S. Karger

Medical and Scientific Publishers

Basel • Freiburg • Paris • London

New York • Bangalore • Bangkok

Singapore • Tokyo • Sydney

Fax +41 61 306 12 34

E-Mail karger@karger.ch

www.karger.com

Disclaimer

The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Drug Dosage

The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved.

No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’).

© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)

Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel

ISBN 978–3–8055–8262–9

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 Münster 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-Univer- sität 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. Jörg 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 Kroll’s personal goal has been to train a few fellows very well and enable them to perform high-standard vitrectomy to

Dr. Eduardo Büchele Rodrigues studied and learned vitreoretinal diseases/surgery under Professor Peter Kroll’s guidance as a German Academic Exchange Service (DAAD) scholar fellow during the years 2001–2004.

work in the interest of their patients. Professor Kroll’s 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-

ments in his lifelong engagement in treating diabetic eye disease include the foundation and presidency of the IFdA, German abbreviation for ‘Initiativgruppe Früherkennung diabetischer Augenerkrankungen’, and the introduction of a classification of proliferative diabetic vitreoretinopathy [1]. Kroll’s classification strengthens the role of the vitreous in the pathogenesis of diabetic vitreoretinopathy, as he has been the world’s 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 [5–7].

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 Büchele Rodrigues

Institute of Vision, Federal University of São Paulo (Brazil)

References

1Hesse 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;219:46–49.

2Kroll P, Meyer-Rusenberg HW, Berg P: Does vitrectomy in proliferative diabetic retinopathy effect an improvement in intraocular metabolic status? Fortschr Ophthalmol 1986;83:471–473.

3Bodanowitz S, Hesse L, Weinand F, Kroll P: Vitrectomy in diabetic patients with a blind fellow eye. Acta Ophthalmol Scand 1996;74:

84–88.

4Hoerle 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;240:197–201.

5 Hesse L, Kroll P: Enzymatically induced posterior vitreous detachment in proliferative diabetic vitreoretinopathy. Klin Monatsbl Augenheilkd 1999;214:84–89.

6Schmidt JC, Rodrigues EB, Hoerle S, Meyer CH, Kroll P: Primary vitrectomy in complicated rhegmatogenous retinal detachment – a survey of 205 eyes. Ophthalmologica 2003;

217:387–392.

7Rodrigues EB, Meyer CH, Kroll P: Chromovitrectomy: a new field in vitreoretinal surgery. Graefes Arch Clin Exp Ophthalmol 2005;243:291–293.

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

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 dou-

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-lower- ing therapy might reduce the severity of retinopathy or the resultant losses in visual acuity. Further prospective trials on the subject are needed [36].

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

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-in- duced 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 Müller 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,