A Novel Technique of Aseptic Manufacture of Autologous Serum Eye Drops (ASEDs) and Sterility Analysis of the Bottled Ophtioles.

PURPOSE: To introduce a novel technique of the aseptic manufacture of autologous serum eye drops (ASEDs) with a prefiltered closed system and to analyze the sterility of the produced ophtioles between 2018 and 2022. METHODS: This is a prospective single-center study conducted at the Department of Ophthalmology at a Swiss University Hospital between 2018 and 2022. For regulatory reasons, closed systems for manufacturing ASEDs are strongly recommended. We attached an upstream sterile filter (Sterivex PES0.22 µm Burlington, USA) to a commercially available closed system (COL System Modena, Italy) for manufacturing ASEDs. The goal of this novel approach was to reduce the microbiological contamination of the donated autologous blood. Using the presented manufacturing method, we are able to produce, on average, 56 ophtioles per batch, containing either 1.45 mL or 2.5 mL of autologous serum per ophtiole. For each batch of ASEDs, we performed a microbiological analysis by automated blood culture testing (BACTEC). This system examines the presence of bacteria and fungi. RESULTS: We analyzed all manufactured batches between 2018 and 2022. None of the 2297 batches and the resulting 129 060 ophtioles showed bacterial or mycotic contamination. During the analyzed period, two batches were discarded: one due to fibrin-lipid aggregations, further microbiological and histological work-up excluded any contamination; another due to false-positive HIV in serological testing. Overall, the contamination rate was 0%, and the batch discharge rate was 0.09%. CONCLUSIONS: The combination of upstream sterile filtration with a commercial closed system for manufacturing ASEDs proved to be effective in ensuring sterility without any contamination over the past 4 years. This is becoming crucial, as the demand for autologous blood products for treating ocular surface disorders, such as refractory dry eyes or nonhealing defects of the corneal epithelium, is on the rise.

Evaluation of Increase in Retinal Thickness as Diagnostic Marker in Central Artery Occlusion.

PURPOSE: To evaluate the increase in retinal thickness as a marker in predicting the onset of central retinal artery occlusions. METHODS: Retrospective clinical study conducted at one Swiss hospital. Electronic records were filtered for patients with artery occlusions. Optical coherence tomography data, including time between the imaging and ischemic event, were reviewed. Increase in relative retinal thickness was measured, defined as an increase in retinal thickness compared to the unaffected partner eye. This was correlated with the time from symptom onset. A cutoff value of relative increase of < 24.5% was applied, as suggested in previous studies. The results were compared to the time gathered from the electronic records, and sensitivity, specificity, positive predictive value as well as negative predictive value were calculated for predicting an ischemia time of < 4.5 h. RESULTS: Forty-two eyes from 41 patients with central artery occlusions were identified. Fourteen were female. Mean age was 66.4 ± 15.8 years. Initial corrected visual acuity was 2.41 ± 0.68 logMAR, and 2.13 ± 0.87 logMAR at the last follow-up (p > 0.05). Of eyes with a visual acuity of counting fingers (n = 38) or worse, 89.5% showed no improvement during follow-up, while eyes with logMAR 1 or better (n = 4) improved. Thirteen eyes (13 patients) presented within 4.5 h of the ischemic event. Four patients received i. v. thrombolysis, with visual recovery in one. In 12 eyes with an ischemia time of < 4.5 h, relative increase was below 24.5%. In the remaining 29 eyes with > 4.5 h, relative increase was below 24.5% in 4 eyes and above 24.5% in 25 eyes. This yielded a sensitivity of 92.3%, a specificity of 86.2%, with a positive predictive value of 75.0% and a negative predictive value of 96.2%. CONCLUSION: Central retinal artery occlusion is associated with severe vision loss. There is no current established therapy. Parameters that objectify the presence of a therapeutic window for thrombolysis are gaining in importance as patient history is often imprecise. Relative retinal thickness increase proved a noninvasive imaging parameter demonstrating adequate performance in detecting patients within the therapeutic window of thrombolysis. Further investigation of this parameter in central retinal occlusion is warranted.

Ophthalmological Outcomes in Patients with Susac Syndrome.

BACKGROUND: To report ophthalmological outcomes and treatment regimen in patients with Susac syndrome. METHODS: This is a retrospective analysis of patients with Susac syndrome treated between November 2015 and March 2023. Multimodal imaging findings, ophthalmic examination data, information on neurological and sensorineural involvement, and therapeutic regimen were reviewed. Visual acuity was recorded as the logarithm of the minimum angle of resolution (logMAR). Ophthalmological manifestations and disease severity were assessed using the previously described clinical activity score (CAS). RESULTS: Ten patients with Susac syndrome m : f = 5 : 5 were identified. The mean follow-up time was 31.2 ± 23.3 months (range 1 to 78 months). The mean age was 41.4 ± 13.8 years (range 21 to 59 years). At baseline, corrected distance visual acuity (CDVA) was 0.03 ± 0.08 logMAR. At the last follow-up, CDVA improved to 0.00 ± 0.03 logMAR (p = 0.029). Three of 20 eyes showed an improvement of 5 letters, while no loss of visual acuity was recorded during the follow-up time. Baseline CAS was 10.65 ± 12.69, and CAS at the last follow-up was 5.15 ± 5.49 (p = 0.068). Except for one patient, all were initially treated with intravenous (i. v.) steroids and subsequent oral tapering. Depending on the treatment response, cyclophosphamide (n = 4), i. v. immunoglobulins (IVIGs) (n = 4), anti-CD20 antibodies (n = 3), or plasmapheresis (n = 1) were applied. All patients under treatment for more than 1 month (n = 9) showed improvement in CAS and CDVA. CONCLUSION: Susac syndrome is a rare autoimmune vascular endotheliopathy. Treatment of Susac syndrome appears to result in improving CAS and CDVA. The majority of patients, in addition to the systemic steroids, required systemic immunosuppressive agents. Interdisciplinary communication is crucial to reduce the time to diagnosis and initiation of therapy in patients with Susac syndrome.

Efficacy of Subthreshold Micropulse Laser for Central Serous Chorioretinopathy.

PURPOSE: To evaluate the efficacy of a subthreshold micropulse laser (SML) in patients with central serous chorioretinopathy (CSCR). METHODS: Retrospective clinical study conducted at the Departments of Ophthalmology at a university and a municipal hospital in Zurich, Switzerland. We enrolled acute and chronic CSCR patients with persistent subretinal fluid (SRF) treated with SML. Two treatment protocols (fluorescein/indocyanine green angiography or optical coherence tomography guided) were evaluated for efficacy after 3 and 6 months. The primary outcomes of the study were reduction and percentage of eyes with complete resolution of SRF 3 and 6 months after SML treatment. Secondary endpoints included changes in central subfield thickness (CST) and visual acuity (VA) after 3 and 6 months. RESULTS: The study involved 37 eyes (35 patients, 48.6% chronic). A statistically significant reduction in SRF height and CST could be shown, irrespective of SRF duration, type of CSCR, or chosen guidance after 3 and 6 months: SRF - 40 µm (p < 0.01), CST - 52 µm (p < 0.01). Percentage of eyes with complete resolution of fluid at 3 and 6 months after SML were 24.3 and 21.6%, respectively. No statistically significant functional improvement (VA) could be shown. Multivariable regression and linear mixed regression analyses did not identify statistically significant differences in SRF reduction, CMT change, or VA improvement with respect to the type of CSCR or the treatment plan used (p > 0.05). CONCLUSION: The effectiveness of SML in CSCR is under continuous debate. Our study findings demonstrate structural but only little functional changes with SML. In view of the shortage of verteporfin for photodynamic therapy, SML remains an important therapeutic option for CSCR patients.

Imaging Assessment of Peripapillary Vessel Diameters in Postmortem Eyes.

PURPOSE: Proof of concept of ex vivo retinal vessel diameter measurements in human postmortem eyes. METHODS: En face near-infrared (IR) images and optical coherence tomography (OCT) of the optic nerve head (ONH) were captured ex vivo with a Heidelberg Engineering Spectralis (Spectralis, version 7.0.4, Image Capture Module, version 1.2.4, Heidelberg Heidelberg, Germany) device, using a custom-made eye chamber holding and positioning the eyes during the image process. Thirty-two formaldehyde-fixated eyes of 16 patients were imaged. In the IR images, two independent graders measured retinal vessel diameters at the intersection of a drawn circle centered on the ONH with diameters of 2.0 mm and 3.4 mm, respectively. The anatomically corresponding measurements between both graders were statistically analyzed using a Wilcoxon signed-rank test. RESULTS: A total of 246 matched measurements of both graders were analyzed across all 32 imaged eyes. Statistically significant differences between the graders were found for arterioles at 2 mm from the ONH. The other measurements did not show statistically significant intergrader differences. The mean values for arteriole diameters were 72.2 µm at 2.0 mm and 61.5 µm at 3.4 mm for grader 1, and 66.4 µm at 2.0 mm and 63.2 µm at 3.4 mm for grader 2. The mean diameter for venules were 75.5 µm at 2.0 mm and 79.3 µm at 3.4 mm for grader 1, and 67.4 µm at 2 mm and 79.1 µm at 3.4 mm for grader 2. CONCLUSION: To the best of our knowledge, this is the first study to present IR image-based retinal vessel diameters in ex vivo postmortem eyes. Retinal IR/OCT imaging is possible, and measurements are reproducible in formaldehyde-fixated human eyes. Fixation artefacts result in lower image quality, and this can impose challenges in correctly detecting, classifying, and measuring retinal vessels.

From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma.

Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research.

Retinal vessel volume reference database derived from volume-rendered optical coherence tomography angiography.

Optical coherence tomography angiography (OCTA) enables three-dimensional reconstruction of the functional blood vessels in the retina. Therefore, it enables the quantification of 3D retinal vessel parameters such as surface area and vessel volume. In spite of the widespread use of OCTA, no representative volume-rendered vessel volume (VV) data are published to date. In this study, OCTA 3 × 3 mm macular cubes were processed with volume-rendering techniques to measure VV in 203 eyes from 107 healthy volunteers. Generalized linear models (GLM) were constructed to assess the impact of age, gender, visual acuity (VA), spherical equivalent (SE), and axial length (AL) on VV. Overall mean VV was 0.23 ± 0.05mm3. Age and axial length showed a negative correlation with VV. However, GLM model analysis found that AL exerted the most pronounced influence on VV. No statistically significant associations were identified between gender or between left and right eyes. This is the first study to assess 3D OCTA VV and its naturally occurring variations in a large series of healthy subjects. It offers novel insights into the characterization of normal retinal vascular anatomy in healthy individuals, contributing to a valuable reference for future research in this field.

Central macular choriocapillaris impairment as a manifestation of microvascular disease in eyes with subretinal drusenoid deposits.

BACKGROUND/OBJECTIVES: Microvascular alterations and choroidal impairment are emerging as a pathologic pathway in age-related macular degeneration (AMD). This study aimed to evaluate the central macular choriocapillaris (CC) in eyes with subretinal drusenoid deposits (SDD) and the retinal microvasculature in patients with early AMD phenotypes. SUBJECTS/METHODS: This was an institutional, multicentric observational cross-sectional study. Ninety-nine eyes of 99 subjects; 33 eyes with SDD only, 33 eyes with conventional drusen (CD) only, and 33 eyes of healthy age-matched subjects were included. Comprehensive ophthalmologic examination and optical coherence tomography angiography (OCTA) was performed. The central macular flow area of the CC was analysed in the SDD group and the vessel density of the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) was analysed in the SDD and CD groups using automated OCTA output parameters. RESULTS: The flow area of the CC in the SDD group was significantly reduced (p ≤ 0.001) with respect to the healthy control group. There was a trend of reduction of vessel density of the SCP and the DCP in the SDD and CD group with respect to controls, although this did not reach statistical significance. CONCLUSIONS: OCTA data in the present report corroborate the role of vascular damage in early AMD with CC impairment in the central macular area in eyes with SDD.

Human selection bias drives the linear nature of the more ground truth effect in explainable deep learning optical coherence tomography image segmentation.

Supervised deep learning (DL) algorithms are highly dependent on training data for which human graders are assigned, for example, for optical coherence tomography (OCT) image annotation. Despite the tremendous success of DL, due to human judgment, these ground truth labels can be inaccurate and/or ambiguous and cause a human selection bias. We therefore investigated the impact of the size of the ground truth and variable numbers of graders on the predictive performance of the same DL architecture and repeated each experiment three times. The largest training dataset delivered a prediction performance close to that of human experts. All DL systems utilized were highly consistent. Nevertheless, the DL under-performers could not achieve any further autonomous improvement even after repeated training. Furthermore, a quantifiable linear relationship between ground truth ambiguity and the beneficial effect of having a larger amount of ground truth data was detected and marked as the more-ground-truth effect.

Vitamin A deficiency retinopathy related to medical interventions in a Swiss cohort: a case series.

AIMS OF THE STUDY: Vitamin A deficiency retinopathy is a potentially blinding disease. In developed countries, vitamin A deficiency due to malnutrition is rare. However, vitamin A deficiency can be caused by malabsorption resulting from bowel resection or medication. In this retrospective study, we present five cases of vitamin A deficiency retinopathy related to malabsorption secondary to medical interventions. METHODS: Electronic charts over a ten-year period (2012-2022) were screened for vitamin A deficiency retinopathy. Only patients with vitamin A deficiency confirmed by laboratory tests were included. Symptoms, medical history, visual acuity, optical coherence tomography, fundus autofluorescence, electrophysiological examination, and vitamin A levels were reviewed. RESULTS: Five eligible cases were identified. Median age was 44.7 years (range 22.2-88.9), median duration of ocular symptoms prior to diagnosis was 14 months, and median visual acuity was 1.0 (range 0.5-1.0, Snellen, decimal). Three patients had a history of bariatric surgery, one patient had a small bowel resection and was on octreotide treatment, and one patient suffered from cystic fibrosis and had a history of small bowel resection and severe hepatopathy. Optical coherence tomography showed various abnormalities, including a reduced interdigitation zone, subretinal drusenoid deposits, and a thinned outer nuclear layer. Electroretinogram findings ranged from abnormal oscillatory potentials to non-recordable rod responses. CONCLUSIONS: Vitamin A deficiency retinopathy can occur following medical interventions associated with malabsorption. In cases of night blindness, vitamin A levels should be measured.

Assessment of Retinal Vessel Tortuosity Index in Patients with Fabry Disease Using Optical Coherence Tomography Angiography (OCTA).

Vessel tortuosity (VT) is a parameter used to assess retinal involvement in patients affected by systemic diseases such as Fabry disease (FD). In this study, we assessed a retinal VT index (VTI) using optical coherence tomography angiography (OCTA) in a group of patients with FD (FD cohort) compared to a healthy control group (HC cohort). This is a single-center, retrospective study analysis of all consecutive patients with genetically tested and confirmed FD who underwent regular ophthalmological visits from December 2017 to January 2020 at the Department of Ophthalmology at the University Hospital of Zurich, Switzerland. VTI was calculated for each OCTA image and the results were compared between FD and HC cohort. A total of 56 participants, 32 (male:female ratio 12:20) in the FD cohort and 24 (male:female ratio 13:11) in the HC cohort. Classic onset was determined in 18 patients. Overall, mean VTI (±SD) was 0.21 (±0.07). Male patients with classic-onset FD had a significantly higher mean VTI (0.33, SD ± 0.35) compared to all other subgroups (p-value < 0.05). Further investigations of retinal VTI in patients with FD could be helpful to use OCTA as a noninvasive screening and follow-up modality to assess disease progression in affected patients.

Severe Complications after Corneal Collagen Cross-Linking (CXL).

PURPOSE: To present a case series of rare and severe complications after corneal collagen cross-linking (CXL) of keratoconus patients. METHODS: Single-center descriptive case series covering the period of 2012 to 2022 at the Department of Ophthalmology at the University Hospital, Zurich, Switzerland. RESULTS: We present four eyes of four patients that showed severe unusual complications within the first month after CXL. Three patients had been treated with the classical epithelium-off "Dresden" protocol. One patient had been treated with the accelerated epithelium-off protocol. One patient presented with extensive corneal edema due to rubbing the eye after treatment. Two patients showed a bacterial infectious keratitis: one due to Streptococcus pneumoniae and the other due to Staphylococcus hominis, Micrococcus luteus, and Streptococcus epidermidis. The latter of the two patients exhibited extensive infectious crystalline keratopathy. The fourth patient showed a severe ulcerative lesion where no infectious cause could be found. Therefore, an autoimmune keratolytic process had to be suspected. Apart from the corneal edema, which resolved ad integrum, the other complications resulted in permanent corneal scarring and thinning. One patient needed an emergency amniotic transplant. CONCLUSION: Severe complications after CXL remain rare. Most common causes are complications that are not directly associated with the treatment as such. Those indirect complications occur after the treatment during the healing course of the epithelium. Associations with bandage contact lenses, topical steroids, atopic disease, and inappropriate patient behavior are often suspected. Correctly performed corneal scrapings with repeated microbiological analysis and a detailed patient history are essential for establishing the correct diagnosis, especially in complicated cases that do not respond to a standard therapeutic regimen. This case series supports the efforts that are currently taken to improve the CXL technique in a way that postoperative complications are further reduced. A more efficient epithelium-on technique might be a step in that direction.