Clinical applications of optical coherence tomography in corneal surgery: Intraoperative optical coherence tomography imaging and exploration of predictors for graft detachment in Descemet membrane endothelial keratoplasty

The aim of this research was to study the utility of intraoperative OCT and investigate predictive factors of graft detachment in DMEK surgery. The first part of this dissertation focuses on the applications of intraoperative OCT in ophthalmic and in particular corneal surgery. Chapter 2 summarizes the current research and practical applications of intraoperative OCT. The review shows that surgeons are increasingly using intra-operative OCT during surgery and that this has a positive impact on surgical decision making. The benefits of OCT for the surgeon have been extensively studied, but the added value for patients is still unclear. Chapter 3 reports on our initial clinical experiences with intraoperative OCT during DMEK surgery and how this impacted the surgical protocol. The result of the study showed promising evidence that intraoperative OCT may lead to lower endothelial cell loss and incidence of postoperative complications in Descemet membrane endothelial keratoplasty surgery. This led to the conceptualization of an intraoperative OCT optimized surgical protocol was conceptualized consisting of OCT guidance for determining orientation, unfolding of the graft, and confirming adherence, while refraining from prolonged pressuring the eye. In chapter 4 the results of the ADVISE-trial are presented: a non-inferiority randomized control trial in which we compare the intraoperative OCT-optimized surgical DMEK protocol with the conventional practice; with prolonged overpressure of the eye and without support of intraoperative OCT. The study revealed the intraoperative OCT-optimized surgical DMEK protocol was non-inferior and overpressure can be obviated. In addition, the intraoperative OCT-optimized surgical DMEK protocol led to an improved surgical decision-making in 40% of surgeries and shorter surgical duration. Chapter 5 describes a case where intra-operative OCT proved crucial in the diagnosis and treatment of an infant with severe corneal edema caused by a rare corneal disease. In Chapter 6, we describe the development of an image analysis algorithm that can automatically determine the orientation of the graft in the eye using intra-operative OCT. The algorithm can automatically segment the graft and determine the top and bottom of the graft, eliminating the current time-consuming manual review of OCT images by surgeons. In the second part of the dissertation data-driven methods and advanced analytical methods are used to decode the causes of graft detachment following endothelial keratoplasty, a frequent and burdensome complication. In Chapter 7, machine learning methods are used to determine the relative contribution of patient and donor characteristics and surgical factors on graft detachment using data from the Dutch Organ Transplant Registry and the surgical protocols of corneal surgeons nationwide. In chapter 8 surgical videos were analyzed to assess the contribution of surgical handling and tissue manipulation on graft detachment. In chapter 9 we present a predictive model using optical coherence tomography scans taken one day after surgery to identify patients who will develop a graft detachment in the following days. The model was able to accurately identify which patients will develop a detachment and how large the area will be aiding clinical decision-making and tailored patient-care

Clinical applications of optical coherence tomography in corneal surgery: Intraoperative optical coherence tomography imaging and exploration of predictors for graft detachment in Descemet membrane endothelial keratoplasty

The aim of this research was to study the utility of intraoperative OCT and investigate predictive factors of graft detachment in DMEK surgery. The first part of this dissertation focuses on the applications of intraoperative OCT in ophthalmic and in particular corneal surgery. Chapter 2 summarizes the current research and practical applications of intraoperative OCT. The review shows that surgeons are increasingly using intra-operative OCT during surgery and that this has a positive impact on surgical decision making. The benefits of OCT for the surgeon have been extensively studied, but the added value for patients is still unclear. Chapter 3 reports on our initial clinical experiences with intraoperative OCT during DMEK surgery and how this impacted the surgical protocol. The result of the study showed promising evidence that intraoperative OCT may lead to lower endothelial cell loss and incidence of postoperative complications in Descemet membrane endothelial keratoplasty surgery. This led to the conceptualization of an intraoperative OCT optimized surgical protocol was conceptualized consisting of OCT guidance for determining orientation, unfolding of the graft, and confirming adherence, while refraining from prolonged pressuring the eye. In chapter 4 the results of the ADVISE-trial are presented: a non-inferiority randomized control trial in which we compare the intraoperative OCT-optimized surgical DMEK protocol with the conventional practice; with prolonged overpressure of the eye and without support of intraoperative OCT. The study revealed the intraoperative OCT-optimized surgical DMEK protocol was non-inferior and overpressure can be obviated. In addition, the intraoperative OCT-optimized surgical DMEK protocol led to an improved surgical decision-making in 40% of surgeries and shorter surgical duration. Chapter 5 describes a case where intra-operative OCT proved crucial in the diagnosis and treatment of an infant with severe corneal edema caused by a rare corneal disease. In Chapter 6, we describe the development of an image analysis algorithm that can automatically determine the orientation of the graft in the eye using intra-operative OCT. The algorithm can automatically segment the graft and determine the top and bottom of the graft, eliminating the current time-consuming manual review of OCT images by surgeons. In the second part of the dissertation data-driven methods and advanced analytical methods are used to decode the causes of graft detachment following endothelial keratoplasty, a frequent and burdensome complication. In Chapter 7, machine learning methods are used to determine the relative contribution of patient and donor characteristics and surgical factors on graft detachment using data from the Dutch Organ Transplant Registry and the surgical protocols of corneal surgeons nationwide. In chapter 8 surgical videos were analyzed to assess the contribution of surgical handling and tissue manipulation on graft detachment. In chapter 9 we present a predictive model using optical coherence tomography scans taken one day after surgery to identify patients who will develop a graft detachment in the following days. The model was able to accurately identify which patients will develop a detachment and how large the area will be aiding clinical decision-making and tailored patient-care

Autorefraction versus manifest refraction in patients with keratoconus

PURPOSE: To compare visual performance using autorefraction and manifest refraction assessments in patients with keratoconus and investigate whether autorefraction measurements lead to suboptimal visual performance. METHODS: Corrected distance visual acuity (CDVA) was measured in 90 eyes of 61 patients with keratoconus with both autorefraction and manifest refraction, in a random order. Maximum keratometry (Kmax), cone location, and wavefront aberration were determined with Scheimpflug tomography. The difference between the autorefraction and manifest refraction outcomes was converted to vectors and a multivariable analysis was performed to identify potential underlying causes of this difference. RESULTS: A significantly better CDVA was achieved with manifest refraction (0.06 vs 0.29 logMAR [20/23 vs 20/38 Snellen], P <.001). After vector analysis, a mean difference of 4.83 diopters was found between autorefraction and manifest refraction. Increased Kmax was strongly and significantly associated with better visual performance of manifest refraction compared to autorefraction (B = 0.496, P =.002). CONCLUSIONS: This study showed that a superior CDVA is achieved with manifest refraction compared to autorefraction in patients with keratoconus. Furthermore, the difference between the two refraction methods increases as the cornea steepens. According to this study, autorefraction is unreliable in patients with keratoconus and should be avoided

Validation of an Independent Web-Based Tool for Measuring Visual Acuity and Refractive Error (the Manifest versus Online Refractive Evaluation Trial) : Prospective open-label noninferiority clinical trial

BACKGROUND: Digital tools provide a unique opportunity to increase access to eye care. We developed a Web-based test that measures visual acuity and both spherical and cylindrical refractive errors. This test is Conformité Européenne marked and available on the Easee website. The purpose of this study was to compare the efficacy of this Web-based tool with traditional subjective manifest refraction in a prospective open-label noninferiority clinical trial. OBJECTIVE: The aim of this study was to evaluate the outcome of a Web-based refraction compared with a manifest refraction (golden standard). METHODS: Healthy volunteers from 18 to 40 years of age, with a refraction error between -6 and +4 diopter (D), were eligible. Each participant performed the Web-based test, and the reference test was performed by an optometrist. An absolute difference in refractive error of 1.0 in 90% (n=77) of participants. CONCLUSIONS: Our results indicate that Web-based eye testing is a valid and safe method for measuring visual acuity and refractive error in healthy eyes, particularly for mild myopia. This tool can be used for screening purposes, and it is an easily accessible alternative to the subjective manifest refraction test. TRIAL REGISTRATION: Clinicaltrials.gov NCT03313921; https://clinicaltrials.gov/ct2/show/NCT03313921

Automatic evaluation of graft orientation during Descemet membrane endothelial keratoplasty using intraoperative OCT

Correct Descemet Membrane Endothelial Keratoplasty (DMEK) graft orientation is imperative for success of DMEK surgery, but intraoperative evaluation can be challenging. We present a method for automatic evaluation of the graft orientation in intraoperative optical coherence tomography (iOCT), exploiting the natural rolling behavior of the graft. The method encompasses a deep learning model for graft segmentation, post-processing to obtain a smooth line representation, and curvature calculations to determine graft orientation. For an independent test set of 100 iOCT-frames, the automatic method correctly identified graft orientation in 78 frames and obtained an area under the receiver operating characteristic curve (AUC) of 0.84. When we replaced the automatic segmentation with the manual masks, the AUC increased to 0.92, corresponding to an accuracy of 86%. In comparison, two corneal specialists correctly identified graft orientation in 90% and 91% of the iOCT-frames

Clinical Evaluation and Validation of the Dutch Crosslinking for Keratoconus Score

Importance: Defining keratoconus progression is fundamental in clinical decision making because crosslinking treatments are indicated when the disease is considered progressive. Currently, there is no consensus which parameters should be used to define progression. Objective: To assess and validate a novel clinical scoring system as an easy-to-use assessment tool for crosslinking treatment in patients with keratoconus. Design, Setting, and Participants: Prospective cohort study at 2 academic treatment centers. Patients with keratoconus referred between January 1, 2012, and June 30, 2014, with 2-year follow-up were included. Analysis began March 2017. Interventions: The Dutch Crosslinking for Keratoconus (DUCK) score is based on changes in 5 clinical parameters that are routinely assessed: age, visual acuity, refraction error, keratometry, and subjective patient experience. The DUCK score is derived by scoring 0 to 2 points per item, and cutoffs were determined by clinical experience. We compared the DUCK scores to the conventional 1.0-diopter increase in maximum keratometry criterion, within the last 12 months, in a longitudinal discovery and a validation cohort. Sensitivity analyses and intraitem correlations were performed. Main Outcomes and Measures: Overall treatment rate reduction and the duly withheld treatment rate. Results: A total of 504 eyes of 388 patients were available for analysis on disease progression in the course of 12 and 24 months. Baseline patient characteristics of the discovery cohort and the validation cohort were comparable in terms of age (mean [SD], 26.8 [8.3] years vs 26.3 [9.1]), sex (216 of 332 [65%] vs 123 of 172 [72%] men), and maximum keratometry (mean [SD], 53.5 [7.1] vs 52.7 [6.3]). Adhering to the DUCK score, rather than maximum keratometry, was associated with a reduction in overall treatment rate by 23% (95% CI, 18%-30%), without increasing the risk of disease progression (ie, the rate of progression for both groups was equal; ±0%). The DUCK score appears to better identify eyes that were duly withheld treatment by 35% (95% CI, 22%-49%). Conclusions and Relevance: These results provide validation of the DUCK score as a tool to determine whether a crosslinking treatment might be warranted. Compared with the conventional maximum keratometry criterion of more than 1.0 diopter, the DUCK score may better select patients who might benefit from crosslinking treatment. Potentially, it may prevent unnecessary treatments, reduce exposure to treatment risks, and improve the cost effectiveness of crosslinking

Video Grading of Descemet Membrane Endothelial Keratoplasty Surgery to Identify Surgeon Risk Factors for Graft Detachment and Rebubbling: A Post Hoc Observational Analysis of the Advanced Visualization In Corneal Surgery Evaluation Trial

PURPOSE: The aim of this study was to explore video-graded intraoperative risk factors for graft detachment (GD) and rebubbling in Descemet membrane endothelial keratoplasty surgery. METHODS: A post hoc analysis of 65 eyes of 65 pseudophakic subjects with Fuchs endothelial dystrophy that underwent Descemet membrane endothelial keratoplasty surgery as part of the Advanced Visualization In Corneal Surgery Evaluation trial. All surgical recordings were assessed by 2 graders using a structured assessment form. A multinominal regression was performed to estimate the independent effect of video-graded intraoperative factors on the incidence of GD and rebubbling. Secondary outcomes are corrected distance visual acuity and endothelial cell density. RESULTS: In total, 33 GDs were recorded, of which 17 required rebubbling. No significant predictors for GD or rebubbling were identified. However, the results revealed 2 clinically relevant patterns. An unfavorable graft configuration (ie, wrinkled, tight scroll, or taco-shaped) and a gas-bubble size smaller than the graft diameter were associated with an increased risk of GD [odds ratio (OR) 2.5 and OR 2.26, respectively] and rebubbling (OR 2.0 and OR 2.60, respectively). Inversely, a larger gas-bubble size was associated with a reduced risk of GD (OR 0.37) and rebubbling (OR 0.36). At 3 and 6 months postoperatively, corrected distance visual acuity was poorer in subjects requiring a rebubbling and endothelial cell density loss was higher in subjects with a partial GD. CONCLUSIONS: Our analysis revealed that the gas-bubble size and graft shape/geometry seem to be relevant clinical factors for GD and rebubbling, whereas descemetorhexis difficulty, degree of graft manipulation, graft overlap, and surgical iridectomy were not associated with an increased risk

Prospective evaluation of clinical outcomes between pre-cut corneal grafts prepared using a manual or automated technique : with one-year follow-up

Purpose: Posterior lamellar corneal surgery is considered the standard of care for irreversible endothelial cell dysfunction. Pre-cut grafts can be prepared either manually (Descemet stripping endothelial keratoplasty; DSEK) or mechanically (Descemet stripping automated endothelial keratoplasty; DSAEK). We performed a head-to-head clinical comparison between DSEK and DSAEK grafts. Methods: All DSEK and DSAEK procedures performed by two corneal specialists at the University Medical Center Utrecht from 1 January 2016 through 31 October 2016 were prospectively included. Pre-cut grafts were delivered by two eye banks, which either exclusively prepared the DSEK or DSAEK grafts. Preoperative and postoperative measurements were obtained, and all surgical events and adverse events were recorded. Results: A total of 21 DSEK and 53 DSAEK procedures were included for analysis; the two groups were similar at baseline, with the exception of graft endothelial cell density, which was 2531 ± 67 versus 2748 ± 148 cells/mm 2 , respectively (p < 0.001). At the one-year follow-up visit, corrected distance visual acuity and endothelial cell loss were similar between the groups. Mean pachymetry was significantly lower in the DSEK group (521 ± 39 versus 588 ± 59 μm; p < 0.001), whereas the rebubbling rate was significantly higher in the DSEK group (47.6% versus 18.9%; p = 0.001). Finally, three grafts in the DSEK group experienced failure compared to one graft in the DSAEK group (14% versus 1.9%, respectively). Conclusion: Manually dissected and microkeratome-dissected grafts performed similarly with respect to vision and endothelial cell loss assessed one year after surgery. The higher incidence of graft failure among manually dissected (i.e. DSEK) grafts may be attributable to reduced relative thickness compared to DSAEK grafts and/or the resulting differences in tissue handling and the surgeon's learning curve

Prospective evaluation of clinical outcomes between pre‐cut corneal grafts prepared using a manual or automated technique: with one‐year follow‐up

Purpose: Posterior lamellar corneal surgery is considered the standard of care for irreversible endothelial cell dysfunction. Pre-cut grafts can be prepared either manually (Descemet stripping endothelial keratoplasty; DSEK) or mechanically (Descemet stripping automated endothelial keratoplasty; DSAEK). We performed a head-to-head clinical comparison between DSEK and DSAEK grafts. Methods: All DSEK and DSAEK procedures performed by two corneal specialists at the University Medical Center Utrecht from 1 January 2016 through 31 October 2016 were prospectively included. Pre-cut grafts were delivered by two eye banks, which either exclusively prepared the DSEK or DSAEK grafts. Preoperative and postoperative measurements were obtained, and all surgical events and adverse events were recorded. Results: A total of 21 DSEK and 53 DSAEK procedures were included for analysis; the two groups were similar at baseline, with the exception of graft endothelial cell density, which was 2531 ± 67 versus 2748 ± 148 cells/mm 2 , respectively (p < 0.001). At the one-year follow-up visit, corrected distance visual acuity and endothelial cell loss were similar between the groups. Mean pachymetry was significantly lower in the DSEK group (521 ± 39 versus 588 ± 59 μm; p < 0.001), whereas the rebubbling rate was significantly higher in the DSEK group (47.6% versus 18.9%; p = 0.001). Finally, three grafts in the DSEK group experienced failure compared to one graft in the DSAEK group (14% versus 1.9%, respectively). Conclusion: Manually dissected and microkeratome-dissected grafts performed similarly with respect to vision and endothelial cell loss assessed one year after surgery. The higher incidence of graft failure among manually dissected (i.e. DSEK) grafts may be attributable to reduced relative thickness compared to DSAEK grafts and/or the resulting differences in tissue handling and the surgeon's learning curve