José Cunha-Vaz

The active transport of fluorescein by the retinal vessels and the retina

1. The movement of fluorescein across the retinal surface of the rabbits eye was estimated by measuring the concentration gradient of the dye in the vitreous body. These measurements were made in vivo by means of a slit‐lamp fluorophotometer, or were taken from frozen sections of enucleated eyes.

Studies on the permeability of the blood-retinal barrier: IV. Junctional complexes of the retinal vessels and their role in the permeability of the blood-retinal barrier

The interendothelial junctions of retinal and iris vessels have been surveyed and compared in a number of animals. Thorium dioxide particles were also injected into the circulation to investigate their passage through these junctions when the eye was submitted to paracentesis or local application of histamine. The junctions between the endothelial cells of the retinal vessels constantly showed a continuous zonula occludens as the predominant feature of their junctional complexes, reinforced occasionally by a desmosomal component. In these junctions the injected particles were always arrested at the side facing the lumen, and the outer leaflets of the plasma membranes of the endothelial cells remained fused together in an intermediate line even when the eye was submitted to paracentesis, local application of histamine, or when the endothelial cells were made highly swollen or shrunken. By contrast, the interendothelial junctions of the iris vessels which showed a discontinuous zonula occludens were seen to open after local application of histamine and when the intraocular pressure was drastically lowered by paracentesis. The significance of these findings is discussed and it is considered that the junctional complexes of the retinal vessels play an important role in the mechanism of the blood-retinal barrier.

Polypoidal choroidal vasculopathy and photodynamic therapy with verteporfin

BackgroundWe evaluated, in a nonrandomised, institutional, prospective study, the efficacy of photodynamic therapy (PDT) with verteporfin in age-related macular degeneration (AMD) eyes with polypoidal choroidal vasculopathy (PCV) and subfoveal exudation.MethodsA prospective clinical and angiographic study was done in 40 consecutive eyes with PCV treated with PDT using masked best-corrected visual acuity (VA) and fluorescein and indocyanine green angiographic features at baseline and over 2 years.ResultsTwenty-one eyes completed 1-year follow-up and showed, after a mean 2.9 PDT sessions, VA improvement in 12 eyes, no change in five eyes, and VA decrease in four eyes. Leakage was absent at the retinal and choroidal level in 14 eyes at 1 year. Recurrence occurred in one eye during the first year. Six eyes completed 2 years of follow-up and showed, after a mean 4 PDT sessions, VA improvement in five eyes and VA decrease in one eye. Leakage was absent at the retinal and choroidal level in five eyes. Recurrence occurred in four of these six eyes during the second year of follow-up. No serious adverse events were observed during the 2 years of follow-up.ConclusionsPDT with verteporfin was shown to be safe and effective for treating AMD eyes with PCV with subfoveal involvement. VA improvement and absence of leakage were achieved, respectively, in 57.1% and 66.6% of the eyes at 1 year. Recurrences were more frequent during the second year of follow-up.

The blood-ocular barriers: past, present, and future

The blood-ocular barriers system is formed by two main barriers: the blood-aqueous barrier and the blood-retinal barrier. They combine to maintain the eye as a privileged site and are essential for normal visual function. After reviewing where the blood-aqueous barrier and blood-retinal barrier are located and the main transport mechanisms involved in the regulation of the microenvironment of ocular tissues, special attention is given to the clinical significance of breakdown of the blood-retinal barrier. New perspectives on the clinical significance of breakdown of the blood-retinal barrier are offered by the demonstration of a specific alteration of the glucose transport in diabetes, by the development of new diagnostic instrumentation, and by the utilization of the blood-retinal barrier for new strategies for drug delivery to the retina. New diagnostic instrumentation includes the topographic imaging vitreous fluorometer, which simultaneously measures the localized blood-retinal barrier and images the retinal region, and the retinal thickness analyzer for mapping retinal edema. Drug delivery to the retina may be improved by modification of blood-retinal barrier permeability, chemical modification of the drug for better blood-retinal barrier penetration, and liposome encapsulation or coupling of the drug to specific vectors.

Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema

Aim: The study was a prospective randomised controlled double-masked trial performed in two centres to compare sub-threshold micropulse diode laser photocoagulation (MPDL) with conventional green laser photocoagulation (CGL) in the treatment of clinically significant diabetic macular oedema (CSMO). Methods: Fifty-three patients (84 eyes) with diabetic CSMO were randomly assigned to MPDL (n = 44) or CGL (n = 40) according to the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Treatments were performed after baseline and re-treatments were allowed at or after the 4 month visit if necessary. Parameters noted included the best corrected visual acuity (BCVA), colour fundus photographs, central retinal thickness using optical coherence tomography (OCT), vision contrast sensitivity with Pelli–Robson charts and presence of visible laser scars at baseline and at 4 and 12 months. The primary outcome was BCVA at 12 months. Results: All patients completed 12 months of follow-up after treatment at baseline. There were no statistically significant differences in BCVA, contrast sensitivity and retinal thickness between the two laser modalities at 0, 4 and 12 months. We found that laser scarring was much more apparent with CGL than with the sub-threshold approach (MPDL). Laser scars were identified at the 12 month visits in 13.9% of the MPDL-treated eyes compared with 59.0% of the CGL-treated eyes (p<0.001). Conclusion: Sub-threshold micropulse diode laser photocoagulation is equally as effective as CGL treatment for CSMO. Trial registration number: ISTRN 90646644.

Comparison of topical travoprost eye drops given once daily and timolol 0.5% given twice daily in patients with open-angle glaucoma or ocular hypertension.

PurposeThis 9-month study compared the intraocular pressure (IOP)-lowering efficacy and safety of once-daily travoprost ophthalmic solutions (0.0015% and 0.004%) with twice-daily timolol 0.5%. Patients and MethodsThis study was conducted using a double-masked, randomized, parallel-group design; adult patients with open-angle glaucoma or ocular hypertension (IOP between 24 and 36 mm Hg, inclusive at 9 am and between 21 and 36 mm Hg, inclusive, at 11 am and 4 pm on two eligibility visits after an appropriate washout of previous treatments). In both eyes, the travoprost vehicle (placebo) was instilled at 9 am and travoprost (0.0015% or 0.004%) was instilled at 9 pm, or timolol 0.5% was instilled at both times. The primary efficacy variable was mean IOP measured at 9 am, 11 am, and 4 pm at baseline and follow-up visits. ResultsFive hundred seventy-three patients were randomized to the study treatments. Mean IOP, which was combined across study visits, was lower with travoprost 0.004% than with timolol 0.5% at 9 am (P = 0.0246), 11 am (P = 0.0039), and 4 pm (P = 0.0004). Intraocular pressure was lower with travoprost 0.004% than with travoprost 0.0015% at 11 am (P = 0.0314), the time of peak drug activity. Mean IOP was consistently lower with travoprost 0.0015% than with timolol 0.5%. Mean IOP reductions from baseline were significantly (P ≦ 0.0001) greater with travoprost 0.004% (8.0–8.9 mm Hg) than with timolol 0.5% (6.3–7.9 mm Hg). The most frequent related adverse events were hyperemia, pruritus, discomfort, pain, and iris pigmentation changes. The local tolerance was better in the timolol group compared with patients receiving travoprost. There were no serious unexpected treatment-related adverse events in any group. ConclusionsTravoprost 0.004% reduced diurnal mean intraocular pressure significantly more than timolol 0.5%. Both concentrations of travoprost were well tolerated and safe for use in patients with open-angle glaucoma or ocular hypertension.

Macular alterations after small-incision cataract surgery

Purpose: To characterize macular edema that occurs after uneventful cataract surgery. Setting: Centre of Ophthalmology, University Hospital, Institute of Biomedical Research on Light and Image, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Methods: Thirty‐two eyes of 32 patients had uneventful phacoemulsification with implantation of a foldable intraocular lens. Postoperatively, patients were examined at 3, 6, 12, and 30 weeks. The examinations included retinal leakage analysis (Zeiss CSLO), optical coherence tomography (Humphrey Instruments), and retinal thickness analysis (Talia Technology, Ltd.). Results were compared with those in a control group comprising healthy subjects. Results: Increases in retinal thickness (ie, over the mean ± 2 SD in the control group) reached a maximum at 6 weeks in 13 of 32 eyes (41%), after which recovery was progressive. At 30 weeks, all eyes had good visual acuity, but 7 eyes (22%) still had macular edema. The edema was located primarily in the central macular region. Leaking sites involving the vascular areas of the macula, which indicated areas of abnormal blood–retinal barrier permeability, were a frequent finding. The number of sites remained relatively stable during the first 12 weeks (88%) and decreased to 68% at 30 weeks, indicating a trend toward recovery. Conclusion: Macular edema after cataract surgery occurred primarily in the central region of the macula and was associated with the presence of leaking sites, which were located predominantly in the vascular regions of the central macula.

Improved adaptive complex diffusion despeckling filter

Despeckling optical coherence tomograms from the human retina is a fundamental step to a better diagnosis or as a preprocessing stage for retinal layer segmentation. Both of these applications are particularly important in monitoring the progression of retinal disorders. In this study we propose a new formulation for a well-known nonlinear complex diffusion filter. A regularization factor is now made to be dependent on data, and the process itself is now an adaptive one. Experimental results making use of synthetic data show the good performance of the proposed formulation by achieving better quantitative results and increasing computation speed.

Blood-retinal barrier

The blood-ocular barrier system is formed by 2 main barriers: the blood-aqueous barrier and the blood-retinal barrier (BRB). The BRB is particularly tight and restrictive and is a physiologic barrier that regulates ion, protein, and water flux into and out of the retina. The BRB consists of inner and outer components, the inner BRB being formed of tight junctions between retinal capillary endothelial cells and the outer BRB of tight junctions between retinal pigment epithelial cells. The BRB is essential to maintaining the eye as a privileged site and is essential for normal visual function. Methods of clinical evaluation of the BRB are reviewed and new directions using optical coherence tomography are presented. Alterations of the BRB play a crucial role in the development of retinal diseases. The 2 most frequent and relevant retinal diseases, diabetic retinopathy and age-related macular degeneration (AMD), are directly associated with alterations of the BRB. Diabetic retinopathy is initiated by an alteration of the inner BRB and neovascular AMD is a result of an alteration of the outer BRB. Macular edema is a direct result of alterations of the BRB.

New approaches for the treatment of diabetic macular oedema: recommendations by an expert panel

The current standard therapy for patients with diabetic macular oedema (DME)—focal/grid laser photocoagulation—usually does not improve impaired vision, and many patients lose vision despite laser therapy. Recent approval of ranibizumab by the European Medicines Agency to treat visual impairment due to DME fulfils the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients. We reviewed 1- and 2-year clinical trial findings for ranibizumab used as treatment for DME to formulate evidence-based treatment recommendations in the context of this new therapy. DME with or without visual impairment should be considered for treatment when it fulfils the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria for clinically significant oedema. For DME with centre involvement and associated vision loss due to DME, monthly ranibizumab monotherapy with treatment interruption and re-initiation based on VA stability is recommended. Laser therapy based on ETDRS guidelines is recommended for other forms of clinically significant DME without centre involvement or when no vision loss has occurred, despite centre involvement. Because these recommendations are based on randomised controlled trials of 1–2 years duration, guidance may need updating as long-term ranibizumab data become available and as additional therapeutic agents are assessed in clinical trials.