Controlled Subretinal Injection Pressure Prevents Damage in Pigs.

INTRODUCTION: Administration of retinal gene and stem cell therapy in patients with retinal degenerative diseases is in many cases dependent on a subretinal approach. It has been indicated that manual subretinal injection is associated with outer retinal damage, which may be explained by a high flow rate in the injection cannula. In the present porcine study, we evaluated flow-related retinal damage after controlled subretinal injection at different flow rates. METHODS: The flow rate through a 41G cannula was estimated at different injection pressures (6-48 pounds per square inch [PSI]) in an in vitro setup. A linear correlation between the flow rate and injection pressure was found from 6 to 32 PSI. In full anesthesia, 12 pigs were vitrectomized and received a controlled subretinal injection of 300 µL balanced saline solution at injection pressures of 14, 24, and 32 PSI (four in each group). Prior to surgery and 2 and 4 weeks after surgery, the eyes were examined by multifocal electroretinogram (mfERG) and fundus photographs. At the end of follow-up, the eyes were enucleated for histology. RESULTS: The in vitro flow study determined that the flow in a 41G cannula shifts from laminar to turbulent at 32 PSI and that the manual injection flow is turbulent. In the porcine study, we showed a significant difference in retinal pigment epithelium (RPE) damage between the three pressure groups (p = 0.0096). There was no significant difference in damage to the outer retina (p = 0.1526), but the high-pressure group (32 PSI) had the most outer retinal damage. The middle-pressure group (24 PSI) showed minimum retinal damage. There was no significant change in the mfERG ratios during follow-up. DISCUSSION/CONCLUSION: This study indicates that an injection pressure at approximately 24 PSI might be safe for subretinal delivery. Retinal damage at low injection pressures may be explained by mechanical damage to the RPE due to prolonged needle time in the subretinal space, while retinal damage at high pressures can be related to high flow in the injection cannula. Controlled subretinal injection pressure of 24 PSI showed minimum mechanical- and flow-related damage to the porcine retina.

ROBOT-ASSISTED VITREORETINAL SURGERY IMPROVES SURGICAL ACCURACY COMPARED WITH MANUAL SURGERY: A Randomized Trial in a Simulated Setting.

PURPOSE: To compare manual and robot-assisted vitreoretinal surgery using a virtual-reality surgical simulator. METHODS: Randomized controlled crossover study. Ten experienced vitreoretinal surgeons and 10 novice ophthalmic surgeons were included. The participants were randomized to start with either manual or robot-assisted surgery. Participants completed a test session consisting of three vitreoretinal modules on the Eyesi virtual-reality simulator. The automated metrics of performance supplied by the Eyesi simulator were used as outcome measures. Primary outcome measures were time with instruments inserted (seconds), instrument movement (mm), and tissue treatment (mm). RESULTS: Robot-assisted surgery was slower than manual surgery for both novices and vitreoretinal surgeons, 0.24 SD units (P = 0.024) and 0.73 SD units (P < 0.001), respectively. Robot-assisted surgery allowed for greater precision in novices and vitreoretinal surgeons, -0.96 SD units (P < 0.001) and -0.47 SD units (P < 0.001), respectively. Finally, novices using robot-assisted surgery inflicted less tissue damage when compared with that using manual surgery, -0.59 SD units (P = 0.009). CONCLUSION: At the cost of time, robot-assisted vitreoretinal surgery seems to improve precision and limit tissue damage compared with that of manual surgery. In particular, the performance of novice surgeons is enhanced with robot-assisted vitreoretinal surgery.

Simulators in the training of surgeons: is it worth the investment in money and time? 2018 Jules Gonin lecture of the Retina Research Foundation.

This paper describes transfer of skills obtained from training with the EyeSI virtual reality simulator of ophthalmic surgery to real-life surgical performance. Skills in real-life phacoemulsification surgery were assessed by systematic blinded evaluation of surgical videos based on the OSACCS system. Nineteen Danish cataract surgeons with varying clinical experience levels had their cataract surgery skills evaluated before and after completing a standardized mastery learning program on the EyeSI. It was found that transfer of skills could be demonstrated only for surgeons with a real-life experience of less than 75 completed, independent cases. We could not demonstrate transfer of skills from the EyeSI cataract module to the EyeSI vitreoretinal module, so each subspecialty seems to require specific training. Finally, the discriminative power of EyeSI simulation between emerging surgeons and experts was found to reside only in the first training sessions. The EyeSI simulator in its current state of development, and our implementation of it, seems to require further development before it can be used as a tool to select residents for surgical training and to re-certify more senior surgeons.

GAS-FOVEAL CONTACT: A New Approach to Evaluating Positioning Regimens in Macular Hole Surgery.

PURPOSE: To compare gas-foveal contact in face-down positioning (FDP) and nonsupine positioning (NSP), to analyze causes of gas-foveal separation and to determine how gas-foveal contact affects clinical outcome after idiopathic macular hole repair. METHODS: Single center, randomized controlled study. Participants with an idiopathic macular hole were allocated to either FDP or NSP. Primary outcome was gas-foveal contact, calculated by analyzing positioning in relation to intraocular gas fill. Positioning was measured with an electronic device recording positioning for 72 hours postoperatively. RESULTS: Positioning data were available for 33/35 in the FDP group and 35/37 in the NSP group, thus results are based on 68 analyzed participants. Median gas-foveal contact was 99.82% (range 73.6-100.0) in the FDP group and 99.57% (range 85.3-100.0) in the NSP group (P = 0.22). In a statistical model, gas fill had a significant relation to gas-foveal contact (P < 0.0001), whereas whether the surgeon prescribed FDP or NSP was not significant (P = 0.20). Of clinical relevance, gas-foveal contact seemed to influence idiopathic macular hole closure (P = 0.02). CONCLUSION: We found no significant difference in gas-foveal contact between the positioning groups. The role of positioning after idiopathic macular hole surgery seems to be better characterized from examining both patient positioning and gas fill objectively. We propose gas-foveal contact as a new outcome for evaluating positioning regimens.

NONSUPINE POSITIONING IN MACULAR HOLE SURGERY: A Noninferiority Randomized Clinical Trial.

PURPOSE: To determine whether nonsupine positioning (NSP) is noninferior to face-down positioning (FDP) in full-thickness macular hole (FTMH) surgery. METHODS: This is a single-center, open-label, randomized controlled trial. Between October 2013 and October 2014, pseudophakic participants underwent pars plana vitrectomy, internal limiting membrane peeling, and perfluoropropane gas tamponade and were randomly allocated to either FDP or NSP. The primary (noninferior) outcome was FTMH closure. The sample size was based on an estimated 95% closure rate and a -15% noninferiority margin for the NSP group. The secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at 3 months. Additionally, intraocular gas fill on postoperative Day 4 was measured. RESULTS: Eighty-one participants were enrolled. Final analysis of 68 participants demonstrated equal closure rates in both positioning groups: 33/34 (97.1%; 95% confidence interval: 84.7-99.9). Closure rates in the ≥400-µm FTMH subgroup were similar, 93.8% and 100.0% in the FDP and NSP groups, respectively (P = 0.43). Final visual acuity did not differ significantly between the groups (P = 0.60). Median gas fill was 78% (range: 57-86) in the FDP group and 76% (range: 56-85) in the NSP group (P = 0.51). Gas fill in closed FTMHs was significantly higher than in unclosed FTMHs (P = 0.02). CONCLUSION: Nonsupine positioning is noninferior to FDP in FTMH surgery. Furthermore, results suggest that the degree of gas fill affects FTMH closure.

Preoperative Positioning and Progression of Fovea-on Retinal Detachments.

PURPOSE: To study the relationship between positioning and rhegmatogenous retinal detachment (RRD) progression before surgery in patients with a fovea-on RRD. DESIGN: Prospective, single-cohort study. SUBJECTS: Patients with fovea-on RRD admitted to hospital for bedrest before surgical treatment were recruited. METHODS: Primary outcome was the shortest distance from the foveal center to the retinal detachment border on OCT. Secondary outcomes were measured with a head-mounted positioning sensor and included measures of head movement (linear acceleration and angular velocity) as well as measures of positioning regimen compliance. MAIN OUTCOME MEASURES: Distance from the fovea to the retinal detachment border. RESULTS: Overall, 50 patients with fovea-on positioned before RRD repair. One patient (1/50, 2%) progressed from fovea-on to fovea-off. Of the positioning measures, angular velocity demonstrated the strongest correlation with RRD border movement, whereas measures of positioning compliance showed nonsignificant correlation. After defining 3 movement groups: stable, intermediate, and mobile RRDs, we found that a doubling of head movement (angular velocity) correlated with a median RRD border progression of -6 µm/h, -75 µm/h, and -219 µm/h in the 3 groups, respectively. CONCLUSIONS: Rhegmatogenous retinal detachment border movement is correlated to angular velocity of the head, whereas compliance with our current positioning regimen does not have a significant impact on RRD border movement. Not all RRDs progress rapidly toward the fovea, but those that do seem to be highly influenced by head movement. For limiting RRD progression, a reduced movement positioning regimen may be superior to our current gravity-based approach. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The role of phacoemulsification surgery in the incidence rate of rhegmatogenous retinal detachment.

PURPOSE: To investigate changes in the incidence rate of primary rhegmatogenous retinal detachment (RRD) surgery over time and to determine to what extent these changes can be attributed to pseudophakia. METHODS: This nationwide cohort study was based on national patient registries. The study population comprised individuals at risk of RRD aged 40 years and above from 2006 to 2021 in Denmark. The primary outcome was RRD incidence, and the exposure was phacoemulsification surgery. A chart review was conducted to validate and examine the lens status of the outcome. RESULTS: The crude and age-adjusted incidence rate of RRD in the Danish population increased significantly during the study period. The largest increase in RRD was seen in phakic RRD (phRRD) (65%), whereas pseudophakic RRD (pRRD) accounted for 35% of the total increase. A chart review revealed that 17% of phRRDs were misclassified as pseudophakic, resulting in pRRD accounting for a total of 45% of the increase in RRD. The prevalence of pseudophakia in Denmark grew significantly for all age groups and for both sexes (p = 10-6) from 2006 to 2021, but the 1-year incidence of pRRD in the pseudophakic population was constant throughout the entire period. CONCLUSION: The incidence rate of RRD is continuing to increase in Denmark. The increase in phRRD remains undetermined, and while the risk of pRRD seemed to be constant during the study period, 45% of the overall increase in RRD could be attributed to the rise of a growing pseudophakic population.

Assessment of Anterior Uveitis Through Anterior-Segment Optical Coherence Tomography and Artificial Intelligence-Based Image Analyses.

Purpose: The purpose of this study was to develop an automated artificial intelligence (AI) based method to quantify inflammation in the anterior chamber (AC) using anterior-segment optical coherence tomography (AS-OCT) and to explore the correlation between AI assisted AS-OCT based inflammation analyses and clinical grading of anterior uveitis by Standardization of Uveitis Nomenclature (SUN). Methods: A prospective double blinded study of AS-OCT images of 32 eyes of 19 patients acquired by Tomey CASIA-II. OCT images were analyzed with proprietary AI-based software. Anatomic boundaries of the AC were segmented automatically by the AI software and Spearman's rank correlation between parameters related to AC cellular inflammation were calculated. Results: No significant (p = 0.6602) differences were found between the analyzed AC areas between samples of the different SUN grading, suggesting accurate and unbiased border detection/AC segmentation. Segmented AC areas were processed by the AI software and particles within the borders of AC were automatically counted by the software. Statistical analysis found significant (p < 0.001) correlation between clinical SUN grading and AI software detected particle count (Spearman ρ = 0.7077) and particle density (Spearman ρ = 0.7035). Significant (p < 0.001) correlation (Pearson's r = 0.9948) between manually and AI detected particles was found. No significant (p = 0.8080) difference was found between the sizes of the AI detected particles for all studies. Conclusions: AI-based image analysis of AS-OCT slides show significant and independent correlation with clinical SUN assessment. Translational Relevance: Automated AI-based AS-OCT image analysis suggests a noninvasive and quantitative assessment of AC inflammation with clear potential application in early detection and management of anterior uveitis.

Quantifying surgical skill in macular surgery.

PURPOSE: To evaluate the relationship between patient outcome and surgical experience by developing an objective quality measure of macular hole surgery based on forceps damage to the inner retina. METHODS: We retrospectively examined 3 macular hole case series >1 year after pars plana vitrectomy, internal limiting membrane peeling and gas tamponade. The patients were operated by (1) a novice surgeon (<20 cases), (2) an intermediate (150+ cases) and (3) an experienced surgeon (2000+ cases). Primary outcome was inner retinal volume defect as segmented from optical coherence tomography (GCL++: thickness from internal limiting membrane to inner plexiform layer). Secondary outcome was retinal function measured by confocal microperimetry using a custom scanning protocol. RESULTS: Thirty-two patients were examined: 11, 10 and 11 patients in the novice, intermediate and experienced surgeon group, respectively. Median GCL++ volume defect was 23.68 × 106 µm3 (IQR: 22.77 × 106 -44.81 × 106 µm3 ), 8.42 × 106 µm3 (IQR: 4.86 × 106 -10.03 × 106 µm3 ) and 3.55 × 106 µm3 (IQR: 1.44 × 103 -7.94 × 106 µm3 ) in the novice, intermediate and experienced surgeon group, respectively (p = 0.0004). The novice surgeon volume defect differed significantly from the intermediate and experienced surgeon (p = 0.016 and p = 0.0002, respectively). A subset of 12 patients underwent microperimetry measurements demonstrating correlation between inner retinal volume defect and reduced retinal sensitivity (p = 0.02). CONCLUSIONS: Forceps induced inner retinal damage commonly occurs during initiation of internal limiting membrane peeling in macular hole surgery. Damage to the structure and function of the inner retina seems to correlate to surgical experience.

Immune Checkpoint Inhibitor Treatment and Ophthalmologist Consultations in Patients with Malignant Melanoma or Lung Cancer-A Nationwide Cohort Study.

PURPOSE: To estimate the frequency of first-time ocular events in patients treated with immune checkpoint inhibitors (ICI). METHODS: Patients with cancer in 2011-2018 in Denmark were included and followed. The outcomes were first-time ophthalmologist consultation and ocular inflammation. One-year absolute risks of outcomes and hazard ratios were estimated. RESULTS: 112,289 patients with cancer were included, and 2195 were treated with ICI. One year after the first ICI treatment, 6% of the patients with cancer, 5% and 8% of the lung cancer (LC) and malignant cutaneous melanoma (MM) patients, respectively, had a first-time ophthalmologist consultation. The risk of ocular inflammation was 1% (95% confidence interval (CI) 0.4-1.2). Among patients with MM, ICI was associated with ocular inflammation in women (HR 12.6 (95% CI 5.83-27.31) and men (4.87 (95% CI 1.79-13.29)). Comparing patients with and without ICI treatment, the risk of first-time ophthalmologist consultation was increased in patients with LC (HR 1.74 (95% CI 1.29-2.34) and MM (HR 3.21 (95% CI 2.31-4.44). CONCLUSIONS: The one-year risks of first-time ophthalmologist consultation and ocular inflammation were 6% and 1%, respectively, in patients treated with ICI. In patients with LC and MM, the risk was increased in patients with ICI compared with patients without ICI.

Corneal pachymetry by AS-OCT after Descemet's membrane endothelial keratoplasty.

Corneal thickness (pachymetry) maps can be used to monitor restoration of corneal endothelial function, for example after Descemet's membrane endothelial keratoplasty (DMEK). Automated delineation of the corneal interfaces in anterior segment optical coherence tomography (AS-OCT) can be challenging for corneas that are irregularly shaped due to pathology, or as a consequence of surgery, leading to incorrect thickness measurements. In this research, deep learning is used to automatically delineate the corneal interfaces and measure corneal thickness with high accuracy in post-DMEK AS-OCT B-scans. Three different deep learning strategies were developed based on 960 B-scans from 50 patients. On an independent test set of 320 B-scans, corneal thickness could be measured with an error of 13.98 to 15.50 µm for the central 9 mm range, which is less than 3% of the average corneal thickness. The accurate thickness measurements were used to construct detailed pachymetry maps. Moreover, follow-up scans could be registered based on anatomical landmarks to obtain differential pachymetry maps. These maps may enable a more comprehensive understanding of the restoration of the endothelial function after DMEK, where thickness often varies throughout different regions of the cornea, and subsequently contribute to a standardized postoperative regime.

The incidence of rhegmatogenous retinal detachment is increasing.

PURPOSE: To study the development over time of the age- and sex-standardized incidence of rhegmatogenous retinal detachment (RRD) in Denmark. METHODS: Registry study, based on the Danish National Patient Registry data. End-point: Individuals undergoing the first surgery for RRD. RESULTS: During 2000-2016 we identified 11 769 individuals with a primary RRD surgery in either eye. The age- and sex-standardized incidence rate of RRD increased by more than 50% during the study period. We found a significant increase in this incidence rate for both men and women older than 50 years, and in men, but not in women, younger than 50 years (p < 0.001). However, the increase of primary RRD surgery during the study period was most pronounced in men aged 50 years or older, where the rate of increase was 1.7 ± 0.1 cases per 100 000 person-years per year (p < 10-11 ). CONCLUSION: The incidence of RRD is increasing, and this increase is primarily driven by men aged 50 years or older.

Quantifying Graft Detachment after Descemet's Membrane Endothelial Keratoplasty with Deep Convolutional Neural Networks.

Purpose: We developed a method to automatically locate and quantify graft detachment after Descemet's membrane endothelial keratoplasty (DMEK) in anterior segment optical coherence tomography (AS-OCT) scans. Methods: A total of 1280 AS-OCT B-scans were annotated by a DMEK expert. Using the annotations, a deep learning pipeline was developed to localize scleral spur, center the AS-OCT B-scans and segment the detached graft sections. Detachment segmentation model performance was evaluated per B-scan by comparing (1) length of detachment and (2) horizontal projection of the detached sections with the expert annotations. Horizontal projections were used to construct graft detachment maps. All final evaluations were done on a test set that was set apart during training of the models. A second DMEK expert annotated the test set to determine interrater performance. Results: Mean scleral spur localization error was 0.155 mm, whereas the interrater difference was 0.090 mm. The estimated graft detachment lengths were in 69% of the cases within a 10-pixel (∼150 µm) difference from the ground truth (77% for the second DMEK expert). Dice scores for the horizontal projections of all B-scans with detachments were 0.896 and 0.880 for our model and the second DMEK expert, respectively. Conclusions: Our deep learning model can be used to automatically and instantly localize graft detachment in AS-OCT B-scans. Horizontal detachment projections can be determined with the same accuracy as a human DMEK expert, allowing for the construction of accurate graft detachment maps. Translational Relevance: Automated localization and quantification of graft detachment can support DMEK research and standardize clinical decision-making.

Melanopsin-mediated pupillary light reflex and sleep quality in patients with normal tension glaucoma.

PURPOSE: The intrinsically photosensitive retinal ganglion cells (ipRGCs) and sleep quality are impaired in patients with primary open-angle glaucoma (POAG). In this study, we investigated whether ipRGCs and sleep quality were also impaired in patients with normal tension glaucoma (NTG). METHODS: We performed pupillometry and sleep quality assessment in 15 patients with NTG and 17 healthy age-matched controls. Pupillometry protocol consisted of monocular stimulation with high illuminance (100 lux) red (633 nm, 300 cd/m2 or 15.23 log quanta/cm2 /s) and blue light (463 nm, 332 cd/m2 or 15.27 log quanta/cm2 /s) and binocular pupil measurements. Prior to light stimulation, patients were dark-adapted for 5 min. The late postillumination pupillary response (PIPRL ate ) to blue light was used as marker of ipRGC activity. Sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI) questionnaire. RESULTS: The PIPRL ate to blue light was significantly reduced in patients with NTG compared to healthy subjects (p < 0.001), indicating impairment of the melanopsin-mediated pupillary pathway. There was no significant difference in the response elicited by red light (p = 0.6). Baseline pupil diameter and pupillary constriction amplitude to both red and blue light were reduced in patients with NTG (p < 0.05). The global score in PSQI was not significantly different between healthy controls and patients with NTG, indicating normal sleep quality (p = 0.6). Furthermore, we found no correlation between sleep parameters and pupillary light reflex parameters. CONCLUSION: Patients with NTG exhibited reduced ipRGC activity compared to healthy subjects, while no differences were observed in sleep quality.

Gas-Graft Coverage After DMEK: A Clinically Validated Numeric Study.

PURPOSE: We investigate the influence of positioning, gas fill, and anterior chamber size on bubble configuration and graft coverage after Descemet's membrane endothelial keratoplasty (DMEK). METHODS: We use a mathematical model to study the bubble shape and graft coverage in eyes of varying anterior chamber depths (ACD). The governing equations are solved numericly using the open source software OpenFOAM. Numeric results are validated clinically so that clinical gas fill measures can be correlated with numeric results providing gas-graft coverage information otherwise clinically inaccessible. RESULTS: In a phakic eye (ACD = 2.65 mm) with a gas fill of 35%, graft contact ranged from 35% to 38% depending on positioning and increased to 85% to 92% with a 70% fill. In contrast, positioning of a pseudophakic eye (ACD = 4.35) with a gas fill of 35% results in graft contact ranging from 8% to 52%, increasing to 63% to 94% with a 70% fill. The mathematical model demonstrates negligible differences between air and SF6 results and interestingly, a very thin central patch of aqueous humor within the gas bubble is found in some cases. CONCLUSIONS: Graft coverage in phakic eyes (ACD ≤ 3 mm) is dominated by the gas fill and less sensitive to patient positioning. In pseudophakic eyes with larger values of ACD, the graft coverage depends on gas fill and patient positioning with positioning even more important as ACD increases. TRANSLATIONAL RELEVANCE: Anterior chamber depth markedly influences the role of patient positioning in gas-filled eyes after DMEK due to the interplay between anterior chamber anatomy and gas bubble morphology.

Face-down positioning versus non-supine positioning in macular hole surgery.

AIM: To evaluate the full thickness macular hole (FTMH) closure rate in patients positioning non-supine (NSP) compared with patients positioning face-down (FDP). METHODS: We retrospectively reviewed two FTMH case series-postoperative positioning was FDP and NSP, respectively. All eyes were pseudophakic and treatment consisted of pars plana vitrectomy, internal limiting membrane peeling and perfluoropropane gas tamponade. Primary outcome measure was FTMH closure verified by optical coherence tomography. Secondary outcome was ETDRS visual acuity 6 months postoperatively. RESULTS: Over 13.7 months 122 eyes were included in this study, 66 eyes in the FDP group and 56 eyes in the NSP group. Closure rates were 95.5% and 96.4% in the FDP group and the NSP group, respectively. Median postoperative visual acuity at 6 months was 69 ETDRS letters in both positioning groups (p=0.64). Neither positioning group fully complied with the recommended positioning protocol. CONCLUSIONS: Results from consistent FTMH repair indicate similar anatomical success rates in FDP and NSP groups, suggesting that FDP is unnecessary. Objective monitoring of positioning would be beneficial in future FTMH studies to be able to adjust for positioning protocol compliance.