Synchronous Diagnosis of Diabetic Retinopathy by a Handheld Retinal Camera, Artificial Intelligence, and Simultaneous Specialist Confirmation.

PURPOSE: Diabetic retinopathy (DR) is a leading cause of preventable blindness, particularly in underserved regions where access to ophthalmic care is limited. This study presents a proof of concept for utilizing a portable handheld retinal camera with an embedded artificial intelligence (AI) platform, complemented by a synchronous remote confirmation by retina specialists, for DR screening in an underserved rural area. DESIGN: Retrospective cohort study SUBJECTS: 1,115 individuals with diabetes. METHODS: A retrospective analysis of a screening initiative conducted in four municipalities in Northeastern Brazil, targeting the diabetic population. A portable handheld retinal camera captured macula-centered and disc-centered images, which were analyzed by the AI system. Immediate push notifications were sent out to retina specialists upon the detection of significant abnormalities, enabling synchronous verification and confirmation, with on-site patient feedback within minutes. Referral criteria were established, and all referred patients underwent a complete ophthalmic work-up and subsequent treatment. MAIN OUTCOME MEASURES: Proof-of-concept implementation success. RESULTS: Out of 2,052 invited individuals, 1,115 participated, with a mean age of 60.93 years and diabetes duration of 7.52 years, of whom 66.03% were women. The screening covered 2,222 eyes, revealing various retinal conditions. Referable eyes for DR were 11.84%, with an additional 13% for other conditions (diagnoses included various stages of DR, media opacity, nevus, drusen, enlarged cup-to-disc ratio, pigmentary changes, and other). AI performance for overall detection of referable cases (both DR and other conditions) was: sensitivity- 84.23% (95% CI- 82.63-85.84), specificity- 80.79% (95% CI- 79.05- 82.53). When we assessed whether AI matched any clinical diagnosis, be it referable or not, sensitivity was 85.67% (95% CI- 84.12-87.22), specificity was 98.86 (95% CI- 98.39-99.33), and AUC was 0.92 (95% CI- 0.91-0.94). CONCLUSIONS: The integration of a portable device, AI analysis, and synchronous medical validation has the potential to play a crucial role in preventing blindness from DR, especially in socially unequal scenarios.

Automated Identification of Different Severity Levels of Diabetic Retinopathy Using a Handheld Fundus Camera and Single-Image Protocol.

Purpose: To evaluate the performance of artificial intelligence (AI) systems embedded in a mobile, handheld retinal camera, with a single retinal image protocol, in detecting both diabetic retinopathy (DR) and more-than-mild diabetic retinopathy (mtmDR). Design: Multicenter cross-sectional diagnostic study, conducted at 3 diabetes care and eye care facilities. Participants: A total of 327 individuals with diabetes mellitus (type 1 or type 2) underwent a retinal imaging protocol enabling expert reading and automated analysis. Methods: Participants underwent fundus photographs using a portable retinal camera (Phelcom Eyer). The captured images were automatically analyzed by deep learning algorithms retinal alteration score (RAS) and diabetic retinopathy alteration score (DRAS), consisting of convolutional neural networks trained on EyePACS data sets and fine-tuned using data sets of portable device fundus images. The ground truth was the classification of DR corresponding to adjudicated expert reading, performed by 3 certified ophthalmologists. Main Outcome Measures: Primary outcome measures included the sensitivity and specificity of the AI system in detecting DR and/or mtmDR using a single-field, macula-centered fundus photograph for each eye, compared with a rigorous clinical reference standard comprising the reading center grading of 2-field imaging protocol using the International Classification of Diabetic Retinopathy severity scale. Results: Of 327 analyzed patients (mean age, 57.0 ± 16.8 years; mean diabetes duration, 16.3 ± 9.7 years), 307 completed the study protocol. Sensitivity and specificity of the AI system were high in detecting any DR with DRAS (sensitivity, 90.48% [95% confidence interval (CI), 84.99%-94.46%]; specificity, 90.65% [95% CI, 84.54%-94.93%]) and mtmDR with the combination of RAS and DRAS (sensitivity, 90.23% [95% CI, 83.87%-94.69%]; specificity, 85.06% [95% CI, 78.88%-90.00%]). The area under the receiver operating characteristic curve was 0.95 for any DR and 0.89 for mtmDR. Conclusions: This study showed a high accuracy for the detection of DR in different levels of severity with a single retinal photo per eye in an all-in-one solution, composed of a portable retinal camera powered by AI. Such a strategy holds great potential for increasing coverage rates of screening programs, contributing to prevention of avoidable blindness. Financial Disclosures: F.K.M. is a medical consultant for Phelcom Technologies. J.A.S. is Chief Executive Officer and proprietary of Phelcom Technologies. D.L. is Chief Technology Officer and proprietary of Phelcom Technologies. P.V.P. is an employee at Phelcom Technologies.

Review of real-world evidence of dual inhibition of VEGF-A and ANG-2 with faricimab in NAMD and DME.

Management of vitreoretinal disorders (e.g., neovascular age-related macular degeneration [nAMD] and diabetic macular edema [DME]) have assumed the standard therapy of lifelong anti-VEGF injections with drugs like aflibercept, brolucizumab, ranibizumab and bevacizumab. However, the burden imposed on patients is a major deterrent for continual therapy and recovery. Faricimab, a bispecific antibody, blocking both VEGF-A and Ang-2 molecules, produces a comparable functional and anatomical results, with less injections, significantly reducing patient burden. Visual acuity, safety, adverse effects, and anatomical outcomes are discussed in the pivotal clinical trials (YOSEMITE/RHINE and TENAYA/LUCERNE), and early data from real-world studies (TRUCKEE, TAHOE, FARWIDE-DME, FARETINA and others). In YOSEMITE and RHINE, faricimab demonstrated non-inferior vision gains, better anatomical outcomes compared to aflibercept every 8 weeks. Faricimab in the personalized treatment interval (PTI), after week 96, achieved 12-week interval in 78.1% of the patients and 16-week interval in 62.3%. TENAYA and LUCERNE reported comparable best corrected visual acuity (BCVA) improvement and better anatomic outcomes during head-to-head phase, parallel to aflibercept, at its 8-week treatment schedule. Faricimab in the PTI regimen, after week 96 achieved 12-week interval in 77.8% of the patients and 16-week interval in 63.1%. Safety of faricimab has been comparable to aflibercept in these pivotal trials. Real-world data supports the data from the pivotal studies regarding the efficacy and safety profile of faricimab in heterogenous real world patient population. Moreover, in previously treated patients, it also demonstrated a faster fluid resolution, good safety profile. Considering faricimab has demonstrated anatomic and durability benefit in the treatment of nAMD and DME, additional data from ongoing extension clinical trials, AVONELLE-X and RHONE-X will help understand longer term outcomes for patients treated with faricimab as well as patients switching from aflibercept to faricimab after finishing the pivotal trials. Longer term data from the real-world studies will also continue to contribute to our understanding of long-term efficacy, safety and durability in the real world patient population.

Anti-complement drugs for the treatment of geographic atrophy and the release of silicone oil.

Intravitreal injections are a common procedure in ophthalmology, often using syringes coated with silicone to aid piston movement and needles coated with silicone oil to facilitate penetration of the sclera. Pegcetacoplan and avacincaptad pegol, recently approved for clinical use by the US Food and Drug Administration, have higher viscosity and seem more susceptible to entrap air bubbles compared to anti-VEGF drugs.It is plausible that both anti-complement drugs could be associated with a higher likelihood of introducing silicone oil in the vitreous because of higher viscosity, with potentially higher friction at the inner surface of syringe barrel, in the vicinity of silicone oil. In addition to this, undesirable agitation might be inadvertently promoted by some retina specialists to remove air bubbles from the drug solution.In conclusion, recent reports of silicone oil droplets in the vitreous of patients receiving pegcetacoplan injection might be related to both its viscosity and to agitation of the syringe to remove air bubbles. Since avacincaptad pegol also is viscous, though with different pH, syringe and filter needle, we might expect similar reports for this agent soon. We also recommend further studies be carried not only to clarify the current matter but also the potential association between the combination of agitation, silicone oil and inflammation or any immune response.

Can intravitreal injections with higher volume cause higher intraocular eye pressure? Considerations for anti-complement injections in normal and glaucomatous eyes.

The approval of Syfovre® (pegcetacoplan) and Iverzay® (avacincaptad pegol) for the treatment of geographic atrophy (GA) marks a significant advancement in retinal disease therapy, offering both complement 3 and complement 5 inhibitors. With this breakthrough, an increase in intravitreal injections (IVI) is expected to treat GA, raising questions about potential effects on intraocular pressure (IOP). This concern is exacerbated by the larger injection volume required for GA treatment, potentially impacting IOP. Previous studies have shown that IVI can lead to a temporary increase in IOP with a 0.05 ml injection. This transient elevation is challenging to manage with glaucoma drops, and a preventive approach, such as paracentesis immediately before IVIs, may be more effective. Despite concerns, clinical significance and long-term effects of IOP changes with a 0.05 ml injection remain uncertain. To address these concerns, routine evaluations including macular optical coherence tomography (OCT), fundus autofluorescence, IOP measurements, and retinal nerve fiber layer OCT before the first IVI with avacincaptad pegol and pegcetacoplan are recommended to detect potential changes early. Further research is needed to determine the extent to which IOP changes impact GA patients and whether cumulative effects occur with repeated IVIs, especially in those with additional eye conditions.

Accuracy, Precision, and Residual Volume of Commonly Used Syringes for Intravitreal Injections and the Impact on Intraocular Pressure.

PURPOSE: To compare accuracy, precision, and residual volume of commonly used syringes for intravitreal injections (IVIs) and to assess the intraocular pressure (IOP) rise by variations in volumes delivered. DESIGN: Experimental laboratory study. SUBJECTS: No subjects were involved in this study. METHODS: We tested 8 syringe models with 2 different needle setups, with 2 different solutions (distilled water or glycerin) and target volumes (50 and 70 µL). To obtain the delivered and residual volumes, we weighed the syringe-needle setups with scale before liquid withdrawal, with liquid, and after liquid release. We also created an experimental eye model to determine the transient rise in IOP following stepwise 10-µL increases in injection volumes. MAIN OUTCOME MEASURES: Delivered and residual volumes, IOP rise. RESULTS: We tested a total of 600 syringe-needle setups. Becton Dickinson (BD) Ultra-Fine (0.34 ± 0.28 µL), Zero Residual (1.53 ± 1.15 µL), and Zero Residual Silicone Oil-free (1.40 ± 1.16 µL) syringes showed the lowest residual volume (P < 0.001) in comparison with the others (range: 24.86 ± 1.78 µL for Injekt-F to 51.97 ± 3.37 µL for Omnifix-F). The most accurate setups were (percentage deviation from target volume): Zero Residual Silicone Oil-free (+ 0.70%), Zero Residual 0.3 ml (+ 4.49%), BD Ultra-Fine (+ 7.83%), Injekt-F (9.42%), Norm-Ject (+ 15.88%), Omnifix-F (+ 16.96%), BD Plastipak Brazil (+17.96%), and BD Plastipak Spain syringes (+ 19.41%). There was a statistically significant difference between the Zero Residual Silicone Oil-free syringe and all other syringes (P < 0.0001), except for the Zero Residual 0.3-ml syringe (P = 0.029). The coefficient of variation was low for all syringes. The modeled IOP rise ranged from 32.3 (standard deviation [SD], 1.4) mmHg for 20-µL injection volume to 76.5 (SD, 1.0) mmHg for 80-µL injection volume. For the standard 50-µL injection volume, the peak pressure was 50.7 (SD, 0.1) mmHg, and the pressure rise duration was 28 (SD, 2) minutes. CONCLUSIONS: There were significant differences in accuracy and residual volume between syringes, whereas they showed a high precision. Volume excess results in a considerable increase in IOP rise after injection. These findings may provide a relevant overview to clinicians and to both device and drug manufacturers regarding pharmacoeconomic, safety, and efficacy issues. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical validation of a smartphone-based retinal camera for diabetic retinopathy screening.

AIMS: This study aims to compare the performance of a handheld fundus camera (Eyer) and standard tabletop fundus cameras (Visucam 500, Visucam 540, and Canon CR-2) for diabetic retinopathy and diabetic macular edema screening. METHODS: This was a multicenter, cross-sectional study that included images from 327 individuals with diabetes. The participants underwent pharmacological mydriasis and fundus photography in two fields (macula and optic disk centered) with both strategies. All images were acquired by trained healthcare professionals, de-identified, and graded independently by two masked ophthalmologists, with a third senior ophthalmologist adjudicating in discordant cases. The International Classification of Diabetic Retinopathy was used for grading, and demographic data, diabetic retinopathy classification, artifacts, and image quality were compared between devices. The tabletop senior ophthalmologist adjudication label was used as the ground truth for comparative analysis. A univariate and stepwise multivariate logistic regression was performed to determine the relationship of each independent factor in referable diabetic retinopathy. RESULTS: The mean age of participants was 57.03 years (SD 16.82, 9-90 years), and the mean duration of diabetes was 16.35 years (SD 9.69, 1-60 years). Age (P = .005), diabetes duration (P = .004), body mass index (P = .005), and hypertension (P < .001) were statistically different between referable and non-referable patients. Multivariate logistic regression analysis revealed a positive association between male sex (OR 1.687) and hypertension (OR 3.603) with referable diabetic retinopathy. The agreement between devices for diabetic retinopathy classification was 73.18%, with a weighted kappa of 0.808 (almost perfect). The agreement for macular edema was 88.48%, with a kappa of 0.809 (almost perfect). For referable diabetic retinopathy, the agreement was 85.88%, with a kappa of 0.716 (substantial), sensitivity of 0.906, and specificity of 0.808. As for image quality, 84.02% of tabletop fundus camera images were gradable and 85.31% of the Eyer images were gradable. CONCLUSIONS: Our study shows that the handheld retinal camera Eyer performed comparably to standard tabletop fundus cameras for diabetic retinopathy and macular edema screening. The high agreement with tabletop devices, portability, and low costs makes the handheld retinal camera a promising tool for increasing coverage of diabetic retinopathy screening programs, particularly in low-income countries. Early diagnosis and treatment have the potential to prevent avoidable blindness, and the present validation study brings evidence that supports its contribution to diabetic retinopathy early diagnosis and treatment.

Prevalence of diabetic retinopathy in Brazil: a systematic review with meta-analysis.

AIMS: To evaluate the prevalence of diabetic retinopathy (DR) in Brazilian adults with diabetes mellitus via a systematic review with meta-analysis. METHODS: A systematic review using PubMed, EMBASE, and Lilacs was conducted, searching for studies published up to February 2022. Random effect meta-analysis was performed to estimate the DR prevalence. RESULTS: We included 72 studies (n = 29,527 individuals). Among individuals with diabetes in Brazil, DR prevalence was 36.28% (95% CI 32.66-39.97, I2 98%). Diabetic retinopathy prevalence was highest in patients with longer duration of diabetes and in patients from Southern Brazil. CONCLUSION: This review shows a similar prevalence of DR as compared to other low- and middle-income countries. However, the high heterogeneity observed-expected in systematic reviews of prevalence-raises concerns about the interpretation of these results, suggesting the need for multicenter studies with representative samples and standardized methodology.

Quantitative assessment of silicone oil release with siliconized and silicone oil-free syringes by microflow imaging microscopy / Avaliação quantitativa da liberação de óleo de silicone por seringas siliconizadas e sem óleo de silicone usando microflow imaging microscopy

ABSTRACT Purpose: Since particles are released in syringes during intravitreal injections, we assessed them quantitatively after agitating syringes commonly used for intravitreal injections. Methods: With and without agitation, the SR 1-ml insulin, Becton-Dickinson Ultra-Fine 0.3-ml Short Needle with a half-unit scale, HSW Norm-Ject Tuberculin, and Becton-Di­ckinson 1-ml Luer Lok Tip were examined with buffer and bevacizumab, aflibercept, and ziv-aflibercept. Flow imaging microscopy was performed to assess the particle numbers, concentrations, morphology, and size distribution. Results: Using the Becton-Dickinson Ultra-Fine syringe, the average particle count after agitation was higher than in the no-agitation group. For particles greater than 10 and 25 µm, differences were observed using the SR syringe between the two studied conditions. There were no significant differences in the means for the other syringes. Without agitation, the SR syringe had the highest number of particles (2,417,361.7 ± 3,421,575.5) followed by the Becton-Dickinson Ultra-Fine with 812.530,9 ± 996.187,2. The Becton-Dickinson Luer Lok Tip and HSW Norm-Ject performed equally with 398,396.8 ± 484,239.2 and 416,016.4 ± 242,650.1 particles, respectively. Conclusions: Flicking syringes to eliminate air bubbles results in increased numbers of particles released during intravitreal injections into the human vitreous.

RESUMO Objetivo: Visto que partículas são liberadas nas seringas durante as injeções intravítreas (IVIs), estas foram avaliadas quantitativamente após a agitação das seringas mais comumente usadas para injeções intravítreas. Métodos: A seringa SR de 1 ml de insulina, a agulha curta Becton-Dickinson Ultra-Fine 0,3 ml com escala de meia unidade, HSW Norm-Ject Tuberculin e a Becton-Dickinson Luer Lok Tip de 1 ml foram estudadas com placedo e com bevacizumabe, aflibercept e ziv-aflibercept, com e sem agitação. MicroFlow Imaging Mi­croscopy foi realizada para avaliar o número de partículas, con­centração, morfologia e distribuição das mesmas por tamanho. Resultados: A contagem média de partículas após agitação foi maior do que no grupo sem agitação usando a seringa Becton-Di­ckinson Ultra-Fine. Diferenças foram observadas usando a seringa SR entre as duas condições estudadas para partículas maiores que 10 e 25 µm. Para as demais seringas, não foram observadas diferenças significativas nas médias. A seringa SR apresentou o maior número de partículas sem agitação (2.417.361,7 ± 3.421.575,5) seguida da Becton-Dickinson Ultra-Fine com 812.530,9 ± 996.187,2. A BD Luer Lok Tip e a HSW Norm-Ject se comportaram de forma semelhante com 398.396,8 ± 484.239,2 e 416.016,4 ± 242.650,1 partículas, respectivamente. Conclusões: Agitar seringas para remover bolhas de ar resulta em um maior número de partículas liberadas durante Becton-Dickinson no vítreo humano.

Feasibility of screening for diabetic retinopathy using artificial intelligence, Brazil.

Problem: There is currently no national strategy or standardized approach to diabetic retinopathy screening in the Brazilian public health system, and multiple socioeconomic barriers prevent access to eye examination in Brazil's poorest regions. Approach: From September 2021 to March 2022 we carried out a pilot project with an artificial intelligence system for diabetic retinopathy screening, embedded in a portable retinal camera. Patients with a diagnosis of diabetes according to the municipality registry were invited to attend nearby clinics for screening on designated days. Trained health-care technicians acquired images which were automatically evaluated by the system, with instant remote evaluation by retinal specialists in selected cases. Local setting: Our study was based in Sergipe State, located at a region with high illiteracy rates and no local availability of specialized retina care. The average number of laser treatments performed annually in the last 5 years is 126, for a total State population of 2.3 million. Relevant changes: Even though screening was performed free of charge in a convenient location for patients, from a total 2052 eligible individuals, only 1083 attended for screening. Lessons learnt: Efforts to raise awareness on the condition screened and to provide health education for patients and local health-care personnel are fundamental for increased attendance. Tailoring screening systems to the local setting, such as determining the trade-off between sensitivity and specificity, is challenging in regions with no current benchmarks. Standards for retinopathy screening based on the strategies adopted by high-income countries may not be realistic in low- and middle-income countries.

Quantitative assessment of silicone oil release with siliconized and silicone oil-free syringes by microflow imaging microscopy.

PURPOSE: Since particles are released in syringes during intravitreal injections, we assessed them quantitatively after agitating syringes commonly used for intravitreal injections. METHODS: With and without agitation, the SR 1-ml insulin, Becton-Dickinson Ultra-Fine 0.3-ml Short Needle with a half-unit scale, HSW Norm-Ject Tuberculin, and Becton-Di-ckinson 1-ml Luer Lok Tip were examined with buffer and bevacizumab, aflibercept, and ziv-aflibercept. Flow imaging microscopy was performed to assess the particle numbers, concentrations, morphology, and size distribution. RESULTS: Using the Becton-Dickinson Ultra-Fine syringe, the average particle count after agitation was higher than in the no-agitation group. For particles greater than 10 and 25 µm, differences were observed using the SR syringe between the two studied conditions. There were no significant differences in the means for the other syringes. Without agitation, the SR syringe had the highest number of particles (2,417,361.7 ± 3,421,575.5) followed by the Becton-Dickinson Ultra-Fine with 812.530,9 ± 996.187,2. The Becton-Dickinson Luer Lok Tip and HSW Norm-Ject performed equally with 398,396.8 ± 484,239.2 and 416,016.4 ± 242,650.1 particles, respectively. CONCLUSIONS: Flicking syringes to eliminate air bubbles results in increased numbers of particles released during intravitreal injections into the human vitreous.

Ocular inflammation after agitation of siliconized and silicone oil-free syringes: a randomized, double-blind, controlled clinical trial.

BACKGROUND: Noninfectious endophthalmitis may be misdiagnosed, leading to serious clinical implications. So far, its causative factors remain unknown. Therefore, this study assessed the role of silicone oil and syringe agitation in the development of inflammation after intravitreal injection of aflibercept. METHODS: A randomized, double-blind, controlled clinical trial included subjects with an indication of intravitreal antiangiogenic therapy prior to vitrectomy for proliferative diabetic retinopathy. Aflibercept was injected 48 h before surgery. The control group received the injection without agitation, while the intervention group was injected with a previously agitated syringe by flicking with either a siliconized or silicone oil-free syringe. The primary endpoint was the presence of anterior chamber reaction (ACR) at 48 h. Aqueous samples were collected and underwent cytometric bead array analysis for quantification of interleukins and chemokines. RESULTS: Forty-one individuals were included (21 in the agitation group and 20 in the no-agitation group). None of the included eyes showed baseline signs of AC cells, hyperemia or pain complaint, while 10% of control group and 80% of agitation group showed AC cells 48 h after injection of aflibercept with SR syringe. There were no differences in the mean variations of all cytokines and chemokines by agitation status. However, there was a marginally significant increase between the mean variations of IP-10 (p = 0.057) and IL-8 (p = 0.058) in the siliconized one. CONCLUSION: This clinical trial discloses a potential role of agitation and siliconized syringes in the development of inflammation after an intravitreal injection of aflibercept. These findings have important clinical implications for all healthcare practitioners who perform intravitreal injections. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials, RBR-95ddhp. Registered 12 May 2019, http://www.ensaiosclinicos.gov.br/rg/RBR-95ddhp/.

The risks behind the widespread use of siliconized syringes in the healthcare practice.

Injections are widely performed in the healthcare practice. Silicone has long been thought to be an inert and harmless material. Although used for decades in medical implants, including heart valves, breast implants, and as a tamponade for retinal detachment surgery, silicone oil might have deleterious effects. Agitation of the syringe to expel air at the moment of drug preparation not only leads to silicone oil release but also to therapeutic protein aggregation. Lab studies have shown that silicone oil microdroplets can act as an adjuvant to promote a break in immunological tolerance and induce antibody response. Similarly, recent studies have suggested a causal link between agitation of siliconized syringes and ocular inflammation after intravitreal injection. Systemically, silicone oil has been reported in association with autoimmune diseases and skin granuloma after either direct injection of dermal fillers or secondary leakage from silicone breast implant. However, it has not been established yet a potential link between the silicone oil released by the syringes and such relevant systemic adverse events. Few professionals are aware that agitation of a siliconized syringe might lead to silicone oil release, which, in turn, acts an adjuvant to an increased immunogenicity. We strongly recommend that every healthcare professional be aware of the use of silicone oil in the syringe manufacturing process, the factors that promote its release and the potential complications to the organism. Ultimately, we recommend that safer syringes be widely available.

In-vitro assessment of release of silicone oil droplets with the use of variety of syringes and needles used in intravitreal injections.

PURPOSE: To assess the variability of silicone oil (SO) particles released across syringes from the same lot and the role of different needle gauges. MATERIALS AND METHODS: Four syringe models and six needle models were assessed for SO release. About 50 microliters of a buffer solution were loaded into the syringe, needle or syringe/needle setup. The data were analyzed by imaging flow cytometry with fluorescently labeling for SO. RESULTS: All syringe models had a high coefficient of variation in SO release across syringes from the same lot. The amount of SO was significantly greater in the syringe when the needle was attached. SO particles with the BD 30G needle attached to the syringe were statistically greater than the 27G counterpart (p = 0.005). None of the other comparisons was statistically different. Finally, the number of SO particles was higher in the syringe/needle setup than in needles only (p = 0.0024). CONCLUSION: We found a high variability in SO content across syringes from the same lot. Additionally, there was no clear association between needle gauge and the number of SO particles, as well as their coefficient of variation. Finally, the needles accounted for a small number of SO particles in comparison to the combined syringe-needle setup.

Mechanisms of sterile inflammation after intravitreal injection of antiangiogenic drugs: a narrative review.

BACKGROUND: Intraocular inflammation is an uncommon but potentially vision-threatening adverse event related to anti-VEGF therapy. This is of increasing importance given both the volume of injections performed, as well as the increased prevalence of inflammation seen with newer anti-VEGF agents. Brolucizumab, the newest anti-VEGF agent, has been associated with an inflammatory retinal vasculitis and the underlying mechanism is unclear. Reviewing potential mechanisms and clinical differences of intraocular inflammation may assist clinicians and scientists in reducing the risk of these events in the future. OBSERVATIONS: Two types of inflammation are seen with intravitreal injections, acute onset sterile inflammation and delayed onset inflammatory vasculitis. Acute onset inflammation can be subcategorized into subclinical anterior chamber inflammation and sterile uveitis/endophthalmitis. Subclinical anterior chamber inflammation can occur at rates as high as 19% after intravitreal anti-VEGF injection. Rates of sterile uveitis/endophthalmitis range from 0.05% to 4.4% depending on the anti-VEGF agent. Inflammatory vasculitis is only associated with brolucizumab and occurred in 3.3% of injections according to the post hoc review of the HAWK/HARRIER data. In addition, silicone oil from syringes can induce immunogenic protein aggregates. Agitation of the syringe, freeze thawing, shipping and improper storage prior to injection may increase the amount of silicone oil released from the syringe. CONCLUSION: The main factors which play a role in intraocular inflammation after anti-VEGF injection can be divided into three causes: patient-specific, medication-specific and delivery-specific. The majority of clinically significant inflammation seen after intravitreal injection is an acute onset inflammatory response with most patients recovering baseline VA in 3-5 weeks. The presence of pain, hypopyon, severe anterior chamber reaction, hyperemia and significant vision loss may help distinguish infectious from non-infectious etiologies of post injection inflammation. Avoiding temperature fluctuation, mechanical shock, agitation during transport and handling of syringes/drugs, and the use of SO-free syringes may help minimize intraocular inflammation. While a definitive mechanism has not yet been established, current knowledge of the clinical presentation and vitreous histopathology of brolucizumab-retinal vasculitis favors an auto-immune type IV hypersensitivity reaction.

Silicone oil-free syringes, siliconized syringes and needles: quantitative assessment of silicone oil release with drugs used for intravitreal injection.

PURPOSE: This study aimed to quantify the amount of silicone oil (SO) released across a variety of syringe and needle models routinely used for intravitreal injection. METHODS: The release of SO was assessed in eight models of syringes, two of which were reported to be 'SO-free', and eleven models of needles with unknown SO content. To evaluate SO release within the context of anti-VEGF therapeutics, syringes were evaluated using aflibercept, bevacizumab, buffer, ziv-aflibercept and formulation buffer. All syringe tests were performed with or without agitation by flicking for syringes. Needles were evaluated without agitation only. Samples were fluorescently labelled to identify SO, and triplicate measurements were collected using imaging flow cytometry. RESULTS: Seven out of 8 syringe models showed a statistically significant increase in the SO particle count after agitation. The two SO-free syringe models (HSW Norm-Ject, Daikyo Crystal Zenith) released the least SO particles, with or without agitation, whereas the BD Ultra-Fine and Saldanha-Rodrigues syringes released the most. More SO was released when the syringes were prefilled with formulation buffer than with ziv-aflibercept. Syringes filled with aflibercept and bevacizumab had intermediate levels. Agitation increased the release of SO into each of the drug solutions. Silicone oil (SO) was detected in all needles. CONCLUSIONS: Agitation of the syringe by flicking leads to a substantial increase in the number of SO particles. Silicone oil (SO)-free syringes had the best performance, but physicians must also be aware that needles are siliconized and also contribute to the injection of SO into the vitreous.

High particle variability across siliconized and oil-free syringes and needles from the same lots.

Previous studies have reported silicone oil (SO) applied to needles and syringes in the vitreous of patients after intravitreal injections. We evaluated four syringes (SR 1-mL insulin, Saldanha-Rodrigues; BD 1-mL Tuberculin Slip Tip, Becton-Dickinson; BD Ultra-Fine 0.3 mL, HSW Norm-Ject Tuberculin, Henke Sass Wolf) and 10 needles (BD PrecisionGlide 27- and 30-gauge (G); BD Eclipse and JBP Nanoneedle 27-, 30-, 33- and 34-G; TSK Invisible Needle and 27 and 30-G Steriject Control Hub). The protein-free buffer samples injected into the syringes and needles under study were collected in an Eppendorf tube and taken to Flow imaging microscopy, that characterized the concentration and morphology of the microsized particles. The number of particles was analyzed. The coefficients of variation (CV) were the primary outcome. The Feltz and Miller test compared the CVs. The significance level was 5%. Numerous particles and high CVs were associated with both devices, needles and syringes; the comparisons among them did not reach significance. The BD Ultrafine 0.3 mL syringe (149.7%) had the highest CV and the SO-free HSW Norm-Ject (66.4%) syringe the lowest, and the TSK Invisible needle (149.5%) had the highest and the BD Precision Glide 30G needle (35.9%) needle the lowest. In conclusion, particle release, including those with SO morphology, varied greatly among instruments, even from the same lots, which is relevant considering that fewer particles are injected into some eyes compared with others.