Gadi Wollstein

Detection of Macular Ganglion Cell Loss in Glaucoma by Fourier-Domain Optical Coherence Tomography

PURPOSE To map ganglion cell complex (GCC) thickness with high-speed Fourier-domain optical coherence tomography (FD-OCT) and compute novel macular parameters for glaucoma diagnosis. DESIGN Observational, cross-sectional study. PARTICIPANTS One hundred seventy-eight participants in the Advanced Imaging for Glaucoma Study, divided into 3 groups: 65 persons in the normal group, 78 in the perimetric glaucoma group (PG), and 52 in the preperimetric glaucoma group (PPG). METHODS The RTVue FD-OCT system was used to map the macula over a 7 x 6 mm region. The macular OCT images were exported for automatic segmentation using software we developed. The program measured macular retinal (MR) thickness and GCC thickness. The GCC was defined as the combination of nerve fiber, ganglion cell, and inner plexiform layers. Pattern analysis was applied to the GCC map and the diagnostic powers of pattern-based diagnostic parameters were investigated. Results were compared with time-domain (TD) Stratus OCT measurements of MR and circumpapillary nerve fiber layer (NFL) thickness. MAIN OUTCOME MEASURES Repeatability was assessed by intraclass correlation, pooled standard deviation, and coefficient of variation. Diagnostic power was assessed by the area under the receiver operator characteristic (AROC) curve. Measurements in the PG group were the primary measures of performance. RESULTS The FD-OCT measurements of MR and GCC averages had significantly better repeatability than TD-OCT measurements of MR and NFL averages. The FD-OCT GCC average had significantly (P = 0.02) higher diagnostic power (AROC = 0.90) than MR (AROC = 0.85 for both FD-OCT and TD-OCT) in differentiating between PG and normal. One GCC pattern parameter, global loss volume, had significantly higher AROC (0.92) than the overall average (P = 0.01). The diagnostic powers of the best GCC parameters were statistically equal to TD-OCT NFL average. CONCLUSIONS The higher speed and resolution of FD-OCT improved the repeatability of macular imaging compared with standard TD-OCT. Ganglion cell mapping and pattern analysis improved diagnostic power. The improved diagnostic power of macular GCC imaging is on par with, and complementary to, peripapillary NFL imaging. Macular imaging with FD-OCT is a useful method for glaucoma diagnosis and has potential for tracking glaucoma progression.

Optical Coherence Tomography Measurement of Macular and Nerve Fiber Layer Thickness in Normal and Glaucomatous Human Eyes

PURPOSE To evaluate the hypothesis that macular thickness correlates with the diagnosis of glaucoma. DESIGN Cross-sectional study. PARTICIPANTS We studied 367 subjects (534 eyes), including 166 eyes of 109 normal subjects, 83 eyes of 58 glaucoma suspects, 196 eyes of 132 early glaucoma patients, and 89 eyes of 68 advanced glaucoma patients. METHODS We used optical coherence tomography (OCT) to measure macular and nerve fiber layer (NFL) thickness and to analyze their correlation with each other and with glaucoma status. We used both the commercial and prototype OCT units and evaluated correspondence between measurements performed on the same eyes on the same days. MAIN OUTCOME MEASURE Macular and NFL thickness as measured by OCT. RESULTS All NFL parameters both in prototype and commercial OCT units were statistically significantly different comparing normal subjects and either early or advanced glaucoma (P < 0.001). Inner ring, outer ring, and mean macular thickness both in prototype and commercial OCT devices were found to be significantly different between normal subjects and advanced glaucomatous eyes (P < 0.001). The outer ring was the only macular parameter that could significantly differentiate between normal and early glaucoma with either the prototype or commercial OCT unit (P = 0.003, P = 0.008, respectively). The area under the receiver operator characteristic (AROC) curves comparing mean NFL thickness between normal and advanced glaucomatous eyes was 1.00 for both the prototype and commercial OCT devices for eyes scanned on both machines on the same day. The AROC comparing mean macular thickness in normal and advanced glaucomatous eyes scanned on both machines on the same day was 0.88 for the prototype OCT device and 0.80 for the commercial OCT. CONCLUSIONS Both macular and NFL thickness as measured by OCT showed statistically significant correlations with glaucoma, although NFL thickness showed a stronger association than macular thickness. There was good correspondence between findings using both the prototype and commercial OCT units. Macular and NFL thickness measurements made with OCT may have usefulness in the clinical assessment of glaucoma.

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Comparison of optic nerve head measurements obtained by optical coherence tomography and confocal scanning laser ophthalmoscopy.

PURPOSE To evaluate the relationship between optic nerve head (ONH) measurements generated by optical coherence tomography (OCT; versions 2 and 3) and confocal scanning laser ophthalmoscopy (CSLO) and to compare the association between OCT and CSLO ONH measurements with glaucoma disease status, as determined by clinical evaluation and perimetry. DESIGN Cross-sectional study. METHODS In a prospective study in the glaucoma service of an academic department of ophthalmology, 159 eyes (97 subjects) and 77 eyes (44 subjects) were recruited in two separate periods. All subjects were scanned with a CSLO device. Subjects tested within the first period of recruitment were scanned with OCT version 2 and in the second period with OCT version 3. The main outcome measure was the correlation between automatic and manually defined OCT ONH measurements and the correlation of CSLO and OCT ONH measurements between devices and with glaucoma disease status. RESULTS A high correlation was found between ONH measurements obtained by the automatic determination of ONH margin and those obtained by manual tracing of the disk margin (r =.93 to.98). Optical coherence tomography and CSLO ONH measurements were highly correlated. Optical coherence tomography-measured mean disk area was significantly larger than that measured by CSLO, as were all other disk size-related parameters. The areas under the receiver operator characteristic (AROC) curves for the associations between CSLO and OCT ONH measurements and clinical diagnosis were found to be similar and in the range of 0.47 to 0.79 for both devices. CONCLUSIONS Automated OCT ONH measurements correlate highly with those obtained by manual tracing of disk margin. Optical coherence tomography and CSLO ONH analyses are highly correlated and have similar associations with glaucoma disease status.

Optical Coherence Tomography: History, Current Status, and Laboratory Work

Optical coherence tomography (OCT) imaging has become widespread in ophthalmology over the past 15 years, because of its ability to visualize ocular structures at high resolution. This article reviews the history of OCT imaging of the eye, its current status, and the laboratory work that is driving the future of the technology.

Effects of Age on Optical Coherence Tomography Measurements of Healthy Retinal Nerve Fiber Layer, Macula, and Optic Nerve Head

PURPOSE To determine the effects of age on global and sectoral peripapillary retinal nerve fiber layer (RNFL), macular thicknesses, and optic nerve head (ONH) parameters in healthy subjects using optical coherence tomography (OCT). DESIGN Retrospective, cross-sectional observational study. PARTICIPANTS A total of 226 eyes from 124 healthy subjects were included. METHODS Healthy subjects were scanned using the Fast RNFL, Fast Macula, and Fast ONH scan patterns on a Stratus OCT (Carl Zeiss Meditec, Dublin, CA). All global and sectoral RNFL and macular parameters and global ONH parameters were modeled in terms of age using linear mixed effects models. Normalized slopes were also calculated by dividing the slopes by the mean value of the OCT parameter for interparameter comparison. MAIN OUTCOME MEASURES Slope of each OCT parameter across age. RESULTS All global and sectoral RNFL thickness parameters statistically significantly decreased with increasing age, except for the temporal quadrant and clock hours 8 to 10, which were not statistically different from a slope of zero. Highest absolute slopes were in the inferior and superior quadrant RNFL and clock hour 1 (superior nasal). Normalized slopes showed a similar rate in all sectors except for the temporal clock hours (8-10). All macular thickness parameters statistically significantly decreased with increasing age, except for the central fovea sector, which had a slight positive slope that was not statistically significant. The nasal outer sector had the greatest absolute slope. Normalized macular slope in the outer ring was similar to the normalized slopes in the RNFL. Normalized inner ring had shallower slope than the outer ring with a similar rate in all quadrants. Disc area remained nearly constant across the ages, but cup area increased and rim area decreased with age, both of which were statistically significant. CONCLUSIONS Global and regional changes caused by the effects of age on RNFL, macula, and ONH OCT measurements should be considered when assessing eyes over time. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Retinal nerve fibre layer thickness measurement reproducibility improved with spectral domain optical coherence tomography

Background/aims: To investigate retinal nerve fibre layer (RNFL) thickness measurement reproducibility using conventional time-domain optical coherence tomography (TD-OCT) and spectral-domain OCT (SD-OCT), and to evaluate two methods defining the optic nerve head (ONH) centring: Centred Each Time (CET) vs Centred Once (CO), in terms of RNFL thickness measurement variability on SD-OCT. Methods: Twenty-seven eyes (14 healthy subjects) had three circumpapillary scans with TD-OCT and three raster scans (three-dimensional or 3D image data) around ONH with SD-OCT. SD-OCT images were analysed in two ways: (1) CET: ONH centre was defined on each image separately and (2) CO: ONH centre was defined on one image and exported to other images after scan registration. After defining the ONH centre, a 3.4 mm diameter virtual circular OCT was resampled on SD-OCT images to mimic the conventional circumpapillary RNFL thickness measurements taken with TD-OCT. Results: CET and CO showed statistically significantly better reproducibility than TD-OCT except for 11:00 with CET. CET and CO methods showed similar reproducibility. Conclusions: SD-OCT 3D cube data generally showed better RNFL measurement reproducibility than TD-OCT. The choice of ONH centring methods did not affect RNFL measurement reproducibility.

OCT for glaucoma diagnosis, screening and detection of glaucoma progression

Optical coherence tomography (OCT) is a commonly used imaging modality in the evaluation of glaucomatous damage. The commercially available spectral domain (SD)-OCT offers benefits in glaucoma assessment over the earlier generation of time domain-OCT due to increased axial resolution, faster scanning speeds and has been reported to have improved reproducibility but similar diagnostic accuracy. The capabilities of SD-OCT are rapidly advancing with 3D imaging, reproducible registration, and advanced segmentation algorithms of macular and optic nerve head regions. A review of the evidence to date suggests that retinal nerve fibre layer remains the dominant parameter for glaucoma diagnosis and detection of progression while initial studies of macular and optic nerve head parameters have shown promising results. SD-OCT still currently lacks the diagnostic performance for glaucoma screening.

Variation in optic nerve and macular structure with age and race with spectral-domain optical coherence tomography.

PURPOSE To evaluate the effects of age and race on optic disc, retinal nerve fiber layer (RNFL), and macular measurements with spectral-domain optical coherence tomography (SD OCT). DESIGN Cross-sectional observational study. PARTICIPANTS Three hundred fifty adult subjects without ocular disease. METHODS Data from SD OCT imaging of the optic nerve head, peripapillary RNFL, and macula of 632 eyes from 350 subjects without ocular disease were imaged with SD OCT. Multivariate models were used to determine the effect of age and race on quantitative measurements of optic disc, RNFL, and macula. MAIN OUTCOME MEASURES Optic nerve, RNFL, and macular measurements with SD OCT across racial strata and age. RESULTS For optic nerve parameters, participants of European descent had significantly smaller optic disc area than other groups (P<0.0001), and Indian participants had significantly smaller rim area than other groups (P<0.0001). Indian and Hispanic participants had thicker global RNFL measurements than other groups (P<0.0001). Participants of African descent were associated with thinner inner retinal thickness in the macula (P<0.0001). Age was associated with several parameters, with rim area reducing by 0.005 mm(2)/year, RNFL thickness reducing by 0.18 μm/year, and inner retinal thickness reducing by 0.1 μm/year (P<0.0001 for all age associations). CONCLUSIONS Optic nerve, RNFL, and macular measurements with SD OCT all varied across racial groups and with age. These differences are important in defining the range of normal variation in differing populations and should be considered in the use of these instruments in the detection of optic nerve and macular disease across these population groups. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Identification and Assessment of Schlemm's Canal by Spectral-Domain Optical Coherence Tomography

PURPOSE Measurements of human Schlemms canal (SC) have been limited to histologic sections. The purpose of this study was to demonstrate noninvasive measurements of aqueous outflow (AO) structures in the human eye, examining regional variation in cross-sectional SC areas (on/off collector channel [CC] ostia [SC/CC] and nasal/temporal) in the eyes of living humans. METHODS SC was imaged by spectral-domain optical coherence tomography with a 200-nm bandwidth light source. Both eyes of 21 healthy subjects and one glaucomatous eye of three subjects were imaged nasally and temporally. Contrast and magnification were adjusted to maximize visualization. Cross-sectional SC on and off SC/CC was traced three times by two independent masked observers using ImageJ (ImageJ 1.40g, http://rsb.info.nih.gov/ij/ Wayne Rasband, developer, National Institutes of Health, Bethesda, MD). The mean SC area was recorded. A linear mixed-effects model was used to analyze eye, nasal/temporal laterality, and SC area on or off SC/CC. RESULTS SC area was significantly larger on SC/CCs than off (12,890 vs. 7,391 micorm(2), P < 0.0001) and was significantly larger on the nasal side than on the temporal (10,983 vs. 8,308 micorm(2), P = 0.009). SC areas were significantly smaller in glaucoma patients than in normal subjects, whether pooled (P = 0.0073) or grouped by on (P = 0.0215) or off (P = 0.0114) SC/CC. CONCLUSIONS Aqueous outflow structures, including SC and CCs, can be noninvasively assessed in the human eye. These measurements will be useful in physiological studies of AO and will be clinically useful in the determination of the impact of glaucoma therapies on IOP as well as presurgical planning.