Mary K. Durbin

Glaucoma Diagnostic Accuracy of Ganglion Cell–Inner Plexiform Layer Thickness: Comparison with Nerve Fiber Layer and Optic Nerve Head

PURPOSE To determine the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness measured with the Cirrus high-definition optical coherence tomography (HD-OCT) ganglion cell analysis (GCA) algorithm (Carl Zeiss Meditec, Dublin, CA) to discriminate normal eyes and eyes with early glaucoma and to compare it with that of peripapillary retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) measurements. DESIGN Evaluation of diagnostic test or technology. PARTICIPANTS Fifty-eight patients with early glaucoma and 99 age-matched normal subjects. METHODS Macular GCIPL and peripapillary RNFL thicknesses and ONH parameters were measured in each participant, and their diagnostic abilities were compared. MAIN OUTCOME MEASURES Area under the curve (AUC) of the receiver operating characteristic. RESULTS The GCIPL parameters with the best AUCs were the minimum (0.959), inferotemporal (0.956), average (0.935), superotemporal (0.919), and inferior sector (0.918). There were no significant differences between these AUCs and those of inferior quadrant (0.939), average (0.936), and superior quadrant RNFL (0.933); vertical cup-to-disc diameter ratio (0.962); cup-to-disc area ratio (0.933); and rim area (0.910), all P>0.05. CONCLUSIONS The ability of macular GCIPL parameters to discriminate normal eyes and eyes with early glaucoma is high and comparable to that of the best peripapillary RNFL and ONH parameters. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis

Post-mortem ganglion cell dropout has been observed in multiple sclerosis; however, longitudinal in vivo assessment of retinal neuronal layers following acute optic neuritis remains largely unexplored. Peripapillary retinal nerve fibre layer thickness, measured by optical coherence tomography, has been proposed as an outcome measure in studies of neuroprotective agents in multiple sclerosis, yet potential swelling during the acute stages of optic neuritis may confound baseline measurements. The objective of this study was to ascertain whether patients with multiple sclerosis or neuromyelitis optica develop retinal neuronal layer pathology following acute optic neuritis, and to systematically characterize such changes in vivo over time. Spectral domain optical coherence tomography imaging, including automated retinal layer segmentation, was performed serially in 20 participants during the acute phase of optic neuritis, and again 3 and 6 months later. Imaging was performed cross-sectionally in 98 multiple sclerosis participants, 22 neuromyelitis optica participants and 72 healthy controls. Neuronal thinning was observed in the ganglion cell layer of eyes affected by acute optic neuritis 3 and 6 months after onset (P < 0.001). Baseline ganglion cell layer thicknesses did not demonstrate swelling when compared with contralateral unaffected eyes, whereas peripapillary retinal nerve fibre layer oedema was observed in affected eyes (P = 0.008) and subsequently thinned over the course of this study. Ganglion cell layer thickness was lower in both participants with multiple sclerosis and participants with neuromyelitis optica, with and without a history of optic neuritis, when compared with healthy controls (P < 0.001) and correlated with visual function. Of all patient groups investigated, those with neuromyelitis optica and a history of optic neuritis exhibited the greatest reduction in ganglion cell layer thickness. Results from our in vivo longitudinal study demonstrate retinal neuronal layer thinning following acute optic neuritis, corroborating the hypothesis that axonal injury may cause neuronal pathology in multiple sclerosis. Further, these data provide evidence of subclinical disease activity, in both participants with multiple sclerosis and with neuromyelitis optica without a history of optic neuritis, a disease in which subclinical disease activity has not been widely appreciated. No pathology was seen in the inner or outer nuclear layers of eyes with optic neuritis, suggesting that retrograde degeneration after optic neuritis may not extend into the deeper retinal layers. The subsequent thinning of the ganglion cell layer following acute optic neuritis, in the absence of evidence of baseline swelling, suggests the potential utility of quantitative optical coherence tomography retinal layer segmentation to monitor neuroprotective effects of novel agents in therapeutic trials.

Reproducibility of peripapillary retinal nerve fiber layer thickness and optic nerve head parameters measured with cirrus HD-OCT in glaucomatous eyes.

PURPOSE To assess the reproducibility of peripapillary retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) parameters measured with Cirrus HD-OCT in glaucomatous eyes. METHODS Fifty-five glaucomatous eyes were included in the study. The optic disc cube 200 × 200 protocol was used to obtain three scans during the same visit to evaluate the intravisit reproducibility. One scan on 4 additional days within a 2-month period of the first session was obtained to assess intervisit reproducibility. Intraclass correlation coefficient (ICC), coefficient of variation (CV), and test-retest SD (TRT SD) were calculated for each RNFL and ONH parameter. The formula 1.645 × √2 × intervisit TRT SD provides an upper tolerance limit to variability beyond which nonphysiologic change should be considered. RESULTS All ICCs were excellent, ranging from 83.9% to 99.2% for intravisit measurements and from 80.8% to 99.1% for intervisit measurements. Cup/disc area ratio had the lowest CV (1.1%) in either type of measurement, followed by average RNFL thickness (1.9% and 2.7%). Nasal clock hours and quadrants showed the poorest reproducibility as did the clock hour directly temporally. The intervisit tolerance limit for average RNFL thickness was 3.89 μm. CONCLUSIONS Intravisit and intervisit measurements of peripapillary RNFL thickness and ONH parameters with Cirrus HD-OCT showed excellent reproducibility, indicating that this instrument may be useful in monitoring glaucoma progression. When comparing two measurements from the same eye on two different visits, a reproducible decrease in average RNFL thickness of approximately 4 μm or more may be considered a statistically significant change from baseline.

Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness

Background: Post-mortem analyses of multiple sclerosis (MS) eyes demonstrate prominent retinal neuronal ganglion cell layer (GCL) loss, in addition to related axonal retinal nerve fiber layer (RNFL) loss. Despite this, clinical correlations of retinal neuronal layers remain largely unexplored in MS. Objectives: To determine if MS patients exhibit in vivo retinal neuronal GCL loss, deeper retinal neuronal loss, and investigate correlations between retinal layer thicknesses, MS clinical subtype and validated clinical measures. Methods: Cirrus HD-optical coherence tomography (OCT), utilizing automated intra-retinal layer segmentation, was performed in 132 MS patients and 78 healthy controls. MS classification, Expanded Disability Status Scale (EDSS) and visual function were recorded in study subjects. Results: GCL+inner plexiform layer (GCIP) was thinner in relapsing–remitting MS (RRMS; n = 96, 71.6 µm), secondary progressive MS (SPMS; n = 20, 66.4 µm) and primary progressive MS (PPMS; n = 16, 74.1 µm) than in healthy controls (81.8 µm; p < 0.001 for all). GCIP thickness was most decreased in SPMS, and although GCIP thickness correlated significantly with disease duration, after adjusting for this, GCIP thickness remained significantly lower in SPMS than RRMS. GCIP thickness correlated significantly, and better than RNFL thickness, with EDSS, high-contrast, 2.5% low-contrast and 1.25% low-contrast letter acuity in MS. 13.6% of patients also demonstrated inner or outer nuclear layer thinning. Conclusions: OCT segmentation demonstrates in vivo GCIP thinning in all MS subtypes. GCIP thickness demonstrates better structure-function correlations (with vision and disability) in MS than RNFL thickness. In addition to commonly observed RNFL/GCIP thinning, retinal inner and outer nuclear layer thinning occur in MS.

Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis.

OBJECTIVE To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS). DESIGN Cross-sectional study. SETTING Johns Hopkins University, Baltimore, Maryland. PARTICIPANTS A total of 84 patients with MS and 24 healthy control subjects. MAIN OUTCOME MEASURES High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes. RESULTS Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer+inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P=.01 and P=.04, respectively) and caudate (P=.04 and P=.03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P=.007) and inversely associated with normal-appearing white matter volume (P=.005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning.

ABSTRACT Objective: To determine the effect of clinical and radiologic disease activity on the rate of thinning of the ganglion cell/inner plexiform (GCIP) layer and the retinal nerve fiber layer in patients with multiple sclerosis (MS) using optical coherence tomography (OCT). Methods: One hundred sixty-four patients with MS and 59 healthy controls underwent spectral-domain OCT scans every 6 months for a mean follow-up period of 21.1 months. Baseline and annual contrast-enhanced brain MRIs were performed. Patients who developed optic neuritis during follow-up were excluded from analysis. Results: Patients with the following features of disease activity during follow-up had faster rates of annualized GCIP thinning: relapses (42% faster, p = 0.007), new gadolinium-enhancing lesions (54% faster, p < 0.001), and new T2 lesions (36% faster, p = 0.02). Annual GCIP thinning was 37% faster in those with disability progression during follow-up, and 43% faster in those with disease duration <5 years vs >5 years (p = 0.003). Annual rates of GCIP thinning were highest in patients exhibiting combinations of new gadolinium-enhancing lesions, new T2 lesions, and disease duration <5 years (70% faster in patients with vs without all 3 characteristics, p < 0.001). Conclusions: MS patients with clinical and/or radiologic nonocular disease activity, particularly early in the disease course, exhibit accelerated GCIP thinning. Our findings suggest that retinal changes in MS reflect global CNS processes, and that OCT-derived GCIP thickness measures may have utility as an outcome measure for assessing neuroprotective agents, particularly in early, active MS.

Spatial distribution of posterior pole choroidal thickness by spectral domain optical coherence tomography.

PURPOSE To study the spatial distribution of posterior pole choroidal thickness (CT) in healthy eyes using spectral domain optical coherence tomography (SD-OCT). METHODS Fifty-nine eyes from 30 subjects with no retinal or choroidal disease were examined with high-definition (HD) OCT using macular volume cube scanning protocols. A randomly chosen subset also had multifield analysis performed (volume scans centered on and surrounding the optic nerve head [ONH]). CT was manually quantified using a validated reading center tool. For macular scans, mean CT was calculated for each Early Treatment Diabetic Retinopathy Study subfield. Compound posterior pole CT maps were also created through the alignment of OCT projection images. Regression analyses were used to evaluate the correlation between CT and axial length (AL), refractive error, age, sex, and ethnicity. RESULTS Subfoveal CT was 297.8 ± 82.2 μm, which did not differ significantly from that of the inner macular subfields. CT was greatest in the superior outer subfield and thinnest in the nasal outer subfield. The most predictive models for macular CT included AL and/or age. Outside the macula, CT was thinnest inferonasal to the ONH. CONCLUSIONS CT demonstrates large variations between individuals, but also at different locations within the posterior pole; substantial choroidal thinning inferonasal to the ONH was demonstrated. CT appears to correlate more with distance from the optic nerve than from the fovea and, thus, in future studies, the ONH may serve as a better reference point than the foveal center for expressing or depicting regional CT variations.

Swept-source OCT angiography of the retinal vasculature using intensity differentiation-based optical microangiography algorithms.

BACKGROUND AND OBJECTIVE To demonstrate the feasibility of using a 1,050-nm swept-source optical coherence tomography (SS-OCT) system to achieve noninvasive retinal vasculature imaging in human eyes. MATERIALS AND METHODS Volumetric data sets were acquired using a 1-µm SS-OCT prototype that operated at a 100-kHz A-line rate. A scanning protocol designed to allow for motion contrast processing, referred to as OCT angiography or optical microangiography (OMAG), was used to scan an approximately 3 × 3–mm area in the central macular region of the retina within approximately 4.5 seconds. An intensity differentiation-based OMAG algorithm was used to extract three-dimensional retinal functional microvasculature information. RESULTS Intensity signal differentiation generated capillary-level resolution en face OMAG images of the retina. The parafoveal capillaries were clearly visible, thereby allowing visualization of the foveal avascular zone in healthy subjects. CONCLUSION The capability of OMAG to produce retinal vascular images was demonstrated using the 1-µm SS-OCT prototype. This technique has potential clinical value for studying retinal vasculature abnormalities.

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.