Comparing the Effectiveness of Bevacizumab to Ranibizumab in Patients with Exudative Age-Related Macular Degeneration. The BRAMD Study.

PURPOSE: To compare the effectiveness of bevacizumab and ranibizumab in the treatment of exudative age-related macular degeneration (AMD). DESIGN: Multicentre, randomized, controlled, double-masked clinical trial in 327 patients. The non-inferiority margin was 4 letters. PATIENTS: Patients ≥ 60 years of age with primary or recurrent sub- or juxtafoveal choroidal neovascularization (CNV) secondary to AMD with a total area of CNV < 12 disc areas and a best corrected visual acuity (BCVA) score between 20 and 78 letters on an EDTRS like chart in the study eye. METHODS: Monthly intravitreal injections with 1.25 mg bevacizumab or 0.5 mg ranibizumab were given during one year. Intention to treat with last observation carried forward analysis was performed. MAIN OUTCOME MEASURES: Primary outcome was the change in BCVA in the study eye from baseline to 12 months. RESULTS: The mean gain in BCVA was 5.1 (±14.1) letters in the bevacizumab group (n = 161) and 6.4 (±12.2) letters in the ranibizumab group (n = 166) (p = 0.37). The lower limit of the 95% confidence interval of the difference in BCVA gain was 3.72. The response to bevacizumab was more varied; 24% of patients showed a gain of ≥15 letters, 11% a loss of ≥15 letters and 65% a gain or loss < 15 letters compared to 19%, 5% and 76% respectively for ranibizumab (p = 0.038). No significant differences in absolute CRT and CRT change (p = 0.13) or in the presence of subretinal or intraretinal fluid (p = 0.14 and 0.10, respectively) were observed. However, the presence of any fluid on SD-OCT (subretinal and/or intraretinal) differed significantly (p = 0.020), with definite fluid on SD-OCT in 45% of the patients for bevacizumab versus 31% for ranibizumab. The occurrence of serious adverse events and adverse events was similar, with 34 SAEs and 256 AEs in the bevacizumab group and 37 SAEs and 299 AEs in the ranibizumab group (p = 0.87 and p = 0.48, respectively). CONCLUSIONS: Bevacizumab was not inferior to ranibizumab. The response to bevacizumab was more varied with higher percentages of both gainers and losers and more frequently observed retinal fluid on SD-OCT at 12 months when compared to the ranibizumab group. TRIAL REGISTRATION: Trialregister.nl NTR1704.

Comparing the effectiveness and costs of Bevacizumab to Ranibizumab in patients with Diabetic Macular Edema: a randomized clinical trial (the BRDME study).

BACKGROUND: The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. AIM: To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. DESIGN: This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. OUTCOMES: The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments.

Skin autofluorescence is elevated in neovascular age-related macular degeneration.

BACKGROUND/AIMS Skin autofluorescence (AF) is a non-invasive marker for advanced glycation endproducts (AGE) in tissues, making use of their characteristic AF pattern. The aim of this study was to investigate whether skin AF is increased in patients with neovascular age-related macular degeneration (AMD) compared with healthy controls. METHODS Skin AF was assessed in 73 consecutive patients with active and documented neovascular AMD without evidence for diabetic or hypertensive retinopathy and in 31 healthy age-matched controls. Exclusion criteria were: known renal disease, current inflammatory or malignant disease, or skin type V or VI. Skin AF was measured on the forearm and was calculated as a ratio of mean intensities detected from the skin between 420-600 and 300-420 nm. Student t test and chi(2) test were used to compare differences between groups. RESULTS Skin AF was increased in neovascular AMD compared with controls (2.57+/-0.68 vs 2.23+/-0.63 arbitrary units x 10(-2); p=0.018). In patients without vascular risk factors or cardiovascular disease, skin AF was not significantly higher than that of the controls. Skin AF correlated with age in both patients and controls. CONCLUSION Skin AF is increased in patients with neovascular AMD, suggesting that AMD is accompanied by enhanced systemic AGE accumulation, which may indicate a role in the pathophysiology of AMD.

Pentosidine accumulates in the aging vitreous body: a gender effect.

The human vitreous body undergoes structural changes with aging. This can be followed by a posterior vitreous detachment, which can result in ocular pathology. As in many collagenous tissues, age-related changes in the vitreous could be caused by the formation of advanced glycation end products (AGEs). The goal of this study was to find out whether the AGE pentosidine accumulates in the human vitreous with aging. With this data we were able to estimate the half-life of vitreous collagen. Furthermore, we analyzed whether there was a gender difference in pentosidine accumulation, as this was seen in other tissues as well. Using high performance liquid chromatography, pentosidine contents were determined in whole vitreous bodies and in separate parts of vitreous bodies, which were all obtained from human donor eyes. Our results show that pentosidine accumulates in the human vitreous. From the rate of accumulation we could roughly estimate that vitreous collagen has as a similar or shorter half-life compared to skin collagen. This supports the concept of collagen turnover in the vitreous. In general, the female vitreous experiences a faster pentosidine accumulation than the male vitreous, and most of the pentosidine accumulation in the former occurs after 50 years of age.

Development of an accommodating intra-ocular lens--in vitro prevention of re-growth of pig and rabbit lens capsule epithelial cells.

Cataract surgery is routinely performed to replace the clouded lens by a rigid polymeric intra-ocular lens unable to accommodate. By implanting a silicone gel into an intact capsular bag the accommodating properties of the natural lens can be maintained or enhanced. The implantation success of accommodating lenses is hampered by the occurrence of capsular opacification (PCO) due to lens epithelial cell (LEC) growth. In order to prevent LEC proliferation, a treatment regime using actinomycin D, cycloheximide and water was developed. The effectiveness of treatment was analyzed using an in vitro, MTT-based cell culture system and an ex vivo pig eye model in which the implanted lens-in-the-bag is cultured as a whole. LEC were exposed to treatment solutions for 5 min, then the cells were allowed to recover and to re-colonize the substratum. MTT conversion by cells was transiently inhibited by cycloheximide dissolved in water and by water alone. Exposure to actinomycin D resulted in a lasting inhibition of MTT conversion and consequently cell proliferation. These in vitro data could not be fully reproduced in the ex vivo pig eye model due to essential differences between both models. Treatment with actinomycin D containing solutions, however, resulted in a nearly complete absence of cells on the capsular wall. The pig eye model is a promising approach to further evaluate the effects of peri-surgical treatment during the accommodating intra-ocular lens implantation.

Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial.

Despite advances in revascularization techniques, limb salvage and relief of pain cannot be achieved in many diabetic patients with diffuse peripheral vascular disease. Our objective was to determine the effect of intramuscular administration of phVEGF165 (vascular endothelial growth factor gene-carrying plasmid) on critical limb ischemia (CLI) compared with placebo (0.9% NaCl). A double-blind, placebo-controlled study was performed in 54 adult diabetic patients with CLI. The primary end point was the amputation rate at 100 days. Secondary end points were a 15% increase in pressure indices (ankle-to-brachial index and toe-to-brachial index), clinical improvement (skin, pain, and Quality of Life score), and safety. In patients (n=27) treated with placebo versus phVEGF165-treated patients (n=27) the following results were found: 6 amputations versus 3 (p=not significant [NS]); hemodynamic improvement in 1 versus 7 (p=0.05); improvement in skin ulcers, 0 versus 7 (p=0.01); decrease in pain, 2 versus 5 (p=NS); and overall, 3 versus 14 responding patients (p=0.003). No grade 3 or 4 adverse effects were seen in these patients. We conclude that this small, randomized gene therapy study failed to meet the primary objective of significant amputation reduction. However, significant and meaningful improvement was found in patients treated with a VEGF165-containing plasmid. There were no substantial adverse events.

Diffuse choroidal haemangioma in Sturge-Weber syndrome treated with photodynamic therapy under general anaesthesia.

PURPOSE: To report the treatment outcome of photodynamic therapy with verteporfin (PDT) for exudative retinal detachment associated with diffuse choroidal haemangioma in Sturge-Weber syndrome. METHODS: An interventional case report of a 12-year-old girl with Sturge-Weber syndrome who developed an exudative retinal detachment (visual acuity 20/400) that was treated with PDT under general anaesthesia. PDT was performed according to the standard (macular degeneration) protocol, using three nonoverlapping spots of 4,000 microm. RESULTS: Subretinal fluid resolved completely over a period of 5 months and visual acuity increased to 20/50. No side effects of the PDT treatment were encountered during 9 months' follow-up. CONCLUSION: In our patient PDT with verteporfin effectively resolved the exudative retinal detachment associated with a diffuse choroidal haemangioma. Resolution of subretinal fluid occurred over several months without retreatment. We noted no side effects of the combination PDT and general anaesthesia, nor did we encounter ocular side effects of the treatment.

Multiple surface properties of worn RGP lenses and adhesion of Pseudomonas aeruginosa.

The aim of this study is to determine rigid gas permeable (RGP) lens surface properties prior to and after wear that are influential on adhesion of Pseudomonas aeruginosa. After 10 and 50 days of wear and after end-stage use, lenses were collected for determination of physico-chemical surface properties and bacterial adhesion in a parallel plate flow chamber. Water contact angles on unused RGP lenses amounted 47+/-13 degrees and were affected by wear. In addition, %O at the lens surfaces, as determined by X-ray photoelectron spectroscopy increased after use for 10 and 50 days, but decreased after end-stage wear. The %N hardly increased after wear and, in line, SDS-PAGE did not indicate adsorbed proteins. The surface roughness of the lenses, as measured by atomic force microscopy amounted 9 nm after 10 and 50 days of use, but end-stage lenses were significantly rougher (48+/-23 nm). Moreover, initial deposition of P. aeruginosa #3 increased with increasing roughness for end-stage lenses. Multiple regression analysis, however, revealed that both physical and chemical surface properties were predictive for initial bacterial deposition to lens surfaces. After 10 days of wear, bacterial deposition was governed by the water contact angle, surface roughness, %O, %N, and %Si, while after 50 days of wear the surface roughness, %N, and %Si were found predictive for bacterial deposition. Initial bacterial deposition to end-stage lenses was solely dependent on the surface roughness. Summarizing, physico-chemical surface properties of RGP lenses change slightly during the first 10-50 days of wear, but end-stage lenses all had increased surface roughness, concurrent with increased bacterial adhesion.

Two-field photography can identify patients with vision-threatening diabetic retinopathy: a screening approach in the primary care setting.

OBJECTIVE: To compare the effectiveness of two 45 degrees photographic fields per eye in the screening for diabetic retinopathy with the routine ophthalmologist's examination and to study the effectiveness of visual acuity measurement in the detection of diabetic macular edema. RESEARCH DESIGN AND METHODS: Type 1 and 2 diabetic patients without a known history of more than minimal retinopathy (n = 469) had a routine examination by an ophthalmologist, including visual acuity measurement, indirect retinoscopy, and biomicroscopy. At the same time, two-field nonstereoscopic retinal photographs were made of both eyes and assessed in a masked fashion by a retinal specialist. The results were compared. RESULTS: The prevalence was 4.3% for vision-threatening retinopathy and 24% for any retinopathy. The sensitivity of two-field photography in identifying diabetic patients with sight-threatening retinopathy was 95% (specificity 99%) and sensitivity for detecting any retinopathy was 83% (specificity 88%). The percentage of referrals to an ophthalmologist was 6.2%. All patients with macular edema detected by biomicroscopy were classified as having vision-threatening retinopathy on the photographs. CONCLUSIONS: Two-field retinal photography is a promising alternative to the routine ophthalmologist's examination in the screening for diabetic retinopathy. Visual acuity measurement is not a sensitive tool for the detection of macular edema. Screening for diabetic retinopathy using two-field retinal photography is feasible in a primary care setting and can substantially lower the number of ophthalmic referrals.

Formation of proliferative vitreoretinopathy in primary rhegmatogenous retinal detachment.

Proliferative vitreoretinopathy (PVR) is the only cause of ultimate failure following retinal detachment surgery. This study aimed to review the rate of postoperative PVR in a series of 186 consecutive patients with primary rhegmatogenous retinal detachments. All 186 detachments were repaired with a scleral buckling procedure combined with cryotherapy. Drainage of subretinal fluid was done at the discretion of the surgeon. The mean follow-up was 12 months. In this series 152 (82%) of primary detachments were repaired succesfully with a single operation. Sixty-eight percent of patients regained 0.3 or better visual acuity, and 3% of patients were left with visual acuity of 1/60 or less. After two or more operations the retina was attached in 96% of the cases. In 12 (6%) eyes PVR was responsible for the initial surgical failure. In 4 cases PVR (grade B and limited C) was present prior to surgery. In 3 cases PVR developed within 2 days postoperatively, in 3 cases after 3-6 weeks and in another 2 cases after 8-10 months. Eight out of 12 (66%) PVR patients had undergone cataract surgery. One PVR case had preoperative intraocular inflammation. An association between the duration of retinal detachment, or drainage of subretinal fluid and the development of PVR could not be demonstrated. In conclusion, the rate of postoperative PVR in primary rhegmatogenous retinal detachments was low. PVR preoperatively present and pseudophakia may be risk factors.

Acute bacterial endophthalmitis after cataract extraction: results of treatment.

In order to evaluate the results, we reviewed all 34 patients treated in our hospital for endophthalmitis after cataract surgery between January 1994 and January 1998. After cultures were taken, all patients received intraocular, subconjunctival and topical vancomycin and ceftazidime. Additionally, twelve patients received the same antibiotics systemically. Besides steroids were administered in all patients. In 79% of the patients the bacterial culture was positive. Coagulase negative Staphylococcus was the most frequently isolated microorganism (48%). After treatment a visual acuity of 0.1 or more was achieved in 62% of the patients. The best final results were achieved in the patients with an initial visual acuity of 1/300 or more, and in the patients from whom a coagulase negative Staphylococcus was isolated.

Fibrotic scar formation in central serous chorioretinopathy developed during systemic treatment with corticosteroids.

BACKGROUND: The purpose of the study is to demonstrate the development of subretinal fibrotic scar formation in central serous chorioretinopathy (CSCR) that developed during systemic corticosteroid treatment. METHODS: The clinical and photographic records of a patient in whom an unusual manifestation of severe central serous chorioretinopathy developed during systemic corticosteroid treatment were reviewed. RESULTS: A 34-year-old man received high dosages of corticosteroids for several years because of severe asthma. There was no previous history of idiopathic CSCR. He developed three successive attacks of CSCR. On the third occasion, an unusual variant of severe CSCR was observed which presented as a bullous sensory retinal detachment with subretinal serofibrinous exudate followed by subretinal fibrosis and fibrotic scar formation with contracting bands. After tapering of the corticosteroid dosage to a low level the retinal detachment resolved without laser treatment. CONCLUSION: The finding suggests that during systemic corticosteroid treatment atypical manifestations of CSCR may develop with subretinal fibrosis and scar formation.

[Clinical thinking and decision making in practice. A patient with decreased vision and a skin disorder]. / Klinisch denken en beslissen in de praktijk. Een patiënt met visusdaling en huidafwijkingen.

In a 48-year-old man who suffered from progressive loss of vision in his left eye and metamorphopsia, pseudoxanthoma elasticum was diagnosed. Angioid streaks were observed in both eyes and the skin showed small yellow papules in a linear pattern. The right retina was twice treated by laser coagulation which resulted in temporary regression of neovascularization. Pseudoxanthoma elasticum is a genetic disorder with variable penetrance. There is no treatment. Patients should be told to refrain from contact sports and to avoid using aspirin.

Reproducibility of vitreous fluorophotometry in patients with type 1 diabetes mellitus.

We assessed the day-to-day reproducible of vitreous fluorophotometry in 7 type 1 diabetic patients and in 1 healthy control subject. The coefficient of variation for duplicate measurements was 33.7, 40.3 and 23.6%, for the right eyes, the left eyes and mean values of both eyes, respectively. Assessment of reproducibility in 1 healthy subject, measured 4 times, resulted in coefficients of variation of about 60%. These values are somewhat worse than those obtained by others in healthy subjects. Since technical problems do not seem to play a significant role in this regard, our reproducibility results reflect the true biological variability of the permeability of the blood-retina barrier assessed by vitreous fluorophotometry in diabetic patients. This variability is substantial. Therefore, we conclude that this method is not precise enough to be used in intervention studies with a limited number of subjects.

Myelinated nerve fibers and retinal vascular abnormalities.

BACKGROUND/PURPOSE: Abnormal retinal vessels may develop in a region of myelinated nerve fibers, and these vessels may cause vitreous hemorrhages. METHODS: The clinical histories of seven patients with retinovascular abnormalities in a patch of myelinated nerve fibers are presented. None of the reported patients had other evidence of systemic disease. The cases were traced by a multicentric retrospective study. RESULTS: Retinal vascular abnormalities ranged from mild telangiectasis to frank neovascularization, with or without obstruction of the capillary network and signs of branch artery and vein occlusion. Age at diagnosis ranged from 15 to 68 years. Vitreous hemorrhages occurred in the four youngest patients and occurred at 15, 27, 27, and 43 years of age. Laser photocoagulation was applied in three patients and vitrectomy was performed in one. CONCLUSION: The authors' findings suggest that the abnormal structure of the myelinated nerve fibers and the thickened nerve fiber layer of the affected portions of retina may play a role in the onset of retinal vascular abnormalities and eventually cause telangiectasis, branch artery and vein occlusion, neovascularization, and vitreous hemorrhages. This suggestion is based on the absence of other causes of neovascularization or vitreous hemorrhage in all seven patients, and on the relatively young age of four of the patients with this association.

The effects of an aldose reductase inhibitor on the progression of diabetic retinopathy.

The polyol pathway has long been associated with diabetic retinopathy. Glucose is converted to sorbitol with the aid of the enzyme aldose reductase. Aldose reductase inhibitors can prevent changes induced by diabetes. A total of 30 patients with minimal background retinopathy were randomly divided into a ponalrestat-taking group and a placebo-taking group. All were followed for 6 months and twenty-three were followed for 12 months. The baseline microaneurysm count was 2.6 +/- 1.9 (mean +/- SD) for the ponalrestat group and 3.5 +/- 2.9 for the placebo group. At 6 months the counts were 3.1 +/- 3.5 and 2.9 +/- 3.6 and after 12 months 3.0 +/- 4.1 and 2.9 +/- 3.4. There is no statistically significant difference between the groups at 0, 6 or 12 months of study. The change in retinopathy severity level did not significantly differ between the two groups at either 6 or 12 months. Ponalrestat administration at a dosage of 600 mg daily for 12 months has no significant effect on the course of minimal retinopathy in diabetic patients.

Intraocular non-Hodgkin's lymphoma.

Usually eye symptoms precede the infiltration of non-Hodgkin's lymphoma in the central nervous system or in other organs. Early treatment of the tumor by irradiation, to which it is highly sensitive, can preserve the vision and prolong the life of the patient. Such therapy however is often delayed when the diagnosis cannot be confirmed cytologically. We present two patients with large, yellow, solid subpigmental tumors in fundo. This picture is pathognomonic, even in the absence of uveitis.

Periorbital necrotising fasciitis due to Cryptococcus neoformans in a healthy young man.

A case report is presented of a healthy 25-year-old man who developed a periorbital necrotising fasciitis after a trivial trauma with a wooden splinter. Necrotising fasciitis of the eyelids occurs rarely. Cryptococcus neoformans is not described as a causative factor of necrotizing fasciitis. Cryptococcus neoformans usually infects patients with immunodeficiencies, diabetes mellitus or steroid therapy. This patient was healthy and developed a periorbital necrotising fasciitis due to Cryptococcus neoformans.