Karen B. Schaal

OUTER RETINAL TUBULATION IN ADVANCED AGE-RELATED MACULAR DEGENERATION: Optical Coherence Tomographic Findings Correspond to Histology.

Purpose: To compare optical coherence tomography (OCT) and histology of outer retinal tubulation (ORT) secondary to advanced age-related macular degeneration in patients and in postmortem specimens, with particular attention to the basis of the hyperreflective border of ORT. Method: A private referral practice (imaging) and an academic research laboratory (histology) collaborated on two retrospective case series. High-resolution OCT raster scans of 43 eyes (34 patients) manifesting ORT secondary to advanced age-related macular degeneration were compared to high-resolution histologic sections through the fovea and superior perifovea of donor eyes (13 atrophic age-related macular degeneration and 40 neovascular age-related macular degeneration) preserved ⩽4 hours after death. Results: Outer retinal tubulation seen on OCT correlated with histologic findings of tubular structures consisted largely of cones lacking outer segments and lacking inner segments. Four phases of cone degeneration were histologically distinguishable in ORT lumenal walls, nascent, mature, degenerate, and end stage (inner segments and outer segments, inner segments only, no inner segments, and no photoreceptors and only Müller cells forming external limiting membrane, respectively). Mitochondria, which are normally long and bundled within inner segment ellipsoids, were small and scattered within shrunken inner segments and cell bodies of surviving cones. A lumenal border was delimited by an external limiting membrane. Outer retinal tubulation observed in closed and open configurations was distinguishable from cysts and photoreceptor islands on both OCT and histology. Hyperreflective lumenal material seen on OCT represents trapped retinal pigment epithelium and nonretinal pigment epithelium cells. Conclusion: The defining OCT features of ORT are location in the outer nuclear layer, a hyperreflective band differentiating it from cysts, and retinal pigment epithelium that is either dysmorphic or absent. Histologic and OCT findings of outer retinal tubulation corresponded in regard to composition, location, shape, and stages of formation. The reflectivity of ORT lumenal walls on OCT apparently does not require an outer segment or an inner/outer segment junction, indicating an independent reflectivity source, possibly mitochondria, in the inner segments.

ZEISS Angioplex™ Spectral Domain Optical Coherence Tomography Angiography: Technical Aspects

ZEISS Angioplex™ optical coherence tomography (OCT) angiography generates high-resolution three-dimensional maps of the retinal and choroidal microvasculature while retaining all of the capabilities of the existing CIRRUS™ HD-OCT Model 5000 instrument. Angioplex™ OCT angiographic imaging on the CIRRUS™ HD-OCT platform was made possible by increasing the scanning rate to 68,000 A-scans per second and introducing improved tracking software known as FastTrac™ retinal-tracking technology. The generation of en face microvascular flow images with Angioplex™ OCT uses an algorithm known as OCT microangiography-complex, which incorporates differences in both the phase and intensity information contained within sequential B-scans performed at the same position. Current scanning patterns for en face angiographic visualization include a 3 × 3 and a 6 × 6 mm scan pattern on the retina. A volumetric dataset showing erythrocyte flow information can then be displayed as a color-coded retinal depth map in which the microvasculature of the superficial, deep, and avascular layers of the retina are displayed together with the colors red, representing the superficial microvasculature; green, representing the deep retinal vasculature; and blue, representing any vessels present in the normally avascular outer retina. Each retinal layer can be viewed separately, and the microvascular layers representing the choriocapillaris and the remaining choroid can be viewed separately as well. In addition, readjusting the contours of the slabs to target different layers of interest can generate custom en face flow images. Moreover, each en face flow image is accompanied by an en face intensity image to help with the interpretation of the flow results. Current clinical experience with this technology would suggest that OCT angiography should replace fluorescein angiography for retinovascular diseases involving any area of the retina that can be currently scanned with the CIRRUS™ HD-OCT instrument and may replace fluorescein angiography and indocyanine green angiography for some choroidal vascular diseases.

Anatomic Clinical Trial Endpoints for Nonexudative Age-Related Macular Degeneration

TOPIC To review the role of anatomic endpoints in clinical trials for the study of nonexudative age-related macular degeneration (AMD) with an emphasis on a novel composite endpoint for the study of emerging therapies for intermediate AMD (iAMD). CLINICAL RELEVANCE Unlike clinical trials for exudative AMD, it is impractical to use the change in visual acuity (VA) as a primary endpoint for the study of nonexudative AMD. By the time VA has been lost in nonexudative AMD, proof-of-concept early-stage clinical trials would take years to run, and drug development would be a near impossible task. Surrogate endpoints are needed that reliably predict future vision loss and can be easily measured. Anatomic changes that correlate with disease progression in nonexudative AMD offer the greatest promise as primary endpoints. METHODS In preparation for this review, the electronic PubMed database was searched for relevant research pertaining to anatomic endpoints for the study of nonexudative AMD. Paper selection was based on our knowledge of the field with the goal to be as inclusive as possible. Whenever possible, recent review articles and results from large clinical trials, preferably with outcomes from many years of follow-up were favored over trials of short duration. RESULTS The most commonly used anatomic endpoint for the study of late, nonexudative AMD is the growth of geographic atrophy (GA). The advantages of studying GA include the appreciation that its enlargement through the foveal center leads to significant vision loss through the availability of natural history studies, the understanding that prevention of this growth would preserve vision in the future, the ability to reliably measure GA using different imaging strategies, and the development appropriate statistical tools that reliably predict the growth of GA over time. The major disadvantage of using GA is that significant, irreversible disease progression has already occurred. The use of drusen volume as a predictor of disease progression and the use of a composite endpoint that incorporates drusen growth, formation of GA, and formation of neovascularization offers an opportunity to study therapies at an earlier stage of AMD with a greater likelihood of preserving better vision over a lifetime. CONCLUSIONS Anatomic endpoints for the study of nonexudative AMD are needed to accelerate drug development, and the availability of optical coherence tomography algorithms capable of reliably measuring drusen morphology offer the best opportunity to study therapies for iAMD.

The Premacular Bursa's Shape Revealed In Vivo by Swept-Source Optical Coherence Tomography

OBJECTIVE To resolve the controversy surrounding the shape and relationship of posterior vitreous spaces by characterizing the connections between the premacular bursa, the area of Martegiani, and Cloquets canal. DESIGN Comprehensive posterior vitreous maps were created using swept-source optical coherence tomography (SS OCT) in a cross-sectional study. PARTICIPANTS The posterior vitreous of 102 eyes of 51 volunteers 21 to 54 years of age without ocular pathologic features was imaged using SS OCT. METHODS The DRI OCT-1 Atlantis 3D SS OCT (Topcon Medical Systems, Oakland, NJ) was used to acquire scans of the posterior vitreous over an 18×18-mm area. MAIN OUTCOME MEASURES Posterior vitreous spaces and their relationships were identified. RESULTS The premacular bursa was identified in all 102 eyes and was found to extend superiorly beyond our scanning ability at a variable angle. No discernible superior borders could be identified. Instead, a connection of the bursa with the preoptic area of Martegiani or its extension, Cloquets canal, was found in 101 of 102 eyes. This connection occurred at a variable distance from the optic nerve, where it formed a flat and broad superior channel. The skyward direction of this channel was found to be gravity dependent in all 14 eyes of the 7 subjects examined in various head positions. Although SS OCT was able to identify vitreous degeneration, the above changes were present in 28 eyes even without any discernible vitreous degeneration. CONCLUSIONS The premacular bursa, also called the posterior precortical vitreous pocket, was found to continue superiorly beyond the posterior pole without a detectable border. The bursa fused broadly with the extension of the preoptic area of Martegiani, namely Cloquets canal, or the hyaloidal tract of Eisner. These findings suggest that there is a direct anteroposterior connection between the retrolental and premacular and preoptic spaces already existent in the eyes of young adults before the occurrence of vitreous degeneration. This observation may have important implications with respect to the movement of intrinsic and extrinsic mediators between the anterior and posterior segments.

Comparison Between Spectral-Domain and Swept-Source Optical Coherence Tomography Angiographic Imaging of Choroidal Neovascularization

Purpose The purpose of this study was to compare imaging of choroidal neovascularization (CNV) using swept-source (SS) and spectral-domain (SD) optical coherence tomography angiography (OCTA). Methods Optical coherence tomography angiography was performed using a 100-kHz SS-OCT instrument and a 68-kHz SD-OCTA instrument (Carl Zeiss Meditec, Inc.). Both 3 × 3- and 6 × 6-mm2 scans were obtained on both instruments. The 3 × 3-mm2 SS-OCTA scans consisted of 300 A-scans per B-scan at 300 B-scan positions, and the SD-OCTA scans consisted of 245 A-scans at 245 B-scan positions. The 6 × 6-mm2 SS-OCTA scans consisted of 420 A-scans per B-scan at 420 B-scan positions, and the SD-OCTA scans consisted of 350 A-scans and 350 B-scan positions. B-scans were repeated four times at each position in the 3 × 3-mm2 scans and twice in the 6 × 6-mm2 scans. Choroidal neovascularization was excluded if not fully contained within the 3 × 3-mm2 scans. The same algorithm was used to detect CNV on both instruments. Two graders outlined the CNV, and the lesion areas were compared between instruments. Results Twenty-seven consecutive eyes from 23 patients were analyzed. For the 3 × 3-mm2 scans, the mean lesion areas for the SS-OCTA and SD-OCTA instruments were 1.17 and 1.01 mm2, respectively (P = 0.047). For the 6 × 6-mm2 scans, the mean lesion areas for the SS-OCTA and SD-OCTA instruments were 1.24 and 0.74 mm2 (P = 0.003). Conclusions The areas of CNV tended to be larger when imaged with SS-OCTA than with SD-OCTA, and this difference was greater for the 6 × 6-mm2 scans.

Automated Quantitation of Choroidal Neovascularization: A Comparison Study Between Spectral-Domain and Swept-Source OCT Angiograms

Purpose To compare the lesion sizes of choroidal neovascularization (CNV) imaged with spectral-domain (SD) and swept-source (SS) optical coherence tomography angiography (OCTA) and measured using an automated detection algorithm. Methods Patients diagnosed with CNV were imaged by SD-OCTA and SS-OCTA systems using 3 × 3-mm and 6 × 6-mm scans. The complex optical microangiography (OMAGC) algorithm was used to generate the OCTA images. Optical coherence tomography A datasets for imaging CNV were derived by segmenting from the outer retina to 8 μm below Bruchs membrane. An artifact removal algorithm was used to generate angiograms free of retinal vessel projection artifacts. An automated detection algorithm was developed to quantify the size of the CNV. Automated measurements were compared with manual measurements. Measurements from SD-OCTA and SS-OCTA instruments were compared as well. Results Twenty-seven eyes from 23 subjects diagnosed with CNV were analyzed. No significant differences were detected between manual and automatic measurements: SD-OCTA 3 × 3-mm (P = 0.61, paired t-test) and 6 × 6-mm (P = 0.09, paired t-test) scans and the SS-OCTA 3 × 3-mm (P = 0.41, paired t-test) and 6 × 6-mm (P = 0.16, paired t-test) scans. Bland-Altman analyses were performed to confirm the agreement between automatic and manual measurements. Mean lesion sizes were significantly larger for the SS-OCTA images compared with the SD-OCTA images: 3 × 3-mm scans (P = 0.011, paired sample t-test) and the 6 × 6-mm scans (P = 0.021, paired t-test). Conclusions The automated algorithm measurements of CNV were in agreement with the hand-drawn measurements. On average, automated SS-OCTA measurements were larger than SD-OCTA measurements and consistent with the results from using hand-drawn measurements.

Widefield En Face Optical Coherence Tomography Imaging of Subretinal Drusenoid Deposits

BACKGROUND AND OBJECTIVE To determine whether subretinal drusenoid deposits (SDD) can be detected on widefield en face slab images derived from spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT) volume scans. PATIENTS AND METHODS Retrospective study of patients with dry age-related macular degeneration (AMD) enrolled prospectively in an OCT imaging study using SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) with a central wavelength of 840 nm, and a prototype 100-kHz SS-OCT instrument (Carl Zeiss Meditec) with a central wavelength of 1,050 nm. Seven en face slabs were evaluated with thicknesses from 20 to 55 µm and positioned at distances up to 55 µm above the retinal pigment epithelium (RPE). A montage of 6 × 6 mm SD-OCT en face images of the posterior pole from each patient was compared with a 9 × 12 mm SS-OCT single en face slab image and with color, autofluorescence, and infrared reflectance images. RESULTS A total of 160 patients (256 eyes) underwent scanning with both OCT instruments; 57 patients (95 eyes) also underwent multimodal fundus imaging. Of 95 eyes, 32 (34%) were diagnosed with reticular pseudodrusen (RPD) using multimodal imaging. All eyes with RPD demonstrated a pattern of SDD on widefield en face OCT similar to that observed for RPD. The en face slab image that consistently identified SDD was the 20-µm thick slab with boundaries from 35 to 55 µm above the RPE. CONCLUSION Widefield en face slab imaging with SD-OCT and SS-OCT can detect SDD and could replace multimodal imaging for the diagnosis of RPD in the future.

Artifactual Flow Signals Within Drusen Detected by OCT Angiography.

BACKGROUND AND OBJECTIVE To demonstrate possible flow artifacts when imaging drusen with optical coherence tomography angiography (OCTA). PATIENTS AND METHODS Patients with drusen were enrolled in a prospective OCT study using the Zeiss AngioPlex OCTA instrument (Carl Zeiss Meditec, Dublin, CA). Two kinds of en face slabs were created for visualizing both structure and flow. The first slab followed the contour of Bruchs membrane. The second slab had an inner boundary following the retinal pigment epithelium (RPE) contour and an outer boundary following the contour of Bruchs membrane. The structure and flow signals from within the drusen were compared. RESULTS Eleven eyes of nine patients with age-related macular degeneration and drusen were imaged. In all 11 eyes, an artifactual flow signal was seen on the first slab where it intersected the RPE. This flow signal was a projection artifact from the overlying retinal vessels. The second slab did not show evidence of flow within drusen. CONCLUSION OCTA decorrelation projection artifacts can be misinterpreted as apparent flow within drusen if the slab region includes hyperreflective boundary layers such as the RPE. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:517-522.].

Choroidal thickness and choroidal vessel density in nonexudative age-related macular degeneration using swept-source optical coherence tomography imaging

Purpose To analyze the relationship between choroidal thickness and the distribution of choroidal blood vessels in eyes with nonexudative AMD. Methods Eyes with a diagnosis of nonexudative AMD were imaged using a prototype 100-kHz swept-source (SS) optical coherence tomography (OCT) instrument (Carl Zeiss Meditec, Dublin, CA, USA) with a central wavelength of 1050 nm. We used an OCT cube scan pattern consisting of 512 × 512 A-scans over a 12 × 12 mm retinal area. The eyes were partitioned into two groups based on the presence or absence of reticular pseudodrusen (RPD). All scans were segmented using an automated algorithm. In addition, five eyes from each of the two groups were randomly chosen for manual segmentation. Binary choroidal vessels maps were generated from suitable OCT choroidal slabs, and the relationship between the density of large choroidal vessels and choroidal thickness was analyzed using an Early Treatment Diabetic Retinopathy Study–like target centered on the fovea. Results Twenty-five eyes were enrolled in each group. The automated algorithm produced accurate choroidal thickness maps with an average difference between the manual and automated segmentations of 13.7 μm. There was a significant and stable correlation between choroidal thickness and choroidal vessel density across the two groups. Both average choroidal thickness and vessel density were significantly lower in eyes with RPD. Conclusions Our fully automated choroidal segmentation algorithm was able to capture the different patterns of choroidal thickness over a wide area. Choroidal thickness has a clear relationship with the density of large choroid vessels in our sample, irrespective of the presence or absence of RPD.

ASSOCIATION OF PREVASCULAR VITREOUS FISSURES AND CISTERNS WITH VITREOUS DEGENERATION AS ASSESSED BY SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY.

Purpose: To demonstrate the presence of prevascular vitreous fissures (PVF) and posterior vitreous cisterns in vivo and correlate with the degree of vitreous degeneration (VD). Methods: This was a cross-sectional study using Topcon Deep Range Imaging OCT-1 Atlantis 3D swept source optical coherence tomography for acquiring scans of posterior vitreous covering an 18 × 18-mm area in 104 eyes of 52 healthy volunteers without posterior vitreous detachment. Results: We observed that increasing age was associated with higher VD grades (P < 0.05). Prevascular vitreous fissures, characterized by areas of lower optical density overlying the retinal blood vessels, were identified in 93 (89%) eyes, and the presence of PVF correlated with lower VD grades (P < 0.05). Presence of cisterns correlated with higher VD grades (P < 0.05). All eyes with absence of PVF were found to have established cisterns. Prevascular vitreous fissures were connected with cisterns in 44 of the 71 (62%) eyes with cisterns, while the base of the cistern was directly above retinal blood vessels in 38 (54%) eyes, which suggests that the cisterns could be derived from PVF. Conclusion: Swept source optical coherence tomography imaging can identify PVF and cisterns occurring in the context of age-related VD, and PVF appeared to be possible precursors of cisterns.