitreous Society. Professor Kroll has made remarkable contributions to the understanding and treatment of diabetic retinopathy and implemented substantial innovations. Major achieve-
2007 S. Karger AG, Basel 00303755/07/22120075$23.50/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/oph
ments in his lifelong engagement in treating diabetic eye disease include the foundation and presidency of the IFdA, German abbreviation for Initiativgruppe Frherkennung diabetischer Augenerkrankungen, and the introduction of a classification of proliferative diabetic vitreoretinopathy [1]. Krolls classification strengthens the role of the vitreous in the pathogenesis of diabetic vitreoretinopathy, as he has been the worlds pioneer in determining the vitreoretinal interface key for proliferative diabetic vitreoretinopathy disease progression [2]. Consequently, early vitrectomy may provide better outcomes in rapidly progressing diabetic vitreoretinopathy patients [3, 4]. His struggle in this field as head of the IFdA association promoted significant reduction in blindness due to diabetic retinopathy in Europe. Further remarkable scientific contributions by Professor Kroll and his assistants in Marburg include the enzymatic removal of the posterior vitreous cortex, therapy of proliferative vitreoretinopathy secondary to rhegmatogenous retinal detachment and advances in chromovitrectomy [57].
As a chairman and leader Professor Kroll possesses remarkable emotional intelligence to select assistants with integrity as the main criterion. He enjoys having young German and foreign fellows around and taking care of them. To his fellows and colleagues, he has been a leader and motivator of original and innovative thinking. Besides being a great surgeon, teacher and researcher, he is an extraordinary human being with an incredible appetite for the world and all of its beauty. His tremendous dignity, simplicity with elegance and pleasant humor are remembered by all those who spend time with him. Professor Kroll has maintained a close and strong friendship with Professor C. Ohrloff, Professor H. Kaufmann and Professor H. Busse for many decades. It is with great pleasure that the journal Ophthalmologica and his retina colleagues acknowledge Professor Peter Kroll, one of the most impressive leaders in diabetic retinopathy and vitreoretinal surgery, for his multitude of contributions. Eduardo Bchele Rodrigues
Institute of Vision, Federal University of So Paulo (Brazil)
References
1 Hesse L, Heller G, Kraushaar N, Wesp A, Schroeder B, Kroll P: The predictive value of a classification for proliferative diabetic vitreoretinopathy. Klin Monatsbl Augenheilkd 2002;219:4649. 2 Kroll P, Meyer-Rusenberg HW, Berg P: Does vitrectomy in proliferative diabetic retinopathy effect an improvement in intraocular metabolic status? Fortschr Ophthalmol 1986;83:471473. 3 Bodanowitz S, Hesse L, Weinand F, Kroll P: Vitrectomy in diabetic patients with a blind fellow eye. Acta Ophthalmol Scand 1996;74: 8488. 4 Hoerle S, Poestgens H, Schmidt J, Kroll P: Effect of pars plana vitrectomy for proliferative diabetic vitreoretinopathy on preexisting diabetic maculopathy. Graefes Arch Clin Exp Ophthalmol 2002;240:197201. 5 Hesse L, Kroll P: Enzymatically induced posterior vitreous detachment in proliferative diabetic vitreoretinopathy. Klin Monatsbl Augenheilkd 1999;214:8489. 6 Schmidt JC, Rodrigues EB, Hoerle S, Meyer CH, Kroll P: Primary vitrectomy in complicated rhegmatogenous retinal detachment a survey of 205 eyes. Ophthalmologica 2003; 217:387392. 7 Rodrigues EB, Meyer CH, Kroll P: Chromovitrectomy: a new field in vitreoretinal surgery. Graefes Arch Clin Exp Ophthalmol 2005;243:291293.
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Ophthalmologica 2007;221:7576
Laudatio
Editorial
Microvascular complications of diabetes mellitus such as diabetic retinopathy and diabetic maculopathy continue to be the most frequent causes for blindness in working-age adults in industrialized countries. This is only surpassed by age-related macular degeneration in higher age groups. While a few years ago only about 5% of the population suffered from diabetes, a massive increase in the prevalence of up to 16% must be expected. As a consequence, the rate of blindness due to diabetes will rise, despite all interdisciplinary and ophthalmologic therapeutic efforts. For that reason, I was very enthusiastic about planning this special issue of Ophthalmologica with the publisher, to point out diabetes-induced ocular complications in order to prevent them by timely diagnosis and therapy. This issue consists of review articles on the pathogenesis of diabetic retinopathy and maculopathy and their classification and staging. On that basis up-to-date therapeutic modalities are discussed in detail. The treatment of diabetic complications is evidence based due to excellent studies published in the literature. However, a tendency towards pharmacologic treatment of ocular diabetic complications seems to be increasing when taking newer publications into account.
Panretinal laser photocoagulation continues to be the gold standard for the treatment of diabetic retinopathy, followed by pars plana vitrectomy for more advanced cases such as proliferative diabetic vitreoretinopathy with vitreous hemorrhages and tractions. Diabetic maculopathy in particular is increasingly treated with pharmacologic agents, such as triamcinolone acetate and antivascular endothelial growth factor, which might one day replace pars plana vitrectomy with or without inner limiting membrane peeling at the posterior pole. A similar development was observed in abdominal surgery at the end of the last century, when Helicobacter pylori was discovered to cause gastric ulcers, thus replacing often invasive surgical procedures by a simple pharmacologic treatment. To even better prevent diabetic patients from going blind, further insight into the pathogenesis of this disease is necessary, as a basis for improvement of pharmacologic therapy. Only this will enable us to assess whether vitreoretinal procedures can be replaced in the future. Peter Kroll
Pathogenesis and Classification of Proliferative Diabetic Vitreoretinopathy

Peter Kroll Eduardo Bchele Rodrigues Steffen Hoerle
Department of Ophthalmology, Philipps University Marburg, Marburg, Germany
Key Words Proliferative diabetic vitreoretinopathy Proliferative diabetic retinopathy Diabetes Neovascularization Retina Vascular endothelial growth factor
communication about and the therapy of diabetic retinopathy. Furthermore, it is the only reliable classification for predicting the surgical outcome in diabetics.
Copyright 2007 S. Karger AG, Basel
Abstract Purpose: To review the current knowledge regarding the pathogenesis of proliferative diabetic vitreoretinopathy (PDVR) and to present recommendations for its clinical staging. Design: Focused literature review and authors clinical experience. Results: Although several biochemical mediators may be responsible for the pathogenesis of PDVR, no common biochemical pathway exists. Of those mediators, vascular endothelial growth factor is the one most studied so far. However, since in proliferative diabetic retinopathy (PDR) the thickened posterior vitreous cortex is one of the main factors in the development of proliferations, a consequent shrinkage of the posterior vitreous cortex leads to hemorrhages and tractive retinal detachments. Therefore, PDR should be called PDVR. In consequence, the authors present a new morphological classification of PDVR. Conclusions: There is no consensus about the biochemical pathway responsible for the progression of PDVR. Although several classifications are described in the literature, the classification suggested here is important in the judgment of, the
Introduction
Diabetic retinopathy is one of the leading causes of blindness in the Western world [31, 55, 75, 88, 103]. Diabetic retinopathy may be subdivided into a nonproliferative (non-PDR) and a proliferative (PDR) form. While non-PDR is characterized by a microangiopathy involving intraluminal, intramural and extravascular damage, proliferative diabetic vitreoretinopathy (PDVR) is an entirely different disease entity, as the disease hallmark is the formation of new vessels at the vitreoretinal interface and in the vitreous itself. Furthermore, PDVR is the stage of diabetic retinopathy in which fibrovascular tissue proliferates on the surface of the retina and/or the optic disc and/or the iris. After 1520 years of diabetes, this proliferative form of diabetic retinopathy affects about 50% of patients with type 1 diabetes, 510% of patients with noninsulin-dependent type 2 diabetes and 30% of patients with insulin-dependent type 2 diabetes [67].
Prof. Peter Kroll, MD Klinik fr Augenheilkunde Robert-Koch-Strasse 4 DE35033 Marburg (Germany) Tel. +49 6421 286 2600, Fax +49 6421 286 5678, E-Mail krollp@med.uni-marburg.de
Although some risk factors for diabetic retinopathy have been determined, the exact pathogenesis is yet unknown [28]. This study aims first to describe hypothetic pathogenic mechanisms of PDVR. Also, the current classifications are reviewed, with an emphasis on the authors classification.
Hypothetical Pathogenesis of PDVR
Systemic Factors Influencing Disease Progression The most important determinants for the beginning and progression of diabetic retinopathy to PDVR are the disease duration and the degree of metabolic control maintained over the years [114]. Additional factors such as microalbuminuria, hyperlipidemia and ocular perfusion pressure influence diabetic disease progression as well [88]. Several clinical trials in Europe and North America have defined the role of various metabolic risk factors in the progression of diabetic retinopathy and PDVR. The EURODIAB Prospective Complications Study has investigated the effect of several systemic factors on the progression of PDVR [22, 89]. HbA1c, presence and severity of retinopathy at baseline, age !12 years at diagnosis, diastolic blood pressure and waist-to-hip ratio remained significant predictors for progression to PDVR. Although metabolic control was the strongest modifiable risk factor for the deterioration of retinopathy, it may not be sufficient to prevent progression to PDVR. In particular, there may be no glycemic threshold below which a patient is protected from the development of PDVR. In summary, the EURODIAB study suggested a strict control of blood glucose and blood pressure with regular ophthalmic screening for retinopathy to be the current best available options for intervention on modifiable risk factors. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) reported that glycated hemoglobin, duration of diabetes, severity of retinopathy at baseline and diastolic blood pressure are among the key factors associated with progression to PDVR [66]. The most crucial perturbation implicated in the development of diabetic complications is the metabolic milieu of the patients, and especially hyperglycemia. Hyperglycemia in turn leads to a variety of biochemical disturbances and functional changes. Sato and Lee [93] investigated the relationship between long-term glycemic control and the proportion of patients with pre-PDR developing PDVR. They concluded that the number of patients progressing to PDVR douPathogenesis and Classification of PDVR
bled with each 1% increase in the mean HbA1c, and the cumulative rate of PDVR at the end of the 10-year followup was 60% in cases with a mean HbA1c of 68.6%, and 14% if the HbA1c was !8.6% [93]. Glycemic control has been demonstrated by others to reduce the development of diabetic retinopathy, decrease visual loss and reduce the need for laser treatment [36, 68]. The Diabetes Control and Complications Trial (DCCT) [28], the United Kingdom Prospective Diabetes Study (UKPDS) [116] and the Japanese studies [84] showed that glycemic control is protective for all levels of diabetic retinopathy. There was no glycemic threshold below which a reduction in microvascular complications was not observed [28, 116]. The DDCT reported a delay in the development of diabetic retinopathy in 76% of patients with type 1 diabetes within a primary prevention group over an average of 6.5 years. The UKPDS, a randomized controlled clinical trial, postulated that diet control reduces the need for laser photocoagulation treatment and the chance of diabetic retinopathy progression by 29% [116]. The UKPDS determined that the effect of strict blood glucose control reduces the risk of progression of diabetic retinopathy as well as the chance of vitreous hemorrhage in PDVR. Control of blood pressure has been postulated to contribute to the prevention of moderate visual loss in diabetic retinopathy [36]. Epidemiologic studies suggest that systemic hypertension increases the risk and/or progression of diabetic retinopathy. The WESDR described worsening of diabetic retinopathy related to higher diastolic blood pressure at baseline and an increase in diastolic blood pressure in a 4-year follow-up period [66]. In the UKPDS, tight control of systemic blood pressure reduced the progression of retinopathy in 34% of the patients, and 47% experienced a lesser risk of deterioration in visual acuity of 3 lines [117]. Diastolic blood pressure was also a significant predictor of progression of diabetic retinopathy and the incidence of PDVR in patients with youngeronset type 1 diabetes mellitus [66, 69]. Both the WESDR and the ETDRS found evidence that elevated lipids may increase the morbidity of macular edema. Elevated serum cholesterol levels were significantly associated with the presence of hard retinal exudates. Since the risk of loss in visual acuity was correlated with the degree of hard exudates, which in turn might also lead to subretinal fibrosis, an intensive lipid-lowering therapy might reduce the severity of retinopathy or the resultant losses in visual acuity. Further prospective trials on the subject are needed [36].
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The rationale for the influence of growth hormones in the development of PDVR dates back to the 1950s, when Poulsen [90] presented a woman with late PDVR who experienced regression of the disease after panhypopituitarism. Later studies hypothesized that growth hormone secretion is increased in patients with advanced diabetic disease, and there is clear recovery of the PDVR alterations as growth hormone is suppressed [42]. The mechanism by which growth hormone induces PDVR is not totally clear, though it was already shown to lead to proliferation of human retinal microvascular endothelial cells in vitro [92]. Besides, growth hormones may also stimulate the production of insulin-like growth factors, and these mediators have been demonstrated to play a role in the pathogenesis of PDVR [19]. Biochemistry in PDVR Several biochemical pathogenic mechanisms may be responsible for the progression of diabetic retinopathy and later PDVR, although the exact biochemical initiating factor is not yet well defined in this multifactorial pathogenesis. The biochemical alterations in diabetic retinopathy are complex, as several growth factors and cytokines act in the disease process. For example, one growth factor may have a direct effect and it may stimulate a second mediator, which potentiates or inhibits its effect. Some authors postulated the importance of a combination of advanced glycosylated end products and accumulation of vascular endothelial growth factor (VEGF) at the vitreous as a trigger mechanism for initiation of the proliferative stage of diabetic vitreoretinopathy [34, 72, 83]. The biochemical mechanisms of pathogenesis of diabetic retinopathy and PDVR may be separated into those caused by hyperglycemia and those related to hypoxia. Biochemical Effects of Hyperglycemia The biochemical pathways responsible for the molecular diabetic changes secondary to hyperglycemia vary. Hyperglycemia could allow the generation of irreversible advanced glycation end products in diabetes [111]. Hyperglycemia could also lead to a decrease of superoxide dismutase and glutathione peroxidase enzymes, which means an impaired defense system against free radical scavenging resulting in oxidative stress [106]. Furthermore, in the polyol pathway chronic hyperglycemia leads to an increased nonenzymatic glycosylation of cell membranes and extracellular matrix as well as to an accumulation of sorbitol by an increased aldose reductase expression. The increased levels of sorbitol in pericytes of retinal vessels lead to hyperosmolarity of many
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retinal capillary cells and thus to cell death [41]. A further mechanism of cellular damage secondary to polyol disturbance is the reduction of glutathione-reductase-induced reduction of NADPH to NAD, which should cause dysfunction of endothelial enzymes [108]. Hyperglycemia leads to functional changes in the retinal vasculature, resulting in a change of retinal tissue blood flow and release of biochemical mediators. These molecules form 2 groups: endothelium-derived relaxing factors (nitric oxide and prostacyclin) and endotheliumderived contracting factors (endothelin, cyclo-oxygenase products), which inhibit or stimulate the underlying smooth muscles and pericytes [15]. Nitric oxide is possibly the main endothelium-derived relaxing factor associated with the development and progression of diabetic retinopathy and PDVR. It is a free radical gas synthesized from L-arginine by nitric oxide synthase, which may participate in the modulation of blood flow, vasodilatation, inflammation and neurotoxicity. Nitric oxide may induce diabetic damage followed by hyperglycemia after the activation of protein kinase C by diacylglycerol. In turn, protein kinase C activation leads to expression of superoxide in endothelial cells, which affects nitric oxide [59, 121]. There are 2 biological consequences of increased levels of nitric oxide in retinas of subjects with diabetes: neurotoxicity and angiogenesis. Regarding the neurotoxic effects, while nitric oxide should have beneficial effects as a vasodilator, it may be highly neurotoxic in high concentrations. Nitric oxide released from Mller cells has led to neuronal cell death in cultures of retinal neurons [27, 109]. Levels of nitric oxide increased by hyperglycemia could affect the equilibrium in the regulation of blood flow in the diabetic patient and be an important mediator in the angiogenic process. Although the exact mechanisms by which nitric oxide enhances angiogenesis are not exactly understood, nitric oxide may also be an important mediator of angiogenesis in living tissues as it stimulates both migration and proliferation of endothelial cells, being then responsible for diabetic vascular damage. Besides its effect on the stimulation of endothelial cell proliferation, nitric oxide may enhance angiogenesis by inhibiting apoptosis of endothelial cells and increasing the dissolution of the extracellular matrix [11, 27, 76, 115, 123]. Beyond its direct damage in diabetic retinopathy, elevated nitric oxide levels could participate in the pathogenesis of the retinal local angiogenic response to VEGF. Nitric oxide expression may be upregulated by VEGF,
Kroll/Bchele Rodrigues/Hoerle
which in turn produces a dose-dependent upregulation of nitric oxide generation in human endothelial cells and is involved in signaling the permeability-enhancing effects of VEGF [40, 123]. Whereas nitric oxide levels were higher in PDVR with retinal detachment than in normal controls, Hernandz et al. [49] found no relationship between VEGF and nitric oxide concentrations in the vitreous fluid of patients with PDVR. Nitric oxide also regulates the release of other cytokines such as platelet-activating factor, tumor necrosis factor and transforming growth factor 1, but the exact pathways are still uncertain [87]. Oku et al. [86] investigated the involvement of nitric oxide and endothelin-1 by examining the levels of both mediators in the vitreous of diabetic patients with PDVR. After observing a significant difference between patients with PDVR and controls, they concluded that both endothelin-1 and nitric oxide could have an active participation in the pathogenesis of PDVR. A second endothelium-derived relaxing factor associated with the pathogenesis of diabetic retinopathy is prostacyclin. Prostacyclin is released after inflammation and is closely related to nitric oxide. Whereas early hyperglycemia decreases prostacyclin synthesis, in advanced cases of diabetic retinopathy such as PDVR, normal or elevated levels of prostacyclin have been reported [104]. Endothelium-derived contracting factors may be dysregulated in the progression of diabetic retinopathy and PDVR. The most studied of these mediators is endothelin, a strong vasoconstricting peptide that regulates capillary homeostasis in the retinal vascular cells. Hyperglycemia leads to higher levels of endothelin in the retina and disturbance of vasoactive regulators [18]. The effect of hyperglycemia may also mediate several biochemical pathways in the production of growth factors. High glucose levels produce glycated proteins that are biologically active and that may enhance the expression of growth factors [83]. Studies in the last decade have demonstrated hyperglycemia to stimulate the release of several growth factors including transforming growth factor, fibroblast growth factor, platelet-derived growth factor and VEGF. A prominent mediator of the effect of hyperglycemia to diabetes damage may be related to the activation of protein kinase C. Protein kinase C is a serine/theorine kinase enzyme with a variety of biological functions, including the modulation of cell structures, receptor responsiveness, gene transcription and cell growth. While protein kinase C is a family of at least 12 isoenzymes, each with different enzymatic properties, only the isoenPathogenesis and Classification of PDVR
zymes and 2 are present in the retina. Studies in animals revealed that only the 2 isoform becomes activated in the vascular tissue of diabetic models [119]. Protein kinase C exerts its influence in the progression of diabetic retinopathy in 2 ways. First, protein kinase C promotes the activation of several growth factors such as transforming growth factor, VEGF and pigment-derived growth factor [3], which in turn are potent angiogenesis factors. Second, binding of VEGF to the target phosphorylation receptors demands the function of signaling proteins, including protein kinase C itself [39]. Experimental studies have shown that one critical component in the mitogenic and permeability-inducing effects of VEGF is the activation of protein kinase C (PKC-) [3]. Inhibition of the PKC- isoform prevents VEGF-mediated cell growth in vitro and reduces ischemia-induced retinal neovascularization in animal models in vivo [5, 24]. Moreover, oral administration of PKC- inhibitor has been reported to slow down the progression of diabetesinduced retinal vascular permeability and to normalize changes in retinal blood flow caused by PDVR [59]. These findings suggested that PKC- may be an important pathogenic factor in the evolution of diabetic retinopathy and PDVR. Biochemical Effects of Hypoxia In diabetic retinopathy, whereas acute hypoxia stimulates the release of cytokines, the chronic hypoxia facilitates the expression of the several growth factors involved in the formation of new vessels [15]. Although a mediator called hypoxia inducible factor 1 has been identified as stimulator of neovascularization, the exact molecular mechanism of new vessel formation after hypoxia remains unknown. There are a few theories, besides the effect of hyperglycemia, in which diabetes mellitus may result in ischemia, such as thickened basement membrane, platelet aggregation and leukocyte activation [15]. First, diabetic retinopathy is reported to co-occur with a retinal basement membrane thickening by an increase in the production of fibronectin and collagen [110]. A second hypothesis concerns the formation of thrombin leading to capillary obliteration and retinal ischemia. Diabetes stimulates protein kinase C, which in turn upregulates the production of endothelial cells, leukocytes and platelets to produce platelet-activating factor [113]. The third mechanism early in diabetic retinopathy by which hyperglycemia causes hypoxia is related to the leukocyte activation and adherence as leukocytes adhere to vascular endothelium. As Joussen et al. [6062] suggest, the inhibition of
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VEGF bioactivity may prove useful in the treatment of early diabetic retinopathy in the future [14]. Regarding the progression of PDVR, recent evidence has indicated that the tissue hypoxia-associated proliferative vitreoretinopathy leads to an upregulation of angiogenic cytokines such as growth factors and vasoactive hormones. Regarding the growth factors, their presence in the vitreous and epiretinal membranes supports their role in the pathogenesis of PDVR. Each angiogenic factor may likely operate coordinated or in cascade with other growth factors [23]. VEGF is probably the most important biochemical agent in the development of diabetic neovascularization. Although several growth factors including insulin-like growth factors 1 and 2 and basic fibroblast growth factor have been implicated in retinal neovascularization [19], experimental and clinical investigations showed that VEGF is the dominant biochemical factor involved in the onset and progression of diabetic retinopathy and PDVR. VEGF possesses the characteristics of a mediator of proliferative retinopathies: it is produced by the retina, induced by hypoxia, is proangiogenic, induces permeability and is diffusible through the eye. Numerous retinal cells produce VEGF, including retinal pigment epithelial cells, pericytes, endothelial cells, Mller cells and astrocytes [23]. Retinal vascular endothelial cells express VEGF and have numerous high affinity receptors to VEGF. Epiretinal neovascular membranes in PDVR disease demonstrated overall VEGF-A expression. Besides, high oxygen consumption by rod photoreceptors in the dark-adapted state may be a powerful driving force of hypoxia and VEGF stimulation [7]. Hammes et al. [43, 44] postulated that, when disregulated, Mller cells may express VEGF. Intraocular VEGF concentrations are increased during proliferation and diminished after laser treatment for PDVR [4, 58]. Evidence of the role of VEGF in new vessel formation has been based on the experiments in primate models of iris neovascularization and in murine models of retinopathy of prematurity. VEGF exerts a potent stimulus for new blood vessel formation by binding to the high affinity tyrosine kinase receptors VEGFR-1 and VEGFR-2. However, the genetic expression of VEGF precedes the new vessel growth, since animal models have an abundant amount of VEGF before the appearance of diabetic morphological changes. Most importantly, experiments with transgenic mouse models indicated that VEGF expression in the retina is sufficient to determine retinal neovascularization [35, 43, 44, 46, 85]. Additionally, the blockade of VEGF is sufficient to inhibit retinal neovas82
cularization in several experimental models of ischemic retinopathy [1, 5]. Not only may the neuroretinal cells be involved with the new vessel formation in PDVR, but also retinal pigment epithelium cells may induce the progression of PDVR because retinal pigment epithelium cells produce VEFG. Moreover, several biochemical mediators implicated in the pathogenesis of diabetic retinopathy have been demonstrated to increase the expression of VEGF, including glucose, advanced glycation products, adenosin, cytokines (transforming growth factor-, interleukin-1) and numerous growth factors (fibroblast growth factor and pigment-epithelium-derived growth factor, plateletderived growth factor, insulin-like growth factor-1, transforming growth factor-) [19, 20, 21, 23, 82, 83, 105, 108, 120]. High numbers of glycation end products, for example, have been seen in the blood of patients with diabetic retinopathy, and this increase is believed to be a stimulator of VEGF release and then a causal factor in the development of diabetic retinopathy [112]. Other growth factors including hepatocyte growth factor, pigment-derived growth factor and insulin-like growth factor-1 probably act in conjunction with VEGF in the development of PDVR. Hepatocyte growth factor is an endothelium-specific growth factor that seems to have an important function in the pathogenesis of PDVR. Hepatocyte growth factor is a mesenchyme-derived pleiotropic factor that regulates cell motility and growth. Canton et al. [16] postulated that preretinal membranes of PDVR synthesize hepatocyte growth factor in diabetic patients. However, regarding the progression of advanced diabetic retinal disease, the production of tumor necrosis factor- may, in addition to the effect of VEGF, lead to a breakdown of the blood-retina barrier. Phagocyte invasion and production of mediators of inflammation are important factors leading to worsening of fibrovascular proliferation in severe PDVR. Tumor necrosis factor- basically promotes angiogenesis and adhesion of leukocytes to endothelial cells. Tumor necrosis factor- also stimulates the production of monocyte chemotactic protein by retinal pigment epithelial cells [8]. It is reasonable that hepatocyte growth factor plays a role in retinal neovascularization in cooperation with other factors. Tumor necrosis factor- also stimulates the VEGF production directly. Given its role in inhibiting angiogenesis and inducing cell differentiation, much investigation arose regarding pigment-epithelium-derived growth factor. Pigment-epithelium-derived growth factor is a potent endogenous angiogenic inhibitor with a neurotrophic influence on
the retina and is essential for maintaining angiogenic homeostasis in the retina. Also, this factor favors an inhibitory environment when oxygen concentrations are normal or high [26]. Then, pigment-epithelium-derived growth factor plays a considerable role in protecting the retina from pathological angiogenesis [120]. The production of pigment-epithelium-derived growth factor is downregulated by hypoxia, which is the central pathogenic stimulus of VEGF-A. Pigment-epithelium-derived growth factor possibly participates in the regulation of blood vessel in the eye by creating a permissive environment for angiogenesis when oxygen levels are low. Insulin-like growth factor-1 was the first growth factor implicated in the occurrence of PDVR, based on the observation of reduced incidence of PDVR on growth hormone or insulin-like growth factor-1 deficient dwarfs [81]. Moreover, others reported an acute increase in serum insulin-like growth factor-1 soon before the onset of PDVR [81]. Also, insulin-like growth factor is present at PDVR vitreous in a higher amount in comparison to patients without neovascularization. However, whereas insulin-like growth factor-1 has been recently established to regulate not only neovascularization but also VEGF action in the mouse model of ischemia-induced PDVR, Sim et al. [102] described no correlation between insulin-like growth factor-1 and VEGF in the vitreous of patients with PDVR, although both were simultaneously increased. Regarding the vasoactive hormones, there is some evidence that the renin-angiotensin system may be associated with angiogenesis in the eye in PDVR. The reninangiotensin system is present in the kidney, heart, ovary and adrenal gland [120]. The most important enzyme of this system is angiotensin-converting enzyme, which cleaves angiotensin I to the effector molecule of the renin-angiotensin system called angiotensin II. Physiologically, angiotensin II regulates the intraocular blood flow and pressure as renin inhibitors lower the intraocular pressure. Angiotensin II has been postulated to reduce microvascular leakage by unknown reasons. Animal studies revealed angiotensin II to induce contraction of perycites and angiogenesis [80]. The increased levels in the vitreous of the renin-angiotensin system components (mostly renin) in PDVR suggest a pathogenic role [94]. Also, glomerular hypertension and angiotensin II increase the expression of growth factors [64]. There is some evidence of a direct relation between the renin-angiotensin system and VEGF, as both VEGF and VEGF receptor mRNA are localized in the ganglion cell layer, Mller cells, the outer nuclear layer and the retinal pigPathogenesis and Classification of PDVR
ment epithelium, all sites of renin and angiotensin synthesis. Besides, both prorenin and VEGF were found to be simultaneously elevated in the vitreous fluid of patients with PDVR [2]. Angiostatin, a fragment of plasminogen, has been identified and characterized as a potent inhibitor of neovascularization, as it has been measured in the vitreous of patients without an underlying proliferative retinal disease and in patients with PDVR with or without previous laser photocoagulation. Spranger et al. [107] demonstrated the association between release of the angiogenesis inhibitor angiostatin and diminished production of the angiogenic growth factor VEGF in eyes with previous retinal scatter photocoagulation. Augustin et al. [9] investigated the vitreous and epiretinal membranes of patients with PDVR to search for oxidative metabolites, i.e. lipid peroxides, and VEGF and to correlate them with retinal coagulation status. They concluded that several oxidative metabolites are able to modulate growth activity and exert this effect via induction of VEGF. Changes in Retinal Cells in PDVR There are several hypotheses to explain how hyperglycemia causes tissue and cell damage in diabetic retinopathy. In general, the glucose molecules interact with proteins and cells of the pericytes and endothelial cells. High glucose levels could even damage endothelial cells by hampering the capacity of the cells to eliminate free radicals, and this effect is most likely caused by increased glucose uptake and depletion of glutathione reductase cofactor NADPH reserves. A further mechanism of glucose cell damage, involving the glycation of collagen, changes the basement membranes and affects retinal vascular cell interaction. Others suggest that hyperglycemia activates protein C kinase, leading to an excess of second messengers, which in turn cause plasma membrane damage including loss of tight junctions and abnormal growth factor receptor expression [98]. Diabetic retinopathy is characterized clinically by microaneurysms, cotton-wool spots, lipid exudates, macular edema, capillary occlusion and finally neovascularization with consecutive hemorrhages. While the retinal vascular endothelial tight junction is formed by 2 proteins called occludin and claudin, studies in diabetic animals revealed that diabetes reduces the quantity of occludin at those tight junctions, leading to disorganization in the arterioles and capillaries. This effect was observed to be caused also by VEGF in the retinal cells. However, it is not yet known if the primary effect of VEGF in diaOphthalmologica 2007;221:7894
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betic retinopathy is to increase the vascular permeability or to protect neurons from degeneration [40]. Another important component of diabetic retinopathy is microvascular occlusion. Both intravascular alterations (leucostasis and microthrombosis) and extravascular processes (invasion of Mller cells into the vascular lumen) are related to the microvascular occlusions in diabetic retinopathy. While the presence of vascular alterations induces us to believe that diabetic retinopathy is a pure microvascular disease, several changes such as the neurodegeneration of retinal cells occur in addition to those microvascular changes [78]. The neuroretinal cells are protected from the circulation of inflammatory cells and their cytotoxic products by the blood-retinal barrier, more specifically the tight junctions in the endothelial cells. Gardner et al. [40] divided the neuroretinal cells into 4 classes and described the changes induced by diabetic retinopathy. The first class of cells are the pericytes and endothelial cells of the capillaries. Pericytes are involved in the stability and control of endothelial proliferation. Retinal capillary coverage with pericytes may be crucial for the survival of endothelial cells in stress-induced PDVR [45]. While pericytes are modified smooth muscle cells which regulate the retinal vascular flow by dilating and contracting, endothelial cells constitute the bloodretinal barrier. As impairment in the retinal microcirculation results in retinal ischemia, its histological hallmark is the appearance of acellular capillaries. Early in diabetic retinopathy, histological examination of the retina of diabetic patients demonstrated the presence of ghost vessels consisting solely of basement membrane [63]. The damage of retinal capillary cells including pericytes and endothelial cells is responsible for microaneurysms and vascular obstruction. These changes, including pericyte loss, evolve over many years before the onset of PDVR [15]. Whereas diabetic retinopathy has been considered a systemic disease, the absence of pericyte changes in the optic nerve of diabetic patients suggests a local ocular disease [65]. There is also evidence that hyperglycemia may directly worsen ischemia by promoting endothelial cell proliferation and diminishing the inhibitory effects of pericytes on endothelial cells [98]. Hyperglycemia could also alter the status of circulating platelets and leukocytes. These cells may adhere to the capillaries in end-stage PDVR and thereby worsen ischemia. The second category comprises the glial cells, either Mller cells or astrocytes. Whereas Mller cells mainly
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span the thickness of the retina from the retinal pigment epithelium to the internal limiting membrane, the astrocytes are limited to wrapping the small retinal blood vessels. Astrocytes undergo severe changes in diabetes, as the production of their intermediate filament and glial fibrillary acidic protein are markedly decreased. As the Mller cells have a direct effect in the formation of diabetic epiretinal membranes in PDVR, Mller cells may be affected much earlier in the course of the disease [10]. In conclusion, the structural glial retinal cells may be severely damaged by diabetic retinopathy when the bloodretinal barrier function is impaired [40]. A third class of cells, the neurons, may be subdivided into photoreceptors, bipolar cells, amacrine cells and ganglion cells. These neurons physiologically convey the electric impulses to the brain. As they are the cells responsible for vision itself, any loss of visual acuity in diabetic retinopathy necessarily implies disturbance of their function. There is evidence that retinal ganglion cells and inner nuclear cells die by apoptosis early in the course of diabetes. Moreover, it has been shown that a continuous atrophy of the thickness of the inner retina and reduction of the number of ganglion cells occurs up to the late stages of diabetic retinopathy including PDVR [40]. The last class of retinal cells, the microglia, are responsible for phagocytosis in the retinal environment. Diabetes has been shown to activate the normally quiescent microglial cells. Because microglial cells may release several mediators of inflammation such as VEGF and tumor necrosis factor, microglial cells seem to play an active role in the progression of diabetic retinopathy to PDVR [91]. Although diabetic retinopathy is mainly characterized as a microvascular disease with concomitant lesions of the neuroretinal cells, there is much evidence that diabetic retinopathy is also an inflammatory disease [60 62]. As observed in ophthalmoscopic examination, diabetic retinopathy frequently presents with tissue destruction and attempts of tissue repair. Experimental studies revealed the presence of several mediators of inflammation in diabetic retinopathy, including leucostasis, adhesion molecule activation, prostacyclin upregulation, VEGF expression and retinal accumulation of macrophages [12, 40, 47]. Tissue loss is exemplified by neuroretinal cell apoptosis. Limb et al. [77] examined the vitreous of patients with PDVR in order to search for the intravitreous presence of vascular cell adhesion molecules that mediate steps of inflammation. They found increased numbers of several molecular inflammatory molecules including vascular
cell adhesion molecule 1 and sE-selectin in patients with PDVR compared to controls. Inflammatory mechanisms may contribute to the onset of new vessels and fibrosis as an endothelial, Mller and retinal pigment epithelial cell activator. The Vitreous in PDVR The human vitreous is constituted of several intercellular connective tissues including type II collagen, hyaluronic acid and hyalocytes. Vessels are normally excluded from the vitreous, a compartment which has been shown to have antiangiogenic properties [107]. Several clinical and experimental studies have demonstrated that the vitreous plays a primary role in the pathogenesis of PDVR. The studies have shown the presence of new vessels microproliferating inside the vitreous cavity, indicating the vitreous to be active in the angiogenesis process [34]. There is also evidence that epiretinal membranes in the vitreous of patients with PDVR produce a high amount of growth factors as the retinal cells do [43, 44, 46, 79]. There must be a biochemical factor in the vitreous tissue that directly regulates the ischemic retina in diabetic retinopathy. An increased presence of advanced glycation products has already been found in the vitreous of diabetic eyes. In diabetic retinopathy, proteins in the vitreous that inhibit angiogenesis undergo marked nonenzymatic glycosylation of collagen and other proteins and this may represent an initial and trigger finding for proliferative changes in diabetic retinopathy [48, 100]. Sebag [99] described presenile changes in the vitreous in diabetics. Hyperglycemia eventually leads to changes of type II collagen and consequently to liquefaction and syneresis of the vitreous. The instability of the vitreous resulting from this loss of the gel state without dehiscence at the vitreoretinal interface may also induce traction on the retina, which in turn might not only lead to retinal tears but can also contribute to the neovascular process itself. Thus, in addition to providing a scaffold for retinal capillary endothelial and other vasoproliferative cells as postulated by Faulborn and Bowald in 1985 [34], the vitreous may aggravate the process of neovascularization because of changes in the rheologic state. The vitreous cortex seems to be involved in early stages of the diabetic disease, whereas the vitreous gel influences the late stages. At the posterior pole the vitreous cortex is composed of parallel collagen fibers that are attached to the retinal surface formed by the foot plates of the Mller cells. This attachment consists of extracellular matrix proteins, mainly fibronectin and laminin [71].
Pathogenesis and Classification of PDVR
Table 1. Development of PDVR
Non-PDR f PDVR f 1st step of pathogenesis: Thickening of vitreoretinal interface Ingrowth of newly formed vessels into the posterior vitreous cortex f 2nd step of pathogenesis: Shrinkage of the vitreous gel through crosslinking of collagen fibers (possibly induced by factor 13)
New vessels reach the vitreous by invading the internal limiting membrane, although the exact mechanisms are not totally clear yet. Previous clinical findings indicated that PDVR is rare if the vitreous cortex has detached completely in myopics with PVD and after vitrectomy, since the scaffold for proliferating cells is destroyed [97]. In high myopia lesser diabetic involvements of the fundus oculi have been observed [57], which may serve as a proof for the involvement of the vitreous in the development of diabetic retinal changes and therefore justifies the term PDVR. Because of a long-standing diabetes-induced breakdown of the blood-retinal barrier, serum proteins, especially fibronectin, accumulate up to 10-fold at the vitreoretinal border region [70]. Fibronectin mediates the migration and adhesion of proliferating endothelial cells supported by growth factors like transforming growth factor-, which bind at specific domains [17]. In the late stages of the disease, the vitreous gel contracts, leading to vitreous hemorrhage due to the rupture of the proliferative vessels, vitreoschisis, as well as tractive or rhegmatogenous retinal detachment. Shrinkage of the vitreous indicates crosslinking of collagen fibers probably induced by transglutaminase (factor 13a) in the presence of fibronectin [6]. Angiogenic cells migrate and then neovascular proliferation arises in this vicious circle. Morphological Evolution of the PDVR Disease In the above chapter we learned that PDVR develops as new vessels arise and proliferate at the border region between the retina and the vitreous cortex accompanied by a fibroglia scaffolding (table 1). Multifactorial reasons, such as hypoxemia and ischemia followed by the accumulation of growth factors lead
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to a thickening of the posterior vitreous cortex, which occurs as a first step prior to an ingrowth of proliferating new vessels into the posterior vitreous cortex (fig. 1) [37, 38]. In this process Faulborn and Bowald [34] found small proliferations arising multifocally and growing within the vitreous cortex. They described the fibrous material of the vitreous cortex being densely interconnected with and obviously being incorporated into the newly formed proliferated tissue and thus providing a scaffold for proliferating cells. In 1990 Yu et al. [122] found in animal experiments that vitreal PO2 increased as a function of the distance from the internal limiting membrane, if inspired oxygen tension was increased. Vice versa, hypoxemia leads to a decrease in vitreal oxygen tension. In 1991 Vlodavsky et al. [118] described that basic fibroblast growth factor promotes the formation of new blood capillaries. It binds to heparan sulfate, both on the cell surface and in the extracellular matrix. Enzymes such as heparanase lead to a degradation of the basic fibroblast growth factor/heparan sulfate complex and thus regulate the growth of capillary blood vessels in normal and pathological situations. The extracellular matrix also serves as a storage depot for other growth factors and enzymes which generate the proliferation of newly formed vessels growing from the retina into the vitreoretinal interface. Sebag et al. [96] in 1992 analyzed vitreous samples from patients with PDVR and from patients without diabetes for collagen crosslinks, as well as for the early glycation products glucitolyllysine and glucitolylhydroxylysine. They found that early glycation products were elevated in diabetic vitreous, while the levels of advanced glycation end products were even 20 times higher in diabetic vitreous compared with the vitreous of controls. These diabetes-induced alterations of human vitreous were regarded as particularly important for proliferations of vessels into the vitreoretinal interface. That is why the authors give the vitreous in PDR an important role and agree on the term PDVR instead of PDR [100]. In a second step of the pathogenesis of PDVR, shrinking of the vitreous body occurs, especially of the posterior vitreous cortex. This step occurs for reasons not yet very clear, although Akiba et al. [6] hypothesized that the factor 13 (transglutaminasae) of the hematopoietic system may play a central role. The clinical alterations in the PDVR stage of diabetic retinopathy are a consequence of both thickening and shrinking at the vitreoretinal interface. Due to vitreous shrinking, neovascu86
larizations in the vitreous are torn and typical vitreous bleeding or if there are more extended adhesions between vitreous and retina tractive retinal detachment results, which may be worsened by rhegmatogenous retinal detachment.
Classification of PDVR
Starting with the introduction of photocoagulation and vitrectomy as therapeutic options of diabetic retinopathy to avoid blindness, several classification systems were presented. The Airlie House classification, which was introduced purely for assessing results of photocoagulation studies in the 1960s, suggested 2 types of diabetic retinopathy: non-PDR and PDR [25]. The division into 2 patterns has remained until now because it is simple and informative. Diabetic retinopathy is probably one of the diseases in which medicine-based evidence principles were applied early and very extensively. While major clinical trials started in the 1970s and 1980s to evaluate the benefits of laser treatment and surgery for diabetic retinopathy, they also determined the evolution and consequently the classification systems were developed. The 5 multicenter clinical trials which established the basic concepts for the current classification and treatment of diabetic retinopathy are the Diabetic Retinopathy Study, the Early Treatment Diabetic Retinopathy Study (ETDRS), the Diabetic Retinopathy Vitrectomy Study (DRVS), the DCCT and the UKPDS. The ETDRS study group classified the proliferative form of diabetic retinopathy in early, high-risk and severe PDR. The ETDRS severity scale was based on the modified Airlie House classification of diabetic retinopathy [29, 32]. The limitation of this scale is that it has proven to be useful in clinical practice only for the outcome of panretinal photocoagulation. Several contemporary surveys have documented that most physicians managing patients with diabetes do not use the full ETDRS severity scale because of its complexity [119]. PDR was classified by the ETDRS severity scale into mild, moderate and high-risk PDR for the initial cases of the disease. If either retinal detachment, traction, rubeosis iridis or fundus obscuration were visualized, it was called advanced PDR (ETDRS, 1991). Further on, the ETDRS confirmed the need of scatter laser coagulation for cases of high-risk PDVR.
Vitreous cortex Fibronectin Laminin Mller cells vitreoretinal interface
Fig. 1. The vitreoretinal interface is believed to play a key role in the development of PDVR (see text).
Fig. 2. PDVR, stage A: this stage is characterized by proliferative changes in vitreous and retina, especially around the optic disc and in the posterior vitreous cortex. The retina is still totally attached.
Although at first pars plana vitrectomy was used for cases of critical forms of PDVR like advanced tractional detachment, in 1983 Shea [101] recommended vitrectomy at earlier stages of the PDVR disease in order to improve surgical outcomes and help in the preservation of useful vision. The DRVS used morphological criteria to define early as a stage of the disease prior to extensive contraction causing retinal detachment [30]. The DRVS postulated that early vitrectomy increased the chance of visual
acuity restoration to over 20/40, at least for eyes with very severe new vessels. However, this major clinical trial was conducted prior to the introduction of surgical advances such as endolaser now commonly employed during vitreoretinal surgery in patients with diabetic retinopathy, and caution is therefore needed to interpret its results. For instance, bimanual surgery with delamination or en bloc dissection of epiretinal membranes were not mentioned in that study.
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Fig. 3. ac PDVR, stage B: this stage is characterized by shrinkage of the posterior vitreous cortex. In places where the vitreous adheres to the retina circumscribed retinal detachments are found. b If a tractive detachment is nasal to the optic disc, this is described as stage Bn. c Proliferative and tractive changes in the area of the temporal superior and inferior vascular arcade, which may be followed by a macular detachment, are categorized as stage Bt.
Fig. 4. a PDVR, stage C. Stage C is similarly to the PVR classification characterized by a tractive retinal detachment which includes the macula.
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Fig. 4. be PDVR, stage C. According to the number of quadrants involved stages C1C 4 are distinguished.
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Table 2. Classification systems of diabetic retinopathy
1969 1981 2003
Airlie House classification [25] Modified Airlie House classification (ETDRS) [29] International Clinical Diabetic Retinopathy Severity Scale (American Academy of Ophthalmology) [119]
In 2003, Wilkinson et al. [120] reported the results of a workshop for a proposed international diabetic retinopathy severity scale. It was agreed among the participants that, in addition to mild, moderate and severe, there is a level for no retinopathy and second, a PDR level for the presence of any neovascularization. However, the international clinical diabetic retinopathy disease severity scale proposed no division of PDR into subgroups. The inclusion of no apparent retinopathy and minimal non-PDR were seen as disagreement in the discussion (table 2). It could be shown that most publications nowadays are based on vitreous hemorrhages with macula on or off, tractive retinal detachments and progressive fibrovascular proliferations as indication criteria for surgery. Therefore, a standard definition and classification of diabetic retinopathy is necessary. It should be clear and critical for the clinical decision process and for communication among ophthalmologists, internists and diabetologists and also for communication with the patient. Furthermore, a classification of PDVR may also be essential to define the indications of surgery and to serve as a predictive factor for surgical outcomes. Krolls Classification As the vitreous has a defined role in the pathogenesis of PDVR, vitreous removal, either by pars plana vitrectomy [13, 33, 56, 74, 95] or by enzymatic means [52, 53], is an appropriate technique to interrupt this process and to prevent final stages. Various studies have demonstrated that vitrectomy earlier in the course of the disease prevents the onset of severe complications [50, 101]. However, a good postoperative visual outcome is difficult to predict even though various factors like preoperative visual acuity, short duration of visual loss, absence of iris neovascularization, a clear lens and partial panretinal photocoagulation are known [50]. Therefore, Kroll et al. [73] established a classification of PDVR that clearly differentiated between early and late stages of the disease and was based on the described hypothetic pathogenesis of PDVR and on clinical observations with preoperative examination techniques as well as intraoperative observations.
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Since the posterior vitreous cortex is mainly responsible for this disease entity, the term PDR has been changed to PDVR in analogy to the term proliferative vitreoretinopathy [73, 100]. The dynamic morphological stages are differentiated as follows: Stage A (fig 2a, b) is characterized by proliferative changes in the vitreous throughout the retina, especially around the optic disc but also elsewhere; however, the retina is totally attached. Stage B (fig. 3ac) consists of circumscribed tractive retinal detachment around the optic disc and at the retinal arcade vessels, as a result of shrinkage of the vitreoretinal interface. However, the macula is attached, so good visual acuity is still present, as long as no hemorrhage or diabetic macular disease occurs. As stage Bn (fig. 3a) one recognizes the tractive detachment nasal to the optic nerve and Bt (fig. 3b) temporal to it. Stages C1C4 (fig. 4ae) are characterized by tractive retinal detachment involving the macula depending on the number of quadrants involved. Due to macular detachment visual function is always reduced [72]. In further studies, our group investigated the importance of Krolls classification as a prognostic value regarding the postoperative results of vitreoretinal surgery. We analyzed 563 patients who underwent a pars plana vitrectomy for PDVR and calculated the operative risks in a multivariate logistic regression analysis. The results showed that postoperative increase of visual acuity of 13 lines was significantly less frequent in stages B and C in comparison to stage A. It may be concluded that Krolls classification for PDVR has a high prognostic value for postoperative visual outcome and surgical management indications [51, 54].
Final Considerations and Conclusions
While pathogenesis and morphological changes of non-PDR seem to be clear (a classification was set up by the ETDRS), currently applied classification systems of PDR are still insufficient. Molecular biological examinations show a very complex system of growth factors and multiple other factors involved in the pathogenesis of the disease. As we could show above, in our opinion, the posterior vitreous cortex seems to be the main cause of morphological changes in PDVR. First, in diabetic eyes vessels grow into the thickened posterior vitreous cortex, maintained by molecular processes in the vitreoretinal interface. Second, a shrinkKroll/Bchele Rodrigues/Hoerle
ing of the posterior hyaloid entails different tractional retinal detachments, which leads us to a morphological classification of PDVR. That is why the term PDR should be changed to PDVR. Furthermore, our classification maps the dynamic morphologic development of PDVR, rather than just giving a static picture of a present fundus finding as older classifications do. This newly inaugurated classification serves (1) to document morphological fundus changes in PDVR, (2) to grade disease severity to improve interobserver communication, (3) to indicate proper treatment, such as la-
ser coagulation or pars plana vitrectomy, (4) to communicate disease severity to the patient, (5) as a predictive indicator for disease progress and (6) for retro- or prospective analysis and studies about PDVR.
Acknowledgments
This research was supported by the German Academic Exchange Service (DAAD), grant A/01/16770, and by the Fehr Foundation.
References
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55 Hoerle S, Gruner F, Kroll P: Epidemiology of diabetes-induced blindness a review. Klin Monatsbl Augenheilkd 2002;219:777784. 56 Hoerle S, Poestgens H, Schmidt J, Kroll P: Effect of pars plana vitrectomy for proliferative diabetic vitreoretinopathy on preexisting diabetic maculopathy. Graefes Arch Clin Exp Ophthalmol 2002;240:197201. 57 Hovener G: The influence of refraction on diabetic retinopathy. Klin Monatsbl Augenheilkd 1975; 167:733736. 58 Ishida S, Shinoda K, Kawashima S, Oguchi Y, Okada Y, Ikeda E: Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 2000;41:16491656. 59 Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL: Amelioration of vascular disfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272:728731. 60 Joussen AM, Fauser S, Krohne TU, Lemmen KD, Lang GE, Kirchhof B: Diabetic retinopathy: pathophysiology and therapy of hypoxia-induced inflammation. Ophthalmologe 2003;100:363370. 61 Joussen AM, Kirchhof B, Gottstein C: Molecular mechanisms of vasculogenesis and angiogenesis: what regulates vascular growth? Ophthalmologe 2003;100:284291. 62 Joussen AM: Angiogenesis in ophthalmology. 2. Current considerations on the pathogenesis of diabetic and hypoxia-induced retinopathy. Ophthalmologe 2003; 100: 361 362. 63 Kador PF, Takahashi Y, Wyman M, Ferris F 3rd: Diabetes-like proliferative retinal changes in galactose-fed dogs. Arch Ophthalmol 1995;113:352354. 64 Kagami S, Border WA, Miller DE, Noble NA: Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 1994;93:24312437. 65 Kerty E, Russell D, Bakke SJ, Nyberg-Hansen R, Rootwell K: Regional cerebral blood flow (rCBF) and cerebral vasoreactivity in patients with retinal ischaemic symptoms. J Neurol Neurosurg Psychiatry 1989;52:1345 1350. 66 Klein R, Klein BE, Moss SE, Cruickshanks KJ: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type I diabetes. Ophthalmology 1998;105:18011815. 67 Klein R, Klein BE, Moss SE: Epidemiology of proliferative diabetic retinopathy. Diabetes Care 1992;15:18751891. 68 Klein R: Has the frequency of proliferative diabetic retinopathy declined in the US. Diabetes Care 2003;26:26912692. 69 Klein R: Prevention of visual loss from diabetic retinopathy. Surv Ophthalmol 2002;47: S246S252.
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70 Kohno T, Sorgente N, Goodnight R, Ryan SJ: Alterations in the distribution of fibronectin and laminin in the diabetic human eye. Invest Ophthalmol Vis Sci 1987;28:515521. 71 Kohno T, Sorgente N, Ishibashi T, Goodnight R, Ryan SJ: Immunofluorescent studies of fibronectin and laminin in the human eye. Invest Ophthalmol Vis Sci 1987;28:506 514. 72 Kroll P, Meyer-Rusenberg HW, Berg P: Does vitrectomy in case of proliferative diabetic retinopathy lead to a better intraocular metabolism? Fortschr Ophthalmol 1986; 83: 471473. 73 Kroll P, Meyer-Rusenberg HW, Busse H: Recommendation for staging of proliferative diabetic retinopathy. Fortschr Ophthalmol 1987;84:360363. 74 Kroll P, Wiegand W, Schmidt J: Vitreopapillary traction in proliferative diabetic vitreoretinopathy. Br J Ophthalmol 1999; 83: 261 264. 75 Krumpaszky HG, Klauss V: Epidemiology of blindness and eye disease. Ophthalmologica 1996;210:186. 76 Lakshminarayanan S, Antonetti DA, Gardner TW, Tarbell JM: Effect of VEGF on retinal microvascular endothelial hydraulic conductivity: the role of NO. Invest Ophthalmol Vis Sci 2000;41:42564261. 77 Limb GA, Hickman-Casey J, Hollifield RD, Chignell AH: Vascular adhesion molecules in vitreous from eyes with proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 1999;40:24532457. 78 Lonneville YH, Ozdek SC, Onol M, Yetkin I, Gurelik G, Hasanreisoglu B: The effect of blood glucose regulation on retinal nerve fiber layer thickness in diabetic patients. Ophthalmologica 2003;217:347350. 79 Malecaze F, Clamens S, Simorre-Pinatel V, Mathis A, Chollet P, Favard C, Bayard F, Plouet J: Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch Ophthalmol 1994;112:14761482. 80 Matsugi T, Chen Q, Anderson DR: Contractile responses of cultured bovine retinal pericytes to angiotensin II. Arch Ophthalmol 1997;115:12811285. 81 Merimee TJ: Diabetic retinopathy: a synthesis of perspectives. N Engl J Med 1990; 322: 978983. 82 Mitamura Y, Takeuchi S, Ohtsuka K, Matsuda A, Yamamoto T, Yamamoto S, Hiraiwa N, Kusakabe M: Tenascin-C levels in the vitreous of patients with proliferative vitreoretinopathy. Ophthalmologica 2003; 217: 422 425. 83 Murata T, Nagai R, Ishibashi T, Inomuta H, Ikeda K, Horiuchi S: The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas. Diabetologia 1997;40:764769.
84 Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103117. 85 Okamoto N, Tobe T, Hackett SF, Ozaki H, Vinores MA, LaRochelle W, Zack DJ, Campochiaro PA: Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 1997;151:281291. 86 Oku H, Kida T, Sugiyama T, Hamada J, Sato B, Ikeda T: Possible involvement of endothelin-1 and nitric oxide in the pathogenesis of proliferative diabetic retinopathy. Retina 2001;21:647651. 87 Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC: Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest 1997; 100: 31313139. 88 Porta M, Bandello F: Diabetic retinopathy: a clinical update. Diabetologia 2002; 45: 1617 1634. 89 Porta M, Sjoelie AK, Chaturvedi N, Stevens L, Rottiers R, Veglio M, Fuller JH; EURODIAB Prospective Complications Study Group: Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study. Diabetologia 2001;44:22032209. 90 Poulsen JE: The Houssay phenomenon in man: recovery from retinopathy in a case of diabetes with Simmonds disease. Diabetes 1953;2:712. 91 Rungger-Brandle E, Dosso AA, Leuenberger PM: Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 2000;41:19711980. 92 Rymaszewski Z, Cohen RM, Chomczynski P: Human growth hormone stimulates proliferation of human retinal microvascular endothelial cells in vitro. Proc Natl Acad Sci USA: 1991;88:617621. 93 Sato Y, Lee Z: The subclassification and longterm prognosis of preproliferative diabetic retinopathy. Jpn J Ophthalmol 2002;46:323 329. 94 Schalekamp MADH: Renin-angiotensin system components and endothelial proteins as markers of diabetic microvascular disease. Clin Invest 1993;71:S3S6. 95 Schulze S, Schulze S, Schmidt J, Kroll P: Air endotamponade in 52 vitrectomies due to proliferative diabetic retinopathy retrospective comparison with 40 vitrectomies without endotamponade. Klin Monatsbl Augenheilkd 2000;217:329333. 96 Sebag J, Buckingham B, Charles MA, Reiser K: Biochemical abnormalities in vitreous of humans with proliferative diabetic retinopathy. Arch Ophthalmol 1992;110:14721476.
97 Sebag J, Buzney SM, Belyea DA, Kado M, McMeel JW, Trempe CL: Posterior vitreous detachment following panretinal laser photocoagulation. Graefes Arch Clin Exp Ophthalmol 1990;228:58. 98 Sebag J, Hageman GS: Interfaces. Rome, Fondazione GB Bietti, 2000, chap IV, pp 6265. 99 Sebag J: The Vitreous Structure, Function and Pathobiology. New York, Springer, 1989, pp 106107. 100 Sebag J: Diabetic vitreopathy. Ophthalmology 1996;103:205206. 101 Shea M: Early vitrectomy in proliferative diabetic retinopathy. Arch Ophthalmol 1983;101:12041205. 102 Simo R, Lecube A, Segura RM, Garcia Arumi J, Hernandez C: Free insulin-like growth factor-I and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Am J Ophthalmol 2002;134:376382. 103 Sjolie AK, Stephenson J, Aldington S, Kohner E, Janka H, Stevens L, Fuller J: Retinopathy and vision loss in insulin-dependent diabetes in Europe. Ophthalmology 1997; 104:252260. 104 Smith JA, Davis CL, Burgess GM: Prostaglandin E2-induced sensitization of bradykinin-evoked responses in rat dorsal root ganglion neurons is mediated by cAMP-dependent protein kinase A. Eur J Neurosci 2000;12:32503258. 105 Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR: Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999;5:13901395. 106 Sozmen EY, Sozmen B, Delen Y, Onat T: Catalase/superoxide dismutase (SOD) and catalase/paraoxonase (PON) ratios may implicate poor glycemic control. Arch Med Res 2001;32:283287. 107 Spranger J, Hammes HP, Preissner KT, Schatz H, Pfeiffer AF: Release of the angiogenesis inhibitor angiostatin in patients with proliferative diabetic retinopathy: association with retinal photocoagulation. Diabetologia 2000;43:14041407. 108 Stavri GT, Zachary IC, Baskerville PA, Martin JF, Erusalimsky JD: Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells: synergistic interaction with hypoxia. Circulation 1995; 92:1114. 109 Stevens MJ, Dananberg J, Feldman EL, Lattimer SA, Kamijo M, Thomas TP, Shindo H, Sima AA, Greene DA: The linked roles of nitric oxide, aldose reductase and Na+, K+ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest 1994;94:853859.
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Laser Treatment in Diabetic Retinopathy

Aljoscha S. Neubauer Michael W. Ulbig
Department of Ophthalmology, Ludwig Maximilians University Munich, Munich, Germany
Key Words Diabetes Laser therapy Diabetic Retinopathy Study
Abstract Diabetic retinopathy is a leading cause of visual impairment and blindness in developed countries due to macular edema and proliferative diabetic retinopathy (PDR). For both complications laser treatment may offer proven therapy: the Diabetic Retinopathy Study demonstrated that panretinal scatter photocoagulation reduces the risk of severe visual loss by 150% in eyes with high-risk characteristics. Panretinal scatter coagulation may also be beneficial in other PDR and severe nonproliferative diabetic retinopathy (NPDR) under certain conditions. For clinically significant macular edema the Early Treatment of Diabetic Retinopathy Study could show that immediate focal laser photocoagulation reduces the risk of moderate visual loss by at least 50%. When and how to perform laser treatment is described in detail, offering a proven treatment for many problems associated with diabetic retinopathy based on a high evidence level. Copyright 2007 S. Karger AG, Basel
tients, while proliferative retinopathy is another common cause [1]. For both of these retinal complications of diabetes laser treatment can, if timely applied, greatly reduce the probability of vision loss. Of course, the other modifiable risk factors of disease progression have to be optimized in adjunction to any laser therapy, especially optimizing blood glucose control [2, 3] and tight blood pressure control [4].
History of Laser Treatment
Introduction
Diabetic retinopathy is a leading cause of visual impairment and blindness in developed countries. Macular edema is the major cause of vision loss in diabetic pa-
While H.G. Wells foresaw the development of lasers in his book The War of the Worlds in 1897, it was not until 1960 that Maiman built the first working laser. A flash of light was used to deliver light energy to a ruby crystal. Due to 1 totally and 1 partially reflecting mirror at each end a light amplification by stimulated emission of radiation (LASER) device is obtained. The typical characteristics are monochromatic light, spatial coherence and a high density of electrons. Several different wavelengths have been and are being developed, including ruby (694 nm), argon green (514 nm), krypton (647 nm), Nd:YAG (1,064 and frequency doubled to 532 nm), diode (810 nm), excimer (193 nm). The previously used xenon light photocoagulator had been developed by the German ophthalmologist MeyerSchwickerath together with Littmann from Zeiss in the 1950s and made photocoagulation independent of sunlight and weather conditions. Its spot size was variable
Prof. Michael Ulbig Department of Ophthalmology, Ludwig Maximilians University Mathildenstrasse 8, DE80336 Mnchen (Germany) Tel. +49 89 5160 3811, Fax +49 89 5160 5160 E-Mail Michael.Ulbig@med.uni-muenchen.de
ranging from 3 to 8 (i.e. minimum spot size approx. 1500 m) and the burns had greater power than laser burns, therefore usually yielding full thickness burns. In contrast, the laser effects include (depending on laser type, tissue characteristics and settings) photochemical effects, photoirradiation, photocoagulation and photodisruption. Lasers became available for ophthalmologic applications in the late 1960s and became more frequently used in the 1970s. Coagulation treatment of the retina for diabetic retinopathy became a standard of care since the Diabetic Retinopathy Study (DRS) results were published in the late 1970s. It showed a great reduction of severe vision loss in high-risk proliferative disease for both xenon and argon laser photocoagulation [5].
Panretinal Laser Treatment for Proliferative Diabetic Retinopathy
The DRS enrolled 1,742 patients, 876 of whom were randomized to the argon group and 875 to the xenon group [6]. Argon photocoagulation involved the placement of 8001,600 burns with 500 m diameter or 500 1,000 burns with 1,000 m diameter, both at 0.1 s of duration. The areas treated included the retina to or beyond the vortex veins in 1 or 2 sessions, also covering neovascularization of the optic disc (NVD), which is no longer typically performed today. The primary endpoint of the study was a visual acuity of !5/200 on 2 consecutive visits 4 months apart. After 3 years argon laser coagulation could decrease the rate of severe visual loss to 13.3%, and xenon coagulation to 18.5%, while untreated eyes had 26.4%. Thus at least a 50% reduction in the rate of severe visual loss could be demonstrated for panretinal laser treatment, which was maintained during a 5-year follow-up period [7]. The harmful effects of photocoagulation were more pronounced for xenon coagulation than for argon laser coagulation and included a reduction of visual acuity due to treatment and loss of peripheral visual field. For laser treatment a decrease by 61 lines occurred in 10% and a mild constriction of visual fields in 5% [7]. Macular edema, which may be exacerbated by panretinal photocoagulation and will be discussed in detail later, was not evaluated in the DRS. Finally the socalled high-risk characteristics, for which the benefits of peripheral coagulation outweigh the risks, were defined as [7, 8]: 1 NVD 61/4 to 1/3 disc area in extent 2 New vessels on or within 1 disc diameter of the optic disc (NVD)
96
3 Any new vessels within 1 disc diameter of the optic disc and associated with vitreous or preretinal hemorrhage 4 Proliferation elsewhere at least 1/2 disc area in size and associated with vitreous or preretinal hemorrhage The risk of severe visual loss was 26% for eyes exhibiting these high-risk characteristics (at least 3 of 4 signs) as compared to 7% in proliferative diabetic retinopathy (PDR) without those characteristics after 2 years [9]. Photocoagulation reduced this risk by 50%. Therefore the DRS recommends panretinal laser treatment for (1) eyes with new vessels and preretinal or vitreous hemorrhage; and (2) eyes with new vessels on or within 1 disc diameter of the optic disc (NVD) 61/4 to 1/3 disc area in extent (with or without preretinal or vitreous hemorrhage) [7]. It was not able to give recommendations on earlier stages such as severe nonproliferative patients. The current international clinical diabetic retinopathy disease severity scale distinguishes 5 levels of retinopathy [10]: (0) no apparent retinopathy; (1) mild nonproliferative diabetic retinopathy (NPDR, only microaneurysms); (2) moderate NPDR; (3) severe NPDR (including any of: 120 intraretinal hemorrhages in each quadrant, venous beading in 62 quadrants, intra-retinal microvascular abnormalities (IRMA) in 61 quadrant, but no proliferations), and (4) proliferative retinopathy (defined by neovascularization and/or vitreous/preretinal hemorrhage). The subgroup with high-risk characteristics has been described by the DRS above. A summary of current treatment recommendations for laser therapy using this disease scale [1113] is given in figure 1. In supplementation to the DRS criteria it is recommended at a high evidence level [9] to perform panretinal laser coagulation for PDR, NVD, proliferation elsewhere 11/2 disc area, vitreous/preretinal hemorrhage and neovascularization of the iris under certain conditions. Additionally, for severe NPDR scatter laser coagulation may be indicated in some cases (see fig. 1). Laser treatment should be performed over a period of 46 weeks at 500 m spot size, spaced 0.5 burn widths from each other with 0.10.2 s of duration (for green lasers). Intensity should be regulated so that mild white bleaching is obtained, the treatment area reaches from the temporal arcade to the equator and up to 2 disc diameters temporal from the macular center. Around the optic disc some space (e.g. 1 disc diameter) should be spared (see fig. 2) to avoid central visual field defects [14].
Neubauer/Ulbig
(0) No Retinopathy (1) Mild NPDR (2) Moderate NPDR (3) Severe NPDR (4) PDR
No
poor compliance with follow-up impending cataract extraction impending pregnancy status of the fellow eye type1/2 diabetes
High Risk Characteristics
Yes
Fig. 1. Algorithm for panretinal scatter co-
No
agulation of the retina [1113]. For details of the used classification see text. A macular edema must be assessed separately (see text and fig. 2). Type 2 diabetes (older patients) may benefit more from early scatter photocoagulation [60].
Yes
Observe
Scatter (Panretinal) Laser Coagulation
Fig. 2. Illustration of treatment area for
panretinal scatter photocoagulation on widefield imaging (Optomap, Optos, Dunfermline, Fife, Scotland, UK). For details please see text.
Laser Treatment of Macular Edema
Macular edema is responsible for a major part of visual impairment associated with diabetic retinopathy [1]. Correct and timely treatment is of vital importance to
avoid severe visual loss. The Early Treatment of Diabetic Retinopathy Study (ETDRS) formed the basis of current treatment regimens by laser. The multicenter randomized study was designed to investigate the effect of photocoagulation and aspirin treatment in patients with
97
No Macular Edema
Macular Edema (Levels: Mild, moderate, severe)
CSME
No Yes
Exclude Ischemia
No Yes
No Focal Laser Coagulation

(consider other treatment modalities)
Focal edema
No, diuse Yes
Fig. 3. Algorithm for laser treatment for
macular edema. Please note that proliferative disease must be assessed separately as discussed in the text and shown in figure 1. CSME = clinically significant macular edema.
Observe
Focal Laser Coagulation
Grid Laser Coagulation

(option for visual acuity >20/200; consider other treatment modalities)
NPDR and early proliferative retinopathy. It enrolled a total of 3,711 patients between 1980 and 1985 who met the following criteria: (1) no macular edema with visual acuity 120/40 and (2) macular edema with visual acuity 120/200. As one result the ETDRS showed that the randomized intake of 650 mg aspirin per day did not alter the clinical course [15]. It also investigated as a second question when in the course of diabetic retinopathy panretinal laser coagulation is most effective. To answer both these questions, patients without macular edema were randomized to either early (mild or full) scatter photocoagulation or deferral. Eyes with macular edema were randomized to either deferral or immediate focal or immediate panretinal plus follow-up focal photocoagulation. Full scatter photocoagulation was defined as in the DRS, and mild scatter photocoagulation consisted of 500-m spots spaced 1 burn width apart from each other. For eyes without macular edema, no benefit resulted from immediate photocoagulation (either mild or full scatter, focal where needed) to prevent moderate or severe visual loss. For eyes with macular edema and more severe retinopathy a small reduction of the risk for severe visual loss was found with early photocoagulation [16]. However, there was an increased risk of moderate visual loss in the treatment group after 6 weeks, which after 1 year reversed. The least visual loss was in the group treated by mild scatter to98
gether with immediate focal photocoagulation [16]. This supports the algorithm given in figures 1 and 3 regarding timing of scatter photocoagulation and further justifies photocoagulation in non-high-risk characteristic eyes [16]. The third and main question to be answered by the ETDRS was the efficacy of laser treatment for macular edema (fig. 3). Macular edema was defined as: (1) thickening of the retina at or within 500 m of the center of the macula; (2) hard exudates at or within 500 m of the center of the macula, if associated with thickening of adjacent retina, and (3) a zone of retinal thickening 61 disc area, any part of which is within 1 disc diameter of the center of the macula. Any of these 3 criteria defined clinically significant macular edema (CSME, see fig. 4). Focal laser treatment consisted of 50- to 100-m laser burns of 0.050.1 s duration directed at microaneurysms between 500 and 3,000 m from the macular center achieving whitening around or (if 1 40 m) color change of the microaneurysm. Treatment closer than 300 m from the fovea was not recommended (rarely !500 m). Diffuse leakage or nonperfusion were treated in a more indirect way focused at the retinal pigment epithelium: within 2 disc areas of the fovea a grid pattern with 50- to 200-m spots, spaced 1 burn width apart, was applied [17]. Figure 4 illustrates the size relationships. Moderate visual loss, defined as 115
Neubauer/Ulbig
Fig. 4. Illustration of treatment area for focal (and grid) photoco-
agulation for CSME. For details please see text and figure 3.
plied in a more grid-like fashion directed towards thickened areas. In contrast, in diffuse macular edema, leakage occurs diffusely from the retinal capillaries. Retinal microaneurysms, hard exudates and retinal hemorrhages tend to be few in number and small in size. Subtypes include central diffuse edema caused by leakage of the capillaries immediately adjacent to the foveal arcade and generalized diffuse edema [22]. In the latter a more widespread retinal thickening is observed across the posterior pole. Laser treatment has been evaluated using 100- to 200-m spot size and just threshold burns at the level of the pigment epithelium. Usually spots are applied spaced 1 spot size apart and 100200 burns are required. The socalled grid pattern depends on the pattern of leakage and may be performed circularly around the macular center (including the papillomacular bundle). Visual acuity !20/200 (0.1) is a contraindication for grid laser treatment [11, 12]. The results of such treatment are contradictory [23, 24] and not of high evidence. Other treatment modalities such as pars plana vitrectomy [25] or different medical treatment options [26, 27] may be more promising. Ischemic Macular Edema While the accompanying edema may be variable, central ischemia is characterized by a loss of foveal capillaries/capillary nonperfusion. The clinical diagnosis is difficult, while fluorescein angiography shows an enlarged foveal avascular zone (i.e. 1500 m diameter) [12, 28, 29]. An example is shown in figure 5. Laser therapy should not be applied if significant ischemia exists [22]. The complete algorithm for laser treatment of macular edema is given in figure 3.
letters (i.e. 63 lines), was the primary endpoint. In brief, the ETDRS could show that immediate focal laser coagulation in eyes with CSME could reduce the percentage of eyes with moderate visual loss by at least 50%. This effect was maintained over follow-up time, for example after 3 years 12% as opposed to untreated 24% was achieved [16]. However, visual improvement was observed in a minority of cases; for the majority of cases the goal of photocoagulation is to stabilize visual acuity. Therefore patients with good visual acuity and CSME should definitely be considered for treatment [18]. On average 34 treatment sessions 24 months apart were needed [19]. The side effects of focal photocoagulation include an initial decrease in central vision and rarely subretinal fibrosis with choroidal neovascularization. The development of subretinal fibrosis is associated with the degree of subretinal exudates and only 8% were directly attributable to laser coagulation [20]. Paracentral scotomas may be noted by the patient with burns close to the macular center, especially when confluent [21]. Diffuse Macular Edema In focal macular edema well-defined focal areas of leakage with retinal thickening are seen. As described above for the ETDRS, treatment may consist of either direct treatment of leaking microaneurysms or indirect treatment of the retinal pigment epithelium, usually apLaser Treatment in Diabetic Retinopathy
Coexistent Macular Edema and Proliferative Disease
When scatter photocoagulation is to be carried out in eyes with coexisting CSME, there is evidence that first performing focal laser treatment may be beneficial. Both the DRS and ETDRS showed that full scatter photocoagulation may exacerbate macular edema leading to moderate visual loss [16]. This effect was quantified later [30]. The ETDRS could also show some advantage for immediate focal as compared to delayed focal coagulation together with panretinal laser therapy. Therefore it is advisable to first perform focal before panretinal photocoagulation. In cases with high-risk PDR simultaneous focal and scatter photocoagulation should be performed [11, 13].
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Diode Laser Treatment
Fig. 5. Illustration of severe macular capillary dropout, i.e. macular ischemia. Focal laser coagulation should be avoided in such cases.
Cataracts
Various studies suggest that diabetic retinopathy, especially macular edema, may progress following cataract surgery [9, 31, 32]. Therefore, if the ocular media are clear enough, necessary laser therapy should be performed preoperatively. If this is impossible due to media opacities, re-evaluation and necessary therapy should be performed as soon as possible [11]. Regarding the implanted intraocular lens it is important to choose a model with a large optical zone facilitating further photocoagulation. Silicone material should definitely be avoided, since in the case of vitrectomy, especially with silicone oil, precipitates will occur [33].
The diode laser is widespread due to its ease of maintenance, small size and lower costs. Due to its wavelength of 810 nm the biologic properties are different from other wavelengths such as the green lasers. Especially more profound effects of the diode laser in the choroid are known, which may be more painful for the patient during application. Regarding the effectiveness of avoiding progression of PDR no differences exist [37, 38]. On the other hand functional parameters such as color contrast sensitivity or pattern electroretinograms after panretinal photocoagulation may be more in favor of diode laser treatment [39], while expansion of laser spots over time appears to be more likely with the longer wavelength of the diode laser [40]. Regarding macular edema, gentle threshold diode laser coagulation is suitable for focal laser therapy [41], although some studies suggest that it may be to some degree less effective than green laser wavelengths [42]. Subthreshold treatment minimizes damage but is to some extent less effective in promoting resolution of edema, though the difference was not significant [43]. Micropulsed application of subthreshold diode laser burns may increase its effectiveness [44, 45].
Objective Retinal Thickness Measurements
Laser Therapy for Subhyaloidal Hemorrhage
In case of dense subhyaloidal hemorrhage located at the macular center disrupting the inner limiting membrane by an Nd:YAG laser [34] or green laser [35] may allow the blood to dissolve in the vitreous and be absorbed much faster. Panretinal laser treatment should be performed beforehand to avoid unnecessary delays. Complications of the method include macular hole formation and retinal detachment [36]. Other treatment options such as vitrectomy should also be considered in such cases.
While the ETDRS used stereoscopic clinical examination and stereo fundus photographs to define macular changes [46, 47], over the last decade much more sensitive methods have become available to quantify retinal thickness objectively. Optical coherence tomography (OCT, Carl Zeiss Meditec, Jena, Germany) has rapidly become a standard method of analyzing macular changes [48] offering high resolution cross-section images. OCT and another instrument, the retinal thickness analyzer (Talia Technology, Neve-Ilan, Israel) having less resolution, can reliably detect small increases of retinal thickness of at least 2040 m [4951]. Stereoscopic fundus examination usually only detects retinal thickening of approximately 100 m [52]. The new objective methods have been shown to be superior to clinical examination for investigating the extent of diabetic macular edema [53, 54]. By these means it could also be shown that non-clinically significant retinal thickening occurs in most diabetic patients even in the absence of visible retinopathy [55]. This raises the question whether treatment of nonclinically significant (subclinical) macular edema may
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be indicated under certain conditions no such groups had been identified with the methods used in the ETDRS [16]. On the other hand methods like OCT and retinal thickness analyzer offer sensitive tools to follow changes in retinal thickness objectively, which allows better assessment of treatment success of e.g. focal laser treatment. The OCT can also identify membranes and vitreomacular traction [56, 57], cases in which pars plana vitrectomy might be more beneficial than other treatment modalities [25, 58, 59].
Conclusions
Laser therapy remains the main treatment modality for diabetic retinopathy. The DRS demonstrated that panretinal scatter photocoagulation reduced the risk of severe visual loss by 150% in eyes with high-risk characteristics. It may also be beneficial in other PDR and severe NPDR under certain conditions. The ETDRS could show
that immediate focal laser photocoagulation reduced the risk of moderate visual loss for CSME by at least 50%. Usually several treatment sessions are required. In cases of both PDR and CSME, first the macula should be addressed unless high-risk characteristics warrant simultaneous panretinal treatment. In summary, laser treatment offers proven treatments for many problems associated with diabetic retinopathy at a high evidence level. However, for certain situations such as macular ischemia, tractive components, severe proliferations and maybe diffuse macular edema other treatment modalities may be more beneficial. Surgery is definitely indicated for some situations and recently emerging medical therapies offer a variety of new approaches, which alone or in adjunction with laser therapy may help to further improve the outcome of treating diabetic retinopathy. However, their value still has to be proven at the same high level of evidence as that which exists for laser therapy.
References
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35 Kroll P, Busse H: Therapy of preretinal macular hemorrhages. Klin Monatsbl Augenheilkd 1986;188:610612. 36 Ulbig MW, Mangouritsas G, Rothbacher HH, Hamilton AM, McHugh JD: Long-term results after drainage of premacular subhyaloid hemorrhage into the vitreous with a pulsed Nd:YAG laser. Arch Ophthalmol 1998;116:14651469. 37 Ulbig MW, Hamilton AM: Comparative use of diode and argon laser for panretinal photocoagulation in diabetic retinopathy. Ophthalmologe 1993;90:457462. 38 Bandello F, Brancato R, Trabucchi G, Lattanzio R, Malegori A: Diode versus argongreen laser panretinal photocoagulation in proliferative diabetic retinopathy: a randomized study in 44 eyes with a long followup time. Graefes Arch Clin Exp Ophthalmol 1993;231:491494. 39 Ulbig MR, Arden GB, Hamilton AM: Color contrast sensitivity and pattern electroretinographic findings after diode and argon laser photocoagulation in diabetic retinopathy. Am J Ophthalmol 1994;117:583588. 40 Maeshima K, Utsugi-Sutoh N, Otani T, Kishi S: Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina 2004;24:507511. 41 Akduman L, Olk RJ: Diode laser (810 nm) versus argon green (514 nm) modified grid photocoagulation for diffuse diabetic macular edema. Ophthalmology 1997; 104: 1433 1441. 42 Gupta V, Gupta A, Kaur R, Narang S, Dogra MR: Efficacy of various laser wavelengths in the treatment of clinically significant macular edema in diabetics. Ophthalmic Surg Lasers 2001;32:397405. 43 Friberg TR: Infrared micropulsed laser treatment for diabetic macular edema subthreshold versus threshold lesions. Semin Ophthalmol 2001;16:1924. 44 Luttrull JK, Musch DC, Mainster MA: Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol 2005;89:7480. 45 Laursen ML, Moeller F, Sander B, Sjoelie AK: Subthreshold micropulse diode laser treatment in diabetic macular oedema. Br J Ophthalmol 2004;88:11731179. 46 EDTRS: Grading diabetic retinopathy from stereoscopic color fundus photographs an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98:786 806. 47 Kinyoun J, Barton F, Fisher M, Hubbard L, Aiello L, Ferris F 3rd: Detection of diabetic macular edema: ophthalmoscopy versus photography Early Treatment Diabetic Retinopathy Study Report Number 5. The ETDRS Research Group. Ophthalmology 1989;96:746750; discussion 750741.
48 Puliafito CA, Hee MR, Lin CP, Reichel E, Schuman JS, Duker JS, Izatt JA, Swanson EA, Fujimoto JG: Imaging of macular diseases with optical coherence tomography. Ophthalmology 1995;102:217229. 49 Neubauer AS, Priglinger S, Ullrich S, Bechmann M, Thiel MJ, Ulbig MW, Kampik A: Comparison of foveal thickness measured with the retinal thickness analyzer and optical coherence tomography. Retina 2001; 21: 596601. 50 Neubauer AS, Priglinger S, Thiel MJ, Bechmann M, Ulbig MW: Retinal maps: Retinal thickness analyzer (RTA) compared to optical coherence tomography (OCT). IOVS Suppl 2001;42:S793. 51 Polito A, Shah SM, Haller JA, Zimmer-Galler I, Zeimer R, Campochiaro PA, Vitale S: Comparison between retinal thickness analyzer and optical coherence tomography for assessment of foveal thickness in eyes with macular disease. Am J Ophthalmol 2002; 134:240251. 52 Shahidi M, Ogura Y, Blair NP, Rusin MM, Zeimer R: Retinal thickness analysis for quantitative assessment of diabetic macular edema. Arch Ophthalmol 1991; 109: 1115 1119. 53 Brown JC, Solomon SD, Bressler SB, Schachat AP, DiBernardo C, Bressler NM: Detection of diabetic foveal edema: contact lens biomicroscopy compared with optical coherence tomography. Arch Ophthalmol 2004;122:330335. 54 Browning DJ, McOwen MD, Bowen RM Jr., OMarah TL: Comparison of the clinical diagnosis of diabetic macular edema with diagnosis by optical coherence tomography. Ophthalmology 2004; 111:712715. 55 Sanchez-Tocino H, Alvarez-Vidal A, Maldonado MJ, Moreno-Montanes J, Garcia-Layana A: Retinal thickness study with optical coherence tomography in patients with diabetes. Invest Ophthalmol Vis Sci 2002; 43: 15881594. 56 Giovannini A, Amato GP, Mariotti C, Ripa E: Diabetic maculopathy induced by vitreomacular traction: evaluation by optical coherence tomography (OCT). Doc Ophthalmol 1999;97:361366. 57 Gallemore RP, Jumper JM, McCuen BW 2nd, Jaffe GJ, Postel EA, Toth CA: Diagnosis of vitreoretinal adhesions in macular disease with optical coherence tomography. Retina 2000;20:115120. 58 Massin P, Duguid G, Erginay A, Haouchine B, Gaudric A: Optical coherence tomography for evaluating diabetic macular edema before and after vitrectomy. Am J Ophthalmol 2003;135:169177. 59 Parolini B, Panozzo G, Gusson E, Pinackatt S, Bertoldo G, Rottini S, Pignatto S: Diode laser, vitrectomy and intravitreal triamcinolone: a comparative study for the treatment of diffuse non tractional diabetic macular edema. Semin Ophthalmol 2004;19:112. 60 Ferris F: Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc 1996;94:505537.
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Surgery for Diabetic Retinopathy

Horst Helbig
Department Ophthalmology, University Hospital Zurich, Zurich, Switzerland
Key Words Diabetic retinopathy Surgery Vitrectomy Vitreous hemorrhage Tractional retinal detachment
Introduction
Abstract Surgery for diabetic retinopathy addresses late secondary complications of a primary microvascular disease. Since surgery is not a causative therapy, the functional outcome of surgery depends on the degree of retinal ischemia and may be disappointing even in technically and anatomically successfully operated eyes. Typical indications for vitrectomy are vitreous hemorrhage, tractional retinal detachment, combined tractional rhegmatogenous retinal detachment and tractive macular edema. More recently diffuse diabetic macular edema has been shown to improve after removal of an attached vitreous in several cases. Neovascular glaucoma requires aggressive surgical intervention to salvage the eye. Cataract surgery is commonly performed in eyes with diabetic retinopathy. It may however deteriorate diabetic eye disease. Vitreous surgery also has a potential for severe complications in diabetic eyes which can be ameliorated but not eliminated by proper surgical strategies and techniques. The decision for an intervention in diabetic eyes always requires a careful weighing of risks and benefits of surgery.
Only a few decades ago diabetic retinopathy was regarded as an untreatable disease, in many eyes inevitably running its course to blindness [1]. Desperate therapeutic approaches such as hypophysectomy were performed in order to ameliorate the course of the disease [2]. Within a short period of time various effective treatment strategies have been introduced. Photocoagulation of the retina has been shown to improve the course of proliferative retinopathy [3] and macular edema [4]. Improved insulin treatment with near normoglycemic control [5, 6] and intense treatment of arterial hypertension [7] have been shown to have a prophylactic benefit. Possibly in the near future drug therapy directly targeting steps involved in the pathobiochemistry may be available [8, 9]. The enthusiasm and optimistic hopes that blindness due to diabetic retinopathy could be eliminated has been disappointed. The major problem today is to translate the available knowledge into clinical practice [10, 11]. Successful surgical treatment of diabetic retinopathy began with the introduction of pars plana vitrectomy by Machemer [12, 13] in the 1970s. Eyes with blinding complications such as vitreous hemorrhage or tractional retinal detachment, being untreatable before, could be salvaged and vision could be restored. However, surgery can only treat late secondary complications of a primarily microvascular disease. Surgery is not a causative therapeutic approach. Therefore functional results of vitreous sur-
Prof. Dr. med. H. Helbig Augenklinik, Universittsspital Zrich Frauenklinikstrasse 24 CH8092 Zrich (Schweiz) Tel. +41 44 255 4993, Fax +41 44 255 4472, E-Mail horst.helbig@usz.ch
gery are commonly disappointing even if anatomical success rates have continuously improved with better understanding of the pathophysiology and technical instrumentation [1418].
Effect of Surgery on Diabetic Eye Disease
Surgery can address various therapeutical goals in diabetic retinopathy. Media opacities, especially vitreous hemorrhage but also lens opacities, can be removed and a clear optical system can be restored. After removal of media opacities intraoperative laser treatment of the ischemic retina becomes possible and the neovascular stimulus with production of vasoproliferative growth factors can be reduced. A detached retina can be surgically reattached and the contact between photoreceptors and retinal pigment epithelium can be restored. Mechanical traction on the retina by active or atrophic membranes can be relieved and retinal function can recover. However, in addition to these more passive effects, vitreous surgery also has effects on the future development of diabetic eye disease. A partially attached vitreous is an ideal schaffold for the ingrowth of diabetic neovascularizations. After complete removal of the vitreous the tendency for ingrowth of fibrovascular membranes is reduced, since a proper matrix for neovascularizations is missing. On the other hand, it is important to realize that active preretinal neovascularizations contribute to the oxygen and nutrient supply of the inner retina. After surgical removal of these neovascularizations it must be assumed that retinal ischemia is worsened and the neovascular stimulus is increased by surgery. Therefore, eyes in which active neovascularizations are removed require intense immediate intraoperative photocoagulation. In addition, removal of the vitreous and replacement by a balanced salt solution and later by aqueous humor changes diffusion properties and fluid currents in the vitreous cavity. On the one hand, oxygen [19, 20] and nutrients (possibly from the ciliary body) can more easily diffuse from the vitreous cavity to the inner retina, improving the metabolic situation for the ischemic retina. On the other hand, growth factors can more easily leave the retinal tissue into the vitreous cavity. This may have 2 effects. First, the concentration of these cytokines within the retinal tissue is decreasing. This may have a positive effect, possibly explaining the improvement of diabetic macular edema after removing an attached vitreous. And second, these cytokines derived from the ischemic retina can more easily reach the anterior segment of the eye,
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where their vasoproliferative effects may lead to iris neovascularizations and neovascular glaucoma [1418]. An altered environment in an eye after vitrectomy is probably also responsible for the development of lens opacities and the nearly mandatory acceleration of cataract formation after vitrectomy. It is speculated that the lens, being a very low oxygen compartment [21], is exposed to higher oxygen tension after vitrectomy [19]. This may be due to a facilitated diffusion of oxygen if the lens is in direct contact with the fluid currents in the vitreous cavity after vitrectomy and not with the vitreous itself.
Indications
Vitreous Hemorrhage Diabetic vitreous hemorrhage is a common indication for surgery. The first pars plana vitrectomy was performed 35 years ago by Machemer [12, 13] in an eye with diabetic vitreous hemorrhage. Vitreous hemorrhage occurs if neovascularizations tear. This usually happens in eyes which undergo partial vitreous detachment or contraction of the fibrovascular membranes which may occasionally occur shortly after retinal photocoagulation. A nonclearing diabetic vitreous hemorrhage is generally considered to be an indication for surgery. However, should we wait 2 weeks or 1 year for clearing before surgery is advised? The individual decision for surgery is commonly not as easy and other factors have to be included in the considerations for or against surgery. In the presence of retinal detachment, iris neovascularizations or macular edema, irreversible damage may be avoided if immediate surgery is performed. If the hemorrhage is very dense or recurrent, it may also be advisable to perform early surgery. Other patients however will regain vision without surgery if the hemorrhage clears spontaneously within several months. The Diabetic Retinopathy Vitrectomy Study had randomized eyes with vitreous hemorrhage for early surgery or observation. This study only showed a benefit for early surgery in younger diabetics [22, 23]. Younger diabetics more commonly have an attached vitreous and traction on the retina. Ultrasound echography allows identifying tractional membranes at the posterior pole, even if the ophthalmoscopic view is obscured by the hemorrhage. In eyes with known traction on the central retina or evidence of traction in ultrasound echography [24] surgery should not be delayed (fig. 1).
Helbig
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, duraSurgery for Diabetic Retinopathy
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
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fibrovascular membranes require retinal photocoagulation. Laser treatment induces fibrotic transformation of the neovascularizations and possibly contraction of the membranes, which may eventually lead to progression of the tractional detachment [27]. Before vitreous surgery was available, these eyes had a very poor prognosis and laser treatment was considered to be dangerous in these eyes. Now that we can surgically treat these tractional membranes, scatter laser treatment is recommended if active neovascularizations are present, but a close followup is mandatory. Vitrectomy is recommended if the detachment progresses and threatens the fovea or if significant vitreous hemorrhage develops. Tractional Rhegmatogenous Retinal Detachment Traction by diabetic fibrovascular membranes may create retinal tears and a rhegmatogenous retinal detachment may develop (fig. 4). This combined tractional and rhegmatogenous retinal detachment is relatively rare and shows both features of a tractional detachment with membranes tightly adhering to the retina and a retinal tear. The retinal tear itself may be difficult to identify, but the shape of the retinal detachment is quite different. A pure tractional detachment is usually concave, tent-like shaped and the retina is not mobile. The appearance of rhegmatogenous detachment is convex, bullous and mobile. While a tractional detachment progresses slowly and does not require emergency surgery, a tractional-rhegmatogenous detachment usually progresses rapidly and has to be operated without delay. The prognosis of tractional rhegmatogenous retinal detachment is less favorable than for pure tractional detachments. Intraoperatively it is more difficult to separate the membranes from a mobile retina than from a fixed and relatively stable retina. Perfluorcarbon should not be used until the membranes are removed from the posterior pole. Intraoperative complications are relatively common in this type of surgery [28]. In addition, we occasionally observe reproliferations in the postoperative course which represent a combination of diabetic fibrovascular membranes and the typical proliferative vitreoretinopathy. These proliferations are surgically very difficult to manage. Tractive Macular Edema In some cases traction on the fovea may cause tractive macular edema, even if the fovea itself is not detached. Traction of diabetic fibrovascular membranes may cause an ophthalmoscopic appearance with typical hard exudates (fig. 5). Atrophic fibrovascular membranes may
Helbig
Fig. 3. Tractional retinal detachment nasally to the fovea. The
membranes were atrophic after scatter laser treatment and the traction did not threaten the fovea. Vision was 20/25 and no further therapy was performed.
Fig. 4. Tractional rhegmatogenous retinal detachment, visual
acuity hand movement. The retinal tear is marked with an arrow.
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Fig. 5. a Diabetic tractional macular edema with hard exudates. Vision was 20/400. Vitrectomy with removal of the tractional membranes was performed in combination with endolaser treatment. b One year later, slow
resolution of exudates and edema was observed, vision had improved to 20/40.
also create a picture similar to macular pucker with distortion of the central retina. The best therapy for tractional edema is to remove the traction. Tractional membranes may often be easily visible, but in other cases biomicroscopy only shows minimal changes. In some instances ocular coherence tomography can clearly demonstrate the fine membranous structures exerting tractional forces and creating swelling of the macula [29]. Thus, ocular coherence tomography imaging should be included in the diagnostic workup of diabetic macular edema. In cases without traction, laser treatment is a valuable approach; focal laser treatment is not recommended if mechanical traction is the cause for macular edema. Visual recovery after surgery is mainly dependent on the degree of macular ischemia; therefore preoperative fluorescein angiography is helpful to give a picture of the status of macular microcirculation. Diffuse Macular Edema Several recent reports have described an improvement of diffuse diabetic macular edema without visible traction after vitrectomy in eyes with attached vitreous [30]. The pathophysiological basis for this attempt was to improve access of oxygen and nutrients from the vitreous to
the retina, and vice versa, to facilitate diffusion of cytokines from the retinal tissue into the vitreous, avoiding accumulation of factors triggering macular edema within the macular tissue. Despite significant anatomical improvement of the edema after removal of the vitreous, recovery of vision was rather unsatisfactory in many cases. It is still controversial whether this approach with or without removal of the inner limiting membrane significantly improves the long-term course of the disease in eyes with diffuse diabetic macular edema without traction [31, 32]. Surgery for Neovascular Glaucoma The cause for neovascularizations of the iris and chamber angle is believed to be the ischemic retina, which produces vasoproliferative growth factors. These cytokines may diffuse to the anterior segment of the eye, triggering anterior segment neovascularizations. In aphacic and vitrectomized eyes there is no diffusion barrier between the anterior and posterior segment of the eye. Therefore these eyes are particularly at risk for the development of neovascular glaucoma. Therapy has to be primarily directed to the cause of the neovascular stimulus, the ischemic retina. The most important element of treatment is thereOphthalmologica 2007;221:103111
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fore retinal ablation by laser or cryotreatment [33]. Since this treatment can induce fibrotic regression but not complete dissolution of the membranes in the chamber angle, retinal ablation is often not sufficient to regulate intraocular pressure. Therefore additional treatment to lower intraocular pressure is usually necessary. Filtering surgery has a poor prognosis, since the high levels of cytokines in the aqueous humor stimulate fibrosis which is obstructing the fistula. Antimetabolites or glaucoma drainage devices [34] may be used to improve success rates but have an increased risk for complications. Transscleral cryotherapy [35] or transscleral laser treatment to the ciliary body is an alternative to reduce aqueous humor production but has a relatively narrow therapeutic window; overtreatment may induce phthisis of the globe. If other diabetic complications are present, requiring vitreoretinal surgery, direct endolaser treatment to the ciliary processes can be applied to reduce aqueous humor production [36]. In severe cases instillation of liquid silicone can form a diffusion barrier between the retina and the anterior segment of the eye and may contribute to a stabilization of anterior segment neovascularization [37]. Cataract Surgery Second to age, diabetes is the main epidemiological risk factor for the development of cataracts. Cataract surgery in eyes with diabetic retinopathy is performed to improve vision for the patient, but it also allows a clear view to the fundus for diagnosis and treatment of the retinopathy. However, cataract surgery may worsen retinopathy [38]. Neovascularizations and macular edema may be stimulated to grow after cataract surgery [39, 40]. Nevertheless, conventional cataract surgery with phacoemulsification and implantation of an intraocular lens can be safely performed in most eyes with diabetic retinopathy [41, 42]. Intracapsular surgery is associated with an increased risk for neovascular glaucoma [43] and should be avoided in diabetic eyes. Several other aspects should be taken into account. Whenever possible retinopathy should be treated and stabilized before surgery using adequate laser photocoagulation. Especially eyes with iris neovascularizations require intense preoperative laser coagulation or transscleral cryotreatment of the retina. If this is not possible before surgery or not sufficient, a combined procedure with cataract and vitreous surgery including endolaser treatment of the retina should be considered. Fibrinous reaction after cataract surgery alone may render postoperative laser treatment in eyes with iris rubeosis difficult.
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If macular edema is present, preoperative focal laser treatment should be used. If it is not possible to have a completely dry macula at the time of cataract surgery, there is a high risk for worsening of macular edema and visual loss. If cataract surgery has to be performed in the presence of diabetic macular edema, it may be recommended to combine cataract surgery with an intravitreal injection of triamcinolone [4446]. Intravitreal triamcinolone has been shown to successfully improve vision and retinal thickening in diabetic macular edema [47]. Other specific aspects for cataract surgery in eyes with diabetic retinopathy include a large capsulorhexis and an intraocular lens with large optics to facilitate possible subsequent diagnosis and laser treatment of the retina. Silicone intraocular lenses should be avoided because they interact with liquid silicone which possibly has to be used for endotamponade in the later course of diabetic eye disease. Diabetic eyes have an increased risk for postoperative fibrin exudation and formation of synechiae between the lens capsule and the iris due to an impaired blood retinal barrier [4850].
Complications of Surgery for Diabetic Retinopathy
Cataract Opacification of the lens is a mandatory consequence of vitrectomy independently of the cause for vitrectomy. Generally, development of cataracts appears to occur faster in diabetic eyes after vitrectomy than after vitrectomy in nondiabetic eyes. Silicone tamponade leads to an acceleration of cataract formation. Gas tamponade induces an immediate posterior subcapsular opacification occurring a few hours after surgery, which is mostly reversible. Later nuclear sclerosis develops, which does not appear to be much faster after gas tamponade than after vitrectomy with Ringers solution [48]. In young patients cataract formation occurs more slowly, and the lens may remain clear for many years or decades before surgery becomes necessary [51]. In older patients significant cataracts may form within a few months after vitrectomy. The rapid development of cataract after vitrectomy especially in older diabetics has led some surgeons to perform combined viteoretinal and cataract surgery even for eyes with primarily clear lenses. This approach has been shown to be successful and saves the patient a second surgery [52, 53]. Combined surgery however appears to be associated with a higher rate of inflammatory responses with fibrin in the anterior chamber and the formation of synechiae compared to a 2-step procedure [50]. It may
Helbig
therefore be safer to operate on the lens in a second surgery if possible. Combined cataract and vitreoretinal procedure may only be performed if lens opacities are disturbing intraoperative visualization of the posterior segment. Retinal Detachment Rhegmatogenous retinal detachment is a typical complication of vitrectomy [54]. Retinal holes may be created intraoperatively when traction to the vitreous base is exerted. The most common location of iatrogenic holes is close to the sclerotomies where intraocular instruments are introduced into the eye. The more instruments are exchanged during surgery, the higher the risk for creating holes. The risk can be reduced by carefully removing the anterior vitreous next to the sclerotomies with the cutter before instruments like scissors are introduced. In righthanded surgeons the most common location is temporal superior in the right eye and nasal superior in the left eye. Careful inspection of the peripheral retina out to the ora serrata at the end of the surgery under indentation using a wide angle viewing system may identify such retinal tears [55]. Adequate treatment can reduce the risk for postoperative retinal detachment. If postvitrectomy rhegmatogenous retinal detachment occurs, pneumatic retinopexy as a minimum invasive procedure is often the treatment of choice. The tears are anteriorly located and can be reached with transscleral cryotherapy without opening the conjunctiva. The holes are mostly located in the superior quadrants and gas injection in a vitrectomized eye is not associated with a high risk of creating new holes. Another possible cause for postoperative retinal detachment after vitrectomy for diabetic retinopathy are retinal holes located more posteriorly. These holes may be created during the preparation of membranes tightly adhering to the thin and atrophic retina mostly being located close to the major vascular arcades. If such holes are recognized intraoperatively, all traction surrounding the hole has to be released, the hole should be encircled with laser spots and an adequate internal tamponade, often liquid silicone, should be used. Tractive redetachment may occur if severe reproliferations develop. The traction of reproliferation may also tear off laser scars and create a combined tractional rhegmatogenous retinal detachment. Reproliferations Reproliferation of diabetic fibrovascular membranes is a severe complication after vitrectomy for diabetic retSurgery for Diabetic Retinopathy
inopathy. Since the ischemic retina is believed to secrete the proliferative stimuli, the ischemic retina has to be adequately treated with laser. Especially in eyes with silicone tamponade growth factors may concentrate in the shallow interface between silicone and retina and provide an intense stimulus for reproliferations [56, 57]. Complete removal of all fibrovascular tissue using various techniques (segmentation technique [58], delamination [59] or en bloc [60] technique) eliminates the starting point and the substrate for reproliferations. In rare cases fibrovascular membranes may also develop along the anterior vitreous remnants creating anterior hyaloid fibrovascular membranes. Neovascularizations at the internal side of the sclerotomies may be the source for recurrent hemorrhage, if no neovascularizations are present in the posterior pole. In advanced cases it may be difficult to differentiate between diabetic reproliferations and proliferative vitreoretinopathy reactions, which we also occasionally see after surgery for rhegmatogenous retinal detachment in nondiabetic eyes. Hemorrhage Small amounts of blood are found in most eyes after vitreous surgery for diabetic retinopathy and significant rebleeding is not exceptionally rare. Diabetic neovascularizations are cut or torn off during surgery creating opening of the vessel lumen and a potential source for a vitreous hemorrhage. Bleeding vessels may be identified intraoperatively by lowering the intraocular pressure and should be coagulated intraoperatively using endodiathermia. If the source of hemorrhage is a large vessel or the optic disk, this may not be possible. The bleeding often stops spontaneously or after increasing the infusion pressure, but it may cause hemorrhages in the early postoperative phase when the blood pressure increases. Very dense hemorrhages after vitrectomy may be removed by revitrectomy or by fluid-air exchange [61]. Iris Rubeosis and Neovascular Glaucoma Neovascularizations of the iris and chamber angle may occur if growth factors from the ischemic retina reach the anterior segment of the eye. Obstruction of the trabecular meshwork by fibrovascular membranes and increased intraocular pressure is a severe complication of diabetic retinopathy. Two aspects of vitreous surgery may contribute to the development of postoperative iris rubeosis. First, the removal of preretinal neovascularizations may worsen retinal ischemia and further stimulate the production of growth factors. Second, after removal of the vitreous these cytokines can more easily diffuse to
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the anterior segment of the eye. Especially after additional intracapsular cataract surgery there is no diffusion barrier left between iris and retina. To reduce the stimulus for neovascularizations, endolaser treatment should be applied at the end of vitreous surgery whenever possible.
Iris rubeosis is associated with retinal detachment in diabetic eyes. Sudden appearance of rubeosis in the postoperative course should alert the ophthalmologist to carefully inspect the peripheral retina [62].
References
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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;13:468473. 46 Sakamoto T, Miyazaki M, Hisatomi T, Nakamura T, Ueno A, Itaya K, Ishibashi T: Triamcinolone-assisted pars plana vitrectomy improves the surgical procedures and decreases the postoperative blood-ocular barrier breakdown. Graefes Arch Clin Exp Ophthalmol 2002;240:423429. 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;111:20442049. 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;29:99105. 50 Shinoda K, OHira 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: 276280. 51 Melberg NS, Thomas MA: Nuclear sclerotic cataract after vitrectomy in patients younger than 50 years of age. Ophthalmology 1995; 102:14661471. 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;110:13351339.
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;32:193197. 56 Kroll P, Gerding H, Busse H: Occurrence of retinal complications by reproliferation following vitreoretinal silicone surgery. Klin Monatsbl Augenheilkd 1989;195:145149. 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: 267272. 58 Meredith TA, Kaplan HJ, Aaberg TM: Pars plana vitrectomy techniques for relief of epiretinal traction by membrane segmentation. Am J Ophthalmol 1980;89:408413. 59 Meredith TA: Epiretinal membrane delamination with a diamond knife. Arch Ophthalmol 1997;115:15981599. 60 Meier P, Wiedemann P: Vitrectomy for traction macular detachment in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 1997;235:569574. 61 Martin DF, McCuen BW 2nd: Efficacy of fluid-air exchange for postvitrectomy diabetic vitreous hemorrhage. Am J Ophthalmol 1992;114:457463. 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;1:375381.
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Pharmacological Treatment of Diabetic Retinopathy

Gabriele E. Lang
Universittsklinikum Ulm, Augenklinik, Ulm, Germany
Key Words Diabetic retinopathy Somatostatin analogue Octreotide Protein kinase C inhibitor Ruboxistaurin mesylate
enables a new therapeutical approach for the treatment of diabetic retinopathy. Ongoing prospective clinical trials investigate whether the treatment with the specific PKC- inhibitor can prevent the progression of diabetic retinopathy and diabetic macular edema. Copyright 2007 S. Karger AG, Basel
Abstract Despite the better options of controlling diabetes mellitus and although the prognosis of diabetic retinopathy has markedly improved by laser treatment and vitreoretinal surgery, diabetic retinopathy still is the leading cause of blindness in working age people in industrialized countries. Little has changed in the last decades regarding the prognosis of ocular complications in diabetes mellitus. We therefore need better tools and new therapeutic approaches for the prevention and treatment of diabetic ocular complications. Newer therapeutic options are directed at the causative mechanisms of diabetic retinopathy. Experimental and clinical evidence suggests that pharmacological compounds like somatostatin analogues and protein kinase C (PKC) inhibitors may be effective in the treatment of diabetic retinopathy. Chronic overproduction of growth hormone and insulin-like growth factor 1 play an important role in the pathogenesis of diabetic retinopathy. In the treatment of diabetic retinopathy somatostatin receptors are the targets of somatostatin analogues like octreotide. Octreotide has shown to be a promising treatment of diabetic retinopathy and diabetic macular edema. One important pathomechanism in the development of diabetic retinopathy is the activation of PKC induced by high glucose due to an increased diacylglycerol level. The selective PKC- inhibitor ruboxistaurin mesylate
Laser treatment and vitreoretinal surgery have markedly improved the prognosis of visual problems due to diabetic retinopathy (DR). Nevertheless, DR is still the leading cause of blindness in industrialized countries in adults of working age. There is at present no pharmacological treatment approved for DR. We have however some evidence so far that pharmacological approaches are effective in the treatment of DR. Several approaches to drug treatment are under investigation at present. Two of the new systemical approaches to drug treatment of DR are discussed in this paper.
Pathophysiology of DR
The pathophysiology of DR is complex. Hyperglycemia results in the production of advanced glycation end products, activation of the polyol pathway and changes in the cellular signal transduction. The results are hyperviscosity, proinflammatory milieu, reduced flexibility of white and red blood cells, increased adhesion of leucocytes and increased oxidative stress.
Prof. Dr. Gabriele E. Lang Universittsklinikum Ulm, Augenklinik, Prittwitzstrasse 43 DE89075 Ulm (Germany) Tel. +49 731 500 27551, Fax +49 731 500 27549 E-Mail gabriele.lang@medizin.uni-ulm.de
Fig. 1. Pathomechanism and pharmaco-
Hyperglycemia
logical 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 PCK- activation results in capillary leakage and neovascularization. The effects can be inhibited with the PKC- inhibitor 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.
DAG
AGE
Glycation
+
PKC- inhibitor
+
PKC- Capillary leakage
+
VEGF
+
Capillary occlusion
Somatostatin analogue
IGF-1 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 [24] (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 1030% 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.
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 (Sstr15). 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.
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
Drug Treatment of Diabetic Retinopathy
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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 pro- and 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. Bhm 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
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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 4761. 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 2550% 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-, histidine- and aspartate-/glutamate-specific
Lang
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 PKC- is 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. PKC- is the dominating isoenzyme in the retina. One reason for the privileged activation of PKC- in 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 growthfactor-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-mediated 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 TGF- and connective tissue growth factor. The expression of these growth factors can be blocked by PKC inhibition [25].
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Treatment of DR with PKC- Inhibitors
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].
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 PKC- inhibitor 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, placebo-controlled study the safety and efficacy of the orally administered PKC- inhibitor 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 3646 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-
Conclusion
The most promising drugs for the treatment of DR are octreotide and the PKC- inhibitor 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 PKC- inhibitor 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; 220:526531. 2 Joussen AM, Fauser S, Krohne TU, Lemmen KD, Lang GE, Kirchhof B: Diabetische Retinopathie: Pathophysiologie und Therapie einer hypoxieinduzierten Entzndung. Ophthalmologe 2003;100:363370. 3 Lang GE, Kampmeier J: Die Bedeutung der Proteinkinase C in der Pathophysiologie der diabetischen Retinopathie. Klin Monatsbl Augenheilkd 2002;219:769776. 4 Lang GE: Therapie der diabetischen Retinopathie mit Somatostatinanaloga. Ophthalmologe 2004;101:290293. 5 Grant 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, pp165184. 6 Poulsen JE: Diabetes and anterior pituitary insufficiency: final course and postpartum study of a diabetic patient with Sheehans syndrome. Diabetes 1966;15:7377. 7 Spranger J, Mohlig M, Osterhoff M, Bhnen 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;33:312316. 8 Bhm BO, Lang GE, Volpert O, Jehle PM, Kurkhaus A, Rosinger S, Lang GK, Bouck N: Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy. Diabetologia 2003; 46:394400. 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;180:417424. 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;240:227231. 11 Bhm 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;23:504509.
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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;44:659673. 15 Inoue M, Kishimoto A, Takai Y, Nishizuka Y: Studies on a cyclic nucleotide-independent 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; 255:22732276. 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;43:11221129.
18 Craven PA, Davidson CM, DeRubertis FR: Increase in diacylglycerol mass in isolated glomeruli by glucose from de novo synthesis of glycerolipids. Diabetes 1990;39:667674. 19 Nishizuka Y: The molecular heterogeneity of protein kinase C and its implication for cellular regulation. Nature 1988;334:661665. 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;74:161165. 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: 967973. 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;46:14731480. 25 Fumo P, Kuncio GS, Ziyadeh FN: PKC and high glucose stimulate collagen 1 transcriptional activity in a reporter mesangial cell line. Am J Physiol 1994;267:632638. 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; 272:61466150. 27 Ishii H, Jirousek MR, Koya D, et al: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC- inhibitor. Science 1996;272:728731. 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: 21882197.
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Horst Helbig
Department Ophthalmology, University Hospital Zurich, Zurich, Switzerland
Key Words Diabetic retinopathy Surgery Vitrectomy Vitreous hemorrhage Tractional retinal detachment
Introduction
Abstract Surgery for diabetic retinopathy addresses late secondary complications of a primary microvascular disease. Since surgery is not a causative therapy, the functional outcome of surgery depends on the degree of retinal ischemia and may be disappointing even in technically and anatomically successfully operated eyes. Typical indications for vitrectomy are vitreous hemorrhage, tractional retinal detachment, combined tractional rhegmatogenous retinal detachment and tractive macular edema. More recently diffuse diabetic macular edema has been shown to improve after removal of an attached vitreous in several cases. Neovascular glaucoma requires aggressive surgical intervention to salvage the eye. Cataract surgery is commonly performed in eyes with diabetic retinopathy. It may however deteriorate diabetic eye disease. Vitreous surgery also has a potential for severe complications in diabetic eyes which can be ameliorated but not eliminated by proper surgical strategies and techniques. The decision for an intervention in diabetic eyes always requires a careful weighing of risks and benefits of surgery.
Only a few decades ago diabetic retinopathy was regarded as an untreatable disease, in many eyes inevitably running its course to blindness [1]. Desperate therapeutic approaches such as hypophysectomy were performed in order to ameliorate the course of the disease [2]. Within a short period of time various effective treatment strategies have been introduced. Photocoagulation of the retina has been shown to improve the course of proliferative retinopathy [3] and macular edema [4]. Improved insulin treatment with near normoglycemic control [5, 6] and intense treatment of arterial hypertension [7] have been shown to have a prophylactic benefit. Possibly in the near future drug therapy directly targeting steps involved in the pathobiochemistry may be available [8, 9]. The enthusiasm and optimistic hopes that blindness due to diabetic retinopathy could be eliminated has been disappointed. The major problem today is to translate the available knowledge into clinical practice [10, 11]. Successful surgical treatment of diabetic retinopathy began with the introduction of pars plana vitrectomy by Machemer [12, 13] in the 1970s. Eyes with blinding complications such as vitreous hemorrhage or tractional retinal detachment, being untreatable before, could be salvaged and vision could be restored. However, surgery can only treat late secondary complications of a primarily microvascular disease. Surgery is not a causative therapeutic approach. Therefore functional results of vitreous sur-
Prof. Dr. med. H. Helbig Augenklinik, Universittsspital Zrich Frauenklinikstrasse 24 CH8092 Zrich (Schweiz) Tel. +41 44 255 4993, Fax +41 44 255 4472, E-Mail horst.helbig@usz.ch
gery are commonly disappointing even if anatomical success rates have continuously improved with better understanding of the pathophysiology and technical instrumentation [1418].
Effect of Surgery on Diabetic Eye Disease
Surgery can address various therapeutical goals in diabetic retinopathy. Media opacities, especially vitreous hemorrhage but also lens opacities, can be removed and a clear optical system can be restored. After removal of media opacities intraoperative laser treatment of the ischemic retina becomes possible and the neovascular stimulus with production of vasoproliferative growth factors can be reduced. A detached retina can be surgically reattached and the contact between photoreceptors and retinal pigment epithelium can be restored. Mechanical traction on the retina by active or atrophic membranes can be relieved and retinal function can recover. However, in addition to these more passive effects, vitreous surgery also has effects on the future development of diabetic eye disease. A partially attached vitreous is an ideal schaffold for the ingrowth of diabetic neovascularizations. After complete removal of the vitreous the tendency for ingrowth of fibrovascular membranes is reduced, since a proper matrix for neovascularizations is missing. On the other hand, it is important to realize that active preretinal neovascularizations contribute to the oxygen and nutrient supply of the inner retina. After surgical removal of these neovascularizations it must be assumed that retinal ischemia is worsened and the neovascular stimulus is increased by surgery. Therefore, eyes in which active neovascularizations are removed require intense immediate intraoperative photocoagulation. In addition, removal of the vitreous and replacement by a balanced salt solution and later by aqueous humor changes diffusion properties and fluid currents in the vitreous cavity. On the one hand, oxygen [19, 20] and nutrients (possibly from the ciliary body) can more easily diffuse from the vitreous cavity to the inner retina, improving the metabolic situation for the ischemic retina. On the other hand, growth factors can more easily leave the retinal tissue into the vitreous cavity. This may have 2 effects. First, the concentration of these cytokines within the retinal tissue is decreasing. This may have a positive effect, possibly explaining the improvement of diabetic macular edema after removing an attached vitreous. And second, these cytokines derived from the ischemic retina can more easily reach the anterior segment of the eye,
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where their vasoproliferative effects may lead to iris neovascularizations and neovascular glaucoma [1418]. An altered environment in an eye after vitrectomy is probably also responsible for the development of lens opacities and the nearly mandatory acceleration of cataract formation after vitrectomy. It is speculated that the lens, being a very low oxygen compartment [21], is exposed to higher oxygen tension after vitrectomy [19]. This may be due to a facilitated diffusion of oxygen if the lens is in direct contact with the fluid currents in the vitreous cavity after vitrectomy and not with the vitreous itself.
Indications
Vitreous Hemorrhage Diabetic vitreous hemorrhage is a common indication for surgery. The first pars plana vitrectomy was performed 35 years ago by Machemer [12, 13] in an eye with diabetic vitreous hemorrhage. Vitreous hemorrhage occurs if neovascularizations tear. This usually happens in eyes which undergo partial vitreous detachment or contraction of the fibrovascular membranes which may occasionally occur shortly after retinal photocoagulation. A nonclearing diabetic vitreous hemorrhage is generally considered to be an indication for surgery. However, should we wait 2 weeks or 1 year for clearing before surgery is advised? The individual decision for surgery is commonly not as easy and other factors have to be included in the considerations for or against surgery. In the presence of retinal detachment, iris neovascularizations or macular edema, irreversible damage may be avoided if immediate surgery is performed. If the hemorrhage is very dense or recurrent, it may also be advisable to perform early surgery. Other patients however will regain vision without surgery if the hemorrhage clears spontaneously within several months. The Diabetic Retinopathy Vitrectomy Study had randomized eyes with vitreous hemorrhage for early surgery or observation. This study only showed a benefit for early surgery in younger diabetics [22, 23]. Younger diabetics more commonly have an attached vitreous and traction on the retina. Ultrasound echography allows identifying tractional membranes at the posterior pole, even if the ophthalmoscopic view is obscured by the hemorrhage. In eyes with known traction on the central retina or evidence of traction in ultrasound echography [24] surgery should not be delayed (fig. 1).
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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, duraSurgery for Diabetic Retinopathy
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
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fibrovascular membranes require retinal photocoagulation. Laser treatment induces fibrotic transformation of the neovascularizations and possibly contraction of the membranes, which may eventually lead to progression of the tractional detachment [27]. Before vitreous surgery was available, these eyes had a very poor prognosis and laser treatment was considered to be dangerous in these eyes. Now that we can surgically treat these tractional membranes, scatter laser treatment is recommended if active neovascularizations are present, but a close followup is mandatory. Vitrectomy is recommended if the detachment progresses and threatens the fovea or if significant vitreous hemorrhage develops. Tractional Rhegmatogenous Retinal Detachment Traction by diabetic fibrovascular membranes may create retinal tears and a rhegmatogenous retinal detachment may develop (fig. 4). This combined tractional and rhegmatogenous retinal detachment is relatively rare and shows both features of a tractional detachment with membranes tightly adhering to the retina and a retinal tear. The retinal tear itself may be difficult to identify, but the shape of the retinal detachment is quite different. A pure tractional detachment is usually concave, tent-like shaped and the retina is not mobile. The appearance of rhegmatogenous detachment is convex, bullous and mobile. While a tractional detachment progresses slowly and does not require emergency surgery, a tractional-rhegmatogenous detachment usually progresses rapidly and has to be operated without delay. The prognosis of tractional rhegmatogenous retinal detachment is less favorable than for pure tractional detachments. Intraoperatively it is more difficult to separate the membranes from a mobile retina than from a fixed and relatively stable retina. Perfluorcarbon should not be used until the membranes are removed from the posterior pole. Intraoperative complications are relatively common in this type of surgery [28]. In addition, we occasionally observe reproliferations in the postoperative course which represent a combination of diabetic fibrovascular membranes and the typical proliferative vitreoretinopathy. These proliferations are surgically very difficult to manage. Tractive Macular Edema In some cases traction on the fovea may cause tractive macular edema, even if the fovea itself is not detached. Traction of diabetic fibrovascular membranes may cause an ophthalmoscopic appearance with typical hard exudates (fig. 5). Atrophic fibrovascular membranes may
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Fig. 3. Tractional retinal detachment nasally to the fovea. The
membranes were atrophic after scatter laser treatment and the traction did not threaten the fovea. Vision was 20/25 and no further therapy was performed.
Fig. 4. Tractional rhegmatogenous retinal detachment, visual
acuity hand movement. The retinal tear is marked with an arrow.
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Fig. 5. a Diabetic tractional macular edema with hard exudates. Vision was 20/400. Vitrectomy with removal of the tractional membranes was performed in combination with endolaser treatment. b One year later, slow
resolution of exudates and edema was observed, vision had improved to 20/40.
also create a picture similar to macular pucker with distortion of the central retina. The best therapy for tractional edema is to remove the traction. Tractional membranes may often be easily visible, but in other cases biomicroscopy only shows minimal changes. In some instances ocular coherence tomography can clearly demonstrate the fine membranous structures exerting tractional forces and creating swelling of the macula [29]. Thus, ocular coherence tomography imaging should be included in the diagnostic workup of diabetic macular edema. In cases without traction, laser treatment is a valuable approach; focal laser treatment is not recommended if mechanical traction is the cause for macular edema. Visual recovery after surgery is mainly dependent on the degree of macular ischemia; therefore preoperative fluorescein angiography is helpful to give a picture of the status of macular microcirculation. Diffuse Macular Edema Several recent reports have described an improvement of diffuse diabetic macular edema without visible traction after vitrectomy in eyes with attached vitreous [30]. The pathophysiological basis for this attempt was to improve access of oxygen and nutrients from the vitreous to
the retina, and vice versa, to facilitate diffusion of cytokines from the retinal tissue into the vitreous, avoiding accumulation of factors triggering macular edema within the macular tissue. Despite significant anatomical improvement of the edema after removal of the vitreous, recovery of vision was rather unsatisfactory in many cases. It is still controversial whether this approach with or without removal of the inner limiting membrane significantly improves the long-term course of the disease in eyes with diffuse diabetic macular edema without traction [31, 32]. Surgery for Neovascular Glaucoma The cause for neovascularizations of the iris and chamber angle is believed to be the ischemic retina, which produces vasoproliferative growth factors. These cytokines may diffuse to the anterior segment of the eye, triggering anterior segment neovascularizations. In aphacic and vitrectomized eyes there is no diffusion barrier between the anterior and posterior segment of the eye. Therefore these eyes are particularly at risk for the development of neovascular glaucoma. Therapy has to be primarily directed to the cause of the neovascular stimulus, the ischemic retina. The most important element of treatment is thereOphthalmologica 2007;221:103111
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fore retinal ablation by laser or cryotreatment [33]. Since this treatment can induce fibrotic regression but not complete dissolution of the membranes in the chamber angle, retinal ablation is often not sufficient to regulate intraocular pressure. Therefore additional treatment to lower intraocular pressure is usually necessary. Filtering surgery has a poor prognosis, since the high levels of cytokines in the aqueous humor stimulate fibrosis which is obstructing the fistula. Antimetabolites or glaucoma drainage devices [34] may be used to improve success rates but have an increased risk for complications. Transscleral cryotherapy [35] or transscleral laser treatment to the ciliary body is an alternative to reduce aqueous humor production but has a relatively narrow therapeutic window; overtreatment may induce phthisis of the globe. If other diabetic complications are present, requiring vitreoretinal surgery, direct endolaser treatment to the ciliary processes can be applied to reduce aqueous humor production [36]. In severe cases instillation of liquid silicone can form a diffusion barrier between the retina and the anterior segment of the eye and may contribute to a stabilization of anterior segment neovascularization [37]. Cataract Surgery Second to age, diabetes is the main epidemiological risk factor for the development of cataracts. Cataract surgery in eyes with diabetic retinopathy is performed to improve vision for the patient, but it also allows a clear view to the fundus for diagnosis and treatment of the retinopathy. However, cataract surgery may worsen retinopathy [38]. Neovascularizations and macular edema may be stimulated to grow after cataract surgery [39, 40]. Nevertheless, conventional cataract surgery with phacoemulsification and implantation of an intraocular lens can be safely performed in most eyes with diabetic retinopathy [41, 42]. Intracapsular surgery is associated with an increased risk for neovascular glaucoma [43] and should be avoided in diabetic eyes. Several other aspects should be taken into account. Whenever possible retinopathy should be treated and stabilized before surgery using adequate laser photocoagulation. Especially eyes with iris neovascularizations require intense preoperative laser coagulation or transscleral cryotreatment of the retina. If this is not possible before surgery or not sufficient, a combined procedure with cataract and vitreous surgery including endolaser treatment of the retina should be considered. Fibrinous reaction after cataract surgery alone may render postoperative laser treatment in eyes with iris rubeosis difficult.
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If macular edema is present, preoperative focal laser treatment should be used. If it is not possible to have a completely dry macula at the time of cataract surgery, there is a high risk for worsening of macular edema and visual loss. If cataract surgery has to be performed in the presence of diabetic macular edema, it may be recommended to combine cataract surgery with an intravitreal injection of triamcinolone [4446]. Intravitreal triamcinolone has been shown to successfully improve vision and retinal thickening in diabetic macular edema [47]. Other specific aspects for cataract surgery in eyes with diabetic retinopathy include a large capsulorhexis and an intraocular lens with large optics to facilitate possible subsequent diagnosis and laser treatment of the retina. Silicone intraocular lenses should be avoided because they interact with liquid silicone which possibly has to be used for endotamponade in the later course of diabetic eye disease. Diabetic eyes have an increased risk for postoperative fibrin exudation and formation of synechiae between the lens capsule and the iris due to an impaired blood retinal barrier [4850].
Complications of Surgery for Diabetic Retinopathy
Cataract Opacification of the lens is a mandatory consequence of vitrectomy independently of the cause for vitrectomy. Generally, development of cataracts appears to occur faster in diabetic eyes after vitrectomy than after vitrectomy in nondiabetic eyes. Silicone tamponade leads to an acceleration of cataract formation. Gas tamponade induces an immediate posterior subcapsular opacification occurring a few hours after surgery, which is mostly reversible. Later nuclear sclerosis develops, which does not appear to be much faster after gas tamponade than after vitrectomy with Ringers solution [48]. In young patients cataract formation occurs more slowly, and the lens may remain clear for many years or decades before surgery becomes necessary [51]. In older patients significant cataracts may form within a few months after vitrectomy. The rapid development of cataract after vitrectomy especially in older diabetics has led some surgeons to perform combined viteoretinal and cataract surgery even for eyes with primarily clear lenses. This approach has been shown to be successful and saves the patient a second surgery [52, 53]. Combined surgery however appears to be associated with a higher rate of inflammatory responses with fibrin in the anterior chamber and the formation of synechiae compared to a 2-step procedure [50]. It may
Helbig
therefore be safer to operate on the lens in a second surgery if possible. Combined cataract and vitreoretinal procedure may only be performed if lens opacities are disturbing intraoperative visualization of the posterior segment. Retinal Detachment Rhegmatogenous retinal detachment is a typical complication of vitrectomy [54]. Retinal holes may be created intraoperatively when traction to the vitreous base is exerted. The most common location of iatrogenic holes is close to the sclerotomies where intraocular instruments are introduced into the eye. The more instruments are exchanged during surgery, the higher the risk for creating holes. The risk can be reduced by carefully removing the anterior vitreous next to the sclerotomies with the cutter before instruments like scissors are introduced. In righthanded surgeons the most common location is temporal superior in the right eye and nasal superior in the left eye. Careful inspection of the peripheral retina out to the ora serrata at the end of the surgery under indentation using a wide angle viewing system may identify such retinal tears [55]. Adequate treatment can reduce the risk for postoperative retinal detachment. If postvitrectomy rhegmatogenous retinal detachment occurs, pneumatic retinopexy as a minimum invasive procedure is often the treatment of choice. The tears are anteriorly located and can be reached with transscleral cryotherapy without opening the conjunctiva. The holes are mostly located in the superior quadrants and gas injection in a vitrectomized eye is not associated with a high risk of creating new holes. Another possible cause for postoperative retinal detachment after vitrectomy for diabetic retinopathy are retinal holes located more posteriorly. These holes may be created during the preparation of membranes tightly adhering to the thin and atrophic retina mostly being located close to the major vascular arcades. If such holes are recognized intraoperatively, all traction surrounding the hole has to be released, the hole should be encircled with laser spots and an adequate internal tamponade, often liquid silicone, should be used. Tractive redetachment may occur if severe reproliferations develop. The traction of reproliferation may also tear off laser scars and create a combined tractional rhegmatogenous retinal detachment. Reproliferations Reproliferation of diabetic fibrovascular membranes is a severe complication after vitrectomy for diabetic retSurgery for Diabetic Retinopathy
inopathy. Since the ischemic retina is believed to secrete the proliferative stimuli, the ischemic retina has to be adequately treated with laser. Especially in eyes with silicone tamponade growth factors may concentrate in the shallow interface between silicone and retina and provide an intense stimulus for reproliferations [56, 57]. Complete removal of all fibrovascular tissue using various techniques (segmentation technique [58], delamination [59] or en bloc [60] technique) eliminates the starting point and the substrate for reproliferations. In rare cases fibrovascular membranes may also develop along the anterior vitreous remnants creating anterior hyaloid fibrovascular membranes. Neovascularizations at the internal side of the sclerotomies may be the source for recurrent hemorrhage, if no neovascularizations are present in the posterior pole. In advanced cases it may be difficult to differentiate between diabetic reproliferations and proliferative vitreoretinopathy reactions, which we also occasionally see after surgery for rhegmatogenous retinal detachment in nondiabetic eyes. Hemorrhage Small amounts of blood are found in most eyes after vitreous surgery for diabetic retinopathy and significant rebleeding is not exceptionally rare. Diabetic neovascularizations are cut or torn off during surgery creating opening of the vessel lumen and a potential source for a vitreous hemorrhage. Bleeding vessels may be identified intraoperatively by lowering the intraocular pressure and should be coagulated intraoperatively using endodiathermia. If the source of hemorrhage is a large vessel or the optic disk, this may not be possible. The bleeding often stops spontaneously or after increasing the infusion pressure, but it may cause hemorrhages in the early postoperative phase when the blood pressure increases. Very dense hemorrhages after vitrectomy may be removed by revitrectomy or by fluid-air exchange [61]. Iris Rubeosis and Neovascular Glaucoma Neovascularizations of the iris and chamber angle may occur if growth factors from the ischemic retina reach the anterior segment of the eye. Obstruction of the trabecular meshwork by fibrovascular membranes and increased intraocular pressure is a severe complication of diabetic retinopathy. Two aspects of vitreous surgery may contribute to the development of postoperative iris rubeosis. First, the removal of preretinal neovascularizations may worsen retinal ischemia and further stimulate the production of growth factors. Second, after removal of the vitreous these cytokines can more easily diffuse to
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the anterior segment of the eye. Especially after additional intracapsular cataract surgery there is no diffusion barrier left between iris and retina. To reduce the stimulus for neovascularizations, endolaser treatment should be applied at the end of vitreous surgery whenever possible.
Iris rubeosis is associated with retinal detachment in diabetic eyes. Sudden appearance of rubeosis in the postoperative course should alert the ophthalmologist to carefully inspect the peripheral retina [62].
References
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Arch Ophthalmol 1987; 105:16791682. 28 Thompson JT, de Bustros S, Michels RG, Rice TA: Results and prognostic factors in vitrectomy for diabetic traction-rhegmatogenous retinal detachment. Arch Ophthalmol 1987;105:503507. 29 Gallemore RP, Jumper JM, McCuen BW 2nd, Jaffe GJ, Postel EA, Toth CA: Diagnosis of vitreoretinal adhesions in macular disease with optical coherence tomography. Retina 2000;20:115120. 30 Pendergast SD, Hassan TS, Williams GA, Cox MS, Margherio RR, Ferrone PJ, Garretson BR, Trese MT: Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid. Am J Ophthalmol 2000;130:178186. 31 Gandorfer A, Messmer EM, Ulbig MW, Kampik A: Resolution of diabetic macular edema after surgical removal of the posterior hyaloid and the inner limiting membrane. Retina 2000;20:126133. 32 Yamamoto T, Hitani K, Sato Y, Yamashita H, Takeuchi S: Vitrectomy for diabetic macular edema with and without internal limiting membrane removal. Ophthalmologica 2005; 219:206213. 33 Pauleikhoff D, Gerke E: Photocoagulation in diabetic rubeosis iridis and neovascular glaucoma. Klin Monatsbl Augenheilkd 1987; 190:1116. 34 Honrubia FM, Gomez ML, Hernandez A, Grijalbo MP: Long-term results of silicone tube in filtering surgery for eyes with neovascular glaucoma. Am J Ophthalmol 1984; 97:501504. 35 Nabili S, Kirkness CM: Trans-scleral diode laser cyclophoto-coagulation in the treatment of diabetic neovascular glaucoma. Eye 2004;18:352356.
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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;236:730733. 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;98:21962198. 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;77:208211. 41 Benson GT, Flynn HW, Blankenship GW: Posterior chamber intraocular lens implantation during diabetic pars plana vitrectomy. Ophthalmology 1989;96:603610. 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;90:814820. 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;131:468471.
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;13:468473. 46 Sakamoto T, Miyazaki M, Hisatomi T, Nakamura T, Ueno A, Itaya K, Ishibashi T: Triamcinolone-assisted pars plana vitrectomy improves the surgical procedures and decreases the postoperative blood-ocular barrier breakdown. Graefes Arch Clin Exp Ophthalmol 2002;240:423429. 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;111:20442049. 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;29:99105. 50 Shinoda K, OHira 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: 276280. 51 Melberg NS, Thomas MA: Nuclear sclerotic cataract after vitrectomy in patients younger than 50 years of age. Ophthalmology 1995; 102:14661471. 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;110:13351339.
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;32:193197. 56 Kroll P, Gerding H, Busse H: Occurrence of retinal complications by reproliferation following vitreoretinal silicone surgery. Klin Monatsbl Augenheilkd 1989;195:145149. 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: 267272. 58 Meredith TA, Kaplan HJ, Aaberg TM: Pars plana vitrectomy techniques for relief of epiretinal traction by membrane segmentation. Am J Ophthalmol 1980;89:408413. 59 Meredith TA: Epiretinal membrane delamination with a diamond knife. Arch Ophthalmol 1997;115:15981599. 60 Meier P, Wiedemann P: Vitrectomy for traction macular detachment in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 1997;235:569574. 61 Martin DF, McCuen BW 2nd: Efficacy of fluid-air exchange for postvitrectomy diabetic vitreous hemorrhage. Am J Ophthalmol 1992;114:457463. 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;1:375381.
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Evidence-Based Therapy of Diabetic Retinopathy

S. Hoerle P. Kroll
Klinik fr Augenheilkunde, Universittsklinikum Giessen und Marburg GmbH, Marburg, Germany
Key Words Diabetic retinopathy Treatment, evidence-based Vitrectomy
Abstract Introduction: Evidence-based medicine is often misunderstood as cookbook medicine with standard recipes that does not take clinical experience into account. It is, however, supposed to be a basis for decision making in caring for individual patients under consideration of patients preferences. This seems to be very important, since diabetic retinopathy continues to be the most frequent cause of vision loss in working age adults with negative consequences for patients quality of life and for health economics. Materials and Methods: The most important evidence-based therapy for diabetic retinopathy and maculopathy is laser coagulation. Vitrectomy for proliferative stages has also been proven effective by clinical studies. For more recent treatment options like triamcinolone injection and vitrectomy for diabetic macular edema there is a lower level of evidence so far. Results: The Diabetic Retinopathy Study was the first to show the effectiveness of panfundus laser coagulation for a larger group of patients. The Early Treatment Diabetic Retinopathy Study in turn serves as a basis for laser coagulation of retinopathy and maculopathy. The Diabetic Retinopathy Vitrectomy Study could show the advantages of timely vitrectomy. Both the Diabetes Control and Complications Trial and the United
Kingdom Prospective Diabetes Study could show the value of intensive blood glucose control. Discussion: Evidencebased medicine on the basis of the studies mentioned above is practiced quite self-evidently in ophthalmo-diabetology. It should be regarded as a helpful tool for special therapeutic situations which still leaves room for ones personal clinical experience to be included. It is somewhat problematic that the term evidence-based medicine seems to be restricted to the results of large randomized studies, because even special problems and very individual, difficult therapeutic questions can be placed on an evidence-based foundation, although at a lower level of evidence, using todays modern Copyright 2007 S. Karger AG, Basel means of literature research.
Introduction
Evidence-based medicine (EBM) is often misunderstood and sometimes feared as cookbook medicine with standard recipes that does not take clinical experience into account. However, in 1996 Sackett et al. [44] defined EBM as the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.
Dr. med. Steffen Hrle Klinik fr Augenheilkunde Universittsklinikum Giessen und Marburg GmbH, Standort Marburg Robert-Koch-Strasse 4, DE35037 Marburg (Germany) Tel. +49 6421 286 2600, Fax +49 6421 286 5678, E-Mail Hoerle@med.uni-marburg.de
Table 1. Level of evidence (modified from Centre for Evidence-
Based Medicine [4], 2004) Level of evidence 1a 1b 2a 2b 3a 3b 4 5 Basis systematic review of randomized controlled trials individual randomized controlled trial systematic review of cohort studies individual cohort study systematic review of case-control studies individual case control study case series (and poor quality cohort and case control studies) consensus conference and expert opinion
Table 2. Grade of recommendation (modified from Centre for Evidence-Based Medicine [4], 2004)
Grade of recommendation
A B C D
consistent level 1 studies consistent level 2 or 3 studies or extrapolations from level 1 studies level 4 studies or extrapolations from level 2 or 3 studies level 5 evidence or troublingly inconsistent or inconclusive studies of any level
The implementation of EBM principles into the treatment regimen of diabetic retinopathy seems to be immensely important, since diabetic retinopathy continues to be the most frequent cause of blindness among working age adults in industrialized countries [29] despite various treatment approaches such as laser photocoagulation, cryocoagulation, pars plana vitrectomy, intravitreal triamcinolone and others. In Germany about 1,5002,000 diabetics become legally blind each year. The risk of blindness is thus increased by a factor of 29 compared to nondiabetics. Economic costs of about EUR 100 million arise per year in welfare payments to the blind [18, 20, 29].
Results
Material and Methods

Sackett et al. [44] generated levels of evidence for ranking the validity of evidence and tied them as grades of recommendations to the advice given in a certain report. These levels, which were first brought up as a basis for recommendations about the use of antithrombotic agents [44], have grown increasingly sophisticated [4]. They evolved over time and are now widely used in various fields of medicine (tables 1, 2). In ophthalmo-diabetology EBM has been applied for many years. Laser coagulation has proven effective by randomized, controlled, clinical trials with an evidence level of 1, as well as pars plana vitrectomy for more advanced proliferative stages of diabetic retinopathy. Intravitreal triamcinolone injection and pars plana vitrectomy for treatment of diabetic macular edema so far have only lower levels of evidence. The most important studies which are the basis for todays treatment of diabetic retinopathy and maculopathy are described below. Tables 3 and 4 show classification systems for nonproliferative/proliferative diabetic retinopathy and for diabetic maculopathy and they also show which stages were treated in different studies.
Diabetic Retinopathy Study The Diabetic Retinopathy Study (DRS) was carried out between 1971 and 1975. It tried to determine whether photocoagulation could prevent severe vision loss due to proliferative diabetic retinopathy. Furthermore, efficacy and safety of argon laser coagulation and xenon photocoagulation were compared. It was the first randomized, controlled, clinical trial dealing with laser treatment of proliferative diabetic retinopathy involving 11,700 patients enrolled at 15 medical centers [23, 4953]. The study has an evidence level of 1b. In order to be eligible for the study, patients had to have a visual acuity of at least 20/100 in each eye. In addition, proliferative diabetic retinopathy had to be present in at least 1 eye or severe nonproliferative retinopathy in both eyes. The patients included had 1 eye randomized to a treatment group receiving immediate photocoagulation. The other eye remained untreated and served as control. The treated eye was again randomized to either argon laser coagulation or xenon photocoagulation. The Diabetic Retinopathy Study could show that both types of coagulation could reduce the risk of suffering a severe vision loss by 150%. It was concluded, therefore, that argon laser coagulation and xenon photocoagulation were beneficial over no treatment and that there was only a moderate risk of coagulation induced visual acuity or visual field loss. High-risk proliferative diabetic retinopathy was determined as the stage of retinopathy where benefits of coagulation treatment outweigh its risks. Because of its clear results, the study was terminated early [52].
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Table 3. Classification systems for diabetic retinopathy
International Clinical Diabetic Retinopathy Disease Severity Scale (American Academy of Ophthalmology [2], 2002) no retinopathy mild NPDR moderate NPDR severe NPDR PDR
Clincal disease severity scale of diabetic retinopathy according to ETDRS criteria no retinopathy mild NPDR moderate NPDR severe NPDR Severity of PDVR according to Kroll [29] (NPDR scale identical to ETDRS) PDVR A PDVR BN PDVR BT PDVR C1-C4 early PDR high risk PDR severe PDR
DCCT type 1 DM UKPDS type 2 DM ETDRS
DRS
DRVS
The upper part of the table shows 3 classification systems of diabetic retinopathy. The lower part lists important studies dealing with various stages of diabetic retinopathy. All studies have an evidence level of 1b. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) deal with mild and moderate cases of nonproliferative diabetic retinopathy (NPDR), the Diabetic Retinopathy
Study (DRS) with severe NPDR to high-risk proliferative diabetic retinopathy (PDR). The Early Treatment Diabetic Retinopathy Study (ETDRS) in turn covers cases of mild, moderate and severe NPDR and cases of early PDR. Finally the Diabetic Retinopathy Vitrectomy Study (DRVS; modified from Aiello [1], 2003) was performed on patients with high-risk and severe PDR. PDVR = Proliferative diabetic vitreoretinopathy; DM = diabetes mellitus.
Early Treatment Diabetic Retinopathy Study Between 1979 and 1991, the Early Treatment Diabetic Retinopathy Study, a multicenter, randomized clinical trial, tried to evaluate the effectiveness of both argon laser coagulation and aspirin therapy in delaying or preventing progression of early diabetic retinopathy to severer stages. Moreover, it tried to determine the best time to start laser coagulation therapy. For that purpose, a total of 13,700 patients with nonproliferative or early proliferative diabetic retinopathy were recruited and followed for at least 4 years [715, 23]. The study has an evidence level of 1b. The patients were divided into different groups depending on the degree of macular involvement and on the stage of diabetic retinopathy. One eye was randomized into a treatment group and treated immediately by laser coagulation, the other eye served as a control and was not treated until high-risk proliferative retinopathy developed. The eyes randomized into the treatment group were again randomized into 4 different treatment
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patterns, starting with a focal laser treatment followed by a mild or complete scatter laser coagulation, or starting with a mild or complete scatter laser coagulation followed by a focal laser treatment in the macular area (fig. 1). For focal laser treatment, the Early Treatment Diabetic Retinopathy Study (ETDRS) could show a reduced risk of moderate vision loss, especially in eyes where the fovea was threatened or affected by macular edema. In eyes treated focally even a moderate vision gain could be observed. In eyes with a mild to moderate nonproliferative diabetic retinopathy a scatter treatment turned out not to be necessary. However, eyes with a severe nonproliferative or an early proliferative diabetic retinopathy should be considered for scatter treatment. Finally, eyes with highrisk proliferative diabetic retinopathy should be treated to avoid disease progression. This was found to be true especially for patients with non-insulin-dependent diabetes mellitus. Patients with advanced active proliferative
Hoerle/Kroll
Table 4. Three classification systems of diabetic maculopathy
International Clinical Diabetic Macular Edema Disease Severity Scale (American Academy of Ophthalmology [2], 2002) no macular edema mild macular edema moderate macular edema severe macular edema
Clincal disease severity scale of diabetic maculopathy according to ETDRS criteria no macular edema clinically not significant macular edema clinically significant macular edema
Severity of diabetic maculopathy according to Bresnick [3] no macular edema focal macular edema diffuse macular edema
Early Treatment Diabetic Retinopathy Study Vitrectomy with/without ILM Peeling Intravitreal Triamcinolone
The only large, randomized, controlled, clinical trial dealing with diabetic maculopathy is the Early Treatment of Diabetic Retinopathy Study. Its level of evidence is 1b. For other therapeutic methods such as vitrectomy with or without peeling of the in-
ternal limiting membrane and for intravitreal triamcinolone injections only level 4 studies exist. ILM = Internal limiting membrane.
diabetic retinopathy should be considered for early vitrectomy. All patients with diabetic retinopathy should be monitored closely and followed up carefully. With regard to the use of aspirin, the study could show that aspirin did not affect the progression of retinopathy to the high-risk proliferative stage. It did not even increase the risk of vitreous hemorrhage or affect visual acuity. However, since aspirin was associated with a lower risk of cardiovascular disease, the study concluded that there were no ocular contraindications against aspirin use in cardiovascular or other diseases [715, 23]. Diabetic Retinopathy Vitrectomy Study Between 1979 and 1990, the Diabetic Retinopathy Vitrectomy Study, which consisted of 2 randomized clinical trials, compared early vitrectomy with conventional management of diabetes induced severe vitreous hemorrhage [23, 5458]. The study has an evidence level of 1b. For the first trial 1600 patients with recent severe vitreous hemorrhage, a visual acuity of at least 5/200 and an attached macula in at least 1 eye were recruited. They were randomized into either an early vitrectomy group,
treated by vitrectomy immediately, or a conventional treatment group, treated by vitrectomy if vitreous hemorrhage persisted for 11 year or if retinal detachment involving the macula occurred. For the second trial 381 patients with severe proliferative diabetic retinopathy and a visual acuity 60.2 in at least 1 eye were recruited. Again patients were randomized into either an early vitrectomy group, treated by vitrectomy immediately, or a conventional treatment group, consisting of laser coagulation when indicated and vitrectomy if severe vitreous hemorrhage did not clear after 612 months or if retinal detachment involving the macula occurred In the first trial, 25% of patients vitrectomized early regained a good visual acuity of 60.5 compared with 15% treated conventionally. There was, however, a higher treatment risk. Complications such as loss of light perception occurred in 25% of cases in the early vitrectomy group versus 19% in the conventional treatment group. In the second trial, there was also a higher probability of postoperative visual acuity 10.5 in the early vitrectomy group.
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No macular edema + Any type of NPDR or early PDR Immediate laser coagulation Deferral of laser coagulation
ETDRS patients
Mild scatter + focal later on Complete scatter + focal later on
Macular edema + mild-to-moderate NPDR Immediate laser coagulation Focal + mild scatter later on Mild scatter + focal later on Focal + complete scatter later on Complete scatter + focal later on Deferral of laser coagulation
Macular edema + severe NPDR to early PDR Immediate laser coagulation Mild scatter + focal Mild scatter + focal later on Complete scatter + focal Complete scatter + focal later on Deferral of laser coagulation
Fig. 1. ETDRS randomization scheme. PDR = Proliferative diabetic retinopathy; NPDR = nonproliferative diabetic retinopathy.
It should be kept in mind, however, that surgical techniques have changed considerably since conclusion of the study and that endolaser coagulation for example was not yet available in the late eighties [23, 5458]. Diabetes Control and Complications Trial Between 1983 and 1993 the Diabetes Control and Complications Trial (DCCT) was conducted as a clinical trial in the USA and Canada. Over 1,400 type 1 diabetics between 13 and 39 years of age who were otherwise
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healthy were included [23, 48]. The study has an evidence level of 1b. The study aimed at investigating the effect of improved blood glucose control on the onset and progression of diabetic diseases such as diabetic nephropathy, neuropathy and retinopathy. For that purpose the participants were divided into a primary prevention and a secondary intervention group. The former consisting of patients who had had diabetes for 15 years and did not suffer from diabetic retinoapthy, the latter consisting of patients who
Hoerle/Kroll
Table 5. Studies dealing with pars plana vitrectomy without peeling of the internal limiting membrane for treatment of diabetic mac-
ular edema Authors Lewis et al. [34] Van Effenterre et al. [62] Harbour et al. [19] Tachi and Ogino [48] Ferrari et al. [16] Ikeda et al. [22] Ikeda et al. [21] Otani and Kishi [39] Pendergast et al. [41] Yang [64] La Heij et al. [33] Yamamoto et al. [63] Otani and Kishi [40] Sato et al. [46] Year 1992 1993 1996 1996 1999 1999 2000 2000 2000 2000 2001 Type of study nonrandomized, case control study nonrandomized, case control study nonrandomized, retrospective, case control study nonrandomized, case control study nonrandomized, retrospective, case control study nonrandomized, case control study nonrandomized, case control study nonrandomized, prospective, case control study nonrandomized, retrospective, case control study non randomized, prospectiv, case control study nonrandomized, retrospective, case control study nonrandomized, retrospective, case control study nonrandomized, controlled, prospective, case control study nonrandomized, retrospective, case control study Patients Eyes 10 18 7 41 18 2 5 9 50 11 19 10 22 7 58 18 3 5 13 55 13 21 Edema diffuse diffuse diffuse diffuse 9 diffuse 9 cystoid cystoid cystoid 13 diffuse 8 cystoid diffuse diffuse 11 diffuse 2 cystoid 8 unclear 30 diffuse 12 cystoid 14 diffuse 13 cystoid cystoid Increase of ILM Follow-up visual acuity, % peeling months 602 861 572 532 only temporary 1001 802 382 49.12 84.62 47.62 no no no no no no no no no no 16 14 14.5 12 12 15 6 6 23.2 14.8
only 2! 3
2001 2002 2002
29 7 40
30 14 45
432 572 511
no no no
10.8 5 6
ILM = Internal limiting membrane. 1 Visual acuity increase of 1 line. 2 Visual acuity increase of 2 lines.
had had diabetes for 115 years who had mild to moderate nonoproliferative diabetic retinopathy among other complications. The patients from both groups were randomized into either a conventional treatment group, treated with insulin once or twice daily, urinary or blood sugar self-control once daily, clinical examinations every 3 months, and diet and exercise education or were randomized into an intensive treatment group, treated with an insulin pump or 63 insulin injections daily with an insulin dosage depending on sugar, diet and exercise,
blood sugar self-control at least 4 times a day and an initial hospitalization to start treatment. The study showed that keeping blood glucose levels as close to normal as possible slows the onset and progression of retinopathy, nephropathy and neuropathy caused by diabetes. In fact, it demonstrated that any sustained lowering of blood glucose helps, even if the person has a history of poor control. The DCCT could show that lowering blood glucose in type 1 diabetics by intensive treatment could reduce the
137
Table 6. Studies dealing with pars plana vitrectomy with peeling of the internal limiting membrane for treatment of diabetic macular
edema Authors Gandorfer et al. [17] Kumagai et al. [32] Ndoye Roth et al. [38] Dillinger and Mester [6] Kuhn et al. [31] Radetzky et al. [42] Stefaniotou et al. [47] Rosenblatt et al. [43] Year 2000 2002 2003 2004 2004 2004 2004 2005 Type of study nonrandomized, retrospective, case control study retrospective nonrandomized, retrospective, case control study nonrandomized, prospective, case control study nonrandomized, retrospective, case control study nonrandomized, retrospective, case control study nonrandomized, retrospective, case control study nonrandomized, retrospective, case control study Paients Eyes 11 103 15 55 27 5 52 20 12 135 19 60 30 5 73 26 Edema diffuse diffuse cystoid 60 diffuse 25 cystoid 16 diffuse 14 cystoid diffuse diffuse diffuse and cystoid Increase of ILM visual acuity, % peeling 922 ? 57.81 432 662 602 631 502 yes Follow-up months 16
in some 20 cases yes yes yes yes 55! yes 9.5 3 12 9.4 ? 8
ILM = Internal limiting membrane. 1 Visual acuity increase of 1 line. 2 Visual acuity increase of 2 lines.
risk for developing retinopathy by 76%. In patients with mild or moderate nonproliferative diabetic retinopathy at the beginning of the study, intensive management slowed the progression of the disease by 54%. Furthermore, a reduced risk was found for the development of nephropathy (50%) and for neuropathy (60%) in the intensive treatment group. The most important side effect observed in this group was a higher risk for hypoglycemia, which is why this treatment was not recommended for younger children, older adults, patients with heart disease or advanced complications and those with a history of frequent severe hypoglycemia [23, 48]. United Kingdom Prospective Diabetes Study The United Kingdom Prospective Diabetes Study was conducted between 1977 and 1999. Over 5000 type 2 diabetics were included. The patients without diabetic retinopathy were included into a primary prevention group, those with mild to moderate nonproliferative diabetic retinopathy were included into a secondary prevention group [23, 59, 60]. The study has an evidence level of 1b. In this largest clinical research study both groups were then randomized into either a conventional treatment or
138
an intensive treatment group. The former received a diet control first, followed by sulfonylurea, insulin and metformin, the latter was treated right away with sulfonylurea and if necessary with insulin. Metformin was given to overweight patients. After 10 years of follow-up a 17% reduction of diabetic retinopathy progression could be observed, as well as a 29% reduction in need for laser coagulation, a 23% reduction in vitreous hemorrhage and a 16% reduction in legal blindness. The study could also show that each of the existing therapies for treating diabetes (metformin, sulphonylureas, acarbose and insulin) were effective in reducing elevated blood glucose levels. Furthermore, elevated blood pressure could be identified as an independent risk factor for progression of diabetic retinopathy in that trial. Beta-blockers and ACE inhibitors as blood pressure therapy were found to be equally effective in reducing the risk of diabetic complications [23, 59, 60]. Vitrectomy for Diabetic Maculopathy Vitrectomy in cases of diabetic maculopathy was first described in 1992 by Lewis et al.. They found an improvement in patients with a taught, thickened posterior hyaHoerle/Kroll
Table 7. Studies dealing with intravitreal triamcinolone injection for treatment of diabetic macular edema
Authors Jonas and Sfker [24] Martidis et al. [36] Jonas and Degenring [25] Jonas et al. [26] Degenring et al. [5] Massin et al. [37]
1
Year 2001 2002 2002 2003 2004 2004
Type of study interventional case report prospective, non-comparative, interventional case study prospective, non-randomized, interventional, case study with control group prospective, non-randomized, interventional, case study with control group prospective, interventional, case study prospective, interventional, case study with control group
Patients Eyes 1 15 8 20 26 12 1 16 10 26 32 12
Increase of Dosage visual acuity, % mg 1002 502 85.71 811 81.31 41.72 20 4 25 25 25 4
Follow-up months 5 6 3.5 6.64 6.8 3
Visual acuity increase of 1 line. 2 Visual acuity increase of 2 lines.
loid if vitrectomy was performed. Their study was an observational , nonrandomized clinical study consisting of 10 patients [33, 34]. In the following years several studies on vitrectomy for diabetic maculopathy were conducted. Table 5 lists all the studies that we found in MedLine. All these studies have in common that they are nonrandomized case reports with a maximum of 58 eyes in the largest study. Most studies were retrospective, a few were prospective. A minimum was controlled. Some authors performed the procedure in cases of diffuse macular edema, some in cases of cystoid macular edema and a few in both. Improvement of visual acuity was observed in 38100% of cases. Some authors regarded a visual acuity increase of 1 line as improvement, others required a 2-line improvement. The follow-up time varied greatly amongst the studies (323 months). The level of evidence for these studies is therefore a maximum of 4. More recently, peeling of the internal limiting membrane was described as adjunct to vitrectomy in cases of diabetic maculopathy. The studies describing this are listed in table 6. For these reports the same holds true as for vitrectomy without peeling of the internal limiting membrane: the authors state that the new therapy might be helpful for some patients. However, the follow-up time is short, the number of cases in each study is small, and they are mostly retrospective case reports. There are practically no larger randomized, controlled, prospective trials. The level of evidence is therefore low as well (level 4).
Intravitreal Triamcinolone Injection for Diabetic Maculopathy In 2001, Jonas and Sofker [24] described the first case of intravitreal triamcinolone injection in a 73-year-old patient with a clinically significant diffuse diabetic macular edema, whose disease progressed despite grid laser coagulation. After the intravitreal injection of triamcinolone acetonide visual acuity improved over a 5-month follow-up period. Both Jonas and Sofker other authors applying that treatment regimen describe it as a possibly useful treatment for diabetic macular edema [27]. Table 7 lists studies using that new therapy. Most of them are interventional case reports. They are nonrandomized studies, only some had a control group. The authors still use very different dosages of the intravitreally applied triamcinolone. These studies have a level of evidence of 4 or 5 according to the grading of the Centre for EvidenceBased Medicine as well (table 1).
Discussion
EBM is practiced quite self-evidently in ophthalmodiabetology on the basis of the studies mentioned above. Treatment regimens such as laser coagulation and vitrectomy for different stages of diabetic retinopathy have been firmly established in clinical practice on a sound evidence-based foundation for many years.
139
EBM should be regarded as a helpful tool for any therapeutic situation which still leaves room for ones personal clinical experience to be included. EBM is by no means restricted to large, prospective, randomized, controlled trials or meta-analyses, although these are the gold standard for most therapeutic questions where different treatment options are compared. One can apply EBM even for special problems and very individual, difficult therapeutic questions, although at a lower level of evidence, using todays modern means of literature research. It is interesting to note that todays modern therapy of diabetic retinopathy includes both high levels of evidence (1b) and very low levels (4 and 5) but hardly any studies of the 2nd or 3rd level of evidence. For established types of therapy such as laser treatment several level 1b studies exist. Newer and smaller studies regarding that established treatment regimen are no longer undertaken, and
therefore lower level of evidence studies are missing. Innovative, new therapies, however, start as a case report or a smaller case control study with a low level of evidence. They are then taken up and frequently modified by other authors. The effort of setting up larger higher level of evidence studies seems to be undertaken only if the new treatment regimen is promising or if it is regarded as highly controversial. Despite the importance of EBM, even studies with high levels of evidence such as the Diabetic Retinopathy Vitrectomy Study need to be evaluated in the context of their time and must be questioned from time to time later on, when treatment techniques change or improve (such as development of endolaser coagulation or 25gauge minimally invasive vitrectomy), just as clinical guidelines are revised every few years and adapted to the newest scientific findings.
References
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41 Pendergast SD, Hassan TS, Williams GA, Cox MS, Margherio RR, Ferrone PJ, Garretson BR, Trese MT: Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid. Am J Ophthalmol 2000;130:178186. 42 Radetzky S, Walter P, Fauser S, Koizumi K, Kirchhof B, Joussen AM: Visual outcome of patients with macular edema after pars plana vitrectomy and indocyanine green-assisted peeling of the internal limiting membrane. Graefes Arch Clin Exp Ophthalmol 2004; 242:273278. 43 Rosenblatt BJ, Shah GK, Sharma S, Bakal J: Pars plana vitrectomy with internal limiting membranectomy for refractory diabetic macular edema without a taut posterior hyaloid. Graefes Arch Clin Exp Ophthalmol 2005;243:2025. 44 Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS: Evidence based medicine: what it is and what it isnt. BMJ 1996; 312:7172. 45 Sackett DL: Rules of evidence and clinical recommendations on use of antithrombotic agents. Chest 1986;89(suppl 2):2S3S. 46 Sato Y, Lee Z, Shimada H: Vitrectomy for diabetic cystoid macular edema. Jpn J Ophthalmol 2002;46:315322. 47 Stefaniotou M, Aspiotis M, Kalogeropoulos C, Christodoulou A, Psylla M, Ioachim E, Alamanos I, Psilas K: Vitrectomy results for diffuse diabetic macular edema with and without inner limiting membrane removal. Eur J Ophthalmol 2004;14:137143. 48 Tachi N, Ogino N: Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. Am J Ophthalmol 1996;122:258260. 49 The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977986. 50 The Diabetic Retinopathy Study Research Group: Preliminary report on the effect of photocoagulation therapy. Am J Ophthalmol 1976;81:383396. 51 The Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic reinopathy: the second report from the Diabetic Retinopathy Study. Arch Ophthalmol 1978,85:81106. 52 The Diabetic Retinopathy Study Research Group: Four risk factors for severe visual loss in diabetic retinopathy: the third report from the Diabetic Retinopathy Study. Arch Ophthalmol 1979,97:654655. 53 The Diabetic Retinopathy Study Research Group: Assessing possible late treatment effects in stopping a clinical trial early: a case study. Diabetic Retinopathy Study (DRS) report No. 9. Control Clin Trials 1984,5: 373 381.
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141
Author Index Vol. 221, No. 2, 2007
Bchele Rodrigues, E. 75, 78 Helbig, H. 103 Hoerle, S. 78, 132 Kroll, P. 77, 78, 132
Lang, G.E. 112 Meyer, C.H. 118 Neubauer, A.S. 95 Ulbig, M.W. 95
Subject Index Vol. 221, No. 2, 2007
Diabetes 78, 95 Diabetic macular edema 118 retinopathy 103, 112, 132 Retinopathy Study 95 Intravitreal injection 118 Laser photocoagulation 118 therapy 95 Neovascularization 78 Octreotide 112 Pars plana vitrectomy 118 Proliferative diabetic retinopathy 78 vitreoretinopathy 78
Protein kinase C inhibitor 112 Retina 78 Ruboxistaurin mesylate 112 Somatostatin analogue 112 Surgery 103 Tractional retinal detachment 103 Treatment, evidence-based 132 Vascular endothelial growth factor 78 Vitrectomy 103, 132 Vitreous hemorrhage 103
2007 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/oph

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Current Aspects of Pathogenesis and Treatment in Diabetic Retinopathy

Peter Kroll, Marburg

30 gures, 13 in color, and 8 tables, 2007

Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com

Vol. 221, No. 2, 2007

Laudatio for Professor Peter Kroll

Ophthalmologica 2007;221:77 DOI: 10.1159/000098252

Ophthalmologica 2007;221:7894 DOI: 10.1159/000098253

Pathogenesis and Classification of Proliferative Diabetic Vitreoretinopathy

Hypothetical Pathogenesis of PDVR

Table 1. Development of PDVR

Vitreous cortex Fibronectin Laminin Mller cells vitreoretinal interface

Pathogenesis and Classification of PDVR

Table 2. Classification systems of diabetic retinopathy

1969 1981 2003

Final Considerations and Conclusions

Pathogenesis and Classification of PDVR

Pathogenesis and Classification of PDVR

Ophthalmologica 2007;221:95102 DOI: 10.1159/000098254

Laser Treatment in Diabetic Retinopathy

Key Words Diabetes Laser therapy Diabetic Retinopathy Study

History of Laser Treatment

Panretinal Laser Treatment for Proliferative Diabetic Retinopathy

High Risk Characteristics

Fig. 1. Algorithm for panretinal scatter co-

Scatter (Panretinal) Laser Coagulation

Fig. 2. Illustration of treatment area for

Laser Treatment of Macular Edema

Macular Edema (Levels: Mild, moderate, severe)

No Focal Laser Coagulation

Fig. 3. Algorithm for laser treatment for

Focal Laser Coagulation

Grid Laser Coagulation

Fig. 4. Illustration of treatment area for focal (and grid) photoco-

Coexistent Macular Edema and Proliferative Disease

Diode Laser Treatment

Objective Retinal Thickness Measurements

Laser Therapy for Subhyaloidal Hemorrhage

Laser Treatment in Diabetic Retinopathy

Ophthalmologica 2007;221:103111 DOI: 10.1159/000098255

Surgery for Diabetic Retinopathy

Effect of Surgery on Diabetic Eye Disease

Fig. 1. Vitreous and subhyaloidal hemorrhage. Fibrovascular

Fig. 3. Tractional retinal detachment nasally to the fovea. The

Fig. 4. Tractional rhegmatogenous retinal detachment, visual

acuity hand movement. The retinal tear is marked with an arrow.

Complications of Surgery for Diabetic Retinopathy

Surgery for Diabetic Retinopathy

Ophthalmologica 2007;221:112117 DOI: 10.1159/000098256

Pharmacological Treatment of Diabetic Retinopathy

Fig. 1. Pathomechanism and pharmaco-

Treatment of DR with PKC- Inhibitors

Drug Treatment of Diabetic Retinopathy

Ophthalmologica 2007;221:103111 DOI: 10.1159/000098255

Surgery for Diabetic Retinopathy

Effect of Surgery on Diabetic Eye Disease

Fig. 1. Vitreous and subhyaloidal hemorrhage. Fibrovascular

Fig. 3. Tractional retinal detachment nasally to the fovea. The

Fig. 4. Tractional rhegmatogenous retinal detachment, visual

acuity hand movement. The retinal tear is marked with an arrow.

Complications of Surgery for Diabetic Retinopathy

Surgery for Diabetic Retinopathy

Ophthalmologica 2007;221:132141 DOI: 10.1159/000098258