Novel oral medications for retinal disease: an update on clinical development.

PURPOSE OF REVIEW: Intravitreal and periocular injections for retinal disease provide a targeted delivery of medication to the eye. However, given risks of injections, including endophthalmitis, pain and treatment burden for both patients and retina specialists, there has been significant interest and effort in developing oral medications for the management of retinal disease. This article provides clinical and preclinical details of new oral medications in the pipeline for management of retinal disease. RECENT FINDINGS: Several new oral medications show clinical and preclinical promise for the management of retinal disease, including macular degeneration, diabetic retinopathy and Stargardt disease. SUMMARY: Oral medications provide promise for treating retinal disease, possibly increasing compliance, and reducing side effects of intravitreal or periocular injections. However, difficulties in this approach include systemic side effects and efficacy targeting the eye. There are multiple medications that are currently under investigation with the potential to act as stand-alone treatment or as an adjunct treatment for management of retinal diseases such as diabetic retinopathy, macular degeneration and Stargardt disease.

In-Office Vitreous Biopsy With a Vitreous Cutter and Manual Actuation.

In-office vitreous biopsy is currently performed with a 25-gauge needle or less frequently with a specialized in-office surgical system. This article demonstrates in-office vitreous biopsy with a standard vitreous cutter, using syringes to actuate the cutter. A 79-year-old woman presented six days after intravitreal bevacizumab with endophthalmitis. After subconjunctival anesthesia, a valved 27-gauge trocar was inserted through the pars plana. Two syringes were connected to a pneumatic 27-gauge Alcon vitrectomy handpiece and manually actuated by an assistant while the physician aspirated with a third syringe to obtain the vitreous biopsy. Intravitreal vancomycin and ceftazidime were injected. A total of 0.5 cc of fluid was collected without complications. Manual actuated vitrectomy reliably collects sufficient vitreous samples for diagnostic evaluation and may be safer and more effective than needle biopsy. [Ophthalmic Surg Lasers Imaging Retina 2024;55:116-118.].

Emerging Oral Pharmaceuticals for Dry Age-Related Macular Degeneration: Mechanism of Action, Current Clinical Status, and Future Directions.

Dry age-related macular degeneration (AMD) has been historically managed with lifestyle modifications, monitoring for conversion to wet AMD, and vitamins. Recently there has been a flurry of research focused on discovering new targets to prevent worsening of dry AMD. In 2023, the US Food and Drug Administration approved the first two intravitreal complement inhibitors to slow the rate of geographic atrophy progression. However, serial intravitreal injections for a chronic progressive disease are burdensome for patients and have procedural risks. Therefore, there is significant research to discover novel oral medications to manage dry AMD. Several oral medications are currently in phase 2 and 3 clinical trials for dry AMD, whereas others have had recent readouts on their clinical trials and efficacy. The purpose of this review is to describe the therapeutic pathways currently being investigated and to provide an update on the clinical status of novel oral medications for the management of dry AMD. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Rapid Improvement in Lipid Maculopathy Following Faricimab Therapy in Recalcitrant Familial Exudative Vitreoretinopathy.

A monocular 22-year-old man with recalcitrant familial exudative vitreoretinopathy presented with progressive subretinal lipid exudation and lipid maculopathy that responded poorly to repeated aflibercept injections. The subretinal exudation started temporally and gradually progressed, involving the macula and the retinal periphery in all 4 quadrants. At the 22-month follow-up visit, macular and peripheral subretinal exudation persisted despite a total of 29 injections. Faricimab was then injected once every 2 weeks for a total of 3 injections, which resulted in rapid dramatic resolution of the macular and most of the peripheral subretinal exudation. No ocular or systemic adverse events were noted. [Ophthalmic Surg Lasers Imaging Retina 2023;54:426-428.].

Ischemic index and distribution of retinal capillary non-perfusion in neovascular glaucoma.

INTRODUCTION: Neovascular Glaucoma (NVG) is a condition normally caused by hypoxic posterior ocular disease, which produces angiogenic factors such as vascular endothelial growth factor (VEGF) that stimulate new vessel proliferation of the anterior segment and angle, eventually leading to angle closure, reduced outflow of aqueous humor and increased intraocular pressure. Without treatment elevated intraocular pressure can rapidly progress to loss of vision. Treatment includes addressing the intraocular pressure and reducing the ischemic drive with panretinal photocoagulation (PRP) of the ischemic retina. Recent imaging advancements allow for ultra-widefield fluorescein angiography (UWFA) which expand the amount of peripheral retina that can be evaluated for non-perfusion. Here we aim to study patterns of non-perfusion in NVG using a group of PRP naïve patients with recent onset NVG. METHODS: This study is a retrospective single-center cross-sectional study of patients seen at LAC + USC Medical Center from January 2015 to April 2020 with new onset NVG, without PRP and with UWFA completed. The percentage of ischemic index of the retina was calculated from the UWFA and evaluated in three distinct zones centered on the fovea: the posterior pole, the mid periphery, and far periphery. To increase sample size, a confirmatory group was included, with PRP allowed prior to UWFA but not before diagnosis. In addition, the time between diagnosis and UWFA was increased to 6 months. RESULTS: A total of 11 eyes met inclusion criteria for the primary group. Ischemic index was found to be 91% in the far periphery, 77% in the mid periphery, and 42% at the posterior pole. The total average ischemic index was 76%. There was a statistically significant difference between the far periphery and posterior pole and mid periphery and posterior pole. A total of 24 eyes met criteria for the confirmatory group. Ischemic index for the confirmatory group was found to be 93% in the far periphery, 75% in the mid periphery, and 35% at the posterior pole. There was a statistically significant difference between the far periphery, posterior pole and mid-periphery. CONCLUSION: This knowledge can be used to further guide treatment and understand risk for NVG.

Metastatic neuroendocrine tumors mimicking as primary ocular disease.

PURPOSE: To report two cases of metastatic neuroendocrine tumors masquerading as primary ocular disease. OBSERVATIONS: Case 1 is a 38-year-old man who was referred with subacute onset diplopia and fluctuating ptosis suggestive of myasthenia gravis. Case 2 is a 21-year-old man who presented with blurry vision and was found to have a pigmented ciliary body mass and retinal detachment suggestive of uveal melanoma. Both patients were ultimately diagnosed with metastatic neuroendocrine tumors. CONCLUSIONS AND IMPORTANCE: Neuroendocrine tumors, though rare and infrequently metastatic to the eye and orbit, can initially present with ocular signs. A broad differential and careful consideration of ocular and systemic symptoms are critical in such challenging cases.

A new dual port cutter system for vitrectomy surgery.

PURPOSE: To evaluate and compare the performance of several designs of 20-gauge dual port (DP) vitreous cutter tips with a standard 20-gauge single port tip. METHODS: Custom 20-gauge pneumatic vitreous DP cutter tips with different sizes and port positions were evaluated through porcine vitreous and water flow rates. Five designed and fabricated DP cutter tips were compared with a normal single port control tip and evaluated by the measurement of water and porcine vitreous flow rates, and surgical examination in enucleated porcine eyes. RESULTS: Some DP tips approached a maximum vitreous and water flow rates, removing water and vitreous faster than the normal control tip. With reference to surgical evaluation, some DP tips performed better than the single port tip for bulk vitrectomy, but none shaved the vitreous base more effectively. CONCLUSION: The DP cutter system has the potential to increase the flow rates depending on the size and position of the extra port. In the future, the DP cutter may allow the surgeon to perform bulk vitrectomy more efficiently.

Effect of Angle Narrowing on Sectoral Variation of Anterior Chamber Angle Width: The Chinese American Eye Study.

PURPOSE: To characterize the relationship between mean and sectoral variation of anterior chamber angle (ACA) width using anterior segment optical coherence tomography (AS-OCT). METHODS: Subjects aged 50 years or older were identified from the Chinese American Eye Study (CHES), a population-based epidemiological study in Los Angeles, CA. Each subject underwent a complete ocular examination including gonioscopy and AS-OCT imaging. Primary angle closure disease (PACD) was defined as inability to visualize pigmented trabecular meshwork in 3 or more quadrants. Four AS-OCT images from one eye per subject were analyzed and parameters describing ACA width were measured at 500 and 750 µm from the scleral spur: angle opening distance (AOD), trabecular iris space area (TISA), and scleral spur angle (SSA). The relationship between mean and sectoral variation of ACA width was assessed using locally-weighted scatterplot smoothing (LOWESS) regression and change-point analyses and Spearman correlation coefficients. RESULTS: 674 eyes (337 with PACD, 337 without PACD) from 674 subjects were analyzed. Overall, sectoral variation of ACA width decreased as mean ACA width decreased. This relationship was divided into two phases based on the change-point analysis. Sectoral variation of ACA width was strongly and significantly correlated (P < 0.001) with mean ACA width with below parameter-specific change points for most parameters: AOD500 (r = 0.599), AOD750 (r = 0.246), TISA500 (r = 0.734), TISA750 (r = 0.664), SSA500 (r = 0.661), SSA750 (r = 0.394). Correlations were weaker but still significant (P < 0.004) above these change points for most parameters: AOD500 (r = 0.321), AOD750 (r = 0.550), TISA500 (r = 0.122), TISA750 (r = 0.275), SSA500 (r = -0.036), SSA750 (r = 0.313). Correlations to the left and right of the change points strengthened when sectoral variation of ACA width was adjusted for mean ACA width. CONCLUSIONS: Correlations between mean and sectoral variation of ACA width strengthen as the severity of angle narrowing worsens. This relationship likely reflects anatomical changes related to chronic angle closure and may be relevant for refining current definitions and management of PACD.

Anterior Segment Optical Coherence Tomography: Applications for Clinical Care and Scientific Research.

Anterior segment optical coherence tomography (AS-OCT) is a non-contact imaging technique that produces high-resolution images and quantitative measurements of the anterior segment and its anatomical structures. There has been rapid development of OCT technology over the past 2 decades, with the transition from time-domain to Fourier-domain OCT devices. By integrating these advancements in OCT technology, AS-OCT devices have evolved into versatile clinical and research tools for studies of the anterior segment and ocular surface. The primary purpose of this article was to review OCT technology and AS-OCT devices as well as applications of AS-OCT for clinical practice and scientific research. We first describe the different types of OCT technology, how they have been adapted for AS-OCT imaging, and differences between various AS-OCT devices. We then review the applications of AS-OCT for characterizing the anatomical structures of the anterior segment and aqueous outflow pathways, including the anterior chamber angle, trabecular meshwork, and Schlemm canal. We also describe glaucoma-related applications of AS-OCT imaging, which include evaluating patients for static and dynamic biometric risk factors of primary angle closure disease and assessing the efficacy of glaucoma interventions, such as laser peripheral iridotomy and glaucoma surgery. Finally, we review other clinical applications of AS-OCT imaging for detection and management of diseases of the ocular surface, cornea, and lens.

Performance analysis of new-generation vitreous cutters.

BACKGROUND: Despite their clinical advantages, smaller-diameter vitrectomy systems pose significant challenges in vitreous removal. The percentage of time the vitreous cutter port is open while cutting (duty cycle) is one of the primary factors that affect flow. Herein, we examine the effect of duty cycle on the flow performance of new-generation cutters relative to current instrumentation. METHODS: Performance of 25-gauge (ga) and 20-ga new-generation spring-return pneumatic cutters (n = 24 and n = 28 respectively) was analyzed relative to current-generation cutters, across their specified cut-speed range under clinical vacuum pressures of 500 mmHg (25-ga) and 200 mmHg (20-ga). A precision balance measured mass of water or porcine vitreous removed from a vial by a cutter; this was recorded in real-time and converted to flow rates. Frame-by-frame analysis of high-speed video was used to determine duty cycle. Data was analyzed using linear regression and the t-test. RESULTS: Compared with the current-generation, the new-generation cutters exhibit increasingly greater water flow rates at higher cut speeds (P < 0.001). Vitreous flow rates of the new-generation cutters are relatively constant as cut speed increases, and are significantly greater than those of the current-generation cutters at cut speeds of 1500 cuts per minute (CPM) or higher (P < 0.001). The new-generation 25-ga cutter exhibits greater vitreous flow rates at higher cut speeds than the current-generation 20-ga cutter: at 2000 and 2500 CPM, the new 25-ga cutter has 1.45 and 11.88 times the vitreous flow rate of the current 20-ga cutter (P < 0.001) respectively. Duty cycles of the new-generation cutters are significantly higher than those of the current-generation at all cut speeds (P < 0.001). CONCLUSIONS: Although a number of factors influence flow, the high and relatively constant vitreous flow rates of the new-generation cutters are most likely due to their maintenance of high duty cycle as cut speed increases. The findings illustrate that in optimizing duty cycle, the vitreous flow efficiency of smaller-diameter cutters can match or exceed that of larger diameter cutters.

Port geometry and its influence on vitrectomy.

PURPOSE: To determine the influence of port geometry on water and vitreous flow rates and test novel vitreous cutter tips in specific surgical situations. METHODS: Custom 20-gauge and 25-gauge vitreous cutter tips with different sized ports were evaluated through porcine vitreous and water flow rates. Five cutter tips were designed and fabricated for specific surgical functionalities. Tips were compared with a normal control tip and evaluated by water and porcine vitreous flow rates, vacuum level required to cut porcine retina, time required to cut and aspirate a porcine lens, and surgical evaluation in enucleated porcine eyes. RESULTS: Both vitreous and water flow asymptotically approached a maximum flow as the port diameter increased. Some tips removed water faster than the normal control tip, but none removed vitreous or lens faster. Several tips required higher vacuum levels to cut retina than the normal tip. CONCLUSIONS: Increasing the port diameter of a vitreous cutter to increase flow becomes less effective as the port becomes larger. Furthermore, modifying the port geometry of a vitreous cutter affects its surgical interactions with tissue. In the future, combinational instruments or surgery specific instruments may allow the surgeon to use an optimal port for a specific surgical task.

A self-stabilizing lens ring for 25-gauge vitrectomy surgery.

PURPOSE: To design an improved self-stabilizing lens ring for 25-gauge vitrectomy. DESIGN: Device report. METHODS: A lens ring was designed to be fixated to the globe using 25-gauge transconjunctival cannulas. RESULTS: This ring consists of a single plastic component with multiple concavities at the ring margin to fit 25-gauge cannulas. The ring can accommodate conventional standard and panoramic vitrectomy lenses. CONCLUSIONS: A lens ring has been designed for 25-gauge vitrectomy and to hold conventional contact lenses. Stability of the lens ring is achieved without the need for sutures and instead is achieved by the three point fixation provided by the existing 25-gauge cannula system.

Evaluation of a stereoscopic camera-based three-dimensional viewing workstation for ophthalmic surgery.

PURPOSE: To evaluate the effectiveness of a prototype stereoscopic camera-based viewing system (Digital Microsurgical Workstation, three-dimensional (3D) Vision Systems, Irvine, California, USA) for anterior and posterior segment ophthalmic surgery. DESIGN: Institutional-based prospective study. METHODS: Anterior and posterior segment surgeons performed designated standardized tasks on porcine eyes after training on prosthetic plastic eyes. RESULTS: Both anterior and posterior segment surgeons were able to complete tasks requiring minimal or moderate stereoscopic viewing. The results indicate that the system provides improved ergonomics. Improvements in key viewing performance areas would further enhance the value over a conventional operating microscope. CONCLUSIONS: The performance of the prototype system is not at par with the planned commercial system. With continued development of this technology, the three- dimensional system may be a novel viewing system in ophthalmic surgery with improved ergonomics with respect to traditional microscopic viewing.

Evaluation of lens hardness in cataract surgery using high-frequency ultrasonic parameters in vitro.

Ultrasonic parameters of sound velocity and frequency-dependent attenuation ranging from 25 to 45 MHz were measured for the purpose of evaluating the hardness of lenses in cataract surgery (phacoemulsification). Measurements were performed with a 35-MHz ultrasonic transducer on porcine lenses in which artificially cataracts were induced. The hardness of the cataractous lens was also evaluated by mechanical measurement of its elastic properties. The results indicated that the ultrasonic attenuation coefficients in normal porcine lenses were approximately 4.49 +/- 0.05 (mean +/- SD) and 6.32 +/- 0.04 dB/mm at 30 and 40 MHz, respectively. The development progression of the cataracts resulted in the attenuation coefficient increasing linearly to 7.36 +/- 0.25 and 11.1 +/- 0.92 dB/mm, respectively, corresponding to an increase of Young's modulus from 2.6 to 101.2 kPa. The sound velocity concomitantly increased from 1639.8 +/- 4.2 to 1735.6 +/- 10.4 m/s. Evaluation of the relationship between the phacoemulsification energy level and ultrasonic parameters in vitro by surgeons revealed that both the attenuation coefficient and sound velocity were linearly correlated with the phacoemulsification energy (r = 0.941 and 0.915, respectively). These results showed that measuring high-frequency ultrasonic parameters provides surgeons with good capability and reproducibility for selecting the optimal energy level for phacoemulsification.

Biomimetic Accommodating Intraocular Lens Using a Valved Deformable Liquid Balloon.

OBJECTIVE: Presbyopia is a common age-related condition that prevents people from focusing on near objects. The etiology of presbyopia continues to be debated, but the end effect of all postulated mechanisms is the lack of deformation of the human lens. Using our understanding of the biomechanical properties of the natural human lens, we created a unique accommodating intraocular lens. Although this lens can be used for lenticular disease such as myopia and hyperoperopia, this study addresses the needs of cataract patients with presbyopia. METHODS: The lens was implanted into presbyopic human cadaver eyes. Focal length of the lens was measured with simulated muscle contraction. Lens dimensions were measured using artificial tissue and a finite-element analysis (FEA) to simulate accommodation. Lens power was measured at various fill volumes. Accelerated soak testing for an equivalent of 7.4 years was performed and lens weight and optical transmittance were measured. RESULTS: Previously presbyopic human eyes were able to accommodate between 2.0 and 7.4 diopters after lens implantation. FEA and lens measurements demonstrated a change in curvature of the anterior and posterior portions of the lens during accommodation. After accelerated aging, lens weight remained unchanged and optical transmission was 96%. Lens power increased with fill volume. CONCLUSION: A deformable liquid lens reversed presbyopia, can be individualized by optically adjusting for each patient, is stable for long periods of time, and is compatible with minimally invasive surgical techniques. SIGNIFICANCE: A deformable liquid-filled lens can significantly improve accommodation over the presbyopic natural lens.

Guillotine performance: duty cycle analysis of vitrectomy systems.

PURPOSE: To evaluate the duty cycle of different vitrectomy cutters and classify their blade movement. METHODS: A precise weighing (0.01 g) high speed (2 samples/s) balance was used to study the 20-gauge and 25-gauge Bausch & Lomb Lightning-Millenium (St. Louis, MO), the 20-gauge (1500 cpm) and the 25-gauge Alcon Accurus (Fort Worth, TX), the 20-gauge Alcon Innovit, and the 23-gauge DORC (Netherlands) cutters. The weight of balanced saline solution (BSS) was recorded in real time using LabView software and then translated into a graph of volume removed versus time. Variable cut rates and vacuum pressures were analyzed in vitreous and BSS. A high-speed (400 frames/s) camera was used to record cutting for each condition. RESULTS: Three types of duty cycle were investigated: parabolic incomplete (pneumatic), sinusoid (electric), and trapezoid (double pneumatic). The parabolic incomplete and trapezoid had a decreased duty cycle at 1500 cuts per minute when it was compared to 600 cuts per minute. The sinusoid had no statistical difference between cut rates. CONCLUSIONS: Systems showed different performances of duty cycle. This new classification will be useful for improved understanding of vitrectomy in these different systems.

Vitreous dynamics: vitreous flow analysis in 20-, 23-, and 25-gauge cutters.

PURPOSE: To evaluate porcine vitreous flow and balanced saline solution (BSS) flow rates in different vitrectomy systems. METHODS: Porcine vitreous was obtained within 24 hours of slaughter. A high-speed (2 samples/s) balance, precise to 0.01 g, was used. Variable cut rates and vacuum pressures were analyzed in vitreous and BSS. The vitreous was labeled with glass microspheres and triamcinolone acetonide. A high-speed (400 frames/s) camera was used to record cutting for each condition. RESULTS: For all cutters, there was no vitreous flow at zero cut rates (off). In 25-gauge cutters, at 500 mmHg of vacuum, the electric cutter produced higher average flow rates at high cut rates (600 cpm, 0.004 mL/s, and 1500 cpm, 0.013 mL/s) than pneumatic, which demonstrated a decreased flow at speeds higher than 1000 cpm (1000 cpm, 0.015 mL/s, and 1500 cpm, 0.006 mL/s). The percentage of vitreous flow rate/BSS flow rate in different aspiration and cut rates showed an ascending curve. This demonstrates evidence of flow obstruction in 25- (all cut rates), 23- (all cut rates), and 20-gauge (all cut rates). Flow obstruction and surge movements were seen in the high-speed videos. CONCLUSIONS: The vitrectomy systems each illustrate different performances of vitreous removal. The physical characteristics of vitreous resulted in nonuniform flow in all vitreous cutters.