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.

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.

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 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.

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.

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.

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.

Single needle revision of failing filtration blebs: a retrospective comparative case series with 5-fluorouracil and mitomycin C.

PURPOSE: To assess the success of needling in failed filtration blebs and the potential benefit of using either 5-fluorouracil (5-FU) or mitomycin C (MMC). METHODS: In this retrospective, comparative observational case series, 107 eyes that underwent needle revision with either 5-FU or MMC between July 2003 and May 2008 at Wills Eye Institute were selected. Exclusion criteria included follow-up less than 1 month and a history of glaucoma drainage device. Intraocular pressure (IOP) and number of glaucoma medications were recorded preoperatively and postoperatively. Success was defined as >20% decrease in IOP if glaucoma medications were resumed or <10% decrease in IOP if medications were not resumed post needling or fewer medications than pre needling. RESULTS: Sixty-five patients received 5-FU and 42 patients received MMC for needling. Mean IOP changed from 23.9 mmHg to 13.8 mmHg in the MMC group and from 23.3 mmHg to 13.02 mmHg in the 5-FU group (both p<0.001). Mean glaucoma medications changed from 1.7 to 0.7 in the MMC group and 2.0 to 0.8 in the 5-FU group (both p<0.001) at the end of follow-up. After a mean follow-up of 14.5 months, overall survival was 49.5%. Mean time to failure was 7.7 months. There was a moderately weak association between survival and the immediate postoperative IOP (r=0.262, p=0.01). In comparing MMC and 5-FU, there was no statistically significant difference in survival rate (p=0.267). CONCLUSIONS: Bleb needling may be a safe and effective means of prolonging bleb survival. The only factor associated with success was the immediate postoperative IOP. There was no apparent difference between the use of 5-FU and MMC in this population. A prospective study may provide further confirmation of this finding.