Michel Eid Farah

Therapeutic monoclonal antibodies in ophthalmology.

Monoclonal antibodies (mAbs) can be used therapeutically by binding to molecular targets with high specificity. Therefore, they have excellent therapeutic applications in ophthalmology. This manuscript presents four aspects of the therapeutic use of mAbs in ophthalmology: the scientific rationale, the unique characteristics of selected mAbs, the current state-of-the-art application, and relevant therapeutic mAbs for future applications in ophthalmology. We identified in the literature various single-agent therapies that inhibit the following targets: tumor necrosis factor (TNF), epithelial growth factor receptor, vascular endothelial growth factor (VEGF) receptor, basic fibroblast growth factor receptor, platelet-derived growth factor, and cluster of differentiation antigens. The roles of all biochemical targets in ocular diseases were evaluated. Current and future mAbs against various cytokines were assessed for the treatment of ocular diseases. The medical literature showed the clinical benefits of mAbs for treating angiogenic and inflammatory ocular diseases. Two anti-VEGF mAbs, bevacizumab and ranibizumab, and three anti-TNF agents, infliximab, etanercept, and adalimumab, control ocular neovascularization and intraocular inflammation. Other mAbs such as rituximab, daclizumab, efalizumab, and alemtuzumab showed positive results in animal and early clinical studies and may represent useful adjuvant therapies for ocular lymphoma or ocular inflammation. Ranibizumab is the only FDA-approved therapy; for other mAbs the so-called off-label application remains the standard. Intravenous administration of mAbs has demonstrated acceptable toxicity profiles, while intraocular injection may decrease the chances of systemic complications and increase the amount of drug available to the retina and choroid. In conclusion, effective clinical use of mAbs in ophthalmology is more commonly seen in the field of angiogenic vitreoretinal and autoimmune inflammatory diseases. The challenge for the future is combining biologic therapies to improve the quality and duration of responses while diminishing side effects. The role of mAbs within ophthalmic treatments will be defined according to future clinical experience and the results of randomized clinical trials.

Randomized Clinical Trial Evaluating mETDRS versus Normal or High-Density Micropulse Photocoagulation for Diabetic Macular Edema

PURPOSE To compare modified Early Treatment Diabetic Retinopathy Study (mETDRS) focal/grid laser photocoagulation with normal-density (ND-SDM) or high-density (HD-SDM) subthreshold diode-laser micropulse photocoagulation for the treatment diabetic macular edema (DME). METHODS A prospective, randomized, controlled, double-masked clinical trial with patients with previously untreated DME and best corrected visual acuity (BCVA) worse than 20/40 and better than 20/400. Patients were randomized to receive either mETDRS focal/grid photocoagulation (42 patients), ND-SDM (39 patients), or HD-SDM (42 patients). Before treatment and 1, 3, 6, and 12 months after treatment, all patients underwent ophthalmic examinations, BCVA, color fundus photography, fluorescein angiography, and optical coherence tomography (OCT). RESULTS At 12 months, the HD-SDM group had the best improvement in BCVA (0.25 logMAR), followed by the mETDRS group (0.08 logMAR), whereas no improvements were seen in the ND-SDM group (0.03 logMAR). All groups showed statistically significant progressive reduction of central macular thickness (CMT) throughout the study (P < 0.001). The HD-SDM group exhibited the greatest CMT reduction (154 μm), which was not significantly different from that of the mETDRS group (126 μm; P = 0.75). CONCLUSIONS At 1 year, the clinical performance of HD-SDM was superior to that of the mETDRS photocoagulation technique, according to the anatomic and functional measures of improvement used in this investigation. A rationale for this treatment modality as a preferable approach is suggested, and the precise role of subthreshold micropulse laser treatment may become more defined as experience grows, guided by optimized treatment guidelines and more comprehensive trials. (Clinicaltrials.gov number, NCT00552435.).

The Use of Vital Dyes in Ocular Surgery

Vital dyes have advanced diagnosis and surgical technique in various specialties, including oncology, gastroenterology, and ophthalmology. In ocular surgery vital dyes are widely used in cataract and vitreoretinal surgery. Worldwide, intra-operative use of trypan blue during cataract surgery has enhanced visualization of the anterior capsule during capsulorrhexis, and patent blue has been recently licensed in Europe for cataract surgery. For chromovitrectomy, the vital dyes indocyanine green, infracyanine green, and brilliant blue stain the internal limiting membrane, and trypan blue and triamcinolone acetonide help visualize epiretinal membranes and vitreous, respectively. Intra-operative vital dyes are finding uses in corneal, glaucoma, orbit, strabismus, and conjunctival surgery. We provide a summary of current knowledge of the use of vital dyes in ocular surgery. We review the properties of dyes, techniques of application, indications, and complications in ocular surgery. Vital dyes represent an expanding area of research, and novel dyes deserve further investigation.

Immediate indocyanine green angiography and optical coherence tomography evaluation after photodynamic therapy for subfoveal choroidal neovascularization.

Purpose To better understand the mechanisms of action of photodynamic therapy (PDT) with verteporfin for subfoveal choroidal neovascularization (CNV), the authors evaluated the retinal and choroidal response immediately after treatment with serial optical coherence tomography (OCT) and indocyanine green angiography (ICGA). Methods This study was a prospective, noncomparative case series. PDT was performed on nine eyes of nine consecutive patients who presented with subfoveal CNV due to age-related macular degeneration, and serial evaluation with OCT as well as ICGA was performed at 20-minute intervals for the first 2 hours and then at 1 week, 1 month, and 3 months. Results In the first 2 hours after PDT, OCT showed an increase in the thickness of the retina in the treatment area due to fluid leakage from the neovascular complex as confirmed by ICGA. At 1 week, marked reduction of intraretinal/subretinal fluid was observed in all patients. Neovascular complex nonperfusion by ICGA was associated with some degree of choroidal hypoperfusion in the treatment area. Return of the foveal contour by OCT was optimal after 1 month of treatment. At 3 months, choroidal reperfusion by ICGA and recurrent intraretinal/subretinal fluid by OCT were observed. Conclusions Serial OCT and ICGA evaluation after PDT suggests that the initial successful CNV nonperfusion as shown by fluorescein angiography at 1 week occurs by means of selective PDT damage to the lesion and/or reduced choroidal blood flow in the treatment area, thereby decreasing intraretinal/subretinal fluid and facilitating restoration of the retinal architecture.

Effects of indocyanine green injection on the retinal surface and into the subretinal space in rabbits.

Purpose To evaluate the effects of indocyanine green (ICG) injection on the retinal surface and into the subretinal space of rabbit eyes. Methods Twenty-two Dutch-belted rabbits underwent two-port vitrectomy followed by injection of ICG (5 mg/mL) on the retinal surface and into the subretinal space. Balanced salt solution (BSS) was also injected subretinally. The locations where ICG was delivered (both epiretinal and subretinal) were exposed to light from an endoilluminator for 7 minutes. The animals were examined at 1, 7, and 14 days after surgery. The eyes were studied by fluorescein angiography as well as light and electron microscopy. Results No damage was observed after epiretinal ICG injection, but subretinal ICG injection resulted in damage to the outer nuclear layer, photoreceptor inner and outer segments, and retinal pigment epithelium. This damage was more severe with longer follow-up. Control experiments without ICG, in which balanced salt solution was injected into the subretinal space or light was delivered on the epiretinal surface, demonstrated only damage to the photoreceptor outer segments. Conclusion Subretinal delivery of ICG (5 mg/mL) in rabbits induces retinal pigment epithelium, photoreceptor inner and outer segment, and outer nuclear layer damage. These mechanisms of damage may explain the retinal pigment epithelium changes that are sometimes seen after ICG-assisted internal limiting membrane peeling in humans.

Twelve-month short-term safety and visual-acuity results from a multicentre prospective study of epiretinal strontium-90 brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration

Background/aims: This study evaluated the short-term safety and feasibility of epiretinal strontium-90 brachytherapy delivered concomitantly with intravitreal bevacizumab for the treatment of subfoveal CNV due to AMD for 12 months. A 3-year follow-up is planned. Methods: In this prospective, non-randomised, multicentre study, 34 treatment-naïve patients with predominantly classic, minimally classic and occult subfoveal CNV lesions received a single treatment with 24 Gy beta radiation (strontium-90) and two injections of the anti-VEGF antibody bevacizumab. Adverse events were observed. BCVA was measured using standard ETDRS vision charts. Results: Twelve months after treatment, no radiation-associated adverse events were observed. In the intent-to-treat (ITT) population, 91% of patients lost <3 lines (15 ETDRS letters) of vision at 12 months, 68% improved or maintained their BCVA at 12 months, and 38% gained ⩾3 lines. The mean change in BCVA observed at month 12 was a gain of 8.9 letters. Conclusion: The safety and efficacy of intraocular, epiretinal brachytherapy delivered concomitantly with anti-VEGF therapy for the treatment of subfoveal CNV secondary to AMD were promising in this small study population. Long-term safety will be assessed for 3 years. This regimen is being evaluated in a large, multicentre, phase III study.

Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy

The neovascular form of age-related macular degeneration (AMD), called wet-AMD or choroidal neovascularisation, begins with damage to the outer retinal cells and retinal pigment epithelium (RPE), which elicits a cascade of inflammatory and angiogenic responses leading to neovascularisation under the macula. Studies showed that oxidative damage, chronic inflammation of the RPE and complement misregulation work at different steps of this disease. After established neovascularisation, several pro- and antiangiogenic agents start to play an important role. Vascular endothelial growth factors (VEGFs) are the most specific and potent regulators of angiogenesis, which are inhibited by intravitreal injections of ranibizumab, bevacizumab, VEGF Trap, pegaptanib sodium and other agents under investigation. Pigment epithelium-derived factor, on the other hand, shows neuroprotective and antiangiogenic activities. Hepatocyte growth factor (HGF) has a mitogenic effect on a wide range of epithelial and endothelial cells, and it is inhibited by an anti-HGF monoclonal antibody. Platelet-derived growth factor is a potent chemoattractant and mitogen for both fibroblasts and retinal RPE cells, which has been inhibited experimentally by VEGF Trap and human anti-platelet-derived growth factor-D monoclonal antibody. Fibroblast growth factor-2 has pleiotropic effects in different cell and organ systems, and it is blocked by anti-FGF antibodies, with a greater benefit regarding antiangiogenesis when combined treatment with anti-VEGF is performed. Tumour necrosis factor alpha is expressed in the retina and the choroid, and its blockade in choroidal neovascularisation includes the use of monoclonals such as infliximab. This paper reviews the most important cytokines involved in the pathogenesis of wet-AMD, with emphasis on potential combined therapies for disease control.

Effects of intravitreal indocyanine green injection in rabbits.

Purpose To report the clinical, electrophysiologic, and histologic findings of different concentrations of indocyanine green (ICG) injected into the vitreous cavity of rabbit eyes. Methods Forty-two rabbits underwent intravitreal injection of 0.1 mL of ICG in three different concentrations: 0.5 mg/mL (250 mOsm), 5 mg/mL (270 mOsm), and 25 mg/mL (170 mOsm). Fellow eyes were injected with 0.1 mL of balanced salt solution. Biomicroscopy, ophthalmoscopy, electroretinography, fluorescein angiography, and histologic evaluation were performed. Results Eyes injected with 0.5 mg/mL of ICG showed b-wave latency delay on the first day after injection. Eyes injected with 5 mg/mL of ICG showed b-wave latency delay and decreased b-wave amplitude on the first and seventh days after injection; delayed a-wave latency on the first day after injection was also observed. Eyes injected with 25 mg/mL of ICG showed b- and a-wave amplitude and latency abnormalities during the entire follow-up. Direct correlation of increasing retinal edema proportional to the progressively increasing ICG concentrations was shown on histologic evaluation. Conclusion Intravitreal ICG injection in rabbit eyes may impair retinal function and morphology proportional to the progressively increasing ICG dosages.

Vital dyes for chromovitrectomy.

Purpose of review The aim of this article is to present the current state-of-the-art in regard to the application of vital dyes during vitreoretinal surgery, ‘chromovitrectomy’, as well as to overview the current literature regarding the properties of dyes, techniques of application, indications, and complications in chromovitrectomy. Recent findings A large body of published research has recently addressed the toxicity profile of indocyanine green for chromovitrectomy. Experimental data demonstrate dose-dependent toxicity of indocyanine green to various retinal cells. Newer generation vital dyes for chromovitrectomy include trypan blue, patent blue, triamcinolone acetonide, infracyanine green, sodium fluorescein, bromophenol blue, fluorometholone acetate and brilliant blue. Novel instruments may enable a selective painting of preretinal tissues during chromovitrectomy. Summary This review suggests that the field of chromovitrectomy represents an expanding area of research. The first line agents for internal limiting membrane staining in chromovitrectomy are indocyanine green, infracyanine green, and brilliant blue. Patent blue, bromophenol blue and trypan blue arose as outstanding biostains for visualization of epiretinal membranes. Novel dyes available for chromovitrectomy deserve further investigation.

Choriocapillaris photodynamic therapy using indocyanine green

PURPOSE To evaluate the potential of photodynamic therapy using indocyanine green for occlusion of choroidal neovascularization, the authors studied efficiency and collateral damage of photodynamic therapy-induced photothrombosis in the rabbit choriocapillary layer. METHODS Fundus photography, fluorescein angiography, and light and transmission electron microscopy were used to study the efficiency of photodynamic therapy-induced photothrombosis using indocyanine green as the photosensitizer, and to assess the resultant collateral damage. The delivery system consisted of a modified infrared diode laser tuned to 810 nm, near the maximum absorption peak of indocyanine green. RESULTS Choriocapillary occlusion was achieved at indocyanine green doses of 10 and 20 mg/kg and a radiant as low as 6.3 J/cm(2). When photodynamic therapy was performed with indocyanine green doses of 10 mg/kg, damage to the neural retina was minimal. Only inner photoreceptor segments showed degeneration, probably secondary to choroidal ischemia. Bruch membrane remained intact. Retinal pigment epithelium was invariably damaged, as seen with other photosensitizers. Temporary occlusion of large choroidal vessels occurred at both dye doses. CONCLUSIONS In this experimental study, photodynamic therapy using indocyanine green and 810-nm light irradiation produced endothelium-bound intraluminal photothrombosis, with preservation of the retinal architecture and minimal loss of visual cells. Membrane targetability, hydrophilic and fluorescent properties, and activation at 805 nm suggest indocyanine green as a potential photosensitizer for choroidal neovascularization. These combined considerations point toward further study of photodynamic therapy using indocyanine green for the treatment of choroidal vascular disease.