Macular Degeneration: Michels S

Michels S, Kurz-Levin M. · Augenklinik, Universitätsspital Zürich. · Ther Umsch. · Pubmed #19266466 No free full text.

Abstract: Today age-related macular degeneration (AMD) is the most frequent cause for legal blindness in western industrialized countries. The prevalence of this disease rises with increasing age. A multifactorial pathogenesis of AMD is postulated including genetic predisposition and environmental risk factors. The most relevant modifiable risk factor is smoking. Up to today there is no cure of this chronic disease. Prophylaxis, including a healthy diet and antioxidants as nutrional supplements for selected patients, aims to slow down the disease progression. Significant progress has been made in the treatment of the neovascular form of the disease using inhibitors of the vascular endothelial growth factor (VEGF).

Michels S, Schmidt-Erfurth U, Rosenfeld PJ. · Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Währinger Gürtel 18-20, Allgemeines Krankenhaus 8i, 1090 Wien/Vienna, Austria. · Expert Opin Investig Drugs. · Pubmed #16787141 No free full text.

Abstract: Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.

Schmidt-Erfurth U, Michels S, Augustin A. · Department of Ophthalmology, University of Vienna, Vienna, Austria. · Arch Ophthalmol. · Pubmed #16606885 No free full text.

This publication has no abstract.

Michels S, Rosenfeld PJ. · Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Osterreich. · Klin Monatsbl Augenheilkd. · Pubmed #15973626 No free full text.

Abstract: Vascular endothelial growth factor (VEGF) is considered to play an essential role in the pathogenesis of age-related macular degeneration due to its vascular permeability-inducing and angiogenic properties. Ranibizumab, a small antibody fragment designed to competitively bind all VEGF isoforms, passes after intravitreal injection all retinal layers reaching the retinal pigment epithelium-choroid complex. Experimental animal models showed the drug to be safe and effective. Subsequently, Phase I/II clinical trials conducted in patients with neovascular AMD demonstrated a good safety profile, and a significant functional benefit. Ranibizumab therapy repeated every four weeks for the treatment of neovascular AMD is currently in Phase III clinical trials. Combination therapy trials aiming for improved treatment durability and effectiveness are currently ongoing as well as new treatment strategies using intermittent, optical coherence tomography (OCT) guided therapy. Anti-VEGF therapy using Ranibizumab is a promising new treatment option for neovascular AMD.

Michels S, Schmidt-Erfurth U. · University Eye Hospital, Lübeck, Germany. · Semin Ophthalmol. · Pubmed #15513441 No free full text.

Abstract: Photodynamic therapy (PDT) with verteporfin is a new treatment modality in ophthalmology that has previously shown its effectiveness in treatment of a variety of neoplastic pathologies. In this therapeutic approach, the photosensitizer verteporfin is activated by non-thermal laser light to obtain closure of neovascular structures. Preclinical and clinical studies have indicated that PDT is a safe, selective, and effective treatment for choroidal neovascularization in age-related macular degeneration. No significant damage to the neurosensory retina was found, which explains why PDT does not cause loss of visual acuity and may be used in a larger population than laser photocoagulation. This review summarizes the mechanisms of action of PDT, and the results of preclinical and clinical studies in ophthalmology.

Lalwani GA, Rosenfeld PJ, Fung AE, Dubovy SR, Michels S, Feuer W, Davis JL, Flynn HW, Esquiabro M. · Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. · Am J Ophthalmol. · Pubmed #19376495 No free full text.

Abstract: PURPOSE: To assess the long-term efficacy of a variable-dosing regimen with ranibizumab in the Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular Age-Related Macular Degeneration (AMD) Treated with intraOcular Ranibizumab (PrONTO) Study, patients were followed for 2 years. DESIGN: A 2-year prospective, uncontrolled, variable-dosing regimen with intravitreal ranibizumab based on OCT. METHODS: In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 microm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg) [Lucentis; Genentech Inc, South San Francisco, California, USA]. During the first year, retreatment with ranibizumab was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 microm or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT. RESULTS: Forty patients were enrolled and 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 microm (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months. CONCLUSIONS: The PrONTO Study using an OCT-guided variable-dosing regimen with intravitreal ranibizumab resulted in VA outcomes comparable with the outcomes from the phase III clinical studies, but fewer intravitreal injections were required.

Prager F, Michels S, Kriechbaum K, Georgopoulos M, Funk M, Geitzenauer W, Polak K, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Waehringer Guertel 18-20, 1190 Wien, Austria. · Br J Ophthalmol. · Pubmed #19074916 No free full text.

Abstract: AIMS: The aim of the study was to evaluate functional and anatomical changes after intravitreal bevacizumab (Avastin) in eyes with persistent macular oedema secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). METHODS: Twenty-nine consecutive eyes with macular oedema secondary to BRVO (21 eyes) or CRVO (eight eyes) were included in a prospective clinical trial. Eyes were treated with three initial intravitreal bevacizumab injections of 1 mg at a monthly interval. Retreatment was based on central retinal thickness (CRT) based on optical coherence tomography. If continuous injections were indicated up to month 6, the dose was increased to 2.5 mg. RESULTS: After 12 months of follow-up, mean visual acuity increased from 50 letters (20/100) at baseline to 66 letters (20/50(+1); +16 letters; p<0.001) at month 12 and CRT decreased from 558 mum at baseline to 309 mum at month 12 (-249 mum; p<0.001). Patients received a mean of eight out of 13 possible injections. No drug-related systemic or ocular side effects following intravitreal bevacizumab treatment were observed. Fluorescein angiography revealed no progression of avascular areas. CONCLUSIONS: Intravitreal therapy using bevacizumab appears to be a safe and effective treatment in patients with macular oedema secondary to retinal vein occlusion. However, the main limitations of this treatment modality are its short-term effectiveness and high recurrence rate.

Geitzenauer W, Michels S, Prager F, Rosenfeld PJ, Kornek G, Vormittag L, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Austria. · Retina. · Pubmed #18784625 No free full text.

Abstract: BACKGROUND: To compare safety, visual acuity (VA), and anatomic outcomes of 2.5 mg/kg and 5 mg/kg intravenous bevacizumab in patients with neovascular age-related macular degeneration. METHODS: In an institutional cohort study, 16 patients (2 cohorts, 27 eyes) with neovascular age-related macular degeneration were treated with 5 mg/kg intravenous bevacizumab and 2.5 mg/kg, respectively. All patients received 3 initial intravenous infusions at 2-week intervals. The main outcome measures were VA, optical coherence tomography, and fluorescein angiography. RESULTS: No serious systemic or ocular adverse events were identified. By Day 7, mean VA increased from 56 letters (20/80(+1)) at baseline to 60 letters (20/63) in the 5 mg/kg group and mean central retinal thickness decreased by 83 microm. In the 2.5 mg/kg group, mean VA increased from 55 letters (20/80) to 66 letters (20/50(+1)) and mean central retinal thickness decreased by 93 microm. By Month 3, VA improved by 10 letters compared to baseline in the 5 mg/kg group and by 9 letters in the 2.5 mg/kg group. Central retinal thickness was reduced by 128 microm in the 5 mg/kg group and by 127 microm in the 2.5 mg/kg group. These benefits were sustained through 6 months. No statistically significant difference was found between both treatment groups regarding safety, VA, and anatomic outcomes. CONCLUSION: Similar VA, optical coherence tomography, and angiographic improvements were observed in both treatment groups up to 6 months. Further follow-up is required to evaluate the long-term durability and safety of both treatment regimens.

Kriechbaum K, Michels S, Prager F, Georgopoulos M, Funk M, Geitzenauer W, Schmidt-Erfurth U. · University Eye Hospital Zürich, Frauenklinikstrasse 24, CH-8091 Zurich, Switzerland. · Br J Ophthalmol. · Pubmed #18211942 No free full text.

Abstract: OBJECTIVE: To evaluate efficacy and safety of intravitreal bevacizumab (Avastin) in eyes with macular oedema secondary to central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). METHODS: Twenty-eight consecutive patients (28 patients, 29 eyes, 8 CRVO, 21 BRVO) were enrolled in the study. Three intravitreal injections of 1 mg bevacizumab (0.04 ml) were administered at 4-week intervals; further retreatment was based on optical coherence tomography (OCT) findings. Follow-up examinations were done at days 1, 7 and 28 and at monthly intervals thereafter. RESULTS: Mean baseline central retinal thickness (CRT) in OCT was 558 microm (range 353-928 microm) and mean BCVA was 20/100. One day after the first injection, CRT significantly decreased to 401 microm (p<0.01). Three injections reduced macular oedema to 328 microm CRT (p<0.01) and improved BCVA to 20/50 (p<0.01). At 6 months, CRT was 382 microm (p<0.01), and BCVA was stable at 20/50(-2) (p<0.01), FA showed no evidence of increased avascular zones. CONCLUSION: Intravitreal injections of bevacizumab appear to be a safe and effective therapy in the treatment of macular oedema secondary to retinal vein occlusion.

Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, Davis JL, Flynn HW, Esquiabro M. · Pacific Eye Associates, California Pacific Medical Center, San Francisco, California, USA. · Am J Ophthalmol. · Pubmed #17386270 No free full text.

Abstract: PURPOSE: To evaluate an optical coherence tomography (OCT)-guided, variable-dosing regimen with intravitreal ranibizumab for the treatment of patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, prospective, single-center, nonrandomized, investigator-sponsored clinical study. METHODS: In this two-year study, neovascular AMD patients with subfoveal choroidal neovascularization (CNV) (n = 40) and a central retinal thickness of at least 300 microm as measured by OCT were enrolled to receive three consecutive monthly intravitreal injections of ranibizumab (0.5 mg). Thereafter, retreatment with ranibizumab was performed if one of the following changes was observed between visits: a loss of five letters in conjunction with fluid in the macula as detected by OCT, an increase in OCT central retinal thickness of at least 100 microm, new-onset classic CNV, new macular hemorrhage, or persistent macular fluid detected by OCT at least one month after the previous injection of ranibizumab. RESULTS: At month 12, the mean visual acuity improved by 9.3 letters (P < .001) and the mean OCT central retinal thickness decreased by 178 microm (P < .001). Visual acuity improved 15 or more letters in 35% of patients. These visual acuity and OCT outcomes were achieved with an average of 5.6 injections over 12 months. After a fluid-free macula was achieved, the mean injection-free interval was 4.5 months before another reinjection was necessary. CONCLUSION: This OCT-guided, variable-dosing regimen with ranibizumab resulted in visual acuity outcomes similar to the Phase III clinical studies, but required fewer intravitreal injections. OCT appears useful for determining when retreatment with ranibizumab is necessary.

Bolz M, Michels S, Geitzenauer W, Prager F, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. · Br J Ophthalmol. · Pubmed #17050580 No free full text.

Abstract: BACKGROUND: To evaluate the effect of systemic bevacizumab (Avastin) therapy on pigment epithelial detachment (PED) secondary to age-related macular degeneration (AMD) and to identify prognostic factors for PED regression and improvement in best corrected visual acuity (BCVA). Study design: Prospective uncontrolled pilot study. METHODS: Nine patients (nine eyes) received three systemic bevacizumab treatments at 2 week intervals and were examined at baseline, weeks 1, 2, 4, 6 and month 3 by using optical coherence tomography (Stratus OC, Carl Zeiss Meditec, Dublin, California, USA). Changes in maximum PED height and greatest linear diameter (GLD) were planimetrically analysed by using Adobe Photoshop CS and correlated with retinal morphological changes and changes in BCVA. RESULTS: Systemic bevacizumab therapy was well tolerated. Mean maximum PED height decreased significantly by 21% as early as 1 week (-96 microm (SD 48.8), p<0.01). At 3 months follow-up, two PEDs resolved completely, mean maximum PED height decreased significantly by 39% (-179 microm (SD 178), p = 0.02) and mean PED GLD by 24% (-714 microm (SD 1010), p = 0.07). Mean BCVA improved significantly by week 2 (+8.7 letters (SD 5.7), p<0.01) and at 3 months with 12.7 letters (SD 6.4) (p<0.01). CONCLUSION: In the examined nine patients, systemic bevacizumab therapy showed evidence for an effect on PED secondary to neovascular AMD in terms of a decrease in lesion height and diameter. A high PED at baseline was found to be a negative predictive factor for visual outcome.

Moshfeghi AA, Rosenfeld PJ, Puliafito CA, Michels S, Marcus EN, Lenchus JD, Venkatraman AS. · Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. · Ophthalmology. · Pubmed #17027972 No free full text.

Abstract: PURPOSE: To evaluate the safety, efficacy, and durability of bevacizumab for the treatment of subfoveal choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, single-center, uncontrolled clinical study. PARTICIPANTS: Age-related macular degeneration patients with subfoveal CNV (n = 18) and best-corrected visual acuity (VA) letter scores of 70 to 20 (approximate Snellen equivalent, 20/40-20/400). METHODS: Patients were treated at baseline with an intravenous infusion of bevacizumab (5 mg/kg) followed by 1 or 2 additional doses given at 2-week intervals. Safety assessments were performed at all visits. Ophthalmologic evaluations included protocol VA measurements, ocular examinations, and optical coherence tomography (OCT) imaging at each visit. Retreatment with bevacizumab was performed if there was evidence of recurrent CNV. MAIN OUTCOME MEASURES: Assessments of safety and changes from baseline in VA scores and OCT measurements were performed through 24 weeks. RESULTS: No serious ocular or systemic adverse events were identified through 24 weeks. The only adverse event identified was a mild elevation of mean systolic and diastolic blood pressure measurements (+11 mmHg, P = 0.004; +8 mmHg, P<0.001) evident by 3 weeks and easily controlled with antihypertensive medications. By 24 weeks, the systolic and diastolic mean blood pressures were at or below baseline measurements. Visual acuity in the study eyes improved within the first 2 weeks, and by 24 weeks, the mean VA letter score increased by 14 letters in the study eyes (P<0.001), and the mean OCT central retinal thickness measurement decreased by 112 microm (P<0.001). By 24 weeks, retreatment was needed for only 6 of the 18 study eyes, and after retreatment, the recurrent leakage was eliminated, with restoration of any lost VA. CONCLUSIONS: Systemic bevacizumab therapy for neovascular AMD was well tolerated and effective for all 18 patients through 24 weeks. By 6 months, most patients did not require any additional treatment beyond the initial 2 or 3 infusions. Despite these impressive results, it is unlikely that systemic bevacizumab will be studied in a large clinical trial because of the potential risks associated with systemic anti-VEGF therapy and the perception that intravitreal therapy is safer.

Michels S, Wachtlin J, Gamulescu MA, Heimann H, Prünte C, Inhoffen W, Krebs I, Schmidt-Erfurth U. · Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Vienna, Austria. · Ophthalmology. · Pubmed #16225928 No free full text.

Abstract: PURPOSE: To compare the efficacy and safety of early retreatment with verteporfin therapy with that of approved standard verteporfin therapy in neovascular age-related macular degeneration. DESIGN: Prospective, randomized, multicenter clinical trial. PARTICIPANTS: Two hundred three patients with predominantly classic choroidal neovascularization secondary to age-related macular degeneration. METHODS: Throughout the first 6 months of follow-up, patients received retreatment with verteporfin therapy either every 2 months (group A) or 3 months (group B). From 6 to 12 months, both groups received retreatment at 3-month intervals. MAIN OUTCOME MEASURES: The primary outcome of the study was best-corrected mean visual acuity as measured using the Early Treatment Diabetic Retinopathy Study protocol. The secondary outcomes were percentage of patients losing at least 3 lines of vision, percentage of patients gaining at least 1 line of vision, and lesion size based on the greatest linear dimension (GLD) documented by fluorescein angiography, impact of initial lesion size, and retreatment rate as well as safety. RESULTS: Visual acuity was similar in both groups at baseline with a mean visual acuity of 20/100(-1). During the 12 months of follow-up, mean visual acuity was better in the early retreatment group at all intervals; however, no statistically significant benefit was seen in the overall population at any time (P>0.1). At month 12, mean visual acuity was 20/160(+1) in group A and 20/160(-1) in group B. There was a trend for better outcomes in the early retreatment group with regard to loss of less than 3 lines of vision at 12 months (61% vs. 51.7%). No statistically significant difference was seen with regard to lesion size for either group throughout follow-up with a final GLD of the lesion of 2790 microm (group A) and 2996 microm (group B). However, subgroup analysis indicated a statistically relevant benefit (P< or =0.004) for patients with small lesions (GLD<2000 microm) at baseline receiving early retreatment. CONCLUSIONS: Early retreatment in 2-month intervals did not show a significant overall benefit at 1 year of follow-up compared with the standard regimen. However, smaller lesions seemed to benefit from early retreatment with verteporfin therapy in contrast to larger lesions.

Schmidt-Erfurth U, Michels S, Michels R, Aue A. · Department of Ophthalmology, University of Vienna, Vienna - Austria. · Eur J Ophthalmol. · Pubmed #16001382 No free full text.

Abstract: PURPOSE: Anecortave acetate is a novel angiostatic cortisene being evaluated clinically for treatment of exudative age-related macular degeneration (ARMD). A randomized, placebo-controlled, efficacy and safety dose duration study of anecortave acetate for depot suspension (3 mg, 15 mg, 30 mg) in this patient population was completed in June 2003. As part of this trial, 128 patients with subfoveal choroidal neovascularization (CNV) secondary to ARMD were enrolled and treated for up to 2 years by 18 clinical sites in the United States and European Union. METHODS: Study patients were evaluated clinically with detailed ophthalmic examinations, general physical examinations, assessments of best-corrected logMAR visual acuity, and angiographic evaluations. The Digital Angiography Reading Center (New York City, NY) assessed lesion eligibility while the clinical investigators assessed overall patient eligibility prior to treatment. As part of this study, study medication was delivered as a posterior juxtascleral depot using a specially designed curved cannula at 6-month intervals if in the masked investigator's opinion the patient's lesion could benefit from additional treatment. RESULTS: The 2-year efficacy results of this placebo-controlled study demonstrated that RETAANE 15 mg (anecortave acetate for depot suspension) was statistically superior to placebo for stabilization of vision (<3 logMAR line change from baseline) and for inhibition of neovascular lesion growth. There were no serious treatment-related safety issues associated with either the study medication or the procedure for administration. CONCLUSIONS: Anecortave acetate 15 mg for depot suspension is clinically efficacious compared to placebo for treatment of subfoveal exudative ARMD lesions when administered at 6-month intervals as a posterior juxtascleral depot.

Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. · Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida 33136, USA. · Ophthalmology. · Pubmed #15936441 No free full text.

Abstract: PURPOSE: To evaluate the short-term safety of systemic bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) and its effects on visual acuity (VA) and subfoveal choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, single-center, uncontrolled clinical study. PARTICIPANTS: Age-related macular degeneration patients with subfoveal CNV (N = 9) and best-corrected VA letter scores of 70 to 20 (approximate Snellen equivalent, 20/40-20/400). METHODS: Patients were treated at baseline with an infusion of bevacizumab (5 mg/kg), followed by 1 or 2 additional doses given at 2-week intervals. Safety assessments were performed at all visits. Ophthalmologic evaluations included protocol VA measurements and ocular examinations, along with optical coherence tomography (OCT) imaging, fluorescein angiography, and indocyanine green angiography. MAIN OUTCOME MEASUREMENTS: Safety assessments were performed, along with assessments of changes from baseline in VA scores, OCT measurements, and angiographic lesion characteristics. RESULTS: There were no serious ocular or systemic adverse events identified. By 6 weeks, the only adverse event identified was a mild elevation of systolic blood pressure (BP) (+12 mmHg; P = 0.035), and this elevation was controlled by either changing or initiating antihypertensive medication. By 12 weeks, the elevation of systolic BP was no longer significant (P = 0.51). In the study eyes, significant increases in VA were evident within 1 week of treatment, and by 12 weeks, the median and mean VA letter scores increased by 8 letters (P = 0.011) and 12 letters (P = 0.008), respectively. The median and mean central retinal thickness measurements decreased by 157 microm (P = 0.008) and 177 microm (P = 0.001), respectively. In the fellow eyes at 12 weeks, the median and mean VA letter scores increased by 27 letters (P = 0.018) and 16 letters (P = 0.012), and the median and mean central retinal thickness measurements decreased by 59 mum (P = 0.028) and 92 microm (P = 0.06). In all study eyes, angiography revealed a marked reduction or an absence of leakage from CNV. CONCLUSION: Overall, bevacizumab therapy was well tolerated, with an improvement in VA, OCT, and angiographic outcomes. Although these preliminary results are promising, a randomized controlled clinical trial is necessary before concluding that systemic bevacizumab therapy is safe and effective for patients with neovascular AMD.

Ahlswede W, Michels S, Birngruber R, Schmidt-Erfurth U. · Augenklinik, Universitätsklinikum Schleswig-Holstein, Lübeck. · Ophthalmologe. · Pubmed #15309484 No free full text.

Abstract: PURPOSE: Photodynamic therapy (PDT) induces occlusive and regenerative effects in choroidal neovascularization (CNV) and physiological choroid. The process of vascular alteration is documented quantitatively and qualitatively by three-dimensional angiography. METHOD: In a prospective, randomized trial 30 patients with subfoveal CNV due to age-related macular degeneration (AMD) were treated with PDT or placebo. Fluorescence series with 32 tomographic images over a 4-mm depth were analyzed topographically and reproduced in a three-dimensional display. RESULTS: At initial presentation CNV lesions were documented as a well-defined prominence in all patients. In the verteporfin group CNV height continuously decreased with each interval. In the placebo group CNV slightly increased in height during the first 6 months and remained stable at about 90% of the initial prominence at long-term follow-up. After 12 months 44% of the patients in the verteporfin group developed an additional choroidal defect. CONCLUSION: Three-dimensional angiography offers a reliable documentation of CNV progression and regression during PDT. A decrease in CNV size is associated with an increase in choroidal perfusion defects.

Schmidt-Erfurth UM, Michels S. · University Eye Hospital, Medical School Luebeck, Ratzeburger Allee 160, D-13538 Luebeck, Germany. · Ophthalmology. · Pubmed #12867383 No free full text.

Abstract: PURPOSE: To evaluate vascular changes documented by confocal indocyanine green angiography (ICGA) through 2 years after photodynamic therapy (PDT) with verteporfin of neovascular age-related macular degeneration (AMD). DESIGN: Single-center, 2-year, randomized, double-masked, interventional, placebo-controlled trial (subset from Treatment of AMD with PDT Study [TAP]). PARTICIPANTS: Sixty patients with subfoveal choroidal neovascularization (CNV) resulting from AMD. INTERVENTION: Patients were randomized in a ratio of 2:1 to a standard regimen using verteporfin therapy at a drug dose of 6 mg/m(2) body surface area and a light dose of 50 J/cm(2) or a sham treatment with placebo infusion and light exposure. Retreatments, if persistent fluorescein leakage from CNV was documented, were scheduled at 3-month intervals for up to 2 years. Confocal ICGA with tomographic sections was performed at baseline and continuously at the month 3, 6, 12, and 24 examinations using a standardized protocol. MAIN OUTCOME MEASURES: Analysis included the size of the neovascular net, the area of late hyperfluorescence, and choroidal hypofluorescence during early- and late-phase imaging. RESULTS: In the verteporfin-treated group, the mean size of the CNV and the mean area of late leakage consistent with active leakage or staining showed no further enlargement at month 12 and were reduced at month 24. In the placebo-treated group, new vessels grew threefold compared with baseline and exhibited persistent late hyperfluorescence resulting from leakage at 24 months. Associated choroidal hypofluorescence within the treated area was significantly increased in eyes treated with verteporfin PDT compared with the control group during the first year, persisted during all ICGA phases, and was irreversible during follow-up. Image analysis revealed choroidal hypoperfusion with choriocapillary dropout, which correlated with chorioretinal atrophy clinically. Progressive destruction of choroidal integrity by fibrosis in control eyes led to a similar extent of collateral hypofluorescence in both groups through the 24-month examination. CONCLUSIONS: Indocyanine green angiography is an important adjunct in the identification of vascular effects associated with verteporfin PDT. Repeated treatments effectively arrested CNV growth and reduced leakage activity. The collateral impairment of choroidal perfusion appears to influence the visual outcome of the treatment.

Kiss CG, Simader C, Michels S, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Austria. · Br J Ophthalmol. · Pubmed #19029163 No free full text.

Abstract: OBJECTIVE: To evaluate verteporfin and same-day ranibizumab on retina, choroid, vasculature, choroidal neovascularisation (CNV) and visual function. METHODS: Eleven patients with occult or predominantly classic subfoveal CNV secondary to age-related macular degeneration received verteporfin and four monthly intravitreal ranibizumab injections. Eyes were examined using fluorescein angiography (FA) and indocyanine green angiography (ICGA), optical coherence tomography (OCT), visual acuity (VA) and microperimetry. RESULTS: Over 9 months, seven patients gained three to 24 letters and one had unchanged VA. Three patients lost eight to 24 letters due to recurrence and received another verteporfin treatment at month 6. Median retinal sensitivity of the central 4 degrees of the macula increased from 0.9 (SD 2.3) dB (baseline) to 5.2 (1.8) dB (only baseline verteporfin) and 4.1 (4.5) dB (second verteporfin treatment) at study end. OCT showed sub- and intraretinal leakage increased with verteporfin, but resolved after 2 weeks. After combination treatment, CNV was completely occluded on FA within 1 week. ICGA showed non-perfusion of small/medium choroidal vessels. Recovery of choroidal perfusion began after 1 month, but remained impaired throughout follow-up. CONCLUSION: Verteporfin/ranibizumab was associated with CNV occlusion, reduced oedema, improved visual function and retinal sensitivity. The clinical significance of these findings requires further investigation.

Sacu S, Stifter E, Vécsei-Marlovits PV, Michels S, Schütze C, Prünte C, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. · Eye. · Pubmed #18756282 No free full text.

Abstract: BACKGROUND: To evaluate the clinical outcomes of subfoveal haemorrhages secondary to neovascular age-related macular degeneration (AMD), which were treated with intravitreal recombinant tissue plasminogen activator (rTPA)/gas and anti-vascular endothelial growth factor (anti-VEGF) drug or with an intravitreal anti-VEGF monotherapy. METHODS: This is a retrospective pilot study. Patients who received intravitreal rTPA/gas and anti-VEGF injections (n=20, bevacizumab or ranibizumab) were included in group A. Patients who refused prone positioning after rTPA/gas injections and were treated with an anti-VEGF monotherapy (bevacizumab) alone were included into group B (n=10). Changes in baseline visual acuity (VA, Snellen), central retinal thickness (CRT) and haemorrhage size were analysed. RESULTS: Mean baseline VA was 0.15+/-0.2 and 0.25+/-0.17 in groups A and B, respectively. At month 4, significant improvement in mean VA was observed in group A (mean difference: +0.1+/-0.14; P=0.003), and a stabilization in group B (mean difference: +0.008+/-0.2; P=0.94). CRT decreased significantly by 70 microm in group A (P=0.001) and by 84 microm in group B (P=0.03). The mean size of subfoveal haemorrhage in groups A and B was 20.2 mm(2) and 19.1 mm(2) at baseline and 0.0 mm(2) and 2.0 mm(2) at month 4, respectively. The anti-VEGF treatment rate was 1.6 in group A and 3.0 in group B. CONCLUSION: In patients with extensive subfoveal haemorrhage secondary to neovascular AMD, the combination therapy of rTPA/pneumatic displacement and anti-VEGF results in mean improvement of VA and stabilization of morphological parameters. If rTPA and pneumatic displacement combination is contraindicated, an anti-VEGF monotherapy may be performed to prevent further visual loss.

Sacu S, Varga A, Michels S, Weigert G, Polak K, Vécsei-Marlovits PV, Schmidt-Erfurth U. · Medical University of Vienna, Department of Ophthalmology, Vienna, Austria. · Br J Ophthalmol. · Pubmed #18586901 No free full text.

Abstract: BACKGROUND: To compare early treatment effect of reduced fluence versus standard photodynamic therapy (rPDT, sPDT, respectively) in combination with intravitreal triamcinolone (IVTA) in neovascular age-related macular degeneration. METHODS: Forty patients received either sPDT (group A, n = 20) or rPDT (group B, n = 20) each followed by same-day 4 mg IVTA. Patients were examined at baseline, day 1, week 1, 4 and 12. Main outcomes were visual acuity, central retinal thickness (CRT), choroidal perfusion and macular sensitivity (MS). RESULTS: Baseline characteristics were well balanced in both groups (p>0.05). At week 12, patients in group A had a mean loss of -3.7 letters compared with a gain of 3.4 letters in group B (p = 0.04, between both groups). Both treatment groups showed a similar course regarding CRT as well as MS (p>0.05). In 70% (14/20) of group A and 15% (3/20) of group B, a choroidal hypoperfusion in the area of treatment was observed after treatment (p<0.001). In 70% of group A and 55% of group B, a repeat treatment was indicated at week 12 (p = 0.55). CONCLUSIONS: At month 3, the rPDT+IVTA group showed a significantly better visual outcome, less alteration of the choroid and a trend for lower recurrence rate than the sPDT+IVTA group. Further follow-up of this study will provide information on long-term functional results and treatment durability.

Prager F, Michels S, Simader C, Geitzenauer W, Schmidt-Erfurth U. · Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria. · Retina. · Pubmed #18463510 No free full text.

Abstract: OBJECTIVE: To evaluate changes in central retinal sensitivity in patients with neovascular age-related macular degeneration after systemic bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) therapy. METHODS: For all eyes, the central 12 x 12 degrees visual field was recorded using the MP 1 Microperimeter (Nidek, Gamagori, Japan) at baseline and 1 week, 1 month, 3 months, and 6 months after initial treatment. Patients received systemic anti-vascular endothelial growth factor (VEGF) therapy with three initial bevacizumab infusions at 2-week intervals. Retreatment during follow-up was performed only in cases of choroidal neovascularization recurrence. Seven patients (12 eyes) received bevacizumab infusions at a dose of 5 mg/kg, and 7 patients (9 eyes), at a dose of 2.5 mg/kg. RESULTS: Of 41 stimulation points, a mean absolute scotoma of 15 missed stimulation points was measured at baseline, which decreased to 10 missed stimulation points at month 3 (-5; P = 0.005) and to 11 stimulation points at month 6 (-4; P = 0.106). The mean absolute scotoma size (in % of total tested area) decreased from 33% to 22% (-11%; P = 0.011) at month 3 and to 23% (-10%, P = 0.123) at month 6. Mean differential light threshold increased significantly throughout the observation period from 3.8 dB at baseline to 5.5 dB (+1.7 dB; P = 0.012) at month 6. CONCLUSIONS: Systemic bevacizumab therapy induced a significant increase in mean retinal sensitivity at month 6 of follow-up and a significant decrease of mean absolute scotoma size at month 3. The MP 1 Microperimeter proved to be a valuable tool in the evaluation of functional benefits and retinal safety of anti-VEGF therapy with systemic bevacizumab.

Weigert G, Michels S, Sacu S, Varga A, Prager F, Geitzenauer W, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. · Br J Ophthalmol. · Pubmed #18303156 No free full text.

Abstract: AIMS: To compare functional and anatomical outcomes of intravitreal bevacizumab (Avastin) and verteporfin (photodynamic) therapy (PDT) combined with intravitreal triamcinolone (IVTA) in patients with neovascular age-related macular degeneration (AMD). METHODS: Twenty-eight patients with neovascular AMD were enrolled in a prospective, randomised, controlled clinical trial. All patients randomly assigned to 1 mg intravitreal bevacizumab (0.04 ml) received three initial treatments at 4-week intervals. In further follow-up retreatment was based on optical coherence tomography (OCT). Patients randomly assigned to standard PDT received a same-day intravitreal injection of 4 mg triamcinolone (Kenalog). Retreatment was based on fluorescein angiography at 3-month intervals. Functional and anatomical results were evaluated using the Early Treatment Diabetic Retinopathy Study protocol vision charts, fluorescein angiography and OCT. RESULTS: In the bevacizumab-treated group mean visual acuity (VA) improved to a 2.2 line gain at 6 months follow-up. Eyes treated in the PDT plus IVTA group had a stable mean VA at month 6 compared with baseline. There was a statistically significant difference (p = 0.03, analysis of variance (ANOVA)) between both groups as early as one day after initial treatment. The reduction in central retinal thickness (CRT) showed no significant difference between both groups (p = 0.3, ANOVA). Mean CRT was reduced from 357 microm at baseline to 239 microm at month 6 in bevacizumab-treated patients and from 326 microm to 222 microm, respectively, in PDT plus IVTA-treated patients. No significant local or systemic safety concerns were detected up to month 6. CONCLUSION: Intravitreal bevacizumab showed promising 6-month results in patients with neovascular AMD. Functional outcomes appear not only to be dependent on a reduction in CRT but also on the treatment modality used.

Michels S, Pircher M, Geitzenauer W, Simader C, Götzinger E, Findl O, Schmidt-Erfurth U, Hitzenberger CK. · Department of Ophthalmology, University Hospital Zurich, Frauenklinikstrasse 24, 8091 Zürich, Switzerland. · Br J Ophthalmol. · Pubmed #18227201 No free full text.

Abstract: OBJECTIVES: To evaluate pathological changes of retinal pigment epithelium (RPE) by polarisation-sensitive optical coherence tomography (PS-OCT). METHODS: Forty-four eyes (22 patients) with significant pathologies of the RPE were evaluated using PS-OCT. A transversal scanning time domain OCT system was used for two-dimensional cross-sectional imaging of retinal polarisation properties. RESULTS: The RPE scrambles the polarisation state of backscattered light (ie, acts as a depolarising layer), while the polarisation state of transmitted light is maintained. In patients with RPE pathologies irregularity, elevation, thickening or absence of the RPE is readily visualised by exploiting the depolarisation information. Polarisation scrambling in the sensory retina can be found in cases with advanced dry age-related macular degeneration. Sclera and fibrosis show characteristic birefringence in PS-OCT. CONCLUSION: PS-OCT allows tissue identification based on polarisation scrambling and birefringence, providing additional information on RPE pathologies. It is a promising new tool for diagnosis, disease follow-up and evaluation of new treatment strategies.

Stifter E, Michels S, Prager F, Georgopoulos M, Polak K, Hirn C, Schmidt-Erfurth U. · Department of Ophthalmology, Medical University of Vienna, Austria. · Am J Ophthalmol. · Pubmed #17916314 No free full text.

Abstract: PURPOSE: To evaluate functional and anatomic effects of intravitreal bevacizumab (Avastin; Roche Pharma, Vienna, Austria) in patients with neovascular age-related macular degeneration (AMD) with large submacular hemorrhages. DESIGN: Retrospective, clinical study. METHODS: Twenty-one eyes of 19 AMD patients with choroidal neovascularization and large submacular hemorrhage involving the fovea comprising more than 50% of the total lesion area were evaluated. All patients completed at least four months of follow-up; 12 patients fulfilled 12 months or more of follow-up. Patients were treated with up to six intravitreal bevacizumab injections (1 mg/0.04 ml) at a minimum of four-week intervals. Changes from baseline visual acuity (VA) scores, retinal measurements by optical coherence tomography (OCT), angiographic lesion characteristics, and hemorrhage size were analyzed. A safety assessment was performed at all visits. RESULTS: Intravitreal bevacizumab injections were well tolerated in all patients. At month 4, VA was stable or improved (visual loss of 3 acuity lines or fewer) in 100% and improved by at least 3 lines in 9.5%. Comparable results were found at month 12. On average, the central foveal thickness decreased significantly by 55 microm four weeks after the first injection (P < .001) and by 52 microm at month 4 (P = .002). A significant anatomic improvement also was found for maximum retinal thickness, minimum retinal thickness, and foveal volume (P < .05) and was maintained during four months of follow-up. Mean size of hemorrhage was significantly reduced from 19.7 mm(2) at baseline to 2.5 mm(2) at the four-month follow-up (P < .001). CONCLUSIONS: Intravitreal bevacizumab seems to be a promising therapeutic option in eyes with neovascular AMD and large submacular hemorrhages, with a stabilization in VA and anatomic improvement.

Hahn R, Sacu S, Michels S, Varga A, Weigert G, Geitzenauer W, Vécsei-Marlovits P, Schmidt-Erfurth U. · Universitätsklinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Währinger Gürtel 18-20, Wien, Osterreich. · Ophthalmologe. · Pubmed #17564719 No free full text.

Abstract: AIM: The aim of this study was to compare intravitreal bevacizumab (IVB) and verteporfin therapy in combination with 4 mg intravitreal triamcinolone (PDT-IVTA) in patients with neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: A total of 30 eyes of 30 patients with neovascular AMD were included in a prospective, randomized study. Ten eyes received PDT-IVTA with a standard light fluence of 50 J/cm(2) (SPDT-IVTA), ten were treated with PDT-IVTA with a reduced light fluence of 25 J/cm(2) (RPDT-IVTA) and ten received IVB. The main outcome was evaluated using early treatment diabetic retinopathy study (ETDRS) visual acuity, fluorescein angiography and optical coherence tomography (OCT) at baseline as well as at day 1, week 1, 1 month and 3 months after therapy. RESULTS: At the beginning of therapy, the distribution of the groups was balanced. After 3 months, the SPDT-IVTA group showed a non-significant vision loss of seven letters (p<0.3) while a vision loss of 0.5 letters (p<0.9) was found in the RPDT-IVTA group. At the same time, the IVB group had a vision improvement of 11.8 letters (p<0.001). This vision improvement was statistically significant compared to the results of both PDT-IVTA groups (p<0.005). Central retinal thickness (CRT) decreased up to month 3 in the SPDT-IVTA group by 132 microm, in the RPDT-IVTA group by 78 mum and in the IVB group by 138 microm, (p<0.05 in the three groups). No significant difference in the decrease of CRT was found between the treatment groups after 3 months. CONCLUSION: IVB shows significantly better results in vision improvement in the short-term compared to the two PDT-IVTA groups. Within 3 months, all groups showed a comparable decrease in CRT. Long-term follow-up is required to evaluate the safety and treatment efficacy of all treatment modalities.