Long-term Follow-up of a Phase 1/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy.

PURPOSE: To report long-term results from a phase 1/2a clinical trial assessment of a scaffold-based human embryonic stem cell-derived retinal pigmented epithelium (RPE) implant in patients with advanced geographic atrophy (GA). DESIGN: A single-arm, open-label phase 1/2a clinical trial approved by the United States Food and Drug Administration. PARTICIPANTS: Patients were 69-85 years of age at the time of enrollment and were legally blind in the treated eye (best-corrected visual acuity [BCVA], ≤ 20/200) as a result of GA involving the fovea. METHODS: The clinical trial enrolled 16 patients, 15 of whom underwent implantation successfully. The implant was administered to the worse-seeing eye with the use of a custom subretinal insertion device. The companion nonimplanted eye served as the control. The primary endpoint was at 1 year; thereafter, patients were followed up at least yearly. MAIN OUTCOME MEASURES: Safety was the primary endpoint of the study. The occurrence and frequency of adverse events (AEs) were determined by scheduled eye examinations, including measurement of BCVA and intraocular pressure and multimodal imaging. Serum antibody titers were collected to monitor systemic humoral immune responses to the implanted cells. RESULTS: At a median follow-up of 3 years, fundus photography revealed no migration of the implant. No unanticipated, severe, implant-related AEs occurred, and the most common anticipated severe AE (severe retinal hemorrhage) was eliminated in the second cohort (9 patients) through improved intraoperative hemostasis. Nonsevere, transient retinal hemorrhages were noted either during or after surgery in all patients as anticipated for a subretinal surgical procedure. Throughout the median 3-year follow-up, results show that implanted eyes were more likely to improve by > 5 letters of BCVA and were less likely to worsen by > 5 letters compared with nonimplanted eyes. CONCLUSIONS: This report details the long-term follow-up of patients with GA to receive a scaffold-based stem cell-derived bioengineered RPE implant. Results show that the implant, at a median 3-year follow-up, is safe and well tolerated in patients with advanced dry age-related macular degeneration. The safety profile, along with the early indication of efficacy, warrants further clinical evaluation of this novel approach for the treatment of GA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Survival of an HLA-mismatched, bioengineered RPE implant in dry age-related macular degeneration.

Cell-based therapies face challenges, including poor cell survival, immune rejection, and integration into pathologic tissue. We conducted an open-label phase 1/2a clinical trial to assess the safety and preliminary efficacy of a subretinal implant consisting of a polarized monolayer of allogeneic human embryonic stem cell-derived retinal pigmented epithelium (RPE) cells in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration. Postmortem histology from one subject with very advanced disease shows the presence of donor RPE cells 2 years after implantation by immunoreactivity for RPE65 and donor-specific human leukocyte antigen (HLA) class I molecules. Markers of RPE cell polarity and phagocytosis suggest donor RPE function. Further histologic examination demonstrated CD34+ structures beneath the implant and CD4+, CD68+, and FoxP3+ cells in the tissue. Despite significant donor-host HLA mismatch, no clinical signs of retinitis, vitreitis, vasculitis, choroiditis, or serologic immune response were detected in the deceased subject or any other subject in the study. Subretinally implanted, HLA-mismatched donor RPE cells survive, express functional markers, and do not elicit clinically detectable intraocular inflammation or serologic immune responses even without long-term immunosuppression.

Capillary density and caliber as assessed by optical coherence tomography angiography may be significant predictors of diabetic retinopathy severity.

PURPOSE: To validate retinal capillary density and caliber associations with diabetic retinopathy (DR) severity in different clinical settings. METHODS: This cross-sectional study assessed retinal capillary density and caliber in the superficial retinal layer of 3-mm OCTA scans centered on the fovea. Images were collected from non-diabetic controls and subjects with mild or referable DR (defined DR worse than mild DR) between February 2016 and December 2019 at secondary and tertiary eye care centers. Vessel Skeleton Density (VSD), a measure of capillary density, and Vessel Diameter Index (VDI), a measure of vascular caliber, were calculated from these images. Discriminatory performance of VSD and VDI was evaluated using multivariable logistic regression models predicting DR severity with adjustments for sex, hypertension, and hyperlipidemia. Area under the curve (AUC) was estimated. Model performance was evaluated in two different cohorts. RESULTS: This study included 594 eyes from 385 subjects. Cohort 1 was a training cohort of 509 eyes including 159 control, 155 mild non-proliferative DR (NPDR) and 195 referable DR eyes. Cohort 2 was a validation cohort consisting of 85 eyes including 16 mild NPDR and 69 referable DR eyes. In Cohort 1, addition of VSD and VDI to a model using only demographic data significantly improved the model's AUC for discrimination of eyes with any DR severity from controls (0.91 [95% CI, 0.88-0.93] versus 0.80 [95% CI, 0.76-0.83], p < 0.001) and eyes with referable DR from mild NPDR (0.90 [95% CI, 0.86-0.93] versus 0.69 [95% CI, 0.64-0.75], p < 0.001). The transportability of this regression model was excellent when implemented in Cohort 2 for the referable DR versus mild NPDR comparison. The odds ratio of having any DR compared to control subjects, and referable DR compared to mild DR decreased by 15% (95% CI: 12-18%), and 13% (95% CI: 10-15%), respectively, for every 0.001 unit increase in VSD after adjusting for comorbidities. CONCLUSION: OCTA-derived capillary density has real world clinical value for rapidly assessing DR severity.

One-Year Follow-Up in a Phase 1/2a Clinical Trial of an Allogeneic RPE Cell Bioengineered Implant for Advanced Dry Age-Related Macular Degeneration.

Purpose: To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD). Methods: The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results. Results: The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant). Conclusions: Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD. Translational Relevance: This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.

Long-term multimodal imaging in acute posterior multifocal placoid pigment epitheliopathy and association with coxsackievirus exposure.

The purpose of this study was to evaluate potential insights into the pathogenesis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) using multimodal diagnostic imaging and laboratory evaluation in long-term follow-up. A retrospective, single-center case series was conducted on seven consecutive patients (14 eyes) who were given a diagnosis of APMPPE from March 1, 2011, through June 30, 2019 with at least three months of follow-up. Clinical characteristics (age, symptoms, visual acuity [VA]), laboratory testing including coxsackievirus titers, and multimodal imaging from fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICG) were analyzed for each patient. The initial median VA was 20/71 and final median VA was 20/22. Coxsackievirus B (CVB) titers were elevated (≥ 1:80) in six of seven patients, with a four-fold increase in convalescent titers seen in two patients suggestive of recent infection. All patients were treated with oral corticosteroids, and five patients underwent corticosteroid-sparing immunomodulatory therapy. Initially, multifocal deep choroidal lesions were observed in the posterior pole corresponding to patches of hypocyanescence on ICG. Overlying retinal pigment epithelium (RPE) disease was observed on FAF, although this finding was not universally observed, suggesting that RPE disease may occur as a sequelae to unchecked choroidal inflammation. SD-OCT architectural changes confirmed outer retina and ellipsoid zone disruption. FA of active lesions showed early hypofluorescence and late hyperfluorescence with surrounding leakage while inactive disease showed areas of staining. Long-term follow-up of multimodal diagnostic imaging in APMPPE revealed that choroidal inflammation likely precedes RPE change and photoreceptor damage. Elevation of coxsackievirus titers with seroconversion may be associated with an infectious trigger in concert with immune-mediated disease in this posterior uveitis syndrome.

The Impact and Implication of Peripheral Vascular Leakage on Ultra-Widefield Fluorescein Angiography in Uveitis.

Purpose: To study if peripheral vascular leakage (PVL) on ultra-widefield fluorescein angiography (UWFFA) prognosticates complications of uveitis or necessitates treatment augmentation. Methods: Retrospective cohort study of uveitis patients imaged with UWFFA and ≥1 yr of follow-up. Results: We included 73 eyes of 42 patients with uveitis. There was no difference in baseline, intermediate, final visual acuity (p = 0.47-0.95) or rates of cystoid macular edema (CME) (p = 0.37-0.87) in eyes with PVL vs. those without. Eyes with PVL receiving baseline treatment augmentation were more likely to have baseline CME but were not more likely to have impaired visual acuity at final follow-up. PVL was independently associated with treatment augmentation on generalized estimating equation analysis with multivariable linear regression (OR: 4.39, p = 0.015). Conclusions: PVL did not confer an increased risk of impaired VA or CME at ≥1 yr follow-up but was possibly an independent driver of treatment augmentation.

The Nine-Step Minnesota Grading System for Eyebank Eyes With Age Related Macular Degeneration: A Systematic Approach to Study Disease Stages.

Purpose: To refine the Minnesota Grading System (MGS) using definitions from the Age-Related Eye Disease Studies (AREDS) into a nine-step grading scale (MGS-9). Methods: A nine-step grading scale descriptive analysis using three key phenotypic features (total drusen area, increased, and decreased pigmentation) of human eyebank eyes that were graded according to definitions from the AREDS criteria in order to harmonize studies of disease progression for research involving human tissue. From 2005 through February 2017, we have analyzed 1159 human eyes, procured from two eyebanks. Each macula was imaged using high-resolution, stereoscopic color fundus photography with both direct- and transillumination. Fundus images were digitally overlaid with a grading template and triangulated for foveal centration. Results: We documented and stratified risk for each globe by applying the AREDS nine-step grading scale to the key clinical features from the MGS-9. We found a good distribution within the MGS categories (1-9) with few level eight globes. Eyes were processed within 12.1 ± 6.3, hours from the time of death through imaging, dissection, and freezing or fixation. Applying the MGS-9 to 331 pairs (662 eyes were simultaneously graded), 84% were within one-grading step and 93% within two steps of the fellow eye. We also document reticular pseudodrusen, basal laminar drusen, and pattern dystrophy. Conclusions: The MGS nine-step grading scale enables researchers using human tissue to refine the risk assessment of donor tissue. This analysis will harmonize results among researchers when grading human tissue using MGS criteria. Most importantly, the MGS-9 links directly to the known risk for progression from the AREDS.

The Value of Diagnostic Work-Up in the Evaluation of White Dot Syndromes.

BACKGROUND AND OBJECTIVE: To determine the diagnostic yield of systemic work-up in white dot syndromes. PATIENTS AND METHODS: A retrospective chart review. RESULTS: Eighty-six consecutive patients with a diagnosis of a white dot syndrome were identified. Forty-three had a diagnosis of birdshot chorioretinopathy. Overall, 395 diagnostic tests were performed with a diagnostic yield of 11.9%. The test with the greatest diagnostic yield was HLA-A29 typing (89%). Four patients had abnormal angiotensin converting enzyme levels. No patients had a positive rapid plasma reagin or fluorescent treponemal antibody absorption test. Four patients had positive tuberculosis testing and required treatment. The mean number of tests performed per diagnosis group ranged from 0.3 in multiple evanescent white dot syndrome to 5.6 in multifocal choroiditis and panuveitis. Diagnostic testing was found to be the most expensive in birdshot chorioretinopathy, with a mean cost of $504.82. CONCLUSIONS: Diagnostic yield of systemic work-up was low in this patient population. Rather than performing an exhaustive work-up, the authors advocate for a limited work-up tailored to pretest clinical suspicion. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:540-545.].

INSIGHTS INTO AUTOSOMAL DOMINANT STARGARDT-LIKE MACULAR DYSTROPHY THROUGH MULTIMODALITY DIAGNOSTIC IMAGING.

PURPOSE: Autosomal dominant Stargardt-like macular dystrophy is a rare juvenile macular dystrophy most commonly because of mutations in ELOVL4 and PROM1 genes. In this study, we review a series of cases of Stargardt-like macular dystrophy and use advanced imaging techniques to describe pathophysiologic manifestations. METHODS: A retrospective medical record review was performed for five patients from two families with ELOVL4 mutation and one patient with PROM1 mutation including reviewing diagnostic imaging, such as fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics flood-illuminated photography. RESULTS: All patients had reduced central visual acuity with varying degree of foveal atrophy. In the ELOVL4 group, best-corrected visual acuity ranged from 20/25 to 20/200. Early pathologic changes included thickening of the external limiting membrane and outer nuclear atrophy followed by retinal pigment epithelium loss in later stages. Adaptive optics imaging revealed photoreceptor loss even in early stages with good visual acuity. The PROM1 patient also had similar central vision loss with significant outer nuclear atrophy. In contrast to ELOVL4 mutation, there was more diffuse and patchy retinal pigment epithelium loss throughout the macula. CONCLUSION: Both ELOVL4- and PROM1-related maculopathies are characterized by progressive photoreceptor atrophy and central vision loss. Using advanced diagnostic imaging, early disease changes and disease progression can be characterized.

DETECTION OF NONEXUDATIVE CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION WITH OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To evaluate eyes with age-related macular degeneration and high-risk characteristics for choroidal neovascularization (CNV) with optical coherence tomographic (OCT) angiography to determine whether earlier detection of CNV is possible. METHODS: Eyes with drusen, pigmentary changes, and with CNV in the fellow eye were scanned with a 70-kHz spectral domain OCT system (Optovue RTVue-XR Avanti). The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm was used to distinguish blood flow from static tissue. Two masked graders reviewed scans for CNV, defined as flow in the outer retinal/sub-RPE slab. Choroidal neovascularization flow area repeatability and between-grader reproducibility were calculated. RESULTS: Of 32 eyes, 2 (6%) were found to have Type 1 CNV with OCT angiography. The lesions were not associated with leakage on fluorescein angiography or fluid on OCT. One case was followed for 8 months without treatment, and the CNV flow area enlarged slightly without fluid buildup on OCT or vision loss. Between-grader reproducibility of the CNV flow area was 9.4% (coefficient of variation) and within-visit repeatability was 5.2% (pooled coefficient of variation). CONCLUSION: Optical coherence tomographic angiography can detect the presence of nonexudative CNV, lesions difficult to identify with fluorescein angiography and OCT. Further study is needed to understand the significance and natural history of these lesions.

Bilateral giant retinal tears in a pediatric patient with leukemia inhibitory factor receptor deficiency (Stuve-Wiedemann syndrome).

PURPOSE: To describe a case of retinal detachment in a patient with Stuve-Wiedemann syndrome. METHODS: This report is a retrospective observational case report. The patient's demographics include age, gender, and race, as well as visual acuity, ophthalmic examination, and surgical intervention were extracted from the medical record. For immunohistochemistry studies, a sample of normal human retina from an enucleated specimen was obtained from the Pathology laboratory. A leukemia inhibitory factor receptor/CD118 antibody was obtained from Santa Cruz Biotechnology. RESULTS: A 13-year-old Hispanic boy with known history of Stuve-Wiedemann syndrome (confirmed by genetic testing) presented with bilateral rhegmatogenous retinal detachments secondary to bilateral giant retinal tears. He underwent multiple surgical repairs in both eyes, resulting in successful reattachment in the right eye and an intractable closed funnel detachment in the left eye. CONCLUSION: This is the first case of vitreoretinal pathology reported in Stuve-Wiedemann syndrome. Using immunohistochemistry staining, the authors found ubiquitous expression of leukemia inhibitory factor receptor protein in the normal human retina. They hypothesize that leukemia inhibitory factor receptor mutation may cause intrinsic weakness of the neurosensory retina predisposing it to injury.

Choroideremia associated with choroidal neovascularization treated with intravitreal bevacizumab.

PURPOSE: To report a rare case of central vision loss in a patient with choroideremia. PATIENTS AND METHODS: A retrospective, interventional case report. RESULTS: A 13-year-old male with history of choroideremia presented with subacute loss of central acuity in his left eye. Examination and diagnostic testing revealed subretinal fibrosis secondary to a choroidal neovascular membrane (CNVM). A trial of anti-vascular endothelial growth factor (VEGF) therapy with the injection of intravitreal bevacizumab was attempted. Mild improvements in acuity and anatomy were noted. CONCLUSION: Choroideremia is a rare hereditary choroidal dystrophy that predominantly affects males in the first and second decades of life. Visual acuity is usually spared until later in life. CNVM is a rare manifestation of choroideremia with only a handful of case reports presented in the literature. This case is unique in that it is the first reported case that received treatment with intravitreal anti-VEGF therapy.

Chorioretinal folds: associated disorders and a related maculopathy.

PURPOSE: To describe a series of chorioretinal folds (CRFs) representing a clinical sign that may be associated with multiple systemic, orbital, and ophthalmologic disorders. We report the associations with systemic disease and describe 3 stages of a CRF-related maculopathy. DESIGN: Observational, retrospective case series. METHODS: We reviewed 57 affected eyes from 40 patients with the clinical sign of CRF from 1 of 2 academic institutions. A careful review of the medical histories and systemic diagnostic evaluations were conducted. Imaging studies were conducted. RESULTS: The mean age at diagnosis was 64 ± 17 years. Most eyes (n = 18) were hyperopic (+2.60 ± +2.90 diopters). There were 20 patients (50%) with some form of autoimmune disorder. Overall, the mean presenting visual acuity was 20/50, declining slightly to 20/60 over 19 ± 30 months. Ten eyes had stage 3 CRF-related maculopathy, more common in older individuals with more chronic CRFs. Four stage 3 eyes had associated choroidal neovascularization, and these eyes had 20/60 presenting visual acuity that decreased to 20/100 over approximately 1.5 years. Stage 3 eyes without choroidal neovascularization had a mean presenting visual acuity of 20/40 that decreased to 20/65 over 2.1 years. CONCLUSIONS: CRFs are associated with numerous ophthalmic and systemic disorders. A careful medical history and evaluation are essential. We describe 3 stages of a unique CRF-related maculopathy. Stage 3 resembles occult choroidal neovascularization, occurs primarily in older individuals with chronic CRFs, and is accompanied by a slow deterioration in central acuity.

Current perspectives on ophthalmic manifestations of childhood rheumatic diseases.

Inflammatory eye diseases are an important manifestation of many pediatric rheumatologic conditions. Early screening and diagnosis are imperative as these illnesses can not only result in significant visual morbidity but are also an indicator of systemic inflammation. Time to presentation of ocular inflammation varies significantly and can range from many years prior to the onset of systemic symptoms to well after the diagnosis of the rheumatologic disorder. Due to this variability in presentation, careful monitoring by an ophthalmologist is vital to preventing ocular complications and preserving vision. Both local and systemic immunosuppressive medications have been effective in the management of ocular disease. In this review, we will focus on the known ophthalmologic manifestations of common pediatric rheumatologic diseases and discuss recent advances in therapeutic considerations for these conditions.

Cortical blindness and choroidal metastases secondary to metastatic breast carcinoma in a male patient.

Male breast carcinoma is a rare entity that often goes undiagnosed until advanced stages. The authors describe the case of a patient with profound vision loss who was found to have bilateral choroidal metastases as well as advanced cerebral metastatic disease. Further medical work-up revealed widespread infiltrative ductal breast carcinoma. Given the presence of large occipital lobe lesions, the etiology of the patient's vision loss was thought to be cortical blindness. Prompt diagnosis and neurologic evaluation with this presentation is crucial because it can be associated with significant morbidity and mortality.

Ocular manifestations of systemic lupus erythematosus: a review of the literature.

About one-third of patients suffering from systemic lupus erythematosus have ocular manifestations. The most common manifestation is keratoconjunctivitis sicca. The most vision threatening are retinal vasculitis and optic neuritis/neuropathy. Prompt diagnosis and treatment of eye disease is paramount as they are often associated with high levels of systemic inflammation and end-organ damage. Initial management with high-dose oral or IV corticosteroids is often necessary. Multiple "steroid-sparing" treatment options exist with the most recently studied being biologic agents.

An aggressive sphenoid wing meningioma causing foster kennedy syndrome.

Foster Kennedy syndrome is a rare neurological condition with ophthalmic significance that can manifest as acute visual loss. It is classically characterised by unilateral optic nerve atrophy and contralateral papilledema resulting from an intracranial neoplasm. Physicians should consider Foster Kennedy syndrome in patients who present with visual loss and who have a history of intracranial neoplasm. In addition to ophthalmologic examination, neuroimaging is essential for the diagnosis of Foster Kennedy syndrome.

Surgical repair of leaking filtering blebs using two different techniques.

PURPOSE: To report the outcomes of two different surgical techniques for the repair of late onset bleb leakage following trabeculectomy. METHODS: This retrospective study includes 21 eyes of 20 patients with prior trabeculectomy and late-onset bleb leaks; 14 eyes underwent excision of the filtering bleb together with conjunctival advancement while in the other 7 eyes the bleb was retained but de-epithelialized before conjunctival advancement. Success was defined as resolution of leakage with no need for additional glaucoma surgery together with intraocular pressure (IOP) of 5-21 mmHg. Complete and qualified success was considered when the above mentioned was achieved without or with glaucoma medications, respectively. RESULTS: Mean duration of follow-up was 20.3±14.4 months. No significant difference was observed between the two groups in terms of complete, qualified and overall success rates (P>0.05), however more antiglaucoma medications were necessary in the bleb excision group (P=0.02). CONCLUSIONS: Both surgical techniques of bleb repair were comparably effective, however the bleb de-epithelialization technique was associated with less need for glaucoma medications after the procedure.