Intravitreal anti-vascular endothelial growth factor therapy for retinal diseases in Norway from 2011 to 2021: A combined registry and survey study.

PURPOSE: To investigate the use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in Norway from 2011 to 2021 and explore how the eye departments organized their injection services. METHODS: We combined data from the Norwegian Patient Registry (NPR) with survey responses from Norway's 22 eye departments. The NPR data encompassed all registered intravitreal injection episodes from 2011 to 2021. The survey contained questions about local treatment practices and emphasized neovascular age-related macular degeneration (nAMD), retinal vein occlusion and diabetic macular edema. RESULTS: A total of 47247 unique patients received 841 646 intravitreal injections in the study period. The number of patients per year increased from 6522 in 2011 to 20 635 in 2021. The number of injections per year increased from 30 926 in 2011 to 125 258 in 2021. The most frequent diagnosis was nAMD. In 2021, the age-adjusted treatment activity in Norway's 11 counties ranged from 47.8 to 75.5 injections per 1000 inhabitants aged ≥50 years. The use of aflibercept gradually exceeded bevacizumab, but the aflibercept proportion per county ranged from 38 to 82% in 2021. The survey revealed varying treatment practices, local guidelines were often absent, and only half of the departments defined a lower visual limit for initiating or maintaining treatment. CONCLUSION: The use of intravitreal anti-VEGF therapy increased considerably from 2011 to 2021, but there was considerable regional variation in treatment activity, drug utilization and organization of injection services. These findings emphasize the need for strengthened governance and national guidelines to ensure equal treatment nationally.

Pharmaceutical compounding and storage of faricimab in a syringe for intravitreal injection do not impair stability and bi-specific binding properties.

BACKGROUND: Intravitreal injection (IVI) of antibody biologics is a key treatment approach in ophthalmology. Pharmaceutical compounding and storage of prefilled syringes for IVI must take place without impairing the structure and function of the biologics. This study investigated the effect of withdrawing and storing the therapeutic antibody faricimab (Vabysmo, Roche, Basel, Switzerland) in the Zero Residual silicone oil-free, 0.2-mL syringe (SJJ Solutions, The Hague, the Netherlands). METHODS: To assess the effect of syringe withdrawal on faricimab, we compared samples from syringes prepared at day 0 with samples taken directly from faricimab vials. To assess the effect of syringe storage on faricimab, we kept prefilled syringes in the dark at 4 oC for 7, 14, or 37 days and compared samples from these syringes with day 0. We measured protein concentration (with spectrophotometry), stability and integrity (with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size-exclusion chromatography (SEC), and melting temperature (Tm)), as well as binding of faricimab to its cognate antigens: vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2) (with enzyme-linked immunosorbent assay (ELISA)). RESULTS: Faricimab migrated in line with its expected molecular mass under both reducing and non-reducing conditions for all time points when analyzed with SDS-PAGE, without any sign of degradation products or aggregation. The SEC elution profiles were identical for all time points. There were slight variations in Tm for different time points compared to day 0 but without consistent relationship with storage time. ELISA did not detect differences in VEGF-A or Ang-2 binding between time points, and faricimab did not bind the neonatal Fc receptor. CONCLUSIONS: Withdrawal and storage of faricimab in syringes for up to day 37 did not impair the structure and bi-specific binding properties of the therapeutic antibody.

En kvinne i 60-årene som ikke lenger gjenkjente det hun så.

BACKGROUND: Neurological disorders can present with a vast array of visual disturbances. The constellation of symptoms and findings in this patient prompted workup for unusual causes of both stroke and neurodegenerative disorder. CASE PRESENTATION: A woman in her sixties presented with visual disturbances, followed by weakness in her right arm and aphasia three days later. Her close acquaintances had suspected progressive cognitive decline during the previous year. CT and MRI showed an occluded left posterior cerebral artery with a subacute occipito-temporal infarction. The finding of extensive white matter lesions and segmental arterial vasoconstriction necessitated further workup of vasculitis and hereditary small vessel disease, which were ruled out. The stroke aetiology was considered to be atherosclerotic intracranial large vessel disease. FDG-PET scan revealed decreased metabolism in the left hemisphere, and cerebrospinal biomarkers had slightly decreased beta-amyloid. The findings were suggestive of early Alzheimer's disease or primary progressive aphasia, but currently inconclusive. INTERPRETATION: Based on clinical-anatomical correlation, the patient's visual disturbances, in this case right hemianopsia and object agnosia, were solely related to the stroke and not to a neurodegenerative disorder. Knowledge and interpretation of visual agnosias can in many cases be clinically valuable.

International Olympic Committee (IOC) consensus paper on sports-related ophthalmology issues in elite sports.

Vision plays an important role in an athletes' success. In sports, nearly 80% of perceptual input is visual, and eye health and sports medicine are closely intertwined fields of utmost importance to athletes. The physical nature of sports activities renders individuals more prone to various eye injuries than the general population. Ocular trauma can lead to lifelong sequelae, and impaired vision requires careful follow-up and management. Apart from injuries, athletes may also experience vision problems that can hamper their performance, including blurred vision, double vision, and light sensitivity. The interdisciplinary nature of sports medicine necessitates collaboration between sports medicine professionals and ophthalmologists. Through such collaborations, athletes can receive appropriate eye care, education on proper eye protection and guidance on adopting good eye health practices. If any inconspicuous symptoms are not detected and treated promptly, athletes may acquire systemic injuries because of defective vision, preventing them from achieving high level athletic performance in competitions. The protection of the elite athlete is the responsibility of all of us in sports medicine. To advance a more unified, evidence-informed approach to ophthalmic health assessment and management in athletes and as relevant for sports medicine physicians, the International Olympic Committee Consensus Group aims for a critical evaluation of the current state of the science and practice of ophthalmologic issues and illness in high-level sports, and present recommendations for a unified approach to this important issue.

Wnt/ß-Catenin Signaling Activation Induces Differentiation in Human Limbal Epithelial Stem Cells Cultured Ex Vivo.

Human limbal epithelial stem cells (hLESCs) continuously replenish lost or damaged human corneal epithelial cells. The percentage of stem/progenitor cells in autologous ex vivo expanded tissue is essential for the long-term success of transplantation in patients with limbal epithelial stem cell deficiency. However, the molecular processes governing the stemness and differentiation state of hLESCs remain uncertain. Therefore, we sought to explore the impact of canonical Wnt/ß-catenin signaling activation on hLESCs by treating ex vivo expanded hLESC cultures with GSK-3 inhibitor LY2090314. Real-time qRT-PCR and microarray data reveal the downregulation of stemness (TP63), progenitor (SOX9), quiescence (CEBPD), and proliferation (MKI67, PCNA) genes and the upregulation of genes for differentiation (CX43, KRT3) in treated- compared to non-treated samples. The pathway activation was shown by AXIN2 upregulation and enhanced levels of accumulated ß-catenin. Immunocytochemistry and Western blot confirmed the findings for most of the above-mentioned markers. The Wnt/ß-catenin signaling profile demonstrated an upregulation of WNT1, WNT3, WNT5A, WNT6, and WNT11 gene expression and a downregulation for WNT7A and DKK1 in the treated samples. No significant differences were found for WNT2, WNT16B, WIF1, and DKK2 gene expression. Overall, our results demonstrate that activation of Wnt/ß-catenin signaling in ex vivo expanded hLESCs governs the cells towards differentiation and reduces proliferation and stem cell maintenance capability.

A Pilot Study of Implementing Diabetic Retinopathy Screening in the Oslo Region, Norway: Baseline Results.

PURPOSE: to gain insight into the baseline parameters of a population with diabetes mellitus (DM) included in a pilot diabetic retinopathy (DR) screening program at Oslo University Hospital (OUH), Norway. METHODS: This was a cross-sectional study of a cohort of adult patients (≥18 years) with type 1 or 2 DM (T1D and T2D). We measured the best-corrected visual acuity (BCVA), blood pressure (BP), heart rate (HR), intraocular pressure (IOP), height and weight. We also collected HbA1c, total serum cholesterol and urine-albumin, -creatinine and -albumin-to-creatinine ratio (ACR), as well as socio-demographic parameters, medications and previous screening history. We obtained color fundus photographs, which were graded by two experienced ophthalmologists according to the International Clinical Disease Severity Scale for DR. RESULTS: The study included 180 eyes of 90 patients: 12 patients (13.3%) had T1D and 78 (86.7%) had T2D. In the T1D group, 5 patients (41.7%) had no DR, and 7 (58.3%) had some degree of DR. In the T2D group, 60 patients (76.9%) had no DR, and 18 (23.1%) had some degree of DR. None of the patients had proliferative DR. Of the 43 patients not newly diagnosed (time of diagnosis > 5 years for T1D and >1 years for T2D), 37.5% of the T1D patients and 5.7% of the T2D patients had previously undergone regular screening. Univariate analyses found for the whole cohort significant associations between DR and age, HbA1c, urine albumin-to-creatinine ratio, body mass index (BMI) and duration of DM. For the T2D group alone, there were significant associations between DR and HbA1c, BMI, urine creatinine, urine albumin-to-creatinine ratio and duration of DM. The analysis also showed three times higher odds for DR in the T1D group than the T2D group. CONCLUSIONS: This study underscores the need for implementing a systematic DR screening program in the Oslo region, Norway, to better reach out to patients with DM and improve their screening adherence. Timely and proper treatment can prevent or mitigate vision loss and improve the prognosis. A considerable number of patients were referred from general practitioners for not being followed by an ophthalmologist.Among patients not newly diagnosed with DM, 62.8% had never had an eye exam, and the duration of DM for these patients was up to 18 years (median: 8 years).

Ex Vivo Pig Eye Model for Studying Diffusion of Acylcarnitines with Different Physicochemical Properties.

Purpose: To explore the diffusion capacities between the anterior and vitreous chambers in a novel ex vivo pig eye model using a mix of stable isotope-labeled acylcarnitines representing metabolites with different physical and chemical properties, and analysis using mass spectrometry (MS). Methods: Enucleated pig eyes were injected in the anterior or vitreous chamber of the eye with a stable isotope-labeled acylcarnitine mix (free carnitine, C2, C3, C4, C8, C12, and C16-having an increasing size and hydrophobicity in that order). Samples were collected from each chamber at 3, 6, and 24 h postincubation for analysis using MS. Results: After injection into the anterior chamber, the concentration of all acylcarnitines increased in the vitreous chamber over the observation period. After injection in the vitreous chamber, the acylcarnitines diffused to the anterior chamber with the highest concentration observed at 3 h postinjection, followed by a decrease in concentration possibly due to an elimination from the anterior chamber despite continued diffusion from the vitreous chamber. C16, the most hydrophobic and longest chain molecule, showed slower diffusion in both experimental settings. Conclusion: We hereby show a distinct diffusion pattern of molecules with different molecular size and hydrophobicity within and between the anterior and vitreous chamber. This model can be useful for optimizing choices and design of therapeutic molecules with higher retaining or depot properties into the two chambers of the eye for future intravitreal, intracameral, and topical treatment purposes.

A Novel Technique of Amniotic Membrane Preparation Mimicking Limbal Epithelial Crypts Enhances the Number of Progenitor Cells upon Expansion.

We aimed to investigate whether a novel technique of human amniotic membrane (HAM) preparation that mimics the crypts in the limbus enhances the number of progenitor cells cultured ex vivo. The HAMs were sutured on polyester membrane (1) standardly, to obtain a flat HAM surface, or (2) loosely, achieving the radial folding to mimic crypts in the limbus. Immunohistochemistry was used to demonstrate a higher number of cells positive for progenitor markers p63α (37.56 ± 3.34% vs. 62.53 ± 3.32%, p = 0.01) and SOX9 (35.53 ± 0.96% vs. 43.23 ± 2.32%, p = 0.04), proliferation marker Ki-67 (8.43 ± 0.38 % vs. 22.38 ± 1.95 %, p = 0.002) in the crypt-like HAMs vs. flat HAMs, while no difference was found for the quiescence marker CEBPD (22.99 ± 2.96% vs. 30.49 ± 3.33 %, p = 0.17). Most of the cells stained negative for the corneal epithelial differentiation marker KRT3/12, and some were positive for N-cadherin in the crypt-like structures, but there was no difference in staining for E-cadherin and CX43 in crypt-like HAMs vs. flat HAMs. This novel HAM preparation method enhanced the number of progenitor cells expanded in the crypt-like HAM compared to cultures on the conventional flat HAM.

Transition from Laser to Intravitreal Injections for Diabetic Retinopathy: Hospital Utilization and Costs from an Extended Healthcare Perspective.

PURPOSE: To describe the trends in hospital utilization and economic outcomes associated with the transition from laser to intravitreal injection (IVI) therapy for diabetic retinopathy (DR) at Oslo University Hospital (OUH), which provides the largest retina service in Norway. METHODS: This descriptive study analyzed hospital administrative data and determined the average utilization and treatment proportions of laser therapy, IVIs and vitrectomy for each patient per year. The Chi-square test was used to compare resource use between treatment groups. From an extended healthcare perspective, the annual cost per patient was calculated using Norwegian tariff data from 2020 and the National Medication Price Registry for patients seen between 2010 and 2018. Bootstrapping was performed to generate 95% confidence intervals for the cost per patient per year. RESULTS: Among the 1838 (41% female) patients treated for DR between 2005 and 2018, OUH provided on average 1.09 laser treatments per DR patient and 0.54 vitrectomies per DR patient in 2005, whose utilization declined to 0.54 and 0.05 treatments per DR patient, respectively, by 2018. Laser treatments declined from 64% to 10%, while vitrectomies declined from 32% to 1%. In contrast, IVI treatments increased from 4.5% to 89% of the total share, representing an average increase, from 0.08 injections per patient in 2005 to 4.73 injections per patient in 2018. Both the increasing number of DR patients and the shift in the type of treatment increased the economic costs of treating DR from a total of EUR 0.605 million (EUR 2935 per patient) in 2010 to EUR 2.240 million (EUR 3665 per patient) in 2018, with IVIs contributing considerably to these costs. CONCLUSIONS: Despite the decline in the use of vitrectomies, the transition from laser to IVI therapy for DR increased the healthcare resource utilization and economic costs of its treatment over the observed time. A main cost driver was the need for long-term IVIs, in addition to the drug cost itself. Trade-offs can be achieved through effective alternative IVI delivery or appropriate drug choice that balances patient needs with the economic burden of treating DR.

Human ocular surface microcirculation quantified by in vivo computer assisted video microscopy and diffuse reflectance spectroscopy.

Non-invasive imaging techniques are increasingly used to objectively quantify anterior segment structures of the eye. In this study, we apply the novel oxygen delivery index (ODIN) concept that, quantifies microvascular capacity for oxygen delivery, to the ocular surface in healthy humans. The purpose of the study was to test the applicability of the technologies used for data acquisition from the human ocular surface. We also validated whether the ODIN concept has sufficient sensitivity to detect and differentiate between microvascular structure and function in limbal and bulbar conjunctiva. Multiple ocular surface measurements using computer-assisted video microscopy (field of view: 1.6 mm × 0.9 mm) and diffuse reflectance spectroscopy (measuring volume: ∼0.1 mm3) were obtained from limbal and bulbar conjunctiva in 20 healthy volunteers. Three parameters were extracted during analyses: Functional capillary density, capillary flow velocity, and microvascular oxygen saturation. Functional capillary density was higher at limbus than in bulbar conjunctiva (11.2 ± 1.8 c/mm versus 5.2 ± 1.2 c/mm, p < 0.01), and microvascular oxygen saturation was lower at limbus (77 ± 8%) as compared to bulbar conjunctiva (89 ± 6%), p < 0.01. More than 80% of scored capillaries had continuous blood flow and no difference was seen between the recording sites (p = 0.68). In conclusion, the ODIN concept is applicable for the assessment of human ocular surface microvascular function and has sufficient sensitivity to detect increased capillary density and oxygen extraction at limbus as compared with bulbar conjunctiva.

Retinal injuries in seven teenage boys from the same handheld laser.

This paper presents retinal injuries in 10 eyes of seven teenagers who had been playing with a handheld laser. They reported different degrees of visual symptoms in the form of central scotomas. Clinical examination revealed light burns in the maculae and disruption of the retinal layers on OCT. One patient developed secondary choroidal neovascularization (CNV), which was successfully treated with intravitreal ranibizumab. For some of the patients, the injuries led to permanent visual sequela. This devastating case series emphasizes the need for awareness among minors, parents and communities about the danger of playing with handheld lasers.

Healthcare expenditure of intravitreal anti-vascular endothelial growth factor inhibitors compared with dexamethasone implant for diabetic macular oedema.

PURPOSE: The aim of this study was to estimate the 1-year costs associated with treating diabetic macular oedema (DME) patients using current intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics compared with the dexamethasone implant. METHODS: We conducted a descriptive cost-evaluation analysis using data from Oslo University Hospital and literature to compare three different intravitreal drugs for DME: bevacizumab, aflibercept and dexamethasone. Stratification of patients into 'Naive' or 'Switch' group was based on treatment history. We estimated the costs from healthcare and 'extended' healthcare perspectives. Sensitivity analysis evaluated the impact of various parameters. RESULTS: The average injections per patient per year for the Naive group (bevacizumab), Switch group (aflibercept) and dexamethasone were 9.5, 9.1 and 3.0 respectively. From a healthcare perspective, the 1-year costs for the Naive group were 15% lower (bevacizumab, €3619), and for the Switch group, 23% higher (aflibercept, €5226) compared with dexamethasone (€4252). The 'extended' healthcare perspective showed the cost per patient per year for bevacizumab remained nominally lower in the Naive group, while dexamethasone remained lower for the Switch group (€5116 for dexamethasone, compared to €4987 for bevacizumab and €6537 for aflibercept). CONCLUSIONS: From a primary healthcare perspective, the dexamethasone as a first-line DME treatment may increase economic costs in settings where bevacizumab is used off-label. Treating resistant DMEwith dexamethasone may reduce the costs and treatment burden compared with switching to aflibercept.

Does Pharmaceutical Compounding of Vascular Endothelial Growth Factor Inhibitors for Intravitreal Use Alter the Risk of Post-injection Endophthalmitis?

PURPOSE: To investigate the safety of pharmaceutically compounded syringes for intravitreal administration of anti-vascular endothelial growth factor (anti-VEGF) drugs. METHODS: Single center, retrospective chart review. From 2015 to 2019, Oslo University Hospital, Norway gradually implemented pharmaceutical compounding and splitting of bevacizumab, ranibizumab, and aflibercept vials into multiple prefilled syringes for intravitreal use. Medical records of all post-injection endophthalmitis (PIE) cases in this 5-year period were reviewed. The incidences of PIE associated with compounded and clinician-withdrawn syringes were compared. RESULTS: In 5 years, the total number of anti-VEGF injections was 112,926; 68,150 procedures (60%) utilized compounded syringes, and 44,776 procedures (40%) utilized clinician-withdrawn syringes. A total of 11 PIE cases were identified (incidence 0.10 per 1000; 95% CI 0.05-0.17). Five PIE cases were associated with compounded syringes (incidence 0.07 per 1000; 95% CI 0.03-0.17); 3 of these were culture positive. Six PIE cases were associated with clinician-withdrawn syringes (incidence 0.13 per 1000; 95% CI 0.06-0.29); 2 of these were culture positive. The relative risk of PIE following procedures utilizing compounded versus clinician-withdrawn syringes was 0.55 (95% CI 0.17-1.79; p = 0.32). CONCLUSION: Use of compounded anti-VEGF drugs in a large clinical setting was not associated with an altered risk of PIE. The finding adds to the evidence that splitting of vials into prefilled syringes for intravitreal injections is safe, provided that an appropriate pharmaceutical compounding procedure is strictly followed.

Ocular surface microcirculation is better preserved with pulsatile versus continuous flow during cardiopulmonary bypass-An experimental pilot.

BACKGROUND: Non-pulsatile cardiopulmonary bypass (CPB) may induce microvascular dysregulation. In piglets, we compared ocular surface microcirculation during pulsatile versus continuous flow (CF) bypass. METHODS: Ocular surface microcirculation in small tissue volumes (~0.1 mm3 ) at limbus (high metabolic rate) and bulbar conjunctiva (low metabolic rate) was examined in a porcine model using computer assisted video microscopy and diffuse reflectance spectroscopy, before and after 3 and 6 h of pulsatile (n = 5 piglets) or CF (n = 3 piglets) CPB. Functional capillary density, capillary flow velocity and microvascular oxygen saturation were quantified. RESULTS: At limbus, velocities improved with pulsatility (p < 0.01) and deteriorated with CF (p < 0.01). In bulbar conjunctiva, velocities were severely reduced with CF (p < 0.01), accompanied by an increase in capillary density (p < 0.01). Microvascular oxygen saturation decreased in both groups. CONCLUSION: Ocular surface capillary densities and flow patterns are better preserved with pulsatile versus CF during 6 h of CPB in sleeping piglets.

Cluster of symptomatic silicone oil droplets following intravitreal injections: a 1-year observational study.

OBJECTIVE: To describe a cluster of symptomatic intravitreal silicone oil (SiO) droplets following intravitreal injections (IVIs) and assess the effect of switching to a SiO-free syringe. METHODS AND ANALYSIS: Observational quality registry study of patients receiving IVI at a large Norwegian ophthalmology centre between April 2018 (start of cluster) and November 2019 (1 year after switching to SiO-free syringes). At onset, anti-vascular endothelial growth factor drugs were administered using SiO-containing insulin syringes. From November 2018, SiO-free syringes were implemented. Spontaneously reported symptomatic SiO cases were confirmed by slit-lamp examination. A follow-up interview was performed after 1 year, assessing visual complaints. The prevalence of non-symptomatic cases was assessed in a sample of 50 eyes from 50 consecutive IVI patients. RESULTS: Among 13 429 IVIs, 50 eyes of 46 patients (29 women) with symptomatic intravitreal SiO droplets were identified. Forty-one patients reported floaters at regular appointments, whereas five patients contacted the department regarding symptoms between scheduled appointments. After 1 year, 34 patients (79%) still experienced floaters, 21 (49%) reported reduced symptoms and 3 (7%) reported worsened symptoms. Eighteen patients (42%) reported being bothered, and eight (18.6%) reported that their lives were negatively affected by the floaters. Among 50 non-symptomatic eyes that had received IVI during the same period, intravitreal SiO was found in 34 (68%). No cases of symptomatic intravitreal SiO droplets were identified after switching to SiO-free syringes. CONCLUSION: Symptomatic intravitreal SiO following IVI can cause significant and prolonged distress for affected patients. It can be avoided by using SiO-free syringes.