Amir H Hariri

Quantification of Ellipsoid Zone Changes in Retinitis Pigmentosa Using en Face Spectral Domain–Optical Coherence Tomography

IMPORTANCE New methods are needed to quantify the change in the outer retinal structures in retinitis pigmentosa (RP). OBJECTIVE To implement an alternate method for tracking ellipsoid zone (EZ) changes in RP by quantifying the EZ area on en face spectral domain-optical coherence tomographic (SD-OCT) images. DESIGN, SETTING, AND PARTICIPANTS Data for this observational case study were collected at the Department of Ophthalmology, University of California, Los Angeles, from May 1 to July 30, 2015, and included SD-OCT images of a subset of patients from the Trial of Oral Valproic Acid for Retinitis Pigmentosa. To be eligible for the en face OCT subanalysis, the preserved EZ area was required to be limited to the SD-OCT scanning field. Cases in which the EZ band extended to the margins of any B-scan or the most superior or inferior B-scan were excluded. The SD-OCT images of all included cases were imported into the manufacturers software to generate en face images at the level of the EZ. Two certified SD-OCT graders independently delineated the boundaries of the preserved EZ on the en face images. MAIN OUTCOMES AND MEASURES Comparison of the 2 masked gradings of the generated en face images of patients with RP for agreement between the graders and the validity of the method. RESULTS Of the 43 available patients with volume SD-OCT data, 45 eyes of 24 patients met the eligibility criteria and were included in this subanalysis. Every patient had 2 visits that were 1 year apart, which included a total of 90 en face OCT images that were graded. The mean (SD) absolute difference and percentage difference between the 2 independent graders for each visit were 0.08 (0.10) mm2 and 4.5% (5.9%), respectively. The EZ area determined by the 2 graders showed excellent agreement with an intraclass correlation coefficient of 0.996 (95% CI, 0.995-0.997; P < .001). CONCLUSIONS AND RELEVANCE Quantification of the preserved EZ area on en face SD-OCT images of patients with RP is a valid and reproducible method. En face SD-OCT quantification may be a useful tool for monitoring the EZ changes of patients with advanced RP and a useful outcome measurement variable in therapeutic trials.

Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5

Importance Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease. Objective To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging. Design, Setting, and Participants In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)–binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 µm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits. Data were collected between August 22, 2013, and December 12, 2014. Data analysis was performed from March 15, 2015, through January 31, 2017. Exposures Images were evaluated by staff at a central reading center. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) were outlined and quantified. Lesion-free survival rates were estimated using Kaplan-Meier survival curves. Main Outcomes and Measures Incidence of atrophic lesions as determined by fundus autofluorescence. Results The 217 patients (mean [SD] age, 21.8 [13.3] years; 127 female [57.5%]; 148 white [68.2%]) contributed 390 eyes for which the mean (SD) follow-up time was 3.9 (1.6) years (range, 0.7-12.1 years). Among eyes without DDAF at first visit, the median time to develop a DDAF lesion was 4.9 years (95% CI, 4.3-5.6 years). Among eyes without QDAF, the median time to develop a QDAF lesion was 6.3 years (95% CI, 5.6-9.7 years). Eyes with a lesion of DDAF at the first visit were less likely to develop a QDAF lesion compared with eyes without a lesion of DDAF (hazard ratio, 0.19; 95% CI, 0.05-0.70; P = .01). Conclusions and Relevance An estimated 50% of the eyes without DDAF at first visit will develop the lesion in less than 5 years, suggesting that incidence of DDAF could serve as an outcome measure for treatment trials.

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9)

Importance Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. Objective To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study. Design, Setting, and Participants A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye. Exposures Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable. Main Outcomes and Measures Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence. Results A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean [SD] age, 29.9 [14.7] years; mean [SD] age of onset of symptoms, 21.9 [13.3] years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean [SD] age, 33.0 [15.1] years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of progression depended on the initial size of the lesion. Conclusions and Relevance In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.

TYPE 1 VERSUS TYPE 3 NEOVASCULARIZATION IN PIGMENT EPITHELIAL DETACHMENTS ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY: A Prospective Study.

Purpose: To evaluate the response to aflibercept therapy for Type 1 and Type 3 neovascularization in pigment epithelial detachments associated with treatment-naive, neovascular age-related macular degeneration. Methods: In this multicentered, prospective study, eligible eyes underwent an intravitreal aflibercept injection protocol for 12 months. Visual acuity and morphologic features of the pigment epithelial detachments were compared at baseline and follow-up intervals between eyes with Type 1 versus Type 3 neovascularization. Results: Thirty-six eyes were analyzed. At 12 months, Type 1 lesions showed a 4.5 ± 23 Early Treatment of Diabetic Retinopathy Study letter improvement (P = 0.1665) versus a 14 ± 11 (P = 0.0072) letter improvement with Type 3 lesions. Both Type 1 and 3 eyes showed a significant decrease in pigment epithelial detachment size, subretinal fluid, and subretinal hyperreflective material; however, Type 3 eyes had a greater reduction in pigment epithelial detachment size and subretinal hyperreflective material, as well as a reduction in central retinal thickness. Type 1 eyes required an average of 1.636 (range, 1–4) injections to resolve fluid, which was greater than Type 3 eyes, which required an average of 1.143 (range, 1–2) injections (P = 0.0251). Conclusion: Intravitreal aflibercept injections were efficacious for pigment epithelial detachments, but baseline and follow-up anatomical and functional outcomes differed in Type 1 versus Type 3 neovascularization. The better response of Type 3 eyes with fewer injections suggests that differentiation of the neovascularization subtype at the initial diagnosis may allow for a more tailored, optimal therapy.

Quantitative Characteristics of Spectral-Domain Optical Coherence Tomography in Corresponding Areas of Increased Autofluorescence at the Margin of Geographic Atrophy in Patients With Age-Related Macular Degeneration

BACKGROUND AND OBJECTIVE To evaluate the spectral-domain optical coherence tomography (SD-OCT) characteristics of the junctional zone corresponding to areas of increased autofluorescence (IAF) at the margin of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS SD-OCT and fundus autofluorescence (FAF) images from untreated eyes with GA available from archived studies at Doheny Image Reading Center were evaluated. Areas of definite decreased autofluorescence (DDAF) corresponding to GA, and areas of IAF at the margins of the GA were manually segmented. Eyes with evidence of IAF were selected. Following manual registration of FAF and OCT data, areas of IAF and normal fluorescence were correlated with OCT features at these locations. RESULTS Thirty eyes were included. The mean retinal pigment epithelium (RPE) thickness in areas of IAF was 40.6 µm ± 7.69 µm, compared to 28.8 µm ± 7.09 µm in normal adjacent areas (P < .001). CONCLUSION Regions of IAF at the junctional zone of GA lesions appear to correspond to thickening of the presumed RPE band on OCT. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:523-527.].

Reproducibility of Macular Thickness Measurements in Eyes Affected by Dry Age-Related Macular Degeneration From Two Different SD-OCT Instruments

BACKGROUND AND OBJECTIVE To compare macular thickness measurement algorithms of two different spectral-domain optical coherence tomography (SD-OCT) devices in eyes affected by dry age-related macular degeneration (AMD). PATIENTS AND METHODS Patients with dry AMD and healthy volunteers from the retina clinic of the Doheny Eye Center - UCLA were imaged using two different SD-OCT devices: the RS-3000 Advance (Nidek, Padova, Italy) and the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). All patients had been previously diagnosed with drusen or geographic atrophy due to AMD. The commercial instrument software was used to generate the macular retinal thickness measurements, and measurements were compared between devices. RESULTS Eighty-five diseased eyes from 49 patients and 16 healthy control eyes from eight normal volunteers were included in this study. The macular thickness measurements generated by the two instruments in eyes with AMD differed significantly in mean retinal thickness in the foveal center subfield (257.34 μm ± 51.72 μm using the Nidek OCT vs. 238.20 μm ± 51.89 μm using the Cirrus OCT; P < .001). The mean difference in macular thickness between the two devices was 19.14 μm ± 5.84 μm for diseased eyes and 17.06 μm ± 5.28 μm in normal control eyes, and this was not statistically different between the two groups (P > .05). The macular thickness measurements in diseased eyes, as evaluated by the two different instruments, however, showed excellent correlation (r = 0.99; P < .001), with an intraclass correlation coefficient of 0.99 (95% confidence interval, 0.98-0.99). Post hoc evaluation of cases with larger differences also showed differences in foveal center selection and variabilities in boundary selection with specific pathology. CONCLUSION Macular thickness measurements provided by the Nidek and Cirrus OCT instruments in eyes with dry AMD are highly correlated but show a consistent difference, which may allow the use of a standard correction factor to be applied to better interrelate measurements between the devices. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:410-415.].

Comparison of short-wavelength blue-light autofluorescence and conventional blue-light autofluorescence in geographic atrophy

Background/aims To systematically compare the intermodality and inter-reader agreement for two blue-light confocal fundus autofluorescence (FAF) systems. Methods Thirty eyes (21 patients) with a diagnosis of geographic atrophy (GA) were enrolled. Eyes were imaged using two confocal blue-light FAF devices: (1) Spectralis device with a 488 nm excitation wavelength (488-FAF); (2) EIDON device with 450 nm excitation wavelength and the capability for ‘colour’ FAF imaging including both the individual red and green components of the emission spectrum. Furthermore, a third imaging modality (450-RF image) isolating and highlighting the red emission fluorescence component (REFC) was obtained and graded. Each image was graded by two readers to assess inter-reader variability and a single image for each modality was used to assess the intermodality variability. Results The 95% coefficient of repeatability (1.35 mm2 for the 488-FAF-based grading, 8.13 mm2 for the 450-FAF-based grading and 1.08 mm2 for the 450-RF-based grading), the coefficient of variation (1.11 for 488-FAF, 2.05 for 450-FAF, 0.92 for 450-RF) and the intraclass correlation coefficient (0.994 for 488-FAF, 0.711 for 450-FAF, 0.997 for 450-RF) indicated that 450-FAF-based and 450-RF-based grading have the lowest and highest inter-reader agreements, respectively. The GA area was larger for 488-FAF images (median (IQR) 2.1 mm2 (0.8–6.4 mm2)) than for 450-FAF images (median (IQR) 1.0 mm2 (0.3–4.3 mm2); p<0.0001). There was no significant difference in lesion area measurement between 488-FAF-based and 450-RF-based grading (median (IQR) 2.6 mm2 (0.8–6.8 mm2); p=1.0). Conclusion The isolation of the REFC from the 450-FAF images allowed for a reproducible quantification of GA. This assessment had good comparability with that obtained with 488-FAF images.

Macular spatial distribution of preserved autofluorescence in patients with choroideremia

Background/Aims To better understand the pattern of degeneration progression in cases with choroideremia. Methods A cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields. Results A total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, p<0.001) and also between outer subfields (F (3,668)=8.348, p<0.001). A Tukey posthoc test revealed that the preserved AF area in the nasal subfields in both the inner and outer subfields was significantly smaller compared with analogue subfields. Conclusion The asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference.

Prevalence of vitreomacular adhesion: an optical coherence tomography analysis in the retina clinic setting.

Purpose The aims of this study were to determine the prevalence of vitreomacular adhesion (VMA) in a random sample of clinical patients at three US retina clinics and to assess comorbid retinal conditions, ocular diseases, prior treatment history, and other medical histories. Patients and methods This observational, retrospective cohort study was based on patients from the Doheny Eye Centers, Duke Eye Center, and Tufts Medical Center who received a bilateral spectral domain optical coherence tomography (SD-OCT) scan (one scan/eye) for clinical evaluation with available medical records. The study had three phases: 1) collection of retrospective patient data; 2) review of OCT scans at a reading center to assess VMA and associated conditions; and 3) analyses and reporting of data on the prevalence of VMA, patient demographics, and comorbid conditions. Data were obtained from electronic health records and OCT grading forms. Outcome measures from bilateral SD-OCT scans and medical records included OCT evaluation of VMA and retinal comorbid conditions. Results In 719 patients with 1,483 reviewable OCT scans, the prevalence of VMA was estimated at 14.74% (90% CI, 12.58%–16.92%). The prevalence of unilateral VMA was estimated at 12.39%, while bilateral VMA was 2.36%. In patients with VMA, 34 out of 123 eyes with VMA (27.64%) also had fovea deformed by vitreomacular traction. Macular hole (MH) was significantly more prevalent in VMA-diagnosed eyes versus non-VMA-diagnosed eyes (6.5% versus 1.9%; P=0.02). There was a significantly higher incidence of full-thickness MH (P=0.008), operculum/flaps (P<0.0001), and lamellar or pseudo-holes (P=0.048) in VMA-diagnosed versus non-VMA-diagnosed eyes. Age, MH as a comorbid condition, full-thickness MH, lamellar or pseudo-holes, and operculum were predictive of a VMA diagnosis. Conclusion The prevalence of VMA was estimated at 14.74% in a random sample of patients from three retina clinics. VMA diagnosis can be predicted by factors, including age, MH as a comorbid condition, and lamellar or pseudo-holes.