Fellow Eye Comparisons for 7-Year Outcomes in Ranibizumab-Treated AMD Subjects from ANCHOR, MARINA, and HORIZON (SEVEN-UP Study).

PURPOSE: To compare study and fellow eyes in subjects with age-related macular degeneration (AMD) for 7-year outcomes arising from contrasting treatment histories and disease statuses. DESIGN: Multicenter cohort study, predetermined secondary analysis. PARTICIPANTS: A total of 65 participants from the ranibizumab-treatment arms of the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR), Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA), and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON) trials, recruited for an update evaluation from 14 study sites. METHODS: Seven-year visual outcomes and retinal imaging data were compared with the ANCHOR, MARINA, and HORIZON databases. Under the ANCHOR and MARINA protocols, study eyes had received monthly ranibizumab injections for the initial 2 years, during which fellow eyes were prohibited from anti-vascular endothelial growth factor (VEGF) treatments. MAIN OUTCOME MEASURES: Percentage of subjects with study eye vision better than fellow eye, vision change from baseline to year 7, and mean area of macular atrophy (MA) were predetermined secondary end points. RESULTS: Fellow eyes with exudative AMD had received a mean 7.3 total injections of anti-VEGF agents in the mean 3.4 years off-study. For the 35% of subjects with exudative AMD in both eyes at baseline, within-patient comparisons at year 7 showed better vision in the study eye in 82%, with better mean final vision in study eyes (54.7 vs. 27.3 letters in fellow eyes, P < 0.001). Also in this subgroup, study eyes, which had received 2 years of high-frequency ranibizumab, had less severe MA than the respective fellow eye at year 7 in 88% of patients (mean area ± standard deviation 2.8±2.2 mm(2) vs. 5.8±2.5 mm(2) in the fellow eyes, P = 0.0013). Final fellow eye vision outcome was significantly correlated with MA severity (coefficient -6.95, P < 0.001), and patients' inter-eye vision difference corresponded to the degree of MA asymmetry. CONCLUSIONS: Exudative fellow eyes remained at risk for further vision decline in later years under management with low-frequency anti-VEGF therapy. In patients with bilateral exudative AMD at baseline, final vision at year 7 was significantly better in study eyes than in fellow eyes, and MA was less severe. Macular atrophy area correlated with final visual outcomes, determined inter-eye vision differences, and was not attributable to high-frequency ranibizumab therapy.

Safety and tolerability of intravitreal umedaptanib pegol (anti-FGF2) for neovascular age-related macular degeneration (nAMD): a phase 1, open-label study.

OBJECTIVE: To evaluate the efficacy and safety of a single-dose intravitreal umedaptanib pegol (anti-FGF2, investigational new drug) for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: Nine participants who had a diagnosis of refractory nAMD were enrolled and received a single intravitreal injection of umedaptanib pegol at increasing doses of 0.2, 1.0 or 2.0 mg in the study eye. RESULTS: All three doses of umedaptanib pegol evaluated in the study were safe and well tolerated. No severe adverse event (AE) was observed in the study. There was an improvement in retinal fluid measured by central subfield thickness (CST) in most subjects. Remarkably, all three subjects who received 2.0 mg/eye showed improvement of more than 150 µm. CONCLUSIONS: Intravitreal umedaptanib pegol was safe, well tolerated, and demonstrated an indication of bioactivity in participants that have persistent subretinal fluid refractory to the treatment with anti-VEGFs.

Heterogeneity in disease activity, frequency of treatments, and visual outcomes among patients with retinal vein occlusion: relationship between injection need and vision with as-needed ranibizumab.

BACKGROUND/AIMS: We characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON. METHODS: Patients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7-15) of SHORE and through 12 months of HORIZON. Prespecified PRN re-treatment criteria for each trial were based on protocol-prespecified BCVA and optical coherence tomography outcomes. RESULTS: After the initial 7 monthly ranibizumab injections, patients in SHORE gained a mean of 18.3 letters from baseline. Patients randomised to PRN, on average, maintained these gains. However, some patients experienced additional mean gains, whereas others suffered losses (range 4.0 (95% CI 0.7 to 7.3) to -4.6 (95% CI -11.8 to 2.6) letters in patients who received 0 and 6-7 PRN injections, respectively). In BRAVO and CRUISE (lead-in trials), patients experienced mean gains from baseline to M6 (monthly dosing) of 19.3 and 15.0 letters, respectively, with gains maintained with PRN from M6 to M12. However, mean BCVA changes from baseline to M12 varied in HORIZON (range -0.4 (95% CI -2.5 to 1.6) to -3.6 (95% CI -6.2 to -1.0) letters in patients who received zero and six injections, respectively, during the preceding PRN phase of BRAVO and CRUISE). CONCLUSION: The BRVO/CRVO population is heterogenous with a varied response to ranibizumab treatment.

Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): phase 2 trials in treatment-naïve and anti-VEGF pretreated patients.

BACKGROUND/OBJECTIVE: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are the first-line treatment for exudative age-related macular degeneration (nAMD). Due to the limitations of these standard therapies, targeting alternative mechanisms of action may be helpful for treatment of this very common disease. Here, we investigated an anti-fibroblast growth factor-2 (FGF2) aptamer, umedaptanib pegol, a next generation therapeutic for the treatment of nAMD. METHODS: Three phase 2 studies were designed. First, a multicentre, randomized, double-masked TOFU study assessed the efficacy of intravitreal injections of umedaptanib pegol monotherapy or in combination with aflibercept, compared to aflibercept monotherapy in 86 subjects with anti-VEGF pretreated nAMD. Second, 22 subjects who had exited the TOFU study received 4 monthly intravitreal injections of umedaptanib pegol (extension, RAMEN study). Third, as an investigator-sponsored trial (TEMPURA study), a single-center, open-label, 4-month study was designed to evaluate the safety and treatment efficacy of umedaptanib pegol in five naïve nAMD patients who had not received any prior anti-VEGF treatment. RESULTS: The TOFU study demonstrated that umedaptanib pegol alone or in combination with aflibercept did not improve best-corrected visual acuity (BCVA) and central subfield thickness (CST) over aflibercept alone. However, the change in BCVA and CST at primary endpoint was marginal in all the three treatment groups, suggesting that umedaptanib pegol is effective to prevent the disease progression. The RAMEN study confirmed the cessation of disease progression. In the TEMPURA study, naïve nAMD patients showed improvement and no further macular degeneration, with striking improvement of visual acuity and central subfield thickness in some of the patients. CONCLUSIONS: These results demonstrate, for the first time, clinical proof of concept for aptamer based anti-FGF2 therapy of nAMD.

Subretinal hyperreflective material in regions of atrophy and fibrosis in eyes with neovascular age-related macular degeneration.

BACKGROUND: Subretinal hyperreflective material (SHRM) is a significant biomarker for poor visual outcomes in neovascular age-related macular degeneration (nAMD); however, its relationship with fibrosis and atrophy is not well understood. This study aims to evaluate the relationship between SHRM, atrophy, and fibrosis in eyes receiving antivascular endothelial growth factor therapy for nAMD. METHODS: Post-hoc analysis of the 65 patients enrolled in the SEVEN-UP study, a multicenter cross-sectional study of patients originally enrolled in the ANCHOR and MARINA trials of ranibizumab. Color fundus photographs (CFP) were reviewed and manually segmented to define regions of atrophy and fibrosis. SHRM borders on OCT volume scans were manually delineated, and thickness measurements were computed and compared in corresponding regions of atrophy and fibrosis on the CFPs. RESULTS: Of the 65 subjects, 51 eyes showed atrophy and/or fibrosis on CFP and were included in the final analysis. Both atrophy and fibrosis regions exhibited SHRM on OCT. The mean SHRM thickness on OCT was significantly greater in CFP-fibrosis regions (44.19 ± 46.95 µm) compared with CFP-atrophy regions (14.28 ± 13.35 µm; p < 0.001). Additionally, the average maximum height of SHRM in fibrotic regions (268.04 ± 130.05 µm) was significantly thicker than in atrophic regions (121.95 ± 51.17 µm; p < 0.001). CONCLUSIONS: Although atrophy and fibrosis are thought to be different end-stage outcomes in eyes with nAMD, they both demonstrate SHRM on OCT; the main distinction being thickness. Given these similarities, these regions of nAMD-associated atrophy may be better-termed "atrosis" to distinguish these lesions from typical atrophy in the absence of neovascular disease.

Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography.

PURPOSE: To determine if optical coherence tomography (OCT) at baseline or month 3 in the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Treatment of Macular Edema following Central Retinal Vein Occlusion: Evaluation of Efficacy and Safety (CRUISE) studies provides information that predicts visual outcome. DESIGN: Post hoc analysis from 2 prospective, randomized, controlled clinical trials. PARTICIPANTS: Three hundred ninety-seven patients from the BRAVO study and 392 patients from the CRUISE study. METHODS: Time-domain OCT imaging data were analyzed. MAIN OUTCOME MEASURES: Mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6 and month 12. RESULTS: Among ranibizumab-treated patients, 71.2% (0.3 mg) and 78.5% (0.5 mg) in the CRUISE study and 79.1% (0.3 mg) and 84.7% (0.5 mg) in the BRAVO study had central foveal thickness (CFT) of 250 µm or less at month 3 and therefore were categorized as early ranibizumab responders. Early ranibizumab responders had excellent visual outcomes regardless of ranibizumab dose; mean improvement in BCVA letter score at 6 and 12 months was 15.0 to 16.5 (central retinal vein occlusion [CRVO]) and 17.4 to 19.1 (branch retinal vein occlusion [BRVO]). Late or incomplete ranibizumab responders with CRVO (CFT >250 µm at month 3) did not fare as well as early responders if they were treated with 0.3 mg ranibizumab (month 6, P = 0.012). At month 6, compared with ranibizumab-treated CRVO patients with resolved cystoid macular edema (CME) at month 3, those with persistent CME did worse, on average, and significantly so for 0.5 mg (13.1 vs. 18.6; P = 0.027). At baseline, subretinal fluid (SRF) was present in 57% of patients with CRVO and in 45% of patients with BRVO; its presence did not portend a poor outcome in patients treated with ranibizumab for whom SRF was eliminated in almost all by month 3. CONCLUSIONS: At month 3 of ranibizumab treatment, OCT images provide predictive information for patients with CRVO, but not for those with BRVO. Visual outcome at months 6 and 12 was reduced in 0.5 mg ranibizumab-treated patients with CRVO who had persistent CME at month 3. It also was reduced in CRVO for those with CFT of more than 250 µm at month 3 who were treated with 0.3 mg ranibizumab. The findings suggest that late or incomplete responders may need careful follow-up. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion.

OBJECTIVE: Central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO) causes hypoperfusion, high levels of vascular endothelial growth factor (VEGF), macular edema, and loss of vision. Many patients also show areas of complete closure of retinal vessels (retinal nonperfusion [RNP]) that increase over time. The objective was to assess the effect of blocking VEGF on progression of RNP. DESIGN: Retrospective analysis of prospectively collected data from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: A total of 392 and 397 patients with macular edema due to CRVO or BRVO. METHODS: An independent reading center measured the area of RNP on fluorescein angiograms (FAs) in 2 phase III trials investigating the effect of ranibizumab (RBZ; Lucentis; Genentech, Inc, South San Francisco, CA) in patients with CRVO or BRVO. MAIN OUTCOME MEASURES: The percentage of patients with no posterior RNP at months 0, 3, 6, 9, and 12. RESULTS: There was no difference among treatment groups at baseline, but at the month 6 primary end point the percentage of patients with CRVO and no RNP was significantly greater in the RBZ groups (0.3 mg, 82.0%, P = 0.0092; 0.5 mg, 84.0%, P = 0.0067) versus the sham group (67.0%). Reperfusion of nonperfused retina was rare (1%) in sham-treated patients with CRVO, but occurred in 6% to 8% of patients with CRVO treated with RBZ (30% of those who had RNP and could improve). Results in patients with BRVO mirrored those in patients with CRVO. Crossover to 0.5 mg RBZ from sham at month 6 halted the progression of RNP and resulted in improvement in both CRVO and BRVO. CONCLUSIONS: Treatment with RBZ did not worsen RNP in patients with RVO, but rather reduced its occurrence compared with sham. These data provide an important new insight regarding the pathogenesis of RVO; the initial vein occlusion is a precipitating event that causes baseline ischemia and release of VEGF, which then contributes to progression of RNP and thus worsening of ischemia. Timely, aggressive blockade of VEGF prevents the worsening of RNP, promotes reperfusion, and eliminates a positive feedback loop.

Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP).

PURPOSE: To assess long-term outcomes 7 to 8 years after initiation of intensive ranibizumab therapy in exudative age-related macular degeneration (AMD) patients. DESIGN: Multicenter, noninterventional cohort study. PARTICIPANTS: Sixty-five AMD patients originally treated with ranibizumab in the phase 3 Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial, Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial, and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON). METHODS: Fourteen clinical trial sites recruited their original subjects for a return evaluation. Individual subject comparisons were obtained from the ANCHOR, MARINA, and HORIZON databases. MAIN OUTCOME MEASURES: The primary end point was percentage with best-corrected visual acuity (BCVA) of 20/70 or better; secondary outcomes included mean change in letter score compared with previous time points and anatomic results on fluorescein angiography, spectral-domain ocular coherence tomography (OCT), and fundus autofluorescence (FAF). RESULTS: At a mean of 7.3 years (range, 6.3-8.5 years) after entry into ANCHOR or MARINA, 37% of study eyes met the primary end point of 20/70 or better BCVA, with 23% achieving a BCVA of 20/40 or better. Thirty-seven percent of study eyes had BCVA of 20/200 or worse. Forty-three percent of study eyes had a stable or improved letter score (≥0-letter gain) compared with ANCHOR or MARINA baseline measurements, whereas 34% declined by 15 letters or more, with overall a mean decline of 8.6 letters (P<0.005). Since exit from the HORIZON study, study eyes had received a mean of 6.8 anti-vascular endothelial growth factor (VEGF) injections during the mean 3.4-year interval; a subgroup of patients who received 11 or more anti-VEGF injections had a significantly better mean gain in letter score since HORIZON exit (P<0.05). Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing ocular anti-VEGF treatments. Macular atrophy was detected by FAF in 98% of eyes, with a mean area of 9.4 mm(2); the area of atrophy correlated significantly with poor visual outcome (P<0.0001). CONCLUSIONS: Approximately 7 years after ranibizumab therapy in the ANCHOR or MARINA trials, one third of patients demonstrated good visual outcomes, whereas another third had poor outcomes. Compared with baseline, almost half of eyes were stable, whereas one third declined by 15 letters or more. Even at this late stage in the therapeutic course, exudative AMD patients remain at risk for substantial visual decline.

Injectable Devices for Delivery of Liquid or Solid Protein Formulations.

Sustained delivery of protein therapeutics remains a largely unsolved problem across anatomic locations. Miniaturized devices that can provide sustained delivery of protein formulations have the potential to address this challenge via minimally invasive administration. In particular, methodologies that can optimize protein formulation independent of device manufacture have the greatest potential to provide a platform suitable for wide applications. The techniques developed here demonstrate the fabrication of tubular devices for sustained release of protein therapeutics. Utilizing a dip-casting process, fine-scale tubes can be reliably produced with wall thickness down to 30 µm. Techniques were developed that enabled effective loading of either solid or liquid formulations, while maintaining a cylindrical form-factor compatible with placement in a 22-gauge needle. Further, highly compacted protein pellets that approach the expected density of the raw materials were produced with a diameter (∼300 µm) suitable for miniaturized devices. Release from a solid-loaded device was capable of sustaining release of a model protein in excess of 400 days. Given significant interest in ocular applications, intravitreal injection was demonstrated in a rabbit model with these devices. In addition, to simulate repeated injections in ocular applications, serial intravitreal injection of two devices in a rabbit model demonstrated acceptable ocular safety without significant intraocular inflammation from clinical exam and histology.

Risk factors for retinal detachment following cataract surgery.

PURPOSE OF REVIEW: To review and evaluate the current literature on the incidence and risk factors for rhegmatogenous retinal detachment (RRD) following cataract surgery. RECENT FINDINGS: RRD is a serious complication of cataract surgery that can occur in the early or late postoperative periods. Identifying factors that increase the risk of pseudophakic retinal detachment can aid in management. Recent studies support long established risk factors for retinal detachment including intraoperative complications such as posterior capsular rupture (PCR). In addition, the current literature further defines the risk for pseudophakic retinal detachment associated with younger age at time of surgery, high myopia, and male sex in several large retrospective studies. Two recent articles also examine the state of the vitreous before and after cataract surgery and find that patients are more likely to develop posterior vitreous detachment postoperatively, possibly contributing to the increased risk of RRD. SUMMARY: Younger age, high myopia, and male sex continue to be associated with higher risk of pseudophakic retinal detachment. Intraoperative complications such as PCR also increase the retinal detachment risk. Given the high volume of cataract surgeries performed each year, pseudophakic retinal detachment contributes significantly to visual morbidity in the United States and Europe.

Macular Atrophy Incidence, Progression, and Visual Acuity Effects in 5-Year Treatment of Neovascular Age-Related Macular Degeneration.

BACKGROUND AND OBJECTIVE: Macular atrophy (MA) contributes to declining vision during prolonged anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (nAMD) so greater understanding of its incidence, evolution, and impact on visual acuity is merited. MATERIALS AND METHODS: This is a retrospective review of nAMD patients receiving anti-VEGF therapy for ≥ 5 years. Near-infrared reflectance images and vision data were extracted every 6 months. MA lesion areas were measured using ImageJ. RESULTS: Vision showed a mean decline of -1.2 letters/year. Eyes with MA showed a greater decrease of -1.6 letters/year compared to eyes without MA (-0.7 letters/year). Cumulative incidence of MA was 38% at 5 years. MA was significantly associated with declining vision, showing a -0.7 letter decrease for every 1 mm2 increase in lesion size. CONCLUSION: Over a 5-year course of nAMD treatment, MA affected most eyes, and MA progression was significantly associated with vision decline. [Ophthalmic Surg Lasers Imaging Retina 2022;53:546-552.].

Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study.

PURPOSE: Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO). DESIGN: Prospective, randomized, sham injection-controlled, double-masked, multicenter trial. PARTICIPANTS: A total of 397 patients with macular edema after BRVO. METHODS: Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) ≤20/40 or central subfield thickness ≥250 µm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met. MAIN OUTCOME MEASURES: The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed. RESULTS: Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5-18.4) and 18.3 (15.8-20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6-14.6) in the sham/0.5 mg group (P<0.01, each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 56.0% and 60.3% in the 0.3 mg and 0.5 mg groups, respectively, and 43.9% in the sham/0.5 mg group. On average, there was a marked reduction in central foveal thickness (CFT) after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. No new ocular or nonocular safety events were identified. CONCLUSIONS: At month 12, treatment with ranibizumab as needed during months 6-11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Management of retained lens fragments in complicated cataract surgery.

PURPOSE OF REVIEW: To evaluate and review the current literature on the management of retained lens material with pars plana vitrectomy (PPV) and lensectomy after complicated cataract surgery. RECENT FINDINGS: Recent studies on retained lens fragments in cataract surgery support early referral to a vitreoretinal specialist, and indicate that visual outcomes are favorable with current vitrectomy and lensectomy techniques. Nearly 83% of patients without preexisting eye disease who undergo PPV achieve visual acuity of 20/40, whereas 5.5% of patients have postoperative acuity of 20/200 or worse. In a multivariate analysis, the predictors for 20/40 or better vision were presenting acuity, insertion of a posterior chamber lens at the time of cataract surgery, and absence of preoperative eye disease. Retinal detachment and secondary glaucoma were the major causes of ocular morbidity. Most retrospective studies assessing the timing of vitrectomy and lensectomy show no advantage for early (within 1 week) PPV. Delayed vitrectomy beyond 30 days is associated with poorer outcomes. With technological advances, small gauge vitrectomy is considered a viable alternative surgical approach to standard vitrectomy with phacofragmentation. SUMMARY: Given favorable outcomes reported with planned PPV, the primary intraoperative goals of the cataract surgeon encountering posterior displacement of lens material are to remove lens material that is accessible from the anterior approach, remove vitreous from the anterior segment, and place an anterior or preferably posterior chamber intraocular lens. Early involvement of the retinal surgeon facilitates the evaluation and timing for vitrectomy and lensectomy based on the clinical course.

BILATERAL ENTEROCOCCUS FAECALIS ENDOPHTHALMITIS WITH MULTIPLE RECURRENCES.

PURPOSE: To describe the first case report of a bilateral recurrent Enterococcus faecalis endophthalmitis postcataract surgery. METHODS: Case report with a description of the timeline, diagnosis, and management of a patient with bilateral recurrent E. faecalis endophthalmitis. RESULTS: An 89-year-old man presented 6 weeks' postcataract surgery with pain, tearing, and blurred vision in the left eye. B-scan ultrasonography revealed vitritis and cultures postvitrectomy grew E. faecalis. There was gradual improvement in vision postintravitreal vancomycin administration. Four years later, the patient experienced another episode of E. faecalis endophthalmitis in the right eye postcataract extraction, followed by several additional episodes in both eyes posttreatment. CONCLUSION: Enterococcus faecalis is a rare but highly virulent cause of endophthalmitis that may remain sequestered in the capsular bag, despite aggressive treatment. Even after recurrent episodes, early vitrectomy and aggressive antibiotic therapy may prove to be effective in preventing vision loss.

Rhegmatogenous retinal detachment masquerading as exudative panuveitis with intense anterior chamber inflammatory reaction.

PURPOSE: This is a retrospective case report illustrating the diagnostic and therapeutic challenges associated with a chronic rhegmatogenous retinal detachment masquerading as a severe panuveitis with intense anterior chamber inflammation. We have included clinical features, anterior segment and fundus photography, B-scan ultrasonography, fluorescein angiography, and intraoperative findings. OBSERVATIONS: A 26-year-old male presented with features of unilateral panuveitis: hypotony, anterior segment inflammation (posterior synechiae and anterior chamber cell with fibrin clumping), diffuse choroidal thickening, and retinal detachment. Laboratory investigations for infectious or rheumatologic processes were negative, and empiric systemic corticosteroid therapy was unsuccessful. This prompted suspicion for an alternate primary etiology, and pars plana vitrectomy revealed small retinal breaks as the underlying cause of the retinal detachment and inflammation. CONCLUSIONS: Rhegmatogenous retinal detachments are a known cause of intraocular inflammation. Nevertheless, it remains a challenge to recognize retinal breaks in this setting, particularly with robust anterior segment inflammation and posterior findings resembling severe exudative uveitis. Being aware of this unique presentation may prevent delays in diagnosis and have important prognostic implications.

Glass intraocular foreign body removal with a nitinol stone basket.

PURPOSE: Glass intraocular foreign bodies (IOFBs) complicate up to 14% of all IOFB cases and require specialized instruments for removal. We present a case of ocular trauma with two large glass IOFBs removed using a nitinol stone basket (NSB) designed for kidney stone extraction in the ureter and calyces. OBSERVATIONS: An adult male suffered a restrained motor vehicle accident. Radiographic computed tomography identified a 9-mm polygonal IOFB within the posterior segment of the right eye. A staged procedure was performed with repair of the ruptured globe followed by 23-gauge pars plana vitrectomy, pars plana lensectomy, and removal of the IOFBs using a NSB. CONCLUSION: At post-operative month one, visual acuity was correctable to 20/60. The retina remained attached and the patient was recovering without complication. IMPORTANCE: Large glass IOFBs are poorly gripped by standard ophthalmic forceps due to their smooth surface, large size, and irregular shape. The NSB is an effective instrument for controlled removal of glass IOFBs. Further customized design may adapt this device for additional intraocular procedures.

Anti-Angiogenic and Anti-Scarring Dual Action of an Anti-Fibroblast Growth Factor 2 Aptamer in Animal Models of Retinal Disease.

Currently approved therapies for age-related macular degeneration (AMD) are inhibitors against vascular endothelial growth factor (VEGF), which is a major contributor to the pathogenesis of neovascular AMD (nAMD). Intravitreal injections of anti-VEGF drugs have shown dramatic visual benefits for AMD patients. However, a significant portion of AMD patients exhibit an incomplete response to therapy and, over the extended management course, can lose vision, with the formation of submacular fibrosis as one risk factor. We investigated a novel target for AMD treatments, fibroblast growth factor 2 (FGF2), which has been implicated in the pathophysiology of both angiogenesis and fibrosis in a variety of tissue and organ systems. The anti-FGF2 aptamer, RBM-007, was examined for treatment of nAMD in animal models. In in vivo studies conducted in mice and rats, RBM-007 was able to inhibit FGF2-induced angiogenesis, laser-induced choroidal neovascularization (CNV), and CNV with fibrosis. Pharmacokinetic studies of RBM-007 in the rabbit vitreous revealed high and relatively long-lasting profiles that are superior to other approved anti-VEGF drugs. The anti-angiogenic and anti-scarring dual action of RBM-007 holds promise as an additive or alternative therapy to anti-VEGF treatments for nAMD.

Device design methodology and formulation of a protein therapeutic for sustained release intraocular delivery.

Despite years of effort, sustained delivery of protein therapeutics remains an unmet need due to three primary challenges - dose, duration, and stability. The work presented here provides a design methodology for polycaprolactone reservoir-based thin film devices suitable for long-acting protein delivery to the back of the eye. First, the challenge of formulating highly concentrated protein in a device reservoir was addressed by improving stability with solubility-reducing excipients. Next, predictive correlations between design parameters and device performance were developed to provide a methodology to achieve a target product profile. Prototype devices were designed using this methodology to achieve desired device size, release rate, therapeutic payload, and protein stability, assessed by in vitro studies. Finally, prototype tolerability was established in a non-human primate model. The design methodology presented here is widely applicable to reservoir-based sustained delivery devices for proteins and provides a general device design framework.

Co-Delivery of Timolol and Brimonidine with a Polymer Thin-Film Intraocular Device.

PURPOSE: We developed a polycaprolactone (PCL) co-delivery implant that achieves zero-order release of 2 ocular hypotensive agents, timolol maleate and brimonidine tartrate. We also demonstrate intraocular pressure (IOP)-lowering effects of the implant for 3 months in vivo. METHODS: Two PCL thin-film compartments were attached to form a V-shaped co-delivery device using film thicknesses of ∼40 and 20 µm for timolol and brimonidine compartments, respectively. In vitro release kinetics were measured in pH- and temperature-controlled fluid chambers. Empty or drug-loaded devices were implanted intracamerally in normotensive rabbits for up to 13 weeks with weekly measurements of IOP. For ocular concentrations, rabbits were euthanized at 4, 8, or 13 weeks, aqueous fluid was collected, and ocular tissues were dissected. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: In vitro studies show zero-order release kinetics for both timolol (1.75 µg/day) and brimonidine (0.48 µg/day) for up to 60 days. In rabbit eyes, the device achieved an average aqueous fluid concentration of 98.1 ± 68.3 ng/mL for timolol and 5.5 ± 3.6 ng/mL for brimonidine. Over 13 weeks, the drug-loaded co-delivery device resulted in a statistically significant cumulative reduction in IOP compared to untreated eyes (P < 0.05) and empty-device eyes (P < 0.05). CONCLUSIONS: The co-delivery device demonstrated a zero-order release profile in vitro for 2 hypotensive agents over 60 days. In vivo, the device led to significant cumulative IOP reduction of 3.4 ± 1.6 mmHg over 13 weeks. Acceptable ocular tolerance was seen, and systemic drug levels were unmeasurable.

Spontaneous resolution of a traumatic cataract caused by an intralenticular foreign body.

A 49-year-old man presented with an intralenticular metal foreign body incurred while he was sawing wood. The metal chard had violated the lens capsule and was lodged in the cortex of the lens. It was removed using a lens-preservation technique during open-globe repair. Subsequently, a dense posterior cortical cataract developed, which spontaneously resolved over the ensuing months. The cataract had a cruciate configuration with wave-like disruption of the stromal lamellae. To our knowledge, this is the first case of spontaneous resolution of a cataract after capsule violation by an intralenticular foreign body. The unique appearance of the cataract and its unusual resolution led to a new theory of lens injury by shockwave.