Giovanni Staurenghi

Safety and Efficacy of a Flexible Dosing Regimen of Ranibizumab in Neovascular Age-Related Macular Degeneration: The SUSTAIN Study

OBJECTIVE To evaluate the safety and efficacy of individualized ranibizumab treatment in patients with neovascular age-related macular degeneration. DESIGN Twelve-month, phase III, multicenter, open-label, single-arm study. PARTICIPANTS A total of 513 ranibizumab-naïve SUSTAIN patients. INTERVENTION Three initial monthly injections of ranibizumab (0.3 mg) and thereafter pro re nata (PRN) retreatment for 9 months based on prespecified retreatment criteria. Patients switched to 0.5 mg ranibizumab after approval in Europe. MAIN OUTCOME MEASURES Frequency of adverse events (AEs), monthly change of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline, the time to first re-treatment, and the number of treatments were assessed. RESULTS A total of 249 patients (48.5%) reported ocular AEs, and 8 (1.5%) deaths, 5 (1.2%) patients with ocular serious AEs of the study eye (retinal hemorrhage, cataract, retinal pigment epithelial tear, reduced visual acuity [VA], vitreous hemorrhage), and 19 (3.7%) patients with arteriothromboembolic events were observed. Most frequent AEs in the study eye were reduced VA (18.5%), retinal hemorrhage (7.2%), increased intraocular pressure (7.0%), and conjunctival hemorrhage (5.5%). The average number of re-treatments from months 3 to 11 was 2.7. Mean best-corrected visual acuity increased steadily from baseline to month 3 to reach +5.8 letters, decreased slightly from month 3 to 6, and remained stable from month 6 to 12, reaching +3.6 at month 12. Mean change in CRT was -101.1 μm from baseline to month 3 and -91.5 μm from baseline to month 12. CONCLUSIONS The safety results are comparable to the favorable tolerability profile of ranibizumab observed in previous pivotal clinical studies; individualized treatment with less than monthly re-treatments shows a similar safety profile as observed in previous randomized clinical trials with monthly ranibizumab treatment. Efficacy outcomes were achieved with a low average number of re-treatments. Visual acuity in SUSTAIN patients with individualized re-treatment based on VA/optical coherence tomography assessment reached on average a maximum after the first 3 monthly injections, decreased slightly under PRN during the next 2 to 3 months, and was then sustained throughout the treatment period.

Deep Retinal Vascular Anomalous Complexes in Advanced Age-related Macular Degeneration

PURPOSE The authors describe the clinical characteristics of a group of patients with age-related macular degeneration (AMD), deep retinal vascular anomalous complexes (RVACs), advanced Bruch membrane changes, and severe visual loss. Based on clinical evaluation and imaging studies, the authors hypothesize the cause of such retinal vascular formations. PATIENTS AND METHODS The authors quantified an initial case series of 6 patients and expanded it to 11 patients (14 eyes) with AMD and RVACs diagnosed by fluorescein angiography or slit-lamp examination. Associated pigment epithelial detachments (PEDs) of 13 eyes are described. In addition to the clinical and fluorescein angiography descriptions, infrared imaging and indocyanine green angiography were used to characterize more recently described RVACs and fellow eyes. RESULTS Each study eye had a clearly defined anastomosis connecting the retinal circulation to a vascular complex in the deep retina. The RVACs associated with PEDs assumed a more central location than did typical choroidal neovascularization associated with PEDs. In seven eyes with RVACs, there were clinically recognizable retinovascular findings: intraretinal hemorrhages, telangiectasia, or microaneurysms. Legal blindness occurred in 9 of 11 patients. CONCLUSION These results indicate that retinovascular changes can be associated with nondisciform AMD. The authors speculate that neurodegenerative changes and hypoxia may lead to such changes, the RVAC being a more advanced finding. Closure of an RVAC with photocoagulation is difficult, perhaps because of its higher blood flow. The visual outcome is poor, not only because of the advanced state of the underlying AMD, but also because of the exudative nature of the RVAC.

Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration

Background/aims Real-life anti-vascular endothelial growth factor (VEGF) therapy use in patients with wet age-related macular degeneration (wAMD) was assessed in a retrospective, observational study in Canada, France, Germany, Ireland, Italy, the Netherlands, UK and Venezuela. Methods Medical records of patients with wAMD, who started ranibizumab treatment between 1 January 2009 and 31 August 2009, were evaluated. Data were collected until the end of treatment and/or monitoring or until 31 August 2011. Results 2227 patients who received ≥1 anti-VEGF injection with a baseline visual acuity assessment and ≥1 postbaseline visual acuity assessment for the treated eye were evaluated. Visual acuity improved until about day 120; thereafter, visual acuity gains were not maintained. Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively. Patients received a mean of 5.0 and 2.2 injections in the first and second year, respectively. There were substantial differences in visual outcomes and injection frequency between countries. More frequent visits and injections were associated with greater improvements in visual acuity. Conclusions In clinical practice, fewer injections are administered than in clinical trials. Anti-VEGF treatment resulted in an initial improvement in visual acuity; however, this was not maintained over time. Trial registration number NCT01447043.

Confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia

PURPOSE To report the characteristics of confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia (type 2 IMT). METHODS In a prospective observational cross-sectional study, both eyes of 33 patients with type 2 IMT were examined by means of fundus biomicroscopy, fundus photography, fluorescein angiography, and optical coherence tomography (OCT). Confocal blue reflectance (CBR) imaging was performed using a confocal scanning laser ophthalmoscope (HRA2; Heidelberg Engineering, Heidelberg, Germany). To compare the results derived from different imaging modalities, an analysis was performed using image analysis software (Heidelberg Eye Explorer; Heidelberg Engineering). RESULTS CBR imaging revealed a parafoveal area of increased reflectance that was slightly larger than the area of hyperfluorescence in late-phase fluorescein angiography. The area usually encompassed an oval parafoveal area, but sectors could be spared. A parafoveal area of increased CBR was detected in 98% of eyes that showed angiographic evidence for type 2 IMT. CONCLUSIONS CBR imaging is a new, noninvasive, and sensitive method that may contribute to differentiate type 2 IMT from other diseases. Abnormalities of macular pigment distribution and Müller cell pathology may contribute to the phenomenon of increased CBR and thus the pathophysiology of type 2 IMT.

Bimodal spatial distribution of macular pigment: evidence of a gender relationship

The spatial distribution of the optical density of the human macular pigment measured by two-wavelength autofluorescence imaging exhibits in over half of the subjects an annulus of higher density superimposed on a central exponential-like distribution. This annulus is located at about 0.7 degrees from the fovea. Women have broader distributions than men, and they are more likely to exhibit this bimodal distribution. Maxwells spot reported by subjects matches the measured distribution of their pigment. Evidence that the shape of the foveal depression may be gender related leads us to hypothesize that differences in macular pigment distribution are related to anatomical differences in the shape of the foveal depression.

Evaluation of Retinal Nerve Fiber Layer and Ganglion Cell Layer Thickness in Alzheimer's Disease Using Spectral-Domain Optical Coherence Tomography

PURPOSE To evaluate differences between the retinal nerve fiber layer (RNFL) thickness and RNFL + ganglion cell layer (GCL) thickness in patients affected by Alzheimers disease (AD) and healthy patients using spectral-domain optical coherence tomography (SD-OCT). METHODS This was a case-control prospective study. Twenty-one AD patients and 21 healthy subjects underwent neurological examination, clock-drawing test (CDT), Mini Mental State Examination (MMSE), and comprehensive ophthalmic evaluation with visual acuity. SD-OCT examination was performed using Spectralis and RTVue-100. An RNFL thickness map was obtained using the Spectralis volume protocol with 19 lines on the 30° field centered on the macula. On each B-scan, the outer RNFL limit was manually set. Statistical analysis was performed to assess interoperator RNFL evaluation thickness. An RNFL+GCL thickness map was obtained using the RTVue-100 MM6 protocol. Maps were divided into the nine ETDRS subfields and each map value in every area was evaluated. A single eye from each patient was randomly chosen to perform the analysis. Differences between AD and healthy subjects were assessed. RESULTS The two study groups were age and sex matched. MMSE results were 19.9 ± 3.1 and 27.9 ± 1.3, respectively (P < 0.001). There was good agreement in the manual delimitation of the RNFL layer. There was a significant difference in the thickness of both the RNFL and the RNFL+GCL in all examined fields. For example, in the inferior internal subfield, the RNFL thickness was 28.1 ± 3.1 μm for AD patients and 32.6 ± 3.8 μm for healthy subjects (P < 0.001). CONCLUSIONS These results indicate that RNFL and RNFL+GCL thickness measurements are reduced in AD patients compared with healthy subjects. This finding may represent a useful element for the diagnosis and follow-up of this pathology.

Evolving European guidance on the medical management of neovascular age related macular degeneration

Background: Until recently, only two options were available for the treatment of choroidal neovascularisation (CNV) associated with age related macular degeneration (AMD)—thermal laser photocoagulation and photodynamic therapy with verteporfin (PDT-V). However, new treatments for CNV are in development, and data from phase III clinical trials of some of these pharmacological interventions are now available. In light of these new data, expert guidance is required to enable retina specialists with expertise in the management of AMD to select and use the most appropriate therapies for the treatment of neovascular AMD. Methods: Consensus from a round table of European retina specialists was obtained based on best available scientific data. Data rated at evidence levels 1 and 2 were evaluated for laser photocoagulation, PDT-V, pegaptanib sodium, and ranibizumab. Other treatments discussed are anecortave acetate, triamcinolone acetonide, bevacizumab, rostaporfin (SnET2), squalamine, and transpupillary thermotherapy. Results: PDT-V is currently recommended for subfoveal lesions with predominantly classic CNV, or with occult with no classic CNV with evidence of recent disease progression and a lesion size ⩽4 Macular Photocoagulation Study (MPS) disc areas (DA). The new classes of anti-angiogenic agents—namely, pegaptanib sodium and ranibizumab (the latter when peer reviewed phase III data become available) are recommended for subfoveal lesions with any proportion of classic CNV or occult with no classic CNV. For juxtafoveal classic CNV, PDT-V or anti-angiogenic therapy should be considered if the new vessels are so close to the fovea that laser photocoagulation would almost certainly extend under the centre of the foveal avascular zone. For all other well demarcated juxtafoveal lesions and for extrafoveal classic lesions, laser photocoagulation remains the standard treatment. Therapy should be undertaken within 1 week of the fluorescein angiogram on which the clinical decision to treat is based. At each follow up, fluorescein angiography should be performed and best corrected visual acuity measured as a minimum requirement. Conclusions: These recommendations provide evidence based guidance for the choice and use of non-surgical therapies for the management of neovascular AMD. Revisions of the recommendations may be required as new data become available.

Laser treatment of feeder vessels in subfoveal choroidal neovascular membranes: a revisitation using dynamic indocyanine green angiography.

OBJECTIVE This study aimed to determine whether the indocyanine green angiography (ICGA)-guided laser treatment of feeder vessels (FVs) may be useful in the management of the subfoveal choroidal neovascular membranes (CNVM) in patients with age-related macular degeneration (ARMD). DESIGN Noncomparative case series. PARTICIPANTS The authors considered a series of 15 patients with subfoveal CNVM in whom feeder vessels could be clearly detected by means of dynamic ICGA but not necessarily with fluorescein angiography (FA). On the basis of the indications of the pilot study, the authors also studied a second series of 16 patients with FVs smaller than 85 microm. INTERVENTION Treatment of FV using argon green laser was performed. The ICGA was performed immediately after treatment, after 2, 7, 30 days, and then every 3 months, to assess FV closure. If an FV appeared to be still patent, it was immediately retreated and the follow-up was started again. The follow-up time ranged from 23 to 34 months for the pilot study and from 4 to 12 months for the second series. MAIN OUTCOME MEASURES The obliteration of the membrane and change in visual acuity from baseline were measured. The effect on the treatment of the number and width of the FVs, and the size and location of the membrane, also was evaluated. RESULTS In the pilot study, the CNVM was obliterated after the first treatment in only one patient, five patients needed more than one treatment, and obliteration failed in nine patients (40% success rate). The rate of success was affected by the width and number of the FVs. The success rate in the second series of 16 patients was higher (75%). CONCLUSIONS The success of the laser treatment of FVs depends on their width, length, and number. Dynamic ICGA, which detects smaller FVs and makes it possible to control the laser effect and initiate immediate retreatment in the case of incomplete FV closure, should be considered mandatory for this type of treatment; a comparable success rate would have been unlikely using the other currently available methods of treating subfoveal CNVMs.

Management of Retinal Vein Occlusion – Consensus Document

Retinal vein occlusion (RVO) can have severe consequences for the people affected by the disease, including visual loss with costly social repercussions. Currently, there is no European consensus with regard to the management of RVO. Following a careful review of the medical literature as well as the data from several clinical trials, a collaborative group of retina specialists put forth practical recommendations based on the best available scientific evidence for the clinical approach to RVO. Taking into consideration the recent advances in diagnostic tools and management options, the present document aims to provide the European ophthalmologists with guidelines for clinical practice to the benefit of their patients.

Retinal angiomatous proliferation: natural history and progression of visual loss.

Purpose: To investigate the natural history and visual outcome in eyes with untreated retinal angiomatous proliferation, a neovascular form of age-related macular degeneration. Methods: Fourteen consecutive white patients (11 women, 78%; mean age, 74 years) with 16 eyes affected by retinal angiomatous proliferation were prospectively followed-up without treatment by means of complete ophthalmologic examinations at regular intervals, including best-corrected visual acuity and dynamic fluorescein and indocyanine green angiography using a scanning laser ophthalmoscope. Results: The patients were observed for a mean of 20 months (range, 6–44 months). Mean visual acuity in the eyes with retinal angiomatous proliferation was 0.48 at the initial examination, decreased to 0.23 after 6 months, and was 0.19 at the final examination, with a mean decrease of 6 lines from baseline. In 13 eyes (81%), visual acuity deteriorated by 2 Early Treatment Diabetic Retinopathy Study lines or worse by the time of the 6-month examination, and 31% of the patients had experienced severe loss of vision; the remaining 3 eyes (19%) showed a relatively stable clinical course and visual acuity. By the time of the final examination, visual acuity had decreased to 0.1 or worse in 11 eyes (69%), and 5 of the 14 patients (36%) were legally blind. At the final examination, 10 eyes (62%) showed a subretinal fibrosis and 9 (56%) showed a retinal choroidal anastomosis. Conclusion: Retinal angiomatous proliferation is a distinct form of neovascular age-related macular degeneration with high vasogenic potential, having its own clinical course and visual prognosis. The poor visual outcome is because of the exudative nature of the retinal angiomatous proliferation, and progression to poor vision is common and rapid (within 3 months in faster cases, and within 1 year in slower cases). The treatment options for this type of neovascular lesion should be planned bearing in mind its unfavorable natural history.