[P. Kroll] Diabetic Retinopathy(Bookos.org)

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Basel Freiburg Paris London New YorkBangalore Bangkok Singapore okyo Sydney

Current Aspects ofPathogenesis andTreatment in DiabeticRetinopathy

Guest Editor

Peter Kroll, Marburg

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


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Laudatio

75 Laudatio for Professor Peter Kroll

Bchele Rodrigues, E. (So Paulo)

77 Editorial

Kroll, P. (Marburg)

78 Pathogenesis and Classification of Proliferative DiabeticVitreoretinopathyKroll, 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

Vol. 221, No. 2, 2007

Contents


2007 S. Karger AG, Basel

Access to ull text and tables o contents,including tentative ones or orthcoming issues:www.karger.com/oph_issues


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Laudatio

Ophthalmologica 2007;221:7576

DOI: 10.1159/000098478

Laudatio for

Professor Peter Kroll

work in the interest of their patients. Professor Krolls

productive career comprises over 250 publications in in-ternationally recognized scientific journals and 1 bookof ophthalmology. Through his career he has been rec-ognized as a permanent member of several importantretina societies including the Club Jules Gonin and theformer Vitreous Society.

Professor Kroll has made remarkable contributions tothe understanding and treatment of diabetic retinopathyand implemented substantial innovations. Major achieve-

Peter Kroll was born in Bratislava in the Slovak Repub-lic on 16 May 1943. He graduated from medical school in1971 and wrote his postgraduation thesis in 1973 at theUniversity of Bonn. Peter Kroll also completed a residen-cy in Ophthalmology in 1978 at the University Eye Hos-pital in Bonn. Dr. Kroll joined the University Eye Clinicin Mnster in 1978 as faculty ophthalmologist, where heobtained his professorship in 1983. In 1989 ProfessorPeter Kroll was elected chairman and head Professor inthe Ophthalmology Department of the Philipps-Univer-sitt Marburg.

Professor Kroll made the Department of Ophthal-mology in small historic Marburg achieve internationalrecognition as a major center in vitreoretinal diseasesand surgery. With his great friend and fellow Dr. JrgSchmidt, Professor Kroll developed one of the most out-standing and highest-quality vitreoretinal surgeries inthe world. Throughout the years the reference eye clinicin Marburg has attracted patients and professional visi-tors from all over the world including Mexico, Russia,

USA, France, Spain, Brazil and China. Professor Krollspersonal goal has been to train a few fellows very well andenable them to perform high-standard vitrectomy to

2007 S. Karger AG, Basel00303755/07/22120075$23.50/0

Accessible online at:www.karger.com/oph

Dr. Eduardo Bchele Rodrigues studied and learned vitreoretinal

diseases/surgery under Professor Peter Krolls guidance as a Ger-

man Academic Exchange Service (DAAD) scholar fellow during the

years 20012004.


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LaudatioOphthalmologica 2007;221:757676

ments in his lifelong engagement in treating diabetic eyedisease include the foundation and presidency of theIFdA, German abbreviation for Initiativgruppe Frh-erkennung diabetischer Augenerkrankungen, and theintroduction of a classification of proliferative diabeticvitreoretinopathy [1]. Krolls classification strengthens

the role of the vitreous in the pathogenesis of diabeticvitreoretinopathy, as he has been the worlds pioneer indetermining the vitreoretinal interface key for prolifera-tive diabetic vitreoretinopathy disease progression [2].Consequently, early vitrectomy may provide better out-comes in rapidly progressing diabetic vitreoretinopathypatients [3, 4]. His struggle in this field as head of theIFdA association promoted significant reduction inblindness due to diabetic retinopathy in Europe. Furtherremarkable scientific contributions by Professor Krolland his assistants in Marburg include the enzymatic re-moval of the posterior vitreous cortex, therapy of prolif-

erative vitreoretinopathy secondary to rhegmatogenousretinal detachment and advances in chromovitrectomy[57].

As a chairman and leader Professor Kroll possessesremarkable emotional intelligence to select assistantswith integrity as the main criterion. He enjoys havingyoung German and foreign fellows around and takingcare of them. To his fellows and colleagues, he has been aleader and motivator of original and innovative thinking.

Besides being a great surgeon, teacher and researcher, heis an extraordinary human being with an incredible ap-petite for the world and all of its beauty. His tremendousdignity, simplicity with elegance and pleasant humor areremembered by all those who spend time with him. Pro-fessor Kroll has maintained a close and strong friendshipwith Professor C. Ohrloff, Professor H. Kaufmann andProfessor H. Busse for many decades.

It is with great pleasure that the journal Ophthalmo-logica and his retina colleagues acknowledge ProfessorPeter Kroll, one of the most impressive leaders in diabet-ic retinopathy and vitreoretinal surgery, for his multitude

of contributions.Eduardo Bchele RodriguesInstitute 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 ofa classification for proliferative diabetic vit-reoretinopathy. Klin Monatsbl Augenheilkd2002; 219: 4649.

2 Kroll P, Meyer-Rusenberg HW, Berg P: Doesvitrectomy in proliferat ive diabet ic retinop-athy effect an improvement in intraocularmetabolic status? Fortschr Ophthalmol1986; 83:471473.

3 Bodanowitz S, Hesse L, Weinand F, Kroll P:Vitrectomy in diabetic patients with a blindfellow eye. Acta Ophthalmol Scand 1996; 74:8488.

4 Hoerle S, Poestgens H, Schmidt J, Kroll P: Ef-

fect of pars plana vitrectomy for proliferativediabetic vitreoretinopathy on preexisting di-abetic maculopathy. Graefes Arch Cli n ExpOphthalmol 2002; 240:197201.

5 Hesse L, Kroll P: Enzymatically inducedposterior vitreous detachment in prolifera-tive diabetic vitreoretinopathy. Klin Monats-bl Augenheilkd 1999;214: 8489.

6 Schmidt JC, Rodrigues EB, Hoerle S, MeyerCH, Kroll P: Prima ry vitrectomy in compli-cated rhegmatogenous retinal detachment a survey of 205 eyes. Ophthalmologica 2003; 217:387392.

7 Rodrigues EB, Meyer CH, Kroll P: Chromo-vitrec tomy: a new field in v itreoret inal sur-gery. Graefes Arch Clin Exp Ophthalmol2005;243: 291293.


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DOI: 10.1159/000098252

Editorial

Panretinal laser photocoagulation continues to be thegold standard for the treatment of diabetic retinopathy,followed by pars plana vitrectomy for more advancedcases such as proliferative diabetic vitreoretinopathy with

vitreous hemorrhages and tractions. Diabetic maculopa-thy in particular is increasingly treated with pharma-cologic agents, such as triamcinolone acetate and anti-

vascular endothelial growth factor, which might one dayreplace pars plana vitrectomy with or without inner lim-iting membrane peeling at the posterior pole. A similardevelopment was observed in abdominal surgery at theend of the last century, when Helicobacter pylori wasdiscovered to cause gastric ulcers, thus replacing ofteninvasive surgical procedures by a simple pharmacologictreatment.

To even better prevent diabetic patients from goingblind, further insight into the pathogenesis of this diseaseis necessary, as a basis for improvement of pharmaco-logic therapy. Only this will enable us to assess whether

vitreoretinal procedures can be replaced in the future.Peter Kroll

Microvascular complications of diabetes mellitus suchas diabetic retinopathy and diabetic maculopathy con-tinue to be the most frequent causes for blindness inworking-age adults in industrialized countries. This isonly surpassed by age-related macular degeneration inhigher age groups. While a few years ago only about 5%of the population suffered from diabetes, a massive in-crease in the prevalence of up to 16% must be expected.As a consequence, the rate of blindness due to diabeteswill rise, despite all interdisciplinary and ophthalmolog-ic therapeutic efforts.

For that reason, I was very enthusiastic about planningthis special issue ofOphthalmologica with the publisher,to point out diabetes-induced ocular complications in or-der to prevent them by timely diagnosis and therapy.

This issue consists of review articles on the pathogen-esis of diabetic retinopathy and maculopathy and theirclassification and staging. On that basis up-to-date ther-apeutic modalities are discussed in detail. The treatmentof diabetic complications is evidence based due to excel-lent studies published in the literature. However, a ten-dency towards pharmacologic treatment of ocular dia-betic complications seems to be increasing when taking

newer publications into account.

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DOI: 10.1159/000098253

Pathogenesis and Classification ofProliferative Diabetic Vitreoretinopathy

Peter Kroll Eduardo Bchele Rodrigues Steffen Hoerle

Department of Ophthalmology, Philipps University Marburg, Marburg, Germany

communication about and the therapy of diabetic retinopa-

thy. Furthermore, it is the only reliable classification for pre-

dicting the surgical outcome in diabetics.

Copyright 2007 S. Karger AG, Basel

Introduction

Diabetic retinopathy is one of the leading causes ofblindness in the Western world [31, 55, 75, 88, 103]. Dia-betic retinopathy may be subdivided into a nonprolifera-tive (non-PDR) and a proliferative (PDR) form. Whilenon-PDR is characterized by a microangiopathy involv-ing intraluminal, intramural and extravascular damage,proliferative diabetic vitreoretinopathy (PDVR) is an en-tirely different disease entity, as the disease hallmark isthe formation of new vessels at the vitreoretinal interface

and in the vitreous itself. Furthermore, PDVR is the stageof diabetic retinopathy in which fibrovascular tissue pro-liferates on the surface of the retina and/or the optic discand/or the iris. After 1520 years of diabetes, this prolif-erative form of diabetic retinopathy affects about 50% ofpatients with type 1 diabetes, 510% of patients with non-insulin-dependent type 2 diabetes and 30% of patientswith insulin-dependent type 2 diabetes [67] .

Key Words

Proliferative diabetic vitreoretinopathy Proliferativediabetic retinopathy Diabetes Neovascularization Retina Vascular endothelial growth factor

Abstract

Purpose: To review the current knowledge regarding the

pathogenesis of proliferative diabetic vitreoretinopathy

(PDVR) and to present recommendations for its clinical stag-

ing. Design: Focused literature review and authors clinical

experience. Results: Although several biochemical media-

tors 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 conse-quent 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. Conclu-

sions:There is no consensus about the biochemical pathway

responsible for the progression of PDVR. Although several

classifications are described in the literature, the classifica-

tion suggested here is important in the judgment of, the

Prof. Peter Kroll, MDKlinik fr AugenheilkundeRobert-Koch-Strasse 4DE35033 Marburg (Germany)Tel. +49 6421 286 2600, Fax +49 6421 286 5678, E-Mail [email protected]

2007 S. Karger AG, Basel00303755/07/22120078$23.50/0

http://dx.doi.org/10.1159%2F000098253http://dx.doi.org/10.1159%2F000098253


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Pathogenesis and Classification of PDVR Ophthalmologica 2007;221:7894 79

Although some risk factors for diabetic retinopathyhave been determined, the exact pathogenesis is yet un-known [28]. This study aims first to describe hypotheticpathogenic mechanisms of PDVR. Also, the current clas-sifications are reviewed, with an emphasis on the authorsclassification.

Hypothetical Pathogenesis of PDVR

Systemic Factors Influencing Disease ProgressionThe most important determinants for the beginning

and progression of diabetic retinopathy to PDVR are thedisease duration and the degree of metabolic controlmaintained over the years [114]. Additional factors suchas microalbuminuria, hyperlipidemia and ocular perfu-sion pressure influence diabetic disease progression aswell [88].

Several clinical trials in Europe and North Americahave defined the role of various metabolic risk factors inthe progression of diabetic retinopathy and PDVR. TheEURODIAB Prospective Complications Study has inves-tigated the effect of several systemic factors on the pro-gression of PDVR [22, 89]. HbA1c, presence and severityof retinopathy at baseline, age !12 years at diagnosis, di-astolic blood pressure and waist-to-hip ratio remainedsignificant predictors for progression to PDVR. Althoughmetabolic control was the strongest modifiable risk factorfor the deterioration of retinopathy, it may not be suffi-cient to prevent progression to PDVR. In particular, theremay be no glycemic threshold below which a patient isprotected from the development of PDVR. In summary,the EURODIAB study suggested a strict control of bloodglucose and blood pressure with regular ophthalmicscreening for retinopathy to be the current best availableoptions for intervention on modifiable risk factors.

The Wisconsin Epidemiologic Study of Diabetic Reti-nopathy (WESDR) reported that glycated hemoglobin,duration of diabetes, severity of retinopathy at baselineand diastolic blood pressure are among the key factorsassociated with progression to PDVR [66].

The most crucial perturbation implicated in the devel-opment of diabetic complications is the metabolic milieuof the patients, and especially hyperglycemia. Hypergly-cemia in turn leads to a variety of biochemical distur-bances and functional changes.

Sato and Lee [93] investigated the relationship be-tween long-term glycemic control and the proportion ofpatients with pre-PDR developing PDVR. They conclud-ed that the number of patients progressing to PDVR dou-

bled with each 1% increase in the mean HbA 1c, and thecumulative rate of PDVR at the end of the 10-year follow-up was 60% in cases with a mean HbA1c of68.6%, and14% if the HbA1c was !8.6% [93]. Glycemic control hasbeen demonstrated by others to reduce the developmentof diabetic retinopathy, decrease visual loss and reduce

the need for laser treatment [36, 68]. The Diabetes Con-trol and Complications Trial (DCCT) [28], the UnitedKingdom Prospective Diabetes Study (UKPDS) [116] andthe Japanese studies [84] showed that glycemic control isprotective for all levels of diabetic retinopathy. There wasno glycemic threshold below which a reduction in micro-vascular complications was not observed [28, 116]. TheDDCT reported a delay in the development of diabeticretinopathy in 76% of patients with type 1 diabetes with-in a primary prevention group over an average of 6.5years.

The UKPDS, a randomized controlled clinical trial,

postulated that diet control reduces the need for laserphotocoagulation treatment and the chance of diabeticretinopathy progression by 29% [116]. The UKPDS deter-mined that the effect of strict blood glucose control re-duces the risk of progression of diabetic retinopathy aswell as the chance of vitreous hemorrhage in PDVR.

Control of blood pressure has been postulated to con-tribute to the prevention of moderate visual loss in dia-betic retinopathy [36]. Epidemiologic studies suggest thatsystemic hypertension increases the risk and/or progres-sion of diabetic retinopathy. The WESDR described wors-ening of diabetic retinopathy related to higher diastolicblood pressure at baseline and an increase in diastolicblood pressure in a 4-year follow-up period [66]. In theUKPDS, tight control of systemic blood pressure reducedthe progression of retinopathy in 34% of the patients, and47% experienced a lesser risk of deterioration in visualacuity of 3 lines [117]. Diastolic blood pressure was also asignificant predictor of progression of diabetic retinopa-thy and the incidence of PDVR in patients with younger-onset type 1 diabetes mellitus [66, 69].

Both the WESDR and the ETDRS found evidence thatelevated lipids may increase the morbidity of macular

edema. Elevated serum cholesterol levels were signifi-cantly associated with the presence of hard retinal exu-dates. Since the risk of loss in visual acuity was correlatedwith the degree of hard exudates, which in turn mightalso lead to subretinal fibrosis, an intensive lipid-lower-ing therapy might reduce the severity of retinopathy orthe resultant losses in visual acuity. Further prospectivetrials on the subject are needed [36].


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Kroll/Bchele Rodrigues/Hoerle


The rationale for the influence of growth hormones inthe development of PDVR dates back to the 1950s, whenPoulsen [90] presented a woman with late PDVR who ex-perienced regression of the disease after panhypopituita-rism. Later studies hypothesized that growth hormonesecretion is increased in patients with advanced diabetic

disease, and there is clear recovery of the PDVR altera-tions as growth hormone is suppressed [42]. The mecha-nism by which growth hormone induces PDVR is not to-tally clear, though it was already shown to lead to prolif-eration of human retinal microvascular endothelial cellsin vitro [92]. Besides, growth hormones may also stimu-late the production of insulin-like growth factors, andthese mediators have been demonstrated to play a role inthe pathogenesis of PDVR [19].

Biochemistry in PDVRSeveral biochemical pathogenic mechanisms may be

responsible for the progression of diabetic retinopathyand later PDVR, although the exact biochemical initiat-ing factor is not yet well defined in this multifactorialpathogenesis. The biochemical alterations in diabetic ret-inopathy are complex, as several growth factors and cy-tokines act in the disease process. For example, onegrowth factor may have a direct effect and it may stimu-late a second mediator, which potentiates or inhibits itseffect. Some authors postulated the importance of a com-bination of advanced glycosylated end products and ac-cumulation of vascular endothelial growth factor (VEGF)at the vitreous as a trigger mechanism for initiation of theproliferative stage of diabetic vitreoretinopathy [34, 72,83]. The biochemical mechanisms of pathogenesis of dia-betic retinopathy and PDVR may be separated into thosecaused by hyperglycemia and those related to hypoxia.

Biochemical Effects of HyperglycemiaThe biochemical pathways responsible for the molecu-

lar diabetic changes secondary to hyperglycemia vary.Hyperglycemia could allow the generation of irreversibleadvanced glycation end products in diabetes [111]. Hy-perglycemia could also lead to a decrease of superoxide

dismutase and glutathione peroxidase enzymes, whichmeans an impaired defense system against free radicalscavenging resulting in oxidative stress [106].

Furthermore, in the polyol pathway chronic hypergly-cemia leads to an increased nonenzymatic glycosylationof cell membranes and extracellular matrix as well as toan accumulation of sorbitol by an increased aldose reduc-tase expression. The increased levels of sorbitol in peri-cytes of retinal vessels lead to hyperosmolarity of many

retinal capillary cells and thus to cell death [41]. A furthermechanism of cellular damage secondary to polyol dis-turbance is the reduction of glutathione-reductase-in-duced reduction of NADPH to NAD, which should causedysfunction of endothelial enzymes [108].

Hyperglycemia leads to functional changes in the ret-

inal vasculature, resulting in a change of retinal tissueblood flow and release of biochemical mediators. Thesemolecules form 2 groups: endothelium-derived relaxingfactors (nitric oxide and prostacyclin) and endothelium-derived contracting factors (endothelin, cyclo-oxygenaseproducts), which inhibit or stimulate the underlyingsmooth muscles and pericytes [15].

Nitric oxide is possibly the main endothelium-derivedrelaxing factor associated with the development and pro-gression of diabetic retinopathy and PDVR. It is a freeradical gas synthesized from L-arginine by nitric oxidesynthase, which may participate in the modulation of

blood flow, vasodilatation, inflammation and neurotox-icity. Nitric oxide may induce diabetic damage followedby hyperglycemia after the activation of protein kinase Cby diacylglycerol. In turn, protein kinase C activationleads to expression of superoxide in endothelial cells,which affects nitric oxide [59, 121].

There are 2 biological consequences of increased levelsof nitric oxide in retinas of subjects with diabetes: neuro-toxicity and angiogenesis. Regarding the neurotoxic ef-fects, while nitric oxide should have beneficial effects asa vasodilator, it may be highly neurotoxic in high concen-trations. Nitric oxide released from Mller cells has led toneuronal cell death in cultures of retinal neurons [27,109].

Levels of nitric oxide increased by hyperglycemiacould affect the equilibrium in the regulation of bloodflow in the diabetic patient and be an important mediatorin the angiogenic process. Although the exact mecha-nisms by which nitric oxide enhances angiogenesis arenot exactly understood, nitric oxide may also be an im-portant mediator of angiogenesis in living tissues as itstimulates both migration and proliferation of endothe-lial cells, being then responsible for diabetic vascular

damage. Besides its effect on the stimulation of endothe-lial cell proliferation, nitric oxide may enhance angiogen-esis by inhibiting apoptosis of endothelial cells and in-creasing the dissolution of the extracellular matrix [11, 27,76, 115, 123].

Beyond its direct damage in diabetic retinopathy, el-evated nitric oxide levels could participate in the patho-genesis of the retinal local angiogenic response to VEGF.Nitric oxide expression may be upregulated by VEGF,


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which in turn produces a dose-dependent upregulationof nitric oxide generation in human endothelial cells andis involved in signaling the permeability-enhancing ef-fects of VEGF [40, 123]. Whereas nitric oxide levels werehigher in PDVR with retinal detachment than in normalcontrols, Hernandz et al. [49] found no relationship be-

tween VEGF and nitric oxide concentrations in the vitre-ous fluid of patients with PDVR.Nitric oxide also regulates the release of other cyto-

kines such as platelet-activating factor, tumor necrosisfactor and transforming growth factor1, but the exactpathways are still uncertain [87]. Oku et al. [86] investi-gated the involvement of nitric oxide and endothelin-1 byexamining the levels of both mediators in the vitreous ofdiabetic patients with PDVR. After observing a signifi-cant difference between patients with PDVR and con-trols, they concluded that both endothelin-1 and nitricoxide could have an active participation in the pathogen-

esis of PDVR.A second endothelium-derived relaxing factor associ-

ated with the pathogenesis of diabetic retinopathy is pros-tacyclin. Prostacyclin is released after inflammation andis closely related to nitric oxide. Whereas early hypergly-cemia decreases prostacyclin synthesis, in advanced cas-es of diabetic retinopathy such as PDVR, normal or ele-vated levels of prostacyclin have been reported [104].

Endothelium-derived contracting factors may be dys-regulated in the progression of diabetic retinopathy andPDVR. The most studied of these mediators is endothe-lin, a strong vasoconstricting peptide that regulates capil-lary homeostasis in the retinal vascular cells. Hypergly-cemia leads to higher levels of endothelin in the retinaand disturbance of vasoactive regulators [18].

The effect of hyperglycemia may also mediate severalbiochemical pathways in the production of growth fac-tors. High glucose levels produce glycated proteins thatare biologically active and that may enhance the expres-sion of growth factors [83]. Studies in the last decade havedemonstrated hyperglycemia to stimulate the release ofseveral growth factors including transforming growthfactor, 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 ofprotein kinase C. Protein kinase C is a serine/theorinekinase enzyme with a variety of biological functions, in-cluding the modulation of cell structures, receptor re-sponsiveness, gene transcription and cell growth. Whileprotein kinase C is a family of at least 12 isoenzymes,each with different enzymatic properties, only the isoen-

zymes and 2 are present in the retina. Studies in ani-mals revealed that only the2 isoform becomes activatedin the vascular tissue of diabetic models [119]. Proteinkinase C exerts its influence in the progression of dia-betic retinopathy in 2 ways. First, protein kinase C pro-motes the activation of several growth factors such as

transforming growth factor, VEGF and pigment-derivedgrowth factor [3], which in turn are potent angiogenesisfactors. Second, binding of VEGF to the target phosphor-ylation receptors demands the function of signaling pro-teins, including protein kinase C itself [39]. Experimen-tal studies have shown that one critical component in themitogenic and permeability-inducing effects of VEGF isthe activation of protein kinase C (PKC-) [3]. Inhibi-tion of the PKC- isoform prevents VEGF-mediated cellgrowth in vitro and reduces ischemia-induced retinalneovascularization in animal models in vivo [5, 24].Moreover, oral administration of PKC- inhibitor has

been reported to slow down the progression of diabetes-induced retinal vascular permeability and to normalizechanges in retinal blood flow caused by PDVR [59].These findings suggested that PKC- may be an impor-tant pathogenic factor in the evolution of diabetic reti-nopathy and PDVR.

Biochemical Effects of HypoxiaIn diabetic retinopathy, whereas acute hypoxia stimu-

lates the release of cytokines, the chronic hypoxia facili-tates the expression of the several growth factors involvedin the formation of new vessels [15]. Although a mediatorcalled hypoxia inducible factor 1 has been identified asstimulator of neovascularization, the exact molecularmechanism of new vessel formation after hypoxia re-mains unknown.

There are a few theories, besides the effect of hypergly-cemia, in which diabetes mellitus may result in ischemia,such as thickened basement membrane, platelet aggrega-tion and leukocyte activation [15]. First, diabetic retinop-athy is reported to co-occur with a retinal basementmembrane thickening by an increase in the productionof fibronectin and collagen [110]. A second hypothesis

concerns the formation of thrombin leading to capillaryobliteration and retinal ischemia. Diabetes stimulatesprotein kinase C, which in turn upregulates the produc-tion of endothelial cells, leukocytes and platelets to pro-duce platelet-activating factor [113]. The third mecha-nism early in diabetic retinopathy by which hyperglyce-mia causes hypoxia is related to the leukocyte activationand adherence as leukocytes adhere to vascular endothe-lium. As Joussen et al. [6062] suggest, the inhibition of


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VEGF bioactivity may prove useful in the treatment ofearly diabetic retinopathy in the future [14].

Regarding the progression of PDVR, recent evidencehas indicated that the tissue hypoxia-associated prolif-erative vitreoretinopathy leads to an upregulation of an-giogenic cytokines such as growth factors and vasoactive

hormones. Regarding the growth factors, their presencein the vitreous and epiretinal membranes supports theirrole in the pathogenesis of PDVR. Each angiogenic factormay likely operate coordinated or in cascade with othergrowth factors [23].

VEGF is probably the most important biochemicalagent in the development of diabetic neovascularization.Although several growth factors including insulin-likegrowth factors 1 and 2 and basic fibroblast growth factorhave been implicated in retinal neovascularization [19],experimental and clinical investigations showed thatVEGF is the dominant biochemical factor involved in the

onset and progression of diabetic retinopathy and PDVR.VEGF possesses the characteristics of a mediator of pro-liferative retinopathies: it is produced by the retina, in-duced by hypoxia, is proangiogenic, induces permeabil-ity and is diffusible through the eye.

Numerous retinal cells produce VEGF, including reti-nal pigment epithelial cells, pericytes, endothelial cells,Mller cells and astrocytes [23]. Retinal vascular endo-thelial cells express VEGF and have numerous high af-finity receptors to VEGF. Epiretinal neovascular mem-branes in PDVR disease demonstrated overall VEGF-Aexpression. Besides, high oxygen consumption by rodphotoreceptors in the dark-adapted state may be a power-ful driving force of hypoxia and VEGF stimulation [7].Hammes et al. [43, 44] postulated that, when disregu-lated, Mller cells may express VEGF. Intraocular VEGFconcentrations are increased during proliferation and di-minished after laser treatment for PDVR [4, 58].

Evidence of the role of VEGF in new vessel formationhas been based on the experiments in primate models ofiris neovascularization and in murine models of retinop-athy of prematurity. VEGF exerts a potent stimulus fornew blood vessel formation by binding to the high aff in-

ity tyrosine kinase receptors VEGFR-1 and VEGFR-2.However, the genetic expression of VEGF precedes thenew vessel growth, since animal models have an abun-dant amount of VEGF before the appearance of diabeticmorphological changes. Most importantly, experimentswith transgenic mouse models indicated that VEGF ex-pression in the retina is sufficient to determine retinalneovascularization [35, 43, 44, 46, 85]. Additionally, theblockade of VEGF is sufficient to inhibit retinal neovas-

cularization in several experimental models of ischemicretinopathy [1, 5]. Not only may the neuroretinal cells beinvolved with the new vessel formation in PDVR, but alsoretinal pigment epithelium cells may induce the progres-sion of PDVR because retinal pigment epithelium cellsproduce VEFG.

Moreover, several biochemical mediators implicatedin the pathogenesis of diabetic retinopathy have beendemonstrated to increase the expression of VEGF, in-cluding glucose, advanced glycation products, adenosin,cytokines (transforming growth factor-, interleukin-1)and numerous growth factors (fibroblast growth factorand pigment-epithelium-derived growth factor, platelet-derived growth factor, insulin-like growth factor-1, trans-forming growth factor-) [19, 20, 21, 23, 82, 83, 105, 108,120]. High numbers of glycation end products, for ex-ample, have been seen in the blood of patients with dia-betic retinopathy, and this increase is believed to be a

stimulator of VEGF release and then a causal factor in thedevelopment of diabetic retinopathy [112].

Other growth factors including hepatocyte growthfactor, pigment-derived growth factor and insulin-likegrowth factor-1 probably act in conjunction with VEGFin the development of PDVR. Hepatocyte growth factoris an endothelium-specific growth factor that seems tohave an important function in the pathogenesis of PDVR.Hepatocyte growth factor is a mesenchyme-derivedpleiotropic factor that regulates cell motility and growth.Canton et al. [16] postulated that preretinal membranesof PDVR synthesize hepatocyte growth factor in diabeticpatients. However, regarding the progression of advanceddiabetic retinal disease, the production of tumor necrosisfactor- may, in addition to the effect of VEGF, lead to abreakdown of the blood-retina barrier. Phagocyte inva-sion and production of mediators of inflammation areimportant factors leading to worsening of fibrovascularproliferation in severe PDVR. Tumor necrosis factor-basically promotes angiogenesis and adhesion of leuko-cytes to endothelial cells. Tumor necrosis factor- alsostimulates the production of monocyte chemotactic pro-tein by retinal pigment epithelial cells [8]. It is reasonable

that hepatocyte growth factor plays a role in retinal neo-vascularization in cooperation with other factors. Tumornecrosis factor- also stimulates the VEGF productiondirectly.

Given its role in inhibiting angiogenesis and inducingcell differentiation, much investigation arose regardingpigment-epithelium-derived growth factor. Pigment-epi-thelium-derived growth factor is a potent endogenousangiogenic inhibitor with a neurotrophic influence on


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the retina and is essential for maintaining angiogenic ho-meostasis in the retina. Also, this factor favors an inhibi-tory environment when oxygen concentrations are nor-mal or high [26]. Then, pigment-epithelium-derivedgrowth factor plays a considerable role in protecting theretina from pathological angiogenesis [120]. The produc-

tion of pigment-epithelium-derived growth factor isdownregulated by hypoxia, which is the central patho-genic stimulus of VEGF-A. Pigment-epithelium-derivedgrowth factor possibly participates in the regulation ofblood vessel in the eye by creating a permissive environ-ment for angiogenesis when oxygen levels are low.

Insulin-like growth factor-1 was the first growth fac-tor implicated in the occurrence of PDVR, based on theobservation of reduced incidence of PDVR on growthhormone or insulin-like growth factor-1 deficient dwarfs[81]. Moreover, others reported an acute increase in se-rum insulin-like growth factor-1 soon before the onset of

PDVR [81]. Also, insulin-like growth factor is present atPDVR vitreous in a higher amount in comparison to pa-tients without neovascularization. However, whereas in-sulin-like growth factor-1 has been recently establishedto regulate not only neovascularization but also VEGFaction in the mouse model of ischemia-induced PDVR,Sim et al. [102] described no correlation between insu-lin-like growth factor-1 and VEGF in the vitreous of pa-tients with PDVR, although both were simultaneouslyincreased.

Regarding the vasoactive hormones, there is some ev-idence that the renin-angiotensin system may be associ-ated with angiogenesis in the eye in PDVR. The renin-angiotensin system is present in the kidney, heart, ovaryand adrenal gland [120]. The most important enzyme ofthis system is angiotensin-converting enzyme, whichcleaves angiotensin I to the effector molecule of the re-nin-angiotensin system called angiotensin II. Physiolog-ically, angiotensin II regulates the intraocular blood flowand pressure as renin inhibitors lower the intraocularpressure. Angiotensin II has been postulated to reducemicrovascular leakage by unknown reasons. Animalstudies revealed angiotensin II to induce contraction of

perycites and angiogenesis [80]. The increased levels inthe vitreous of the renin-angiotensin system compo-nents (mostly renin) in PDVR suggest a pathogenic role[94]. Also, glomerular hypertension and angiotensin IIincrease the expression of growth factors [64]. There issome evidence of a direct relation between the renin-an-giotensin system and VEGF, as both VEGF and VEGFreceptor mRNA are localized in the ganglion cell layer,Mller cells, the outer nuclear layer and the retinal pig-

ment epithelium, all sites of renin and angiotensin syn-thesis. Besides, both prorenin and VEGF were found tobe simultaneously elevated in the vitreous fluid of pa-tients with PDVR [2].

Angiostatin, a fragment of plasminogen, has beenidentified and characterized as a potent inhibitor of neo-

vascularization, as it has been measured in the vitreousof patients without an underlying proliferative retinaldisease and in patients with PDVR with or without previ-ous laser photocoagulation. Spranger et al. [107] demon-strated the association between release of the angiogen-esis inhibitor angiostatin and diminished production ofthe angiogenic growth factor VEGF in eyes with previousretinal scatter photocoagulation.

Augustin et al. [9] investigated the vitreous and epiret-inal membranes of patients with PDVR to search for oxi-dative metabolites, i.e. lipid peroxides, and VEGF and tocorrelate them with retinal coagulation status. They con-

cluded that several oxidative metabolites are able to mod-ulate growth activity and exert this effect via inductionof VEGF.

Changes in Retinal Cells in PDVRThere are several hypotheses to explain how hypergly-

cemia causes tissue and cell damage in diabetic retinopa-thy. In general, the glucose molecules interact with pro-teins and cells of the pericytes and endothelial cells. Highglucose levels could even damage endothelial cells byhampering the capacity of the cells to eliminate free rad-icals, and this effect is most likely caused by increasedglucose uptake and depletion of glutathione reductase co-factor NADPH reserves. A further mechanism of glucosecell damage, involving the glycation of collagen, changesthe basement membranes and affects retinal vascular cellinteraction. Others suggest that hyperglycemia activatesprotein C kinase, leading to an excess of second messen-gers, which in turn cause plasma membrane damage in-cluding loss of tight junctions and abnormal growth fac-tor receptor expression [98].

Diabetic retinopathy is characterized clinically by mi-croaneurysms, cotton-wool spots, lipid exudates, macu-

lar edema, capillary occlusion and finally neovascular-ization with consecutive hemorrhages. While the retinalvascular endothelial tight junction is formed by 2 pro-teins called occludin and claudin, studies in diabetic an-imals revealed that diabetes reduces the quantity of oc-cludin at those tight junctions, leading to disorganizationin the arterioles and capillaries. This effect was observedto be caused also by VEGF in the retinal cells. However,it is not yet known if the primary effect of VEGF in dia-


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betic retinopathy is to increase the vascular permeabilityor to protect neurons from degeneration [40].

Another important component of diabetic retinopa-thy is microvascular occlusion. Both intravascular altera-tions (leucostasis and microthrombosis) and extravascu-lar processes (invasion of Mller cells into the vascular

lumen) are related to the microvascular occlusions in di-abetic retinopathy. While the presence of vascular altera-tions induces us to believe that diabetic retinopathy is apure microvascular disease, several changes such as theneurodegeneration of retinal cells occur in addition tothose microvascular changes [78]. The neuroretinal cellsare protected from the circulation of inflammatory cellsand their cytotoxic products by the blood-retinal barrier,more specifically the tight junctions in the endothelialcells.

Gardner et al. [40] divided the neuroretinal cells into4 classes and described the changes induced by diabetic

retinopathy. The first class of cells are the pericytes andendothelial cells of the capillaries. Pericytes are involvedin the stability and control of endothelial proliferation.Retinal capillary coverage with pericytes may be crucialfor the survival of endothelial cells in stress-inducedPDVR [45]. While pericytes are modified smooth musclecells which regulate the retinal vascular flow by dilatingand contracting, endothelial cells constitute the blood-retinal barrier.

As impairment in the retinal microcirculation resultsin retinal ischemia, its histological hallmark is the ap-pearance of acellular capillaries. Early in diabetic reti-nopathy, histological examination of the retina of dia-betic patients demonstrated the presence of ghost ves-sels consisting solely of basement membrane [63]. Thedamage of retinal capillary cells including pericytes andendothelial cells is responsible for microaneurysms andvascular obstruction. These changes, including pericyteloss, evolve over many years before the onset of PDVR[15]. Whereas diabetic retinopathy has been considered asystemic disease, the absence of pericyte changes in theoptic nerve of diabetic patients suggests a local oculardisease [65].

There is also evidence that hyperglycemia may direct-ly worsen ischemia by promoting endothelial cell prolif-eration and diminishing the inhibitory effects of peri-cytes on endothelial cells [98]. Hyperglycemia could alsoalter the status of circulating platelets and leukocytes.These cells may adhere to the capillaries in end-stagePDVR and thereby worsen ischemia.

The second category comprises the glial cells, eitherMller cells or astrocytes. Whereas Mller cells mainly

span the thickness of the retina from the retinal pigmentepithelium to the internal limiting membrane, the astro-cytes are limited to wrapping the small retinal blood ves-sels. Astrocytes undergo severe changes in diabetes, asthe production of their intermediate filament and glialfibrillary acidic protein are markedly decreased. As the

Mller cells have a direct effect in the formation of dia-betic epiretinal membranes in PDVR, Mller cells may beaffected much earlier in the course of the disease [10]. Inconclusion, the structural glial retinal cells may be se-verely damaged by diabetic retinopathy when the blood-retinal barrier function is impaired [40].

A third class of cells, the neurons, may be subdividedinto photoreceptors, bipolar cells, amacrine cells andganglion cells. These neurons physiologically convey theelectric impulses to the brain. As they are the cells re-sponsible for vision itself, any loss of visual acuity in dia-betic retinopathy necessarily implies disturbance of their

function. There is evidence that retinal ganglion cells andinner nuclear cells die by apoptosis early in the course ofdiabetes. Moreover, it has been shown that a continuousatrophy of the thickness of the inner retina and reductionof the number of ganglion cells occurs up to the late stag-es of diabetic retinopathy including PDVR [40].

The last class of retinal cells, the microglia, are re-sponsible for phagocytosis in the retinal environment.Diabetes has been shown to activate the normally quies-cent microglial cells. Because microglial cells may releaseseveral mediators of inflammation such as VEGF andtumor necrosis factor, microglial cells seem to play anactive role in the progression of diabetic retinopathy toPDVR [91].

Although diabetic retinopathy is mainly character-ized as a microvascular disease with concomitant lesionsof the neuroretinal cells, there is much evidence that dia-betic retinopathy is also an inflammatory disease [6062]. As observed in ophthalmoscopic examination, dia-betic retinopathy frequently presents with tissue destruc-tion and attempts of tissue repair. Experimental studiesrevealed the presence of several mediators of inflamma-tion in diabetic retinopathy, including leucostasis, adhe-

sion molecule activation, prostacyclin upregulation,VEGF expression and retinal accumulation of macro-phages [12, 40, 47]. Tissue loss is exemplified by neuro-retinal cell apoptosis.

Limb et al. [77] examined the vitreous of patients withPDVR in order to search for the intravitreous presence ofvascular cell adhesion molecules that mediate steps of in-flammation. They found increased numbers of severalmolecular inflammatory molecules including vascular


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cell adhesion molecule 1 and sE-selectin in patients withPDVR compared to controls. Inflammatory mechanismsmay contribute to the onset of new vessels and f ibrosis asan endothelial, Mller and retinal pigment epithelial cellactivator.

The Vitreous in PDVRThe human vitreous is constituted of several intercel-lular connective tissues including type II collagen, hyal-uronic acid and hyalocytes. Vessels are normally exclud-ed from the vitreous, a compartment which has beenshown to have antiangiogenic properties [107]. Severalclinical and experimental studies have demonstratedthat the vitreous plays a primary role in the pathogenesisof PDVR. The studies have shown the presence of newvessels microproliferating inside the vitreous cavity,indicating the vitreous to be active in the angiogenesisprocess [34]. There is also evidence that epiretinal mem-

branes in the vitreous of patients with PDVR producea high amount of growth factors as the retinal cells do[43, 44, 46, 79].

There must be a biochemical factor in the vitreous tis-sue that directly regulates the ischemic retina in diabeticretinopathy. An increased presence of advanced glyca-tion products has already been found in the vitreous ofdiabetic eyes. In diabetic retinopathy, proteins in the vit-reous that inhibit angiogenesis undergo marked nonen-zymatic glycosylation of collagen and other proteins andthis may represent an initial and trigger finding for pro-liferative changes in diabetic retinopathy [48, 100].

Sebag [99] described presenile changes in the vitreousin diabetics. Hyperglycemia eventually leads to changesof type II collagen and consequently to liquefaction andsyneresis of the vitreous. The instability of the vitreousresulting from this loss of the gel state without dehiscenceat the vitreoretinal interface may also induce traction onthe retina, which in turn might not only lead to retinaltears but can also contribute to the neovascular processitself. Thus, in addition to providing a scaffold for retinalcapillary endothelial and other vasoproliferative cells aspostulated by Faulborn and Bowald in 1985 [34], the vit-

reous may aggravate the process of neovascularizationbecause of changes in the rheologic state.

The vitreous cortex seems to be involved in early stag-es of the diabetic disease, whereas the vitreous gel influ-ences the late stages. At the posterior pole the vitreouscortex is composed of parallel collagen f ibers that are at-tached to the retinal surface formed by the foot plates ofthe Mller cells. This attachment consists of extracellularmatrix proteins, mainly fibronectin and laminin [71].

New vessels reach the vitreous by invading the inter-nal limiting membrane, although the exact mechanisms

are not totally clear yet. Previous clinical findings indi-cated that PDVR is rare if the vitreous cortex has de-tached completely in myopics with PVD and after vitrec-tomy, since the scaffold for proliferating cells is destroyed[97]. In high myopia lesser diabetic involvements of thefundus oculi have been observed [57], which may serveas a proof for the involvement of the vitreous in the de-velopment of diabetic retinal changes and therefore justi-fies the term PDVR.

Because of a long-standing diabetes-induced break-down of the blood-retinal barrier, serum proteins, espe-cially f ibronectin, accumulate up to 10-fold at the vitreo-retinal border region [70]. Fibronectin mediates the mi-gration and adhesion of proliferating endothelial cellssupported by growth factors like transforming growthfactor-, which bind at specific domains [17]. In the latestages of the disease, the vitreous gel contracts, leading tovitreous hemorrhage due to the rupture of the prolifera-tive vessels, vitreoschisis, as well as tractive or rhegmatog-enous retinal detachment. Shrinkage of the vitreous in-dicates crosslinking of collagen fibers probably inducedby transglutaminase (factor 13a) in the presence of fibro-nectin [6]. Angiogenic cells migrate and then neovascu-

lar proliferation arises in this vicious circle.

Morphological Evolution of the PDVR DiseaseIn the above chapter we learned that PDVR develops

as new vessels arise and proliferate at the border regionbetween the retina and the vitreous cortex accompaniedby a fibroglia scaffolding (table 1).

Multifactorial reasons, such as hypoxemia and isch-emia followed by the accumulation of growth factors lead

Table 1. Development of PDVR

Non-PDRf

PDVRf

1st step of pathogenesis:

Thickening of vitreoretinal interfaceIngrowth of newly formed vessels into the posterior vitreouscortexf

2nd step of pathogenesis:Shrinkage of the vitreous gel through crosslinking of collagenfibers (possibly induced by factor 13)


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to a thickening of the posterior vitreous cortex, which oc-curs as a first step prior to an ingrowth of proliferatingnew vessels into the posterior vitreous cortex (fig. 1) [37,38].

In this process Faulborn and Bowald [34] found smallproliferations arising multifocally and growing within

the vitreous cortex. They described the fibrous materialof the vitreous cortex being densely interconnected withand obviously being incorporated into the newly formedproliferated tissue and thus providing a scaffold for pro-liferating cells.

In 1990 Yu et al. [122] found in animal experimentsthat vitreal PO2 increased as a function of the distancefrom the internal limiting membrane, if inspired oxygentension was increased. Vice versa, hypoxemia leads to adecrease in vitreal oxygen tension.

In 1991 Vlodavsky et al. [118] described that basic fi-broblast growth factor promotes the formation of new

blood capillaries. It binds to heparan sulfate, both on thecell surface and in the extracellular matrix. Enzymessuch as heparanase lead to a degradation of the basic fi-broblast growth factor/heparan sulfate complex and thusregulate the growth of capillary blood vessels in normaland pathological situations. The extracellular matrix alsoserves as a storage depot for other growth factors and en-zymes which generate the proliferation of newly formedvessels growing from the retina into the vitreoretinal in-terface.

Sebag et al. [96] in 1992 analyzed vitreous samplesfrom patients with PDVR and from patients without dia-betes for collagen crosslinks, as well as for the early glyca-tion products glucitolyllysine and glucitolylhydroxyly-sine. They found that early glycation products were ele-vated in diabetic vitreous, while the levels of advancedglycation end products were even 20 times higher in dia-betic vitreous compared with the vitreous of controls.These diabetes-induced alterations of human vitreouswere regarded as particularly important for proliferationsof vessels into the vitreoretinal interface. That is why theauthors give the vitreous in PDR an important role andagree on the term PDVR instead of PDR [100].

In a second step of the pathogenesis of PDVR, shrink-ing of the vitreous body occurs, especially of the poste-rior vitreous cortex. This step occurs for reasons not yetvery clear, although Akiba et al. [6] hypothesized thatthe factor 13 (transglutaminasae) of the hematopoieticsystem may play a central role. The clinical alterationsin the PDVR stage of diabetic retinopathy are a conse-quence of both thickening and shrinking at the vitreo-retinal interface. Due to vitreous shrinking, neovascu-

larizations in the vitreous are torn and typical vitreousbleeding or if there are more extended adhesions be-tween vitreous and retina tractive retinal detachmentresults, which may be worsened by rhegmatogenous ret-inal detachment.

Classification of PDVR

Starting with the introduction of photocoagulationand vitrectomy as therapeutic options of diabetic reti-nopathy to avoid blindness, several classification systemswere presented.

The Airlie House classification, which was introducedpurely for assessing results of photocoagulation studiesin the 1960s, suggested 2 types of diabetic retinopathy:non-PDR and PDR [25]. The division into 2 patterns hasremained until now because it is simple and informa-

tive.Diabetic retinopathy is probably one of the diseases in

which medicine-based evidence principles were appliedearly and very extensively. While major clinical trialsstarted in the 1970s and 1980s to evaluate the benefits oflaser treatment and surgery for diabetic retinopathy, theyalso determined the evolution and consequently the clas-sification systems were developed. The 5 multicenterclinical trials which established the basic concepts for thecurrent classification and treatment of diabetic retinopa-thy are the Diabetic Retinopathy Study, the Early Treat-ment Diabetic Retinopathy Study (ETDRS), the DiabeticRetinopathy Vitrectomy Study (DRVS), the DCCT andthe UKPDS.

The ETDRS study group classified the proliferativeform of diabetic retinopathy in early, high-risk and severePDR. The ETDRS severity scale was based on the modi-fied Airlie House classification of diabetic retinopathy[29, 32]. The limitation of this scale is that it has provento be useful in clinical practice only for the outcome ofpanretinal photocoagulation. Several contemporary sur-veys have documented that most physicians managingpatients with diabetes do not use the full ETDRS severity

scale because of its complexity [119]. PDR was classifiedby the ETDRS severity scale into mild, moderate andhigh-risk PDR for the initial cases of the disease. If eitherretinal detachment, traction, rubeosis iridis or fundusobscuration were visualized, it was called advanced PDR(ETDRS, 1991). Further on, the ETDRS confirmed theneed of scatter laser coagulation for cases of high-riskPDVR.


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acuity restoration to over 20/40, at least for eyes with verysevere new vessels. However, this major clinical trial wasconducted prior to the introduction of surgical advancessuch as endolaser now commonly employed during vit-reoretinal surgery in patients with diabetic retinopathy,and caution is therefore needed to interpret its results. Forinstance, bimanual surgery with delamination or en blocdissection of epiretinal membranes were not mentionedin that study.

Although at first pars plana vitrectomy was used forcases of critical forms of PDVR like advanced tractionaldetachment, in 1983 Shea [101] recommended vitrectomyat earlier stages of the PDVR disease in order to improvesurgical outcomes and help in the preservation of usefulvision. The DRVS used morphological criteria to defineearly as a stage of the disease prior to extensive contrac-tion causing retinal detachment [30]. The DRVS postu-lated that early vitrectomy increased the chance of visual

Fig. 1. The vitreoretinal interface is be-lieved to play a key role in the developmentof PDVR (see text).

Vitreous cortex

Fibronectin

Laminin

Mller cells

vitreoretinal

interface

Fig. 2. PDVR, stage A: this stage is characterized by proliferative changes in vitreous and retina, especiallyaround the optic disc and in the posterior vitreous cortex. The retina is still totally attached.


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Fig. 3. ac PDVR, stage B: this stage is characterized by shrinkageof the posterior vitreous cortex. In places where the vitreous ad-heres to the retina circumscribed retinal detachments are found.b If a tractive detachment is nasal to the optic disc, this is de-scribed as stage Bn. c Proliferative and tractive changes in the areaof the temporalsuperior and inferior vascular arcade, which maybe followed by a macular detachment, are categorized as stageBt.

Fig. 4. a PDVR, stage C. Stage C is similarly to the PVR classi-fication characterized by a tractive retinal detachment whichincludes 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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Since the posterior vitreous cortex is mainly respon-sible for this disease entity, the term PDR has beenchanged to PDVR in analogy to the term proliferativevitreoretinopathy [73, 100].

The dynamic morphological stages are differentiatedas follows:

Stage A (fig 2a, b) is characterized by proliferativechanges in the vitreous throughout the retina, especiallyaround the optic disc but also elsewhere; however, theretina is totally attached.

Stage B (fig. 3ac) consists of circumscribed tractiveretinal detachment around the optic disc and at the reti-nal arcade vessels, as a result of shrinkage of the vitreo-retinal interface. However, the macula is attached, sogood visual acuity is still present, as long as no hemor-rhage or diabetic macular disease occurs. As stage B n(fig. 3a) one recognizes the tractive detachment nasal tothe optic nerve and Bt (fig. 3b) temporal to it.

Stages C1C4 (fig. 4ae) are characterized by tractiveretinal detachment involving the macula depending onthe number of quadrants involved. Due to macular de-tachment visual function is always reduced [72].

In further studies, our group investigated the impor-tance of Krolls classification as a prognostic value re-garding the postoperative results of vitreoretinal surgery.We analyzed 563 patients who underwent a pars planavitrectomy for PDVR and calculated the operative risksin a multivariate logistic regression analysis. The resultsshowed that postoperative increase of visual acuity of13lines was significantly less frequent in stages B and C incomparison to stage A. It may be concluded that Krollsclassification for PDVR has a high prognostic value forpostoperative visual outcome and surgical managementindications [51, 54].

Final Considerations and Conclusions

While pathogenesis and morphological changes ofnon-PDR seem to be clear (a classification was set up bythe ETDRS), currently applied classification systems of

PDR are still insufficient.Molecular biological examinations show a very com-

plex system of growth factors and multiple other factorsinvolved in the pathogenesis of the disease. As we couldshow above, in our opinion, the posterior vitreous cortexseems to be the main cause of morphological changes inPDVR. First, in diabetic eyes vessels grow into the thick-ened posterior vitreous cortex, maintained by molecularprocesses in the vitreoretinal interface. Second, a shrink-

In 2003, Wilkinson et al. [120] reported the results ofa workshop for a proposed international diabetic retinop-athy severity scale. It was agreed among the participantsthat, in addition to mild, moderate and severe, there is alevel for no retinopathy and second, a PDR level for thepresence of any neovascularization. However, the interna-tional clinical diabetic retinopathy disease severity scaleproposed no division of PDR into subgroups. The inclu-sion of no apparent retinopathy and minimal non-PDRwere seen as disagreement in the discussion (table 2).

It could be shown that most publications nowadays arebased on vitreous hemorrhages with macula on or off,tractive retinal detachments and progressive fibrovascu-lar proliferations as indication criteria for surgery. There-fore, a standard definition and classification of diabeticretinopathy is necessary. It should be clear and critical forthe clinical decision process and for communicationamong ophthalmologists, internists and diabetologistsand also for communication with the patient. Further-more, a classification of PDVR may also be essential todefine the indications of surgery and to serve as a predic-tive factor for surgical outcomes.

Krolls ClassificationAs the vitreous has a defined role in the pathogenesis

of PDVR, vitreous removal, either by pars plana vitrec-tomy [13, 33, 56, 74, 95] or by enzymatic means [52, 53] ,is an appropriate technique to interrupt this process andto prevent final stages. Various studies have demonstrat-ed that vitrectomy earlier in the course of the disease pre-vents the onset of severe complications [50, 101]. How-ever, a good postoperative visual outcome is difficult topredict even though various factors like preoperative vi-

sual acuity, short duration of visual loss, absence of irisneovascularization, a clear lens and partial panretinalphotocoagulation are known [50]. Therefore, Kroll et al.[73] established a classification of PDVR that clearly dif-ferentiated between early and late stages of the diseaseand was based on the described hypothetic pathogenesisof PDVR and on clinical observations with preoperativeexamination techniques as well as intraoperative obser-vations.

Table 2. Classification systems of diabetic retinopathy

1969 Airlie House classification [25]1981 Modified Airlie House classification (ETDRS) [29]2003 International Clinical Diabetic Retinopathy Severity Scale

(American Academy of Ophthalmology) [119]


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ing of the posterior hyaloid entails different tractionalretinal detachments, which leads us to a morphologicalclassification of PDVR. That is why the term PDR shouldbe changed to PDVR. Furthermore, our classificationmaps 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) todocument morphological fundus changes in PDVR, (2)to grade disease severity to improve interobserver com-munication, (3) to indicate proper treatment, such as la-

ser coagulation or pars plana vitrectomy, (4) to commu-nicate disease severity to the patient, (5) as a predictiveindicator for disease progress and (6) for retro- or pro-spective analysis and studies about PDVR.

Acknowledgments

This research was supported by the German Academic Ex-change Service (DAAD), grant A/01/16770, and by the Fehr Foun-dation.

References

1 Adamis AP, Shima DT, Tolentino MJ, Gra-goudas ES, Ferrara N, Folkman J, DAmorePA, Miller JW: Inhibition of vascular endo-thelial growth factor prevents retinal isch-emia-associated iris neovascularization in anonhuman primate. Arch Ophthalmol 1996;114: 6671.

2 Aiello LP, Avery RL, Arrigg PG, Keyt BA,Jampel HD, Shah ST, Pasquale LR, ThiemeH, Iwamoto MA, Park JE: Vascular endothe-lial growth factor in ocular fluid of patientswith diabetic retinopathy and other retinaldisorders. N Engl J Med 1994; 331: 14801487.

3 Aiello LP, Bursell SE, Clermont A, Duh E,Ishii H, Takagi C, Mori F, Ciul la TA, Ways K,Jirousek M, Smith LE, King GL: Vascular en-

dothelial growth factor-induced retinal per-meability is mediated by protein kinase C invivo and suppressed by an orally effect ivebeta-isoform-selective inhibitor. Diabetes1997; 46: 14731480.

4 Aiello LP: Perspectives on diabetic retinopa-thy. Am J Ophthalmol 2003;136:122135.

5 Aiello LP: The potential role of PKC beta indiabetic retinopathy and macular edema.Surv Ophthalmol 2002; 47:S263S269.

6 Akiba J, Ueno N, Chakrabarti B: Molecularmechanisms of posterior vitreous detach-ment. Graefes Arch Clin Exp Ophthalmol1993; 231: 408412.

7 Arden GB: The absence of diabetic retinopa-thy in patients with retin itis pigmentosa: im-

plications for pathophysiology and possibletreatment. Br J Ophthalmol 2001; 85: 366370.

8 Armstrong D, Augustin AJ, Spengler R, Al-Jada A, Nickola T, Grus F, Koch F: Detectionof vascular endothelial growth factor and tu-mor necrosis factor alpha in epiretinal mem-branes of proliferative diabetic retinopathy,proliferative vitreoretinopathy, a nd macularpucker. Ophthalmologica 1998; 212: 410414.

9 Augustin AJ, Keller A, Koch F, Jurklies B,Dick B: Effect of retinal coagulation statuson oxidative metabolite and VEGF in 208 pa-tients with proliferative diabetic retinopa-thy. Klin Monatsbl Augenheilkd 2001; 218:8994.

10 Barber AJ, Antonetti DA, Gardner TW: Al-tered expression of retinal occludin and glialfibrillary acidic protein in experimental dia-betes. The Penn State Retina Research Group.Invest Ophthalmol Vis Sci 2000; 41: 35613568.

11 Barber AJ, Lieth E, Khin SA, Antonetti DA,Buchanan AG, Gardner TW: Neural apopto-sis in the retina during experimental and hu-man diabetes: early onset and effect of insu-lin. J Clin Invest 1998; 102:783791.

12 Barouch FC, Miyamoto K, Allport JR, FujitaK, Bursell SE, Aiello LP, Luscinskas FW, Ad-amis AP: Integrin-mediated neutrophil ad-hesion and retinal leukostasis in diabetes.Invest Ophthalmol Vis Sci 2000; 41: 11531158.

13 Bodanowitz S, Hesse L, Weinand F, Kroll P:Vitrectomy in diabetic patients with a blindfellow eye. Acta Ophthalmol Scand 1996; 74:8488.

14 Boeri D, Maiello M, Lorenzi M: Increasedprevalence of microthromboses in retinalcapillaries of diabetic individuals. Diabetes2001;50:14321439.

15 Cai J, Boulton M: The pathogenesis of dia-betic retinopathy: old concepts and new

questions. Eye 2002; 16: 242260.16 Canton A, Burgos R, Hernandez C, Mateo C,

Segura RM, Mesa J, Simo R: Hepatocytegrowth factor in vitreous and serum frompatients with proliferative diabetic reti nopa-thy. Br J Ophthalmol 2000 ; 84: 732735.

17 Casarol i Marano RP, Preissner KT, Vilaro S:Fibronectin, laminin, vitronectin and theirreceptors at newly formed capillaries in pro-liferative diabetic retinopathy. Exp Eye Res1995; 60: 517.

18 Chakrabarti S, Cukiernik M, Hileeto D, Ev-ans T, Chen S: Role of vasoactive factors inthe pathogenesis of early changes in diabeticretinopathy. Diabetes Metab Res Rev 2000; 16: 393407.

19 Chantelau E, Kohner EM, Seppel T, SchonauE, Althaus C: Elevation of serum IGF-1 pre-cedes proliferative diabetic retinopathy inMauriacs syndrome. Br J Ophthalmol 1997;81:169170.

20 Chantelau E: Evidence that upregulation ofserum IGF-1 concentration can trigger ac-celeration of diabetic retinopathy. Br J Oph-thalmol 1998; 82: 725730.

21 Chantelau E: Effect of a growth hormone re-ceptor antagonist on proliferative diabeticretinopathy. Ophthalmology 2002 ;109: 2187.

22 Chaturvedi N, Sjolie AK, Stephenson JM,Abrahamian H, Keipes M, Castellarin A,Rogulja-Pepeonik Z, Fuller JH: Effect oflisinopril on progression of retinopathy innormotensive people with type I diabetes.The EUCLID Study Group. EURODIABControlled Trial of Lisinopril in Insul in-De-pendent Diabetes Mellitus. Lancet 1998;351:2831.

23 Chiarelli F, Santilli F, Mohn A: Role ofgrowth factors in the development of diabet-ic complications. Horm Res 2000;53: 5367.

24 Danis RP, Bingaman DP, Jirousek M, Yang Y:Inhibition of intraocular neovascularizationcaused by retinal ischemia in pigs by PKC-beta inhibition with LY333531. Invest Oph-

thalmol Vis Sci 1998;39: 171179.25 Davis MD, Norton EWD, Myers FL: The Air-

lie classification of diabetic retinopathy; inGoldberg MF, Fine SL (eds): Symposium onthe Treatment of Diabetic Retinopathy,Washington, US Government Printing Of-fice, 1969, pp. 722. USPHS pub No 1890.

26 Dawson DW, Volpert OV, Gillis P, CrawfordSE, Xu H, Benedict W, Bouck NP: Pigmentepithelium-derived factor: a potent inhibitorof angiogenesis. Science 1999; 285: 245248.


22/67



27 Dawson VL, Dawson TM: Nitric oxide inneurodegeneration. Prog Brain Res 1998;118: 215229.

28 Diabetes Control and Complications TrialStudy Group: The absence of a glycemicthreshold for the development of long-termcomplications: the perspective of the Diabe-tes Control and Complications Trial. Diabe-tes 1996; 45:12891298.

29 A modification of the Airlie House classifi-cation of diabetic retinopathy. Diabetic Reti-nopathy Study report No 7. Invest Ophthal-mol Vis Sci 1981; 21:210226.

30 Diabetic Retinopathy Vitrectomy Study Re-search Group: Early vitrectomy for severevitreous hemorrhage in diabetic retinopa-thy: two-year results of a randomized trial.Diabetic Retinopathy Vitrectomy Study re-port 2. Arch Ophthalmol 1985; 103: 16441652.

31 Dwyer MS, Melton LJ 3rd, Ballard DJ, Pa-lumbo PJ, Trautmann JC, Chu CP: Incidenceof diabetic retinopathy and blindness: a pop-ulation-based study in Rochester, Minneso-

ta. Diabetes Care 1985;

8:316322.32 Early Treatment Diabetic Retinopathy Study

Research Group: Grading diabetic retinopa-thy from stereoscopic color fundus photo-graphs an extension of the modified AirlieHouse classification. ETDRS report No 10.Ophthalmology 1991;98: 786806.

33 Emmerich KH, Kroll P, Berlage F: Fluores-cein angiographic long-term controls in pa-tients with proliferative diabetic retinopathyand vitrectomy. Fortschr Ophthalmol 1986; 83:474476.

34 Faulborn J, Bowald S: Microproliferations inproliferative diabetic retinopathy and theirrelationship to the vitreous: correspondinglight and electron microscopic studies. Grae-

fes Arch Clin Exp Ophthalmol 1985; 223:130138.

35 Ferrara N: Molecular and biologica l proper-ties of vascular endothelial growth factor. JMol Med 1999; 77: 527543.

36 Fong DS: Changing times for the manage-ment of diabetic retinopathy. Surv Ophthal-mol 2002; 47:S238S245.

37 Foos RY, Wheeler NC: Vitreoret inal junc-ture: synchysis senilis and posterior vitreousdetachment. Ophthalmology 1982;89: 15021512.

38 Foos RY: Vitreoretinal juncture; epiretinalmembranes and vitreous. Invest Ophthal-mol Vis Sci 1977; 16:416422.

39 Frank RN: Potential new medical therapiesfor diabetic retinopathy: protein kinase C in-hibitors. Am J Ophthalmol 2002;133:693698.

40 Gardner TW, Antonetti DA, Barber AJ,LaNoue KF, Levison SW: Diabetic retinopa-thy: more than meets the eye. Surv Ophthal-mol 2002; 47:S253S262.

41 Goldfarb S, Ziyadeh FN, Kern EF, SimmonsDA: Effects of polyol-pathway inhibition anddietary myo-inositol on glomerular hemo-dynamic function in experimental diabetesmellitus in rats. Diabetes 1991;40: 465471.

42 Growth Hormone Antagonist for Prolifera-tive Diabetic Retinopathy Study Group: Theeffect of a growth hormone receptor antago-nist drug on proliferative diabetic retinopa-thy. Ophthalmology 2001; 108:22662272.

43 Hammes HP, Alt A, Niwa T, Clausen JT,Bretzel RG, Brownlee M, Schleicher ED: Dif-ferential accumulation of advanced glyca-tion end products in the course of diabeticretinopathy. Diabetologia 1999; 42: 728736.

44 Hammes HP, Lin J, Bretzel RG, Brownlee M,Breier G: Upregulation of the vascular endo-thelial growth factor/vascular endothelialgrowth factor receptor system in experimen-tal background diabetic retinopathy of therat. Diabetes 1998; 47: 401406.

45 Hammes HP, Lin J, Renner O, Shani M, Lund-qvist A, Betsholtz C, Brownlee M, Deutsch U:Pericytes and the pathogenesis of diabetic

retinopathy. Diabetes 2002;51:31073112.46 Hammes HP, Wellensiek B, Kloti ng I, Sickel

E, Bretzel RG, Brownlee M: The relationshipof glycemic level to advanced glycation end-product (AGE) accumulation and retinal pa-thology in the spontaneous diabetic ham-ster. Diabetologia 1998;41: 165170.

47 Hata Y, Clermont A, Yamauchi T, Pierce EA,Suzuma I, Kagokawa H, Yoshikawa H, Rob-inson GS, Ishibashi T, Hashimoto T, UmedaF, Bursell SE, Aiello LP: Retinal expression,regulation, and functional bioactivity ofprostacyclin-stimulating factor. J Clin Invest2000;106:541550.

48 Hendrikse F, Yeo KT: Role of the vitreousbody in diabetic reti nopathy. Kli n Monatsbl

Augenheilkd 1993; 203:319323.49 Hernandez C, Lecube A, Segura RM, Sara-

rols L, Simo R: Nitric oxide and vascular en-dothelial growth factor concentrations areincreased but not related in vitreous fluid ofpatients with proliferative diabetic reti nopa-thy. Diabet Med 2002; 19: 655660.

50 Hesse L, Bodanowitz S, Hhnermann M,Kroll P: Prediction of visual acuity after ear-ly vitrectomy in diabetics. Ger J Ophthalmol1996; 5: 257261.

51 Hesse L, Heller G, Kraushaar N, Wesp A,Schroeder B, Kroll P: The predictive value ofa classification for proliferative diabetic vit-reoretinopathy. K lin Monatsbl Augenheilkd

2002;219:

4649.52 Hesse L, Kroll P: Enzymatically inducedposterior vitreous detachment in prolifera-tive diabetic vitreoretinopathy. Klin Monats-bl Augenheilkd 1999;214: 8489.

53 Hesse L, Kroll P: TPA-assisted vitrectomy forproliferative diabetic retinopathy. Retina2000;20: 317318.

54 Hesse L, Kroll P: What is the ophthalmolog-ic recommendation for managing diabeteswith reference to d iabetic retinopathy. Inter-nist (Berl) 1993; 34: 477.

55 Hoerle S, Gruner F, Kroll P: Epidemiology ofdiabetes-induced blindness a review. KlinMonatsbl Augenheilkd 2002; 219: 777784.

56 Hoerle S, Poestgens H, Schmidt J, Kroll P: Ef-fect of pars plana vitrectomy for proliferativediabetic vitreoretinopathy on preexisting di-abetic maculopathy. Graefes Arch Clin ExpOphthalmol 2002;240: 197201.

57 Hovener G: The influence of refraction ondiabetic retinopathy. Klin Monatsbl Augen-heilkd 1975; 167:733736.

58 Ishida S, Shinoda K, Kawashima S, OguchiY, Okada Y, Ikeda E: Coexpression of VEGFreceptors VEGF-R2 and neuropilin-1 in pro-liferative diabetic retinopathy. Invest Oph-thalmol Vis Sci 2000; 41: 16491656.

59 Ishii H, Jirousek MR, Koya D, Takagi C, XiaP, Clermont A, Bursell SE, Kern TS, BallasLM, Heath WF, Stramm LE, Feener EP, KingGL: Amelioration of vascular disfunctionsin diabetic rats by an oral PKC beta inhibitor.Science 1996; 272:728731.

60 Joussen AM, Fauser S, Krohne TU, LemmenKD, Lang GE, Kirchhof B: Diabetic retinop-

athy: pathophysiology and therapy of hypox-ia-induced inflammation. Ophthalmologe2003;100:363370.

61 Joussen AM, Kirchhof B, Gottstein C: Mo-lecular mechanisms of vasculogenesis andangiogenesis: what regulates vasculargrowth? Ophthalmologe 2003; 100: 284291.

62 Joussen AM: Angiogenesis in ophthalmolo-gy. 2. Current considerations on the patho-genesis of diabetic and hypoxia-inducedretinopathy. Ophthalmologe 2003; 100: 361362.

63 Kador PF, Takahashi Y, Wyman M, Ferris F3rd: Diabetes-like proliferative retinalchanges in galactose-fed dogs. Arch Oph-thalmol 1995;113: 352354.

64 Kagami S, Border WA, Miller DE, Noble NA:Angiotensin II stimulates extracellular ma-trix protein synthesis through induction oftransforming growth factor-beta expressionin rat glomerular mesangial cells. J Clin In-vest 1994;93: 24312437.

65 Kerty E, Russell D, Bakke SJ, Nyberg-Han-sen R, Rootwell K: Regional cerebral bloodflow (rCBF) and cerebral vasoreactivity inpatients with retinal ischaemic symptoms. JNeurol Neurosurg Psychiatry 1989; 52: 13451350.

66 Klein R, Klein BE, Moss SE, CruickshanksKJ: The Wisconsin Epidemiologic Study ofDiabetic Retinopathy. XVII. The 14-year in-cidence and progression of diabetic retinop-athy and associated risk factors in type I d ia-betes. Ophthalmology 1998; 105: 18011815.

67 Klein R, Klein BE, Moss SE: Epidemiology ofproliferative diabetic retinopathy. DiabetesCare 1992; 15: 18751891.

68 Klein R: Has the frequency of proliferativediabetic retinopathy declined in the US. Dia-betes Care 2003;26: 26912692.

69 Klein R: Prevention of visual loss from dia-betic retinopathy. Surv Ophthalmol 2002;47:S246S252.


23/67


70 Kohno T, Sorgente N, Goodnight R, Ryan SJ:Alterations in the distr ibution of fibronectinand laminin in the diabetic human eye. In-vest Ophthalmol Vis Sci 1987; 28:515521.

71 Kohno T, Sorgente N, Ishibashi T, Good-night R, Ryan SJ: Immunofluorescent stud-ies of fibronectin and laminin in the humaneye. Invest Ophthalmol Vis Sci 1987;28:506514.

72 Kroll P, Meyer-Rusenberg HW, Berg P: Doesvitrectomy in case of proliferat ive diabeticretinopathy lead to a better intraocular me-tabolism? Fortschr Ophthalmol 1986; 83:471473.

73 Kroll P, Meyer-Rusenberg HW, Busse H:Recommendation for staging of proliferativediabetic retinopathy. Fortschr Ophthalmol1987; 84:360363.

74 Kroll P, Wiegand W, Schmidt J: Vitreopapil-lary traction in proliferative diabetic vitreo-retinopathy. Br J Ophthalmol 1999; 83: 261264.

75 Krumpaszky HG, Klauss V: Epidemiology ofblindness and eye disease. Ophthalmologica

1996;

210:186.76 Lakshminarayanan S, Antonetti DA, Gard-

ner TW, Tarbell JM: Effect of VEGF on reti-nal microvascular endothelial hydraulicconductivity: the role of NO. Invest Oph-thalmol Vis Sci 2000;41:42564261.

77 Limb GA, Hickman-Casey J, Hollifield RD,Chignell AH: Vascular adhesion moleculesin vitreous from eyes with proliferative dia-betic retinopathy. Invest Ophthalmol Vis Sci1999; 40:24532457.

78 Lonneville YH, Ozdek SC, Onol M, Yetkin I,Gurelik G, Hasanreisoglu B: The effect ofblood glucose regulation on retinal nerve fi-ber layer thickness in d iabetic patients. Oph-thalmologica 2003;217: 347350.

79 Malecaze F, Clamens S, Simorre-Pi natel V,Mathis A, Chollet P, Favard C, Bayard F,Plouet J: Detection of vascular endothelialgrowth factor messenger RNA and vascularendothelial growth factor-like activity inproliferative diabetic retinopathy. ArchOphthalmol 1994;112:14761482.

80 Matsugi T, Chen Q, Anderson DR: Contrac-tile responses of cultured bovine retinalpericytes to angiotensin II. Arch Ophthal-mol 1997;115: 12811285.

81 Merimee TJ: Diabetic retinopathy: a synthe-sis of perspectives. N Engl J Med 1990; 322:978983.

82 Mitamura Y, Takeuchi S, Ohtsuka K, Mat-

suda A, Yamamoto T, Yamamoto S, HiraiwaN, Kusakabe M: Tenascin-C levels in the vit-reous of patients with proliferative vitreoret-inopathy. Ophthalmologica 2003; 217: 422425.

83 Murata T, Nagai R, Ishibashi T, Inomuta H,Ikeda K, Horiuchi S: The relationship be-tween accumulation of advanced glycationend products and expression of vascular en-dothelial growth factor in human diabeticretinas. Diabetologia 1997; 40:764769.

84 Ohkubo Y, Kishikawa H, Araki E, Miyata T,Isami S, Motoyoshi S, Kojima Y, FuruyoshiN, Shichiri M: Intensive insulin therapy pre-vents the progression of d iabetic microvas-cular complications in Japanese patientswith non-insulin-dependent diabetes melli-tus: a ra ndomized 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, Cam-pochiaro PA: Transgenic mice with increasedexpression of vascular endothelial growthfactor in the retina: a new model of intraret-inal and subretinal neovascularization. AmJ Pathol 1997; 151: 281291.

86 Oku H, Kida T, Sugiyama T, Hamada J, SatoB, Ikeda T: Possible involvement of endothe-lin-1 and nitric oxide in t he pathogenesis ofproliferative diabetic retinopathy. Retina2001;21: 647651.

87 Papapetropoulos A, Garcia-Cardena G,Madri JA, Sessa WC: Nitric oxide productioncontributes to the angiogenic properties ofvascular endothelia l growth factor in human

endothelial cells. J Clin Invest 1997;

100:31313139.

88 Porta M, Bandello F: Diabetic retinopathy: aclinical update. Diabetologia 2002; 45: 16171634.

89 Porta M, Sjoelie AK, Chaturvedi N, StevensL, Rottiers R, Veglio M, Fuller JH; EURO-DIAB Prospective Complications StudyGroup: Risk factors for progression to prolif-erative diabetic retinopathy in the EURODI-AB Prospective Complications Study. Dia-betologia 2001;44: 22032209.

90 Poulsen JE: The Houssay phenomenon inman: recovery from retinopathy in a case ofdiabetes with Simmonds disease. Diabetes1953;2:712.

91 Rungger-Brandle E, Dosso AA, LeuenbergerPM: Glial reactivity, an early feature of d ia-betic retinopathy. Invest Ophthalmol Vis Sci2000;41:19711980.

92 Rymaszewski Z, Cohen RM, ChomczynskiP: Human growth hormone stimulates pro-liferation of human retinal microvascularendothelial cells in vitro. Proc Natl Acad SciUSA: 1991;88: 617621.

93 Sato Y, Lee Z: The subclassi fication and long-term prognosis of preproliferative diabeticretinopathy. Jpn J Ophthalmol 20 02; 46: 323329.

94 Schalekamp MADH: Renin-angiotensinsystem components and endothelial proteins

as markers of diabetic microvascular dis-ease. Clin Invest 1993; 71:S3S6.95 Schulze S, Schulze S, Schmidt J, Kroll P: Air

endotamponade in 52 vitrectomies due toproliferative diabetic retinopathy retro-spective comparison with 40 vitrectomieswithout endotamponade. Klin Monatsbl Au-genheilkd 2000;217: 329333.

96 Sebag J, Buckingham B, Charles MA, ReiserK: Biochemical abnormalities in vitreous ofhumans with proliferative diabetic retinopa-thy. Arch Ophthalmol 1992; 110: 14721476.

97 Sebag J, Buzney SM, Belyea DA, Kado M,McMeel JW, Trempe CL: Posterior vitreousdetachment following panretina l laser pho-tocoagulation. Graefes Arch Clin Exp Oph-thalmol 1990; 228:58.

98 Sebag J, Hageman GS: Interfaces. Rome,Fondazione GB Bietti, 2000, chap IV, pp6265.

99 Sebag J: The Vitreous Structure, Functionand Pathobiology. New York, Springer,1989, pp 106107.

100 Sebag J: Diabetic vitreopathy. Ophthalmol-ogy 1996;103:205206.

101 Shea M: Early vitrectomy in proliferativediabetic retinopathy. Arch Ophthalmol1983;101:12041205.

102 Simo R, Lecube A, Segura RM, Garcia Ar-umi J, Hernandez C: Free insulin-likegrowth factor-I and vascular endothelialgrowth factor in the vitreous fluid of pa-tients with proliferative diabetic retinopa-thy. Am J Ophthalmol 2002;134:376382.

103 Sjolie AK, Stephenson J, Aldington S, Koh-ner E, Janka H, Stevens L, Fuller J: Retinop-

athy and vision loss in insulin-dependentdiabetes in Europe. Ophthalmology 1997;104:252260.

104 Smith JA, Davis CL, Burgess GM: Prosta-glandin E2-induced sensitization of brady-kinin-evoked responses in rat dorsal rootganglion neurons is mediated by cAMP-de-pendent protein kinase A. Eur J Neurosci2000; 12:32503258.

105 Smith LE, Shen W, Perruzzi C, Soker S, Ki-nose F, Xu X, Robinson G, Driver S, Bischof fJ, Zhang B, Schaeffer JM, Senger DR: Regu-lation of vascular endothelial growth fac-tor-dependent retinal neovascularizationby insulin-like growth factor-1 receptor.Nat Med 1999; 5: 13901395.

106 Sozmen EY, Sozmen B, Delen Y, Onat T:Catalase/superoxide dismutase (SOD) andcatalase/paraoxonase (PON) ratios mayimplicate poor glycemic control. Arch MedRes 2001;32:283287.

107 Spranger J, Hammes HP, Preissner KT,Schatz H, Pfeiffer AF: Release of the angio-genesis inhibitor angiostatin in patientswith proliferative diabetic retinopathy: as-sociation with retinal photocoagulation.Diabetologia 2000 ;43:14041407.

108 Stavri GT, Zachary IC, Baskerville PA,Martin JF, Erusalimsky JD: Basic fibroblastgrowth factor upregulates the expression ofvascular endothel ial growt h factor in vas-

cular smooth muscle cells: synergistic in-teraction with hypoxia. Circulation 1995; 92: 1114.

109 Stevens MJ, Dananberg J, Feldman EL, Lat-timer SA, Kamijo M, Thomas TP, Shindo H,Sima AA, Greene DA: The linked roles ofnitric oxide, aldose reductase and Na+, K+-ATPase in the slowing of nerve conductionin the streptozotocin diabetic rat. J Clin In-vest 1994; 94: 853859.


24/67



110 Stitt AW, Gardiner TA, Archer DB: Histo-logical and ultrastructura l investigation ofretinal microaneurysm development in di-abetic patients. Br J Ophthalmol 1995; 79:362367.

111 Stitt AW: Advanced glycation: an impor-tant pathological event in diabetic and agerelated ocular disease. Br J Ophthalmol2001; 85: 746753.

112 Stitt AW: The role of advanced glycation inthe pathogenesis of diabetic retinopathy.Exp Mol Pathol 2003; 75: 95108.

113 Takahashi T, Hato F, Yamane T, FukumasuH, Suzuki K, Ogita S, Nishizawa Y, Kitaga-wa S: Activation of human neutrophil bycytokine-activated endothelial cells. CircRes 2001;88:422429.

114 The Diabetes Control and ComplicationsTrial Research Group: The effect of inten-sive treatment of diabetes on the develop-ment and progression of long-term compli-cations in insulin-dependent diabetesmellitus. N Engl J Med 1993;329:977986.

115 Tsai DC, Chiou SH, Lee FL, Chou CK, Chen

SJ, Peng CH, Kuo YH, Chen CF, Ho LL, H

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[P. Kroll] Diabetic Retinopathy(Bookos.org)