Macular Degeneration: Bartz-Schmidt KU

Ziemssen F, Grisanti S, Bartz-Schmidt KU, Spitzer MS. · University Eye Hospital, Centre for Ophthalmology, Eberhard-Karls University of Tuebingen, Tuebingen, Germany. · Drugs Aging. · Pubmed #19476398 No free full text.

Abstract: There is an active and controversial debate about the role of intravitreal bevacizumab versus approved drugs in the treatment of neovascular age-related macular degeneration (AMD). Because bevacizumab was available prior to the launch of ranibizumab, off-label use of the former became widespread and the cancer drug bevacizumab is the most commonly used medication in ophthalmology nowadays. This review considers every publication identified in MEDLINE using the keywords 'bevacizumab' and 'Avastin' between 1 June 2005 and 31 July 2008. The search identified 511 papers that were evaluated. In 33 studies, there was consistent and clear evidence for the efficacy of bevacizumab in neovascular AMD. However, the highest grade studies (three prospective, randomized, controlled trials) did not attain better than grade 2b level of evidence, and objective evaluation of the benefit of bevacizumab relative to representative controls was therefore not possible. Certainly, the available evidence is inferior to that obtained from the approval studies of ranibizumab and this should influence treatment selection and guidance of patients. These considerations indicate that important quality criteria need to be included in future studies to ensure more meaningful conclusions can be drawn. These include clearly defined inclusion criteria, information about the recruitment procedure (including data on withdrawals, excluded patients, concealed treatment allocation, use of intention-to-treat analyses and blinded assessment procedures). Although preclinical studies have almost exclusively found bevacizumab to be safe, the design utilized in clinical case series cannot rule out a possible increase in adverse events, which already show a high spontaneous incidence in elderly AMD patients. The superior evidence level for ranibizumab and the limited safety data for bevacizumab must be taken into consideration when evaluating the costs that a healthcare system is willing to spend. However, the superior grade of evidence for ranibizumab should not be confused with the (still missing) evidence for superior efficacy. The results of ongoing randomized, controlled, comparative trials will provide further data on the efficacy and cost effectiveness of bevacizumab and ranibizumab in the treatment of AMD. In the meantime, patients should be informed about the alternatives, the price differences and the restricted liability issue when off-label use of bevacizumab is offered.

Jaissle GB, Ziemssen F, Petermeier K, Szurman P, Ladewig M, Gelisken F, Völker M, Holz FG, Bartz-Schmidt KU. · Abt. I, Universitätsaugenklinik Tübingen, Schleichstrasse 12, 72076 Tübingen. · Ophthalmologe. · Pubmed #16763863 No free full text.

Abstract: Application of VEGF inhibitors represents a treatment option for macular edema secondary to retinal vein occlusion that targets the disease at the causal molecular level. First reports on intravitreal injections of bevacizumab show promising morphological and functional effects and demonstrate that bevacizumab is a potent antiedematous agent in this context. A significant reduction of the central retinal thickness followed by a rapid improvement of visual acuity may be achieved within days. In a pilot study with a review period of 3 months, we found a significant improvement of one or more lines in 93% and four or more lines in 27% of eyes. This was associated with a concomitant significant reduction in central retinal thickness, which, however, was not sustained by a single injection (64% reduction after 1 month and 28% after 3 months). No relevant adverse events were noted. The duration of action after intravitreal bevacizumab administration is currently unknown. Reinjections will be necessary to maintain a lasting beneficial effect. Prospective, controlled long-term studies are mandatory to develop standardized treatment protocols that allow a safe and effective application of this off-label therapy.

Ladewig MS, Ziemssen F, Jaissle G, Helb HM, Scholl HP, Eter N, Bartz-Schmidt KU, Holz FG. · Augenklinik, Universität, Ernst-Abbe-Strasse 2, 53127 Bonn. · Ophthalmologe. · Pubmed #16763862 No free full text.

Abstract: The efficacy and safety of the therapeutic anti-VEGF concept has already been demonstrated for pegaptanib and ranibizumab. Bevacizumab acts as an antibody against all VEGF-A isoforms and has been developed for oncological indications with intravenous application. Initial reports on intravitreal administration in patients with neovascular age-related macular disease (AMD) have shown beneficial morphological and functional effects. In the meantime, bevacizumab has been used off-label in thousands of patients with AMD. However, data from prospective, controlled, randomized trials on both safety and efficacy are lacking. Herein recent experiences with bevacizumab are summarized and discussed. Furthermore, a web-based platform for online data registration and pooled analyses is presented.

Lafaut BA, Aisenbrey S, Vanden Broecke C, Di Tizio F, Bartz-Schmidt KU. · University Eye Clinic, Cologne, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #11271462 No free full text.

Abstract: PURPOSE: To report the pathology of surgically removed submacular tissue in recurrent choroidal neovascularization after laser photocoagulation of classic choroidal neovascularization in age-related macular degeneration. METHODS: A recurrent subfoveal choroidal neovascular membrane was surgically removed in two patients. The recurrence was identified as a classic membrane on fluorescein angiography at the foveal border of the laser scar. A net was visualized in the early venous phase of the indocyanine green angiogram, with associated late hyperfluorescence. Both patients had undergone laser photocoagulation for a classic interpapillomacular choroidal neovascular membrane about 1 1/2 years earlier. The specimens were serially sectioned and stained with hematoxylin-eosin, periodic acid-Schiff, Masson trichrome and phosphotungstic acid-hematoxylin. RESULTS: The two specimens consisted of subretinal fibrovascular tissue with fibrin exudation. Fibrovascular tissue bordered subretinal fibrous tissue adherent to Bruch's membrane and remnants of the choroid in one patient. The fibrovascular portion most likely corresponded to the recurrence, whereas the fibrous portion represented the original membrane, being obliterated after photocoagulation. Some peripapillary tissue was additionally removed in the other patient. The latter lesion was invisible on fluorescein angiography but stained in the late phase of indocyanine green angiography and corresponded histopathologically to poorly vascularized intra-Bruch's fibrovascular tissue. Granular deposits, periodic acid-Schiff positive and metachromatically purple on Masson trichrome stain, representing diffuse drusen (basal laminar/linear deposits), were identified in the three specimens. CONCLUSION: A subretinal fibrovascular membrane corresponded with the classic recurrent choroidal neovascularization.

Jaissle GB, Leitritz M, Gelisken F, Ziemssen F, Bartz-Schmidt KU, Szurman P. · University Eye Clinic, Centre for Ophthalmology, Eberhard-Karls University of Tuebingen, Schleichstr. 12, 72076 Tuebingen, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #18696094 No free full text.

Abstract: BACKGROUND: To investigate the long-term effectiveness of intravitreal bevacizumab treatment in eyes with perfused macular edema due to branch retinal vein occlusion (BRVO). METHODS: In this prospective interventional case series, 23 consecutive, previously untreated eyes with perfused macular edema were treated with intravitreal bevacizumab (1.25 mg) injections and followed for 1 year. The main outcome measures were visual acuity (VA) and central retinal thickness (CRT). In addition, VA data were adapted to the non-logarithmic VA charts used in the previously published grid laser photocoagulation BRVO Study. RESULTS: The median VA gained 3.0 lines from baseline at 48 weeks. This was accompanied by a significant decrease of 39% of the median CRT. The mean number of re-injections was 1.6 during the first 6 months of follow-up and only 0.8 during the subsequent 6 months. In 65% of the cases, adapted VA data showed a gain of 1 or more lines and no eye lost more than 1 line. CONCLUSIONS: Repetitive intravitreal bevacizumab injections result in a significant long-term improvement of VA and CRT. The number of re-injections necessary to maintain this effect declined over time. However, the treatment seems to be only slightly better than grid laser photocoagulation.

Brunner R, Widder RA, Walter P, Lüke C, Godehardt E, Bartz-Schmidt KU, Heimann K, Borberg H. · Klinik und Poliklinik für Augenheilkunde, Universität zu Köln, Germany. · Retina. · Pubmed #11039423 No free full text.

Abstract: PURPOSE: Membrane differential filtration is able to optimize rheologic parameters by eliminating high molecular weight proteins and lipoproteins from the blood. Following the hypothesis that these changes result in an improvement of the microcirculation, the authors tested the efficacy of membrane differential filtration in improving visual function in patients with age-related macular degeneration (ARMD). METHODS: Forty patients (40 eyes) were randomized into two groups. The treatment group was treated five times over a period of 21 weeks. In both groups, 9/20 of the eyes showed subfoveolar subretinal neovascularization. The main parameter of the study was visual acuity (VA). Electroretinogram (ERG), electrooculogram, and macular visual evoked potentials were also recorded. Plasma and whole blood viscosity and erythrocyte aggregation were measured. RESULTS: The 20 patients treated repeatedly over a period of 21 weeks showed a mean improvement of 0.63 lines (SD 1.8) of VA on Early Treatment Diabetic Retinopathy Study charts. The control group showed a deterioration of 0.94 lines (SD 1.7) compared to VA at baseline examination. The amplitude of the ERG photopic a-wave and the flicker ERG was significantly increased. The rheologic parameters were lowered in all treated patients. CONCLUSION: Repetitive treatment with membrane differential filtration is able to improve visual acuity of patients with ARMD and the natural course of this disease. Several questions arise from the results of this study. Further research will show if it is possible to optimize the selection of patients for subgroups with predictive responses through morphologic and functional tests and how to create an optimized and individual treatment strategy determined by the quality, intensity, and frequency of treatment sessions.

Thumann G, Aisenbrey S, Schraermeyer U, Lafaut B, Esser P, Walter P, Bartz-Schmidt KU. · University of Cologne, Joseph-Stelzmann-Str 9, 50924 Cologne, Germany. · Arch Ophthalmol. · Pubmed #11030816 No free full text.

Abstract: BACKGROUND: Transplantation of autologous iris pigment epithelium (IPE) into the subretinal space has been suggested as one approach for the treatment of age-related macular degeneration, as well as for other conditions in which loss of retinal pigment epithelium (RPE) occurs. Surgical removal of choroidal neovascular membranes is associated with traumatic loss of the RPE cell layer, disruption of the integrity of the photoreceptor-RPE complex, and limited visual outcome. OBJECTIVE: To examine whether IPE cells can substitute for RPE cells to be transplanted to the subretinal space of patients with either RPE degenerative disease or traumatic loss of the RPE cell layer after subretinal surgery. METHODS: Autologous IPE cells were transplanted to the subretinal space in 20 consecutive patients undergoing removal of subretinal fibrovascular membranes using pars plana vitrectomy. Autologous IPE cells were harvested by iridectomy, isolated, and transplanted directly to the subretinal spaces. Transplants were evaluated for 6 to 11 months by funduscopy, fluorescein angiography, and scanning laser ophthalmoscopic (SLO) microperimetry. RESULTS: For the entire follow-up period, no evidence of any immunologic response was observed. Revisional surgery was necessary in 3 patients because of complications (rhegmatogenous retinal detachment [n = 1]; proliferative vitreoretinopathy [n = 1]; and macular pucker [n = 1]); 1 patient did not receive IPE cells. Five of 19 phakic eyes underwent cataract surgery; in 1 case this was combined with the vitrectomy. Five patients showed improved visual acuity of 3 to 4 lines, 13 patients had stable visual acuity (+/-2 lines), and 2 patients had reduced visual acuity of 6 lines. CONCLUSIONS: In this pilot study, the transplantation of autologous IPE cells was done as an addition to conventional surgical excision of choroidal neovascular membranes. Transplanted cells were well tolerated in the subretinal space and did not adversely affect the function of the photoreceptors, since improvement or stable visual acuity was observed in 18 patients after IPE transplantation. These results suggest that autologous IPE cells may be used as a substitute for autologous RPE cells to transplant to the subretinal space to treat age-related macular degeneration.

Widder RA, Brunner R, Walter P, Bartz-Schmidt KU, Godehardt E, Heimann K, Borberg H. · Klinik und Poliklinik für Augenheilkunde, Universität zu Köln. · Klin Monatsbl Augenheilkd. · Pubmed #10448637 No free full text.

Abstract: BACKGROUND: Membrane differential filtration (MDF) is known to optimize rheological parameters by eliminating high molecular weight proteins und lipoproteins from the blood and was shown to influence ocular perfusion parameters. Following the hypothesis that these changes may influence the natural course of age-related macular degeneration (AMD) we tested their efficacy in improving visual function in these patients in a randomized trial. PATIENTS AND METHODS: 20 patients (36 eyes) were randomized into two groups. Ten patients (18 eyes) were treated with MDF and ten (18 eyes) served as controls. The first group was treated five times over a period of 21 weeks. In both groups 8/18 of the eyes showed subfoveolar subretinal neovascularisations. Main parameter of the study was visual acuity. Macular visual evoked potentials were also recorded. Plasmaviscosity, whole blood viscosity and erythrocyte aggregation were measured. RESULTS: The ten patients, treated repeatedly over a period of 21 weeks, showed a mean improvement 1.1 (SD 1.9) lines after 21 weeks, while the control group showed a deterioration of visual acuity (0.6 lines, SD 1.7). The macular visual evoked potentials showed an increase of 0.28 microV (SD 1.12) for the therapy group and a deterioration of 0.57 microV (SD 1.31) in the control group. The rheological parameters were lowered in all patients. CONCLUSIONS: We conclude that repetitive treatment with MDF is able to improve visual function in patients with AMD. Further research is necessary to show how to optimize the selection of patients and how to create an individual treatment strategy.

Tatar O, Adam A, Shinoda K, Kaiserling E, Boeyden V, Claes C, Eckardt C, Eckert T, Pertile G, Scharioth GB, Yoeruek E, Szurman P, Bartz-Schmidt KU, Grisanti S. · University Eye Hospital at the Centre for Ophthalmology of the Eberhard-Karls University, Tuebingen, Germany. · Arch Ophthalmol. · Pubmed #19273790 No free full text.

Abstract: OBJECTIVE: To evaluate the early effects of triamcinolone acetonide (TA) on inflammation, proliferation, and vascular endothelial growth factor (VEGF) in human choroidal neovascularization (CNV). METHODS: Retrospective review of an interventional case series of 29 patients who underwent macular translocation. Fourteen CNV membranes without previous therapy (control CNV group) and 4 CNV membranes excised 3 days after photodynamic therapy (PDT CNV group) comprised the control groups. Eleven patients were treated with intravitreal TA (TA CNV group; n = 5) or PDT and TA combined (PDT+TA CNV group; n = 6) 3 to 9 days preoperatively. The CNV membranes were stained for cytokeratin 18, CD34, VEGF, intercellular adhesion molecule-1 (ICAM-1), E-selectin, CD68, CD45, Ki-67, and Thy-1. RESULTS: Treatment with TA and PDT+TA resulted in increased immunostaining of ICAM-1 in endothelial cells and the stroma and a higher percentage of Thy-1 expression than controls. The density of macrophages was significantly increased in PDT+TA CNV membranes. Leukocyte density and proliferative activity were lower in TA and PDT+TA CNV membranes. The total VEGF score was significantly increased in TA and PDT+TA CNV membranes compared with the control CNV membranes. Evidence of VEGF in the retinal pigment epithelium of PDT+TA CNV membranes was stronger than in control CNV membranes. CONCLUSIONS: Triamcinolone acetonide has no inhibitory effect on macrophage infiltration or ICAM-1, Thy-1, or VEGF expression in CNV membranes in the early term. The clinical benefits of TA are probably not based on pure antiinflammatory or VEGF-suppressing mechanisms.

Lüke M, Ziemssen F, Völker M, Altpeter E, Beutel J, Besch D, Bartz-Schmidt KU, Gelisken F. · University Eye Hospital, University of Lübeck, Lübeck, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #19214552 No free full text.

Abstract: BACKGROUND: To report the outcome of best-corrected visual acuity (BCVA), near visual acuity (NVA), contrast sensitivity (CS) and vision-related quality of life (VRQOL) in patients 2 years after undergoing photodynamic therapy (PDT) or full macular translocation (FMT) for the treatment of neovascular age-related macular degeneration (AMD). METHODS: Fifty patients with predominantly classic subfoveal choroidal neovascularisation (CNV) secondary to AMD were randomized to PDT or FMT. BCVA was determined according a standardized protocol with ETDRS charts. NVA were calculated after testing with SNAB (Swiss National Association of and for the Blind) visual acuity cards. CS was measured with Pelli-Robson charts. The 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25 plus supplement) was performed. Primary end points were the changes of BCVA, NVA, CS and VRQOL at 24-month examination. RESULTS: A stabilisation of BCVA (+0.3 letters) was found in the FMT group, whereas a decrease of more than 12 letters (-12.6 letters) was found in the PDT group (p = 0.052). Mean NVA improved by 7.0 letters in the FMT group and was superior to the PDT group (-9.6 letters, p = 0.036), while mean CS showed a time-dependent decrease in both treatment groups (FMT: -3.3 letters, PDT: -3.8 letters, p = 0.726). Considering the results of the VRQOL scores, the improvement of the subscales scores for general vision (p = 0.015), mental health (p = 0.028) and near activity (p = 0.020) were significantly higher in the FMT group. CONCLUSIONS: FMT can stabilise BCVA and improve NVA over a period of 2 years in patients with subfoveal classic CNV secondary to neovascular AMD, whereas a decrease of BCVA and NVA was found in the PDT group. CS did not differ between FMT and PDT. A significant increase of VRQOL scores was only found in the FMT group and not in the PDT group. FMT seems to be a therapeutic approach that can increase visual function resulting in an improvement of patient's VRQOL, but exhibits a higher number of severe complications compared to PDT.

Tatar O, Shinoda K, Kaiserling E, Claes C, Eckardt C, Eckert T, Pertile G, Boeyden V, Scharioth GB, Yoeruek E, Szurman P, Bartz-Schmidt KU, Anonymous00069, Grisanti S. · University Eye Clinic at the Centre for Ophthalmology, Eberhard-Karls-University, Tuebingen, Germany. · Br J Ophthalmol. · Pubmed #18838410 No free full text.

Abstract: AIM: To evaluate the implications of intravitreal bevacizumab on proangiogenic vascular endothelial growth factor (VEGF) with regard to the endogenous angiogenesis inhibitor endostatin in human choroidal neovascularisation (CNV) secondary to age-related macular degeneration. METHODS: Retrospective review of an interventional case series of 48 patients who underwent full macular translocation surgery with removal of CNV. Twenty-five patients were treated with intravitreal bevacizumab injection 1 to 154 days prior to surgery (bevacizumab CNV). Twenty-three CNV without any kind of previous treatment were used as controls (control CNV). CNV were stained for CD34, cytokeratin18, VEGF, endostatin and E-selectin. A "predominance score of VEGF over endostatin" (PS) was defined by the difference between VEGF and endostatin staining scores. RESULTS: Bevacizumab CNV revealed a weaker VEGF expression in endothelial cells (p = 0.0245) but significantly more intense endostatin in retina pigment epithelium (RPE) (p = 0.0001) and stroma (p<0.0001). Consequently, PS was significantly lower in RPE (p = 0.02), vessels (p = 0.03) and stroma (p = 0.0004) in bevacizumab CNV. The intensity of E-selectin expression in bevacizumab CNV was comparable with that in control CNV. CONCLUSIONS: A shift within the angiogenic balance in terms of decreased VEGF predominance over endostatin is detected in human CNV treated with bevacizumab.

Tatar O, Yoeruek E, Szurman P, Bartz-Schmidt KU, Anonymous00212, Adam A, Shinoda K, Eckardt C, Boeyden V, Claes C, Pertile G, Scharioth GB, Grisanti S. · University Eye Hospital, Centre for Ophthalmology, Eberhard-Karls University, Tübingen. · Arch Ophthalmol. · Pubmed #18541840 links to  free full text

Abstract: OBJECTIVE: To evaluate the effect of bevacizumab (Avastin; Genentech, Inc, South San Francisco, California) on inflammation and proliferation in human choroidal neovascularization (CNV) secondary to age-related macular degeneration. METHODS: Retrospective review of interventional series of 38 patients who underwent choroidal neaovascular membrane (CNVM) extraction. Twenty-four patients received intravitreal bevacizumab 1 to 154 days preoperatively (bevacizumab CNV group). Fourteen patients received no preoperative therapy (control CNV group). The CNVM were stained for cytokeratin 18, CD68, CD45, intercellular adhesion molecule (ICAM)-1, E-selectin, Ki-67, Thy-1, and endostatin. RESULTS: No significant difference was detected in ICAM-1 and E-selectin expression between groups. The density of leukocytes in the bevacizumab CNV group (median, 271.61 cells/mm(2)) was higher than in the control CNV group (median, 116.87 cells/mm(2); P = .07), but without significance. Density of macrophages (median, 4661.95 cells/mm(2)), proliferative activity (median, 160.19 cells/mm(2)), and percentage of Thy-1-expressing vessels (median, 100%) were significantly higher in the bevacizumab CNV group than in the control CNV group (median, 882.66 cells/mm(2), P < .001; median, 34.34 cells/mm(2), P < .001; and median, 80%, P < .001, respectively). Endostatin immunoreactivity was considerably stronger in the retina pigment epithelium (RPE)-Bruch membrane complex (median, 3; range, 2-3; P < .001), and stroma (median, 3; range, 1-3; P < .001) of the bevacizumab CNV group than control CNV group (median, 1.5; range, 0-3 and median, 1; range, 0-3, respectively). CONCLUSIONS: Unexpectedly, CNVM from patients treated by bevacizumab are characterized by significantly high inflammatory and proliferative activity and enhanced endostatin expression. These characteristics need to be considered when protocols for combination therapies are established.

Tatar O, Shinoda K, Kaiserling E, Pertile G, Eckardt C, Mohr A, Yoeruek E, Szurman P, Bartz-Schmidt KU, Grisanti S. · Centre for Ophthalmology, University Eye Hospital, Eberhard-Karls University, Schleichstrasse 12-15, 72076 Tuebingen, Germany. · Arch Ophthalmol. · Pubmed #18268209 links to  free full text

Abstract: OBJECTIVE: To evaluate the early effects of triamcinolone acetonide as monotherapy or as an adjuvant to ocular verteporfin photodynamic therapy (PDT) on angiogenesis in human choroidal neovascularization (CNV) secondary to age-related macular degeneration. METHODS: Retrospective review of an interventional series of 55 patients who underwent CNV extraction. Eleven patients were treated with intravitreal triamcinolone acetonide (4 mg) monotherapy (triamcinolone-treated CNV group [n = 5]) or with PDT-triamcinolone combination therapy (PDT-triamcinolone-treated CNV group [n = 6]) 3 to 9 days before surgery. Forty patients who underwent CNV extraction without previous therapy (control CNV group) and 4 patients who underwent CNV extraction 3 days after PDT (PDT CNV group) served as control subjects. The CNV samples were stained for CD34, endostatin, cytokeratin 18, and vascular endothelial growth factor (VEGF). RESULTS: Vascular endothelial growth factor expression was stronger in the PDT CNV samples (P < .001), triamcinolone CNV samples (P = .01), and PDT-triamcinolone CNV samples (P = .007) compared with the control CNV samples. There were no statistically significant differences in VEGF expression among the PDT CNV samples, triamcinolone CNV samples, and PDT-triamcinolone CNV samples. Endostatin expression was weaker in the PDT CNV samples than in the control CNV samples (P = .008). Endostatin expression was stronger in the triamcinolone CNV samples and the PDT-triamcinolone CNV samples compared with the control CNV samples (P = .001 and P < .001, respectively) and the PDT CNV samples (P < .001 for both). CONCLUSION: To some extent, triamcinolone monotherapy seems to exert its angiogenesis inhibitory effects on CNV by enhancing endostatin expression rather than by suppressing VEGF expression.

Gelisken F, Ziemssen F, Voelker M, Bartz-Schmidt KU, Inhoffen W. · Center for Ophthalmology, University of Tuebingen, Tuebingen, BW, Germany. · Eye. · Pubmed #18239678 No free full text.

Abstract: PURPOSE: To analyse retinal pigment epithelial (RPE) tears following single administration of intravitreal bevacizumab for neovascular age-related macular degeneration (AMD) during early follow-up. METHODS: Interventional, retrospective, non-comparative case series included 397 patients (409 eyes) of the 746 consecutive patients that met the eligibility criteria. Standardized visual acuity testing, fluorescein angiography, and optical coherence tomography were performed. Data collected included status of the fellow eye, previous treatment, subtypes of choroidal neovascularization (CNV), size and composition of the lesion. Multiple linear regression modelling was used to explore the effect of baseline parameters on the RPE tears. Primary end point was occurrence of RPE tears within 6 weeks after therapy. RESULTS: Fifteen of the 409 eyes (3.6%) developed RPE tear (95% confidence interval: 2.2-6.0, odds ratio: 26.3). The statistical modelling showed significant association between RPE tear and occult without classic CNV/predominantly haemorrhage vspredominantly/minimal classic CNV (P=0.019), as well as medium or large (>4 disc area) vssmall size of the total lesion (P=0.038). Previous treatment and status of the fellow eye did not statistically influence the risk of RPE tears. CONCLUSIONS: An RPE tear can develop in up to 3.6% of eyes with neovascular AMD following single administration of intravitreal bevacizumab in a short-term follow-up. Medium and large lesion size and occult without classic and predominantly haemorrhagic subtype of CNV were important predictive factors. Preoperative assessment of the lesion characteristics may help in identifying the risk of individual patients with neovascular AMD before intravitreal bevacizumab treatment.

Ziemssen F, Lüke M, Bartz-Schmidt KU, Gelisken F. · Department for Ophthalmology, University Eye Hospital, Eberhard-Karls University, Schleichstr. 12-16, 72076 Tuebingen, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #18071731 No free full text.

Abstract: PURPOSE: To report the change of contrast sensitivity (CS) after photodynamic therapy (PDT) vs full macular translocation (FMT) for neovascular age-related macular degeneration (AMD), and to relate this to other measures of visual function (distance and near acuity). METHODS: Fifty patients (50 eyes) with predominantly classic subfoveal choroidal neovascularisation (CNV) secondary to AMD were randomized to PDT or FMT. CS was measured with Pelli-Robson charts. Acuity scores of near visual function (NVS) were calculated after testing with visual acuity cards of the Swiss National Association of and for the Blind (SNAB). Best corrected distance visual acuity (DVA) was determined according to a standardized protocol with EDTRS charts. Primary end point was the change of CS at 12-month examination from baseline. The interaction of the CS with NVS and DVA was analysed. RESULTS: Mean CS showed a decrease in both treatment groups (FMT: -2 letters, PDT: -3 letters, p=0.969) at 12-month examination from baseline. While mean NVS improved by seven letters in the FMT group, a decrease of more than ten letters was seen in the PDT group (p<0.05). We found no agreement between CS and high-contrast acuity (NVS, DVA). In FMT patients, the parameters at baseline (CS, NVS, DVA) correlated poorly with the corresponding 12-month results, therefore providing no informative basis to predict the later functional development. In contrast, PDT patients showed strong baseline-to-outcome coherence with baseline measures also associated with better final values. CONCLUSIONS: Although FMT can initiate recovery of near and distance acuity over the period of 1 year in selected patients with classic CNV, CS did not differ between FMT and PDT. We found no close connection of CS with DVA or NVS, especially after FMT. Knowledge about the unequal variation of visual parameters can provide more comprehensive information when advising patients on different therapeutic options. That also applies in particular to vascular endothelial growth factor inhibitors, which seem to promise an even higher extent of gain in CS and to reach the peak of recovery at an earlier time.

Aisenbrey S, Bartz-Schmidt KU, Walter P, Hilgers RD, Ayertey H, Szurman P, Thumann G. · Department of Ophthalmology, University of Tuebingen, Schleichstrasse 12-16, 72076 Tuebingen, Germany. · Arch Ophthalmol. · Pubmed #17923545 links to  free full text

Abstract: OBJECTIVE: To assess long-term functional and morphological changes after macular translocation in patients with exudative age-related macular degeneration. METHODS: Evaluation of a noncomparative cohort study of 90 patients with a follow-up of 14 to 79 months (mean, 38.2 months). RESULTS: Visual acuity increased by 3 or more lines in 15 patients, remained stable in 35 patients, and deteriorated in 40 patients at final examination. Pigment epithelium atrophy extending to the new fovea was detected in 44 patients; in 25 patients this new atrophy was associated with loss of visual function. CONCLUSIONS: Long-term follow-up of macular translocation with 360 degrees retinotomy showed stabilization or improvement in half of the patients. Progressive atrophy of the pigment epithelium represented one major limiting factor of the beneficial effect of the treatment. Macular translocation may be an option for cases of exudative age-related macular degeneration that are not eligible for or do not respond to alternative treatments.

Ziemssen F, Lüke M, Messias A, Beutel J, Tatar O, Zrenner E, Bartz-Schmidt KU, Anonymous00341. · Department for Ophthalmology, Eberhard-Karls University Tuebingen, Tuebingen, Germany. · Int Ophthalmol. · Pubmed #17634860 No free full text.

Abstract: BACKGROUND: Bevacizumab (Avastin) has been used as off-label treatment for the specific inhibition of the vascular endothelial growth factor (VEGF). Although only intravenous administration of the drug is approved in combination therapy of colorectal carcinoma, promising short-term results have been reported about its intravitreal administration. However, VEGF is also known to exhibit neurotrophic capabilities. Therefore, blockage of all VEGF isoforms by bevacizumab could induce toxic effects. Missing randomized controlled studies and unclear long-term risks require further evaluation. METHODS: Intensified monitoring of bevacizumab treatment was performed in consecutive patients. In ten patients, the functional field score was calculated after obtaining Goldmann visual fields at baseline and 1 year after injection. The other subgroup was examined by means of EOG, ERG and colour testing at baseline and 4 months following treatment. Naka-Rushton plots were calculated to enable statements about retinal function. Lanthony desaturated D15 test was used for repeated colour testing. RESULTS: Baseline parameters already disclosed predominant cone dysfunction. Drug-related effects caused a significant improvement of visual acuity. There was no sign of clinically relevant retinal toxicity following the bevacizumab injection. No progression of visual field defects was seen within the follow-up of 1 year. Performance in EOG testing was affected by restricted fixation stability, but no parameter indicated deterioration within the 4-month-period. CONCLUSIONS: Short-term results underline that intraocular bevacizumab injection promises to be not only a cost-effective, but safe treatment option. Assessed functional parameters as error scores (e.g., Lanthony) corresponded to the impaired retinal function which was presumed to be disease-related. Further long-term results have to confirm the good tolerability in repeated treatment.

Tatar O, Adam A, Shinoda K, Yoeruek E, Szurman P, Bopp S, Eckardt C, Bartz-Schmidt KU, Grisanti S. · University Eye Hospital at the Center for Ophthalmology, Eberhard-Karls University Tuebingen, Germany. · Retina. · Pubmed #17621180 No free full text.

Abstract: PURPOSE: To examine the short- and long-term consequences of verteporfin photodynamic therapy (PDT) on inflammation with regard to infiltration of macrophages and leukocytes and expression of thy-1 in human choroidal neovascularization membranes (CNV) secondary to age-related macular degeneration (AMD). METHODS: Retrospective review of an interventional case series of 43 patients who underwent removal of CNV. Twenty patients were treated with PDT 3 to 246 days preoperatively. Twenty-three CNV without previous treatment were used as control. CNV were stained for CD34, CD105, cytokeratin 18, Ki-67, thy-1, an endothelial cell glycoprotein known to be upregulated only by inflammatory cytokines, CD68 (macrophages), and CD45 (common leukocyte antigen). RESULTS: Specimens treated by PDT 3 days previously showed significantly reduced endothelial thy-1 expression (P = 0.008), leukocyte (P=0.04) and macrophage (P=0.0063) infiltration, and proliferative activity (P=0.02) compared to control CNV. Specimens at longer intervals after PDT, in contrast, disclosed a significantly increased expression of thy-1 (P=0.004), infiltration with leukocytes (P=0.044) and macrophages (P=0.01), and proliferative activity (P=0.03) compared to CNV excised 3 days after PDT. CONCLUSIONS: The rebound effect after PDT seems to be based on an inflammatory response that contributes to enhanced proliferation. These data support the need for an anti-inflammatory therapy as adjuvant to PDT.

Tatar O, Adam A, Shinoda K, Eckert T, Scharioth GB, Klein M, Yoeruek E, Bartz-Schmidt KU, Grisanti S. · University Eye Hospital, Centre for Ophthalmology, Eberhard-Karls University, Tuebingen, Germany. · Br J Ophthalmol. · Pubmed #17475706 No free full text.

Abstract: AIM: To evaluate expression of proangiogenic matrix metalloproteinases (MMP) 2 and 9 at distinct intervals after verteporfin photodynamic therapy (PDT) in human choroidal neovascular membranes (CNV) secondary to age-related macular degeneration (AMD). METHODS: Retrospective review of an interventional case series of 49 patients who underwent removal of CNV. Twenty-six patients were treated with PDT 3 to 383 days prior to surgery. Twenty-three CNV without previous treatment were used as controls. CNV were stained for CD34, cytokeratin 18, endostatin, MMP-2 and MMP-9 by immunohistochemistry. RESULTS: CNV without previous therapy disclosed MMP-2, MMP-9 in RPE-Bruch's membrane, vessels and stroma in different intensities. Three days after PDT, MMP-9 expression was significantly weaker in stroma (p = 0.0019). Endostatin was significantly reduced in vessels (p<0.001). At longer post-PDT intervals, a significant increase of MMP-9 in stroma (p = 0.037) and of endostatin in RPE-Bruch's membrane (p = 0.02), vessels (p = 0.005) and stroma (p<0.001) were disclosed. No significant changes in MMP-2 expression were detected. CONCLUSIONS: PDT induced an early, temporary decrease in MMP-9 and endostatin expression. At longer intervals, MMP-9 increase is possibly associated with the angiogenic process responsible for recurrence after PDT. MMP-9, however, acts as a double-edged sword by concomitant induction of endostatin, an endogenous inhibitor of angiogenesis.

Suesskind D, Voelker M, Bartz-Schmidt KU, Gelisken F. · Center for Ophthalmology, University of Tuebingen, Tuebingen, Germany. · Eye. · Pubmed #17401325 No free full text.

Abstract: PURPOSE: To report the long-term functional and anatomical outcome of full macular translocation (FMT) in eyes with neovascular age-related macular degeneration (AMD) following photodynamic therapy (PDT). METHODS: Twelve eyes of 12 consecutive patients with neovascular AMD who were PDT-nonresponders and underwent FMT were analysed. Best-corrected visual acuity (BCVA) measurement, fundus photography, and fluorescein angiography at baseline and at follow-up examinations in 3 months intervals were performed. Primary end point was change of BCVA from baseline to last visit. RESULTS: Totally 12 eyes of 12 patients were analysed. Mean time interval between the last PDT and FMT was 3.7 months (range 1-10 months). Mean follow-up after FMT was 25.6 months. BCVA ranged at baseline from 20/1000 to 20/80 (mean 20/230). At the last visit, mean BCVA was by 20/185. BCVA improved in 50% (6/12) of eyes by more than 1 line. Twenty five per cent (3/12) of eyes had final BCVA within +/-1 line from baseline. In 25% (3/12) of eyes the BCVA decreased by more than 1 line. One eye had recurrent CNV. In four eyes a cystoid macular oedema developed. No retinal detachment or disturbing diplopia was noted. CONCLUSIONS: In the present study, FMT in PDT-nonresponders stabilised or improved visual acuity in the majority of the eyes in a mean follow-up period of nearly 2 years. FMT can be considered as a therapeutical option in eyes who are nonresponders to the PDT in neovascular AMD.

Lüke M, Januschowski K, Warga M, Beutel J, Leitritz M, Gelisken F, Grisanti S, Schneider T, Lüke C, Bartz-Schmidt KU, Szurman P, Anonymous00138. · Department of Ophthalmology, University of Tuebingen, Schleichstr. 12-16, D-72076 Tuebingen, Germany. · Br J Ophthalmol. · Pubmed #17383998 No free full text.

Abstract: AIM: To investigate the retinal toxicity of bevacizumab in co-application with a commercially available recombinant tissue plasminogen activator (rt-PA), and to facilitate a new therapeutic concept in the treatment of massive subretinal haemorrhage caused by neovascular age-related macular degeneration (AMD). METHODS: Isolated bovine retinas were perfused with an oxygen-preincubated nutrient solution. The electroretinogram (ERG) was recorded as a transretinal potential using Ag/AgCl electrodes. Bevacizumab (0.25 mg/ml) and rt-PA (20 microg/ml) were added to the nutrient solution for 45 min. Thereafter, the retina was reperfused for 60 min with normal nutrient solution. Similarly, the effects of rt-PA (20 microg/ml, 60 microg/ml and 200 mug/ml) on the a- and b-wave amplitudes were investigated. The percentages of a- and b-wave reduction during application and at washout were calculated. RESULTS: During application of bevacizumab (0.25 mg/ml) in co-application with 20 microg/ml (rt-PA), the ERG amplitudes remained stable. The concentrations of rt-PA alone (20 microg/ml and 60 microg/ml) did not induce significant reduction of the b-wave amplitude. In addition, 20 microg/ml rt-PA did not alter the a-wave amplitude. However, 60 microg/ml rt-PA caused a slight but significant reduction of the a-wave amplitude. A full recovery was detected for both concentrations during the washout. At the highest tested concentration of 200 microg/ml rt-PA, a significant reduction of the a- and b-wave amplitudes was provoked during the exposure. The reduction of ERG amplitudes remained irreversible during the washout. CONCLUSION: The present study suggests that a subretinal injection of 20 microg/ml rt-PA in co-application with bevacizumab (0.25 mg/ml) for the treatment of massive subretinal haemorrhage seems possible. This is a safety study. Therefore, we did not test the clinical effectiveness of this combined treatment.

Lüke M, Ziemssen F, Bartz-Schmidt KU, Gelisken F. · University Eye Hospital, Centre for Ophthalmology, Eberhard-Karls University of Tuebingen, Schleichstr. 12-16, 72076 Tuebingen, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #17347809 No free full text.

Abstract: PURPOSE: To assess visual function and its effects on vision-targeted, health-related quality of life (QOL) of patients with neovascular age-related macular degeneration (AMD) treated with photodynamic therapy (PDT) or full macular translocation (FMT). METHODS: Fifty patients with predominantly classic subfoveal choroidal neovascularisation (CNV) secondary to AMD were randomised to PDT or FMT. To test the vision-targeted QOL, the 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25 plus supplement) was administered prior to and 1 year after therapy. The change of vision-related QOL at 1 year in comparison to baseline was defined as primary end point. RESULTS: The vision-related subscales showed a stabilisation or even higher mean scores at 1 year in both treatment groups. A significant improvement in the quality of the subject's vision-related subscales was only observed after FMT correlating with a more frequent increase in visual acuity. Comparing the results of the QOL scores after 1 year, the improvement of the subscale scores general vision (p = 0.03), mental health (p = 0.02) and dependency (p = 0.03) were significantly higher in the FMT arm. CONCLUSIONS: FMT and PDT can achieve a stabilisation in vision-related QOL, in which FMT was superior to the PDT after 1 year. The discrepancy between the amount of patients with an increased visual acuity after FMT and a moderate improvement in QOL might be caused by the onset of complications related to this surgical procedure. Besides visual acuity, the impact of therapy-related complications has to be taken into consideration when evaluating new therapeutic concepts in exudative AMD.

Lüke C, Lüke M, Aisenbrey S, Dietlein TS, Bartz-Schmidt KU, Kirchhof B, Walter P. · Zentrum für Augenheilkunde der Universität Köln, ERG-Labor Joseph-Stelzmann-Strasse 9, 50924 Köln. · Klin Monatsbl Augenheilkd. · Pubmed #17309008 No free full text.

Abstract: BACKGROUND: The aim of the present study was to evaluate potential electrophysiological changes after 360 degrees retinotomy and macular translocation for subfoveal choroidal neovascularisation in patients with age-related macular degeneration. METHODS: A consecutive series of 32 patients suffering from subfoveal choroidal neovascularisation secondary to age-related macular degeneration underwent 360 degrees retinotomy and macular translocation. The scotopic triple-flash ERG (TERG) served as the main parameter of the study and was recorded one day prior to the translocation surgery and no earlier than 4 weeks after the silicone oil removal. RESULTS: The TERG amplitudes were significantly reduced after translocation surgery. Depending on the applied flash luminance the mean amplitude reduction of the first b-wave varied between 67 % (0.2 cds/m (2)) and 74 % (0.03 cds/m (2)). The latency of the second b-wave of the preoperative TERG proved to have predictive power with reference to the postoperative visual acuity. A statistically significant correlation between the latency of the second b-wave for a flash intensity of 0.03 and 0.1 cds/m (2) and the postoperative visual acuity was shown (p = 0,016 and p = 0,049). CONCLUSIONS: In accordance with previous studies the present study indicates that a significant electrophysiological decrease is caused by surgical procedures associated with macular translocation. In future, due to predictive parameters of the TERG the preoperative selection of patients could be improved.

Aisenbrey S, Gelisken F, Szurman P, Bartz-Schmidt KU. · Center of Ophthalmology, University of Tuebingen, Schleichstr. 12, D-72076 Tuebingen, Germany. · Br J Ophthalmol. · Pubmed #17301123 No free full text.

Abstract: OBJECTIVE: To report the functional and morphological outcome of surgical treatment of peripapillary choroidal neovascularisation due to age-related macular degeneration. METHODS: Consecutive interventional case series of eight patients with extensive peripapillary choroidal neovascularisation and accompanying haemorrhage who underwent subretinal surgery including extraction of the neovascular complex. Ophthalmic examination, including visual acuity testing, colour photography and fluorescein angiography, was performed at baseline and at 3, 6, 9 and 12 months, and then yearly. RESULTS: Mean follow-up was 26 months (12-60 months). Preoperative best corrected visual acuity (BCVA) ranged from logMAR (logarithm of minimum angle of acuity) 1.0 (20/200) to logMAR 0.0 (20/20), with a mean of logMAR 0.5 (20/63). Mean postoperative BCVA was logMAR 0.3 (20/40). BCVA improved in six patients, was stable in one patient and deteriorated in one patient. Two years after surgery, one patient developed recurrence of the CNV that was removed surgically. One patient showed retinal detachment 5 years after subretinal surgery. CONCLUSIONS: In this small case series of PPCNV, functional improvement was achieved after surgery in the majority of patients. Surgical extraction of the CNV represents an alternative treatment option in eyes with vision-threatening extensive PPCNV. Randomised controlled studies seem to be justified to evaluate further the beneficial effect and long-term functional outcome of this therapy approach.

Gelisken F, Voelker M, Schwabe R, Besch D, Aisenbrey S, Szurman P, Grisanti S, Herzau V, Bartz-Schmidt KU. · Centre for Ophthalmology, University of Tuebingen, Schleichstr. 12, 72076 Tuebingen, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #17219106 No free full text.

Abstract: BACKGROUND: The purpose of this study was to compare full macular translocation (FMT) with photodynamic therapy (PDT) in the treatment of neovascular age-related macular degeneration (AMD). METHODS: In a prospective, randomised, non-masked, mono-center, pilot-trial, 50 eyes of 50 patients were assigned to either FMT or PDT. Baseline and control examinations in 3-monthly intervals over a 12-month period included standardized protocol refraction, visual acuity testing and fluorescein angiography. Primary outcome measurements were made to establish the change in distant visual acuity from the baseline to the 12-month examination. The statistical analyses were carried out on the intent-to-treat principle. RESULTS: The improvement of one or more ETDRS lines was 56% (14/25) of the eyes in the FMT and 16% (4/25) of the eyes in the PDT arm (P = 0.007). Twenty eyes (80%) in the FMT and 16 eyes (64%) in the PDT group had less than three ETDRS lines of vision loss (P = 0.35). Retinal detachment (six eyes) and diplopia (five patients) were recorded in the FMT group. None of the eyes treated in the FMT group had phtysis. CONCLUSION: This pilot study showed that no statistically significant difference existed between the FMT and PDT in terms of the vision loss of less than three ETDRS lines in eyes with neovascular AMD. The chance of vision improvement was significantly higher for the patients in the FMT group. However, in the era of promising therapy with anti-vascular endothelial growth factor for neovascular AMD, FMT should not be offered as a standard primary procedure for neovascular AMD.