Retinal Detachment Rates After Uncomplicated DMEK Versus Cataract Surgery Combined (Triple-)DMEK.

PURPOSE: To evaluate the rate of and risk factors for rhegmatogenous retinal detachment (RRD) after Descemet membrane endothelial keratoplasty (DMEK) either alone or in combination with cataract surgery. DESIGN: Retrospective analysis of prospective database. METHODS: Consecutive eyes with Fuchs endothelial corneal dystrophy (FECD) that received DMEK surgery with a minimum follow-up of 1 year between July 2011 and January 2021 at the Department of Ophthalmology at the University of Cologne were analyzed. Exclusion criteria were complicated history including repeat DMEK within 1-year, previous retinal or glaucoma surgery, complicated phacoemulsification, congenital cataract, history of trauma. RESULTS: From 3858 consecutive DMEKs, 1961 patients were identified suitable for analysis. 846 (43.1%) were pseudophakic DMEK, 91 (4.6%) phakic DMEK and 1,024 (52.2%) combined with cataract surgery. RRD occurred in 13 eyes (12 patients). Within two years after DMEK RRD occurred in 0.49% and 0.47% after DMEK and DMEK with cataract surgery, respectively. Mean age of 59.24 ± 8.42 years with subsequent RRD was significantly lower than overall 68.81 ± 9.89 years (t-test two-tailed; p < 0.001). The spherical equivalent was -4.69 ± 3.98 D (range -9.00 to 0.5) in RRD after pseudophakic DMEK compared to -2.79 ± 3.54 D (range -7.5 to 0.75) in combined procedures. Re-bubbling had no influence on RRD rate. CONCLUSIONS: DMEK alone or in combination with cataract surgery showed similar postoperative RRD rates in the first two years, generally in the range of pseudophakic RRDs. Risk factors such as myopia and younger age could be identified. Re-bubbling has no influence on RRD rates.

Susceptibility of optic nerve head in children with posture-related elevation of intraocular pressure.

BACKGROUND/AIMS: This work aimed to investigate changes in optic nerve head (ONH) morphometry based on Bruch membrane opening in children with extensive nocturnal intraocular pressure (IOP) elevations. METHODS: The course of Bruch membrane opening-based optic nerve head (ONH) morphometry was analysed in thirty-two patients younger than 18 years with evaluable SD-OCT examinations of the ONH and nocturnal posture-dependent IOP elevation above 25 mmHg. Longitudinal changes in neuroretinal rim tissue, as measured by Bruch Membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness, were assessed. RESULTS: One year after the 24 h IOP measurement, global BMO-MRW (- 1.61 ± 16.8 µm, n.s.; p = 0.611) and RNFL (+ 0.64 ± 3.17 µm; n.s.; p = 0.292) measurements were not significantly different from the baseline. No significant BMO-MRW reduction (- 3.91 ± 24.3 µm; n.s. p = 0.458) or deviation in RNFL thickness (+ 1.10 ± 3.52 µm) was observed at the four-year follow-up. Absolute IOP values measured in the supine position did not correlate with changes in global BMO-MRW or RNFL thickness. CONCLUSION: Posture-dependent IOP elevations do not seem to influence retinal nerve fibre layer thickness or Bruch membrane opening-based morphometric data in childhood.

Posture-related fluctuations of intraocular pressure in healthy children with suspicion of glaucoma.

PURPOSE: Currently, there are no specific data on the circadian course of intraocular pressure (IOP) in children, especially for IOP measurements in the supine position. The study aimed to characterize the diurnal and nocturnal IOP fluctuations in supine and sitting positions in patients less than 18 years of age. METHODS: Seventy-nine eyes of 79 patients under 18 years of age with suspicious optic nerve heads or ocular hypertension could be included in this study. All included patients showed an inconspicuous retinal nerve fiber layer thickness and Bruch's membrane minimum rim width by coherence tomography. IOP measurements during the 24-h IOP profile were retrospectively evaluated. Measurements were taken at 10:00, 16:00, 20:00, and 23:00 h in the sitting position and at 6:00 h in the morning in the supine position using iCare rebound tonometry on 2 consecutive days. RESULTS: Thirty-four of 79 children (43.0%) had peak nocturnal IOP values > 25 mmHg. The mean daily IOP was 18.8 ± 5.6 mmHg, and the mean daily fluctuation was 6.1 ± 4.0 mmHg. At 6 am, supine measurements were elevated to 25.1 ± 8.0 mmHg. Extensive fluctuations with values > 40 mmHg in the nocturnal supine measurement occurred in a relevant share of patients (n = 5). CONCLUSION: There appear to be relevant diurnal and nocturnal IOP fluctuations in healthy children (< 18 years). Nocturnal IOP measurements in supine patients with risk factors for glaucoma may provide important additional information to identify critical patients for further follow-up.

Intraoperative primary partial occlusion of the PreserFlo MicroShunt to prevent initial postoperative hypotony.

PURPOSE: The aim of the underlying study was to present a new surgical method in PreserFlo MicroShunt surgery for glaucoma. A removable polyamide suture was placed into the lumen of the MicroShunt during implantation to prevent early postoperative hypotony. METHODS: Thirty-one patients undergoing stand-alone glaucoma surgery with implantation of a PreserFlo MicroShunt and an intraluminal occlusion were retrospectively reviewed and compared to a control group without occlusion. Inclusion criteria were diagnosis of primary open-angle glaucoma or secondary open-angle glaucoma due to pseudoexfoliation or pigment dispersion. Patients with a history of filtrating glaucoma surgery were excluded. RESULTS: IOP decreased from 26.9 ± 6.6 to 18.0 ± 9.5 mmHg at the first postoperative day after PreserFlo MicroShunt implantation. Postoperative removal of the occluding suture resulted in a mean IOP reduction in 11.1 ± 7.6 mmHg. Mean visual acuity was 0.43 ± 0.24 logMAR during the first postoperative examination. The interval with the occluding intraluminal suture in place varied from days to 2-3 weeks. Patients were followed up to 1 year. CONCLUSION: Implantation of a PreserFlo MicroShunt combined with an intraluminal suture prevented postoperative hypotony in all patients. Mean postoperative pressure was reduced despite the occluding suture in place.

[Revision of the PRESERFLO® MicroShunt with ologen and mitomycin C]. / Revision des PRESERFLO® MicroShunts mit Ologen und Mitomycin C.

Bleb failure after implantation of filtering stents (e.g. Preserflo Stent) is a frequent challenge in glaucoma surgery that has occurred in recent years. In the following, a technique for open bleb revision with mitomycin C (0.2 mg/ml) and ologen implantation is presented, which is intended to re-establish the filtration volume lost due to fibrosis and a long-term preservation.

Retrospective analysis of OCT parameters after intravitreal anti-VEGF inhibitors in neovascular AMD patients in a real-world setting.

PURPOSE: The aim of the present study was to evaluate changes of best corrected visual acuity (BCVA), retinal nerve fiber layer thickness (RNFL), total macular volume (TMV), intraocular pressure (IOP) and central retinal thickness (CRT) after intravitreal injection of ranibizumab, bevacizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD) in a clinical real world setting. METHODS: In a retrospective clinical study design, 120 patients (80 women and 40 men) were analyzed after being diagnosed with nAMD within 8 years (2010-2018). Every patient received at least 6 anti-VEGF injections in a Pro-Re-Nata or Treat-and-Extend regimen. OCT parameters (RNFL, TMV, CRT) and visual acuity (BCVA) were assessed at first diagnosis, at treatment day and during the course. RESULTS: Intraretinal fluid was reduced significantly in a magnitude of 88-64 µm (CRT) and 0.75-0.55 mm3 (TMV). Apart from a significant reduction immediately after the therapy start (post-3 injections) with ranibizumab (- 1.4 µm, p = 0.03), RNFL thickness remained constant. A slight improvement in visual acuity of 0.06 logMAR could initially be observed. If further injections were required, only stabilization was achieved compared to baseline visual acuity. CONCLUSION: The changes of OCT parameters CRT, TMV, and RNFL as well as the stabilization of functional results (BCVA) as illustrated in this study comparing effects of different anti-VEGF-agents provide evidence for the transferability of former results to a clinical real-world setting.

Influence of Body Position on Intraocular Pressure After Descemet Membrane Endothelial Keratoplasty: A Prospective Randomized Trial.

PURPOSE: The purpose of this study was to analyze the influence of patient positioning on intraocular pressure (IOP) after Descemet membrane endothelial keratoplasty (DMEK) in pseudophakic patients treated for Fuchs endothelial corneal dystrophy. METHODS: Forty patients were included in this prospective, single-blinded, randomized controlled clinical trial. Patients received a YAG iridotomy 1 day before surgery and an 80% anterior chamber tamponade [20% concentration of sulfur hexafluoride (SF6)]. Postoperative positioning was either supine (group 1) or seated (group 2, at least 30 degrees upper-body high position). IOP was measured with iCare. RESULTS: There was no statistically significant difference in IOP postoperatively [group 1 vs. group 2-after 1h: 13.9 mm Hg (±4.2 mm Hg) versus 13.6 mm Hg (±4.1 mm Hg) ( P = 1.00); after 2h: 13.9 mm Hg (±5.4 mm Hg) versus 15.3 mm Hg (±4.6 mm Hg) ( P = 0.370); after 4h: 13.8 mm Hg (±4.2 mm Hg) versus 15.2 mm Hg (±4.2 mm Hg) ( P = 0.401]. In group 1, 10% of patients showed IOP decompensations well above 30 mm Hg, and in group 2, there were no IOP decompensations. Seated position led to relative risk reduction of 100% and absolute risk reduction of 10% regarding IOP decompensations. The number of patients needed to position seated to prevent 1 additional IOP decompensation was 10. Rebubbling rates, best spectacle-corrected visual acuity, and reduction of corneal thickness were comparable between the 2 groups in the follow-up period up to 1 month. CONCLUSIONS: After DMEK in pseudophakic eyes with 80% anterior chamber tamponade, positioning patients with at least 30 degrees elevation of the upper body up immediately after surgery until bedtime prevents IOP decompensations.

Outcomes of deep anterior lamellar keratoplasty and penetrating keratoplasty in keratoconic eyes with and without previous hydrops.

PURPOSE: The study aims to compare outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) in keratoconic eyes with or without previous hydrops. METHODS: Retrospective analysis of 211 eyes who received PK (group 1, n = 74 [history of hydrops: n = 33]) or DALK (group 2, n = 137 [history of hydrops: n = 9]) from 2012 to 2019 at the Department of Ophthalmology, University of Cologne, Germany. Analysis included best spectacle-corrected visual acuity (BSCVA), complications, immune reactions, graft survival and keratometry, and subgroup analyses for subjects with or without previous hydrops. RESULTS: Follow-up was 34.0 ± 23.6 months in group 1 and 30.7 ± 22.5 months in group 2. No significant difference was found in the course of BSCVA between groups 1 and 2 (p = 0.182) and in postoperative BSCVA between eyes with and without previous hydrops, regardless of the surgical method (p = 0.768). Endothelial immune reactions occurred exclusively in group 1 and did not occur more frequently in eyes with previous hydrops (p = 0.377). A higher risk of complications for eyes with previous hydrops was observed (p = 0.022). There was no difference in astigmatism and maximum keratometry (Kmax) preoperatively and postoperatively between eyes with and without history of hydrops. CONCLUSION: The prognosis for visual outcome after keratoplasty including visual acuity, astigmatism, and Kmax for keratoconic eyes with previous hydrops is as good as for keratoconic eyes without previous hydrops, irrespective of the surgical method. However, eyes after hydrops seem to have an increased risk of complications.

Short-term changes in Bruch's membrane opening-based morphometrics during the first week after trabeculectomy.

PURPOSE: To evaluate the dynamics of Bruch's membrane opening-based morphometrics of the optic nerve head (ONH) using spectral-domain optical coherence tomography (SD-OCT) during the first week after glaucoma surgery by trabeculectomy with mitomycin C. METHODS: Prospective, longitudinal analysis of 25 eyes of 25 patients treated by trabeculectomy. Twenty-four eyes had evaluable postoperative SD-OCT examinations. Bruch's membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness were analyzed at baseline before surgery, 1 day, 2 to 3 days, and 1 week after surgery. Changes compared to baseline were correlated to intraocular pressure (IOP). RESULTS: One day after surgery, the mean BMO-MRW changed by + 26.17 µm, p = 0.001 (mean IOP reduction by 17.01 mmHg). This increase persisted on day 2-3 with a mean increase of BMO-MRW of + 25.33 µm, p = 0.001 (mean IOP reduction by 20.46 mmHg) and by week 1 with a mean BMO-MRW increase of + 33.17 µm, p < 0.001 (mean IOP reduction by 22.55 mmHg). The increase in BMO-MRW correlated significantly with the reduction of IOP on day 1 (Spearman's rho ρ = 0.656, p = 0.003) and d2-3 (Spearman's rho ρ = 0.479, p = 0.038). There was no statistically significant correlation found between the IOP and the increase in BMO-MRW in week 1. RNFL thickness showed no significant changes at day 1 as well as days 2-3 (p ≥ 0.078, respectively). It showed a small but significant increase in week 1 by 3.94 µm, p = 0.015. CONCLUSIONS: Structural reversal of disc cupping in BMO-MRW occurs as early as 1 day after trabeculectomy and correlates to the extent of the IOP reduction. During the whole first week after surgery, a strong increase in BMO-MRW can be noted. The changes in BMO-based parameters need to be considered when evaluating patients' longitudinal follow-up.

Retinal Vessel Responses to Flicker Stimulation Are Impaired in Ca v 2.3-Deficient Mice-An in-vivo Evaluation Using Retinal Vessel Analysis (RVA).

Objective: Metabolic demand increases with neuronal activity and adequate energy supply is ensured by neurovascular coupling (NVC). Impairments of NVC have been reported in the context of several diseases and may correlate with disease severity and outcome. Voltage-gated Ca2+-channels (VGCCs) are involved in the regulation of vasomotor tone. In the present study, we compared arterial and venous responses to flicker stimulation in Cav2.3-competent (Cav2.3[+/+]) and -deficient (Cav2.3[-/-]) mice using retinal vessel analysis. Methods: The mice were anesthetized and the pupil of one eye was dilated by application of a mydriaticum. An adapted prototype of retinal vessel analyzer was used to perform dynamic retinal vessel analysis. Arterial and venous responses were quantified in terms of the area under the curve (AUCart/AUCven) during flicker application, mean maximum dilation (mMDart/mMDven) and time to maximum dilation (tMDart/tMDven) during the flicker, dilation at flicker cessation (DFCart/DFCven), mean maximum constriction (mMCart/mMCven), time to maximum constriction (tMCart/tMCven) after the flicker and reactive magnitude (RMart/RMven). Results: A total of 33 retinal scans were conducted in 22 Cav2.3[+/+] and 11 Cav2.3[-/-] mice. Cav2.3[-/-] mice were characterized by attenuated and partially reversed arterial and venous responses, as reflected in significantly lower AUCart (p = 0.031) and AUCven (p = 0.047), a trend toward reduced DFCart (p = 0.100), DFCven (p = 0.100), mMDven (p = 0.075), and RMart (p = 0.090) and a trend toward increased tMDart (p = 0.096). Conclusion: To our knowledge, this is the first study using a novel, non-invasive analysis technique to document impairment of retinal vessel responses in VGCC-deficient mice. We propose that Cav2.3 channels could be involved in NVC and may contribute to the impairment of vasomotor responses under pathophysiological conditions.

Submicromolar copper (II) ions stimulate transretinal signaling in the isolated retina from wild type but not from Cav2.3-deficient mice.

BACKGROUND: So far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+, Zn2+ and Cu2+. To further confirm the interpretation of these findings, we compared the effects of Cu2+ application and chelation (using kainic acid, KA) on the neural retina from wildtype and Cav2.3-deficient mice. Furthermore, the immediately effect of KA on the ERG b-wave modulation was assessed. METHODS: Transretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Cav2.3-deficient mice. RESULTS: In mice, the stimulating effect of 100 nM CuCl2 is absent in the retinae from Cav2.3-deficient mice, but prominent in Cav2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 µM KA significantly increased the b-wave amplitude in wild type and Cav2.3 (-|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study. CONCLUSION: Cu2+-dependent modulation of transretinal signaling only occurs in the murine retina from Cav2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca2+ channels are involved in shaping transretinal responses during light perception.

Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) - Candidate mechanism for UCB-induced neuromodulation and neurotoxicity.

Elevated levels of unbound unconjugated bilirubin (UCB) can lead to bilirubin encephalopathy and kernicterus. In spite of a large number of studies demonstrating UCB-induced changes in central neurotransmission, it is still unclear whether these effects involve alterations in the function of specific ion channels. To assess how different UCB concentrations and UCB:albumin (U/A) molar ratios affect neuronal R-type voltage-gated Ca2+ channels, we evaluated their effects on whole-cell currents through recombinant Cav2.3 + ß3 channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Cav2.3-deficient mice. Our findings show that modestly elevated levels of unbound UCB (U/A = 0.5) produce subtle but significant changes in the voltage-dependence of activation and prepulse inactivation, resulting in a stimulation of currents activated by weak depolarization and inhibition at potentials on the plateau of the activation curve. Saturation of the albumin binding capacity (U/A = 1) produced additional suppression that became significant when albumin was omitted completely and might involve a complete loss of channel function. Acutely administered UCB (U/A = 0.5) has recently been shown to affect transsynaptic signaling in the isolated vertebrate retina. The present report reveals that sustained exposure of the murine retina to UCB significantly suppresses also late responses of the inner retina (b-wave) from wildtype compared to Cav2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Cav2.3 channels. Together, these findings show that UCB affects cloned and native Cav2.3 channels at clinically relevant U/A molar ratios and indicate that supersaturation of albumin is not required for modulation but associated with a loss of channel functional that could contribute to chronic neuronal dysfunction.

Non-invasive evaluation of neurovascular coupling in the murine retina by dynamic retinal vessel analysis.

BACKGROUND: Impairment of neurovascular coupling (NVC) was recently reported in the context of subarachnoid hemorrhage and may correlate with disease severity and outcome. However, previous techniques to evaluate NVC required invasive procedures. Retinal vessels may represent an alternative option for non-invasive assessment of NVC. METHODS: A prototype of an adapted retinal vessel analyzer was used to assess retinal vessel diameter in mice. Dynamic vessel analysis (DVA) included an application of monochromatic flicker light impulses in predefined frequencies for evaluating NVC. All retinae were harvested after DVA and electroretinograms were performed. RESULTS: A total of 104 retinal scans were conducted in 21 male mice (90 scans). Quantitative arterial recordings were feasible only in a minority of animals, showing an emphasized reaction to flicker light impulses (8 mice; 14 scans). A characteristic venous response to flicker light, however, could observed in the majority of animals. Repeated measurements resulted in a significant decrease of baseline venous diameter (7 mice; 7 scans, p < 0.05). Ex-vivo electroretinograms, performed after in-vivo DVA, demonstrated a significant reduction of transretinal signaling in animals with repeated DVA (n = 6, p < 0.001). CONCLUSIONS: To the best of our knowledge, this is the first non-invasive study assessing murine retinal vessel response to flicker light with characteristic changes in NVC. The imaging system can be used for basic research and enables the investigation of retinal vessel dimension and function in control mice and genetically modified animals.

Reciprocal modulation of Cav 2.3 voltage-gated calcium channels by copper(II) ions and kainic acid.

Kainic acid (KA) is a potent agonist at non-N-methyl-D-aspartate (non-NMDA) ionotropic glutamate receptors and commonly used to induce seizures and excitotoxicity in animal models of human temporal lobe epilepsy. Among other factors, Cav 2.3 voltage-gated calcium channels have been implicated in the pathogenesis of KA-induced seizures. At physiologically relevant concentrations, endogenous trace metal ions (Cu2+ , Zn2+ ) occupy an allosteric binding site on the domain I gating module of these channels and interfere with voltage-dependent gating. Using whole-cell patch-clamp recordings in human embryonic kidney (HEK-293) cells stably transfected with human Cav 2.3d and ß3 -subunits, we identified a novel, glutamate receptor-independent mechanism by which KA can potently sensitize these channels. Our findings demonstrate that KA releases these channels from the tonic inhibition exerted by low nanomolar concentrations of Cu2+ and produces a hyperpolarizing shift in channel voltage-dependence by about 10 mV, thereby reconciling the effects of Cu2+ chelation with tricine. When tricine was used as a surrogate to study the receptor-independent action of KA in electroretinographic recordings from the isolated bovine retina, it selectively suppressed a late b-wave component, which we have previously shown to be enhanced by genetic or pharmacological ablation of Cav 2.3 channels. Although the pathophysiological relevance remains to be firmly established, we speculate that reversal of Cu2+ -induced allosteric suppression, presumably via formation of stable kainate-Cu2+ complexes, could contribute to the receptor-mediated excitatory effects of KA. In addition, we discuss experimental implications for the use of KA in vitro, with particular emphasis on the seemingly high incidence of trace metal contamination in common physiological solutions.

Unconjugated bilirubin modulates neuronal signaling only in wild-type mice, but not after ablation of the R-type/Cav 2.3 voltage-gated calcium channel.

INTRODUCTION: The relationship between blood metabolites and hemoglobin degradation products (BMHDPs) formed in the cerebrospinal fluid and the development of vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been the focus of several previous studies, but their molecular and cellular targets remain to be elucidated. METHODS: Because BMHDP-induced changes in Cav 2.3 channel function are thought to contribute to DCI after aSAH, we studied their modulation by unconjugated bilirubin (UCB) in an organotypical neuronal network from wild-type (WT) and Cav 2.3-deficient animals (KO). Murine retinae were isolated from WT and KO and superfused with nutrient solution. Electroretinograms were recorded before, during, and after superfusion with UCB. Transretinal signaling was analyzed as b-wave, implicit time, and area under the curve (AUC). RESULTS: Superfusion of UCB significantly attenuated the b-wave amplitude in the isolated retina from wild-type mice by 14.9% (P < 0.05), followed by gradual partial recovery (P = 0.09). Correspondingly, AUC decreased significantly with superfusion of UCB (P < 0.05). During washout, the b-wave amplitude returned to baseline (P = 0.2839). The effects of UCB were absent in Cav 2.3-deficient mice, lacking the expression of Cav 2.3 as proofed on the biochemical level. CONCLUSIONS: Ex vivo neuronal recording in the murine retina is able to detect transient impairment of transretinal signaling by UCB in WT, but not in KO. This new model may be useful to further clarify the role of calcium channels in neuronal signal alteration in the presence of BHMDPs.