A New Technique of Pars Plana Vitrectomy With Microinterventional Nucleus Disassembly to Reduce the Energy of Fragmatome Lensectomy for Posteriorly Dislocated Crystalline Lens Removal.

PURPOSE: To describe a novel technique of lens disassembly in posteriorly dislocated crystalline lens removal. METHODS: A microinterventional microfilament loop device was introduced through the sclerotomy created for the fragmatome to cleave the lens into smaller, manageable pieces. RESULTS: Five cases were performed with this technique with improved visual acuity and no complications. CONCLUSION: The use of microinterventional nucleus disassembly during pars plana vitrectomy for retained lens material is a novel approach with potential advantages including decreased operating time and reduced complications secondary to excessive production of ultrasound energy.

Chitosan-Polycaprolactone Core-Shell Microparticles for Sustained Delivery of Bevacizumab.

The current therapy for treating neovascular age-related macular degeneration requires monthly intravitreal injection of angiogenesis inhibitors such as bevacizumab or ranibizumab via a 31-gauge needle to inhibit choroidal neovascularization. However, repeated intravitreal injections are associated with poor patient compliance and potential side effects. Microparticle-based injectable devices have shown great promise to address this issue by sustained delivery of protein therapeutics, but critical barriers remain, including limited loading capacity and steady long-term release without compromising the anti-angiogenic activity of drugs. Addressing these challenges, we developed a unique method for synthesizing biodegradable polymer-based core-shell microparticles with sizes around 10 µm, high physical integrity, and uniform size. Subsequent electrostatic and physical interactions to control protein diffusion were designed for the core-shell microparticles to effectively increase the capacity of drug loading to 25%, reduce burst release by almost 30%, and extend the period of drug release from 3 to 6 months. Remarkably, the microparticles enabled a longer-term drug administration and maintained high drug potency up to 6 months in vitro, representing significant advancement compared to conventional microparticle-based delivery platforms or currently commercialized devices. Additionally, the microparticles presented minimal toxicity to human retinal cells in vitro with over 90% cell viability, and they also exhibited good injection feasibility through 31-gauge needles in an ex vivo porcine eye model. These results warrant further studies to evaluate the clinical potential for treating posterior ophthalmic diseases as well as other conditions or injuries requiring long-term local drug administration.

Refractive outcomes and accuracy of IOL power calculation with the SRK/T formula for sutured, scleral-fixated Akreos AO60 intraocular lenses.

BACKGROUND: Scleral fixation of intraocular lenses has become a popular procedure for treating aphakia in the absence of capsular support. However, the lens formulas used to predict refractive outcomes were designed for in-the-bag lens placement. This study evaluates the accuracy of the SRK/T formula in predicting a target postoperative refraction when suturing a scleral-fixated intraocular lens (IOL) implant 3 mm posterior to the limbus. METHODS: This is a retrospective, case series including 20 eyes of 20 patients who underwent scleral fixation of Akreos AO60 IOLs (Bausch & Lomb, Rochester, NY) by a single surgeon at the OSU Wexner Medical Center. Preoperative measurements were performed with optical biometry, and IOL power was calculated with the SRK/T formula. Following surgery, the actual refractive spherical equivalent (SE) was performed and compared with the preoperative prediction. Prediction error (PE), defined as the deviation of actual postoperative SE refraction in diopters (D) from preoperative predicted SE refraction, was the primary outcome measure. RESULTS: The mean attempted (predicted) SE was - 1.12 D (± 0.87). Mean achieved SE was - 0.96 D (± 1.04). Mean PE (actual postoperative SE versus predicted preoperative SE) was 0.16 D (± 0.69). A total of 9 eyes (45%) were within ± 0.5 D of the predicted SE, 16 eyes (80%) were within ± 1.0 D, and all 20 eyes (100%) were within ± 1.5 D. CONCLUSION: IOL power calculation using the SRK/T formula with optical biometry demonstrates reliable postoperative refractive outcomes in patients undergoing scleral fixation of an IOL (Akreos AO60). Further studies are needed to refine the predictive value of the SRK/T and other formulas for application in scleral fixation of IOLs.

Known and novel ocular toxicities of biologics, targeted agents, and traditional chemotherapeutics.

PURPOSE: Increases in cancer with an aging population and the rapid development of new chemotherapeutics underscore the need for ophthalmologists to identify and manage potential ocular toxicities. This retrospective case series reports the ocular side effects of traditional and novel chemotherapeutic agents from a large center. METHODS: The medical records of 3537 adult patients 18 years and older who presented to an academic ophthalmology department on high-risk medications identified by ICD-9 search between January 2010 and February 2015 were reviewed. A cancer diagnosis, as well as a temporal association with chemotherapeutic use and ocular side effect, was deemed necessary for inclusion in the study. The main measures were ocular side effects in cancer patients taking chemotherapy, ocular imaging abnormalities, and the outcome of each side effect. RESULTS: Of the 161 oncology patients referred to the ophthalmology clinic for chemotherapeutic screening or ocular side effect, 31 (19.3%) were identified as having an ocular adverse reaction due to a novel or traditional chemotherapeutic medication. A novel flattening of the corneal curvature with hyperopic shift and corneal microcysts was identified in a patient taking the antibody-drug conjugate mirvetuximab soravtansine and was reversible with topical steroids. A bilateral medium-vessel choroidal vasculopathy with serous retinal detachment was seen with ipilimumab. The most frequent medication with ocular toxicity was interferon-α(2b) (IFN-α(2b)) (6/31, 19.4%); headache was typical in these patients (83.3%). Ibrutinib ocular toxicity was second most common (5/31, 16.1%), usually causing red or dry eye, while one patient developed branch retinal artery occlusion. Retinal abnormalities documented on OCT imaging occurred with IFN-α(2b), ipilimumab, binimetinib, and docetaxel, while rod-cone ERG abnormality was seen with cisplatin. Inflammatory conditions included anterior scleritis with zoledronic acid, focal eyelid inflammation with veliparib, bilateral chemosis with R-CHOP, iritis, and blepharospasm with IFN-α(2b). AION occurred with pemetrexed, and transient vision loss with hyperemic disc OS was seen with FOLFOX. Two patients (2/31, 6.5%) developed permanent vision loss. Six patients were lost to follow-up, and the clinical course was unknown (6/31, 19.4%). CONCLUSIONS AND RELEVANCE: Cases of permanent visual loss were observed; yet, in the majority of side effects, they improved with topical therapy and/or holding the medication. Further research is needed to elucidate the incidence and the pathophysiology of these side effects and maximize patient quality of life.

Novel microarchitectural dynamics in rhegmatogenous retinal detachments identified with intraoperative optical coherence tomography.

PURPOSE: To evaluate ultrastructural macular changes during rhegmatogenous retinal detachment repair using intraoperative optical coherence tomography (iOCT). METHODS: A multisurgeon, single-center consecutive case series of 9 eyes undergoing surgical repair for macula-involving rhegmatogenous retinal detachment with iOCT imaging using a custom microscope-mounted spectral domain OCT system. All patients underwent combined vitrectomy/scleral buckle repair. Imaging characteristics were analyzed, including persistence of subclinical intraoperative subretinal fluid and architectural changes associated with intraoperative maneuvers. Clinical characteristics were analyzed. RESULTS: Nine eyes of nine patients were identified that underwent iOCT imaging during macula-involving rhegmatogenous retinal detachment repair. Persistent subclinical subretinal fluid was identified in 100% of eyes after perfluoro-n-octane instillation. Significant alterations to the foveal architecture were detected with iOCT in 100% of cases. Three foveal configurations were noted based on iOCT findings. Stage 1 was characterized by a small area of subfoveal hyporeflectivity (3/9 eyes), Stage 2 had prominent subretinal hyporeflectivity and foveal thinning with indeterminate macular hole (MH) formation (3/9 eyes), and Stage 3 demonstrated definitive full-thickness MH (3/9 eyes). No eyes were noted to have a MH preoperatively or in the immediate postoperative period. One Stage 3 eye developed a full-thickness MH 7 months postoperatively. Stage 3 configuration was associated with poorer final postoperative visual acuity (P = 0.009). CONCLUSION: Microarchitectural changes occur during intraoperative repair of retinal detachments, including significant alterations in foveal configuration and persistent subretinal fluid. These features may help to prognosticate outcomes. These findings also suggest a possible novel mechanism for postrhegmatogenous retinal detachment MH formation.

High Resolution Imaging of the Outer Retina in Type 2 Acute Macular Neuroretinopathy.

PURPOSE: To investigate the outer retinal changes in a patient with type 2 acute macular neuroretinopathy (AMN). METHODS: A 35-year-old Caucasian female complaining of a unilateral blind spot was imaged using various retinal imaging modalities including clinical optical coherence tomography (OCT), OCT-angiography, fundus fluorescein angiography and adaptive optics (AO). RESULTS: Fundus examination revealed multiple paracentral reddish-brown petaloid lesions in the symptomatic left eye, while the other eye was unremarkable. Clinical OCT showed areas of hyper-reflectance at the outer plexiform layer / outer nuclear layer complex with a disrupted inner /outer segment junction, which are characteristic features of type 2 AMN. AO imaging further revealed either shortening or absence of cone outer segments within the AMN lesions attributing to the darker features observed in the enface images from fundus photography and scanning laser ophthalmoscopy. CONCLUSION: The AO findings indicate that the petaloid lesions in type 2 AMN are caused by a combination of the shortening and absence of the outer segment in individual cone photoreceptors.

Foveal Phase Retardation Correlates With Optically Measured Henle Fiber Layer Thickness.

This study quantified and compared phase retardation distribution in the central macula with the thickness of the Henle fiber layer (HFL). A scanning laser polarimeter (SLP) was used to acquire 20° × 40° macular-centered images, either with fixed corneal compensation or with variable corneal compensation, in two cohorts of clinically normal subjects (N = 36). Phase retardation maps from SLP imaging were used to generate a macular cross pattern (fixed compensation) or an annulus pattern (variable compensation) centered on the macula. Intensity profiles in the phase retardation maps were produced using annular regions of interest at eccentricities from 0.25° to 3°. Pixel intensity was averaged at each eccentricity, acting as a surrogate for macular phase retardation. Directional OCT images were acquired in the horizontal and vertical meridians in all subjects, allowing visualization of the HFL thickness. HFL thickness was manually segmented in each meridian and averaged. In both cohorts, phase retardation and HFL thickness were highly correlated in the central 3° assessed, providing further evidence that the source of the phase retardation signal in the central macula is dominated by the HFL and that the center of the macula on cross sectional imaging corresponds closely with the center of the macular cross on SLP imaging.

Quantifying the pattern of retinal vascular orientation in diabetic retinopathy using optical coherence tomography angiography.

Quantitative imaging using optical coherence tomography angiography (OCTA) could provide objective tools for the detection and characterization of diabetic retinopathy (DR). In this study, an operator combining the second derivative and Gaussian multiscale convolution is applied to identify the retinal orientation at each pixel in the OCTA image. We quantified the pattern of retinal vascular orientation and developed three novel quantitative metrics including vessel preferred orientation, vessel anisotropy, and vessel area. Each of eight 45º sectors of the circular disk centered at the macular region was defined as the region of interest. Significant sectoral differences were observed in the preferred orientation (p < 0.0001) and vessel area (p < 0.0001) in the 34 healthy subjects, whereas vessel anisotropy did not demonstrate a significant difference among the eight sectors (p = 0.054). Differential retinal microvascular orientation patterns were observed between healthy controls (n = 34) and the DR subjects (n = 7). The vessel area characterized from the vascular orientation pattern was shown to be strongly correlated with the traditionally reported vessel density (Pearson R > 0.97, p < 0.0001). With three metrics calculated from the vascular orientation pattern simultaneously and sectorally, our quantitative assessment for retinal microvasculature provides more information than vessel density alone and thereby may enhance the detection of DR. These preliminary results suggest the feasibility and advantage of our vessel orientation-based quantitative approach using OCTA to characterize DR-associated changes in retinal microvasculature.

Injectable biodegradable bi-layered capsule for sustained delivery of bevacizumab in treating wet age-related macular degeneration.

Vascular endothelial growth factor (VEGF) is a key regulator of abnormal blood vessel growth. As such, bevacizumab-based inhibition of VEGF has been the clinically adopted strategy to treat colorectal and breast cancers as well as age-related macular degeneration (AMD). However, as the treatment of vascular diseases often requires a high drug concentration for a long period, the burst release of bevacizumab remains a critical limitation in anti-VEGF-based therapies. Maintaining bevacizumab at high concentrations over extended periods remains challenging due to insufficient drug loading capacity and drug-device interactions. We report the development of a polymeric based bi-layered capsule that could address these challenges by extending the release over one year, thereby providing an effective platform enabling treatment of chronic vascular diseases. Remarkably, the developed capsules have a bi-layered structure which ensures the structural integrity of the injectable capsules and appropriate diffusion of bevacizumab by providing optimal physical trapping and electrostatic interaction. Meanwhile, the central hollow design enables a higher drug loading to meet the need for long-term release of bevacizumab for several months to one year. Using an in vitro drug release assay, we demonstrated that the bi-layered capsule could produce longer-term local drug administration by intravitreal injection compared to previously reported devices. The capsules also present minimal toxicity and maintain anti-VEGF potency, suggesting that our approach may have the potential to treat vascular-related diseases using bevacizumab.

The effects of steep trendelenburg positioning on intraocular pressure during robotic radical prostatectomy.

BACKGROUND: Intraocular pressure (IOP) increases in steep Trendelenburg positioning, but the magnitude of the increase has not been quantified. In addition, the factors contributing to this increase have not been studied in robot-assisted prostatectomy cases. In this study, we sought to quantify the changes in IOP and examine perioperative factors responsible for these changes while patients are in the steep Trendelenburg position during robotic prostatectomy. METHODS: In this prospective study, we measured IOP using a Tono-pen XL in 33 patients undergoing robot-assisted prostatectomy. The IOP was measured before anesthesia while supine and awake (baseline T1), anesthetized and supine (T2), anesthetized after insufflation of the abdomen with carbon dioxide (CO(2)) (T3), anesthetized in steep Trendelenburg (T4), anesthetized in steep Trendelenburg at the end of the procedure (T5), anesthetized supine before awakening (T6), and 1 hr after awakening in the supine position (T7). RESULTS: On average, IOP was 13.3 +/- 0.58 (mean +/- SE) mm Hg higher at the end of the period of steep Trendelenburg position (T5) compared with supine position T1 (P < 0.0001). The least square estimates for each time point in mm Hg were as follows: T1 = 15.7, T2 = 10.7, T3 = 14.6, T4 = 25.2, T5 = 29.0, T6 = 22.2, T7 = 17.0. Using univariate mixed effects models for the T1-T5 time periods, peak airway pressure, mean arterial blood pressure, ETco(2), and time were significant predictors of the IOP increase, whereas age, body mass index, blood loss, volume of IV fluid administered, mean airway pressure, and desflurane concentration were not predictive. In T4-T5, which involved no significant positional or perioperative interventions, we performed a multivariate analysis to evaluate predictors of IOP increases. Surgical duration (in minutes) and ETco(2) were the only significant variables predicting changes in IOP during stable and prolonged Trendelenburg positioning. On average, IOP increased 0.21 mm Hg per mm Hg increase in ETco(2) after adjusting for time. An increase of 0.05 mm Hg in IOP per minute of surgery on average was observed during this period in the Trendelenburg position after adjusting for ETco(2). CONCLUSIONS: IOP reached peak levels at the end of steep Trendelenburg position (T5), on average 13 mm Hg higher than the preanesthesia induction (T1) value. Surgical duration and ETco(2) were the only significant predictors of IOP increase in the Trendelenburg position (T4-T5).

Comparison of fibrin sealant versus suture for wound closure in Müller muscle-conjunctiva resection ptosis repair.

PURPOSE: To compare fibrin sealant (Tisseel) versus suture for wound closure in Müller muscle-conjunctiva resection ptosis repair. METHODS: The charts of 114 patients (211 eyelids) who had undergone Müller muscle-conjunctiva resection were retrospectively reviewed. Suture versus Tisseel were used for wound closure. Preoperative and postoperative eyelid measurements, postoperative symmetry within 0.5 mm, and complications were compared. RESULTS: Müller muscle-conjunctiva resection ptosis repair was performed on 211 eyelids of 114 patients. Seventeen cases were unilateral and 97 cases were bilateral. Method of wound closure included suture (45 eyelids of 31 patients) versus Tisseel (166 eyelids of 83 patients). For the suture group, the mean preoperative MRD1 was 1.2 mm and the postoperative MRD1 was 3.0 mm; the difference was 1.9. For the Tisseel group, the mean preoperative MRD1 was 1.2 mm and the postoperative MRD1 was 3.0 mm; the difference was 1.8. The 2 groups did not differ statistically in preoperative (p = 0.97) or postoperative MRD1 values (p = 0.53), the difference (p = 0.63), or postoperative symmetry within 0.5 mm (p = 0.39). In the suture group, complications included moderate to severe pain (10%), suture granuloma (6%), corneal abrasion (3%), loose suture (3%), and persistent keratopathy (3%). We found no evidence of keratopathy attributable to the Tisseel (p = 0.0001). This difference in the prevalence of complications was statistically significant (p = 0.0001). Four patients in the suture group (13%) underwent subsequent procedures including suture granuloma removal (2) and suture removal (1); 1 patient (3%) required levator resection. Three patients in the Tisseel group (4%) subsequently underwent levator resection. CONCLUSIONS: Müller muscle-conjunctiva resection ptosis repair using fibrin sealant for wound closure offers comparable eyelid position results compared with suture. Use of Tisseel showed fewer postoperative complications and was associated with fewer subsequent surgical procedures.

Ocular Siderosis Secondary to Retained Intraocular Foreign Body: A Case Report.

Intraocular foreign bodies (IOFBs) can present in an insidious manner. A 20-year-old male presented with gradual visual loss in the right eye over a six-month period. He was found to have a dense cataract. During examination he was noted to have a small, healed corneal scar and subtle iris heterochromia. Further questioning revealed a previously undisclosed metal-on-metal hammering injury concerning for an IOFB. B-scan ultrasonography was inconclusive and CT studies confirmed the presence of IOFB. The patient underwent a combined cataract extraction with intraocular lens implantation with a pars plan vitrectomy, removal of IOFB, and endolaser. He had an excellent visual outcome, despite developing siderosis. A high index of suspicion should be raised for any asymmetric cataract formation, especially in younger patients. Careful examination for findings such as healed corneal scars or iris heterochromia may aid in diagnosing previously undisclosed injuries.

Structural Integrity of Individual Cone Photoreceptors After Short-Wavelength Subthreshold Micropulse Laser Therapy for Diabetic Macular Edema.

BACKGROUND AND OBJECTIVE: Subthreshold micropulse laser (SML) treatment at 577 nm has been proposed as a safe and efficacious therapy for diabetic macular edema (DME). The study objective was to evaluate the integrity of individual cone photoreceptors after SML treatment using high-resolution retinal imaging. PATIENTS AND METHODS: An observational cohort study of four subjects with DME treated using SML was followed over time. Cone inner and outer segment lengths and total retinal thicknesses (TRT) were measured as the edema resolved. The primary outcome was the detection of any laser-induced photoreceptor damage / change following the SML treatment using adaptive optics imaging. RESULTS: Individual cones observed pre-treatment remained visible, whereas cones that were initially obscured by the DME became more discernable after the treatment. TRT showed statistically significant thinning in half of the subjects. One subject showed no significant change, whereas another showed a statistically significant increase in TRT despite the treatment. No subject was found to have photoreceptor damage following treatment. CONCLUSIONS: SML at 577 nm did not result in measurable structural damage to the underlying photoreceptor layer, supporting previous work that SML is a safe alternative for treating DME. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:946-954.].

Forming a Consensus: Data and Guidance for Physicians Treating Diabetic Macular Edema.

The diabetic macular edema (DME) treatment paradigm has evolved as the understanding of the disease pathology has grown. Since 2012, four pharmacotherapies have been approved by the U.S. Food and Drug Administration for the treatment of DME. First-line treatment of DME with anti-vascular endothelial growth factor [VEGF] agents has become the gold standard; however, an appreciable percentage of patients do not respond to anti-VEGF therapies. In patients who inadequately respond to anti-VEGF therapies, the underlying disease pathology may be mediated by a multitude of growth factors and inflammatory cytokines. For these patients, corticosteroids are an attractive treatment option because they not only downregulate VEGF, but also an array of cytokines. The phase 3 MEAD and FAME trials demonstrated significant visual acuity improvements associated with dexamethasone and fluocinolone acetonide, respectively, in patients with DME; however, class-specific adverse events, including increased intraocular pressure and cataract development, must be considered before use. A panel of experts gathered during the 2015 annual meeting of the American Academy of Ophthalmology for a roundtable discussion focused on patient selection and adverse event management associated with the use of the 0.19 mg fluocinolone acetonide intravitreal implant.

Aflibercept in wet age-related macular degeneration: a perspective review.

In the treatment of neovascular age-related macular degeneration (AMD), vascular endothelial growth factor (VEGF) has emerged as a key target of therapy. Currently, patients with neovascular AMD are treated with monthly intravitreal injections of anti-VEGF medications. Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF-A, VEGF-B, and placental growth factor. It is the latest medication to receive US Federal Drug Administration (FDA) approval for the treatment of neovascular AMD. Theoretical models suggest this molecule may have a longer duration of action compared with current treatments. The results of the VEGF Trap-Eye: Investigation of Efficacy and Safety in wet Age-related Macular Degeneration studies (VIEW 1 and VIEW 2) support this by demonstrating that aflibercept, dosed every 2 months after a monthly loading dose for 3 months, was noninferior in the proportion of patients who maintained or improved vision at 52 weeks compared with monthly injections of ranibizumab. These results were maintained over the 2 years of the studies. Aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA and Bayer, Basel, Switzerland) was approved by the FDA for the treatment of neovascular AMD on 18 November 2011.

Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration.

INTRODUCTION: Age-related macular degeneration (AMD) continues to be a leading cause of blindness worldwide. The neovascular form of the disease can lead to rapid and progressive vision loss. Vascular endothelial growth factor (VEGF) has emerged as a key target of treatment, with inhibitors of VEGF being shown to arrest the angiogenic process and avoid the visual damage typically associated with its presence. AREAS COVERED: This manuscript reviews the treatment history for wet AMD and examines aflibercept , a new, fully human, recombinant fusion protein designed to bind all isoforms of VEGF-A, as well as placental growth factor (PGF), thereby inhibiting the binding and activation of VEGF receptors. EXPERT OPINION: The results of Phase I, II and III studies have proven aflibercept to be a safe and effective treatment for wet AMD. Recent results of Phase III studies demonstrate the efficacy of aflibercept, dosed every 8 weeks after three initial monthly doses, and show that this regimen is clinically equivalent to monthly ranibizumab therapy. Eylea™ (aflibercept) was approved by the FDA for the treatment of wet AMD on 18 November 2011.