Noriko Nakano

A novel method to detect local ganglion cell loss in early glaucoma using spectral-domain optical coherence tomography.

PURPOSE To test the glaucoma-discriminating ability of a new method for detecting local ganglion cell loss using spectral-domain optical coherence tomography (OCT). METHODS This study included 58 glaucomatous and 48 healthy eyes from Japanese subjects. Combined thickness of the ganglion cell layer and inner plexus layer (GCIPL) was measured on a macular cube scan in Cirrus HD-OCT. Average GCIPL thickness within a macular elliptical annulus and minimum GCIPL thickness on 360 spokes extending from the inner to the outer radius of the elliptical annulus were calculated. Area under the receiver operating characteristic curve (AROC) to discriminate between healthy eyes and early (mean deviation [MD], ≥-6 dB)/advanced (MD, <-6 dB) glaucomatous were compared between parameters. RESULTS Forty-three were normal-tension glaucoma, and 15 were high-tension glaucoma. The mean minimum GCIPL thickness was 77.0 μm in healthy eyes and 60.6 μm in glaucomatous eyes (P < 0.001). For the intersession repeatability, the coefficients of variation for average GCIPL and minimum GCIPL were 0.98 and 1.85 in glaucomatous eyes, and 0.89 and 1.85 in healthy eyes, respectively. Minimum GCIPL thickness AROC (0.896) was significantly higher (P = 0.0062) than average GCIPL thickness (0.821) for early glaucoma, whereas minimum GCIPL AROC (0.991) was comparable (P = 0.103) to average GCIPL (0.964) for advanced glaucoma. The minimum GCIPL thickness AROC was comparable (P = 0.861) to average circumpapillary retinal nerve fiber layer (cpRNFL) thickness (0.890) for early glaucoma. CONCLUSIONS In Japanese patients with 74.1% of normal-tension glaucoma, the minimum GCIPL on spokes may be useful for detecting early glaucoma.

Macular Ganglion Cell Layer Imaging in Preperimetric Glaucoma with Speckle Noise–Reduced Spectral Domain Optical Coherence Tomography

OBJECTIVE To visualize the macular ganglion cell layer (GCL) and measure its thickness in normal eyes and eyes with preperimetric glaucoma, using speckle noise-reduced spectral domain optical coherence tomography (SD-OCT). DESIGN Retrospective consecutive case series. PARTICIPANTS Thirty-seven eyes of 37 patients with preperimetric glaucoma and 39 normal eyes of 39 volunteers. METHODS Vertical and horizontal SD-OCT B-scan images were acquired with minimal speckle noise by using eye-tracking to obtain and average 50 B-scans at each identical location of interest. B-scan images were manually analyzed for GCL, retinal nerve fiber layer (RNFL), and inner plexiform layer shapes and thicknesses in the macula. MAIN OUTCOME MEASURES Macular GCL images and thickness in normal eyes and in eyes with preperimetric glaucoma. RESULTS The macular GCL was clearly seen on speckle noise-reduced SD-OCT images in normal eyes and eyes with preperimetric glaucoma. In each eye with preperimetric glaucoma, thinning of the macular GCL was visually apparent, particularly on vertical scans. The mean regional macular GCL was most severely thinned in the inferior perifoveal region, where its thickness was <70% of its normal thickness in 30 (81.1%) of the 37 eyes and <50% of its normal thickness in 13 (35.1%) of the 37 eyes. When the sensitivity and specificity for detecting abnormal thinning (outside the lower limit of 99% confidence interval [CI] for the means in the 39 normal eyes) in at least one 0.5-mm segment or sector were compared, the macular GCL on vertical B-scans exhibited higher sensitivity (81.1%) than the other layers on vertical B-scans (99% CI, 5.4%-59.5%; P = 0.00075-0.02100), the macular GCL (99% CI, 40.5%; P = 0.00027) on horizontal B-scans, the other layers (99% CI, 5.4%-48.6%; P<0.00048-0.00400) on horizontal B-scans, and circumpapillary RNFL automatically measured on SD-OCT (54.1%; P = 0.021), and scanning laser polarimetry with variable corneal compensation (24.3%; P = 0.00095). All the macular layers on both the vertical and horizontal B-scans and circumpapillary RNFL thickness exhibited comparable specificity (91.4-100.0%, statistically not different). CONCLUSIONS Speckle noise-reduced SD-OCT imaging allowed clear visualization and measurement of the macular GCL, which was severely thinned in eyes with preperimetric glaucoma. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Longitudinal and Simultaneous Imaging of Retinal Ganglion Cells and Inner Retinal Layers in a Mouse Model of Glaucoma Induced by N-Methyl-D-Aspartate

PURPOSE To investigate the longitudinal profile of N-methyl-D-aspartate (NMDA) injection-induced damage in retinal ganglion cells (RGCs) by imaging retinal Thy 1-cyan fluorescent protein (CFP) expression and inner retinal layers using a custom-made imaging device containing short-wavelength confocal scanning laser ophthalmoscope (scSLO) and speckle noise-reduced spectral-domain optical coherence tomography (SD-OCT). METHODS Simultaneous scSLO and SD-OCT examinations were performed in Thy 1-CFP mice injected with NMDA (1-20 nanomoles). CFP-expressing RGCs were counted using scSLO images. Ganglion cell complex (GCC: retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer) thickness around the optic disc was measured in SD-OCT images. RESULTS The RGCs rapidly decreased 1 day after NMDA injection in a dose-dependent manner (65.3%, 71.7%, 49.5%, and 27.1% of the preinjection level, 2, 5, 10, and 20 nanomoles, respectively) and continued to decrease slightly (to 53.7%, 44.1%, 28.3%, and 20.2% of the preinjection level on days 14, 2, 5, 10, and 20 nanomoles, respectively). In contrast, dose-dependent reduction of GCC thickness was first detected 4 days after injection. The thickness further decreased to 84.6%, 75.7%, 76.5%, and 71.4% of the preinjection level on day 14 (2, 5, 10, and 20 nanomoles, respectively). CONCLUSIONS NMDA-induced RGC damage is characterized by rapid RGCs loss followed by gradual reduction in GCC thickness. Simultaneous imaging of CFP expression in the RGCs and inner retinal layers provides a sensitive, reliable, and new method for longitudinal evaluation of progressive RGC damage in experimental models of glaucoma.

Detection of localized retinal nerve fiber layer defects in glaucoma using enhanced spectral-domain optical coherence tomography.

OBJECTIVE To compare retinal nerve fiber layer (RNFL) defects on fundus photographs with circumpapillary RNFL (cpRNFL) thinning or disruption on images obtained by speckle-noise-reduced spectral-domain optical coherence tomography (enhanced SD OCT), single-scan SD OCT, and single-scan time-domain OCT (TD OCT). DESIGN Retrospective, comparative case series. PARTICIPANTS Forty-four eyes of 44 patients with open-angle glaucoma with localized, wedge-shaped RNFL defects on red-free photographs and 35 normal eyes of 35 volunteers. METHODS Cross-sectional images of the cpRNFL and cpRNFL thinning, compared with the confidence interval limit of the normative database where the RNFL defect was photographically identified, were compared between the 3 types of OCT instruments: enhanced SD OCT (SD OCT with eye tracking and averaging of 16 images at the same location to reduce speckle noise; Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany), single-scan SD OCT (RTVue-100; Optovue, Fremont, CA), and single-scan TD OCT (Stratus; Carl Zeiss-Meditec, Dublin, CA). MAIN OUTCOME MEASURES Cross-sectional images of localized RNFL defects on red-free fundus photographs, sensitivity for detecting the photographic RNFL defect, and sensitivity and specificity for detecting glaucoma as having at least 1 abnormally thinned sector on the cpRNFL thickness map on OCT. RESULTS Among the 44 eyes with glaucoma, 65 RNFL defects were identified on red-free fundus photographs. The cpRNFL boundaries were clearer on enhanced SD OCT images than on single-scan SD OCT or TD OCT images, particularly in regions corresponding to the RNFL defects. Enhanced SD OCT revealed various degrees of cpRNFL thinning, and disruption of cpRNFL reflectivity was seen in the same location as the photographic RNFL defect for 23 (35.4%) of the 65 RNFL defects. The RNFL defects were significantly less likely to be detected by single-scan TD OCT or SD OCT (P = 0.002 and P = 0.006, respectively) when the RNFL was not disrupted. Enhanced SD OCT was more sensitive in detecting the RNFL defects that were not disrupted compared with single-scan TD OCT (P<0.0001) or SD OCT (P<0.0001). Enhanced SD OCT had better sensitivity and specificity for detecting glaucoma compared with single-scan TD OCT or SD OCT (sensitivity, P = 0.006 and P = 0.001; specificity, P = 0.001 and P = 0.004, respectively). CONCLUSIONS These results suggest that speckle-noise reduction can improve the detection of photographic RNFL defects in which cpRNFL reflectivity on OCT images is not disrupted. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Alterations in the Neural and Connective Tissue Components of Glaucomatous Cupping After Glaucoma Surgery Using Swept-Source Optical Coherence Tomography

PURPOSE To visualize changes in deep optic nerve head (ONH) structures following glaucoma surgery using (3-dimensional [3D]) swept-source optical coherence tomography (SS-OCT) and to determine the clinical and structural factors associated with postoperative lamina cribrosa (LC) and prelaminar neural tissue (PLT) changes. METHODS In this prospective observational case series, SS-OCT thin-sliced datasets of the ONH covering a 3- × 3-mm area comprised of 256 B-scans (interval between scans = ∼12 μm) were obtained before and 3 months after the surgery and evaluated in 73 eyes of 73 patients with glaucoma. Bruchs membrane opening (BMO) and anterior LC boundary were manually delineated by two methods; one in every four B-scans (64 B-scans per eye) and 15 equally spaced horizontal B-scans in BMO area, excluding both ends (interval between scans = 96-120 μm). After former delineation, the point with maximum LC depth among 64 B-scans was automatically calculated, and LC depth and PLT thickness were averaged among 5 points adding 4 points 100 μm apart from this point vertically and horizontally. Associations between the percent change in LC depth and other clinical and structural parameters were tested for statistical analysis. RESULTS Lamina cribrosa depth and axial length significantly decreased and PLT thickness significantly increased after surgery. The percent change of maximum LC depth correlated significantly with the percent change of IOP (P = 0.008), baseline LC depth (P = 0.032), and visual field mean deviation (P = 0.035; at the point with maximum LC depth), while the percent change of axial length correlated with IOP reduction (P = 0.002) but not with visual field mean deviation. CONCLUSIONS Swept-source optical coherence tomography enables 3D analysis of deep ONH structures, and the change in LC depth after glaucoma surgery have association with IOP change and the severity of glaucomatous optic neuropathy.

Wide 3-dimensional macular ganglion cell complex imaging with spectral-domain optical coherence tomography in glaucoma.

PURPOSE To determine whether measurement of ganglion cell complex (GCC) thickness over a wide area (8-mm diameter) can improve the glaucoma-discriminating ability of spectral-domain optical coherence tomography (SD-OCT) compared to that in the standard macular area (6-mm diameter). METHODS Ninety-three subjects were enrolled, including 46 healthy eyes of 46 volunteers and 47 eyes of 47 glaucoma patients (23 eyes with preperimetric glaucoma [PPG] and 24 eyes with early glaucoma [EG]). All patients underwent SD-OCT raster scanning over a 9 mm × 9 mm square area centered on the fovea. Areas under the receiver operating characteristic curves (AROCs) were compared between wide sector (1-8-mm ring) and standard-size sector (1-6-mm ring) charts. RESULTS AROCs for average GCC thickness in the wide chart were significantly greater than those of the standard chart in eyes with PPG (0.928 vs. 0.891; P = 0.038), EG (0.912 vs. 0.861; P = 0.003), and both (0.920 vs. 0.876; P = 0.004). Overall, the AROCs of regional GCC thicknesses were nearly comparable between the middle ring (4-6 mm) and outer ring (6-8 mm). Coefficients of variation were 0.68% and 0.97% in the standard and wide sector charts, respectively, in eyes with PPG, and 0.45% and 0.72% in the standard and wide sector charts, respectively, in eyes with EG. CONCLUSIONS Addition of the GCC thickness outside the macula to the standard macular GCC thickness significantly increased the glaucoma-discriminating ability of SD-OCT.

Real-Time Imaging of Rabbit Retina with Retinal Degeneration by Using Spectral-Domain Optical Coherence Tomography

Background Recently, a transgenic rabbit with rhodopsin Pro 347 Leu mutation was generated as a model of retinitis pigmentosa (RP), which is characterized by a gradual loss of vision due to photoreceptor degeneration. The purpose of the current study is to noninvasively visualize and assess time-dependent changes in the retinal structures of a rabbit model of retinal degeneration by using speckle noise-reduced spectral-domain optical coherence tomography (SD-OCT). Methodology/Principal Findings Wild type (WT) and RP rabbits (aged 4–20 weeks) were investigated using SD-OCT. The total retinal thickness in RP rabbits decreased with age. The thickness of the outer nuclear layer (ONL) and between the external limiting membrane and Bruchs membrane (ELM–BM) were reduced in RP rabbits around the visual streak, compared to WT rabbits even at 4 weeks of age, and the differences increased with age. However, inner nuclear layer (INL) thickness in RP rabbits did not differ from that of WT during the observation period. The ganglion cell complex (GCC) thickness in RP rabbits increased near the optic nerve head but not around the visual streak in the later stages of the observation period. Hyper-reflective change was widely observed in the inner segments (IS) and outer segments (OS) of the photoreceptors in the OCT images of RP rabbits. Ultrastructural findings in RP retinas included the appearance of small rhodopsin-containing vesicles scattered in the extracellular space around the photoreceptors. Conclusions/Significance In the current study, SD-OCT provided the pattern of photoreceptor degeneration in RP rabbits and the longitudinal changes in each retinal layer through the evaluation of identical areas over time. The time-dependent changes in the retinal structure of RP rabbits showed regional and time-stage variations. In vivo imaging of RP rabbit retinas by using SD-OCT is a powerful method for characterizing disease dynamics and for assessing the therapeutic effects of experimental interventions.

Frequency-doubling technology and retinal measurements with spectral-domain optical coherence tomography in preperimetric glaucoma.

BackgroundTo determine the relationship between visual fields and retinal structures measured with spectral-domain optical coherence tomography in preperimetric glaucoma (PPG).MethodsTwenty-six eyes of 26 patients with PPG and 20 healthy eyes of 20 volunteers were included. All patients underwent Heidelberg retina tomography-2 (HRT2), standard automated perimetry (SAP), frequency-doubling technology (FDT) perimetry, and RTVue-100. SAP and FDT indices, HRT parameters, and circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex (mGCC) thicknesses were correlated using Pearson’s test. Areas under the receiver operating characteristic curves (AUROCs) and sensitivity/specificity based on each parameter’s definition of abnormalities were compared between parameters.ResultsSignificant differences were found in FDT-MD, FDT-PSD, SAP-PSD, cpRNFL, and mGCC parameters (p < 0.001–0.015), but not in SAP-MD or HRT parameters, between PPG and control groups. Significant correlations were not found between visual field indices and structural parameters, except between FDT-MD and HRT rim area (r = 0.450, p = 0.021) and between FDT-PSD and temporal cpRNFL thickness (r = 0.402, p = 0.021). AUROCs for cpRNFL (p = 0.0047–0.033) and mGCC (p = 0.0082–0.049) parameters were significantly better than those of HRT parameters, whereas significant differences were not found between FDT indices and cpRNFL or mGCC parameters or between cpRNFL and mGCC parameters. Adding average cpRNFL or mGCC thickness to FDT-MD significantly increased sensitivity compared to single parameters (p = 0.016–0.031).ConclusionsStructural and functional parameters were poorly correlated but complementary for glaucoma detection in PPG. Combining these parameters may improve PPG diagnosis.

Asymmetry Analysis of Macular Inner Retinal Layers for Glaucoma Diagnosis

PURPOSE To determine if asymmetry in thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer, ganglion cell complex, and total retina between upper and lower macula halves can predict glaucoma. DESIGN Retrospective case-control series. METHODS One hundred twenty-two eyes of 122 patients (30 normal eyes and 30 preperimetric, 31 early, and 31 advanced glaucoma eyes) were studied. The RNFL, ganglion cell layer, ganglion cell complex, and total retina were segmented and measured on 10 vertical B-scans over a 30 × 15 degree macular area. The equation asymmetry index =|log10 (lower hemiretinal thickness/upper hemiretinal thickness)| was used to calculate asymmetry indices for 8 pairs of upper and lower 0.5-mm segments equidistant from the fovea on each scan. Areas under the receiver operating characteristic curve (AROCs) for mean thickness and mean asymmetry index of 10 B-scans were compared. RESULTS The overlap in values for normal and glaucomatous eyes was minimal for the ganglion cell layer asymmetry index. Thickness parameters decreased with the severity of glaucoma, whereas asymmetry indices did not. AROCs for thickness measurements tended to increase with increasing glaucoma severity (preperimetric, 0.746-0.808; early, 0.842-0.940; advanced, 0.943-0.995), whereas AROCs for asymmetry indices did not have distinct ranges according to glaucoma severity (advanced, 0.819-0.996; early, 0.861-0.998; preperimetric, 0.773-0.994). The AROC for the ganglion cell layer asymmetry index remained almost perfect regardless of glaucoma severity (0.994-0.998). CONCLUSIONS Macular retinal layer thickness asymmetry indices, particularly for the ganglion cell layer, show promise as early indicators of glaucomatous retinal damage.

Biometric Features of Peripapillary Atrophy Beta in Eyes with High Myopia

PURPOSE To evaluate peripapillary atrophy β (PPA-β) characteristics in highly myopic eyes, using simultaneous confocal scanning laser ophthalmoscopy (cSLO) and enhanced spectral-domain optical coherence tomography (SD-OCT). METHODS The authors retrospectively analyzed 61 highly myopic (≥ -6.0 D) eyes without myopic retinopathy. cSLO fundus images were used to measure the distances from the foveal center to the temporal and nasal margins of the PPA-β zone; horizontal cross-sectional SD-OCT images, to determine the position where the inner plexiform layer (IPL) terminates within the PPA-β zone; and A-mode ultrasonography, to measure axial length. RESULTS The distance from the foveal center to the PPA-β zone temporal margin (2.68-4.39 mm) correlated with the circumferential extent of PPA-β (P <0.001, r = -0.49). The distance from the foveal center to the nasal margin (3.41-5.60 mm) correlated with the ovality index of the optic disc (P <0.001, r = -0.51) and with the axial length (P <0.05, r = 0.26). PPA-β zone width (0.20-2.05 mm) correlated with the circumferential extent of PPA-β (P <0.001, r = 0.42), ovality index of the optic disc (P <0.001, r = -0.68), and axial length (P <0.05, r = 0.32). The IPL termination within the PPA-β zone was significantly closer to the optic disc when the circumferential extent of PPA-β was large (P <0.01, r = 0.36). CONCLUSIONS Interindividual variations in biometric features of PPA-β in highly myopic eyes showed different associations with axial length, degree of disc ovality, and circumferential extent of PPA-β.