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Purpose To investigate the influence of treatment regularity with intravitreal aflibercept injections (IVT-AFL injections) on visual acuity (VA) outcomes in patients with neovascular age-related macular degeneration (nAMD) enrolled in the PERSEUS trial who received at least 7 IVT-AFL injections during the first year. Methods This was a post hoc analysis of the PERSEUS trial, a prospective, non-interventional, multicenter cohort study, and included 370 patients with nAMD who had received ≥ 7 IVT-AFL injections during year 1. In addition to the prespecified subgroups of treatment-naïve and previously treated patients, results were compared between patients with regular (n = 209) and irregular (n = 161) treatment. Regular treatment was defined as initial dosing with monthly IVT-AFL injections for 3 months, then bimonthly IVT-AFL injections until month 12. Irregular treatment was defined as any deviation from regular treatment (provided ≥ 7 injections were received). The outcome of primary interest was the mean change in VA from baseline after 12 months. Further outcomes of interest included VA gain or loss, proportion of patients achieving reading vision, and percentage of patients with fluid. Results At month 12, the mean (± standard deviation, SD) VA improvement from baseline was 6.1 ± 15.6 Early Treatment Diabetic Retinopathy Study letters in the regular cohort and 2.5 ± 16.7 letters in the irregular cohort with ≥ 7 IVT-AFL injections (P = 0.0514). Best results were obtained in the treatment-naïve regular sub-cohort with a mean ± SD VA improvement of 8.0 ± 17.7 letters, whereas treatment-naïve patients with irregular treatment experienced a considerably lower VA gain (2.8 ± 20.0 letters). Irregular treatment consistently correlated with inferior results in treatment-naïve patients. At month 12, the proportion of treatment-naïve patients who had experienced a worsening of ≥ 5 letters was 29.6% in the irregular sub-cohort versus 13.6% in the regular sub-cohort (P = 0.0049). However, among the treatment-naïve patients, the mean number of injections was significantly higher in the irregular than in the regular sub-cohort (8.0 ± 1.2 vs. 7.4 ± 0.6; P = 0.0001). Furthermore, compared with the treatment-naïve, regular sub-cohort, patients in the irregular sub-cohort had more visits (19.1 ± 8.6 vs. 16.1 ± 5.7), VA tests (14.2 ± 6.9 vs. 12.0 ± 4.6), and optical coherence tomography examinations (5.1 ± 3.7 vs. 3.4.0 ± 3.0). Conclusions Although irregularly treated patients received more injections and more monitoring visits during the first year of IVT-AFL treatment, they experienced worse VA outcomes than regularly treated patients.

Purpose To evaluate the real-world effectiveness of intravitreal aflibercept injections in Germany in patients with neovascular age-related macular degeneration over 24 months. Methods PERSEUS was a prospective, non-interventional cohort study. The primary endpoint was the mean change in visual acuity (VA) from baseline. Secondary endpoints included the proportion of patients with a VA gain or loss of ≥ 15 letters and the frequency of injections and examinations. Patients with regular (bimonthly after 3 monthly injections during year 1 and ≥ 4 injections in year 2) and irregular (any other) treatment were analyzed. The last observation carried forward (LOCF) and the observed cases (OC) approach was applied for primary endpoint analysis to account for missing data. Results 803 patients were considered for effectivity analysis. At month 24, only 38% of the patients were still under observation. The LOCF population included 727, the OC population 279 patients. Treatment-naïve patients improved by 6.3 (LOCF)/8.1 (OC) letters with regular treatment over 24 months but only by 3.3 (LOCF)/3.1 (OC) letters with irregular treatment. The proportion of treatment-naïve patients achieving a VA improvement of ≥ 15 letters was similar between regularly and irregularly treated cohorts. However, considerably more patients in the irregular cohorts experienced a VA worsening of ≥ 15 letters than in the regular cohorts (LOCF: 18.7% vs. 7.4%). Conclusions Regular IVT-AFL treatment resulted in better VA outcomes than irregular treatment at month 24. However, only a minority of patients received regular treatment over a 2-year period.

Purpose To explore real-world effectiveness of intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration (nAMD) in Germany. Design A 24-month, prospective, noninterventional, noncontrolled, multicenter observational cohort study. Participants Patients (n = 848) with nAMD treated with IAI. Methods Patients (n = 988) were screened at 67 study sites. Therapeutic decisions were made by the treating physician. Primary end point analysis was performed after 12 months for the entire study cohort and for predetermined subgroups of treatment-naive and previously treated patients. Additionally, outcomes with regular injection intervals (bimonthly after 3 monthly injections) were compared with those of patients with irregularities in their treatment regimen. Main Outcome Measures The primary end point was the mean change in visual acuity (VA) from baseline after 12 months. Other key end points included the proportions of patients gaining 15 letters or more and patients with reading vision (≥70 letters). Furthermore, the number of injections, anatomic measurements, and safety data were recorded. Results Mean ± standard deviation VA improvement was 5.3±17.4 letters in treatment-naive patients and −0.1±15.6 letters in previously treated patients (P ≤ 0.0001), and that of the total study group was 2.9±16.8 letters. Baseline VA was 53.4±17.9 letters for treatment-naive patients, 52.9±18.4 letters for previously treated patients, and 53.2±18.1 letters for the total patient population. Treatment pattern was associated with VA outcome: best outcomes—an average VA gain of 8.0±17.7 letters—were seen in treatment-naive patients in the regularly treated population, whereas irregularly treated, treatment-naive patients achieved a mean VA gain of only 4.0±17.1 letters. Among previously treated patients, regular treatment also was associated with better outcomes (+3.1±10.7 vs. −1.1±16.8 letters). For the total study group, the mean VA gain was the following: regularly treated population, 6.1±15.6 letters; irregularly treated population, 1.5±17.1 letters (P = 0.008). No cases of endophthalmitis were observed during the first 12 months of the study. Adverse events were in line with the known safety profile of IAI. Conclusions After 12 months of treatment with IAI, treatment-naive patients showed substantial functional benefit, whereas previously treated patients maintained their VA. With regular IAI treatment, it seems that similar results as those in pivotal IAI studies can be achieved in routine clinical practice.

To explore real-world effectiveness of intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration (nAMD) in Germany.A 24-month, prospective, noninterventional, noncontrolled, multicenter observational cohort study.Patients (n = 848) with nAMD treated with IAI.Patients (n = 988) were screened at 67 study sites. Therapeutic decisions were made by the treating physician. Primary end point analysis was performed after 12 months for the entire study cohort and for predetermined subgroups of treatment-naïve and previously treated patients. Additionally, outcomes with regular injection intervals (bimonthly after 3 monthly injections) were compared with those of patients with irregularities in their treatment regimen.The primary end point was the mean change in visual acuity (VA) from baseline after 12 months. Other key end points included the proportions of patients gaining 15 letters or more and patients with reading vision (≥70 letters). Furthermore, the number of injections, anatomic measurements, and safety data were recorded.Mean ± standard deviation VA improvement was 5.3±17.4 letters in treatment-naïve patients and -0.1±15.6 letters in previously treated patients (P ≤ 0.0001), and that of the total study group was 2.9±16.8 letters. Baseline VA was 53.4±17.9 letters for treatment-naïve patients, 52.9±18.4 letters for previously treated patients, and 53.2±18.1 letters for the total patient population. Treatment pattern was associated with VA outcome: best outcomes-an average VA gain of 8.0±17.7 letters-were seen in treatment-naïve patients in the regularly treated population, whereas irregularly treated, treatment-naïve patients achieved a mean VA gain of only 4.0±17.1 letters. Among previously treated patients, regular treatment also was associated with better outcomes (+3.1±10.7 vs. -1.1±16.8 letters). For the total study group, the mean VA gain was the following: regularly treated population, 6.1±15.6 letters; irregularly treated population, 1.5±17.1 letters (P = 0.008). No cases of endophthalmitis were observed during the first 12 months of the study. Adverse events were in line with the known safety profile of IAI.After 12 months of treatment with IAI, treatment-naïve patients showed substantial functional benefit, whereas previously treated patients maintained their VA. With regular IAI treatment, it seems that similar results as those in pivotal IAI studies can be achieved in routine clinical practice.

Based on gene profiling, two entities of uveal melanomas exist. So far, these two entities can be distinguished by the chromosome 3 status which strongly associates with the metastatic potential of the tumours. Reorganization of the extracellular matrix is one of the steps towards dissemination of tumour cells. In the present study, we examined the tissue inhibitor of matrix metalloproteinases (TIMP) 3 expression in 19 uveal melanomas and compared the results with histopathological and genetic features. The expression level of TIMP-3 mRNA as determined by microarray analysis was associated with the chromosome 3 status of the tumour (p = 0.003). All tumours with disomy 3 showed moderate to high expression of TIMP-3 mRNA, whereas TIMP-3 was highly expressed in one tumour, less expressed in 3 tumours and absent in the remaining 6 tumours with monosomy 3. Immunohistochemistry for TIMP-3 was positive in 9/19 tumours, but only in 3 tumours were more than 5% of the tumour cells stained positive. There was no association between immunohistochemical detection of TIMP-3 and chromosome 3 status. In tumours with disomy 3, we found none or very few TIMP-3-positive cells though the mRNA level was high which indirectly postulates posttranscriptional problems in protein biosynthesis in this entity of uveal melanomas. There was a trend between TIMP-3 protein expression and both cell type (p = 0.11) and presence of loops and/or networks (p = 0.06) in tumour which may indicate a role of TIMP-3 in the biology of uveal melanoma.

Background: The development of a visual prosthesis aims to restore partial vision in patients with diseases which lead to total photoreceptor loss. The wireless power supply for a retinal implant may be realized with electromagnetic induction or with optical energy transfer. The present study investigates the feasibility of a photovoltaic power generation in the intraocular lens (IOL) part of an epiretinal implant for long-term tests in rabbits. Methods: IOLs containing an array of photovoltaic cells (PVC) and a light-emitting diode (LED) were implanted into the capsular bag after phacoemulsification in three chinchilla rabbits. Optical energy transfer was established with an infrared laser beam at 850 nm wavelength. Lighting up of the LED proved the functioning of the PVC array. The maximum duration of in vivo functioning of the implant was determined by regular tests involving laser beam application. The explanted microsystems were technically analyzed. Tissues of both eyes underwent routine histological examinations. Results: The lifespan of the microsystems ranged from 14 days to more than 7 months. Final malfunction was caused by PVC defects or by defective contacts between PVC and LED that may originate from the low adhesive strength between the silicone cover and the underlying electronic components. The histological examination showed no alterations of the retinal structure in the treated eyes. Conclusions: The power supply for intraocular microsystems by an array of photovoltaic cells was proven to be feasible in long-term tests in rabbits. An essential prerequisite for a future device is hermetic coating of the electronics.

Background: Cases of endogenous bacterial endophthalmitis were analysed regarding predisposing factors, timing of diagnosis, sources of infection, causative organisms, and visual outcome. The value of an immediate vitrectomy compared to exclusively injected intravitreal antibiotics was evaluated reviewing the literature. Methods: Records of 22 consecutive cases of the last 9 years with endogenous bacterial endophthalmitis were reviewed. The identified source of infection was treated with systemic antibiotics. All affected eyes were treated with intraocular injection of antibiotics, whenever possible combined with vitrectomy. Results: 90% of the patients had severe predisposing diseases, primarily diabetes mellitus combined with renal insufficiency and urinary tract infection (70%). Diagnoses were made 3.5 days after beginning of symptoms. An average of 75% of the patients had gram-positive and 25% gram-negative bacteria as causative organisms. Most common gram-positive bacteria were Staphylococcus aureus and S. epidermidis. In 73 % of all eyes vitrectomy was used as primary treatment. In 57% of the cases the visual outcome was light perception or better (excluding primary enucleations and deceased patients). 7% of the eyes had no light perception, 36% underwent secondary enucleation. Especially in cases of early diagnoses (less than or equal to 2 days) therapy was successful (60% of the patients); in contrast to delayed diagnoses (33%). The literature review suggests that immediate vitrectomy is superior to exclusive intravitreal injection of antibiotics concerning bulb conservation and remaining function. Conclusions: Immediate diagnosis and therapy are crucial for a positive outcome in this ophthalmological emergency. Immediate pars plana vitrectomy with intraocular antibiotic instillation seems to improve the prognosis of the affected eyes.

Background Two cases of acute retinal necrosis (ARN-) syndrome caused by an infection with varicella zoster virus (VZV) are demonstrated. VZV-DNA was detected in vitreous biopsies by polymerase-chain-reaction (PCR). The course of retinal necrosis was decisively improved by changing antiviral therapy from aciclovir and/or ganciclovir to brivudine. Material and methods Patient 1: 51 years, male, initial visual acuity 20/40; patient 2: 17 years, female, initial visual acuity 20/30. Both patients were immunocompetent and presented with an unilateral acute retinal necrosis syndrome with peripheral chorioretinitis, retinal vasculitis, vitreous inflammation and optic disc swelling, which resulted in progressive visual loss in a few days. Results In both patients VZV-DNA was detected in vitreous biopsies with PCR. A regression of intraocular inflammation and necrotic retinal foci was only observed after changing the initial systemic therapy from aciclovir (Zovirax) intravenously 1500 mg/day) and/or ganciclovir (Cymeven) intravenously 250 mg/day) to brivudine (Zostex) per os 500 mg/day). Vitreoretinal surgery was necessary in both patients because of rhegmatogenous retinal detachment. Visual acuity stabilised in patient 1 to 20/200 and in patient 2 to 20/25 during a follow-up of 16 or 32 months, respectively. Conclusion Brivudine represents an alternative therapy, if standard treatment with aciclovir and/or ganciclovir failed in cases of ARN-syndrome due to presumed drug-resistant varicella zoster virus-subtypes. Complete remission and preservation of a satisfactory function can be achieved.

To compare the complications and outcomes of implantation of a foldable intraocular lens (IOL) through a clear corneal incision and implantation of a poly(methyl methacrylate) (PMMA) IOL through a scleral incision in combined phacoemulsification and pars plana vitrectomy.Departments of Ophthalmology, St. Franziskus Hospital, Muenster, Eye Hospital, Muelheim, and University of Essen, Essen, Germany.This prospective randomized study included 62 eyes having implantation of a PMMA IOL (811B, Pharmacia) through a scleral incision and 61 eyes having implantation of a polyacrylic (AcrySof, Alcon) IOL through a clear corneal incision. The preoperative visual acuity, underlying retinal disease, and vitreoretinal surgical maneuvers did not differ between groups. The surgical methods and intraoperative complications were noted. Examinations 2 days and 3 months after surgery included visual acuity, refractive error, keratometry, slitlamp evaluation, tonometry, and ophthalmoscopy.Intraoperatively, both incisions were stable and no serious complications occurred. Two days after surgery, the incidence and quantity of cells and fibrin in the anterior chamber were lower in the clear corneal incision group than in the scleral incision group (P.05). Corneal endothelial dysfunction was more common in the clear corneal group than in the scleral group (P.05). Three months after surgery, the astigmatic changes did not differ significantly between groups and the incidence of posterior capsule opacification (PCO) was lower in the clear corneal group (P.05). Postoperative visual acuity improved significantly in 63% of eyes and 61% of eyes in the scleral group and clear corneal group, respectively. Visual acuity was limited by macular pathology.Both clear corneal and scleral incisions were safe in combined phacoemulsification and vitrectomy. Eyes with smaller clear corneal incisions and foldable IOLs had less postoperative inflammation and PCO.

In cases of large volume and highly prominent melanomas of the uvea, it is rare for conventional methods of radiation therapy to enable salvage of the globe or even residual functionality of the affected eye. Complications due to the massive amount of accumulated necrotic tissue often necessitate subsequent enucleation of the blinded eye. Tumor-destroying, single-dose convergence irradiation (radiosurgery) of such tumors applied shortly before endoresection can represent a possible therapeutic alternative in these types of cases.

BACKGROUND The interaction of the integrin receptors with their ligands (collagen, laminin, fibronectin, and others) has a crucial role during the reorganisation of the extracellular matrix and the metastatic process. The presence of particular vascular patterns in uveal melanoma is associated with the development of metastases. There is some evidence that interactions between the tumour cells and the extracellular matrix are responsible for the shape of these patterns. METHODS The expression of VLA-2, VLA-3, and αv integrin receptors was examined by immunohistochemistry on paraffin embedded tumour specimens from 92 uveal melanomas (iris melanomas excluded). Possible correlations between these results and the tumour vascular patterns, the histological features of the tumours as well as the clinical outcome of the patients, were investigated. RESULTS The expression of VLA-2 in tumours was associated with the presence of vascular networks (p = 0.05). Tumours with less than 25% VLA-3 positive cells infiltrated the sclera more frequently than those with more than 25% VLA-3 cell positivity (p = 0.05). Tumours expressing less than 50% αv positive cells were associated with the mixed or epithelioid cell type (p = 0.05) and, with less statistical precision, with the presence of extraocular growth (p = 0.07). The univariate logistic regression analysis showed that the risk of developing metastases within the first 5 years after diagnosis did not depend on the expression of the integrin receptors investigated. CONCLUSION The potential biological importance of the associations between integrin expression and the histopathological features of the tumours found in the present study remains to be elucidated in future experiments. The immunohistochemical detection of VLA-2, VLA-3, and αvintegrins had no prognostic value in our preliminary report.

Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis-free 5-year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety-six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell-cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A 'favourable outcome' was defined as survival of at least 5 years after diagnosis, without metastases (n=57). An 'unfavourable outcome' was defined as death from metastases within the first 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4. 2, 95% confidence interval 1.5-11.8, p=0.006; for p53: odds ratio=3. 2, 95% confidence interval 1.1-9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour (p=0.01), with the mixed or epithelioid cell type (p=0. 02), and with the tumour cell MIB-1 positivity (p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% confidence interval 0.8-5. 8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma.

To investigate the relationship between the expression of the cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) in uveal melanoma and the metastatic spread in the first 5 years after diagnosis, we performed a hospital-based case-control study with human tissue from 90 patients who underwent enucleation for primary uveal melanoma (iris melanoma excluded). Thirty-five patients developed metastasis within the first 5 years, and 55 patients lived metastasis-free for at least 5 years after enucleation. The paraffin-embedded and formalin-fixed globes were studied by immunohistochemistry with monoclonal antibodies for ICAM-1, VCAM-1 and NCAM. A strong ICAM-1 positivity (more than 75% of the tumor cells stained positive) was detected in 73 tumors (81%). The expression of 75% or less ICAM-1 positive cells in tumors was strongly associated with the development of metastases (odds ratio: 7.5, p = 0.001). Multiple logistic regression models showed that ICAM-1 is an independent risk factor for metastasis even after control for important prognostic markers like extraocular growth, ciliary body involvement, scleral infiltration and cell type. VCAM-1 was expressed in 24 out of 88 tumors (27.3%) and NCAM only in 14 out of 87 tumors (16%). Only spindle cells stained positive with anti-NCAM. NCAM and VCAM-1 expression was not related to metastasis. Our results show that the loss of ICAM-1 expression is associated with an increased risk of metastasis within the first 5 years after diagnosis.

Aim/background—The most common choice of treatment for choroidal haemangiomas (CH) in the past has been the employment of scatter photocoagulation of the surface. This management often requires repetitive treatment or additional invasive management due to massive exudative detachment of the retina. The aim of this retrospective study was to investigate the outcome of the alternative application of low dose external beam irradiation with high energetic photons on these tumours. Methods—A total absorbed dose of 20 Gy was applied to a total of 51 symptomatic eyes: 36 with a circumscribed CH of the posterior pole and 15 with diVuse CH as part of the Sturge‐Weber syndrome. The indication for treatment was an exudative retinal detachment including or threatening the fovea. The mean follow up times in each group were 4.5 and 5.3 years, respectively. Out of a group of 33 patients from whom reliable data could be derived, 17 had symptoms lasting longer than 6 months. Results—In 23 cases (63.8%) with circumscribed CH complete resolution of the subretinalfluid was achieved; the remaining 13 cases (36.2%) showed residual serous detachment distant to the fovea. The visual acuity improved by two or more lines in 14 cases (38.9%), remained stable in 14 cases (38.9%), and decreased in eight cases (22.2%). The functional success was dependent on the lag duration between onset of first subjective symptoms and treatment. The morphological results with diVuse CH were similar to those of the group of circumscribed CH. The visual acuity (VA) at last examination was improved in seven cases (46.6%);in the remaining eight cases, VA was unchanged or had deteriorated. The poor functional outcome in the latter was mainly attributable to secondary glaucoma. Conclusion—External beam irradiation is a useful and a low invasive therapeutic option for CH. A successful functional outcome is dependent on the time delay between first onset of symptoms and the beginning of therapy, the formation of subretinal fibrosis, and also on secondary glaucoma in the case of Sturge‐Weber syndrome. (Br J Ophthalmol 1997;81:267‐273) Haemangiomas of the choroid are rare vascular hamartomas that can occur in two forms: circumscribed choroidal haemangiomas (CH), which are solitary and predominantly located at the posterior pole, and diVuse CH, which are usually part of the Sturge‐Weber syndrome. Histological examination of these tumours shows a vascular pattern, dominated by cavernous portions, but capillary tumours and mixed patterns are also observed. 12

Mutations in the peripherin/RDS gene, which encodes a photoreceptor-specific membrane glycoprotein, have been identified in a variety of retinal phenotypes. However, the mechanisms by which specific mutations in this gene can cause typical features of retinal dystrophies clinically as distinct as retinitis pigmentosa or macular degeneration are still unknown. Recently, a single case of adult vitelliform macular dystrophy (AVMD) has been associated with a Y258Stop mutation. To assess the frequency of peripherin/RDS mutations in the clinically heterogeneous group of AVMD, we analyzed the entire coding region of the gene in 28 unrelated patients. We identified five novel mutations including two presumed null allele mutations. Thus, our results demonstrate that a significant portion of AVMD patients (18%) carry point mutations in peripherin/RDS, suggesting that this gene is frequently involved in the pathogenesis of this macular disorder. In addition, this study shows that the variable phenotypes in AVMD are due, at least in part, to genetic heterogeneity and are likely to be caused by mutations in disease genes thus far unknown.

Die Interpretation subretinaler choroidaler Neovaskularisationen (CNV) in der Indozyaningrunangiographie (ICG-A) ist nicht einheitlich. Zur Klarung der Frage, wie exakt eine umschriebene Hyperfluoreszenz in der ICG-A die tatsachliche Morphologie wiedergibt, wurden die Befunde von okkulten und klassisch-demarkierten CNV der konventionellen Fluoresceinangiographie (FLA) mit denen der ICG-A verglichen. Von 168 retrospektiv analysierten ICG-A mit CNV lag in 153 Fallen eine altersabhangige Makuladegeneration (AMD) mit 114 okkult wachsenden und 39 klassischen Membranen vor. Die Angiographien wurden mit beiden Farbstoffen an einer modifizierten Zeiss-Funduskamera kombiniert mit digitaler Bildverarbeitung durchgefuhrt. In 42 Fallen (36,8%) der AMD-Patienten mit okkulter CNV zeigte die ICG-A eine demarkierte Membran. Die Morphologie und die zeitliche Darstellung waren extrem variabel. In der Gruppe der AMD-Patienten mit abgrenzbarer, klassischer Membran zeigte sich keine Anfarbung in 3 (7%), eine Demarkierung in Fruh- und Spatphase in 14 (36%), ausschlieslich in der Fruhphase in 5 (13%) und nur in der Spatphase in 17 (44%) der 39 Falle. Von diesen 17 Fallen war die Membran in 8 Befunden groser und in 9 kleiner als in der FLA. Die in der Fruh- bzw. Fruh- und Spatphase gesehenen, demarkierten Membranen waren in beiden Angiographien stets grosengleich. Das Muster der Darstellung einer CNV in der ICG-A ist komplex. Ein alleiniger Befund in der Spatphase der ICG-A sollte v. a. im Hinblick auf die Planung einer Laserkoagulation mit groser Zuruckhaltung interpretiert werden.

Fifty-six globes that had to be enucleated following ruthenium plaque therapy were examined histopathologically. These eyes account for 10% of all uveal melanomas treated at the University Eye Clinic Essen up until 1985. All but one revealed at least some supposedly viable tumor cells. The most prominent findings within the tumors were tumor cell necrosis, vacuolization and balloon cell degeneration, vascular obstruction and fibrosis of the tumor stroma with accumulation of pigmented macrophages. Tumor necrosis was complete or nearly complete in five cases. Tumor regression correlated with cell type and pigmentary characteristics of the tumor, with epithelioid and heavily pigmented tumor cells being more radiosensitive. Tumor regression was inhomogeneous, possibly due to polyclonality, with tumor cells of varying radiosensitivity, or due to patchy areas of vascular obliteration. Among other ocular structures, extensive subretinal gliosis, chorioretinal atrophy and scarring of the sclera within the field of radiation were observed. Scleral necrosis was present in only five cases and was limited to areas in which the tumor had infiltrated the deep scleral layers. The findings described were considered to reflect radiation injury rather than spontaneous tumor regression when compared to 70 control eyes that had been enucleated without prior treatment for uveal melanoma.

Ocular symptoms of Behcet's syndrome in 16 patients and the results of cytostatic and immunosuppressive therapy with cyclosporin A (6 patients), chlorambucil (6 patients), and a combination of cyclophosphamide and procarbacin (4 patients) are described. The clinical course and therapeutic outcome were compared to the patients' visual acuity and the duration of the disease prior to institution of cytostatic therapy. Average follow-up was 4.6 years, maximum 9 years. The principal ocular symptom in all patients was hemorrhagic, occlusive periphlebitis. Other symptoms, in descending order of frequency, were chorioretinitis, iridocyclitis, complicated cataract, secondary glaucoma and exudative retinal detachment. The patients in whom cytostatic therapy was instituted no later than 6 months after onset of the disease showed an improvement in or stabilization of visual acuity, as well as a clear reduction in signs of intraocular inflammation and frequency of recurrence. No improvement in visual acuity or ocular symptoms was achieved in cases where the disease was very advanced, despite cytostatic-immunosuppressive therapy. The results support early institution of immunosuppressive therapy in cases with Behcet's syndrome where severe, irreversible damage has not yet occurred and in which vision is threatened in both eyes. However, due consideration must be given to the potential risks of immunosuppressive therapy, in particular the risk of a malignant tumor.

Aim: To investigate the safety and efficacy of β ray brachytherapy in treatment of vasoproliferative tumours of the retina (VTR). Methods: 35 consecutive patients with symptomatic VTR were treated with a ruthenium-106 (106Ru) plaque. Three tumours had been treated previously (two with cryotherapy; one with transpupillary thermotherapy). 32 VTR (91.4%) were located in the lower half of the retina and all of them were found between the mid-periphery and the ora serrata. The mean tumour thickness was 2.8 mm. An exudative retinal detachment was present in 25 eyes (71.4%) and in 15 cases (42.9%) hard exudates were found in the macula. The major symptom was loss of vision (77.1%). Results: Brachytherapy was well tolerated by every patient. The mean applied dose was 416 Gy at the sclera and 108 Gy at the tumour apex. In all but four eyes (88.6%), it was possible to control the VTR activity. The median follow up time was 24 months. Three of the above mentioned four eyes with treatment failure had had secondary glaucoma before therapy. There was no case of radiation induced neuropathy or retinopathy. Cataract surgery was necessary for five patients. The development of epiretinal gliosis was the most common event during follow up (n = 10, 28.6%). The mean visual acuity decreased slightly (0.33 before and 0.29 after brachytherapy). Multivariate analysis showed that the presence of macular pathology before treatment was associated with a 6.1-fold risk of vision of 0.25 or better (p = 0.03). Conclusions: β ray brachytherapy with 1106Ru plaques was able to control the activity of VTR and retain vision. Cases with secondary glaucoma before treatment had a very poor prognosis.

Purpose: A retrospective analysis of 134 patients who received 106 Ru brachytherapy for retinoblastomas (175 tumors in 140 eyes). Treatment and follow-up were analyzed with special emphasis on tumor control organ, preservation, and late complications. Results: Treated tumors had a mean height and diameter of 3.7 ± 1.4 mm and 5.0 ± 2.8 disk diameters, respectively. The radiation dose values were recalculated according to the calibration standard recently introduced by the National Institute of Standards and Technology. The recalculation revealed a mean applied dose of 419 Gy at the sclera (SD, 207 Gy) and 138 Gy (SD, 67 Gy) at the tumor apex. The 5-year tumor control rate was 94.4%. Tumor recurrence was more frequent in eyes with vitreous tumor cell seeding or fish-flesh regression. The estimated 5-year eye preservation rate was 86.5%. Previous treatment by brachytherapy or external beam radiotherapy, as well as a large tumor diameter, were significant factors for enucleation. The radiotherapy-induced complications after 5 years of follow-up were retinopathy (22%), optic neuropathy (21%), and cataract (17%). These complications were significantly more frequent after prior brachytherapy or external beam radiotherapy. Conclusion: Brachytherapy using 106 Ru plaques is a highly efficient therapy with excellent local tumor control and an acceptable incidence of side effects.

Aim: To investigate the safety and efficacy of photodynamic therapy with verteporfin (PDT) in patients with choroidal neovascularization associated with angioid streaks (CNVAS). Methods: A nonrandomized, prospective clinical investigation of 12 patients with CNVAS was performed. PDT was based on the criteria concerning the treatment of age-related macular degeneration. Results: The mean follow-up was 41.75 months (range 24–60). The mean number of (re)treatments was 3.3 (range 2–7). Visual acuity improved by at least 1 line in 42%, was stable within ±2 lines in 33%, decreased by at least 1 line in 58% and by >3 lines in 25% of the patients. The mean visual acuity was 0.30 (range 0.2–0.5) prior to and 0.17 (range 0.03–0.6) after the final PDT. The mean visual acuity of the contralateral eye was 0.1. 75% of contralateral eyes and 25% of the treated eyes had a final visual acuity of ≤0.1 (20/200). At the final follow-up, a significant enlargement of the lesion size was noted in 92% of the cases. Conclusion: Using the current (re)treatment criteria, PDT does not appear to limit the growth of CNVAS. Compared to the aggressive natural course and to the limited treatment options, PDT may at least in part help to stabilize macular function over a limited period of time.

PURPOSE To assess the long-term effect of acetazolamide treatment on patients with cystoid macular edema (CME) in the course of intermediate or posterior chronic uveitis and to define those patients who may particularly benefit from the drug. METHODS Fifty-two eyes (45 patients) with chronic uveitic CME were treated with acetazolamide at an initial dosage of 500 mg/d. The effect of treatment was assessed by fluorescein angiography, ophthalmoscopy, visual acuity, and Amsler testing. Therapy was withdrawn when CME did not improve at 3 weeks. In cases with CME improvement, the dosage was gradually tapered. RESULTS The mean follow-up was 3.1 years (minimum, 1.5 years). Two subgroups were identified: group 1, quiescence of uveitis with acetazolamide as the single therapeutic agent (33 eyes); and group 2, chronically active uveitis requiring additional systemic antiinflammatory drugs (19 eyes). In both groups, visual acuity improvement was statistically significant (group 1, P = 0.012; group 2, P = 0.025). In 12 patients with a stable visual acuity gain, the medication dose could be tapered off completely without any recurrent edema shown by fluorescein angiography after a minimum follow-up of 1 year. Sixteen patients required a maintenance dosage, ranging from 125 to 500 mg daily. No major adverse effects of the medication were observed. CONCLUSIONS During long-term follow-up, low-dose acetazolamide can be a useful therapeutic option for chronic CME in uveitis. The effect was better in patients with quiescence of uveitis than in those with chronically active uveitis. Permanent therapy is not imperative in every case.

Cases of endogenous bacterial endophthalmitis were analysed regarding predisposing factors, timing of diagnosis, sources of infection, causative organisms, and visual outcome. The value of an immediate vitrectomy compared to exclusively injected intravitreal antibiotics was evaluated reviewing the literature.Records of 22 consecutive cases of the last 9 years with endogenous bacterial endophthalmitis were reviewed. The identified source of infection was treated with systemic antibiotics. All affected eyes were treated with intraocular injection of antibiotics, whenever possible combined with vitrectomy.90% of the patients had severe predisposing diseases, primarily diabetes mellitus combined with renal insufficiency and urinary tract infection (70%). Diagnoses were made 3.5 days after beginning of symptoms. An average of 75% of the patients had gram-positive and 25% gram-negative bacteria as causative organisms. Most common gram-positive bacteria were Staphylococcus aureus and S. epidermidis. In 73% of all eyes vitrectomy was used as primary treatment. In 57% of the cases the visual outcome was light perception or better (excluding primary enucleations and deceased patients). 7% of the eyes had no light perception, 36% underwent secondary enucleation. Especially in cases of early diagnoses (less than or equal to 2 days) therapy was successful (60% of the patients); in contrast to delayed diagnoses (33%). The literature review suggests that immediate vitrectomy is superior to exclusive intravitreal injection of antibiotics concerning bulb conservation and remaining function.Immediate diagnosis and therapy are crucial for a positive outcome in this ophthalmological emergency. Immediate pars plana vitrectomy with intraocular antibiotic instillation seems to improve the prognosis of the affected eyes.

In this study, the importance of angiogenesis (the growth of new blood vessels from existing ones) for the growth of retinoblastoma was investigated by a retrospective immunohistochemical analysis. An individual vessel index for each tumor was determined using the endothelial-specific antibody CD 31 for vessel staining. The obtained data were correlated with clinical features, pathohistological characteristics, and the presence of metastasis. In 107 retinoblastomas collected between 1980 and 1990, we found no difference in the vessel densities between uni- and bilateral retinoblastomas (P = 0.41). However, tumors that had invaded the chorioid and/or the optic nerve statistically showed higher vessel densities than tumors without local invasive growth (P = 0.05 and P = 0.024). A tendency of higher vessel densities in retinoblastomas presenting with metastasis at the time of diagnosis was observed (P = 0.11). Based on this observation, we proceeded to examine all retinoblastomas presenting with metastasis at the time of diagnosis. These included patients that were treated between 1968 and 1993. The 18 investigated retinoblastomas had significantly higher vessel densities than all other retinoblastomas presenting without metastasis (P = 0.025). Our data indicate that in retinoblastoma, blood vessels are essential for local and systemic invasive growth. Therefore, an anti-angiogenic therapy could be considered in the multimodal therapy concept for retinoblastomas with invasive growth, both locally and systemically.

Two cases of acute retinal necrosis (ARN-) syndrome caused by an infection with varicella zoster virus (VZV) are demonstrated. VZV-DNA was detected in vitreous biopsies by polymerase-chain-reaction (PCR). The course of retinal necrosis was decisively improved by changing antiviral therapy from aciclovir and/or ganciclovir to brivudine.Patient 1: 51 years, male, initial visual acuity 20/40; patient 2: 17 years, female, initial visual acuity 20/30. Both patients were immunocompetent and presented with an unilateral acute retinal necrosis syndrome with peripheral chorioretinitis, retinal vasculitis, vitreous inflammation and optic disc swelling, which resulted in progressive visual loss in a few days.In both patients VZV-DNA was detected in vitreous biopsies with PCR. A regression of intraocular inflammation and necrotic retinal foci was only observed after changing the initial systemic therapy from aciclovir (Zovirax) intravenously 1500 mg/day) and/or ganciclovir (Cymeven) intravenously 250 mg/day) to brivudine (Zostex) per os 500 mg/day). Vitreoretinal surgery was necessary in both patients because of rhegmatogenous retinal detachment. Visual acuity stabilised in patient 1 to 20/200 and in patient 2 to 20/25 during a follow-up of 16 or 32 months, respectively.Brivudine represents an alternative therapy, if standard treatment with aciclovir and/or ganciclovir failed in cases of ARN-syndrome due to presumed drug-resistant varicella zoster virus-subtypes. Complete remission and preservation of a satisfactory function can be achieved.

Uveal melanoma is the most common intraocular malignancy. About 50% of patients die of metastases, which almost exclusively originate from primary tumors that have lost one chromosome 3 (monosomy 3). To gain insight into the biological mechanisms that underlie the various metastasizing potential of uveal melanoma, we have determined gene expression levels in 20 primary tumors using oligonucleotide microarrays containing 12500 probe sets. The expression measurements of those 7902 genes that were expressed in more than 10% of tumors were analyzed using two different statistical approaches. We used a modified Wilcoxon rank-sum test to identify genes differentially expressed between tumors with and without monosomy 3. Seven genes showed complete loss of expression in tumors with monosomy 3 but were expressed in tumors with disomy 3. Two of them, CHL1 and fls485, are located within or close to the uveal melanoma susceptibility locus UVM2 at 3p25. However, mutation analysis of both genes in eight tumors with monosomy 3 did not reveal structural or epigenetic alteration. To identify tumor classes, we performed unsupervised hierarchical cluster analysis; this approach separated uveal melanomas into two groups. We found that this classification is strikingly robust because, when tested by "resampling," the same grouping is obtained from 47 of 50 subsamples of genes. In clusterings of the three remaining subsamples, the grouping of only one tumor does not conform with the original classification. Excluding this tumor, cluster analyses of subsamples containing as few as 300 randomly chosen genes consistently result in the same classification, thus indicating that the difference between the two tumor classes is pervasive. Interestingly, all of the tumors in one of the groups have disomy 3, whereas all of the others have monosomy 3. Our findings suggest that there are two distinct entities of uveal melanoma that were previously unrecognized because they are not obviously distinguishable by clinicopathological features.

Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.

Radiotherapy has become increasingly important for the treatment of complicated choroidal hemangiomas. In recent years, a broad spectrum of different radiotherapeutic options that either replace or complement the conventional therapeutic approach by photocoagulation has been recommended. This article reviews the various treatment modalities and their indications with a special focus on the long-term outcome of low-dose external beam irradiation.

The interaction between Fas and Fas ligand is one possible immune escape mechanism used by tumour cells. In the present study, melanoma tissue from 103 patients who underwent enucleation for malignant uveal melanoma (iris melanomas excluded) was stained by immunohistochemistry with monoclonal antibodies specific for Fas, Fas ligand, CD3, CD8, and CD68. Histological and clinical data for these tumours were assessed. Both Fas and Fas ligand were detected in uveal melanomas. Cells of the monocyte/macrophage lineage rather than T-cells were the predominant group of tumour-infiltrating cells. The metastasis-free 5-year survival rates in the univariate analyses were considerably lower in patients with tumours that lacked Fas ligand expression (< 35% of the tumour cells), in the presence of more than 50 CD8-positive cells in 20 high-power fields and in the presence of more than 100 CD3-positive cells in 20 high-power fields. Fas and Fas ligand expression was associated with scleral infiltration. After adjustment for scleral infiltration, the predictive value of both Fas and Fas ligand expression was markedly decreased. In addition, the CD3- and CD8-positive cell count was positively associated with the histological cell type. Cox proportional hazards models showed that the presence of CD3- and CD8-positive cells was not an independent prognostic factor after adjusting for histological cell type. This preliminary observation deserves further investigation, which may shed more light on the immune escape mechanisms of this tumour and thus enable novel therapeutic strategies. The clinical relevance of this observation is limited, as more predictive parameters have been described for uveal melanoma.