Drug Approval for the Treatment of Geographic Atrophy: How We Got Here and Where We Need to Go.

PURPOSE: To discuss the clinical trial results leading to the US Food and Drug Administration (FDA) approval of anti-complement therapies for geographic atrophy (GA), perspectives on functional data from the GA clinical trials, and how lessons from the FDA approval may guide future directions for basic and clinical research in AMD. DESIGN: Selected literature review with analysis and perspective METHODS: We performed a targeted review of publicly available data from the clinical trials of pegcetacoplan and avacincaptad for the treatment of GA, as well as scientific literature on the natural history of GA and the genetics and basic science of complement in AMD. RESULTS: The approval of pegcetacoplan and avacincaptad was based on an anatomic endpoint of a reduction in the rate of GA expansion over time. However, functional data from 2 phase 3 clinical trials for each drug demonstrated no visual benefit to patients in the treatment groups. Review of the genetics of AMD and the basic science of the role for complement in AMD provides only modest support for targeting complement as treatment for GA expansion, and alternative molecular targets for GA treatment are therefore discussed. Reasons for the disconnect between anatomic and functional outcomes in the clinical trials of anti-complement therapies are discussed, providing insight to guide the configuration of future clinical studies for GA. CONCLUSION: Although avacincaptad and pegcetacoplan are our first FDA-approved treatments for GA, results from the clinical trials failed to show any functional improvement after 1 and 2 years, respectively, calling into question whether the drugs represent a "clinically relevant outcome." To improve the chances of more impactful therapies in the future, we provide basic-science rationale for pursuing non-complement targets; emphasize the importance of ongoing clinical research that more closely pins anatomic features of GA to functional outcomes; and provide suggestions for clinical endpoints for future clinical trials on GA.

Compassionomics: The Science and Practice of Caring.

PURPOSE: To summarize the scientific evidence that compassion can measurably improve patient outcomes, health care quality and safety, and the well-being of health care providers, and to consider specific strategies for cultivating compassion and better communicating it to patients. DESIGN: Perspective. METHODS: We selectively reviewed the literature on compassion in health care, including obstacles to its expression and the demonstrated effects of provider compassion on patient outcomes, health care quality and cost, and provider well-being. We also review evidence regarding the trainability of compassion, discuss proven methods for cultivating individual compassion, and recommend strategies for incorporating it into routine medical practice. RESULTS: Compassion is the emotional response to another's pain or suffering, accompanied by a desire to alleviate it. Review of the literature shows that compassionate health care measurably improves physical and psychological patient outcomes, increases patient adherence, improves health care quality and safety, increases financial margins, and prevents physician burnout. Psychophysiological research shows that empathy and compassion can be actively cultivated through intentional practice. Validated models of compassion-based interactions can facilitate the consistent expression of compassion in daily medical practice. CONCLUSIONS: Given its many proven benefits to patients, health care organizations, and providers, compassion should be cultivated by health care providers and systems and considered an essential component of optimal medical care.

RHEGMATOGENOUS RETINAL DETACHMENT AFTER INITIATION OF PILOCARPINE HYDROCHLORIDE OPHTHALMIC SOLUTION 1.25% FOR TREATMENT OF PRESBYOPIA.

BACKGROUND/PURPOSE: Retinal detachment has previously been reported in association with topical miotic use for the treatment of glaucoma. Pilocarpine hydrochloride 1.25% was recently approved by the Food and Drug Administration for the treatment of presbyopia, with no reports of associated retinal detachments in the clinical trial data. METHODS: Case report. RESULTS: Two novel cases of unilateral retinal detachment occurring within 10 days of the initiation of pilocarpine 1.25% for the treatment of presbyopia were described. The patients were pseudophakic men in their 60s or 70s with preexisting retinal detachment risk factors, such as high myopia, lattice degeneration, and prior retinal detachment. Both affected eyes were treated with pars plana vitrectomy and gas endotamponade with an uncomplicated postoperative course. CONCLUSION: Retinal detachment may be associated with the use of pilocarpine 1.25%. Caution should be used when considering prescribing this medication in patients with preexisting retinal abnormality.

Increase in Retinal Detachment Repair Over a Ten-Year Period at an Academic Center Compared to National Trends.

BACKGROUND AND OBJECTIVE: This study aimed to determine whether cases of surgical retinal detachment (RD) repair at a tertiary care center from January 1, 2011 to December 31, 2020 increased proportionately to macular surgery cases as a control and to national trends. PATIENTS AND METHODS: Current Procedural Terminology codes were used to identify cases of primary RD repair (67107, 67108), complex RD repair (67113), pneumatic retinopexy (67110), and vitrectomy with membrane peeling (67041, 67042) at an academic center and in the Part B National Summary Data Files. Numbers of cases and mean case times at the academic center were determined. RESULTS: We identified 5,183 and 948,831 operative cases locally and nationally, respectively. Between 2011 and 2019, the total volume of RD repair at the academic center increased by 118.7%, compared to 23.3% for cases of membrane peeling. In contrast, surgical RD repairs and membrane peelings increased by 26.0% and 6.8% cases nationally. The ratio of RD repairs to membrane peelings from 2011 to 2019 increased from 1.5 to 2.6 locally compared to 0.6 to 0.7 nationally. Complex RD repairs increased more than primary RD repairs locally (129.3% vs 110.9% cases) and less than primary RD repairs nationally (20.6% versus 30.2% cases). CONCLUSION: Cases of surgical RD repair increased disproportionately compared to macular surgery at our institution and compared to RD repairs nationwide. [Ophthalmic Surg Lasers Imaging Retina 2023;54:505-511.].

Myopic Traction Maculopathy in Low Myopia.

We describe a case of myopic traction maculopathy (MTM) in a patient with low myopia that resolved with surgical intervention. Our patient demonstrated no other features of myopic degeneration and none of the typical tractional elements that cause MTM, such as vitreomacular traction due to partial posterior vitreous detachment (PVD) with vitreomacular adhesion, epiretinal membrane, or a remnant cortical vitreous layer following PVD. Possible pathogenic mechanisms in our patient include reduced compliance of the aging internal limiting membrane and/or traction from elasticity within the thin cortical vitreous layer that forms the posterior wall of the premacular liquefied pocket. [Ophthalmic Surg Lasers Imaging Retina 2023;54:481-484.].

RETINAL DEPOSITS OF TRIAMCINOLONE-MOXIFLOXACIN AFTER DROPLESS CATARACT SURGERY.

PURPOSE: To report a case of epiretinal crystalline deposits observed on fundus examination and optical coherence tomography 2 years after transzonular intravitreal injection of triamcinolone-moxifloxacin (TriMoxi) during "dropless" cataract surgery. METHODS: Observational case report with literature review of toxic effects of intravitreal triamcinolone and differential diagnosis of retinal crystalline deposits. RESULTS: A 37-year-old asymptomatic pseudophakic man presented with refractile crystalline retinal deposits that had prompted an extensive systemic embolic workup. The systemic evaluation for emboli was negative. OCT imaging revealed that the crystalline deposits were confined to the anterior surface of the internal limiting membrane. Further historical inquiry determined that transzonular intravitreal triamcinolone-moxifloxacin injection had been performed at the time of cataract surgery 2 years earlier. CONCLUSION: Transzonular triamcinolone acetonide delivered during cataract surgery can deposit on the retinal surface for long periods. These epiretinal crystalline deposits are benign and generally do not interfere with visual acuity. Nevertheless, clinicians should be aware of this differential diagnosis because clinical misdiagnosis can lead to unwarranted evaluation and treatment.

Personalized Tacrolimus Dosing After Liver Transplantation: A Randomized Clinical Trial.

Background: Inter- and intra-individual variability in tacrolimus dose requirements mandates empirical clinician-titrated dosing that frequently results in deviation from a narrow target range. Improved methods to individually dose tacrolimus are needed. Our objective was to determine whether a quantitative, dynamically-customized, phenotypic-outcome-guided dosing method termed Phenotypic Personalized Medicine (PPM) would improve target drug trough maintenance. Methods: In a single-center, randomized, pragmatic clinical trial ( NCT03527238 ), 62 adults were screened, enrolled, and randomized prior to liver transplantation 1:1 to standard-of-care (SOC) clinician-determined or PPM-guided dosing of tacrolimus. The primary outcome measure was percent days with large (>2 ng/mL) deviation from target range from transplant to discharge. Secondary outcomes included percent days outside-of-target-range and mean area-under-the-curve (AUC) outside-of-target-range per day. Safety measures included rejection, graft failure, death, infection, nephrotoxicity, or neurotoxicity. Results: 56 (29 SOC, 27 PPM) patients completed the study. The primary outcome measure was found to be significantly different between the two groups. Patients in the SOC group had a mean of 38.4% of post-transplant days with large deviations from target range; the PPM group had 24.3% of post-transplant days with large deviations; (difference -14.1%, 95% CI: -26.7 to -1.5 %, P=0.029). No significant differences were found in the secondary outcomes. In post-hoc analysis, the SOC group had a 50% longer median length-of-stay than the PPM group [15 days (Q1-Q3: 11-20) versus 10 days (Q1-Q3: 8.5-12); difference 5 days, 95% CI: 2-8 days, P=0.0026]. Conclusions: PPM guided tacrolimus dosing leads to better drug level maintenance than SOC. The PPM approach leads to actionable dosing recommendations on a day-to-day basis. Lay Summary: In a study on 62 adults who underwent liver transplantation, researchers investigated whether a new dosing method called Phenotypic Personalized Medicine (PPM) would improve daily dosing of the immunosuppression drug tacrolimus. They found that PPM guided tacrolimus dosing leads to better drug level maintenance than the standard-of-care clinician-determined dosing. This means that the PPM approach leads to actionable dosing recommendations on a day-to-day basis and can help improve patient outcomes.

Macular Retinoschisis from Optic Disc without a Visible Optic Pit or Advanced Glaucomatous Cupping (No Optic Pit Retinoschisis [NOPIR]).

PURPOSE: To review eyes with peripapillary and macular retinoschisis without a visible optic pit or advanced glaucomatous optic atrophy, or No Optic Pit Retinoschisis (NOPIR). DESIGN: Retrospective multicenter case series. SUBJECTS: The study included 11 eyes of 11 patients. METHODS: Retrospective study of eyes with macular retinoschisis without a visible optic pit, advanced optic nerve head cupping, or macular leakage on fluorescein angiography. MAIN OUTCOME MEASURES: Visual acuity (VA), retinoschisis resolution, months to resolution, and recurrence of retinoschisis RESULTS: The mean age was 68.1 ± 17.6 years, mean intraocular pressure was 17.4 ± 3.8 mmHg, and the mean spherical equivalent refractive error was -3.1 ± 2.9 diopters. No subject had pathologic myopia. Seven subjects were treated for glaucoma, and 9 subjects had nerve fiber layer defects on OCT. All eyes had retinoschisis in the outer nuclear layer (ONL) in the nasal macula and extending to the edge of the optic disc, and 8 subjects had fovea-involving retinoschisis. Three nonfoveal and 4 fovea-involved eyes were observed, and 4 fovea-involved eyes with vision loss underwent surgery. Surgery involved preoperative juxtapapillary laser followed by vitrectomy and membrane and internal limiting membrane peeling with intraocular gas and face-down position. The mean baseline VA was significantly worse in the surgery group than that in the observation group (P = 0.020). Retinoschisis resolved and vision improved in all surgical cases. The mean resolution time for the surgery group was 2.75 ± 0.96 months, which was shorter than that for the observation group (28.0 ± 21.2 months; P = 0.014). No eye developed recurrence of the retinoschisis after surgery. CONCLUSIONS: Peripapillary and macular retinoschisis can develop in eyes without a visible optic pit or advanced glaucomatous cupping. Eyes without foveal involvement and those with foveal involvement but only mild decrease in vision can be observed for spontaneous resolution. If there is persistent foveal involvement with vision loss, surgery can improve vision by resolving the macular retinoschisis. Surgery for fovea-involved macular retinoschisis without a visible optic pit resulted in faster anatomic resolution and better vision recovery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Emergence of Treadmill Running Ability and Quantitative Assessment of Gait Dynamics in Young Ts65Dn Mice: A Mouse Model for Down Syndrome.

Down syndrome (DS), which results from the complete or partial trisomy of chromosome 21 (trisomy-21), is the most common genetically defined cause of intellectual disability. Trisomy-21 also produces, or is associated with, many neurodevelopmental phenotypes and neurological comorbidities, including delays and deficits in fine and gross motor development. The Ts65Dn mouse is the most studied animal model for DS and displays the largest known subset of DS-like phenotypes. To date, however, only a small number of developmental phenotypes have been quantitatively defined in these animals. Here, we used a commercially available high-speed, video-based system to record and analyze the gait of Ts65Dn and euploid control mice. Longitudinal treadmill recordings were performed from p17 to p35. One of the main findings was the detection of genotype- and sex-dependent developmental delays in the emergence of consistent, progressive-intensity gait in Ts65Dn mice when compared to control mice. Gait dynamic analysis showed wider normalized front and hind stances in Ts65Dn mice compared to control mice, which may reflect deficits in dynamic postural balance. Ts65Dn mice also displayed statistically significant differences in the variability in several normalized gait measures, which were indicative of deficits in precise motor control in generating gait.

Severe Multifocal Placoid Chorioretinitis Associated with Immune Checkpoint Inhibitor Therapy.

PURPOSE: To report a case of severe bilateral multifocal placoid chorioretinitis in a patient receiving ipilimumab and nivolumab therapy for metastatic melanoma. METHODS: Retrospective, observational case report. RESULTS: A 31-year-old woman on ipilimumab and nivolumab for metastatic melanoma developed severe multifocal placoid chorioretinitis in both eyes. The patient was started on topical and systemic corticosteroid therapy and immune checkpoint inhibitor therapy was paused. Following resolution of ocular inflammation, the patient was restarted on immune checkpoint inhibitor therapy without return of ocular symptoms. CONCLUSION: Extensive multifocal placoid chorioretinitis may occur in patients undergoing immune checkpoint inhibitor (ICPI) therapy. Some patients with ICPI-related uveitis may successfully resume ICPI therapy under close collaboration with the treating oncologist.

Surgical classification for large macular hole: based on different surgical techniques results: the CLOSE study group.

BACKGROUND: The CLOSE study group proposes an updated surgical classification for large macular holes based on a systematic review of new treatments. Recently, many new techniques have been introduced to treat large full-thickness macular holes (FTMH); although the indications are not clear. An updated surgical classification is needed to help surgical decision-making. METHODS: We gathered published series by the CLOSE Study Group members and from literature search until June 2021. Techniques included: internal limiting membrane peeling (ILM peeling), ILM flaps, macular hydrodissection (macular hydro), human amniotic membrane graft (hAM), and autologous retinal transplantation (ART). Within each technique, chi-square test assessed association between the minimal linear diameter (MLD) (in µm) and closure rate; the postoperative best-corrected visual acuity (BCVA) gains were compared among groups. RESULTS: Data extraction included 31 published articles: total of 1135 eyes. Eyes were divided into the following groups: ILM peel (n: 683), ILM Flap (n: 233), macular hydrodissection (n: 64), hAM (n: 59), and ART (n: 96). The initial BCVA and size were heterogenous between the groups. ILM peel showed the best results in large FTMH ≤ 535 µm (closure rate 96.8%); adjusted mean BCVA: 0.49 (LogMAR) with a statistical difference among groups. Large FTMH between 535 and 799 µm: ILM flap technique showed better results (closure rate 99.0%); adjusted mean BCVA: 0.67(LogMAR); also with a statistical difference. For large FTMH ≥ 800 µm more invasive techniques are required. Use of hAM, macular hydrodissection and ART showed higher closure rates for this category (100%, 83.3% and 90.5% respectively), and adjusted mean BCVA varied from 0.76 to 0.89. Although there was no statistical difference between those techniques for this group due to the smaller number of cases. CONCLUSIONS: The CLOSE study group demonstrated the potential usefulness of a new surgical classification for large FTMHs and propose OCT biomarkers for use in clinical practice and future research. This new classification demonstrated that Large (400-550 µm) and X-Large (550-800 µm) holes can be treated highly successfully with ILM peel and ILM flap techniques, respectively. Further studies are necessary for the larger FTMHs (XX-Large and Giant), using the CLOSE classification, in order to determine which technique is better suited for each hole size and characteristics.

Large Internal Limiting Membrane Tears: Prevalence, Clinical Characteristics, and Surgical Utility.

PURPOSE: To describe the prevalence, clinical and imaging characteristics, and surgical utility of large internal limiting membrane (ILM) tears in eyes with epiretinal membrane (ERM). DESIGN: Retrospective interventional case series. METHODS: This was a single-institution study including 71 eyes of 70 consecutive patients that underwent ERM peeling by a single vitreoretinal surgeon between 2016 and 2019. Demographic and clinical data were collected from the medical record. ERMs and large ILM tears were identified and analyzed on multimodal imaging. The main outcome measures were the prevalence and characteristics of large ILM tears in eyes undergoing ERM peeling. RESULTS: Large ILM tears were present in 23 of 71 eyes (32.4%) with ERM that underwent surgical management. A review of patients with ERM during the same period who did not undergo surgical management found large ILM tears in 8 of 100 eyes (8.0%). Large ILM tears were commonly associated with other signs of ERM-induced retinal traction, including retinal nerve fiber layer schisis in 20 of 23 eyes (87.0%), inner retinal dimpling in 8 of 23 eyes (34.8%), and discrete paravascular red lesions in 16 of 19 eyes (84.2%). In all eyes stained with brilliant blue G, the preoperative diagnosis of large ILM tear was confirmed and the scrolled ILM edge was used successfully to initiate ILM peeling. CONCLUSIONS: Large ILM tears are often present in eyes undergoing surgery for ERM and are likely caused by ERM contracture. Careful preoperative identification of these tears is helpful for surgical planning because the scrolled flap of ILM provides a convenient and safe "handle" for initiating membrane peeling.

OPHTHALMOMYIASIS INTERNA WITH INVASION OF THE OPTIC NERVE.

PURPOSE: To report a case of ophthalmomyiasis interna with optic nerve invasion that was treated with oral ivermectin and prednisone. METHODS: Case report with retrospective review of medical records and multimodal imaging studies. RESULTS: A Christmas tree farmer in his sixties presented with expanding multicolored, spiraling photopsias in the left eye. The visual acuity measured 20/50, and examination and imaging findings showed subretinal tracks consistent with ophthalmomyiasis interna. After several weeks of spontaneous improvement, the visual acuity decreased to 20/150 and fundus examination showed new optic disc edema that was treated with ivermectin and prednisone. Despite the development of optic disc pallor, the visual acuity improved to 20/25. CONCLUSION: Subretinal fly larvae can occasionally exit the eye by invading the optic nerve. Treatment of optic nerve involvement with ivermectin and prednisone can result in an excellent visual outcome.