Joe L. Wheat

Linking Structure and Function in Glaucoma

The glaucomas are a group of relatively common optic neuropathies, in which the pathological loss of retinal ganglion cells causes a progressive loss of sight and associated alterations in the retinal nerve fiber layer and optic nerve head. The diagnosis and management of glaucoma are often dependent on methods of clinical testing that either, 1) identify and quantify patterns of functional visual abnormality, or 2) quantify structural abnormality in the retinal nerve fiber layer, both of which are caused by loss of retinal ganglion cells. Although it is evident that the abnormalities in structure and function should be correlated, propositions to link losses in structure and function in glaucoma have been formulated only recently. The present report describes an attempt to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structure-function model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease.

Age-Related Losses of Retinal Ganglion Cells and Axons

PURPOSE Age-related losses in retinal nerve fiber layer (RNFL) thickness have been assumed to be the result of an age-dependent reduction of retinal ganglion cells (RGCs), but the published rates differ: age-related losses of RGCs of approximately 0.6%/year compared to 0.2%/year for thinning of the RNFL. An analysis of normative data for standard automated perimetry (SAP) sensitivities and optical coherence tomography (OCT) measures of RNFL thickness showed that the apparent disagreement in age-dependent losses of RGCs and axons in the RNFL can be reconciled by an age-dependent decrease in the proportion of the RNFL thickness that is composed of axons. The purpose of the present study was to determine whether the mechanisms of age-related losses that were suggested by the normative data can be confirmed with data from healthy, normal eyes. METHODS Data were obtained from visual fields (normal results in a Glaucoma Hemifield Test [GHT] on standard automated perimetry [SAP] 24-2 fields) and RNFL thickness measurements (standard OCT scan) of 55 patients (age range, 18-80 years; mean, 44.5 +/- 17.3). The SAP measures of visual sensitivity and OCT measures of RNFL thickness for one eye of each patient were used to estimate neuron counts by each procedure. RESULTS The age-related thinning of RNFL was 0.27%/year when a constant axon density was used to derive axon counts from RNFL thickness, compared with 0.50%/year for the age-related loss of RGCs from SAP. In agreement with the model developed with normative clinical data, concordance between losses of axons and soma was achieved by an age-dependent reduction of 0.46%/year in the density of axons in the RNFL. CONCLUSIONS The results suggest that the proportion of RNFL that is composed of RGC axons is not constant with age; rather, the proportion of the total thickness from non-neuronal tissue increases with age. If a similar compensation occurs in the RNFL thickness with axon loss from glaucoma, then a stage-dependent correction to translate OCT measurements to neuronal components is needed, in addition to the age-dependent correction.

Retinal Nerve Fiber Layer Assessment: Area versus Thickness Measurements from Elliptical Scans Centered on the Optic Nerve

PURPOSE An evaluation of the retinal nerve fiber layer (RNFL) provides important information on the health of the optic nerve. Standard measurements of the RNFL consider only thickness, but an accurate assessment should also consider axial length, size of the optic nerve head (ONH), blood vessel contribution, and distance of the scan from the ONH margin. In addition, although most primate ONHs are elliptical, the circular scan centered on the ONH is the mainstay in both clinical and research analyses. The purpose of this study was to evaluate thickness and area measures of RNFL cross sections when axial length and ONH shape are included. METHODS Circular, raster, and radial scans of left eye optic nerves were acquired from 40 normal rhesus monkeys (Macaca mulatta) using spectral domain optical coherence tomography. The disc margin was identified by manually selecting the RPE/Bruchs membrane opening and ONH border tissue. With a pixel-to-micrometer conversion computed from a three-surface schematic eye, RNFL scans were interpolated at 300 to 600 μm (50-μm increments) from the edge of the ONH. The thickness and area of the RNFL at each distance were obtained by custom programs. Blood vessels in the RNFL were selected and removed from the overall RNFL measures. RESULTS The average RNFL thickness decreased systematically from 149 ± 12.0 μm for scans 300 μm from the disc margin to 113 ± 7.2 μm at an eccentricity of 600 μm (P < 0.05). In contrast, the cross-sectional areas of the RNFL did not vary with scan location from the disc margin (0.85 ± 0.07 mm(2) at 300 μm compared with 0.86 ± 0.06 mm(2) at 600 μm). Blood vessels accounted for 9.3% of total RNFL thickness or area, but varied with retinal location. On average, 17.6% of the superior and 14.2% of the inferior RNFL was vascular, whereas blood vessels accounted for only 2.3% of areas of the temporal and nasal RNFL regions. CONCLUSIONS In nonhuman primates, with appropriate transverse scaling and ONH shape analysis, the cross-sectional area of the RNFL is independent of scan distance, up to 600 μm from the rim margin, indicating that the axonal composition changes little over this range. The results suggest that, with incorporation of transverse scaling, the RNFL cross-sectional area, rather than RNFL thickness, provides an accurate assessment of the retinal ganglion cell axonal content within the eye.

Agreement between Retinal Nerve Fiber Layer Measures from Spectralis and Cirrus Spectral Domain OCT

Purpose. An assessment of the retinal nerve fiber layer (RNFL) provides important information on the health of the optic nerve. There are several non-invasive technologies, including spectral domain optical coherence tomography (SD OCT), that can be used for in vivo imaging and quantification of the RNFL, but often there is disagreement in RNFL thickness between clinical instruments. The purpose of this study was to investigate the influence of scan centration, ocular magnification, and segmentation on the degree of agreement of RNFL thickness measures by two SD OCT instruments. Methods. RNFL scans were acquired from 45 normal eyes using two commercially available SD OCT systems. Agreement between RNFL thickness measures was determined using each instruments algorithm for segmentation and a custom algorithm for segmentation. The custom algorithm included ocular biometry measures to compute the transverse scaling for each eye. Major retinal vessels were identified and removed from RNFL measures in 1:1 scaled images. Transverse scaling was also used to compute the RNFL area for each scan. Results. Instrument-derived global RNFL thickness measured from the two instruments correlated well (R2 = 0.70, p < 0.01) but with significant differences between instruments (mean of 6.7 &mgr;m; 95% limits of agreement of 16.0 &mgr;m to −2.5 &mgr;m, intraclass correlation coefficient = 0.62). For recentered scans with custom RNFL segmentation, the mean difference was reduced to 0.1 &mgr;m (95% limits of agreement 6.1 to −5.8 &mgr;m, intraclass correlation coefficient = 0.92). Global RNFL thickness was related to axial length (R2 = 0.24, p < 0.01), whereas global RNFL area measures were not (R2 = 0.004, p = 0.66). Major retinal vasculature accounted for 11.3 ± 1.6% (Cirrus) or 11.8 ± 1.4% (Spectralis) of the RNFL thickness/area measures. Conclusions. Sources of disagreement in RNFL measures between SD-OCT instruments can be attributed to the location of the scan path and differences in their retinal layer segmentation algorithms. In normal eyes, the major retinal vasculature accounts for a significant percentage of the RNFL and is similar between instruments. With incorporation of an individuals ocular biometry, RNFL area measures are independent of axial length, with either instrument.

Correlating RNFL Thickness by OCT with Perimetric Sensitivity in Glaucoma Patients

PurposeTo determine whether a structure-function model developed for normal age-related losses of retinal ganglion cells also models the retinal ganglion cell losses in glaucomatous optic neuropathy. MethodsThe model to relate age-related loss of retinal nerve fiber layer thickness and reduced sensitivity for standard automated perimetry was evaluated with data from 30 glaucoma patients and 40 normal individuals. Perimetry thresholds were translated into separate retinal ganglion cell body estimates for test locations in the superior and inferior visual fields. The retinal nerve fiber layer thickness from optical coherence tomography was also divided into regions representing the superior and inferior hemifields to obtain estimates of the axons in each hemifield. The 2 estimates of retinal ganglion cell populations were compared for corresponding regions. ResultsAgreement between neural estimates was good for normal individuals and patients with early glaucomatous damage. Results for individuals with advanced glaucoma showed disparities between neural estimates that were proportional to the stage of disease. A correction factor for the stage of disease was introduced for the derivation of ganglion cell populations from the nerve fiber layer measurements, which produced agreement between the optical coherence tomography and perimetric estimates for all patients. ConclusionsThe modified structure-function model provided well-correlated relationships between the subjective measures of visual sensitivity and the objective measures of retinal nerve fiber layer thickness when parameters for the patients age and the severity of the disease were included. The results suggest constitutive relationships between structure and function for the full spectrum of normal-to-advanced glaucomatous neuropathy.