Stephan Michels

Intravitreal bevacizumab (Avastin) therapy versus photodynamic therapy plus intravitreal triamcinolone for neovascular age-related macular degeneration: 6-month results of a prospective, randomised, controlled clinical study

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 μm at baseline to 239 μm at month 6 in bevacizumab-treated patients and from 326 μm to 222 μm, 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.

Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections

Acta Ophthalmol. 2011: 89: 70–75

Value of polarisation-sensitive optical coherence tomography in diseases affecting the retinal pigment epithelium

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.

Management of extensive subfoveal haemorrhage secondary to neovascular age-related macular degeneration

BackgroundTo 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.MethodsThis 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.ResultsMean 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 μm in group A (P=0.001) and by 84 μm in group B (P=0.03). The mean size of subfoveal haemorrhage in groups A and B was 20.2 mm2 and 19.1 mm2 at baseline and 0.0 mm2 and 2.0 mm2 at month 4, respectively. The anti-VEGF treatmentrate was 1.6 in group A and 3.0 in group B.ConclusionIn 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.

Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety

OBJECTIVES This study sought to examine the effects and underlying mechanisms of systemic VEGF inhibition in experimental atherosclerosis and aortic endothelial cells. BACKGROUND Pharmacological inhibition of vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, has become a widely applied treatment of certain cancers and multiple ocular diseases including age-related macular degeneration. However, recent clinical trials raise concern for systemic vascular adverse effects, prompting the Food and Drug Administration to revoke the approval of bevacizumab for metastatic breast cancer. METHODS Eight-week old apolipoprotein E knockout mice received a high-cholesterol diet (1.25% cholesterol) for 24 weeks and were exposed to a systemic pan-VEGF receptor inhibitor (PTK787/ZK222584, 50mg/kg/d) or placebo (gavage) for the last 10 weeks. Atherosclerotic lesions were characterized in thoraco-abdominal aortae and aortic arches. Mechanistic analyses were performed in cultured human aortic endothelial cells. RESULTS Systemic VEGF inhibition increased atherosclerotic lesions by 33% whereas features of plaque vulnerability (i.e. necrotic core size, fibrous cap thickness) remained unchanged compared with controls. Aortic eNOS expression was decreased (trend). In human endothelial cells VEGF inhibition induced a dose-dependent increase in mitochondrial superoxide generation with an uncoupling of eNOS, resulting in reduced NO availability and decreased proliferation. CONCLUSION Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. Cardiovascular safety profiles of currently applied anti-angiogenic regimens should be determined to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk.

Randomised clinical trial of intravitreal Avastin vs photodynamic therapy and intravitreal triamcinolone: long-term results

PurposeTo compare 1-year functional and anatomic outcomes of intravitreal bevacizumab (IVB) and photodynamic therapy plus intravitreal triamcinolone (PDT+IVTA) combination in patients with neovascular age-related macular degeneration (AMD).MethodsIn this prospective, randomised, controlled clinical trial, 28 patients were included. All patients were randomised 1 : 1 to 0.04 ml/1 mg of IVB or PDT plus same day 0.1 ml/4 mg IVTA (PDT+IVTA). Follow-up examinations were performed in monthly intervals in IVB group and every 3 months in PDT+IVTA group. Main outcomes were change in mean visual acuity (VA), mean central retinal thickness (CRT) and the mean number of treatments.ResultsAt month 12, mean VA improved to a 1.5-line gain in IVB group, and lost three letters in PDT+IVTA group (P=0.02). Mean CRT was reduced from 357 μm at baseline to 244 μm at month 12 in IVB group and from 326 μm to 254 μm, respectively, in PDT+IVTA group (P=0.8). The mean number of treatments was 6.8 in the IVB group vs1.9 in the PDT+IVTA group. No significant local or systemic safety concerns were detected during follow-up time.ConclusionsPatients treated with IVB showed a significant better VA outcome compared with the PDT+IVTA group despite the fact that both modalities showed equal potency in reducing CRT during a 12-month period.

Response to Ranibizumab Therapy in Neovascular AMD – An Evaluation of Good and Bad Responders

BACKGROUND Treatment of neovascular age-related macular degeneration (AMD) with Lucentis shows a broad spectrum regarding the course of visual acuity (VA). While some patients show a good response (increase in VA), others disclose much less promising results. PATIENTS AND METHODS A retrospective data analysis of all eyes treated for neovascular AMD at the University Hospital of Zurich, Switzerland for at least 12 months was carried out. The courses of VA between the 90th (good responders, GR) and the 10th (bad responders, BR) percentiles were compared at 3, 12 and 24 months from baseline. An analysis regarding demographic data, lesion type and size as well as injection frequency and visits was done and predictive factors for GR and BR were evaluated. RESULTS Marked differences in the course of VA between GR (n = 30) and BR (n = 30) are already observed 3 months from baseline. In GR the gains in VA after 3, 12 and 24 were 15.7 +/- 9 letters ETDRS, 25.3 +/- 7 and 14.0 +/- 14. BR showed a deterioration of 8.3 +/- 11 letters ETDRS after 3, 22.1 +/- 8 after 12 and 23.6 +/- 13 after 24 months. The gender distribution was equal with a higher percentage of female patients (64 % in BR and 66 % in GR). The baseline VA was statistically significantly lower in GR (45.7 +/- 10 vs. 55.4 +/- 11, p < 0.05) than in BR. No other significant differences in baseline data were found, and no predictor for group membership could be identified. CONCLUSIONS Only the course of VA in the first three months seems to be of value for an estimation of the response to treatment. In the future the response to treatment in the early phase may influence the treatment algorithm and the injection frequency.

Effect of intravitreal bevacizumab (Avastin®) in neovascular age-related macular degeneration using a treatment regimen based on optical coherence tomography: 6- and 12-month results

Purpose:  To study the effect of intravitreal bevacizumab therapy on visual and anatomical outcomes in patients with neovascular age‐related macular degeneration (AMD) within a follow‐up period of 6 and 12 months.

Combination of verteporfin photodynamic therapy and ranibizumab: effects on retinal anatomy, choroidal perfusion and visual function in the protect study

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° 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.

Change in choroidal thickness after intravitreal aflibercept in pretreated and treatment-naive eyes for neovascular age-related macular degeneration

Aim Evaluation of effects of intravitreal aflibercept therapy on choroidal thickness (CT) in neovascular age-related macular degeneration. Methods Retrospective cohort study evaluating the change in CT following a loading dose of three intravitreal aflibercept injections at 4 weeks interval. Pretreated and treatment-naive eyes as well as untreated fellow eyes were evaluated at five retinal locations (subfoveal, 300 and 2500 µm nasal and temporal to the fovea) using spectral domain optical coherence tomography prior to and 4 weeks after a loading dose of three intravitreal aflibercept injections. Results A total of 84 treated eyes (61 pretreated, 23 treatment naive) and 48 fellow eyes were enrolled into the study. Treatment-naive and pretreated eyes showed a significant reduction in CT at all retinal locations. The effect was more pronounced in treatment-naive eyes. In the pretreated group, the mean reduction in CT was greatest at 2500 µm temporal to the fovea at 10.7 µm compared with 22.4 at 300 µm nasal to the fovea in the treatment-naive group. Only the fellow eyes in the treatment-naive group showed a significant CT reduction 12 weeks after initiation of therapy to the partner eye. Conclusions Aflibercept induces a reduction in CT in treatment-naive and pretreated eyes with neovascular age-related macular degeneration. There is some evidence of a systemic effect of aflibercept reflected by CT reduction in untreated fellow eyes.