Dirk Uwe Bartsch

Choroidal Volume Variations with Age, Axial Length, and Sex in Healthy Subjects: A Three-Dimensional Analysis

PURPOSE To demonstrate the 3-dimensional choroidal volume distribution in healthy subjects using enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with age, sex, and axial length. DESIGN Retrospective case series. PARTICIPANTS A total of 176 eyes from 114 subjects with no retinal or choroidal disease. METHODS The EDI SD-OCT imaging studies of healthy patients who had undergone a 31-raster scanning protocol on a commercial SD-OCT device were reviewed. Manual segmentation of the choroid was performed by 2 retinal specialists. A macular choroidal volume map and 3-dimensional topography were automatically created by the built-in software of the device. Mean choroidal volume was calculated for each Early Treatment Diabetic Retinopathy Study (ETDRS) subfield. Regression analyses were used to evaluate the correlation between macular choroidal volume and age, sex, and axial length. MAIN OUTCOME MEASURES Three-dimensional topography and ETDRS-style volume map of the choroid. RESULTS Three-dimensional topography of the choroid and volume map was obtained in all cases. The mean choroidal volume was 0.228 ± 0.077 mm(3) for the center ring and 7.374 ± 2.181 mm(3) for the total ETDRS grid. The nasal quadrant showed the lowest choroidal volume, and the superior quadrant showed the highest choroidal volume. The temporal and inferior quadrants did not show different choroidal volume values. Choroidal volume in all the EDTRS rings was significantly correlated with axial length after adjustment for age (P < 0.0001), age after adjustment for axial length (P < 0.0001), and sex after adjustment for axial length (P < 0.05). Choroidal volume decreases by 0.54 mm(3) (7.32%) for every decade and by 0.56 mm(3) (7.59%) for every millimeter of axial length. Male subjects have a 7.37% greater choroidal volume compared with that of female subjects. CONCLUSIONS Enhanced depth imaging SD-OCT is a noninvasive and well-tolerated procedure with an excellent ability to visualize 3-dimensional topography of the choroid and to measure choroidal volume at the posterior pole using manual segmentation. Age and axial length are inversely correlated with choroidal volume, most likely leading to changes in retinal metabolic support in elderly, highly myopic patients. Sexual differences should be considered when interpreting an EDI SD-OCT scan of the choroid. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Repeatability and Reproducibility of Manual Choroidal Volume Measurements Using Enhanced Depth Imaging Optical Coherence Tomography

PURPOSE To evaluate the repeatability and reproducibility of manual choroidal volume (CV) measurements by spectral domain- optical coherence tomography (SD-OCT) using enhanced depth imaging (EDI). METHODS Sixty eyes of 32 patients with or without any ocular chorioretinal diseases were enrolled prospectively. Thirty-one choroidal scans were performed on each eye, centered at the fovea, using a raster protocol. Two masked observers demarcated choroidal boundaries by using built-in automated retinal segmentation software on two separate sessions. Observers were masked to each others and their own previous readings. A standardized grid centered on the fovea was positioned automatically by OCT software, and values for average CVs and total CVs in three concentric rings were noted. The agreement between the intraobserver measurements or interobserver measurements was assessed using the concordance correlation coefficient (CCC). Bland-Altman plots were used to assess the clinically relevant magnitude of differences between inter- and intraobserver measurements. RESULTS The interobserver CCC for the overall average CV was very high, 0.9956 (95% confidence interval [CI], 0.991-0.9968). CCCs for all three Early Treatment Diabetic Retinopathy Study concentric rings between two graders was 0.98 to 0.99 (95% CI, 0.97-0.98). Similarly intraobserver repeatability of two graders also ranged from 0.98 to 0.99. The interobserver coefficient of reproducibility was approximately 0.42 (95% CI, 0.34-0.5 mm(3)) for the average CV. CONCLUSIONS CV measurement by manual segmentation using built-in automated retinal segmentation software on EDI-SD-OCT is highly reproducible and repeatable and has a very small range of variability.

Evaluation of microvascularization pattern visibility in human choroidal melanomas: comparison of confocal fluorescein with indocyanine green angiography

Abstract · Background: The presence of specific microvascularization patterns (networks, parallel with and without crosslinking, silent) in histological sections of human choroidal melanomas has prognostic significance for survival. We showed previously in selected patients that the identification of these microvascularization patterns is possible in vivo by using confocal scanning laser indocyanine green angiography and that this technique is superior to fluorescein angiography using a conventional acquisition technique with a fundus camera. We now routinely use simultaneous confocal fluorescein/indocyanine green angiography to study microvascularization patterns in choroidal melanomas. The purpose of this study was to compare the visibility of tumor vessels and microvascularization patterns in fluorescein and indocyanine green angiography in simultaneous confocal series taken with the same instrument in a large prospective series of patients. · Patients and methods: The simultaneously procured confocal fluorescein and indocyanine green angiograms of 50 patients with untreated choroidal melanomas (maximal apical height according to standardized A-scan between 2 and 8 mm) were studied for the visibility of tumor vessels and microvascularization patterns. At least one simultaneous confocal optical series (32 images in sequential depth order) during the early arterial venous phase was obtained per patient. · Results: Confocal forescein angiography disclosed signs of tumor vascularization in 12 (24%) of the 50 patients examined. However, in only 3 patients (6%) could microvascularization patterns be identified using confocal fluorescein angiography, and only in the very early arterial phase, which is often difficult to capture. In contrast, simultaneously obtained confocal indocyanine green angiograms disclosed tumor vessels in 47 (94%) of the examined 50 patients and microvascularization patterns could be identified in all of these cases. In 3 patients (6%) no tumor vessels could be detected within the tumor borders. · Conclusion: This study demonstrates that confocal indocyanine green angiography images microvascularization patterns in choroidal melanomas better than fluorescein angiography, even when the images are acquired with the same technique. This can be explained with the different absorption, fluorescence and exudation characteristics of these dyes. In vivo imaging of these microvascularization patterns using confocal indocyanine green angiography offers the possibility of assessing the prognosis of choroidal melanomas without the removal of tissue.

A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration

Late-onset retinal macular degeneration (L-ORD) is an autosomal dominant inherited disorder caused by a single missense mutation (S163R) in the CTRP5/C1QTNF5 protein. Early phenotypic features of L-ORD include: dark adaptation abnormalities, nyctalopia, and drusen deposits in the peripheral macular region. Apart from posterior segment abnormalities, these patients also develop abnormally long anterior lens zonules. In the sixth decade of life the rod and cone function declines, accompanied by electroretinogram (ERG) abnormalities. Some patients also develop choroidal neovascularization and glaucoma. In order to understand the disease pathology and mechanisms involved in retinal dystrophy, we generated a knock-in (Ctrp5(+/-)) mouse model carrying the disease-associated mutation in the mouse Ctrp5/C1QTNF5 gene. These mice develop slower rod-b wave recovery consistent with early dark adaptation abnormalities, accumulation of hyperautofluorescence spots, retinal pigment epithelium abnormalities, drusen, Bruchs membrane abnormalities, loss of photoreceptors, and retinal vascular leakage. The Ctrp5(+/-) mice, which have most of the pathological features of age-related macular degeneration, are unique and may serve as a valuable model both to understand the molecular pathology of late-onset retinal degeneration and to evaluate therapies.

Accuracy of the Heidelberg Spectralis in the alignment between near-infrared image and tomographic scan in a model eye: a multicenter study

PURPOSE To evaluate temporal changes and predictors of accuracy in the alignment between simultaneous near-infrared image and optical coherence tomography (OCT) scan on the Heidelberg Spectralis using a model eye. DESIGN Laboratory investigation. METHODS After calibrating the device, 6 sites performed weekly testing of the alignment for 12 weeks using a model eye. The maximum error was compared with multiple variables to evaluate predictors of inaccurate alignment. Variables included the number of weekly scanned patients, total number of OCT scans and B-scans performed, room temperature and its variation, and working time of the scanning laser. A 4-week extension study was subsequently performed to analyze short-term changes in the alignment. RESULTS The average maximum error in the alignment was 15 ± 6 μm; the greatest error was 35 μm. The error increased significantly at week 1 (P = .01), specifically after the second imaging study (P < .05); reached a maximum after the eighth patient (P < .001); and then varied randomly over time. Predictors for inaccurate alignment were temperature variation and scans per patient (P < .001). For each 1 unit of increase in temperature variation, the estimated increase in maximum error was 1.26 μm. For the average number of scans per patient, each increase of 1 unit increased the error by 0.34 μm. CONCLUSION Overall, the accuracy of the Heidelberg Spectralis was excellent. The greatest error happened in the first week after calibration, and specifically after the second imaging study. To improve the accuracy, room temperature should be kept stable and unnecessary scans should be avoided. The alignment of the device does not need to be checked on a regular basis in the clinical setting, but it should be checked after every other patient for more precise research purposes.

Assessment of retinal function in patients with HIV without infectious retinitis by multifocal electroretinogram and automated perimetry.

Purpose: To determine if multifocal electroretinogram (mfERG) testing shows abnormalities that correspond to perimetric defects in HIV positive patients without infectious retinitis. Methods: We studied three groups of patients: HIV negative controls, HIV high CD4 nadir patients (lowest CD4 T cell count is over 100) and low CD4 nadir patients (below 100 for over 6 months). Twenty-six HIV positive eyes and 16 HIV negative control eyes were studied by mfERG. A subset of 10 eyes also underwent computerized perimetry for comparison. We analyzed mfERG by hexagons as well as by quadrants and rings. Results: Of 103 hexagon locations there was no significant difference in the amplitudes P1 and N1 (nV/degree2) between the three studied groups (p>0.05), similarly, the latencies were not different (p>0.05). All eyes with significant visual field defects at the 0.01 and 0.005 level (Humphrey pattern deviation; 24-2) were compared to mfERG amplitudes and latencies at those locations–there were no corresponding defects in mfERG data (p>0.2). Conclusion: In the era of HAART there are still demonstrable visual field defects and other evidence of damage to the retinal nerve fiber layer in HIV patients. Our mfERG studies show that the damage appears to affect the inner retina, the outer retina is spared. Further studies of inner retinal structure and function are indicated to elucidate this process.

Visual Function Assessment in Simulated Real-Life Situations in HIV-Infected Subjects

Visual function abnormalities are common in people living with HIV disease (PLWH) without retinitis, even after improvement in immune status. Abnormalities such as reduced contrast sensitivity, altered color vision, peripheral visual field loss, and electrophysiological changes are related to a combination of retinal dysfunctions, involving inner and outer retinal structures. The standard protocol for testing vision performance in clinical practice is the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. However, this method poorly correlates with activities of daily living that require patients to assess visual stimuli in multiple light/contrast conditions, and with limited time. We utilized a novel interactive computer program (Central Vision Analyzer) to analyze vision performance in PLWH under a variety of light/contrast conditions that simulate stressful and real-world environments. The program tests vision in a time-dependent way that we believe better correlates with daily living activities than the non-timed ETDRS chart. We also aimed to correlate visual scores with retinal neuro-fiber layer thickness on optical coherence tomography. Here we show that visual acuity is more affected in PLWH in comparison to HIV-seronegative controls in varying contrast and luminance, especially if the nadir CD4+ T-cell count was lower than 100 cells/mm3. Visual impairment reflects the loss of retinal nerve fiber layer thickness especially of the temporal-inferior sector. In PLWH the ETDRS chart test led to better visual acuity compared to the Central Vision Analyzer equivalent test, likely because patients had indefinite time to guess the letters. This study confirms and strengthens the finding that visual function is affected in PLWH even in absence of retinitis, since we found that the HIV serostatus is the best predictor of visual loss. The Central Vision Analyzer may be useful in the diagnosis of subclinical HIV-associated visual loss in multiple light/contrast conditions, and may offer better understanding of this entity called “neuroretinal disorder”.

Imaging the microcirculation of untreated and treated human choroidal melanomas.

Introduction: Histologically demonstrable microcirculation patterns (microcirculation pattern) of human choroidal melanomas have prognostic significance for the patient. We report on our experience in imaging these microcirculation pattern in vivo using simultaneous confocal Fluorescein (FA)- and Indocyaninegreen (ICG) angiography before and after brachytherapy. Patients and methods: The simultaneously procured confocal FA- and ICG angiograms of 50 patients with untreated choroidal melanomas were studied for the visibility of microcirculation pattern. Patients were also followed with simultaneous FA/ICG after brachytherapy. Results: Confocal FA disclosed signs of tumor vascularization in 12 (24%) of the 50 examined patients but microcirculation pattern only in 3 patients (6%). In contrast, simultaneously obtained confocal ICG disclosed microcirculation pattern in 47 patients (94%). In 10 (77%) of the 13 patients the tumor microcirculation changed considerably after brachytherapy: Distortion, thickening, thinning, as well as complete obliteration of vessels could be observed. Conclusion: Histologically demonstrated microcirculation pattern can be imaged in vivo. This offers the possibility to assess the likely biologic behavior of the individual tumor without the need for obtaining a cytologic or histologic specimen via enucleation or fine-needle biopsy. Confocal ICG angiogiography images microcirculation pattern better than FA which can be explained by the different absorption-, fluorescence- and exudation-characteristics ICG. Follow-up with confocal ICG of choroidal melanomas after brachytherapy shows different features and allows for visualization of the micro-circulation reaction to the treatment which might be a useful tool for studying the effects of future anti-angiogenesis based tumor therapies.

Fluorescent infrared scanning-laser ophthalmoscope for three-dimensional visualization: automatic random-eye-motion correction and deconvolution.

Scanning-laser ophthalmoscope (SLO) technology has provided, among other possibilities, the potential for three-dimensional (3-D) visualization of anatomy in the posterior pole of the eye. The use of indocyanine green (ICG) as an infrared fluorescent marker of vasculature in combination with aninfrared SLO (the Heidelberg Retina Angiograph) is presented. Presently, two main factors among others discussed impede the visualization of 3-D structures in observed SLO data. Random eye motion between optical sections and (to a lesser degree) motion between raster scan lines prevent assessment of spatial orientation and connectivity of vasculature. Second, smear along the optic axis owing to the optics prevents accurate determination of vessel or lesion size and shape, especially for features spanning several optical sections. A novel, to our knowledge, deconvolution algorithm is described that automatically corrects for the poor axial (optical-sectioning) resolution of the SLO and for patient random eye motion during target fixation. Encouraging preliminary results are presented showing the usefulness of applying blind deconvolution toward improving the 3-D clarity of SLO data. Although clinical and medical research applications are broad, the specific medical sample selected shows the potential of examining microvascular 3-D morphology for diagnosis and treatment of choroidal tumors.

A new objective digital computerized vision screening system.

PURPOSE Fewer than 40% of children in the crucial younger-than-4 age group are evaluated for visual problems by pediatricians. This is due to impracticality from either a clinical or practice efficiency standpoint. Current photoscreening methods require trained readers and suffer from significant subjectivity and interobserver variability. We report a cross-sectional, double-masked study using new digital imaging with objective, automated, computerized image analysis. METHODS Two-hundred six children aged 9 months to 16 years were prospectively studied in a University-based pediatric ophthalmology practice. Images were taken by volunteers with a modified digital camera which, when downloaded, were analyzed within 35 seconds by new image analysis software. The analysis was compared to a masked review of a complete pediatric ophthalmic exam. RESULTS Overall agreement between physician and the objective computerized analysis was 86.9%. Positive predictive value was 91%, sensitivity was 89%, and specificity was 83%. CONCLUSIONS This automated digital imaging screening system eliminates human bias and provides accurate and immediate results. The system requires no special expertise.