A patient with concurrent Axenfeld-Rieger and Stickler syndromes verified by molecular genetics.

Purpose: To report a case of Axenfeld-Rieger and Stickler Syndrome in a pediatric patient. Observations: A 3-month-old male was referred to the glaucoma clinic after he was noted to have elevated intraocular pressures in both eyes. His family history was notable for infantile glaucoma on his maternal side and retinal detachment on his paternal side. He was found to have anterior segment dysgenesis with iris strands, iridocorneal adhesions, and corectopia, as well as veil-like vitreous in both eyes. He required trabeculotomy, goniotomy, and multiple Baerveldt glaucoma implants in both eyes to achieve intraocular pressure control. Furthermore, the patient later developed macula-involving retinal detachments in both eyes, requiring pars plana vitrectomy with silicone oil tamponade. Genetic analysis confirmed heterozygous pathogenic variants in both the FOXC1 and COL2A1 genes, leading to the concurrent diagnoses of Axenfeld-Rieger and Stickler syndromes. Conclusions and importance: This is a rare case of a patient with concurrent Axenfeld-Rieger and Stickler syndromes. The severity of pathology in both the anterior and posterior segments required a collaborative multidisciplinary approach. In the diagnostic evaluation of congenital eye diseases, if there is strong family history of atypical findings for a given diagnosis, concurrent syndromes should be considered and ruled out. A comprehensive eye genetics panel may be a useful tool in these cases.

Retinopathy of Prematurity Screening of Preterm Infants With Icteric Vitreous.

Purpose: To present 2 cases of premature newborns with hyperbilirubinemia and retinopathy of prematurity (ROP) who could not be examined properly to assess for disease progression because of vitreous opacification in the setting of an icteric vitreous and frail health status. Methods: The cases and their findings were analyzed. Results: Given the sickness of the neonates and examination difficulty, intravitreal bevacizumab was administered in both eyes to prevent disease progression. During subsequent examinations, the patients remained stable until discharge from the neonatal intensive care unit and were followed in the outpatient clinic without complication. Conclusions: The ROP and vitreous opacification in our cases were thought to be caused by hyperbilirubinemia. Because of vitreous opacification, these patients could not be properly examined for ROP. Treatment with an intravitreal antivascular endothelial growth factor injection might be considered to delay disease development until the newborn is healthier and able to be examined.

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/.

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.

Effects of phosphodiesterase type 5 inhibitors on choroid and ocular vasculature: a literature review.

To provide information on the effects of phosphodiesterase type 5 (PDE5) inhibitors on choroidal vessels and central serous chorioretinopathy (CSC) and possible implications for development of exudative age-related macular degeneration (AMD). Two independent investigators conducted a qualitative review of PubMed to identify studies on the choroidal effect of PDE5 inhibitors in June 2019. The search used key words that included PDE5 inhibitors, sildenafil, tadalafil, vardenafil, choroid, choroidal flow, choroidal vessels, choroidal thickness, CSC, AMD or a combination. Only studies which assessed choroidal findings were included. Many ocular diseases are related to changes in choroidal thickness and perfusion. Patients with AMD, who have decreased choroidal perfusion, may manifest more severely diminished choroidal ability to deliver oxygen and other metabolites to the retina, leading to growth of neovascular tissue. As a result of this engorgement of the choroidal vasculature, some patients may have leakage across the retinal pigment epithelium (RPE) and accumulation of subretinal fluid, resulting in CSC. Transient visual symptoms, i.e., changes in color perception and increased light sensitivity, are well-known adverse effects, but there have been rare reports of vision-threatening ocular complications in users of PDE5 inhibitors, such as nonarteritic anterior ischemic optic neuropathy and cilioretinal artery occlusion. The choroid is a vascular tissue analogous in many respects to the corpus cavernosum, and PDE5 inhibitors may increase the choroidal thickness and perfusion. While it is intuitively obvious that thickness of the choroid alone does not guarantee better choriocapillaris oxygenation, it is a reasonable step towards ameliorating ischemia. These drugs have numerous physiologic effects on the choroid related to blood flow, such as clinical consequences in CSC and AMD.

Optical coherence tomography angiography using the black-and-white pixel binarization histogram software: a new technique for evaluating healing of macular holes in two surgical techniques.

BACKGROUND: Many factors can influence the functional outcomes of macular hole surgery and some studies have tried to describe anatomical features that could predict successful treatment. The purpose of this study is to describe a new technique for evaluating the healing of macular holes after two surgical techniques using a black-and-white pixel binarization histogram software by optical coherence tomography angiography and its potential functional implications. METHODS: This was a retrospective, observational case series of patients who presented with idiopathic full-thickness macular holes and underwent vitreoretinal surgery for successful macular hole closure using the internal limiting membrane peeling technique or the inverted peeling technique or the free internal limiting membrane flap technique. Optical coherence tomography angiography 3.0 × 3.0-mm scans were obtained postoperatively. The outer retina layer was analyzed separately; three different analyses were performed within a 3.0-mm-diameter area central circle, a 1.5-mm-diameter area, and a 0.5-mm-diameter area from the foveal center. The outer retinal layer images were evaluated by counting the number of black and white pixels. The inclusion criteria were patients with idiopathic macular holes who underwent ophthalmologic examinations and swept-source optical coherence tomography 1 week and 1 and 6 months postoperatively. The exclusion criteria were a traumatic macular hole or a history of eye trauma and a diagnosis of glaucoma or any other chronic ocular disease. The Mann-Whitney test was used to determine significance; P < 0.05 was considered significant. RESULTS: Ten eyes of 10 patients who underwent vitreoretinal surgery to treat a macular hole either with the conventional peeling technique (n = 5) or the inverted/free internal limiting membrane flap technique (n = 5) were included. In the peeling group, the percentage of white pixels ranged from 7.22% to 18.40% in the 0.5 × 0.5-millimeter area in the macular center; the mean postoperative logarithm of the minimum angle of resolution best-corrected visual acuity was 0.3 ± 0.2. In the inverted flap group, the percentage of white pixels ranged from 3.65% to 8.93% in the 0.5 × 0.5-millimeter area in the macular center; the mean logarithm of the minimum angle of resolution best-corrected visual acuity was 0.9 ± 0.4. CONCLUSIONS: A simple method of optical coherence tomography angiography imaging analysis of the outer retina using a binarization technique of the black and white pixels was created and may have functional implications during the analysis of the healing process after macular hole surgery. We hypothesized that higher numbers of white pixels correspond to viable cellularity and better prognoses postoperatively.

Non-contact wide-angled visualization with chandelier-assisted scleral buckling for primary uncomplicated rhegmatogenous retinal detachment.

PURPOSE: To report our experience in non-contact wide-angled visualization with chandelier-assisted scleral buckling (SB) in uncomplicated primary rhegmatogenous retinal detachments (RRD). METHODS: Retrospective case series of 282 eyes that underwent non-contact wide-angled visualization with chandelier-assisted SB and were followed for a mean of 13.5 months. RESULTS: There were 160 male patients. The average age was 42.6 years old. There were 262 eyes that were phakic, 18 pseudophakic, and 2 aphakic. Two-thirds of eyes presented with the macula detached. Eyes had an average of 1.6 breaks. The single operation anatomic success rate was 85.1% (240/282). The pre-op visual acuity improved from 1.21 to 0.76 logMAR at 6 months (p < 0.0001). Complications included a case of scleral laceration, choroidal hemorrhage, 3 epiretinal membranes, 1 macular fold, and 4 eyes with buckle exposure. CONCLUSION: Non-contact wide-angled visualization with chandelier-assisted SB compares favorably with conventional SB for primary uncomplicated primary RRD.