Early Visibility of Cellular Aggregates and Changes in Central Corneal Thickness as Predictors of Successful Corneal Endothelial Cell Injection Therapy.

(1) Background: Cell injection therapy is an emerging treatment for bullous keratopathy (BK). Anterior segment optical coherence tomography (AS-OCT) imaging allows the high-resolution assessment of the anterior chamber. Our study aimed to investigate the predictive value of the visibility of cellular aggregates for corneal deturgescence in an animal model of bullous keratopathy. (2) Methods: Cell injections of corneal endothelial cells were performed in 45 eyes in a rabbit model of BK. AS-OCT imaging and central corneal thickness (CCT) measurement were performed at baseline and on day 1, day 4, day 7 and day 14 following cell injection. A logistic regression was modelled to predict successful corneal deturgescence and its failure with cell aggregate visibility and CCT. Receiver-operating characteristic (ROC) curves were plotted, and areas under the curve (AUC) calculated for each time point in these models. (3) Results: Cellular aggregates were identified on days 1, 4, 7 and 14 in 86.7%, 39.5%, 20.0% and 4.4% of eyes, respectively. The positive predictive value of cellular aggregate visibility for successful corneal deturgescence was 71.8%, 64.7%, 66.7% and 100.0% at each time point, respectively. Using logistic regression modelling, the visibility of cellular aggregates on day 1 appeared to increase the likelihood of successful corneal deturgescence, but this did not reach statistical significance. An increase in pachymetry, however, resulted in a small but statistically significant decreased likelihood of success, with an odds ratio of 0.996 for days 1 (95% CI 0.993-1.000), 2 (95% CI 0.993-0.999) and 14 (95% CI 0.994-0.998) and an odds ratio of 0.994 (95% CI 0.991-0.998) for day 7. The ROC curves were plotted, and the AUC values were 0.72 (95% CI 0.55-0.89), 0.80 (95% CI 0. 62-0.98), 0.86 (95% CI 0.71-1.00) and 0.90 (95% CI 0.80-0.99) for days 1, 4, 7 and 14, respectively. (4) Conclusions: Logistic regression modelling of cell aggregate visibility and CCT was predictive of successful corneal endothelial cell injection therapy.

Cell therapy in corneal endothelial disease.

PURPOSE OF REVIEW: Endothelial keratoplasty is the current gold standard for treating corneal endothelial diseases, achieving excellent visual outcomes and rapid rehabilitation. There are, however, severe limitations to donor tissue supply and uneven access to surgical teams and facilities across the globe. Cell therapy is an exciting approach that has shown promising early results. Herein, we review the latest developments in cell therapy for corneal endothelial disease. RECENT FINDINGS: We highlight the work of several groups that have reported successful functional outcomes of cell therapy in animal models, with the utilization of human embryonic stem cells, human-induced pluripotent stem cells and cadaveric human corneal endothelial cells (CECs) to generate populations of CECs for intracameral injection. The use of corneal endothelial progenitors, viability of cryopreserved cells and efficacy of simple noncultured cells, in treating corneal decompensation is of particular interest. Further additions to the collective understanding of CEC physiology, and the process of cultivating and administering effective cell therapy are reviewed as well. SUMMARY: The latest developments in cell therapy for corneal endothelial disease are presented. The continuous growth in this field gives rise to the hope that a viable solution to the large numbers of corneal blind around the world will one day be reality.

Interpreting MAIA Microperimetry Using Age- and Retinal Loci-Specific Reference Thresholds.

Purpose: Macular Integrity Assessment (MAIA) microperimetry is used widely in clinical trials and routine practice to assess paracentral scotoma. Current interpretation of MAIA is based on an assumed uniform 25 decibel (dB) cutoff for normal function irrespective of subject age and retinal location. We examined this convention by establishing an age- and loci-specific reference in healthy eyes and comparing this to the <25 dB cutoff. Methods: Retrospective MAIA results from healthy eyes were analyzed for prevalence of loci with <25 dB. At each locus, a new reference cutoff was derived from quantile regression of sensitivity against age at the 2.5th percentile. Two clinical cases of serial MAIA testing were analyzed using the new approach and compared to the <25 dB cutoff. Results: Fifty-four and 56 age-matched (range: 16-75 years) healthy eyes underwent small (37 loci) and large (68 loci) grid testing, respectively. Retinal sensitivity <25 dB was found in 5% of the small grid (1998 data points) and 10% of the large grid (3808 data points). These were found predominantly in older subjects and at the central point or in the perifoveal region. Quantile regression at each individual locus showed age-related decline with a median gradient of 0.6 dB/decade. Conclusions: We caution against using <25 dB cutoff in MAIA interpretation and advocate an age- and loci-specific cutoff criterion. Translational Relevance: Our study suggests that MAIA interpretation is influenced by the criterion used for defining abnormal pointwise measurement.

Posterior Choroidal Stroma Reduces Accuracy of Automated Segmentation of Outer Choroidal Boundary in Swept Source Optical Coherence Tomography.

Purpose: To determine the influence of choroidal boundary morphology on the accuracy of automated measurements of subfoveal choroidal thickness (SFCT) in swept source optical coherence tomography (SSOCT). Methods: A retrospective image analysis of foveal-centered horizontal line scans from normal and diseased eyes using the Topcon DRI OCT-1 Atlantis SSOCT was conducted. Subfoveal choroid-scleral junction (CSJ) and retina-choroidal junction (RCJ) morphologies were graded by two observers. Automated SFCT (A-SFCT) was compared with manual SFCT (M-SFCT) measurements from Bruch's membrane to the posterior limits of choroidal vessel, hyperreflective stroma, and hyporeflective lamina fusca. Agreement in boundary grading was assessed by Cohen's kappa. A-SFCT and M-SFCT were compared using Bland-Altman analysis and paired t-tests. Results: A total of 200 eyes of 100 patients with a mean (SD) age of 62 (18) years were included. The choroidal vessel, stromal, and lamina fusca boundaries were visible in 100%, 58%, and 38% of the eyes, respectively. Interobserver agreement in RCJ and CSJ grading was high (kappa = 0.974 and 0.851). Mean A-SFCT differed from M-SFCT by only 2 µm at posterior choroidal vessel boundary (P = 0.801). A-SFCT overestimated SFCT at the posterior vessel wall boundary by 17 µm (P = 0.026) and 23 µm (P = 0.001) in the presence of a visible posterior choroidal stroma and lamina fusca, respectively. Conclusions: Automated outer choroidal boundary segmentation tends to identify the posterior limit of the choroidal vessel. Agreement between A-SFCT and M-SFCT is reduced by the presence of posterior stromal layer and lamina fusca. A-SFCT should be interpreted with RCJ and CSJ boundary grading.

Intersession Test-Retest Variability of Microperimetry in Type 2 Macular Telangiectasia.

PURPOSE: Microperimetry is used as an endpoint in type 2 macular telangiectasia (mactel) trials. The change required for defining disease progression depends on measurement error. We determined the threshold of test-retest variability (TRV) of microperimetry in mactel. METHODS: A prospective study was done of 24 patients with stable mactel enrolled in a tertiary eye clinic. Each patient underwent three sessions of microperimetry separated by a median of 28 days. An identical testing protocol was used: 4-2 staircase algorithm at 37 loci radial grid covering central 6°. Microperimetry variables were compared across three visits. TRV was quantified by calculating the coefficients of repeatability (CRs) for mean and median foveal sensitivity and the number of loci with dense scotoma (DS) or normal sensitivity (NS). The 95% confidence intervals (CIs) for CRs were calculated. RESULTS: Mean and median foveal sensitivity increased from first to second testing sessions. Test duration, visual acuity, number of loci with DS, and fixation stability remained stable through the three test sessions. The intersession CRs for mean and median foveal sensitivity were 2.6 (95% CI, 1.8-3.3) and 2.4 (95% CI, 1.7-3.1) dB, respectively. CRs for the number of DS and NS loci were 5 and 12 loci. CR for both logBCEA63 and logBCEA95 was 1.0 (95% CI, 0.8-1.2). CONCLUSIONS: The first microperimetry examination should be discarded due to learning effects. TRV in foveal sensitivity may be as high as 3.3 and 3.1 dB (∼0.3 log unit; 2× change) for its mean and median. TRANSLATIONAL RELEVANCE: Our results have implications for the design of clinical trials in mactel.

Intersession test-retest variability of 10-2 MAIA microperimetry in fixation-threatening glaucoma.

PURPOSE: To determine the intersession test-retest variability (TRV) of CenterVue Macular Integrity Assessment (MAIA) microperimeter in glaucoma patients with fixation-threatening field defects. METHODS: This is a prospective case-control study of 27 participants consisting of 13 patients with stable primary open-angle glaucoma and 14 control subjects including 5 healthy individuals and 9 retinal patients (5 with non-neovascular age-related macular degeneration and 4 with inherited retinal disease). Each participant underwent three microperimetry tests in one eye at 1-month intervals. Each test used an identical test strategy of 10-2 Cartesian grid and 4-2 staircase algorithm. We investigated TRV by calculating the coefficient of repeatability (CR) for mean sensitivity (MS) and point-wise sensitivity (PWS) for glaucomatous subjects and retinal and normal subjects. 95% confidence intervals (CIs) for CRs were calculated. RESULTS: There was no significant change in MS, and the median durations of microperimetry sessions were 9'26″, 8'52″, and 8'46″ across the three study visits. The intersession CRs for MS were 1.1, 2.5, and 1.8 dB, and the average CRs for PWS were 3.5, 7.4, and 8.6 dB for healthy controls and retinal and glaucoma patients, respectively. For test loci with 25-34 dB at baseline, CRs for PWS were 8.2 (95% CI: 7.5-8.9) and 4.3 (95% CI: 4.0-4.6) dB for glaucoma and control subjects, respectively. CONCLUSION: We found differences in TRV of test loci depending on the baseline sensitivity value. Glaucoma patients had significantly worse TRV for loci that had sensitivity values within the normal range at baseline. The estimated CR has implications for sample size calculation in future glaucoma treatment trials using microperimetry as a clinical endpoint.

The Use of Microperimetry to Detect Functional Progression in Non-Neovascular Age-Related Macular Degeneration: A Systematic Review.

We reviewed the current literature on the ability of microperimetry to detect non-neovascular age-related macular degeneration (AMD) disease progression. The index test was retinal sensitivity measurement assessed by microperimetry and comparators were other functional measures (best-corrected and low-luminance visual acuities, and fixation stability) and structural parameters [retinal thickness, choroidal thickness, and area of geographic atrophy (GA) determined by color fundus photographs, short-wave or near-infrared fundus autofluorescence]. The reference standard was area of GA. The literature search was conducted in January 2016 and included MEDLINE, EMBASE, the Cochrane Library, Biosis, Science Citation Index, ProQuest Health and Medicine, CINAHL, and Highwire Press. We included 6 studies that enrolled 41 eyes with intermediate AMD (from a single study) and 80 eyes with GA secondary to AMD. Retinal sensitivity measured by microperimetry was the only functional measure that consistently detected progression in each cohort. Insufficient reported data precluded meta-analysis. Various microperimetry parameters were used to assess cohort-level change in retinal sensitivity, but the methods of analysis have yet to mature in complexity in comparison with established glaucoma field progression analysis. Microperimetry-assessed retinal sensitivity measurement may be more sensitive in detecting progression than other functional measures in non-neovascular AMD. However, the lack of standardized testing protocol and methods of progression analysis hindered comparison. Harmonization of testing protocol and development of more robust methods of analyzing raw microperimetric data will facilitate clinical implementation of this valuable retinal assessment tool.

Impact of retinal pigment epithelium pathology on spectral-domain optical coherence tomography-derived macular thickness and volume metrics and their intersession repeatability.

BACKGROUND: To determine the impact of retinal pigment epithelium (RPE) pathology on intersession repeatability of retinal thickness and volume metrics derived from Spectralis spectral-domain optical coherence tomography (Heidelberg Engineering, Heidelberg, Germany). DESIGN: Prospective cross-sectional single centre study. PARTICIPANTS: A total of 56 eyes of 56 subjects were divided into three groups: (i) normal RPE band (25 eyes); (ii) RPE elevation: macular soft drusen (13 eyes); and (iii) RPE attenuation: geographic atrophy or inherited retinal diseases (18 eyes). METHODS: Each subject underwent three consecutive follow-up macular raster scans (61 B-scans at 119 µm separation) at 1-month intervals. MAIN OUTCOME MEASURES: Retinal thicknesses and volumes for each zone of the macular subfields before and after manual correction of segmentation error. Coefficients of repeatability (CR) were calculated. RESULTS: Mean (range) age was 57 (21-88) years. Mean central subfield thickness (CST) and total macular volume were 264 and 258 µm (P = 0.62), and 8.0 and 7.8 mm3 (P = 0.31), before and after manual correction. Intersession CR (95% confidence interval) for CST and total macular volume were reduced from 40 (38-41) to 8.3 (8.1-8.5) and 0.62 to 0.16 mm3 after manual correction of segmentation lines. CR for CST were 7.4, 23.5 and 66.7 µm before and 7.0, 10.9 and 7.6 µm after manual correction in groups i, ii and iii. CONCLUSIONS: Segmentation error in eyes with RPE disease has a significant impact on intersession repeatability of Spectralis spectral-domain optical coherence tomography macular thickness and volume metrics. Careful examination of each B-scan and manual adjustment can enhance the utility of quantitative measurement. Improved automated segmentation algorithms are needed.

Intersession test-retest variability of conventional and novel parameters using the MP-1 microperimeter.

PURPOSE: To investigate the intersession test-retest variability (TRV) of topography- and threshold-based parameters derived from the Nidek MP-1. DESIGN: Prospective observational study. METHODS: Sixteen participants with and without central scotoma underwent microperimetry in one eye over three sessions at 1-month intervals in a single institution. We calculated 95% coefficient of repeatability (CR) for the number of normal-suspect (NS) loci, relative scotoma (RS) and dense scotoma (DS), median macular sensitivity (MS), mean sensitivity of responding loci (RLS), perilesional loci (PLS), and extralesional loci (ELS). Topographical agreement score of mapping NS and DS loci (TASNS and TASDS) were also calculated for each patient. RESULTS: Mean (range) age was 50 (21-86) years. The CR (95% confidence intervals) for NS, RS, and DS were 9.9 (6.5-13.3), 9.5 (6.2-12.7), and 3.0 (1.1-4.1) respectively. CR (95% CIs) for median MS, mean RLS, PLS, and ELS were 3.4 (2.3-4.5), 1.6 (1.1-2.2), 1.8 (0.9-2.6), and 2.8 (1.5-4.0) dB. We found significant change in thresholds between Test 1, and Tests 2 and 3 (both P=0.03), but not between Tests 2 and 3 (P=0.8). Medians (range) TASNS and TASDS were 74% (39%-100%) and 77% (0%-97%), respectively, between Tests 2 and 3. CONCLUSION: We recommend the use of four DS loci (upper limit of CR) as the limit of TRV for assessing change. There was large interindividual variability in NS or DS mapping agreement. We recommend discarding the first microperimetry test and caution the use of a change in spatial distribution to determine disease progression.

Inter-device comparison of retinal sensitivity measurements: the CenterVue MAIA and the Nidek MP-1.

BACKGROUND: Our aim is to compare retinal sensitivity measurements obtained on two microperimeters: the CenterVue MAIA and the Nidek MP-1. DESIGN: A prospective study was conducted in a private ophthalmology clinic. PARTICIPANTS: Seventeen individuals with a range of stable macular function were recruited as participants. METHODS: Microperimetry in one eye with identical test strategy in both devices, with randomized testing order, is used. MAIN OUTCOME MEASURES: The main outcome measures include differences in mean sensitivity (MS), point-wise sensitivity (PWS) and duration. Limits of agreement (LoA) in MS and pooled PWS were calculated. Concordance in scotoma assessment was analysed by kappa (κ) agreement of local defect classification (LDC), LoA in number of scotomatous loci detected and congruence in scotoma localization (CSL). RESULTS: Median (interquartile range) MS of the MP-1 and MAIA was 13.3 (5.6-18.1) and 21.2 (14.5-27.0) dB, (P < 0.05). Mean difference in PWS was 7.3 dB (MAIA > MP-1). Median (interquartile range) duration for the MP-1 and MAIA was 10'28″ (7'17″-11'53″) and 8'46″ (8'30″-9'06″), (P = 0.21). LoA for MS and pooled PWS was 1.4 to 13.3 dB and -3.9 to 18.5 dB. There was moderate agreement between the devices for LDC (weighted κ = 0.55, P < 0.05). LoA in number of scotomatous loci detected was -13 to 18. CSL varied from 0 to 100% and correlated strongly with increasing scotoma size. CONCLUSIONS: The large LoA and variation in scotoma mapping concordance suggest that the same microperimeter should be used for follow-up examination. We recommend caution in comparing results derived from different types of microperimeters.

Novel optical coherence tomography classification of torpedo maculopathy.

BACKGROUND: Torpedo maculopathy is a rare condition with a twofold clinical significance. Firstly, it is a differential of atypical congenital hypertrophy of the retinal pigment epithelium. Secondly, visual field loss has been reported. We demonstrate the spectrum of structural abnormality of torpedo maculopathy as seen on optical coherence tomography, and correlate this with age of presentation, fundus autofluorescence, retinal sensitivity loss and visual field abnormality. DESIGN: A retrospective, observational case series. PARTICIPANTS: Five Australian patients seen between 2008 and 2013. METHODS: Fundus photography, optical coherence tomography, fundus autofluorescence and visual field analysis. One patient underwent fluorescein angiography. MAIN OUTCOME MEASURES: Lesion appearance on each imaging modality, and visual field analysis. RESULTS: We consistently observed a flat, hypopigmented lesion located in the temporal macula, with a distinctive tip pointing toward the fovea. Optical coherence tomography demonstrated variable retinochoroidal features ranging from mild outer retinal disturbance (type 1) to outer retinal cavitation (type 2). Lesion appearance on short-wave autofluorescence showed varying degrees of hypo-autofluorescence. Near-infrared autofluorescence was performed in two patients and showed a well-defined region of hypo-autofluorescence. Microperimetry showed normal sensitivity over the lesion in one patient and a dense paracentral scotoma over the temporal portion of the lesion in another. On Humphrey field analysis, only one of two patients tested had a paracentral scotoma. CONCLUSION: Two types of torpedo maculopathy lesions are described here with unique optical coherence tomography, demographic, fundus autofluorescence and retinal sensitivity features. These may represent different stages of the same disease that evolve over several decades.