Ninel Z. Gregori

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies

BACKGROUND Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. METHODS In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardts macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardts macular dystrophy) and NCT01344993 (age-related macular degeneration). FINDINGS There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardts macular dystrophy. INTERPRETATION The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. FUNDING Advanced Cell Technology.

Novel method for analyzing snellen visual acuity measurements.

Purpose: Most retrospective reviews convert Snellen visual acuity measurements obtained during routine clinic visits to logarithm of the minimum angle of resolution (logMAR) units so that statistical manipulations can be performed. However, visual acuity measurements expressed as logMAR units are not intuitively interpretable by clinicians. A more intuitive approach is presented here which uses the conversion of Snellen visual acuity fractions to Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores for statistical manipulations. Methods: Snellen visual acuity measurements were converted to approximate ETDRS (approxETDRS) letter scores for statistical manipulations and then converted back to Snellen equivalent fractions. The formula to convert Snellen visual acuity measurements to approxETDRS letter scores is 85 + 50 × log (Snellen fraction), which may be rounded to the nearest letter. Results: A linear relationship exists between true ETDRS letter scores, approxETDRS letter scores, and logMAR units. The interconversion between Snellen visual acuity measurements, logMAR units, and approxETDRS letter scores was prepared in a tabular form for easy reference. The same outcomes (in Snellen fractions) were obtained with statistical manipulation of either approxETDRS letter scores or logMAR conversions. Conclusion: Conversion of Snellen visual acuity fractions to approxETDRS letter scores for the purpose of performing statistical manipulations provides more readily interpretable outcomes compared with the current strategy of converting Snellen visual acuity fractions to logMAR units.

Spectral Domain Optical Coherence Tomography Imaging of Drusen in Nonexudative Age-Related Macular Degeneration

PURPOSE To measure drusen area and volume in eyes with nonexudative age-related macular degeneration (AMD) using spectral domain optical coherence tomography imaging (SD-OCT). DESIGN Evaluation of diagnostic technology. PARTICIPANTS One hundred three eyes from 74 patients with drusen. METHODS Patients with drusen secondary to nonexudative AMD were enrolled in this study. Five separate SD-OCT scans, each consisting of 40 000 uniformly spaced A-scans organized as 200 A-scans in each B-scan and 200 horizontal B-scans, were performed on each eye. Each scan covered a retinal area of 6×6 mm centered on the fovea. A novel algorithm was used to quantitatively assess drusen area and volume. Measurements from the entire scans, as well as in regions contained within 3- and 5-mm circles centered on the fovea, were analyzed. Test-retest standard deviations of drusen area and volume measurements were calculated for each eye. MAIN OUTCOME MEASURES Drusen area and volume. RESULTS The algorithm created drusen maps that permitted both qualitative and quantitative assessment of drusen area and volume. Both the qualitative appearance and the quantitative measurements of drusen area and volume were highly reproducible over the 5 different datasets. The intraclass correlation coefficient was >0.99 for both area and volume measurements on the entire dataset as well as the 3- and 5-mm circles. The correlation between lesion size and the test-retest standard deviations can be eliminated by performing a square root transformation of the area measurements and a cube root transformation of the volume measurements. These transformed data allowed for the inclusion of all drusen sizes in the calculation of an estimated single pooled test-retest standard deviation, which will be useful for longitudinal studies of drusen natural history. CONCLUSIONS A novel algorithm for the qualitative and quantitative assessment of drusen imaged using SD-OCT was shown to be highly reproducible. The ability to assess drusen volume reliably represents a new quantitative parameter to measure in AMD and may be useful when assessing disease progression, particularly in trials for treatments of nonexudative AMD.

One-year Safety And Efficacy Of Intravitreal Triamcinolone Acetonide For The Management Of Macular Edema Secondary To Central Retinal Vein Occlusion

Purpose: To evaluate the safety and efficacy of intravitreal triamcinolone acetonide (IVTA) as treatment for macular edema associated with central retinal vein occlusion (CRVO). Methods: A retrospective review was performed of data for 40 consecutive patients (40 eyes) with CRVO and macular edema treated with IVTA at the Bascom Palmer Eye Institute (Miami, FL). Results: Median duration of symptoms before the first injection was 3 months (range, 1 day to 8 years). Median Snellen visual acuity was 20/400 at baseline (range, 20/60 to light perception; n = 40), 20/300 at 1 month (P = 0.010; n = 37), 20/300 at 3 months (P = 0.007; n = 33), 20/400 at 6 months (P = 0.726; n = 28), and 8/200 at 1 year (P = 0.569; n = 17). Vision improved by ≥3 lines in 21% of eyes at 1 month, 27% at 3 months, 14% at 6 months, and 12% at 1 year. Visual acuity was unchanged from baseline in 71% of eyes at 6 months and 1 year. By 1 year, 50% of eyes received more than one injection (mean = 1.6 injections; range 1–4 injections). Overall, intraocular pressure increased by ≥10 mmHg in 24% of eyes at 1 year. Trabeculectomy was performed on 2 of 12 eyes with preexisting open-angle glaucoma. Conclusion: IVTA can substantially improve vision in some patients, but most patients have stable visual acuity compared with baseline at 1 year despite repeated injections.

Macular spectral-domain optical coherence tomography in patients with X linked retinoschisis

Aim: To evaluate macular anatomy in patients with X linked retinoschisis (XLRS) using spectral-domain optical coherence tomography (SD-OCT). Methods: Consecutive observational case series. Clinical features were obtained through retrospective chart review. Only eyes without prior surgical interventions and those scanned with SD-OCT were included. The OCT images were analysed. Results: Fourteen eyes of seven males with XLRS scanned with SD-OCT, age 5 to 45 years, were identified. On clinical examination, stellate spoke-like cystic maculopathy was present in nine eyes, and an atrophic foveal lesion in five eyes. SD-OCT revealed cystoid spaces accounting for retinal splitting in the inner nuclear layer in 12 eyes, and outer plexiform layer in two eyes of one patient. A few small cysts, not accounting for the foveal splitting, were seen in the outer nuclear layer in four eyes and in the ganglion cell layer and/or nerve fibre layer in six eyes. Conclusions: SD-OCT localised the foveomacular retinoschisis in XLRS to the retinal layers deeper than the nerve fibre layer. In the present study, the foveomacular schisis was seen most frequently in the inner nuclear layer.

Safety and efficacy of intravitreal bevacizumab (Avastin) for the management of branch and hemiretinal vein occlusion

Purpose: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin, Genentech) for the treatment of macular edema (ME) secondary to branch retinal vein occlusion (BRVO) and hemiretinal vein occlusion (HRVO). Methods: A retrospective review was performed of consecutive patients treated with intravitreal bevacizumab (1.25 mg) for ME secondary to BRVO/HRVO from May 2005 to August 2006 with follow-up through February 2007. Re-treatment was performed at monthly or longer intervals at the discretion of the treating physician. Results: Fifty-two eyes with a BRVO and 13 eyes with an HRVO received intravitreal bevacizumab at baseline. Visual acuity improved by a mean of 12 letters at 1 month (n = 51; P < 0.001), 13 letters at 3 months (n = 61; P < 0.001), 13 letters at 6 months (n = 42; P < 0.001), 14 letters at 9 months (n = 27; P < 0.001), and 15 letters at 12 months (n = 17; P = 0.015). The mean optical coherence tomography (OCT) thickness decreased by 184 &mgr;m (P < 0.001), 131 &mgr;m (P < 0.001), 161 &mgr;m (P < 0.001), 158 &mgr;m (P = 0.002), and 205 &mgr;m (P = 0.002) at 1 month, 3 months, 6 months, 9 months, and 12 months, respectively. The mean number of injections was 1.4, 2.1, 2.7, and 3.1, and 3.3 at 1 month, 3 months, 6 months, 9 months, and 12 months, respectively. No ocular or systemic adverse events were observed. Conclusion: Improvements in visual acuity and OCT outcomes were observed during the first year after intravitreal bevacizumab in patients with ME secondary to BRVO and HRVO.

Long-term safety and efficacy of intravitreal bevacizumab (avastin) for the management of central retinal vein occlusion

Purpose: To evaluate the long-term safety and efficacy of intravitreal bevacizumab injections (Avastin®, Genentech Inc., San Francisco, CA) for the treatment of macular edema secondary to central retinal vein occlusions. Methods: A retrospective review was performed of eyes treated from May 2005 to August 2006 with follow-up through February 2007. The dose of bevacizumab was 1.25 mg (0.05 mL). Retreatment was performed at monthly or longer intervals at the discretion of the treating physician. Results: Fifty-seven eyes received intravitreal bevacizumab at baseline. Visual acuity improved by a mean of 14 letters (N = 53; P < 0.001) at 1 month, 13 letters at 3 months (N = 53; P < 0.001), 9 letters at 6 months (N = 30; P = 0.001), 9 letters at 12 months (N = 17; P = 0.004). The mean optical coherence tomography thickness decreased by 299 &mgr;m at 1 month (N = 53; P < 0.001), 144 &mgr;m at 3 months, (N = 53; P < 0.001), 127 &mgr;m at 6 months (N = 30; P = 0.011), and 276 &mgr;m at 12 months (N = 17; P < 0.001). No ocular or systemic adverse events were observed. Conclusion: Improvements in visual acuity and optical coherence tomography were observed during the first year following intravitreal bevacizumab for macular edema secondary to central retinal vein occlusions. These retrospective results provide additional evidence to support the perceived safety and efficacy of intravitreal bevacizumab in this disorder.

Current Infectious Endophthalmitis Rates After Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents and Outcomes of Treatment.

BACKGROUND AND OBJECTIVE To assess the incidence and outcomes of infectious endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. PATIENTS AND METHODS Patient records at the Bascom Palmer Eye Institute (BPEI) from January 1, 2005, through December 31, 2014, were reviewed. The largest commercial claims and encounters database in the U.S. (MarketScan) was utilized to calculate the population-based endophthalmitis rate for 2011 to 2013. RESULTS The population-based rate of endophthalmitis after anti-VEGF injections for 2011 to 2013 was 391/740,757 (0.053%). BPEIs rate was 20/121,285 (0.016%) during the study period: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection. Nine BPEI cases (45%) were culture-positive: Streptococcus species (5), coagulase-negative Staphylococcus (3), and non-anthracis Bacillus (1). Final visual acuity varied from 20/25 to no light perception. CONCLUSION Endophthalmitis after anti-VEGF injection was uncommon in our institution and in the population-based database. Treatment outcomes were variable but generally fared better in the culture-negative cases.

Surgical and refractive outcomes of cataract surgery with toric intraocular lens implantation at a resident-teaching institution.

PURPOSE: To evaluate the refractive and surgical outcomes of cataract surgery with toric intraocular lens (IOL) implantation performed at a teaching institution. SETTING: Miami Veterans Affairs Medical Center, Miami, Florida, USA. DESIGN: Retrospective case series. METHODS: All data were obtained by a retrospective chart review and entered into a standard computerized database for analysis. Main outcome measures included refractive and surgical outcomes after Acrysof toric IOL placement, including the deviation from the expected spherical and cylindrical correction and the incidence of ocular complications. RESULTS: The study comprised 94 eyes (80 patients). The mean deviation from the anticipated spherical correction (94 eyes) was +0.06 diopter (D) ± 0.8 (range −2.6 D to +3.6 D), with 80% of eyes achieving a spherical equivalent within ±1.00 D of the target refraction. The postoperative refractive cylinder was significantly reduced from baseline, with 79% of eyes having at least a 0.50 D improvement in astigmatism after surgery (P<.0005). The mean deviation from the anticipated refractive cylinder (85 eyes) was −0.48 ± 1.2 D (range −5.0 to +2.8 D). The IOL was placed in an incorrect position in 2 patients, requiring a reoperation with IOL rotation into the proper axis. The mean follow‐up was 7 months (range 1 to 28 months). CONCLUSION: The added complexity associated with toric IOL placement resulted in spherical and astigmatic improvements without compromising patient safety beyond a level inherent in resident‐based cataract surgery. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Worldwide Argus II implantation: recommendations to optimize patient outcomes.

BackgroundA position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation.MethodsRetinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined.ResultsFactors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon’s capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical.ConclusionsBringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.