Georgios Mangioris

Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration.

OBJECTIVE To study the effect of intravitreal (IVT) ranibizumab (Lucentis; Genentech, Inc, San Francisco, CA) on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD). DESIGN Prospective consecutive interventional case series. PARTICIPANTS Eleven eyes of eleven patients with previously untreated neovascular AMD. METHODS All eyes had 3 monthly IVT injections of ranibizumab. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyzer (RVA) before the first IVT injection and then 7 and 30 days after the first, second, and third injections. MAIN OUTCOME MEASURES Primary end points were changes in retinal arteriolar diameter and mean arterial pressure (MAP) after IVT ranibizumab. Secondary end points were changes in best-corrected visual acuity (BCVA), central retinal thickness, and intraocular pressure after IVT ranibizumab, and appearance of adverse events during the follow-up period. RESULTS A significant decrease of the retinal arteriolar diameter was observed after each IVT injection of ranibizumab. Thirty days after the first, second, and third injections, there was a mean decrease of 8.1+/-3.2%, 11.5+/-4.4%, and 17.6+/-7.4%, respectively, of the retinal arteriolar diameter compared with baseline values (P<0.01). There was no significant change in MAP during the period of follow-up (P>0.05). Thirty days after the third IVT injection of ranibizumab, mean BCVA improved by 6.5+/-4.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central retinal thickness decreased by 91+/-122 microm (P = 0.03). CONCLUSIONS These results suggest that IVT ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular AMD after IVT ranibizumab. Further studies evaluating larger sample sizes are needed to confirm these results and potential adverse effects on the retinal circulation in patients with AMD and retinal vascular diseases. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Long‐term results of the effect of intravitreal ranibizumab on the retinal arteriolar diameter in patients with neovascular age‐related macular degeneration

Purpose:  To study the effect of intravitreal (IVT) ranibizumab on the retinal arteriolar diameter in patients with neovascular age‐related macular degeneration (AMD).

Lactate-Induced Retinal Arteriolar Vasodilation Implicates Neuronal Nitric Oxide Synthesis in Minipigs

PURPOSE To investigate the role of neuronal nitric oxide (NO) synthesis in the retinal vasodilatory response to lactate in minipigs. METHODS Thirteen eyes of 13 minipigs were evaluated. Ten eyes received an intravenous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME). After 1 hour, the same eyes received an intravitreous juxta-arteriolar microinjection of 30 microL of L-lactate 0.5 M (pH 7.4) through a micropipette. Ten minutes later, 9 of 10 eyes received an intravitreous juxta-arteriolar microinjection of 30 microL of L-NAME 0.01 M (pH 7.4), and 1 received physiologic saline solution (PSS). The remaining three eyes received a microinjection of 30 microL of L-lactate 0.5 M (pH 7.4), without intravenous or intravitreous L-NAME. RESULTS The three eyes that received juxta-arteriolar injection of L-lactate only showed a reproducible increase in retinal arteriolar diameter that persisted during the entire study period (maximum effect at 20 minutes, 40.9% +/- 3.2%). Retinal arteriolar diameter decreased by 4.1% 1 hour after intravenous L-NAME when compared with baseline but the difference did not reach significance. The juxta-arteriolar injection of L-lactate induced a significant increase in retinal arteriolar diameter (22.7% and 28.7% at 5 and 10 minutes, respectively; P < 0.01), followed by a significant decrease (8.6%; P < 0.01) 10 minutes after juxta-arteriolar injection of L-NAME. Injection of PSS had no effect on retinal arteriolar diameter. CONCLUSIONS Juxta-arteriolar administration of L-lactate induced vasodilation, which was also observed with continuous intravenous infusion of L-NAME. Moreover, juxta-arteriolar L-NAME microinjection significantly suppressed the vasodilatory effect of L-lactate. These data suggest that neuronal-derived NO is an important mediator of lactate-induced vasodilation in minipigs.

Retinal vessel analyzer measurements of the effect of panretinal photocoagulation on the retinal arteriolar diameter in diabetic retinopathy.

Purpose: The purpose of this study was to investigate the effect of panretinal photocoagulation (PRP) on the retinal arteriolar diameter in patients with diabetic retinopathy using a retinal vessel analyzer. Methods: Ten eyes of 6 consecutive patients with type II diabetes and severe nonproliferative or proliferative diabetic retinopathy were studied prospectively. Measurements of the retinal arteriolar diameter were performed before the first photocoagulation session and after the end of the PRP treatment. Results: Retinal arteriolar diameter before PRP was 131 ± 15 arbitrary units and decreased to 112 ± 14 arbitrary units after PRP (P = 0.012). There was a significant vasoconstriction of 13.8% ± 8.3% following PRP. Mean visual acuity before and after PRP was 0.31 ± 0.36 logarithm of the minimal angle of resolution and 0.28 ± 0.30 logarithm of the minimal angle of resolution, respectively (P = 0.68). There was no significant change in mean arterial pressure before and after PRP (P = 0.89). There was no correlation between the visual acuity change or the number of laser burns and the percentage change in the retinal arteriolar diameter (P > 0.1). Conclusion: Panretinal photocoagulation has a vasoconstrictive effect on retinal arterioles in patients with severe nonproliferative or proliferative diabetic retinopathy. These results are consistent with an autoregulatory response of the retinal circulation to increased inner retinal oxygen tension after PRP. The retinal vessel analyzer is a fast, accurate, noninvasive, online measuring system for the study of the retinal vascular response to PRP in patients with diabetic retinopathy.

Vasomotor effect of intravitreal juxta-arteriolar injection of L-lactate on the retinal arterioles after acute branch retinal vein occlusion in minipigs.

PURPOSE To investigate the effect of L-lactate on retinal arteriolar diameter after acute branch retinal vein occlusion (BRVO) in minipigs. METHODS Thirteen eyes of 13 minipigs were evaluated, with the animals under general anesthesia. BRVO was induced by a standard method of argon laser endophotocoagulation. Two hours after BRVO, an intravitreal, juxta-arteriolar microinjection of 50 μL L-lactate 0.5 M (pH 7.4) was performed in nine eyes. Four eyes received a microinjection of 50 μL of the solvent (pH 7.4) that was used to prepare the solution of L-lactate and served as controls. Retinal arteriolar diameter changes were measured using a retinal vessel analyzer. RESULTS Overall (n = 13), 2 hours after BRVO, there was a 9.0% ± 1.4% decrease in the retinal arteriolar diameter in the affected ares compared to baseline (P < 0.001). An increase of 26.2% ± 8.2% (P = 0.004) of the arteriolar diameter was evidenced 5 minutes after L-lactate juxta-arteriolar microinjection (n = 9) compared with the diameter before L-lactate microinjection. Thereafter, the vasodilatory effect of L-lactate persisted and remained significant until the end of the study period (27.7% ± 7.8% at 30 minutes) compared with the diameter before L-lactate microinjection (P = 0.002). Microinjection of the solvent alone (n = 4) did not produce any significant effect on the retinal arterioles, which remained constricted at all time-points (P > 0.1). CONCLUSIONS These findings demonstrate a significant arteriolar vasodilation after intravitreal juxta-arteriolar L-lactate microinjection in eyes with experimental BRVO in the affected areas. L-lactate microinjection can reverse the arteriolar vasoconstriction that occurs in acute experimental BRVO.

Intravitreal L-Arginine injection reverses the retinal arteriolar vasoconstriction that occurs after experimental acute branch retinal vein occlusion

To investigate the effect of l-Arginine on the retinal arteriolar diameter following acute branch retinal vein occlusion (BRVO) in minipigs. Under general anesthesia, 10 eyes of 10 minipigs were evaluated. Two hours after BRVO, an intravitreal juxta-arteriolar micro-injection of 30 microl l-Arginine 1 mM (pH = 7.4) was performed in 7 eyes. Three eyes received a micro-injection of 30 microl of the solvent (pH = 7.4) that was used to prepare the solution of l-Arginine and served as controls. Retinal arteriolar diameter changes were measured using a Retinal Vessel Analyzer. Overall (n = 10), 2 h after BRVO there was a 10.5 +/- 1.9% decrease in the retinal arteriolar diameter in the affected territories compared to baseline (p < 0.001). An increase of 16.0 +/- 3.0% (p = 0.001) and 21.0 +/- 7.0% (p = 0.013) of the arteriolar diameter was evidenced 10 and 15 min respectively after l-Arginine injection (n = 7) compared to the diameter prior to l-Arginine injection. Thereafter, the vasodilatory effect of l-Arginine started to decrease but persisted and remained significant at the end of the study period (5.0 +/- 1.5% at 30 min, p = 0.007). Micro-injection of the solvent alone (n = 3) did not produce any significant effect on the retinal arterioles, which remained constricted at all time-points (p > 0.1). These findings demonstrate a significant arteriolar vasodilation after intravitreal juxta-arteriolar l-Arginine micro-injection in eyes with experimental BRVO in the affected territories. l-Arginine micro-injection can reverse the arteriolar vasoconstriction that occurs in acute experimental BRVO by stimulating nitric oxide production.

Development of an intravitreal peptide (BQ123) sustained release system based on poly(2-hydroxyoctanoic acid) aiming at a retinal vasodilator response.

PURPOSE Development of a novel formulation for intravitreal administration, in which the endothelinA receptor antagonist BQ123 is incorporated in a biodegradable and injectable polymer drug delivery system, poly(2-hydroxyoctanoic acid), aiming at a prolonged retinal vasodilator response. METHODS BQ123 was incorporated in poly(2-hydroxyoctanoic acid), leading to an easily injectable, homogenous mixture. In vitro release profiles were obtained in porcine vitreous humor (n=6). The ex vivo biocompatibility was studied by placing the formulation in contact with porcine retinal tissues and performing histology. In a pilot in vivo study, the change in retinal vessel diameter of mini pigs (n=2) was followed over 3 h after an intravitreal injection of the formulation, as well as the release of BQ123 from the polymer system for approximately 7 days (n=6). RESULTS In vitro, a constant release profile was obtained, releasing approximately 91% of BQ123 within 7 days. Histology on the porcine retinal tissues showed good ex vivo biocompatibility. In vivo, a vasodilative response was observed, with a retinal vessel diameter increase from 14% after 15 min, for approximately 39% after 3 h. At t=3 h, the BQ123 concentration in the vitreous humor was 0.7±0.2 μg/mL, followed by 1.5±1.0 and 1.1±0.8 μg/mL after 3 and 7 days, respectively. 39.9%±6.0% of BQ123 was still present in the polymer depot at t=7 days. CONCLUSIONS The results show that an intravitreal injection of this drug delivery system leads to a prolonged vasodilative response and a BQ123 release over 7 days, suggesting its therapeutic potential in the management of retinal ischemic conditions.

New strategy to study corneal endothelial cell transplantation: the chick cornea model.

Purpose: To set up a culture assay of chick corneal endothelial cells (CECs) for transplantation into host corneas. Methods: Histology sections were performed at 6, 9, 12, 15, and 18 embryonic days of development of the chick embryo. Visualization of the gross morphology of CECs and of epithelium, stroma, and Descemet membrane was performed. Transplantation of CECs at 18 embryonic days of development into explanted, denuded from endothelial cell, host corneas of the same stage was attempted. Results: The results from the histological sections clearly indicate that after embryonic day 12, the endothelial cells are well differentiated and the proliferation is complete. Transplanted CECs were able to migrate and integrate into the denuded host corneas. Conclusions: This study demonstrated its feasibility using an easy accessible model of chick cornea. With this technique, sufficient CECs may be obtained for biochemical and functional investigations using only nonhatched chickens that are easily accessible and easy to manipulate.

Experimental application of tissue adhesives in corneal traumas.

Purpose To evaluate intraoperative difficulties of the use of glues for corneal trauma. Methods Partial or full-thickness perpendicular corneal incisions (3–4 mm straight cuts) near the limbus (perpendicular or parallel to it) were made in 8 albino rabbits and were then sealed with fibrin or cyanoacrylate glue. Follow-up examinations were performed under the surgical microscope. Tissue specimens were also taken for light microscopic evaluation. Results The cyanoacrylate glue polymerized almost immediately after application on the tissue, limiting the ability of the surgeon to oppose the corneal incisions appropriately. The fibrin glue polymerized more gradually, giving enough time for manipulations to reconstruct the wound properly and for removal of excessive glue, especially when the 2 components were applied separately. Excessive glue and crust formation on the eye surface induced irritation. Conclusions Fibrin glue for the reconstruction of corneal wounds was easier to use than cyanoacrylate glue and caused less glue crust formation on the corneal surface. The speed of polymerization is an important factor. Excessive glue on the cornea was irritating.

Optical coherence tomography of wound architecture of 20-gauge sutureless transconjunctival sclerotomies

toreceptors caused by fast resolution of the macular oedema after IVB may be sufficient to trigger the occurrence of CBS. In the present study, 5 patients (2.5%) with neovascular AMD reported symptoms of CBS after IVB, indicating that CBS in this population is not rare. It has been suggested that the prevalence of CBS may be underestimated, as many patients do not reveal their hallucinations unless confronted with a direct question posed in the correct manner (Singh & Sørensen 2010). We believe that it is important for physicians to be aware of the possibility of CBS after IVB in patients with AMD and to educate their patients on the benign nature of this condition. Owing to the small number of CBS cases, we were unable to determine the risk factors for CBS after IVB. However, in the present study, all the patients with CBS were over 65 years of age and had visual acuity in the better-seeing eye of 0.3 or less. A large prospective study has indicated that increasing age and poor visual acuity in the better-seeing eye are common risk factors of CBS (Teunisse et al. 1995). As more patients are examined, it may be possible to determine the predictive factors for CBS after IVB.