Subretinal hyperreflective material in regions of atrophy and fibrosis in eyes with neovascular age-related macular degeneration.

BACKGROUND: Subretinal hyperreflective material (SHRM) is a significant biomarker for poor visual outcomes in neovascular age-related macular degeneration (nAMD); however, its relationship with fibrosis and atrophy is not well understood. This study aims to evaluate the relationship between SHRM, atrophy, and fibrosis in eyes receiving antivascular endothelial growth factor therapy for nAMD. METHODS: Post-hoc analysis of the 65 patients enrolled in the SEVEN-UP study, a multicenter cross-sectional study of patients originally enrolled in the ANCHOR and MARINA trials of ranibizumab. Color fundus photographs (CFP) were reviewed and manually segmented to define regions of atrophy and fibrosis. SHRM borders on OCT volume scans were manually delineated, and thickness measurements were computed and compared in corresponding regions of atrophy and fibrosis on the CFPs. RESULTS: Of the 65 subjects, 51 eyes showed atrophy and/or fibrosis on CFP and were included in the final analysis. Both atrophy and fibrosis regions exhibited SHRM on OCT. The mean SHRM thickness on OCT was significantly greater in CFP-fibrosis regions (44.19 ± 46.95 µm) compared with CFP-atrophy regions (14.28 ± 13.35 µm; p < 0.001). Additionally, the average maximum height of SHRM in fibrotic regions (268.04 ± 130.05 µm) was significantly thicker than in atrophic regions (121.95 ± 51.17 µm; p < 0.001). CONCLUSIONS: Although atrophy and fibrosis are thought to be different end-stage outcomes in eyes with nAMD, they both demonstrate SHRM on OCT; the main distinction being thickness. Given these similarities, these regions of nAMD-associated atrophy may be better-termed "atrosis" to distinguish these lesions from typical atrophy in the absence of neovascular disease.

Longitudinal Evaluation of the Distribution of Intraretinal Hyper-Reflective Foci in Eyes with Intermediate Age-Related Macular Degeneration.

PURPOSE: Intraretinal hyper-reflective foci (IHRF) are optical coherence tomography (OCT) risk factors for progression of age-related macular degeneration (AMD). In this study we assess the change in the number and distribution of IHRF over two years. METHODS: The axial distribution of IHRF were quantified in eyes with intermediate AMD (iAMD) at baseline and 24 months, using a series of 5 sequential equidistant en face OCT retinal slabs generated between the outer border of the internal limiting membrane (ILM) and the inner border of the retinal pigment epithelium (RPE). Following thresholding and binarization, IHRF were quantified in each retinal slab using ImageJ. The change in IHRF number in each slab between baseline and month 24 was calculated. RESULTS: Fifty-two eyes showed evidence of IHRF at baseline, and all continued to show evidence of IHRF at 24 months (M24). The total average IHRF count/eye increased significantly from 4.67 ± 0.63 at baseline to 11.62 ± 13.86 at M24 (p < 0.001) with a mean increase of 6.94 ± 11.12 (range: - 9 to + 60). Overall, at M24, 76.9% eyes showed an increase in IHRF whereas 15.4% of eyes showed a decrease (3 eyes [5.7%] showed no change). There was a greater number of IHRF and a greater increase in IHRF over M24 in the outer slabs. CONCLUSIONS: IHRF are most common in the outer retinal layers and tend to increase in number over time. The impact of the distribution and frequency of these IHRF on the overall progression of AMD requires further study.

Relationship between the distribution of intra-retinal hyper-reflective foci and the progression of intermediate age-related macular degeneration.

PURPOSE: To assess the relationship between the distribution of intra-retinal hyper-reflective foci (IHRF) on optical coherence tomography (OCT) and progression of intermediate age-related macular degeneration (iAMD) over 2 years. METHODS: Cirrus OCT volumes of the macula of subjects enrolled in the Amish Eye Study with 2 years of follow-up were evaluated for the presence of iAMD and IHRF at baseline. The IHRF were counted in a series of 5 sequential en face slabs from outer to inner retina. The number of IHRF in each slab at baseline and the change in IHRF from baseline to year 2 were correlated with progression to late AMD at 2 years. RESULTS: Among 120 eyes from 71 patients with iAMD, 52 eyes (43.3%) of 42 patients had evidence of both iAMD and IHRF at baseline. Twenty-three eyes (19.0%) showed progression to late AMD after 2 years. The total IHRF count increased from 243 at baseline to 604 at 2 years, with a significant increase in the IHRF number in each slab, except for the innermost slab 5 which had no IHRF at baseline or follow-up. The IHRF count increased from 121 to 340 in eyes that showed progression to late AMD. The presence of IHRF in the outermost retinal slabs 1 and 2 was independently associated with a significant risk of progression to late AMD. A greater increase in IHRF count over 2 years in these same slabs 1 and 2 was also associated with a higher risk of conversion to late AMD. CONCLUSIONS: The risk of progression to late AMD appears to be significantly associated with the distribution and extent of IHRF in the outermost retinal layers. This observation may point to significant pathophysiologic differences of IHRF in inner versus outer layers of the retina.

Comparison of diabetic retinopathy severity grading on ETDRS 7-field versus ultrawide-field assessment.

OBJECTIVES: To compare the diabetic retinopathy (DR) severity level determined when considering only the ETDRS 7-field region versus the entire ultrawidefield (UWF) image. METHODS: In this retrospective, cross-sectional study, UWF pseudocolor images were graded on the Eyenuk image viewing, grading, and annotation platform for the severity of DR considering only the regions within the ETDRS 7-fields as well as the entire UWF image using two different protocols: 1) the simple International Classification of Diabetic Retinopathy (ICDR) scale and 2) the more complex DRCR.net Protocol AA grading scale. RESULTS: A total of 250 eyes from 157 patients were included in this analysis. Six eyes (2.4%) demonstrated a discrepancy in severity level between the ETDRS 7-field region and the entire UWF image when using the ICDR classification system. The discrepancies were due to the presence of lesions [intraretinal haemorrhage (n = 2), neovascular disease (n = 4)] in the peripheral fields which were not identified in the ETDRS 7-fields. Fourteen eyes (5.6%) had a discrepancy in severity level between the ETDRS 7-field region and the entire UWF image when using the ETDRS DRSS Protocol AA grading scale. The discrepancies were due to the presence of a higher level of disease [intraretinal haemorrhage (n = 4), neovascularization (n = 4), preretinal haemorrhage (n = 2), scatter laser scars (n = 4)] in the peripheral fields. CONCLUSION: Although considering regions outside of the ETDRS 7-fields altered the DR severity level assessment in <5% of cases in this cohort, significant and potentially vision-threatening lesions including neovascularization and preretinal haemorrhage were identified in these peripheral regions. This highlights the importance of evaluating the entire UWF region when assessing patients with diabetic retinopathy.

Risk Factors for Progression of Age-Related Macular Degeneration: Population-Based Amish Eye Study.

Objective: To evaluate the optical coherence tomography (OCT)-based risk factors for progression to late age-related macular degeneration (AMD) in a population-based study of elderly Amish. Methods: A total of 1332 eyes of 666 consecutive subjects who completed a 2-year follow-up visit were included in this multicenter, prospective, longitudinal, observational study. Imaging features were correlated with 2-year incidence of late AMD development. Odds ratios for imaging features were estimated from logistic regression. Baseline OCT images were reviewed for the presence of drusen volume ≥0.03 mm3 in the central 3 mm ring, intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDD), and drusenoid pigment epithelium detachment (PED). Subfoveal choroidal thickness, drusen area, and drusen volume within 3 and 5 mm circles centered on the fovea were also assessed. Results: Twenty-one (1.5%) of 1332 eyes progressed to late AMD by 2 years. The mean age of the study subjects was 65 ± 10.17 (±SD) years and 410 subjects were female. Univariate logistic regression showed that drusen area and volume in both 3 mm and 5 mm circles, subfoveal choroidal thickness, drusen volume ≥ 0.03 mm3 in the 3 mm ring, SDD, IHRF, and hDC were all associated with an increased risk for development of late AMD. The multivariate regression model identified that drusen volume in the 3 mm ring (OR: 2.59, p = 0.049) and presence of IHRF (OR: 57.06, p < 0.001) remained as independent and significant risk factors for progression to late AMD. Conclusions: This population-based study confirms previous findings from clinic-based studies that high central drusen volume and IHRF are associated with an increased risk of progression to late AMD. These findings may be of value in risk-stratifying patients in clinical practice or identifying subjects for early intervention clinical trials.

Pentosan Polysulfate Maculopathy: Prevalence, Spectrum of Disease, and Choroidal Imaging Analysis Based on Prospective Screening.

PURPOSE: To describe the prevalence and spectrum of disease of pentosan polysulfate (PPS) maculopathy in a large multimodal retinal imaging study and to report the results of choroidal vascularity index (CVI) analysis. DESIGN: Prospective cohort study Methods: Of 741 patients prescribed PPS within a large university database, 100 (13.4%) with any consumption agreed to participate in a prospective screening investigation. Multimodal retinal imaging including near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) was performed in all patients. Characteristic findings of affected patients were identified, and affected and unaffected cohorts were compared. CVI, defined as stromal choroidal area (SCA) divided by the total choroidal area, was analyzed. RESULTS: The prevalence of PPS maculopathy was 16%. NIR illustrated punctate hyperreflective lesions with early presentation. FAF illustrated a speckled macular network of hypo- and hyperautofluorescence colocalized with multifocal hyperreflective retinal pigment epithelial lesions on SD-OCT. Advanced cases demonstrated varying degrees of atrophy. The affected cohort exhibited significantly greater mean PPS therapy duration, mean daily dosage, and mean cumulative dosage (19.5±5.5 years, 433.9±137.6 mg, 3,103.1±1,402.2 g) compared with the unaffected cohort (7.1±6.6 years, 291.6±177.6 mg, 768.4±754.8 g). SCA was significantly lower and CVI was significantly greater in the affected vs the unaffected group. CONCLUSIONS: This prospective cohort study identified a prevalence of PPS maculopathy of 15%-20% among PPS users who agreed to participate. A spectrum of findings may be observed with multimodal retinal imaging. Significant choroidal abnormalities associated with this characteristic maculopathy may provide surrogate markers of macular toxicity.

Reproducibility of qualitative assessment of drusen volume in eyes with age related macular degeneration.

BACKGROUND: Although an optical coherence tomography (OCT)-derived central drusen volume ≥0.03 mm3 has been found to be a risk factor for progression to late age-related macular degeneration (AMD), this parameter is not currently available on most OCT devices or acquisition protocols. The purpose of this study was to evaluate the ability of human graders to qualitatively assess drusen volume by inspection of OCT B-scans. METHODS: 100 subjects (200 eyes) from the Amish Eye Study diagnosed with early or intermediate AMD underwent OCT imaging with both Cirrus OCT and Spectralis OCT. Drusen volume was automatically computed from the Cirrus OCT volumes using the Cirrus Advanced RPE Analysis software. Spectralis volume scans were reviewed by two independent, masked graders who were asked to determine whether the central drusen volume was ≥0.03 mm3. Cohen's kappa coefficients were computed to assess the agreement. RESULTS: After excluding 11 eyes with poor image quality and 5 eyes used for training of the graders, the remaining 184 eyes were included in this analysis. The agreement between the graders and the automated evaluation of drusen volume by the Cirrus OCT was excellent with K = 0.88 for grader 1 and K = 0.82 for grader 2. The agreement between graders was also excellent with a K = 0.88. CONCLUSIONS: The presence of a high central drusen volume can be assessed reliably by qualitative inspection of OCT B-scans. This approach may be useful in the assessment of risk for progression to late AMD.

Quantitative Assessment of the Severity of Diabetic Retinopathy.

PURPOSE: To determine whether a quantitative approach to assessment of the severity of diabetic retinopathy (DR) lesions on ultrawide field (UWF) images can provide new parameters to predict progression to proliferative diabetic retinopathy (PDR). METHODS: One hundred forty six eyes from 73 participants with DR and 4 years of follow-up data were included in this post hoc analysis, which was based on a cohort of 100 diabetic patients enrolled in a previously published prospective, comparative study of UWF imaging at the Joslin Diabetes Center. Diabetic Retinopathy Severity Score level was determined at baseline and 4-year follow-up visits using mydriatic 7-standard field Early Treatment Diabetic Retinopathy Study (ETDRS) photographs. All individual DR lesions (hemorrhage [H], microaneurysm [ma], cotton wool spot [CWS], intraretinal microvascular abnormality [IRMA]) were manually segmented on stereographic projected UWF. For each lesion type, the frequency/number, surface area, and distances from the optic nerve head (ONH) were computed. These quantitative parameters were compared between eyes that progressed to PDR in 4 years and eyes that did not progress. Univariable and multivariable logistic regression analyses were performed to identify parameters that were associated with an increased risk for progression to PDR. RESULTS: A total of 146 eyes of 73 subjects were included in the final analysis. The mean age of the study cohort was 53.1 years, and 42 (56.8%) subjects were female. The number and surface area of H/ma's and CWSs were significantly (P ≤ .05) higher in eyes that progressed to PDR compared with eyes that did not progress by 4 years. Similarly, H/ma's and CWSs were located further away from the ONH (ie, more peripheral) in eyes that progressed (P < .05). DR lesion parameters that conferred a statistically significant increased risk for proliferative diabetic retinopathy in the multivariate model included hemorrhage area (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.25-5.53), and greater distance of hemorrhages from the ONH (OR, 1.24; 95% CI, 0.97-1.59). CONCLUSIONS: Quantitative analysis of DR lesions on UWF images identifies new risk parameters for progression to PDR including the surface area of hemorrhages and the distance of hemorrhages from the ONH. Although these risk factors will need to be confirmed in larger, prospective studies, they highlight the potential for quantitative lesion analysis to inform the design of a more precise and complete staging system for diabetic retinopathy severity in the future. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

CHOROIDAL VASCULARITY INDEX AND CHOROIDAL THICKNESS IN EYES WITH RETICULAR PSEUDODRUSEN.

PURPOSE: To evaluate choroidal vascularity index (CVI), choroidal thickness, choroidal volume, and choroidal intensity in subjects with nonneovascular age-related macular degeneration (NNVAMD) with and without reticular pseudodrusen (RPD). METHODS: We included 60 eyes of 35 subjects with NNVAMD (including 30 eyes of 18 subjects with RPD) and 30 eyes of 17 age-matched healthy individuals from the ongoing Amish Eye study. The choroid was segmented from dense volume spectral domain optical coherence tomography scans and choroidal thickness (microns), choroidal intensity (log units), and choroidal volume (mm) from the entire macula (6 × 6 mm) were computed. A central horizontal B-scan was binarized and the luminal and stromal portions of the choroid were segmented. Choroidal vascularity index (%) was calculated as the ratio of luminal area to total choroid area. Choroidal parameters were compared between the groups by pairwise comparisons using the Student's t-test. RESULTS: The CVI was significantly lower in healthy eyes compared to those with RPD (53.43 ± 8.51 vs. 54.76 ± 4.83, P < 0.001). The CVI was also significantly lower in NNVAMD eyes without RPD compared to those with RPD (50.09 ± 7.51 vs. 54.76 ± 4.83, P = 0.006). There was no difference in CVI between healthy eyes and NNVAMD eyes without RPD (P = 0.84). Choroidal thickness and choroidal volume were significantly higher in NNVAMD without RPD (P < 0.05); and significantly lower in NNVAMD with RPD (P < 0.05) when compared with normal eyes. Choroidal intensity was significantly higher in NNVAMD with RPD when compared with normal eyes (P = 0.02) and NNVAMD eyes without RPD (P = 0.001). CONCLUSION: Multiple choroidal parameters reflecting the status of the choroidal vasculature and stroma seem to be altered in eyes with RPD compared with both normal eyes and NNVAMD eyes without RPD. These findings may provide insights into the pathophysiology of RPD.

Distribution of Nonperfusion and Neovascularization on Ultrawide-Field Fluorescein Angiography in Proliferative Diabetic Retinopathy (RECOVERY Study): Report 1.

PURPOSE: To explore the distribution of nonperfusion area (NPA) on ultrawide-field fluorescein angiography (UWF FA) in proliferative diabetic retinopathy (PDR) and its relationship with the presence of neovascularization of the optic disc (NVD) and distribution of neovascularization elsewhere (NVE). DESIGN: Prospective, observational case series. METHODS: Baseline Optos 200Tx UWF FA images of 38 eyes with treatment-naïve early-stage PDR from the RECOVERY (NCT02863354) study were stereographically projected at the Doheny Image Reading Center. Two independent/masked certified graders manually delineated the NPA and the total visible retinal area (TRA). NPA and TRA were then computed in square millimeters using the manufacturer software. Ischemic index (ISI) was calculated by dividing NPA by TRA. NPA and ISI were correlated with the presence and distribution of neovascularization in the corresponding zones. RESULTS: Eyes with NVD appeared to have more severe global NPA than those without (P = .026). Although the ISI appeared to increase with increasing distance from the foveal center (P < .001), NVE was more likely to be located in the posterior pole than the midperiphery or far-periphery (P < .001). Presence of NVE in the posterior polar retina appeared to demonstrate more severe ischemia in the posterior pole and midperiphery than those without (P < .05), but interestingly, was not correlated with the severity of overall global ischemia or of ischemia in the far-periphery alone (P > .05). CONCLUSIONS: Whereas the presence of NVD was associated with the severity of global ischemia, the distribution of NVE did not appear to be influenced by the distribution of ischemia.

AMISH EYE STUDY: Baseline Spectral Domain Optical Coherence Tomography Characteristics of Age-Related Macular Degeneration.

PURPOSE: To describe spectral domain optical coherence tomography (SD-OCT) findings in an Amish cohort to assess SD-OCT markers for early age-related macular degeneration (AMD). METHODS: The authors performed a family-based prospective cohort study of 1,146 elderly Amish subjects (age range 50-99 years) (2,292 eyes) who had a family history of at least 1 individual with AMD. All subjects underwent complete ophthalmic examinations, SD-OCT using both Cirrus and Spectralis (20 × 20° scan area) instruments, fundus autofluorescence, infrared imaging, and color fundus photography. Spectral domain optical coherence tomography characteristics were analyzed in subjects with AMD (with and without subretinal drusenoid deposits [SDDs]) and normal healthy cohorts. RESULTS: Participants' mean age was 65.2 years (SD ± 11). Color fundus photographic findings in 596 (53%) subjects (1,009 eyes) were consistent with AMD; the remaining 478 (43%) subjects showed no signs of AMD. The choroid was significantly thinner on OCT (242 ± 76 µm, P < 0.001) in those with AMD compared with those without (263 ± 63 µm). Subretinal drusenoid deposits were found in 143 eyes (7%); 11 of the 143 eyes (8%) had no other manifestations of AMD. Drusen volume (P < 0.001) and area of geographic atrophy (P < 0.001) were significantly greater, and choroid was significantly (P < 0.001) thinner in subjects with SDDs versus those without SDDs. CONCLUSION: The authors describe spectral domain optical coherence tomography characteristics in an elderly Amish population with and without AMD, including the frequency of SDD. Although relatively uncommon in this population, the authors confirmed that SDDs can be found in the absence of other features of AMD and that eyes with SDDs have thinner choroids.

Automated detection of diabetic retinopathy lesions on ultrawidefield pseudocolour images.

PURPOSE: We examined the sensitivity and specificity of an automated algorithm for detecting referral-warranted diabetic retinopathy (DR) on Optos ultrawidefield (UWF) pseudocolour images. METHODS: Patients with diabetes were recruited for UWF imaging. A total of 383 subjects (754 eyes) were enrolled. Nonproliferative DR graded to be moderate or higher on the 5-level International Clinical Diabetic Retinopathy (ICDR) severity scale was considered as grounds for referral. The software automatically detected DR lesions using the previously trained classifiers and classified each image in the test set as referral-warranted or not warranted. Sensitivity, specificity and the area under the receiver operating curve (AUROC) of the algorithm were computed. RESULTS: The automated algorithm achieved a 91.7%/90.3% sensitivity (95% CI 90.1-93.9/80.4-89.4) with a 50.0%/53.6% specificity (95% CI 31.7-72.8/36.5-71.4) for detecting referral-warranted retinopathy at the patient/eye levels, respectively; the AUROC was 0.873/0.851 (95% CI 0.819-0.922/0.804-0.894). CONCLUSION: Diabetic retinopathy (DR) lesions were detected from Optos pseudocolour UWF images using an automated algorithm. Images were classified as referral-warranted DR with a high degree of sensitivity and moderate specificity. Automated analysis of UWF images could be of value in DR screening programmes and could allow for more complete and accurate disease staging.

Measurement and Reproducibility of Preserved Ellipsoid Zone Area and Preserved Retinal Pigment Epithelium Area in Eyes With Choroideremia.

PURPOSE: To identify valid and reproducible methods for quantifying anatomic outcome measures for eyes with choroideremia (CHM) in clinical trials. DESIGN: Reliability analysis study. METHODS: In this multicenter study, patients with confirmed genetic diagnosis of CHM were enrolled. All cases underwent spectral-domain optical coherence tomography (SDOCT) and fundus autofluorescence (FAF) imaging. Two graders independently delineated boundaries of preserved autofluorescence (PAF) and preserved ellipsoid zone (EZ) on FAF and OCT images, respectively. The results of the 2 independent gradings of both FAF and OCT images were compared to assess the reproducibility of the grading methods. RESULTS: A total of 148 eyes from 75 cases were included. In 21% of eyes PAF and in 43% of eyes preserved EZ had extended beyond the image capture area. After exclusion of these eyes and low-quality images, 114 FAF and 77 OCT images were graded. The mean PAF areas from 2 independent gradings were 3.720 ± 3.340 mm2 and 3.692 ± 3.253 mm2, respectively. Intraclass correlation coefficient (ICC) for these gradings was 0.996. The mean preserved EZ areas from 2 independent gradings were 2.746 ± 2.319 mm2 and 2.858 ± 2.446 mm2, respectively. ICC for these gradings was 0.991. CONCLUSIONS: Quantifying preserved retinal pigment epithelium and EZ areas on FAF and OCT images, respectively, in CHM patients is highly reproducible. These variables would be potential anatomic outcome measures for CHM clinical trials and could be studied and tracked longitudinally in choroideremia.

ASSOCIATION OF DRUSEN VOLUME WITH CHOROIDAL PARAMETERS IN NONNEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: The choroid is thought to be relevant to the pathogenesis of nonneovascular age-related macular degeneration, but its role has not yet been fully defined. In this study, we evaluate the relationship between the extent of macular drusen and specific choroidal parameters, including thickness and intensity. METHODS: Spectral domain optical coherence tomography images were collected from two distinct, independent cohorts with nonneovascular age-related macular degeneration: Amish (53 eyes of 34 subjects) and non-Amish (40 eyes from 26 subjects). All spectral domain optical coherence tomography scans were obtained using the Cirrus HD-OCT with a 512 × 128 macular cube (6 × 6 mm) protocol. The Cirrus advanced retinal pigment epithelium analysis tool was used to automatically compute drusen volume within 3 mm (DV3) and 5 mm (DV5) circles centered on the fovea. The inner and outer borders of the choroid were manually segmented, and the mean choroidal thickness and choroidal intensity (i.e., brightness) were calculated. The choroidal intensity was normalized against the vitreous and nerve fiber layer reflectivity. The correlation between DV and these choroidal parameters was assessed using Pearson and linear regression analysis. RESULTS: A significant positive correlation was observed between normalized choroidal intensity and DV5 in the Amish (r = 0.42, P = 0.002) and non-Amish (r = 0.33, P = 0.03) cohorts. Also, DV3 showed a significant positive correlation with normalized choroidal intensity in both the groups (Amish: r = 0.30, P = 0.02; non-Amish: r = 0.32, P = 0.04). Choroidal thickness was negatively correlated with normalized choroidal intensity in both Amish (r = -0.71, P = 0.001) and non-Amish (r = -0.43, P = 0.01) groups. Normalized choroidal intensity was the most significant constant predictor of DV in both the Amish and non-Amish groups. CONCLUSION: Choroidal intensity, but not choroidal thickness, seems to be associated with drusen volume in Amish and non-Amish populations. These observations suggest that choroidal parameters beyond thickness warrant further study in the setting of age-related macular degeneration.

Correlation between retinal sensitivity and cystoid space characteristics in diabetic macular edema.

PURPOSE: To evaluate the correlation between retinal sensitivity and cystoid space characteristics in eyes with diabetic macular edema (DME). MATERIALS AND METHODS: Prospective cross-sectional study of 22 subjects with DME (32 treatment-naïve eyes). All study subjects underwent complete ophthalmic examination, including slit-lamp biomicroscopy and dilated fundus examination. All subjects underwent spectral domain optical coherence tomography (SD-OCT) and microperimetry (MP). Intraretinal cystoid space (ICS) volume was generated after manual delineation of cystoid space boundaries using the three-dimensional-OCT software. Various SD-OCT parameters, including retinal thickness, retinal volume, cystoid space volume, cystoid space intensity, and outer retinal structure integrity, were correlated with MP parameters and best-corrected visual acuity (BCVA). RESULTS: Subject's mean age was 57 ± 9 years. The mean logarithm of minimum angle of resolution BCVA was 0.4 ± 0.2. The intraclass correlation coefficient for inter- and intra-grader assessment of cystoid space volume by manual delineation was 0.99 and 0.99, respectively. Mean total ICS volume was 0.4 ± 0.4 mm 3 and for the foveal center, subfield was 0.1 ± 0.1 mm 3 . Mean retinal sensitivity was 12.89 ± 10 dB; however, foveal retinal sensitivity was 12.3 ± 11.1 dB. We found no significant correlation between BCVA and total cystoid space volume (r = 0.33, P = 0.06). Correlation between total retinal sensitivity and total ICS was negative and nonsignificant (r = -0.17, P = 0.36). Correlation between foveal retinal sensitivity and foveal cystoid space intensity was moderate and marginally significant (r = -0.43, P = 0.05). CONCLUSION: Total cystoid space volume was not significantly correlated with BCVA or total retinal sensitivity in subjects with DME. Foveal cystoid space optical intensity was negatively correlated with foveal retinal sensitivity. These findings suggest further investigation of cystoid space characteristics in the setting of DME may be of value.