RELATIONSHIP BETWEEN OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS AND NUMBER OF INTRAVITREAL RANIBIZUMAB INJECTIONS IN EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN THE HARBOR STUDY.

PURPOSE: To correlate baseline spectral-domain optical coherence tomography characteristics with the number of as-needed intravitreal injections of ranibizumab over a 24-month follow-up period in eyes with neovascular age-related macular degeneration. METHODS: Two hundred thirty-six eyes of 236 subjects with neovascular age-related macular degeneration treated with ranibizumab 0.5 mg pro re nata in the HARBOR study were enrolled. Baseline spectral-domain optical coherence tomography images were evaluated by certified reading center graders for specific morphologic features of the macular neovascularization lesion and surrounding retina. Baseline optical coherence tomography features and patient demographics correlated with the number of injections over the next 2 years. RESULTS: The mean number of injections in the 0.5 mg pro re nata group was 8.07 (median 8, 3-12) after 12 months and 14.25 (median 14, 3-24) after 24 months of treatment. After multivariate, linear, regression analysis, the only baseline parameter that was independently associated with a higher injection frequency at both 12 and 24 months was a greater baseline subretinal fluid thickness. CONCLUSION: A greater subretinal fluid thickness at baseline was associated with a higher frequency of pro re nata injections over 12 and 24 months in eyes treated with ranibizumab for neovascular age-related macular degeneration. These findings may be of value in counseling patients who are about to initiate therapy for macular neovascularization.

Relationship between retinal fluid characteristics and vision in neovascular age-related macular degeneration: HARBOR post hoc analysis.

PURPOSE: To evaluate the relationship between retinal fluid location, amount/severity, and vision with ranibizumab-treated neovascular age-related macular degeneration (nAMD). METHODS: In the phase 3 HARBOR trial (NCT00891735), treatment-naive patients with nAMD received ranibizumab 0.5 or 2.0 mg through month 24. This post hoc analysis included eyes with subretinal fluid (SRF) and/or intraretinal fluid (IRF) at screening, baseline, or week 1, and optical coherence tomography data at months 12 and 24 (n = 917). Outcomes were best-corrected visual acuity (BCVA) change from baseline and proportion of eyes with 20/40 or better vision at months 12 and 24. Eyes were stratified by the location, amount, and/or severity of fluid. RESULTS: At baseline, 86% and 63% of eyes had SRF and IRF, respectively. Among eyes with residual SRF, mean BCVA gains at each time point were greater in eyes with central versus noncentral SRF; location did not affect the odds of having 20/40 or better vision over 24 months. Eyes with 20/40 or better BCVA at month 12 had significantly lower SRF thickness versus eyes with worse vision; however, no difference was apparent at month 24. Vision was comparatively worse in eyes with residual IRF at months 12 and 24; location and severity did not appear to affect this outcome. CONCLUSION: Residual IRF was associated with worse vision outcomes, regardless of location/severity, whereas, despite continued treatment, residual SRF was not associated with worse vision outcome at 24 months, regardless of location/thickness. These data suggest complex relationships between residual fluid, severity, and vision.

Repeatability of Fluorescence Lifetime Imaging Ophthalmoscopy in Normal Subjects With Mydriasis.

PURPOSE: We evaluate the repeatability of fluorescence lifetime imaging ophthalmoscopy (FLIO) in normal subjects with mydriasis and explore factors that influence FLIO imaging. METHOD: Thirty-two healthy participants (63 eyes) were enrolled in this prospective study. The Heidelberg Engineering FLIO system uses a 473 nm blue laser light and the emitted fluorescence is detected in two wavelength channels, short and long spectral channels (SSC, LSC). The mean fluorescence lifetime (τm) values were computed for the entire scan area as well as in five regions of interest (ROI, 1 × 1 mm) at the fovea and superior, nasal, inferior, and temporal portions of the macula. Intraclass correlation coefficients (ICC) and coefficients of variation (CV) were used to assess the repeatability. Age, macular thickness, and vascular density also were correlated with τm. RESULTS: The repeatability was good for both channels (ICC, 0.956∼0.995; CV, 9∼16%). The τm for the entire scan was 367.8 ± 58.1 picoseconds (ps) in SSC and 322.5 ± 34.0 ps in LSC. τm was the shortest in the fovea and significantly shorter in the temporal region compared to other regions. τm was positively correlated with age (r = 0.588 for SSC and r = 0.584 for LSC, P = 0.000) and retinal thickness (r = 0.298 for SSC and r = 0.322 for LSC, P = 0.000), and negatively correlated with vascular density (r = -0.112, P = 0.055 for SSC and r = -0.119, P = 0.040 for LSC). CONCLUSION: Repeatable fluorescence lifetime values can be obtained with FLIO, but the lifetimes are affected by age, retinal thickness, vessel density, and macular location. TRANSLATIONAL RELEVANCE: Establishing repeatability of FLIO can introduce fluorescence lifetime imaging technique, which is used in basic science for analysis of excitation and emission wavelength spectrum of fixed and living cells into clinical practice.

A pilot study of fluorescence lifetime imaging ophthalmoscopy in preclinical Alzheimer's disease.

PURPOSE: To investigate fluorescence lifetime imaging ophthalmoscopy (FLIO) findings in preclinical Alzheimer's disease (AD). METHODS: This prospective, observational study enrolled patients with early AD undergoing Alzheimer's biomarker analysis and matched controls. Alzheimer-associated parameters (ß-amyloid [Aß], total tau in cerebrospinal fluid [CSF], Mini-Mental Status Examination [MMSE], etc.), risk factor-associated data (body mass index [BMI], hypertension, lipid profile, etc.), ganglion cell layer plus inner plexiform layer (GCIPL) thickness in structural optical coherence tomography (OCT), OCT angiography data, and FLIO-derived parameters (τm, τ1, τ2, and τ3) in short and long spectral channels (SSC and LSC) were compared and correlated between the two groups. Additional analyses were performed separately within subgroups of phakic and pseudophakic. RESULTS: A total of 28 eyes from 15 subjects (8 control and 7 AD) were included in this analysis. In FLIO parameters, τm in AD group showed longer lifetimes compared to the controls in phakic subjects (593.9 ± 93.3, 454.4 ± 38.6 ps; 475.0 ± 71.6, 394.1 ± 28.2 ps in SSC and LSC of AD and control groups, respectively, p = 0.036 and 0.024). Aß, tau in CSF, and GCIPL thickness correlated with τm in the LSC for phakic subjects (r = -0.611 to 0.562, p < 0.05 for all), but only the GCIPL thickness showed a correlation with FLIO parameters in pseudophakic subjects (r = -0.893 to -0.795, p < 0.001 for all). CONCLUSION: FLIO-derived parameters appear to correlate with Aß, tau levels in the CSF, and GCIPL thickness on OCT in AD patients. If these findings can be validated in future longitudinal studies, FLIO may prove to be useful as a simple, non-invasive diagnostic tool for AD.

Impact of mydriasis in fluorescence lifetime imaging ophthalmoscopy.

Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a novel technique that measures in vivo autofluorescence intensity decay over time of endogenous fluorophores in the retina. The Heidelberg Engineering FLIO system was used to obtain two 30 degree scans centered on the fovea of both eyes. The FLIO system uses a 473nm blue scanning laser light source and the emitted fluorescence is detected in two wavelengths channels, short and long spectral channels (SSC, LSC). Since the mydriatic status influence the FLIO result, the impact of mydriasis on FLIO need to be clarified. In this prospective, observational study, the impact of mydriasis on measurements from fluorescence lifetime imaging ophthalmoscope (FLIO) images in normal subjects were evaluated. 12 healthy participants (24 eyes) were volunteered and all subjects were scanned twice and the mean fluorescence lifetime (τm) values were computed with dilation and without dilation on different days. Intraclass correlation coefficients (ICC) and coefficients of variation (CV) were calculated from the measured τm in dilated, nondilated and between the dilated and non-dilated setting. Test duration was also compared and correlated with lifetimes in both settings. Repeatability was excellent for both the dilation and non-dilation settings (ICC; 0.967-0.996; 0.926-0.986, respectively). The agreement between the dilation and non-dilation settings, however, were lower (ICC; 0.688-0.970). The τm in the non-dilation setting was significantly longer than in the dilation setting for the SSC (P<0.05). The FLIO test duration in the non-dilation setting was significantly longer than with dilation for the SSC (P <0.05). Although good repeatability in τm measurements between imaging sessions were observed both with and without dilation, the agreement was not as good when comparing dilated with non-dilated measurements. Since FLIO without mydriasis results in longer τm in the SSC and takes a longer time for image acquisition, maximal dilation is recommended for FLIO testing.

Topographic Correspondence of Macular Atrophy With Choroidal Neovascularization in Ranibizumab-treated Eyes of the TREX-AMD Trial.

PURPOSE: To quantify the extent of topographic correspondence between baseline (BSL) choroidal neovascularization (CNV) and macular atrophy (MA) at follow-up in eyes with neovascular age-related macular degeneration (NVAMD). DESIGN: Post hoc analysis of randomized controlled clinical trial data. METHODS: Sixty treatment-naïve NVAMD patients from the TREX-AMD trial were followed for 18 months. Regions of month 18 macular atrophy (MA) were graded on fundus autofluorescence (FAF) with guidance of spectral-domain optical coherence tomography (SDOCT). CNV lesions were graded manually on fluorescein angiography (FA) with lesion components including classic and occult CNV delineated. FAF and FA images were registered to quantitate area and location of overlap between CNV and MA. Outcome measures included overlap of month 18 MA to BSL CNV subtype and progression of MA from BSL to month 18. RESULTS: Twenty-six eyes had both MA at month 18 and CNV at BSL. A total of 84.6% of eyes showed evidence of MA and CNV overlap. MA appeared by month 18 in regions corresponding to BSL classic CNV in 36.4% of eyes and occult CNV in 40.9%, and in both regions in 22.7%, with more area of MA (AMA) in regions of occult than classic CNV. MA position at BSL corresponded to BSL classic CNV in 76.9% of eyes and occult CNV in 61.5%, and to both regions in 15.4%, with more AMA in regions of occult than classic CNV. Among eyes with MA and CNV at BSL but with no overlap, 50% progressed to involve regions with BS -CNV. Six eyes had no BSL MA but developed MA at month 18 within regions of BSL CNV. CONCLUSIONS: In ranibizumab-treated eyes with NVAMD, more MA lesions develop within the region of baseline CNV (type 1, CNV-based MA) than outside (type 2, CNV-independent MA). Baseline-MA also tends to be located within regions of CNV in the pretreatment phase.

Relationship between the Presence of a Cilioretinal Artery and Subretinal Fluid in Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the relationship between presence of a cilioretinal artery (CRA) and the extent of subretinal fluid (SRF) in eyes with treatment-naïve neovascular age-related macular degeneration (nAMD). Eyes with nAMD have varying amounts of SRF, and factors affecting exudation volume are not well established. We hypothesize that presence of CRA may affect the extent of SRF by affecting the hemodynamics of blood flow supplying the choroidal neovascular membrane. DESIGN: Retrospective case-control study. PARTICIPANTS: Two hundred twelve patients with treatment-naïve nAMD in at least 1 eye from anonymized datasets available at the Doheny Image Reading Center. METHODS: Color fundus photographs and fluorescein angiograms of the study eyes were reviewed to identify those with a CRA (cases) and those without (controls). Spectral-domain OCT data were evaluated by 2 masked graders to identify presence and volume of SRF. We identified subtypes of CNV and evaluated other OCT features that could affect SRF, such as presence of subretinal hyperreflective material (SHRM), cystoid macular edema (CME), and pigment epithelial detachment (PED). Nonparametric Mann-Whitney U test and univariate and multivariate analyses were performed to identify significant differences between cases and controls and to evaluate the relationship between these factors and SRF volume. MAIN OUTCOME MEASURES: Presence and volume of SRF, presence of CME, PED types, and CNV types. RESULTS: We identified 44 cases and 168 controls. Mean SRF volume was significantly lower in cases than controls (0.72±0.9 mm3 vs. 1.60±2.36 mm3; P = 0.03). Univariate regression analysis showed a weakly significant correlation between presence of CRA and SRF volume (r = -0.15; P = 0.03) and OCT parameters, including SHRM (r = 0.16; P = 0.023), CME (r = -0.20; P = 0.004), and type 2 CNV (r = 0.16; P = 0.02). Multivariate analysis demonstrated that the presence of a CRA (r = -0.17; P = 0.02) was correlated independently with the presence of SRF. CONCLUSIONS: Presence of a CRA was correlated negatively with the volume of SRF in eyes with nAMD. These findings may draw insights into the potential hemodynamic effect of the CRA, which warrants further investigation.