Ian C. Han

Comparison of Spectral- and Time-Domain Optical Coherence Tomography for Retinal Thickness Measurements in Healthy and Diseased Eyes

PURPOSE To compare retinal thickness (RT) measurements obtained by spectral-domain optical coherence tomography (SD-OCT) and time-domain OCT (TD-OCT) in eyes with and without posterior segment disease diagnoses. DESIGN Retrospective, observational chart review. METHODS Scans of 184 healthy and diseased eyes from 106 patients were included in the study. Pair-wise comparisons of RT measurements from SD-OCT machines from 2 different manufacturers and TD-OCT were performed for all scans and with eyes stratified by disease diagnosis. RESULTS Foveal thickness measurements obtained from both SD-OCT machines were greater than those measured by TD-OCT, by 51.0 +/- 23.8 microm and 72.5 +/- 30.4 microm, respectively. The foveal thickness difference between the 2 SD-OCT models was 24.3 +/- 19.1 microm. Foveal thickness differences varied by disease diagnosis. CONCLUSIONS RT measurements obtained by SD-OCT are consistently greater than those obtained by TD-OCT. RT measurement differences may vary by disease diagnosis or by SD-OCT model. Consideration of these measurement differences is essential when OCT-determined RT measurement data are used in clinical settings.

Evaluation of Artifacts Associated with Macular Spectral-Domain Optical Coherence Tomography

PURPOSE To characterize the types and frequencies of image artifacts associated with macular scanning using 2 common spectral-domain optical coherence tomography (SD OCT) instruments and to evaluate the impact of artifacts on foveal thickness measurements. DESIGN Retrospective, observational chart review. PARTICIPANTS For the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA), scans of 98 eyes from 58 patients were included in the study. For the Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany), scans of 88 eyes from 54 patients were included. METHODS Macular volume scans of healthy and diseased eyes were evaluated systematically for image artifacts within each scan overall and within the center 1-mm area. The frequency of each artifact type was compared for scans stratified by diagnosis category. Artifacts in the center 1-mm area were graded for severity and were corrected manually using each instruments software. Artifacts that resulted in errors of more than 50 microm or more than 10% of retinal thickness or that caused a misdiagnosis of macular edema or retinal thinning were defined as clinically significant and were analyzed further. MAIN OUTCOME MEASURES Overall frequency of image artifacts by artifact type, relative frequency of artifacts in scans stratified by posterior segment disease diagnosis, and retinal thickness measurements of the center 1-mm subfield before and after artifact corrections. RESULTS For Cirrus, 84.7% of scans had artifacts and 32.7% had at least 1 artifact in the center 1-mm area of the scan. For Spectralis, 90.9% of scans had at least 1 artifact, and 37.5% had at least 1 artifact in the center 1-mm area. Certain artifact types were observed more frequently with specific disease states. Clinically significant artifacts involving the center 1-mm area were seen in 5.1% of Cirrus and 8.0% of Spectralis scans. CONCLUSIONS Image artifacts in SD OCT volume scanning are common and frequently involve segmentation errors. Artifacts are relatively less common in the center 1-mm area of scans, but may affect retinal thickness measurements in a clinically significant manner. Careful review of scans for artifacts is important when using SD OCT images and retinal thickness measurements in patient care or clinical trials.

Expression and modulation of RPE cell membrane complement regulatory proteins.

PURPOSE Complement, inflammation, and oxidant injury contribute to age-related macular degeneration (AMD). Membrane complement regulatory proteins (mCRPs) such as CD46, CD55, and CD59, protect host cells from complement attack. The factors that regulate RPE mCRP expression are not well understood. In this study, the authors sought to determine whether cytokines and hydroquinone (HQ) affect mCRP expression in cultured human RPE (hRPE) and cultured mouse RPE (mRPE) cells. METHODS Cultured hRPE and mRPE cells were stimulated with cytokines for various times or with HQ for multiple 6-hour periods. mRNA and protein expression of mCRPs in cultured hRPE cells from 10 donors, native hRPE, and mouse eyecups and native mRPE cells were evaluated by real-time RT-PCR, Western blot analysis, and flow cytometry, respectively. RESULTS Three mCRPs were expressed in cultured hRPE cells (CD59>CD46>CD55). CD46 and CD59 protein were detected in native hRPE cells. CD59 protein levels in cultured hRPE cells were higher than in native hRPE cells. CD46 protein polymorphisms were observed in cultured hRPE cells. Cultured hRPE cell mCRP expression was upregulated by TNF-alpha, IL-1beta, and a repetitive nonlethal dose of HQ. CD59a levels were higher in mouse eyecups than in nonocular tissues. Mouse mCRP mRNA and protein were detected in native mRPE cells. Responsiveness to cytokines in cultured mRPE cells differed from that in cultured hRPE cells. CONCLUSIONS Human and mouse RPE cell mCRPs are upregulated by inflammatory cytokines and repetitive nonlethal oxidant exposure in a species-specific manner. Increased cell mCRPs may help to protect RPE cells from complement- and oxidant-mediated injury in diseases such as AMD.

Macular Vascular Abnormalities Identified by Optical Coherence Tomographic Angiography in Patients With Sickle Cell Disease

IMPORTANCE Patients with sickle cell disease may develop various macular vascular abnormalities that have not been described previously and can be seen using optical coherence tomographic angiography. OBSERVATIONS Ten eyes from 5 consecutive patients (3 men and 2 women) with sickle cell disease (4 patients with hemoglobin SS disease and 1 patient with hemoglobin SC disease) were included. The mean age was 37.6 years. Five of 10 eyes (50%) had retinal thinning that was identified using spectral-domain optical coherence tomography. Each of these eyes had corresponding loss of vascular density in the superficial or deep retinal plexus (or both). CONCLUSIONS AND RELEVANCE Optical coherence tomographic angiography provides a novel way to view the retinal vasculature, including the superficial and deep capillary plexus, and may provide a sensitive method for identifying macular vascular abnormalities in patients with sickle cell disease.

CORRELATION OF MULTIMODAL IMAGING IN SICKLE CELL RETINOPATHY

Purpose: To correlate macular findings on spectral domain optical coherence tomography (SDOCT) and optical coherence tomography angiography (OCTA) with quantitative ischemic index calculations on ultra-wide-field fluorescein angiography (UWFFA) in patients with sickle cell retinopathy. Methods: In this retrospective case series, SDOCT, OCTA, and UWFFA images of patients with sickle cell retinopathy were evaluated. Eyes were staged based on the Goldberg classification of proliferative sickle cell retinopathy. Focal areas of macular thinning were assessed on SDOCT, macular vessel density was derived from OCTA, and peripheral ischemic index was calculated from UWFFA. Results: Eighteen eyes of 10 patients were included. Mean age was 36.8 ± 16.8 years, and 6 patients (11 eyes) were SS, 3 patients (5 eyes) were SC, and 1 patient (2 eyes) was S&bgr; thalassemia in hemoglobin electrophoresis. Abnormal macular findings included inner retinal atrophy in 11 eyes (61%) on SDOCT, vascular remodeling and nonperfusion in the superficial and deep retinal capillary plexus in 12 eyes (67%) on OCTA, and macular microvascular abnormalities in 9 eyes (50%) on UWFFA. Sickle cell retinopathy Stage I was identified in 4 eyes (22.2%), Stage II in 8 eyes (44.4%), and Stage III in 6 eyes (33.3%). Mean ischemic index was 14.1 ± 9.1%. Ischemic index was significantly correlated with hemoglobinopathy subtype (23.7 ± 9.8%, 9.3 ± 5.4%, and 16.3 ± 3.2%, for SC, SS, and S&bgr; thalassemia disease, respectively), stage of sickle cell retinopathy (22.5 ± 9.2%, 12.5 ± 4.9%, and 4.5 ± 0.73% for Stages III, II, and I, respectively), and presence of retinal thinning on SDOCT (17.4 ± 9.7% vs. 8.8 ± 5.1%, respectively). Conclusion: Multimodal imaging can provide a more complete description of the microvascular and structural alterations associated with sickle retinopathy. The correlation between the severity of peripheral nonperfusion and stage and subtype of retinopathy suggests that UWF imaging may be a useful tool in the evaluation of these patients.PURPOSE To correlate macular findings on spectral domain optical coherence tomography (SDOCT) and optical coherence tomography angiography (OCTA) with quantitative ischemic index calculations on ultra-wide-field fluorescein angiography (UWFFA) in patients with sickle cell retinopathy. METHODS In this retrospective case series, SDOCT, OCTA, and UWFFA images of patients with sickle cell retinopathy were evaluated. Eyes were staged based on the Goldberg classification of proliferative sickle cell retinopathy. Focal areas of macular thinning were assessed on SDOCT, macular vessel density was derived from OCTA, and peripheral ischemic index was calculated from UWFFA. RESULTS Eighteen eyes of 10 patients were included. Mean age was 36.8 ± 16.8 years, and 6 patients (11 eyes) were SS, 3 patients (5 eyes) were SC, and 1 patient (2 eyes) was Sβ thalassemia in hemoglobin electrophoresis. Abnormal macular findings included inner retinal atrophy in 11 eyes (61%) on SDOCT, vascular remodeling and nonperfusion in the superficial and deep retinal capillary plexus in 12 eyes (67%) on OCTA, and macular microvascular abnormalities in 9 eyes (50%) on UWFFA. Sickle cell retinopathy Stage I was identified in 4 eyes (22.2%), Stage II in 8 eyes (44.4%), and Stage III in 6 eyes (33.3%). Mean ischemic index was 14.1 ± 9.1%. Ischemic index was significantly correlated with hemoglobinopathy subtype (23.7 ± 9.8%, 9.3 ± 5.4%, and 16.3 ± 3.2%, for SC, SS, and Sβ thalassemia disease, respectively), stage of sickle cell retinopathy (22.5 ± 9.2%, 12.5 ± 4.9%, and 4.5 ± 0.73% for Stages III, II, and I, respectively), and presence of retinal thinning on SDOCT (17.4 ± 9.7% vs. 8.8 ± 5.1%, respectively). CONCLUSION Multimodal imaging can provide a more complete description of the microvascular and structural alterations associated with sickle retinopathy. The correlation between the severity of peripheral nonperfusion and stage and subtype of retinopathy suggests that UWF imaging may be a useful tool in the evaluation of these patients.

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion

PURPOSE To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab. DESIGN Secondary outcome measure in randomized double-masked controlled clinical trial. PARTICIPANTS Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). METHODS Subjects were randomized to 0.5 or 2.0 mg ranibizumab every month for 6 months and then were re-randomized to pro re nata (PRN) groups receiving either ranibizumab plus scatter laser photocoagulation or ranibizumab alone for an additional 30 months. MAIN OUTCOME MEASURES Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5 versus 2.0 mg ranibizumab, during monthly injections versus ranibizumab PRN, and in patients treated with ranibizumab PRN versus ranibizumab PRN plus laser. RESULTS In RVO patients given monthly injections of 0.5 or 2.0 mg ranibizumab for 6 months, there was no significant difference in the percentage who showed reduction or increase in the area of RNP. However, regardless of dose, during the 6-month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared with subsequent periods of ranibizumab PRN treatment. After the 6-month period of monthly injections, BRVO patients, but not CRVO patients, randomized to ranibizumab PRN plus laser showed significantly less progression of RNP compared with patients treated with ranibizumab PRN. CONCLUSIONS Regardless of dose (0.5 or 2.0 mg), monthly ranibizumab injections promote improvement and reduce progression of RNP compared with PRN injections. The addition of scatter photocoagulation to ranibizumab PRN may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO.

Pro-Permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study

PURPOSE To correlate aqueous vasoactive protein changes with macular edema after dexamethasone implant in retinal vein occlusion (RVO). DESIGN Prospective, interventional case series. METHODS Twenty-three central RVO (CRVO) and 17 branch RVO (BRVO) subjects with edema despite prior anti-vascular endothelial growth factor (VEGF) treatment had aqueous taps at baseline and 4 and 16 weeks after dexamethasone implant. Best-corrected visual acuity (BCVA) and center subfield thickness were measured every 4 weeks. Aqueous vasoactive protein levels were measured by protein array or enzyme-linked immunosorbent assay. RESULTS Thirty-two vasoactive proteins were detected in aqueous in untreated eyes with macular edema due to RVO. Reduction in excess foveal thickness after dexamethasone implant correlated with reduction in persephin and pentraxin 3 (Pearson correlation coefficients = 0.682 and 0.638, P = .014 and P = .003). Other protein changes differed among RVO patients as edema decreased, but ≥50% of patients showed reductions in hepatocyte growth factor, endocrine gland VEGF, insulin-like growth factor binding proteins, or endostatin by ≥30%. Enzyme-linked immunosorbent assay in 18 eyes (12 CRVO, 6 BRVO) showed baseline levels of hepatocyte growth factor and VEGF of 168.2 ± 20.1 pg/mL and 78.7 ± 10.0 pg/mL, and each was reduced in 12 eyes after dexamethasone implant. CONCLUSIONS Dexamethasone implants reduce several pro-permeability proteins providing a multitargeted approach in RVO. No single protein in addition to VEGF can be implicated as a contributor in all patients. Candidates for contribution to chronic edema in subgroups of patients that deserve further study include persephin, hepatocyte growth factor, and endocrine gland VEGF.

CRB1-Related Maculopathy With Cystoid Macular Edema

His course was marked by multiple attempts to taper prednisone, which failed owing to simultaneous recurrence of uveitis and tattoo induration (Figure 2B). The uveitis remained active (Figure 2C) despite aggressive management with regional corticosteroids in each eye, fluocinolone acetonide implantation in the left eye, and the following systemic combination: subcutaneous adalimumab, 40 mg weekly; cyclosporine, 100 mg daily; oral methotrexate, 12.5 mg weekly; azathioprine, 100 mg daily; and prednisone, 80 mg daily. The patient underwent vitreous biopsy of the right eye while receiving the systemic medications 7.5 years following symptom onset. Flow cytometry of the vitreous specimen confirmed an atypical T-lymphocyte population (40%-60%) with increased CD8 expression as well as CD3 and CD56 coexpression. Concurrent cytology revealed marked atypia without granulomas (Figure 1B) not thought to be consistent with sarcoidosis. The specimen was negative for infectious organisms, including mycobacteria. Given the concern for a lymphoproliferative disorder, all immunosuppression was discontinued and inflammation of the tattooed skin returned acutely. Repeated skin biopsy confirmed noncaseating granulomas with an atypical infiltrate but with results of T-lymphocyte gene rearrangement studies negative for lymphoma. Following negative results on an evaluation for malignancy, the patient resumed treatment with prednisone, 80 mg daily, with which his uveitis abated and skin changes resolved. Best-corrected visual acuity is 20/30 OD and 20/60 OS.

VARIABLE EXPRESSION OF RETINOPATHY IN A PEDIGREE OF PATIENTS WITH INCONTINENTIA PIGMENTI.

Purpose: To characterize the varied ocular manifestations of incontinentia pigmenti (IP) in a large pedigree. Methods: All available members of the kindred who were affected with IP were examined with ophthalmoscopy, wide-field color photos, and fluorescein angiography. Results: Individual family members demonstrated variable expression of retinopathy characteristic of IP. There was severe retinopathy in two eyes: one associated with concurrent persistent fetal vasculature and another with rhegmatogenous retinal detachment. Another individual with biopsy-confirmed IP demonstrated no retinopathy in either eye. When present, retinopathy manifested asymmetrically between eyes of the same individual. Conclusion: Cutaneous manifestations of IP are irregular and nonuniform due to lyonization of the X chromosome. In this report, we identify asymmetric retinal disease between eyes in the same individual and variable retinal findings within the kindred. These differences may be explained by random inactivation of the X chromosome or other epigenetic modifications.

Extended Follow-up of Treated and Untreated Retinopathy in Incontinentia Pigmenti: Analysis of Peripheral Vascular Changes and Incidence of Retinal Detachment.

IMPORTANCE Extended follow-up of treated and untreated retinopathy in incontinentia pigmenti (IP) has not previously been documented, to our knowledge. OBJECTIVE To determine which eyes with IP are at risk for retinal detachment. DESIGN, SETTING, AND PARTICIPANTS Observational cohort study of patients with IP who were retrospectively identified at a tertiary care academic center between 1976 and 2013. Fifty eyes of 25 female participants meeting clinical criteria for IP were followed up for at least 6 months. The last year of follow-up was between 1987 and 2014. MAIN OUTCOMES AND MEASURES Progression of retinopathy or the development of retinal detachment was assessed with fluorescein angiography, clinical examination, or both. RESULTS The median duration of follow-up was 9.3 years (range, 0.5-22.8 years). Over this period, 11 eyes (22%; 95% CI, 11%-33%) developed retinal detachment. The odds of retinal detachment were increased if there was retinal neovascularization (odds ratio, 11.61; 95% CI, 1.34-100.56; P = .03) or ischemic optic neuropathy (odds ratio, 5.27; 95% CI, 1.61-17.23; P = .006) on initial examination. A bimodal distribution of retinal detachments was observed, with most tractional detachments (7 eyes) occurring by age 2.5 years (median, 1.5 years; range, 14 days-7.0 years) and most rhegmatogenous detachments (4 eyes) occurring in adults (median age, 31.5 years; range, 14.0-47.0 years). Three eyes of young patients (≤2.5 years) developed tractional detachment, despite prophylactic ablation in 4 eyes; only one eye of older patients (≥14.0 years) developed retinal detachment following prophylactic ablation in 6 eyes. Persistent fetal vasculature appears to occur more commonly in IP (14%; 95% CI, 4%-25%) than in the general population. CONCLUSIONS AND RELEVANCE All eyes with retinopathy due to IP should be monitored throughout adulthood for the development of retinal complications. During infancy and early childhood, ophthalmoscopic examination should be performed frequently so that prompt treatment can be initiated if there is progressive disease. Because of the nonrandomized nature of this study, the indications for prophylactic ablation and its success rate remain uncertain. Patients with less than 6 months of follow-up were excluded from the analysis, which could have biased this study cohort toward patients with more severe or less severe disease.