Subfoveal Neovascularization Research Articles

Sustained-Release Microspheres of Rivoceranib for the Treatment of Subfoveal Choroidal Neovascularization.

The wet type of age-related macular degeneration (AMD) accompanies the subfoveal choroidal neovascularization (CNV) caused by the abnormal extension or remodeling of blood vessels to the macula and retinal pigment epithelium (RPE). Vascular endothelial growth factor (VEGF) is known to play a crucial role in the pathogenesis of the disease. In this study, we tried to repurpose an investigational anticancer drug, rivoceranib, which is a selective inhibitor of VEGF receptor-2 (VEGFR2), and evaluate the therapeutic potential of the drug for the treatment of wet-type AMD in a laser-induced CNV mouse model using microsphere-based sustained drug release formulations. The PLGA-based rivoceranib microsphere can carry out a sustained delivery of rivoceranib for 50 days. When administered intravitreally, the sustained microsphere formulation of rivoceranib effectively inhibited the formation of subfoveal neovascular lesions in mice.

Characterization of Drusen and Hyperreflective Foci as Biomarkers for Disease Progression in Age-Related Macular Degeneration Using Artificial Intelligence in Optical Coherence Tomography

The morphologic changes and their pathognomonic distribution in progressing age-related macular degeneration (AMD) are not well understood. To characterize the pathognomonic distribution and time course of morphologic patterns in AMD and to quantify changes distinctive for progression to macular neovascularization (MNV) and macular atrophy (MA). This cohort study included optical coherence tomography (OCT) volumes from study participants with early or intermediate AMD in the fellow eye in the HARBOR (A Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular Age-Related Macular Degeneration) trial. Patients underwent imaging monthly for 2 years (July 1, 2009, to August 31, 2012) following a standardized protocol. Data analysis was performed from June 1, 2018, to January 21, 2020. To obtain topographic correspondence between patients and over time, all scans were mapped into a joint reference frame. The time of progression to MNV and MA was established, and drusen volumes and hyperreflective foci (HRF) volumes were automatically segmented in 3 dimensions using validated artificial intelligence algorithms. Topographically resolved population means of these markers were constructed by averaging quantified drusen and HRF maps in the patient subgroups. Of 1097 patients enrolled in HARBOR, 518 (mean [SD] age, 78.1 [8.2] years; 309 [59.7%] female) had early or intermediate AMD in the fellow eye at baseline. During the 24-month follow-up period, 135 (26%) eyes developed MNV, 50 eyes (10%) developed MA, and 333 (64%) eyes did not progress to advanced AMD. Drusen and HRF had distinct topographic patterns. Mean drusen thickness at the fovea was 29.6 μm (95% CI, 20.2-39.0 μm) for eyes progressing to MNV, 17.2 μm (95% CI, 9.8-24.6 μm) for eyes progressing to MA, and 17.1 μm (95% CI, 12.5-21.7 μm) for eyes without disease progression. At 0.5-mm eccentricity, mean drusen thickness was 25.8 μm (95% CI, 19.1-32.5 μm) for eyes progressing to MNV, 21.7 μm (95% CI, 14.6-28.8 μm) for eyes progressing to MA, and 14.4 μm (95% CI, 11.2-17.6 μm) for eyes without disease progression. The mean HRF thickness at the foveal center was 0.072 μm (95% CI, 0-0.152 μm) for eyes progressing to MNV, 0.059 μm (95% CI, 0-0.126 μm) for eyes progressing to MA, and 0.044 μm (95% CI, 0.007-0.081) for eyes without disease progression. At 0.5-mm eccentricity, the largest mean HRF thickness was seen in eyes progressing to MA (0.227 μm; 95% CI, 0.104-0.349 μm) followed by eyes progressing to MNV (0.161 μm; 95% CI, 0.101-0.221 μm) and eyes without disease progression (0.085 μm; 95% CI, 0.058-0.112 μm). In this study, drusen and HRF represented imaging biomarkers of disease progression in AMD, demonstrating distinct topographic patterns over time that differed between eyes progressing to MNV, eyes progressing to MA, or eyes without disease progression. Automated localization and precise quantification of these factors may help to develop reliable methods of predicting future disease progression.

The Value of Prior Response to Anti–Vascular Endothelial Growth Factor for Age-Related Macular Degeneration: A HARBOR Subanalysis

To evaluate disease activity-free intervals of patients with neovascular age-related macular degeneration (nAMD) in the pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) to determine whether duration of response to previous treatment with ranibizumab informs future disease activity and need for subsequent injections. Retrospective subgroup analysis of the phase 3 HARBOR study (clinicaltrials.gov identifier, NCT00891735). Patients from the ranibizumab 0.5 mg pro re nata arm of the phase 3 HARBOR clinical trial who received all 3 loading injections and missed no more than 1 study visit (N= 217). A disease activity-free interval was defined as a consecutive period in months when treatment was not required because the patient did not meet protocol retreatment criteria. Percentage of disease activity-free eyes at the next 1 and 2 months after a first disease activity-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was evaluated. Additionally, duration that eyes remained untreated after disease activity-free intervals was evaluated by Kaplan-Meier estimates. Key outcome measures included duration of the first treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months achieved by each patient; mean number of additional months patients remained treatment free after a treatment-free interval; and percentage of eyes requiring treatment within 2 months after each treatment-free interval. Percentage of eyes requiring retreatment the month after a treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was 60% (90/151), 33% (33/100), 26% (20/77), 36% (24/66), and 19% (9/48), respectively. Percentage of eyes requiring retreatment within 2 months after a treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was 73% (109/149), 53% (53/100), 53% (40/75), 47% (30/64), and 43% (20/46), respectively. After treatment-free intervals of ≥2, ≥3, ≥4, ≥5, and ≥6 months, mean (standard error of the mean) additional time treatment free was 1.3 months (0.17 month), 2.4 months (0.33 month), 2.9 months (0.44 month), 3.2 months (0.50 month), and 4.0 months (0.60 month), respectively. Longer treatment-free intervals may indicate longer future disease-free intervals; however, this association varies. Thus, although longer intervals suggest greater likelihood of not needing retreatment within 1 to 2 months, regular assessment is warranted owing to the unpredictability of nAMD disease activity.

OCT Risk Factors for Development of Late Age-Related Macular Degeneration in the Fellow Eyes of Patients Enrolled in the HARBOR Study

To evaluate the relationship between OCT features and progression to late age related-macular degeneration (AMD) in the fellow eyes of patients enrolled in the Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular AMD (HARBOR) (ClinicalTrials.gov identifier, NCT00891735). Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial. Evaluable patients (n= 501) with macular neovascularization (MNV) secondary to neovascular AMD and early or intermediate AMD in the fellow eye. Volume OCT scans from 501 fellow eyes of 501 patients with MNV were reviewed. Baseline OCT features that were assessed included intraretinal hypereflective foci (IHRF), hyporeflective foci (hRF) within drusenoid lesions (DLs), subretinal drusenoid deposits (SDDs), and drusen volume (DV) of 0.03 mm3 or more. OCT images obtained at months 6, 12, 18, and 24 were graded by masked graders for late AMD (defined as MNV, complete retinal pigment epithelium and photoreceptor atrophy [cRORA], or both). Participant demographic characteristics (age, gender, and smoke exposure) and baseline OCT features were correlated with progression to late AMD. Incidence of late AMD, hazard ratio (HR) for demographics, and OCT risk factors. At month 24, 33.13% of eyes (166/501) demonstrated late AMD: 20.96% (105/501) demonstrated cRORA, whereas 12.18% (61/501) demonstrated MNV. Baseline demographic factors were not associated significantly with development of late AMD, whereas significant associations were identified for all OCT features. Intraretinal hypereflective foci had an HR of 5.21 (95% confidence interval [CI], 3.29-8.26), hRF within DLs had an HR of 2.42 (95% CI, 1.74-3.38), SDD had an HR of 1.95 (95% CI, 1.34-2.82), and DV of 0.03 mm3 or more had an HR of 1.46 (95% CI, 1.03-2.07). The correlation remained significant when considering only the progression to cRORA and MNV alone, except for DV, which was not associated significantly with progression to MNV. We confirmed that 4 previously reported OCT risk factors were associated with progression to late AMD in the fellow eyes of patients newly diagnosed with MNV. Although outcomes of more than 2 years were not evaluated, these findings may help to identify high-risk AMD patients.

Managing Neovascular Age-Related Macular Degeneration: Is More Research Needed to Improve Real-world Practice?

Population-based data from registries of blind people confirm that antiangiogenic therapy has had a substantial role in reducing the burden of vision loss in patients with neovascular age-related macular degeneration (AMD).1 These data are also affirmed by results obtainedfromrandomizedclinical trials (RCTs). However, in contrast to RCTs, patientrelevantoutcomes fromobservational studies indicate that the initial gain in visual acuity (VA) is not maintained after a few years in thesepatient populations.A comprehensive analysis2 of real-world ranibizumab study data confirmed that patientrelevant outcomes are considerably poorer in observational studies than those reported in RCTs using fixed or as-needed (PRN) regimens, meaning that patients with neovascular AMD are often undertreated and undermonitored in many settings. Obviously, thebest strategy tomaximize the treatment effectof intravitreal antiangiogenicdrugs is fixed treatmentwith frequent injections, suchasmonthly ranibizumab. InPRNregimens, frequent (preferably monthly) monitoring is mandatory for themost effective treatmentoutcome. In clinical practice, extended follow-up intervalsmaybea threat to sustained VA, especially in patientswithdisease recurrence after an initially good response. In addition, the extent to which variation of care may hamper timely neovascular AMD diagnosis and their referral to retinal specialists is unknown. Published research3 suggests that social deprivation also acts as a potential barrier in accessinghealth care in patientswith this blinding condition. Therefore, health care policymakers should be aware of this medical issue. An early self-diagnosis test may possibly help patients becomeaware of the early signs of neovascularAMDor its recurrenceafter intravitreal treatment.Assessments of home-monitoring devices have been conducted, some of which provided encouraging results.4 Asystematic review5basedonhead-to-headstudiesofPRN comparedwithmonthly treatment found that PRN regimens, withmonthlymonitoring to guide retreatment, result in similar positive outcomes comparedwithmonthly treatment. The difference in VA was only 1.9 letters, favoring monthly treatment (95% CI, 0.5-3.3 letters), which is statistically significant but not clinically meaningful. This finding is important for physicians because indirect evidence fromRCTs suggests that patients in PRN studies with less strict monitoring, such as theSAILORstudy,or fixedquarterly injections, suchasPIER, did notmaintain average vision improvement after the first 3 monthly injections.2 In this issue of JAMA Ophthalmology, Stoller et al6 retrospectively analyze the data from HARBOR (Study of RanibizumabAdministeredMonthly or on anAs-neededBasis in Patients With Subfoveal Neovascular Age-related Macular Degeneration) anddescribe thecharacteristics ofpatientswho gained at least 15EarlyTreatmentDiabeticRetinopathy Study letters at 3monthsor later in the first year. Thesepatientswere respectively defined as early (within 3 months) or delayed (3 to 12months) responders andwere 25.2% and 13.7%of all patients, respectively. Thus, overall, 37.9%of patients gained 15 ormore letters at 12months.HARBORalso found that only approximately 5%ofpatients lost 15ormore letters at 12months. Therefore, the final VA of approximately 55% of patients was within±15 letters of baselineVAat 12months. They found that smaller lesionswith thicker retina and lowerVAatbaseline are found in early responders, whereas late responders more oftenhavepigment epithelial detachment. These findings in relation to early and late responders might be useful because identifyingpredictorsofdelayedVAgaincouldencouragephysicians to continue intensive treatment in an attempt tomaximizethepatient’sbenefit, rather thanswitchtoadifferentdrug. The limitation of these analyses is that they are restricted to a subgroup of responders and do not exploit the whole inRelated article page 545 Visual and Anatomical Response to Ranibizumab Original Investigation Research

Twenty-four-Month Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal Neovascular Age-Related Macular Degeneration

To evaluate the 24-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or as needed (pro re nata [PRN]) in patients with neovascular age-related macular degeneration (wet AMD). Twenty-four-month, multicenter, randomized, double-masked, active treatment-controlled phase 3 trial. Patients (n = 1098) ≥ 50 years of age with treatment-naïve subfoveal wet AMD. Patients were randomized to receive intravitreal injections of ranibizumab 0.5 mg or 2.0 mg monthly or PRN after 3 monthly loading doses. The primary efficacy end point was the mean change in best-corrected visual acuity (BCVA) from baseline at month 12. Key secondary end points included mean change in BCVA from baseline at month 24, proportion of patients who gained ≥ 15 letters in BCVA, mean number of ranibizumab injections, and mean change in central foveal thickness from baseline over time by spectral-domain optical coherence tomography. Ocular and systemic safety events also were evaluated through month 24. At month 24, the mean change from baseline in BCVA was (letters) +9.1 (0.5 mg monthly), +7.9 (0.5 mg PRN), +8.0 (2.0 mg monthly), and +7.6 (2.0 mg PRN). The change in mean BCVA from month 12 to 24 was (letters) -1.0, -0.3, -1.2, and -1.0, respectively. The proportion of patients who gained ≥ 15 letters from baseline in BCVA at month 24 was 34.5%, 33.1%, 37.6%, and 34.8%, respectively. The mean number of ranibizumab injections through month 24 was 21.4, 13.3, 21.6, and 11.2, respectively; 5.6 and 4.3 mean injections were required in year 2 in the 0.5 mg and 2.0 mg PRN groups, respectively. The average treatment interval in the 0.5 mg PRN group was 9.9 weeks after 3 monthly loading doses, and 93% of these patients did not require monthly dosing. Ocular and systemic safety profiles over 2 years were similar among all 4 treatment groups and were consistent with previous ranibizumab trials in AMD. At month 24, mean BCVA improvements were clinically meaningful and similar among all 4 ranibizumab treatment groups. The 0.5 mg PRN group achieved a mean gain of 7.9 letters at month 24 with an average of 13.3 injections (5.6 injections in year 2). No new safety events were identified over 24 months.

Best vitelliform macular dystrophy in a Swedish family: genetic analysis and a seven‐year follow‐up of photodynamic treatment of a young boy with choroidal neovascularization

To determine the mutation in a Swedish family with Best disease (vitelliform macular dystrophy; VMD) and to investigate the short- and long-term effects of photodynamic treatment (PDT) on subretinal neovascularization in a young boy. The five members of three generations of a family with VMD underwent a thorough ophthalmological examination, including best-corrected visual acuity (VA), visual field, colour vision, biomicroscopy of the posterior segment (dilated), fundus photography and electro-oculography (EOG). For the proband, an eleven-year-old boy, his father and grandfather, dark adaptation test, angiography and electroretinography (ERG) were also performed. After PCR amplification, the genotype was determined by cleavage with restriction enzyme, specific for the W93C allele. Four family members had an abnormal EOG response. All showed the W93C mutation in the VMD2 gene. Visual acuity ranged from 20/20 to 20/250. The fundus manifestations varied from minor pigmentary changes over egg yolk-like lesions to chorioretinal atrophy, and fluorescein angiography showed corresponding pathology. In the proband, VA decreased during follow-up from 0.5 (20/40) to 0.08 (20/250) due to a subfoveal neovascularization with haemorrhage, and PDT with visudyne was begun. The haemorrhage resolved within 2 months, and after three treatments, VA had increased to 0.25 (20/80). One year later, acuity had improved to 0.5 (20/40), and this result was stable throughout the 7 years of the follow-up. The mutation was determined to be W93C, the most common mutation in VMD in Sweden. In an eleven-year-old boy with subretinal neovascularization, PDT seemed to be beneficial also in a long-term follow-up.

Twelve-Month Efficacy and Safety of 0.5 mg or 2.0 mg Ranibizumab in Patients with Subfoveal Neovascular Age-related Macular Degeneration

To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. Patients aged ≥ 50 years with subfoveal wet AMD. Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥ 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥ 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 μm, -161.2 μm, -163.3 μm, and -172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. Proprietary or commercial disclosure may be found after the references.

Stereotactic radiosurgery with charged-particle beams: technique and clinical experience

Stereotactic radiosurgery using charged-particle beams has been the subject of biomedical research and clinical development for almost 60 years. Energetic beams of charged particles of proton mass or greater (e.g., nuclei of hydrogen, helium or carbon atoms) manifest unique physical and radiobiological properties that offer advantages for neurosurgical application and for neuroscience research. These beams can be readily collimated to any desired cross-sectional size and shape. At higher kinetic energies, the beams can penetrate entirely through the patient in a similar fashion to high-energy photon beams but without exponential fall-off of dose. At lower kinetic energies, the beams exhibit increased dose-deposition (Bragg ionization peak) at a finite depth in tissue that is determined by the beam’s energy as it enters the patient. These properties enable highly precise, 3-dimensional placement of radiation doses to conform to uniquely shaped target volumes anywhere within the brain. Given the radiosurgical requirements for diagnostic image acquisition and fusion, precise target delineation and treatment planning, and millimeter- or even submillimeter-accurate dose delivery, reliable stereotactic fixation and immobilization techniques have been mandatory for intracranial charged particle radiosurgery. Non-invasive approaches initially used thermoplastic masks with coordinate registration made by reference to bony landmarks, a technique later supplemented by using vacuum-assisted dental fixation and implanted titanium fiducial markers for image guidance. More-invasive stereotaxis has utilized surgically fixed reference frames, including those that can be removed and reconnected days later to sockets that have been implanted in the outer table of the patient’s skull. Since 1954 more than 15,000 neurosurgical patients and 12,000 ocular patients worldwide have been treated with stereotactic charged-particle radiosurgery for various localized and systemic malignant and nonmalignant disorders. Therapeutic efficacy has been demonstrated clearly for the treatment of selected intracranial disorders and for uveal melanomas. Its role in the treatment of subfoveal neovascularization and as boost therapy for primary brain tumors are the subjects of ongoing investigation. Charged-particle radiosurgery is particularly advantageous for the conformal treatment of large and/or irregularly shaped target volumes, and for the treatment of lesions located adjacent to sensitive organs at risk, as well as for children due to their increased sensitivity to intellectual deficits and secondary malignancies from ionizing radiation.

THREE-YEAR SAFETY AND VISUAL ACUITY RESULTS OF EPIMACULAR 90STRONTIUM/90YTTRIUM BRACHYTHERAPY WITH BEVACIZUMAB FOR THE TREATMENT OF SUBFOVEAL CHOROIDAL NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION

To evaluate the long-term safety and visual acuity outcomes associated with epimacular strontium 90 brachytherapy combined with intravitreal bevacizumab for the treatment of subfoveal choroidal neovascularization because of age-related macular degeneration. Thirty-four treatment-naive patients with predominantly classic, minimally classic, and occult subfoveal choroidal neovascularization lesions participated in this prospective, 2-year, nonrandomized multicenter study. Subjects from 1 center (n = 19) were reconsented and followed-up for 3 years. Each subject received a single 24-Gy beta irradiation treatment via an intraocular delivery device and 2 planned injections of bevacizumab at treatment and 1 month later. Additional bevacizumab therapy was permitted based on prespecified retreatment criteria. Adverse events were observed, and best-corrected visual acuity was measured using Early Treatment Diabetic Retinopathy Study vision charts. Subjects were evaluated every 3 months during the first year of follow-up and every 6 months during Years 2 and 3 of follow-up. All 34 subjects were followed-up for 24 months and 19 were followed-up through 36 months. With up to 24 months of follow-up, 12 of 24 phakic patients (50%) exhibited ≥ 2 grades of progression in Lens Opacification Classification System (LOCS) II lens classification; 5 eyes underwent cataract extraction before the Month 36 visit. There was 1 case of nonproliferative retinopathy identified at 36 months of follow-up that did not have an adverse effect on visual acuity, was stable at 43 months of follow-up, and was isolated to the parafoveal region. Mean best-corrected visual acuity demonstrated an average gain of +15.0 and -4.9 letters at 12 months and 24 months, respectively; the drop in mean gain at Month 24 was largely attributable to cataract formation. At 36 months (n = 19), the mean best-corrected visual acuity was +3.9, 90% (17 of 19) of eyes had lost <15 letters from baseline, 53% (10 of 19) had gained ≥ 1 letter, and 21% (4 of 19) had gained ≥ 15 letters. Through 36 months, 11 eyes required additional bevacizumab retreatment therapy and received a mean of 3.0 injections (range, 2-7 injections). Epimacular brachytherapy shows promise as a therapeutic option for subfoveal neovascular age-related macular degeneration. The procedure was safe and well tolerated, with a reasonable risk-benefit profile that warrants further study in larger subject populations. The most common adverse event was cataract progression/formation. Surgical complications are similar to those expected from standard vitrectomy trials. This novel device is currently being evaluated in two prospective, randomized, controlled trials in treatment-naive subjects (CABERNET) and in subjects already treated with anti-vascular endothelial growth factor therapy (MERLOT).

Photothérapie dynamique sous huile de silicone pour traiter des néovaisseaux choroïdiens du myope fort

We report a case of a high myopic patient, treated with photodynamic therapy for macular neovascularization in the presence of silicon oil. Four months later, the patient's vision was again at 4/40, with no active neovascularization. Retinal detachment and macular neovascularization are common complications in high myopia patients. Sometimes these two conditions occur simultaneously and their treatment can become more problematic. We report the case of a high myopia patient treated with photodynamic therapy for subfoveal neovascularization through a vitreous cavity filled with silicone oil. The treatment was successfully completed with no problems. Photodynamic therapy can be achieved successfully through a vitreous cavity filled with silicone oil.

Increased Visual Acuity Will Not Necessarily Equal an Increased Reading Ability in Patients with Subfoveal Neovascular Macular Degeneration

Reading ability in the elderly means independence, and quality of life. In age-related macular degeneration (AMD), the main deficit is the loss of reading ability. The neovascular form is the leading cause of vision loss in the developed world among people over 50 years of age. With ranibizumab (Lucentis) a drug treatment has become available, but, despite good outcome of visual acuity, patients often report that their reading ability has been affected. We aimed therefor to study reading performance with Tobii Eye Tracker in patients, treated with intravitrial Lucentis. Twenty patients, 15 female and 5 male (range 74 - 98 year), were recruited from St. Erik Eye Hospital. All had, before and after treatment, their reading speed, comprehension, fixations, saccadic eye movements measured while reading two texts with an equal readability rating. For all eye movement parameters, except the number of regressions per word, there was no statistically significant difference when comparing the results from before and after treatment. However, a statistically significant increase in the number of regressions per word after treatment as well as increased visual acuity and comprehension, were found. Reading is fundamental in our society and should be tested in order to fully understand a patient’s complaints; however, an increased VA will not necessarily equal an increased reading ability. The results also show that the Tobii system is suitable for evaluation of reading performance in a clinical setting, and can together with other tests, give valuable information about the patients complains and the outcome of a treatment.

INTRAVITREAL BEVACIZUMAB FOR EXUDATIVE AGE-RELATED MACULAR DEGENERATION

The purpose of this study was to assess an association between specific types of subfoveal neovascularization and the change in visual acuity after intravitreal injections of bevacizumab (F. Hoffmann-La Roche AG, Basel, Switzerland) as treatment for exudative age-related macular degeneration. This retrospective clinical interventional comparative study included 307 patients (378 eyes) who received 3 consecutive intravitreal injections of bevacizumab at intervals of 2 months each. The study group was divided into eyes with a predominantly or purely classic type of subfoveal neovascular membrane (n = 81), those with an occult type with or without minimally classic subfoveal neovascularization (n = 232), and eyes with a detachment of the retinal pigment epithelium (n = 65). The gain in best-corrected visual acuity did not vary significantly among the 3 subgroups at 2 months after baseline (P = 0.35 and P = 0.27), at 4 months after baseline (P = 0.63 and P = 0.56), or at the final follow-up at 7 months after baseline (P = 0.85 and P = 0.76). In multivariate linear regression analysis, the gain in best-corrected visual acuity at the final follow-up was significantly associated with the best-corrected visual acuity at baseline (P < 0.001). It was not significantly associated with age (P = 0.61), sex (P = 0.12), self-reported diabetes (P = 0.79), lens status (P = 0.84), or type of subfoveal neovascularization (P = 0.53). After an intravitreal application of bevacizumab given as therapy for exudative age-related macular degeneration at 2-month intervals, the patient's gain in visual acuity did not depend on the type of the subfoveal neovascular membranes.

Anetoderma. A possible new risk factor for subretinal neovascularization

Editor, Anetoderma is a rare disease of the elastic connective tissue which is characterized clinically by multiple 5–25 mm-diameter round atrophic papules that bulge outwards from the skin of the trunk, the upper part of extremities and neck. At palpation, the lesions are flaccid and herniate inwards. Histopathologically, there is fragmentation of elastic fibres and loss of elastic tissue in the dermis. The aetiology of anetoderma is unknown, but the disease has been related to antiphospholipid syndrome, systemic lupus erythematosus (Venencie et al. 1984) and infections such as borreliosis (Bauer et al. 2003). In rare cases, the disease has been shown to be inherited or idiopathic. In the eye, anetoderma has been shown to be related to keratoconus, blue sclerae, pseudotumor orbitae and cataract (Brenner et al. 1977, Nuñez et al. 1995), whereas no studies have reported a relation between anetoderma and diseases in the posterior segment of the eye. A 27-year-old otherwise healthy woman with previous normal vision was referred with a 2 weeks history of metamorphopsia and blurred vision on the left eye. There was no history of trauma, choroiditis, or other known risk factors for the development of subretinal neovascularization, but anetoderma (Schweninger–Buzzy type) confirmed by skin biopsy had been diagnosed at the age of 12 years. Laboratory examinations for antinuclear antibodies (ANA), cardiolipin antibody and serological tests for Borrelia, syphilis and HIV were negative. The patient was subjected to a routine clinical examination including measurement of visual acuity, slit lamp examination, optical coherence tomography scanning and fluorescein angiography. The clinical examination showed VAD = 1.2 and VAS = 0.1 and both eyes had emmetropia. All other examinations on the right eye were normal. On the left eye, ophthalmoscopy showed central retinal oedema with haemorrhages and exudates. Optical coherence tomography (OCT) scanning of the left eye showed intra-retinal oedema with a central retinal thickness of 452 microns. Fluorescein angiography revealed a classical subfoveal neovascularization (Fig. 1). After three Intra-vitreal injections of ranibizumab on the left eye with 1 month intervals, the central retinal thickness was reduced to 214 microns and visual acuity had increased to 0.8. An early phase angiography of the normal right eye and the left eye with a subfoveal neovascularization. Subretinal neovascularization is a well documented complication to connective tissue diseases such as pseudoxanthoma elasticum and Ehlers Danlos’ syndrome and may be related to discontinuities or breaks in Bruch’s membrane that forms a barrier for growth of choroidal vessels under normal conditions (Georgalas et al. 2009). The present case report suggests anetoderma as a possible new risk factor for the development of subretinal neovascularization. A more detailed elucidation of the changes in elastic tissue in anetoderma and other connective tissue diseases may help understanding the pathophysiology of subretinal neovascularization in general.

Unilateral Idiopathic Macular Telangiectasia with Choroidal Neovascularization.

A 40-year-old man with decreasing visual acuity in his left eye over 1 year, diagnosed elsewhere as vein occlusion and treated unsuccessfully by systemic steroids was reported. Retrospective analysis of available previous imaging studies was undertaken, and a retrospective diagnosis of idiopathic macular telangiectasia (IMT) was made. Examination revealed subfoveal neovascularization and retinochoroidal anastomosis (RCA) in his left eye with macular edema and exudates surrounding it. The right eye was normal. Current fluorescein angiography (FA) confirmed the presence of choroidal neovascularization and RCA, and optical coherence tomography (OCT) demonstrated cystoid macular edema and subfoveal neovascularization.The patient was diagnosed with unilateral idiopathic macular telangiectasia complicated by subretinal neovascularization. The presences of a choroidal neovascularization process and an RCA have not, to our knowledge, been reported in this type of IMT.

Surgery for CNV and autologous choroidal RPE patch transplantation: exposing the submacular space

To evaluate the feasibility of transplanting a full-thickness patch of choroid, choriocapillaries, Bruch's membrane and RPE (RPE-choroid FTAP) from the peripheral to the subfoveal area of the same eye, after performing a 180 degrees peripheral retinotomy and removing subfoveal choroidal neovascularization. Thereafter, to study the surgical complications, anatomical outcome and patch perfusion during follow-up. A retrospective case series of 13 eyes of 13 consecutive patients with a follow-up of 4 to 20 months. All patients suffered from advanced subfoveal choroidal neovascularization and were non-responders to standard care. After performing a complete vitrectomy, a 180 degrees peripheral temporal retinotomy and the removal of subfoveal neovascularization, a FTAP of choroid, choriocapillaris, Bruch's membrane and the RPE were isolated from the mid periphery of the uveal bed, transpositioned under the fovea and covered with the retina. Patients received a complete ophthalmic examination, fluorescein angiography (FA), indocyanin green angiography (ICGA) and optical coherence tomography (OCT) during follow-up. An FTAP could be harvested in every eye and transplanted under the fovea. No intraoperative complications occurred. The FTAP was recognizable at FA, ICGA and OCT at each time point, up to 20 months postoperatively. Perfusion of the choroidal bed were observed into the FTAP during follow-up, from one week after surgery. The creation of an FTAP through a 180 degrees peripheral retinotomy is feasible and safe. The FTAP is vital and perfused. Further studies are needed to collect more data.

Intravitreal bevacizumab as primary local treatment for choroidal neovascularization secondary to uveitis

Abstract Purpose To report short term results of intravitreal (IVT) bevacizumab as primary local treatment for choroidal neovascularization (CNV) secondary to uveitis. Methods Files of uveitic patients receiving one or more 1.25mg/0,05ml IVT bevacizumab treatment for CNV were reviewed for clinical findings,best‐corrected visual acuity (BCVA), fluorescein angiography (FA) and optical coherence tomography (OCT),concurrent treatments, number and frequency of IVT bevacizumab and treatment related adverse events. Patients previosuly treated with any local therapy were excluded. Results 15 patients included. Underlying diagnosis:multifocal choroiditis and panuveitis in 7, ampiginous choroiditis in 2, and for 6 remaining, serpiginous choroiditis, sympathetic ophthalmia, Vogt‐Koyanagi‐Harada syndrome, punctuate inner choroidopathy, tuberculous uveitis and idiopathic inflammation respectively. Subfoveal neovascularization in 13 eyes, peripapillary in 2. No active intraocular inflammation by time injections were given. 86,66% had a significant decrease in central foveal thickness by the end of follow‐up (mean pre‐treatment OCT 239,06µm, mean post‐treatment OCT 195,2µm). BCVA improved in 80% of eyes at last follow‐up (mean pre‐treatment BCVA logMar 0,53; mean post‐treatment BCVA logMar 0,29). 12 eyes received more than one IVT bevacizumab, mean number of injections in this group was 4,25(2‐8), with a frequency of 1 injection every 13,68 weeks. No adverse effect related to bevacizumab nor to the injection procedure. Median follow‐up 15,93(2‐25 months). Conclusion IVT bevacizumab was safe and effective first local treatment for inflammatory CNV, in patients under adequate control of intraocular inflammation.

Combined cataract extraction and intravitreal bevacizumab in eyes with choroidal neovascularization resulting from age-related macular degeneration

To evaluate the safety and efficacy of phacoemulsification, intraocular lens (IOL) implantation, and a single intravitreal injection of bevacizumab in patients with coexisting visually significant cataract and subfoveal neovascularization due to age-related macular degeneration. Department of Ophthalmology, University of Bari, Bari, Italy. Eyes with predominantly classic subfoveal neovascularization and cataract had phacoemulsification, IOL implantation, and a 1.25 mg intravitreal injection of bevacizumab. One month after combined surgery, corrected distance visual acuity (CDVA), anterior chamber reaction, and intraocular pressure were evaluated and central foveal thickness was measured by optical coherence tomography. Twenty eyes of 20 patients were evaluated. One month postoperatively, the mean CDVA improved significantly, from 20/100 (range 20/160 to 20/80) at baseline to 20/63 (range 20/125 to 20/50) (P<.0001). The mean central foveal thickness decreased significantly, from 353.75 microm +/- 12.50 (SD) (range 334 to 375 microm) at baseline to 275.7 +/- 17.3 microm (range 255 to 323 microm) at 1 month (P<.0001). Intraocular pressure did not change significantly, and anterior chamber reaction was absent. No ocular or systemic adverse events were observed. Combined phacoemulsification, IOL implantation, and intravitreal bevacizumab was a safe and efficacious treatment in patients with visually significant cataract and active subfoveal neovascularization.

Natural History of Predominantly Classic, Minimally Classic, and Occult Subgroups in Exudative Age-related Macular Degeneration

We previously showed that the pattern of vision loss in eyes with subfoveal neovascularization in age-related macular degeneration (AMD) is uniform across a wide range of clinical trials, with apparent differences arising from differences in the time of entry of patients into clinical trials. In the current study, we used a similar analysis to compare the visual loss of untreated control eyes classified as predominantly classic (PC), minimally classic (MC), and occult with no classic (occult) based on fluorescein angiography. Meta-analysis of prior clinical trials. Data from patients enrolled in the Macular Photocoagulation Study (MPS), Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study, Verteporfin in Photodynamic Therapy (VIP) Study, Anecortave Acetate (AA) Trial, VEGF Inhibition Study in Ocular Neovascularization (VISION), and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) Trials. Visual acuity (VA) data of untreated control eyes for each study from appropriate subgroups were plotted on a double reciprocal (Lineweaver-Burke) plot of 1/[letters lost] versus 1/[months]. To correct for differences in time of entry into clinical trials, we introduced a horizontal translation factor to shift each data subset. We determined the coefficient of determination before and after adjustments for visual acuity at the time of enrollment. On a Lineweaver-Burke plot, the cumulative subgroups had an overall coefficient of determination of only r(2)<0.01 for the raw data but improved to a remarkably high r(2) = 0.90 when data were corrected for time of entry into clinical trials. For each subgroup there was excellent correlation between 1/[letters lost] versus 1/[months of exudative disease] for PC (r(2) = 0.91), MC (r(2) = 0.95), and occult (r(2) = 0.98) choroidal neovascularization. We were able to demonstrate a strong correlation for visual acuity as a function of time that is independent of the fluorescein angiography classification of a lesion, suggesting that initial protocol visual acuity, rather than angiographic classification, is the major determinant of the behavior of visual acuity as a function of time in exudative AMD.

Submacular surgery for choroidal neovascularisation secondary to age-related macular degeneration

Vitreoretinal surgeons proposed submacular surgery to remove the fibrovascular tissue causing damage to the centre of the retina, in the attempt to limit central visual loss in people affected by neovascular age-related macular degeneration (AMD). This review aims at assessing the effectiveness of submacular surgery for preserving or improving vision in patients with AMD. We searched CENTRAL, MEDLINE, EMBASE and LILACS. There were no language or date restrictions in the search for trials. The electronic databases were last searched on 11 February 2009. We included randomised or quasi-randomised controlled trials comparing submacular surgery with any other treatment or observation. Two authors independently extracted the data. The risk ratio (RR) of visual loss and visual gain was estimated at one year. Two multicentre studies with a similar design were conducted between 1997 and 2003 and compared submacular surgery with observation in people affected by subfoveal neovascular AMD with (n=336) or without (n=454) extensive blood in the macula. At one year there was high quality evidence of no benefit for preventing visual loss (RR: 0.96; 95% confidence interval (CI): 0.84 to 1.09). No difference could be demonstrated regarding the chance of visual gain (RR: 1.06; 95% CI: 0.75 to 1.51), although this evidence was of low quality because of imprecision. The risk difference was -2% (95% CI: -10% to 5%) and 1% (95% CI: -4% to 6%) for visual loss and visual gain, respectively, thus excluding a large benefit with surgery in terms of absolute risk in this sample. There was high quality evidence that cataract needing surgery (RR: 8.69; 95% CI: 4.06 to 18.61) and retinal detachment (RR: 6.13; 95% CI: 2.81 to 13.38) were more common among operated patients, and detachment occurred in 5% of patients with no extensive blood and in 18% of those with extensive blood beneath the macula.A pilot study compared submacular surgery with laser photocoagulation in 70 patients. No difference between the two treatments could be demonstrated for any outcome measure, but estimates were very imprecise because of small sample size. There is no benefit with submacular surgery in most people with subfoveal choroidal neovascularisation due to AMD in terms of prevention of visual loss. Furthermore, the risk of developing cataract and retinal detachment increases after surgery.