Contributions of Sodium-Hydrogen Exchanger 1 and Mitogen-Activated Protein Kinases to Enhanced Retinal Venular Constriction to Endothelin-1 in Diabetes.

Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1-induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. ET-1-induced vasoconstriction was abolished in the absence of extracellular Ca2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal-regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125. In conclusion, extracellular Ca2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes.

2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure disrupts development of the visceral and ocular vasculature.

The aryl hydrocarbon receptor (AHR) has endogenous functions in mammalian vascular development and is necessary for mediating the toxic effects of a number of environmental contaminants. Studies in mice have demonstrated that AHR is necessary for the formation of the renal, retinal, and hepatic vasculature. In fish, exposure to the prototypic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces expression of the AHR biomarker cyp1a throughout the developing vasculature and produces vascular malformations in the head and heart. However, it is not known whether the vascular structures that are sensitive to loss of AHR function are also disrupted by aberrant AHR activation. Here, we report that TCDD-exposure in zebrafish disrupts development of 1) the subintestinal venous plexus (SIVP), which vascularizes the developing liver, kidney, gut, and pancreas, and 2) the superficial annular vessel (SAV), an essential component of the retinal vasculature. Furthermore, we determined that TCDD exposure increased the expression of bmp4, a key molecular mediator of SIVP morphogenesis. We hypothesize that the observed SIVP phenotypes contribute to one of the hallmarks of TCDD exposure in fish - the failure of the yolk sac to absorb. Together, our data describe novel TCDD-induced vascular phenotypes and provide molecular insight into critical factors producing the observed vascular malformations.

Changes in visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment: a systematic review.

As all the structures of the human eye are characterized by sex hormone receptors, this study tested the hypothesis that assisted reproductive technology (ART) treatment influences visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment. A systematic literature search of all original articles published up to August 2018 was performed using the PubMed database, including all original studies available in the literature. Review articles, studies in which participants underwent mixed interventions (i.e. other than ART treatment), studies reporting data on ocular malformations in ART offspring, and studies written in languages other than English were excluded. All selected articles were analysed to assess the level of evidence according to the Oxford Centre for Evidence-Based Medicine 2011 guidelines, and the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation system. Although sparse data suggest that ART treatment can influence visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment, the available evidence is inconclusive given its low level and quality. More high-quality research is needed to assess the potential interaction between ART treatment and the eye.

Association of Cancer Immunotherapy With Acute Macular Neuroretinopathy and Diffuse Retinal Venulitis.

Importance: Checkpoint inhibition in cancer immunotherapy related to T-cell-driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here. Objective: To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab. Design, Setting, and Participants: Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers. Main Outcomes and Measures: Multimodal imaging including near infrared, optical coherence tomography, and fluorescein angiography were used to characterize retinal vascular abnormalities. Results: Based on optical coherence tomography and multimodal imaging findings, the clinical diagnosis of AMN associated with diffuse retinal venulitis was made in these 2 patients receiving atezolizumab. Conclusions and Relevance: While only 2 cases of patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced AMN and diffuse retinal venulitis are described here, these findings suggest that patients receiving programmed death 1 axis inhibitor therapies may need to be monitored for unexpected immune-related ocular toxicity including abnormalities of the microvasculature and large retinal vessels. Further studies might investigate the potential mechanisms of retinal vascular changes associated with these therapies.

Effect of aflibercept on persistent macular edema secondary to central retinal vein occlusion.

PURPOSE: To evaluate the efficacy of switching treatment from intravitreal ranibizumab to intravitreal aflibercept on the treatment of refractory macular edema secondary to central retinal vein occlusion (CRVO). METHODS: In this retrospective study; 12 eyes with refractory macular edema secondary to CRVO after multiple monthly repeated intravitreal 0.5mg/0.05mL ranibizumab injections prior to switching therapy to intravitreal 2mg/0.05mL aflibercept, between March 2012 and April 2016 were reviewed. The follow-up time was 12 months. Changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), central retinal volume (CRV) and injection interval between baseline and month 1, 3, 6 and 12 after switching therapy to aflibercept were reviewed and evaluated. RESULTS: Mean baseline CRT decreased from 516±101 mic. to 252±114 mic. at month 12 (P=0.008). Mean baseline CRV decreased from 8.74±2.13 mm3 to 6.82±1.64 mm3 at month 12 (P=0.005). Baseline BCVA improved from 0.73±0.21 to 0.53±0.17 logMAR at month 12 (P=0.004). Mean BCVA gain was two logMar lines (10 letters) at month 12. After switching therapy to aflibercept; the mean injection interval increased significantly from 1.34 months at baseline to 1.86 months at month 12, by an increase of 0.52 months (P=0.02). CONCLUSION: Intravitreal aflibercept is evaluated to be presenting significant visual and anatomical improvements in patients with persistent macular edema due to CRVO despite previous intravitreal ranibizumab.

EFFECTS OF INTRAVITREAL RANIBIZUMAB AND BEVACIZUMAB ON THE RETINAL VESSEL SIZE IN DIABETIC MACULAR EDEMA.

PURPOSE: The goal of this study was to assess the effects of a single injection of intravitreal ranibizumab (RAN) or bevacizumab (BEV) on the retinal vessel size in eyes with diabetic macular edema. MATERIALS AND METHODS: In total, 32 patients were enrolled in the RAN group, and 30 patients were included in BEV group. Each of these groups was also subdivided into two others groups: a study group and a control group. The study groups were composed of the injected eyes, whereas the noninjected fellow eyes served as the control groups. The patients underwent complete ophthalmic examinations, including optical coherence tomography and fundus fluorescein angiography, and the primary outcome measures included the central retinal artery equivalent, central retinal vein equivalent, and artery-to-vein ratio. RESULTS: In the RAN study group (n = 32), the preinjection mean central retinal artery equivalent (175.42 µm) decreased to 169.01 µm after 1 week, and to 167.47 µm after 1 month (P < 0.001), whereas the baseline central retinal vein equivalent (235.29 µm) decreased initially to 219.90 µm after 1 week, and to 218.36 µm after 1 month (P < 0.001). In the BEV study group (n = 30), the preinjection central retinal artery equivalent (150.21 µm) decreased to 146.25 µm after 1 week, and to 145.89 µm after 1 month (P < 0.001); whereas the baseline central retinal vein equivalent (211.87 µm) decreased initially to 204.59 µm after 1 week and was 205.24 µm after 1 month (P < 0.001). The preinjection artery-to-vein ratio values changed significantly (P = 0.001) after 1 week and after 1 month in the RAN group, but no significant alteration in the artery-to-vein ratio was observed in the BEV group (P = 0.433). In both the RAN (n = 32) and BEV (n = 30) control groups, none of the 3 parameters changed throughout the study period, when compared with the baseline. CONCLUSION: The results of this study showed that both RAN and BEV injections significantly constricted the retinal blood vessel diameters.

Vessel diameter study: intravitreal vs posterior subtenon triamcinolone acetonide injection for diabetic macular edema.

PurposeTo detect and compare the vessel diameter effect of intravitreal vs subtenon injection of triamcinolone for diabetic macular edema (DME).MethodsSixty patients with DME who underwent triamcinolone injection either intravitreally (N=30) or under the tenon capsule (N=30) were included. Non-injected fellow eyes served as control. The main outcome measures were central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and artery-vein ratio (AVR).ResultsIn the intravitreal group, pre-injection mean CRAE (147.07 µ) decreased to 141.03 µ at 1 week and to 139.43 µ at 1 month (P<0.001) while baseline CRVE (209.61 µ) decreased initially to 198.85 µ at 1 week then to 198.49 µ at 1 month (P<0.001). In the subtenon group, pre-injection CRAE (152.18 µ) decreased to 149.49 µ at 1 week and to 147.47 µ at 1 month (P=0.017), while baseline CRVE (215.60 µ) decreased initially to 208.69 µ at 1 week then to 207.25 µ at 1 month (P=0.003). Pre-injection AVR values did not change at 1 week and at 1 month in both injection groups (P=0.66 and P=0.196, respectively). In the control group, none of the 3 parameters changed throughout the study period compared to the baseline (P>0.28).ConclusionIn eyes with DME, both intravitreal and subtenon triamcinolone injection led to a significant constriction of retinal arteries and veins.

Effect of oral niacin on central retinal vein occlusion.

PURPOSE: Niacin, a treatment for dyslipidemia, is known to induce vasodilation as a secondary effect. Previous instances of patients with chronic central retinal vein occlusion (CRVO) and cystoid macular edema (CME) have been observed to spontaneously improve when placed on systemic niacin for hypercholesterolemia. The purpose of this study was to evaluate the effects of niacin on CRVO and associated ocular complications. METHODS: A prospective, single-center, non-randomized, interventional case series of niacin for CRVO was conducted. Best-correct visual acuity (BCVA), central macular thickness (CMT), and ocular complications were analyzed in 50 patients over 1 year. Eight patients were controls. RESULTS: The mean initial logMAR BCVA was 0.915, and improved with niacin to 0.745 (P = 0.12), 0.665 (P = 0.02) and 0.658 (P = 0.03) after 3, 6, and 12 months of follow-up, respectively. At baseline, mean CMT was 678.9 µm, and improved to 478.1 µm (P = 0.001), 388.6 µm (P < 0.001), and 317.4 µm (P < 0.001) for the same time points. The control group had a mean initial logMAR BCVA of 1.023, which gradually deteriorated to 1.162 (P = 0.36) after 12 months, and baseline CMT of 700.0 µm at baseline, which gradually improved to 490.9 µm (P = 0.06) after 12 months. Panretinal photocoagulation for neovascularization was required in 5 patients (13.2%) receiving niacin and 3 (37.5%) controls. CONCLUSIONS: These data suggest that niacin may be associated with functional and anatomic improvements in eyes with CRVO. Future investigations will help ascertain whether there is a role for niacin as an adjunct therapy to intravitreal injections in the management of CRVO.

QUALITATIVE AND QUANTITATIVE FOLLOW-UP USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF RETINAL VEIN OCCLUSION TREATED WITH ANTI-VEGF: Optical Coherence Tomography Angiography Follow-up of Retinal Vein Occlusion.

PURPOSE: To evaluate changes of vascular flow of patients treated with intravitreal injections of anti-vascular endothelial growth factor for macular edema secondary to retinal vein occlusion (RVO) with optical coherence tomography angiography (OCTA). METHODS: Patients with RVO with macular edema and treated with intravitreal injections of anti-vascular endothelial growth factors were retrospectively evaluated. The following examinations were performed before and after treatment: best-corrected visual acuity, spectral domain optical coherence tomography, fluorescein angiography, and OCTA (Optovue, Inc). Automatic measurement of vascular density of the superficial and deep capillary plexus was also performed and compared with age- and sex-matched healthy subjects. RESULTS: Twenty-eight eyes of 28 patients (mean age 66.2 years; males 19%) were evaluated, including 13 central RVO, 11 branch RVO, and 4 hemicentral RVO. After treatment, mean central macular thickness significantly decreased from 644 µm to 326 µm and best-corrected visual acuity increased from 20/125 to 20/63 (P < 0.01 for both results). On OCTA, perifoveal capillary disruption (P = 0.029) and the number of cysts in the superficial capillary plexus and deep capillary plexus (P < 0.002) significantly decreased after treatment. The mean vascular density in the superficial capillary plexus slightly decreased during follow-up from 46.44% to 45.01% (not significantly). These densities were significantly less than those observed in healthy controls (P < 0.001). CONCLUSION: Optical coherence tomography angiography showed regression of macular edema, reduced capillary disruption and cysts, and slight decrease in mean macular vascular density with time and despite treatment. Thus, OCTA enables qualitative and quantitative evaluation during follow-up of patients treated for RVO.

Retinal vein thrombosis: The Internist's role in the etiologic and therapeutic management.

Retinal vein occlusion is a common and important cause of vision loss. In general, knowledge about this condition is scant within an internist's practice but the condition is relevant because of its association with other chronic ailments. A diagnosis of RVO should prompt the investigation of conditions needing chronic management in these patients. In this review we summarize the clinical presentation of RVO, its classification, associated risk factors, and treatment focused in the internist's scope of practice.

An ultra-low-molecular-weight heparin, fondaparinux, to treat retinal vein occlusion.

Retinal vein occlusions may decrease visual acuity. There is no known therapy to treat ocular thrombosis. The authors used fondaparinux, an ultra-low-molecular-weight heparin, to treat 13 consecutive cases of recent-onset retinal vein occlusions. Two patients with renal insufficiency were not included. Eight central retinal vein occlusions and 5 branch retinal vein occlusions in 13 patients were treated with subcutaneous fondaparinux 2.5 mg once a day. The patients were seen every 2 weeks. Macular edema was treated with intravitreal injections of anti-vascular endothelial growth factor or steroids. Two patients elected to discontinue treatment. Of the remaining 11, 9 occlusions resolved in 1.5 to 13.5 months with rapid resolution of retinal edema and hemorrhage as soon as the occlusions resolved. One patient had a retinal vein that was still occluded after 8 months of therapy and 1 had retinal vein occlusion that partially resolved after 15 months of treatment. Of the 9 eyes with occlusions that resolved, visual acuity improved in 7. In 2, visual acuity decreased due to macular ischemia. Occlusion recurred in 1 2.5 months after the suspension of initial treatment. This patient is again being treated with fondaparinux 2.5 mg. No hemorrhaging occurred. Fondaparinux 2.5 mg can be given subcutaneously once a day to patients with recent-onset retinal vein occlusions without renal insufficiency. An occlusion may take a number of months to resolve. Once the vein occlusion has resolved, retinal edema and hemorrhage rapidly resolve and vision improves. Macular edema should be treated while waiting for the vein occlusion to resolve.

Updated cannulation technique for tissue plasminogen activator injection into peripapillary retinal vein for central retinal vein occlusion.

PURPOSE: To update the surgical technique in which a vitrectomy is performed and a retinal branch vein is cannulated and infused with recombinant tissue plasminogen activator (RTPA) to treat central retinal vein occlusion (CRVO) in patients who present with very low visual acuity (VA). METHODS: Twelve consecutive patients (12 eyes) with CRVO and low VA (logMAR >1.00) at presentation were treated using this method. RESULTS: Cannulation of a peripapillary retinal vein and stable injection of RTPA was successfully performed without surgery-related complications in all 12 eyes. At 12 months after surgery, 8 of the 12 patients (67%) experienced at least one line of improvement in best corrected visual acuity; 6 of the 12 (50%) improved ≥5 lines and 2 (17%) improved ≥8 lines. After additional grid laser and/or subconjunctival or intravitreal corticosteroids, the mean decrease in central foveal thickness was 260 µm, and the mean total macular volume decreased from 12.10 mm(3) to 9.24 mm(3) . Four patients received panretinal photocoagulation to treat either iris neovascularization (n = 2) or neovascularization of the retina and/or disc (n = 2). CONCLUSION: Administration of RTPA via a peripapillary vein using this updated technique provides an alternative or additional treatment option for patients with very low VA after CRVO.

Effect of intracameral carbachol in phacoemulsification surgery on macular morphology and retinal vessel caliber.

OBJECTIVE: To investigate the effects of intracameral carbachol in phacoemulsification surgery on central macular thickness (CMT), total macular volume (TMV) and retinal vessel caliber (RVC). MATERIALS AND METHODS: In this prospective consecutive case series, 82 patients underwent uneventful phacoemulsification and in-the-bag intraocular lens implantation. Unlike patients in the control group (43 eyes), patients in the study group (42 eyes) were injected with intracameral 0.01% carbachol during surgery. Spectral-domain optical coherence tomography (OCT) was used to analyze the parameters of CMT, TMV and RVC. RESULTS: On the first postoperative day, mean CMT and TMV decreased markedly in the carbachol group, though these values did not change significantly in the control group. During follow-up visits, no statistically significant differences between the groups occurred regarding changes in mean CMT (p = 0.25, first day; p = 0.80, first week; p = 0.95, first month). However, change in mean TMV between groups on the first postoperative day was statistically significant (p = 0.01, first day; p = 0.96, first week; p = 0.68, first month). RVC values were similar on the preoperative and postoperative first days in both groups (p > 0.05). DISCUSSION: Results suggest that the effect of intracameral carbachol on macular OCT is related to pharmacological effects, as well as optic events (e.g. miosis). CONCLUSION: Intracameral carbachol given during cataract surgery decreases macular thickness and volume in the early postoperative period but does not exert any gross effect on RVC.

Reversal of early central retinal vein occlusion by alleviating optic nerve edema with an intravitreal dexamethasone implant.

This case describes the reversal of early central retinal vein occlusion (CRVO) with disc swelling after intravitreal dexamethasone implant (Ozurdex) injection. A 44-year-old female presented with sudden-onset intermittent blurred vision in her left eye. Fundus examination revealed multiple retinal hemorrhages without macular edema (ME). Two weeks later, an increased number of retinal hemorrhages with severe disc swelling were noted with still no sign of ME. An intravitreal dexamethasone implant was injected. Five days later, there were improvements in disc swelling and retinal hemorrhage. One month later, her subjective visual symptoms were completely improved, and fundus examination revealed marked improvement along with almost complete resolution of disc swelling. Intravitreal dexamethasone implant injection may potentially change the natural course of CRVO progression and its various subsequent complications.

Reversal of Early Central Retinal Vein Occlusion by Alleviating Optic Nerve Edema with an Intravitreal Dexamethasone Implant

This case describes the reversal of early central retinal vein occlusion (CRVO) with disc swelling after intravitreal dexamethasone implant (Ozurdex) injection. A 44-year-old female presented with sudden-onset intermittent blurred vision in her left eye. Fundus examination revealed multiple retinal hemorrhages without macular edema (ME). Two weeks later, an increased number of retinal hemorrhages with severe disc swelling were noted with still no sign of ME. An intravitreal dexamethasone implant was injected. Five days later, there were improvements in disc swelling and retinal hemorrhage. One month later, her subjective visual symptoms were completely improved, and fundus examination revealed marked improvement along with almost complete resolution of disc swelling. Intravitreal dexamethasone implant injection may potentially change the natural course of CRVO progression and its various subsequent complications.

Retinal vascular changes following intravitreal ranibizumab injections for neovascular AMD over a 1-year period.

PURPOSE: To assess retinal vascular calibre changes in eyes with neovascular age-related macular degeneration (AMD), treated with intravitreal anti-vascular endothelial growth factor agents, over a 1-year period and compare any such changes to untreated fellow eyes. METHODS: Treatment naïve patients with neovascular AMD received three consecutive intravitreal injections of ranibizumab, followed by a pro re nata dosing regimen up to 1 year, with the aim of maintaining a 'fluid-free' macula. Retinal arteriolar and venular calibre was measured from digital fundus photographs at baseline and at three monthly intervals to 1 year, and summarised as central retinal artery equivalent (CRAE) and central retinal venular equivalent (CRVE), respectively. RESULTS: A total of 53 injected eyes and 41 fellow, non-injected eyes were analysed. At baseline, there were no differences in retinal vascular calibre between injected and non-injected eyes (mean CRAE (SD) 144.93 (14.07) vs 145.74 (13.10) µm, P=0.80 and mean CRVE (SD) 216.23 (25.93) vs 219.91 (22.82) µm, P=0.53). Over a 12-month period, retinal venular calibre dilatation occurred in injected eyes (mean CRVE change +5.71 (14.71) µm, P=0.007), with no change in retinal arterioles, +0.69 (14.71) µm, P=0.68. In non-injected eyes, arteriolar narrowing occurred as a whole, mean CRAE change -4.20 (7.00) µm, P=0.001, over 12 months, with a trend for narrowing in venules, -2.16 (11.56) µm, P=0.28. In injected eyes, after controlling for covariates, the changes in CRVE over 12 months mirrored improvements in macular thickness, -0.06 (-0.005, -0.11) µm, P=0.04, and visual acuity, +9.66 (-0.30, +19.32) µm, P=0.06. CONCLUSION: Intravitreal ranibizumab significantly dilated retinal venules after a 1-year period.

Experimental endoscopic endovascular cannulation: a novel approach to thrombolysis in retinal vessel occlusion.

PURPOSE: Recent studies suggest that the cannulation of retinal vessels may provide a potential access route for the administration of thrombolytic agents in retinal vessel occlusion. However, the major problem with available techniques is the limited visualization of retinal vessels with conventional surgical microscopes, making it difficult to effectively control the targeted injection of drugs. METHODS: The authors developed a novel single-piece catheter system for the endoscopically guided puncture of microvessels. Experimental punctures of retinal vessels with injection of fluid were performed in porcine cadaver eyes using a standard high-resolution gradient index microendoscope introduced through the pars plana. RESULTS: Endoscopically guided punctures were successfully performed in porcine branch retinal veins at various distances from the optic disc. Injection of recombinant tissue plasminogen activator (rt-PA), hypertonic solution (hyper HES), or normal saline solution into the vessel lumen was accomplished under direct endoscopic view in a safe and reliable manner. CONCLUSIONS: Endoscopically guided puncture of retinal microvessels is feasible and can be performed through a pars plana entry without additional micromanipulation devices. This novel technique may be a safe and effective approach to catheter-directed endovascular thrombolysis in retinal vascular occlusive diseases.