Jonathan D. Oakley

Macular Ganglion Cell–Inner Plexiform Layer: Automated Detection and Thickness Reproducibility with Spectral Domain–Optical Coherence Tomography in Glaucoma

PURPOSE To demonstrate the capability of SD-OCT to measure macular retinal ganglion cell-inner plexiform layer (GCIPL) thickness and to assess its reproducibility in glaucomatous eyes. METHODS Fifty-one glaucomatous eyes (26 mild, 11 moderate, 14 severe) of 51 patients underwent macular scanning using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) macula 200×200 acquisition protocol. Five scans were obtained on 5 days within 2 months. The ganglion cell analysis (GCA) algorithm was used to detect the macular GCIPL and to measure the thickness of the overall average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal GCIPL. The reproducibility of the measurements was evaluated with intraclass correlation coefficients (ICCs), coefficients of variation (COVs), and test-retest standard deviations (TRTSDs). RESULTS Segmentation and measurement of GCIPL thickness were successful in 50 of 51 subjects. All ICCs ranged between 0.94 and 0.98, but ICCs for average and superior GCIPL parameters (0.97-0.98) were slightly higher than for inferior GCIPL parameters (0.94-0.97). All COVs were <5%, with 1.8% for average GCIPL and COVs for superior GCIPL parameters (2.2%-3.0%) slightly lower than those for inferior GCIPL parameters (2.5%-3.6%). The TRTSD was lowest for average GCIPL (1.16 μm) and varied from 1.43 to 2.15 μm for sectoral GCIPL CONCLUSIONS: The Cirrus HD-OCT GCA algorithm can successfully segment macular GCIPL and measure GCIPL thickness with excellent intervisit reproducibility. Longitudinal monitoring of GCIPL thickness may be possible with Cirrus HD-OCT for assessing glaucoma progression.

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.

Ability of Cirrus™ HD-OCT Optic Nerve Head Parameters to Discriminate Normal from Glaucomatous Eyes

PURPOSE To determine the ability of optic nerve head (ONH) parameters measured with spectral domain Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, CA) to discriminate between normal and glaucomatous eyes and to compare them with the discriminating ability of peripapillary retinal nerve fiber layer (RNFL) thickness measurements performed with Cirrus HD-OCT. DESIGN Evaluation of diagnostic test or technology. PARTICIPANTS Seventy-three subjects with glaucoma and 146 age-matched normal subjects. METHODS Peripapillary ONH parameters and RNFL thickness were measured in 1 randomly selected eye of each participant within a 200 × 200 pixel A-scan acquired with Cirrus HD-OCT centered on the ONH. MAIN OUTCOME MEASURES Optic nerve head topographic parameters, peripapillary RNFL thickness, and area under receiver operating characteristic curves (AUCs). RESULTS To distinguish normal from glaucomatous eyes, regardless of disease stage, the 6 best parameters (expressed as AUC) were vertical rim thickness (VRT, 0.963), rim area (0.962), RNFL thickness at clock-hour 7 (0.957), RNFL thickness of the inferior quadrant (0.953), vertical cup-to-disc ratio (VCDR, 0.951), and average RNFL thickness (0.950). The AUC for distinguishing between normal eyes and eyes with mild glaucoma was greatest for RNFL thickness of clock-hour 7 (0.918), VRT (0.914), rim area (0.912), RNFL thickness of inferior quadrant (0.895), average RNFL thickness (0.893), and VCDR (0.890). There were no statistically significant differences between AUCs for the best ONH parameters and RNFL thickness measurements (P > 0.05). CONCLUSIONS Cirrus HD-OCT ONH parameters are able to discriminate between normal eyes and eyes with glaucoma or even mild glaucoma. There is no difference in the ability of ONH parameters and RNFL thickness measurement, as measured with Cirrus OCT, to distinguish between normal and glaucomatous eyes.

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.

Comparison of automated analysis of cirrus HD OCT spectral-domain optical coherence tomography with stereo photographs of the optic disc

OBJECTIVE To evaluate a new automated analysis of optic disc images obtained by spectral-domain optical coherence tomography (SD OCT). Areas of the optic disc, cup, and neural rim in SD OCT images were compared with these areas from stereoscopic photographs to represent the current traditional optic nerve evaluation. The repeatability of measurements by each method was determined and compared. DESIGN Evaluation of diagnostic technology. PARTICIPANTS One hundred nineteen healthy eyes, 23 eyes with glaucoma, and 7 glaucoma suspect eyes. METHODS Optic disc and cup margins were traced from stereoscopic photographs by 3 individuals independently. Optic disc margins and rim widths were determined automatically in SD OCT. A subset of photographs was examined and traced a second time, and duplicate SD OCT images also were analyzed. MAIN OUTCOME MEASURES Agreement among photograph readers, between duplicate readings, and between SD OCT and photographs were quantified by the intraclass correlation coefficient (ICC), by the root mean square, and by the standard deviation of the differences. RESULTS Optic disc areas tended to be slightly larger when judged in photographs than by SD OCT, whereas cup areas were similar. Cup and optic disc areas showed good correlation (0.8) between the average photographic reading and SD OCT, but only fair correlation of rim areas (0.4). The SD OCT was highly reproducible (ICC, 0.96-0.99). Each reader also was consistent with himself on duplicate readings of 21 photographs (ICC, 0.80-0.88 for rim area and 0.95-0.98 for all other measurements), but reproducibility was not as good as SD OCT. Measurements derived from SD OCT did not differ from photographic readings more than the readings of photographs by different readers differed from each other. CONCLUSIONS Designation of the cup and optic disc boundaries by an automated analysis of SD OCT was within the range of variable designations by different readers from color stereoscopic photographs, but use of different landmarks typically made the designation of the optic disc size somewhat smaller in the automated analysis. There was better repeatability among measurements from SD OCT than from among readers of photographs. The repeatability of automated measurement of SD OCT images is promising for use both in diagnosis and in monitoring of progression.

Optical coherence tomography segmentation analysis in relapsing remitting versus progressive multiple sclerosis

Introduction Optical coherence tomography (OCT) with retinal segmentation analysis is a valuable tool in assessing axonal loss and neuro-degeneration in multiple sclerosis (MS) by in-vivo imaging, delineation and quantification of retinal layers. There is evidence of deep retinal involvement in MS beyond the inner retinal layers. The ultra-structural retinal changes in MS in different MS phenotypes can reflect differences in the pathophysiologic mechanisms. There is limited data on the pattern of deeper retinal layer involvement in progressive MS (PMS) versus relapsing remitting MS (RRMS). We have compared the OCT segmentation analysis in patients with relapsing-remitting MS and progressive MS. Methods Cross-sectional study of 113 MS patients (226 eyes) (29 PMS, 84 RRMS) and 38 healthy controls (72 eyes). Spectral domain OCT (SDOCT) using the macular cube acquisition protocol (Cirrus HDOCT 5000; Carl Zeiss Meditec) and segmentation of the retinal layers for quantifying the thicknesses of the retinal layers. Segmentation of the retinal layers was carried out utilizing Orion software (Voxeleron, USA) for quantifying the thicknesses of individual retinal layers. Results The retinal nerve finer layer (RNFL) (p = 0.023), the ganglion-cell/inner plexiform layer (GCIPL) (p = 0.006) and the outer plexiform layer (OPL) (p = 0.033) were significantly thinner in PMS compared to RRMS. There was significant negative correlation between the outer nuclear layer (ONL) and EDSS (r = -0.554, p = 0.02) in PMS patients. In RRMS patients with prior optic neuritis, the GCIPL correlated negatively (r = -0.317; p = 0.046), while the photoreceptor layer (PR) correlated positively with EDSS (r = 0.478; p = 0.003). Conclusions Patients with PMS exhibit more atrophy of both the inner and outer retinal layers than RRMS. The ONL in PMS and the GCIPL and PR in RRMS can serve as potential surrogate of disease burden and progression (EDSS). The specific retinal layer predilection and its correlation with disability may reflect different pathophysiologic mechanisms and various stages of progression in MS.

Changes in volume of various retinal layers over time in early and intermediate age-related macular degeneration

PurposeTo evaluate longitudinally volume changes in inner and outer retinal layers in early and intermediate age-related macular degeneration (AMD) compared to healthy control eyes using optical coherence tomography (OCT).Methods71 eyes with AMD and 31 control eyes were imaged at two time points: baseline and after 2 years. Automated OCT layer segmentation was performed using OrionTM. This software is able to measure volumes of retinal layers with distinct boundaries including Retinal Nerve Fibre Layer (RNFL), Ganglion Cell-Inner Plexiform Layer (GCIPL), Inner Nuclear Layer (INL), Outer Plexiform Layer (OPL), Outer Nuclear Layer (ONL), Photoreceptors (PR) and Retinal Pigment Epithelium–Bruch’s Membrane complex (RPE-BM). The mean retinal layer volumes and volume changes at 2 years were compared between groups.ResultsMean GCIPL and INL volumes were lower, while PR and RPE-BM volumes were higher in AMD eyes than controls at baseline (all P < 0.05) and year 2 (all P < 0.05). In AMD eyes, RNFL and ONL volumes decreased by 0.0232 (P = 0.033) and 0.0851 (P = 0.001), respectively. In contrast, OPL and RPE-BM volumes increased in AMD eyes by 0.0391 (P = 0.000) and 0.0209 (P = 0.000) respectively. Moreover, there were significant differences in longitudinal volume change of OPL (P = 0.02), ONL (P = 0.008) and RPE-BM (P = 0.02) between AMD eyes and controls.ConclusionsThere were abnormal retinal layer volumes and volume changes in eyes with early and intermediate AMD.