Vitrectomy as an Adjunct to Treat-and-Extend Anti-VEGF Injections for Diabetic Macular Edema: The Vitrectomy in Diabetic Macular Oedema (VIDEO) Randomized Clinical Trial.

Importance: There are reported benefits from vitrectomy for diabetic macular edema (DME); however, data precede anti-vascular endothelial growth therapy (VEGF) therapy, supporting a need to assess the current role of vitrectomy. Objective: To determine rates of recruitment and efficacy outcomes of vitrectomy plus internal limiting membrane (ILM) peeling adjunctive to treat-and-extend (T&E) anti-VEGF injections for diabetic macular edema (DME). Design, Setting, and Participants: This was a single-masked, multicenter randomized clinical trial at 21 sites in the United Kingdom from June 2018 to January 2021, evaluating single eyes of treatment-naive patients with symptomatic vision loss from DME for less than 1 year. Inclusion criteria were best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score greater than 35 (approximate Snellen equivalent, 20/200 or better) and central subfield thickness (CST) greater than 350 µm after 3 monthly intravitreal injections of ranibizumab or aflibercept. Data analysis was performed in July 2023. Interventions: Patients were randomized 1:1 into vitrectomy plus standard care or standard care alone and further stratified into groups with vs without vitreomacular interface abnormality. Both groups received a T&E anti-VEGF injection regimen with aflibercept, 2 mg, or ranibizumab, 0.5 mg. The vitrectomy group additionally underwent pars plana vitrectomy with epiretinal membrane or ILM peel within 1 month of randomization. Main Outcomes and Measures: Rate of recruitment and distance BCVA. Secondary outcome measures were CST, change in BCVA and CST, number of injections, rate of completed follow-up, and withdrawal rate. Results: Over 32 months, 47 of a planned 100 patients were enrolled; 42 (89%; mean [SD] age, 63 [11] years; 26 [62%] male) completed 12-month follow-up visits. Baseline characteristics appeared comparable between the control (n = 23; mean [SD] age, 66 [10] years) and vitrectomy (n = 24; mean [SD] age, 62 [12] years) groups. No difference in 12-month BCVA was noted between groups, with a 12-month median (IQR) BCVA letter score of 73 (65-77) letters (Snellen equivalent, 20/40) in the control group vs 77 (67-81) letters (Snellen equivalent, 20/32) in the vitrectomy group (difference, 4 letters; 95% CI, -8 to 2; P = .24). There was no difference in BCVA change from baseline (median [IQR], -1 [-3 to 2] letters for the control group vs -2 [-8 to 2] letters for the vitrectomy group; difference, 1 letter; 95% CI, -5 to 7; P = .85). No difference was found in CST changes (median [IQR], -94 [-122 to 9] µm for the control group vs -32 [-48 to 25] µm for the vitrectomy group; difference, 62 µm; 95% CI, -110 to 11; P = .11). Conclusions and Relevance: Enrollment goals could not be attained. However, with 47 participants, evidence did not support a clinical benefit of vitrectomy plus ILM peeling as an adjunct to a T&E regimen of anti-VEGF therapy for DME. Trial Registration: isrctn.org Identifier: ISRCTN59902040.

A Population-Based Analysis of Long-Term Costs and Adverse Events after Pneumatic Retinopexy and Pars Plana Vitrectomy.

PURPOSE: To comprehensively examine the cost effectiveness, reattachment rate, and complications of pneumatic retinopexy (PnR) compared with pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) within a universal health care system. DESIGN: Population-based, multicenter, consecutive, retrospective longitudinal cohort analysis. SUBJECTS: We identified consecutive adults aged ≥ 50 years requiring surgery for primary RRD over a 20-year interval between April 1, 2002, and March 31, 2022. Initial surgery was considered the index date for analyses. INTERVENTION: Pneumatic retinopexy was compared with PPV in all analyses. MAIN OUTCOME MEASURES: The primary analysis investigated the mean annualized health care costs comparing PnR to PPV over the 2 years after initial surgery. Secondary analyses examined the primary reattachment rate and complications. RESULTS: In total, 25 665 eligible patients were identified, with 8794 undergoing PnR and 16 871 undergoing PPV. The mean patient age was 65 years and 39% were women. The mean annualized cost after PnR was $8924 and $11 937 after PPV (mean difference, $3013; 95% confidence interval, $2533-$3493; P < 0.001). The primary reattachment rate at 90 days after PnR was 83% and after PPV was 93% (P < 0.001). The risk of cataract or glaucoma surgery was lower after PnR, and the frequency of ophthalmology clinic visits, intravitreal injections, and anxiety was higher after PnR. Hospitalizations and long-term disability were less frequent after PnR. CONCLUSIONS: Pneumatic retinopexy, when compared with PPV, was associated with lower long-term health care costs. Pneumatic retinopexy appeared to be effective, safe, and inexpensive, thus offering a viable option for improving access to RRD repair in appropriately selected cases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

En Face OCT in Diagnosis of Persistent Subretinal Fluid and Outer Retinal Folds after Rhegmatogenous Retinal Detachment Repair.

PURPOSE: To evaluate the role of en face OCT as a diagnostic tool for the detection of persistent subretinal fluid (PSRF) and outer retinal folds (ORFs) after successful rhegmatogenous retinal detachment (RRD) repair. DESIGN: Observational post hoc analysis of 2 prospective surgical trials. PARTICIPANTS: All patients with gradable (signal strength ≥ 5 and no segmentation error) 6 × 6-mm2 macular cube scans obtained using spectral-domain OCT (Carl Zeiss Meditec) between 1 and 2 months after surgery were included in this study. METHODS: The scans were assessed for the presence or absence of PSRF or ORFs using en face OCT and cross-sectional B scans by 2 masked graders, with any disagreements adjudicated by a third senior masked grader. MAIN OUTCOME MEASURES: The sensitivity, specificity, and predictive accuracy (using area under the curve [AUC]) of en face OCT were compared with those of cross-sectional OCT, which is considered the gold standard. RESULTS: Two hundred twenty-three patients were included in this study. The Cohen kappa between the graders in the diagnosis of PSRF and ORFs using en face OCT was 0.84 and 0.86, respectively. The sensitivity of en face OCT was 100% (95% confidence interval [CI], 100%-100%) in the diagnosis of PSRF and 98.8% (95% CI, 96.5%-101.1%) in the diagnosis of ORFs. Similarly, the specificity of en face OCT was 98.7% (95% CI, 96.8%-100.5%) and 84.2% (95% CI, 78.1%-90.2%) in the diagnosis of PSRF and ORFs, respectively. The AUC was 0.99 for PSRF and 0.91 for ORFs. CONCLUSIONS: En face OCT has good sensitivity, specificity, and predictive accuracy (using AUC) in the diagnosis of PSRF and ORFs. En face OCT is an efficient screening tool for postoperative anatomic abnormalities, such as PSRF and ORFs, after RRD repair. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Novel classification system for management of rhegmatogenous retinal detachment with minimally invasive detachment surgery: a network meta-analysis of randomized trials focused on patient-centred outcomes.

OBJECTIVE: To describe a novel classification system for primary rhegmatogenous retinal detachment (RRD) based on level 1 evidence assessing the functional outcomes of repair techniques with the goal of using a minimally invasive detachment surgery. METHODS: A systematic review and network meta-analysis of randomized, controlled trials comparing pneumatic retinopexy (PnR), scleral buckle (SB), or pars plana vitrectomy (PPV) for RRD was conducted. Primary outcomes were best-corrected visual acuity (BCVA), metamorphopsia, and operative complications. A meta-analysis was performed with a random effects maximum likelihood model, with outcomes of standardized mean difference (SMD) or risk ratio (RR) and 95% confidence interval. Inclusion and exclusion criteria were assessed to inform a classification system. RESULTS: Fourteen trials were included. RRDs were classified from categories 1-3 based on configuration (simple to complex). There was no significant difference in final BCVA between PnR and PPV (categories 1 and 2; SMD = -0.10, 95% CI -0.24 to 0.04), nor was a final BVCA difference found between SB and PPV (SMD = 0.01, 95% CI -0.05 to 0.08), combined SB + PPV and PPV (SMD = 0.02, 95% CI -0.08 to 0.12), or combined SB + PPV and SB (SMD = 0.01, 95% CI -0.11 to 0.12). SB had an elevated risk of choroidal detachment (RR = 5.17, 95% CI 1.68-15.97), hypotony (RR = 12.26, 95% CI 1.63-92.04), and strabismus or diplopia (RR = 5.86, 95% CI 1.04-32.91) compared with PPV but a lower risk of iatrogenic breaks (RR = 0.08, 95% CI 0.02-0.43). Vertical metamorphopsia scores were superior for PnR over PPV at 12 months (Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial, p = 0.026). CONCLUSION: This novel classification system may be useful for future trials assessing morphologic categories of RRD in a systematic manner. Minimally invasive detachment surgery may allow for trials to focus on maximizing functional outcomes while minimizing morbidity.

Platelet-rich plasma and macular hole surgery: A clue to their mode of action and the influence of anti-platelet agents.

PURPOSE: To present a case of refractory full-thickness macular hole (FTMH), in which autologous platelet-rich plasma (aPRP) was used on two consecutive occasions, and associated with successful closure only after complete cessation of anti-platelet therapy. METHODS: Interventional case report. RESULTS: A 63-year-old male with Alport syndrome underwent pars plana vitrectomy with internal limiting membrane peeling and gas for a large FTMH. The patient was on systemic anti-platelet agents for coronary disease. Post-operatively, the FTMH remained open and repeated surgery, augmented with aPRP, was performed. Although a thick pre-retinal coagulum was evident on optical coherence tomography on day one post-surgery, the second surgery failed. Ultimately, successful aPRP-augmented surgical closure of the FTMH was achieved only after complete cessation of systemic anti-platelet agents. CONCLUSION: Appropriate management of anti-platelet therapy may be relevant when planning aPRP use, though further large-scale studies are needed to assess the precise effect of anti-platelet therapy on the efficacy of aPRP, and to confirm the potential role of aPRP in patients with Alport syndrome.

A randomised controlled trial evaluating internal limiting membrane peeling forceps in macular hole surgery.

PURPOSE: To assess study design and a range of anatomical and functional changes after internal limiting membrane (ILM) peeling using forceps developed for atraumatic ILM pick-up compared to standard forceps. METHODS: We conducted a masked proof-of concept randomised controlled trial (RCT) on 65 patients who underwent ILM peeling for idiopathic full-thickness macular hole (FTMH) using etched-tip forceps (etched-tip group, 33 eyes) compared to standard ILM forceps (smooth-tip group, 32 eyes). Patients were assessed preoperatively, 3 weeks, 3 and 6 months postoperatively. RESULTS: The primary closure rate was 95.4%. There was no statistically significant difference between the groups in terms of final visual acuity (66.9 vs 70.9 ETDRS letters, p = 0.13), difference of visual field mean deviation (1.32 vs 1.14 decibels), and number of eyes with pick-up-related retinal haemorrhages (16% vs 16%, p = 0.96), swelling of arcuate nerve fibre layer lesions (63% vs 55%, p = 0.54), number of dissociated optic nerve fibre layer lesions (31.4 vs 41.0, p = 0.16), nor inner retina defects (37% vs 22%, p = 0.17). Similar changes in inner retinal volumes were detected in all 9 sectors of an ETDRS grid except for a trend (p = 0.06) towards a lower reduction in the inferior inner sector in the etched-tip group. CONCLUSIONS: The study was successfully completed with masking maintained and a low risk of bias. Multiple endpoints relating to ILM peeling were assessed, and estimates were provided that can be used for future studies. Although the study was not powered to assess any specific endpoint, the anatomical and functional outcomes assessed did not significantly differ.

A paradigm shift in retinal detachment repair: The concept of integrity.

The management of rhegmatogenous retinal detachment has rapidly evolved over recent decades. A range of surgical techniques exist, all of which can achieve retinal reattachment in most cases. In recent years there have also been vast technical advances in retinal imaging that have introduced novel ways of visualizing and studying the retinal macro and microstructural anatomy following retinal detachment repair. Recent clinical trial data demonstrates that functional and patient-reported outcomes of retinal reattachment differ with surgical technique, accompanied by differences in anatomic biomarkers of retinal recovery or 'integrity'. We discuss recent insights into the physiology of retinal reattachment gleaned from multimodal imaging, which shed light on the pathophysiology of various post-operative anatomic abnormalities. The ideal scenario is to achieve retinal reattachment as soon as possible, without retinal displacement, outer retinal folds or discontinuity of the external limiting membrane, ellipsoid zone and interdigitation zone, with an intact foveal bulge. To this end, we present an in-depth contemporary account of current concepts and mechanisms involved during retinal reattachment surgery, supported by clinical data and mathematical modelling, awareness of which can help the vitreoretinal surgeon achieve better post-operative outcomes. In this review we substantiate the case for a paradigm shift in rhegmatogenous retinal detachment repair; beyond the emphasis on single-operation reattachment rates, and instead striving to maximize functional outcomes using minimally invasive techniques. This can only be achieved if vitreoretinal surgeons embrace all of the available techniques, with individualized selection of surgical approach and the resolute goal of optimizing the 'integrity' of retinal reattachment.

An Uncommon Aflibercept Side Effect: Full Thickness Macular Hole Formation After Intravitreal Injections in Patients With Pre-existing Vitreomacular Traction.

Aflibercept is an intravitreally injected anti-vascular endothelial growth factor, commonly used in patients with several retinal pathologies, including neovascular age-related macular degeneration. We report a case series of three patients under treatment with an aflibercept regime for neovascular age-related macular degeneration, who were referred to vitreoretinal service between 2015-2016. In all cases, pre-existing vitreomacular traction was detected with an optical coherence tomography scan. All of them developed full-thickness macular hole after aflibercept intravitreal injections. The combined cataract and macular hole surgery was successful, with improvement in visual acuity. We suggest that dynamic alterations of the size of the pigment epithelium detachment resulting from intravitreal injections might intensify the pre-existing pathological adhesion of the vitreous-retinal interface and subsequently cause the formation of a full-thickness macular hole. Therefore, all practitioners treating patients with aflibercept intravitreal injections and pre-existing vitreomacular traction should be aware of the possible macular hole formation.

Management of acute submacular hemorrhage using intravitreal injection of tissue plasminogen activator and gas: A case series.

The objective of this case series is the evaluation of the efficacy and visual outcomes after displacement of subretinal hemorrhage using intravitreal injection of recombinant tissue plasminogen activator, expansile gas, and in some cases an anti-vascular endothelial growth factor agent. A case series of 28 eyes of 28 patients (16 men and 12 women with age range 67-95 years) suffering from subretinal hemorrhage (duration range 1-15 days) caused by age-related macular degeneration or retinal macroaneurysm is presented. All the patients were treated with intravitreal injection of recombinant tissue plasminogen activator and gas and some of them received an anti-vascular endothelial growth factor agent between January 2013 and December 2016. The outcomes assessed were visual acuity (preoperatively 1 week, and 1 month postoperatively) with respect to duration and dimension of hemorrhage, displacement of hemorrhage, and possible complications of the procedure. Successful displacement of hemorrhage was achieved in 25 patients (89.3%), 18 of 28 patients had significant improvement in visual acuity 1 week after the treatment, and 22 of 28 patients had significant improvement in visual acuity 1 month after the treatment. The mean improvement of all patients with anatomical displacement of the hemorrhage in visual acuity was 0.7 ± 0.5 (LogMAR) in 1 month. Two patients developed vitreous hemorrhage after the procedure and one retinal detachment. Visual outcome a month after therapy displayed week correlation with duration, diameter, and thickness of hemorrhage. The results lead to the conclusion that intravitreal treatment of recombinant tissue plasminogen activator and expansible gas with or without injection of anti-vascular endothelial growth factor agent is effective in improving visual acuity and displacing submacular hemorrhage secondary to age-related macular degeneration and retinal macroaneurysm. The best functional outcomes can be expected in patients regardless of the size and duration of the hemorrhage.

Retinal Displacement Following Pneumatic Retinopexy vs Pars Plana Vitrectomy for Rhegmatogenous Retinal Detachment.

Importance: Retinal displacement following rhegmatogenous retinal detachment repair may have consequences for visual function. It is important to know whether surgical technique is associated with risk of displacement. Objective: To compare retinal displacement following rhegmatogenous retinal detachment repair with pneumatic retinopexy (PR) vs pars plana vitrectomy (PPV). Interventions or Exposures: Fundus autofluorescence images were assessed by graders masked to surgical technique. Design, Setting, and Participants: A multicenter retrospective consecutive case series in Canada and the UK. A total of 238 patients (238 eyes) with rhegmatogenous retinal detachments treated with PR or PPV who underwent fundus autofluorescence imaging from November 11, 2017, to March 22, 2019, were included. Main Outcomes and Measures: Proportion of patients with retinal displacement detected by retinal vessel printings on fundus autofluorescence imaging in PR vs PPV. Results: Of the 238 patients included in the study, 144 were men (60.5%) and 94 were women (39.5%); mean (SD) age was 62.0 (11.0) years. Of the 238 eyes included in this study, 114 underwent PR (47.9%) and 124 underwent PPV (52.1%) as the final procedure to achieve reattachment. Median time from surgical procedure to fundus autofluorescence imaging was 3 months (interquartile range, 1-5 months). Baseline characteristics in both groups were similar. The proportion of eyes with retinal vessel printing on fundus autofluorescence was 7.0% for PR (8 of 114) and 44.4% for PPV (55 of 124) (37.4% difference; 95% CI, 27.4%-47.3%; P < .001). Analysis based on the initial procedure found that 42.4% (42 of 99) of the eyes in the PPV group vs 15.1% (21 of 139) of the eyes in the PR group (including 13 PR failures with subsequent PPV) had displacement (27.3% difference; 95% CI, 15.9%-38.7%; P < .001). Among eyes with displacement in the macula, the mean (SD) displacement was 0.137 (0.086) mm (n = 6) for PR vs 0.297 (0.283) mm (n = 52) for PPV (0.160-mm difference; 95% CI, 0.057-0.263 mm; P = .006). Mean postoperative logMAR visual acuity was 0.31 (0.32) (n = 134) (Snellen equivalent 20/40) in eyes that initially underwent PR and 0.56 (0.42) (n = 84) (Snellen equivalent 20/72) in eyes that had PPV (-0.25 difference; 95% CI, -0.14 to -0.35; P < .001). Among eyes with displacement, mean postoperative logMAR visual acuity was 0.42 (0.42) (n = 20) (Snellen equivalent 20/52) in those that initially underwent PR and 0.66 (0.47) (n = 33) (Snellen equivalent 20/91) in those that initially underwent PPV (-0.24 difference; 95% CI, -0.48 to 0.01; P = .07). Conclusions and Relevance: These findings suggest that retinal displacement occurs more frequently and is more severe with PPV vs PR when considering the initial and final procedure used to achieve retinal reattachment. Recognizing the importance of anatomic integrity by assessing retinal displacement following reattachment may lead to refinements in vitreoretinal surgery techniques.

Contralateral effect of systemic absorption of low dose bevacizumab (Avastin) after unilateral intravitreal injection in severe retinopathy of prematurity (ROP).

An extremely premature baby boy born at 23 weeks' gestational age was treated with unilateral low dose of 0.16 mg/0.025 mL intravitreal bevacizumab in the left eye for aggressive retinopathy of prematurity (ROP). He developed photographically documented changes in his contralateral right eye on imaging 5 days later. Second eye treatment was at 12 days. He has development assessment and ophthalmic review beyond age 2, which is normal. Systemic absorption of the drug caused an end organ effect to slow down and reverse ROP in his untreated right eye. Both eyes vascularised fully. His normal Bayley III developmental score at age 2 is uncommon for a 23-week gestation baby. Even at a low dose, bevacizumab has the potential for end organ effect on the second eye, and therefore other organs. In this case, there are no medium-term measurable neurodevelopmental side-effects. We suggest longer term follow-up is required before excluding unwanted side-effects.

Aqueous Humor Cytokines and Long-Term Response to Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema.

PURPOSE: To determine the association of aqueous humor cytokine concentrations with long-term treatment response to anti-vascular endothelial growth factor (VEGF) agents in diabetic macular edema (DME). DESIGN: Retrospective case series. METHODS: Pooled data of aqueous humor cytokine concentrations collected at baseline and 2-month follow-up (2 injections) for treatment-naïve eyes with center-involving DME previously enrolled in a prospective study were reviewed. Subjects receiving intravitreal anti-VEGF injections outside of study protocol as per standard of care were classified into Responders versus Nonresponders based on qualitative assessment of optical coherence tomography for persistence of DME at longitudinal follow-up visits. RESULTS: Of the 41 eyes, 85% were classified as Responders with a significant decline in baseline central subfield thickness and macular volume (P values < .001), and 15% were identified as Nonresponders to anti-VEGF therapy over 51.4 ± 18.7 months of follow-up. No significant difference in baseline aqueous humor VEGF concentration was noted, while at the 2-month follow-up the Nonresponder group had a significantly higher VEGF concentration compared with the Responder group (451.5 ± 690.9 pg/mL vs 113.7 ± 211.4 pg/mL; P = .02). The Responder group also demonstrated a significant decline from baseline to 2-month follow-up in concentration of intercellular adhesion molecule-1 (P < .001), interleukin-10 (P = .041), monocyte chemotactic protein-1 (P = .046), placental growth factor (P = .027), and transforming growth factor-ß2 (P = .017). CONCLUSIONS: Aqueous humor cytokine concentrations serve as an early biomarker for long-term response to anti-VEGF therapy and may enable more effective treatment regimens that improve anatomical outcomes in eyes with DME.

The Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial (PIVOT).

PURPOSE: The optimal surgery to repair rhegmatogenous retinal detachment (RRD) is unknown. The purpose of this trial was to compare outcomes of pneumatic retinopexy (PnR) versus pars plana vitrectomy (PPV) for the management of primary RRD. DESIGN: Prospective, randomized controlled trial. PARTICIPANTS: Patients with RRD demonstrating a single retinal break or a group of breaks in detached retina within 1 clock hour above the 8- and 4-o'clock meridians, with any number, location and size of retinal breaks or lattice degeneration in attached retina. METHODS: Patients were randomized to undergo either PnR or PPV. Macula-on and macula-off patients were assigned to intervention group by stratified randomization and were treated within 24 and 72 hours, respectively. MAIN OUTCOME MEASURES: The primary outcome was 1-year Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA). Important secondary outcomes were subjective visual function (25-item National Eye Institute Visual Function Questionnaire), metamorphopsia score (M-CHARTS), and primary anatomic success. RESULTS: One hundred seventy-six patients were recruited between August 2012 and May 2016. ETDRS VA after PnR exceeded that after PPV by 4.9 letters at 12 months (79.9±10.4 letters vs. 75.0±15.2 letters; P = 0.024). Mean ETDRS VA also was superior for the PnR group compared with the PPV group at 3 months (78.4±12.3 letters vs. 68.5±17.8 letters) and 6 months (79.2±11.1 letters vs. 68.6±17.2 letters). Composite 25-item National Eye Institute Visual Function Questionnaire scores were superior for PnR at 3 and 6 months. Vertical metamorphopsia scores were superior for the PnR group compared with the PPV group at 12 months (0.14±0.29 vs. 0.28±0.42; P = 0.026). Primary anatomic success at 12 months was achieved by 80.8% of patients undergoing PnR versus 93.2% undergoing PPV (P = 0.045), with 98.7% and 98.6%, respectively, achieving secondary anatomic success. Sixty-five percent of phakic patients in the PPV arm underwent cataract surgery in the study eye before 12 months versus 16% in the PnR group (P < 0.001). CONCLUSIONS: Pneumatic retinopexy should be considered the first line treatment for RRD in patients fulfilling Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial (PIVOT) recruitment criteria. Pneumatic retinopexy offers superior VA, less vertical metamorphopsia, and reduced morbidity when compared with PPV.

Aqueous Humor Cytokine Levels and Anatomic Response to Intravitreal Ranibizumab in Diabetic Macular Edema.

Importance: Variability in response to anti-vascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME) remains a significant clinical challenge. Biomarkers could help anticipate responses to anti-VEGF therapy. Objectives: To investigate aqueous humor cytokine level changes in response to intravitreal ranibizumab therapy for the management of DME, and to determine the association between baseline aqueous levels and anatomic response. Design, Setting, and Participants: In this prospective multicenter cohort study, 49 participants with diabetes mellitus complicated by center-involving DME, with a central subfield thickness of 310 µm or greater on spectral-domain optical coherence tomography (SD-OCT), were recruited from December 22, 2011, to June 13, 2013 and statistical analysis were performed from March 1, 2017, to June 1, 2017. A total of 48 participants proceeded to follow-up. Interventions: Participants received monthly injections of ranibizumab, 0.5 mg, for 3 months. Aqueous fluid for cytokine analysis was obtained at baseline and repeated at the 2-month visit. Multiplex immunoassay was carried out in duplicate for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemoattractant protein 1. Main Outcomes and Measures: Baseline and 2-month change in aqueous cytokine levels, 3-month change in SD-OCT central subfield thickness and macular volume (MV), and the statistical association between baseline aqueous cytokine levels and these measures of anatomic response to ranibizumab in center-involving DME. Results: Among the 48 participants, the mean (SD) age was 61.9 (7.1) years and 36 participants (75.0%) were men. The following cytokines were lower at month 2 vs baseline: ICAM-1 (median change, -190.88; interquartile range [IQR], -634.20 to -26.54; P < .001), VEGF (median change, -639.45; IQR, -1040.61 to -502.61; P < .001), placental growth factor (median change, -1.31; IQR, -5.99 to -0.01; P < .001), IL-6 (median change, -38.61; IQR, -166.72 to -2.80; P < .001), and monocyte chemoattractant protein 1 (median change, -90.13; IQR, -382.74 to 109.47; P = .01). When controlling for age, foveal avascular zone size, and severity of retinopathy, multiple linear regression determined that increasing baseline aqueous ICAM-1 was associated with a favorable anatomic response, in terms of reduced SD-OCT MV at 3 months (every additional 100 pg/mL of baseline ICAM-1 was associated with a reduction of 0.0379 mm3; P = .01). Conversely, increasing baseline aqueous VEGF was associated with a less favorable SD-OCT MV response at 3 months (every additional 100 pg/mL of baseline VEGF was associated with an increase of 0.0731 mm3; P = .02) and was associated with lower odds of being a central subfield thickness responder (odds ratio, 0.868; 95% CI, 0.755-0.998). Conclusions and Relevance: Elevated aqueous ICAM-1 and reduced VEGF levels at baseline are associated with a favorable anatomic response to ranibizumab in DME, although there is not always direct correlation between anatomic and visual acuity response.

Ultra-low-dose intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case series.

BACKGROUND: Intravitreal bevacizumab (IVB) has emerged as an effective treatment modality for the management of retinopathy of prematurity (ROP) where the disease is severe and posterior. Despite evidence of systemic vascular endothelial growth factor suppression and concerns about how this might affect the developing neonate, the optimal dose is unknown to date. We report our experience of using ultra-low-dose (0.16 mg) IVB, one-quarter of the 'standard' dose that has widely been reported in the treatment of ROP. METHODS: A retrospective observational case series of consecutive infants who underwent ultra-low-dose IVB injection for the management of ROP at a regional neonatal intensive care unit in the North East of England, between November 2013 and August 2016. RESULTS: 29 eyes of 15 infants underwent IVB injection. We defined 'treatment success' as complete regression of retinopathy and vascularisation into (or laser ablation of) zone 3. Primary success (in response to IVB 0.16 mg alone) was observed in 23/29 eyes (79.3%). Secondary success (where additional treatment was required) was observed in 27/29 eyes (93.1%). One infant died of respiratory disease during follow-up. Retreatment occurred in 6/29 eyes (20.6%). Retreatments occurred at a mean of 9.8 weeks after initial IVB (range 6-15) and at a mean of 44 weeks postmenstrual age (range 40-50). CONCLUSION: 0.16 mg IVB is effective in the treatment of severe and posterior ROP, with no adverse ocular outcomes occurring in our series.

Diabetic macular edema outcomes in eyes treated with fluocinolone acetonide 0.2 µg/d intravitreal implant: real-world UK experience.

PURPOSE: To conduct an observational, multicenter study to evaluate real-world clinical efficacy and safety of the 0.2 µg/day fluocinolone acetonide (FAc) implant in the treatment of patients with chronic diabetic macular edema (DME) in 3 large hospital ophthalmology departments in the United Kingdom. METHODS: Fluocinolone acetonide implants were inserted into the study eyes following a suitable washout period; phakic eyes received FAc implant following cataract surgery. Follow-up visits took place 2-4 weeks postinjection and then at 3, 6, and 12 months; change in central macular thickness (CMT) from baseline was measured by optical coherence tomography and best-corrected visual acuity (BCVA) was also assessed. Adverse events and changes in intraocular pressure (IOP) were recorded in order to evaluate the safety profile for the FAc implant. RESULTS: Improvements in BCVA and CMT were observed from 3 months and sustained for the duration of observation. At 12 months, the overall mean change from baseline CMT was -126 µm and mean increase in BCVA from baseline was 5.1 letters. Increases in IOP following FAc implant were easily managed with IOP-lowering medication. Implant migration into the anterior chamber occurred in 2 eyes where prior vitrectomy had resulted in a posterior capsule defect; this was rectified and resolved. CONCLUSIONS: The results of this study provide further efficacy and safety profile data for FAc implant treatment of chronic DME in a real-world clinical setting; the FAc implant appears to be a valuable therapeutic approach for patients with chronic DME who have suboptimal response to other treatment options.

AQUEOUS HUMOR CYTOKINE LEVELS AS BIOMARKERS OF DISEASE SEVERITY IN DIABETIC MACULAR EDEMA.

PURPOSE: To determine whether aqueous cytokine levels correlate with disease severity in diabetic macular edema. METHODS: A prospective cross-sectional study of 49 adults with diabetes mellitus, centre-involving diabetic macular edema and central subfield macular thickness ≥310 µm on spectral domain optical coherence tomography. Clinical examination and aqueous sampling were carried out before an initial injection of ranibizumab. Multiplex immunoassay of sample was carried out for vascular endothelial growth factor, placental growth factor, transforming growth factor beta, intercellular adhesion molecule-1, interleukin (IL)-2, IL-3, IL-6, IL-8, IL-10, IL-17, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and epidermal growth factor. Multivariate robust regression models were constructed, and adjusted for age, lens status, or severity of retinopathy, and size of foveal avascular zone. RESULTS: Spectral domain optical coherence tomography macular volume was an excellent measure of disease severity, correlating strongly with central subfield macular thickness (P < 0.001), best-corrected Snellen visual acuity (P < 0.001), and baseline diabetic retinopathy severity (P = 0.01). Elevated aqueous intercellular adhesion molecule-1 correlated with greater macular volume (P = 0.002). No aqueous cytokine, including VEGF, correlated with central subfield macular thickness. There was an association between IL-10 levels and best-corrected Snellen visual acuity (P = 0.03). CONCLUSION: Aqueous intercellular adhesion molecule-1 correlates with disease severity as measured by macular volume on spectral domain optical coherence tomography, and IL-10 is associated with BCVA. Intercellular adhesion molecule-1 may be a clinically useful biomarker for diabetic macular edema severity.

Ultra-low dose of intravitreal bevacizumab in the treatment of retinopathy of prematurity.

Intravitreal bevacizumab is an increasingly common treatment choice for posterior retinopathy of prematurity. Despite concern about its systemic effects, there have been few studies on the lowest effective dose. The authors describe a case that was successfully treated with 0.16 mg of bevacizumab, the first time this dose has been reported.

Bilateral rhegmatogenous retinal detachment in spondyloepimetaphyseal dysplasia-Strudwick type.

PURPOSE: To document the diagnosis and repair of bilateral retinal detachments in a child with spondyloepimetaphyseal dysplasia-Strudwick type, a rare autosomal dominant genetic disorder involving abnormal production of Type II collagen. METHODS: Case report. RESULTS: A 13-year-old patient diagnosed with spondyloepimetaphyseal dysplasia-Strudwick type presented with a localized superior temporal retinal detachment in the right eye and a 180° giant retinal tear with an associated macula-off retinal detachment in the left eye. He was highly myopic and had a visual acuity of 20/80 in the right eye and counting fingers in the left eye. He underwent a pars plana vitrectomy in the left eye and laser retinoplexy in the right eye, achieving complete reattachment and/or stabilization of both retinae, with a visual acuity of 20/60 in the right eye and 20/100 in the left eye at 3 months postoperatively. CONCLUSION: Patients with spondyloepimetaphyseal dysplasia-Strudwick type may be at a higher risk of developing myopia, vitreoretinal degeneration, and a subsequent retinal detachment, although the scientific literature provides a loose association between these conditions. Critically, we propose a temporal association between retinal detachment and the onset of puberty in these patients and suggest that a dilated retinal screening examination should be scheduled at around the time of puberty for patients with spondyloepimetaphyseal dysplasia-Strudwick type to detect any asymptomatic retinal pathology.