Mapping in-vivo optic nerve head strains caused by intraocular and intracranial pressures.

Although it is well documented that abnormal levels of either intraocular (IOP) or intracranial pressure (ICP) can lead to potentially blinding conditions, such as glaucoma and papilledema, little is known about how the pressures actually affect the eye. Even less is known about potential interplay between their effects, namely how the level of one pressure might alter the effects of the other. Our goal was to measure in-vivo the pressure-induced stretch and compression of the lamina cribrosa due to acute changes of IOP and ICP. The lamina cribrosa is a structure within the optic nerve head, in the back of the eye. It is important because it is in the lamina cribrosa that the pressure-induced deformations are believed to initiate damage to neural tissues leading to blindness. An eye of a rhesus macaque monkey was imaged in-vivo with optical coherence tomography while IOP and ICP were controlled through cannulas in the anterior chamber and lateral ventricle, respectively. The image volumes were analyzed with a newly developed digital image correlation technique. The effects of both pressures were highly localized, nonlinear and non-monotonic, with strong interactions. Pressure variations from the baseline normal levels caused substantial stretch and compression of the neural tissues in the posterior pole, sometimes exceeding 20%. Chronic exposure to such high levels of biomechanical insult would likely lead to neural tissue damage and loss of vision. Our results demonstrate the power of digital image correlation technique based on non-invasive imaging technologies to help understand how pressures induce biomechanical insults and lead to vision problems.

Correlation between Cerebral Hemodynamic and Perfusion Pressure Changes in Non-Human Primates.

The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral autoregulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and the oxygen supply might be unstable. Lassen's blood flow autoregulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact autoregulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to autoregulation impairment. Non-invasive methods for monitoring blood flow autoregulation are therefore needed. We propose to use Near infrared spectroscopy (NIRS) to fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We pe erformed experiments on non-human primates during exsanguination to demonstrate that the limits of blood flow autoregulation can be accessed with NIRS.

What is a typical optic nerve head?

Whereas it is known that elevated intraocular pressure (IOP) increases the risk of glaucoma, it is not known why optic nerve heads (ONHs) vary so much in sensitivity to IOP and how this sensitivity depends on the characteristics of the ONH such as tissue mechanical properties and geometry. It is often assumed that ONHs with uncommon or atypical sensitivity to IOP, high sensitivity in normal tension glaucoma or high robustness in ocular hypertension, also have atypical ONH characteristics. Here we address two specific questions quantitatively: Do atypical ONH characteristics necessarily lead to atypical biomechanical responses to elevated IOP? And, do typical biomechanical responses necessarily come from ONHs with typical characteristics. We generated 100,000 ONH numerical models with randomly selected values for the characteristics, all falling within literature ranges of normal ONHs. The models were solved to predict their biomechanical response to an increase in IOP. We classified ONH characteristics and biomechanical responses into typical or atypical using a percentile-based threshold, and calculated the fraction of ONHs for which the answers to the two questions were true and/or false. We then studied the effects of varying the percentile threshold. We found that when we classified the extreme 5% of individual ONH characteristics or responses as atypical, only 28% of ONHs with an atypical characteristic had an atypical response. Further, almost 29% of typical responses came from ONHs with at least one atypical characteristic. Thus, the answer to both questions is no. This answer held irrespective of the threshold for classifying typical or atypical. Our results challenge the assumption that ONHs with atypical sensitivity to IOP must have atypical characteristics. This finding suggests that the traditional approach of identifying risk factors by comparing characteristics between patient groups (e.g. ocular hypertensive vs. primary open angle glaucoma) may not be a sound strategy.

A method to estimate biomechanics and mechanical properties of optic nerve head tissues from parameters measurable using optical coherence tomography.

Optic nerve head (ONH) tissue properties and biomechanics remain mostly unmeasurable in the experiment. We hypothesized that these can be estimated numerically from ocular parameters measurable in vivo with optical coherence tomography (OCT). Using parametric models representing human ONHs we simulated acute intraocular pressure (IOP) increases (10 mmHg). Statistical models were fit to predict, from OCT-measurable parameters, 15 outputs, including ONH tissue properties, stresses, and deformations. The calculations were repeated adding parameters that have recently been proposed as potentially measurable with OCT. We evaluated the sensitivity of the predictions to variations in the experimental parameters. Excellent fits were obtained to predict all outputs from the experimental parameters, with cross-validated R2s between 0.957 and 0.998. Incorporating the potentially measurable parameters improved fits significantly. Predictions of tissue stiffness were accurate to within 0.66 MPa for the sclera and 0.24 MPa for the lamina cribrosa. Predictions of strains and stresses were accurate to within 0.62% and 4.9 kPa, respectively. Estimates of ONH biomechanics and tissue properties can be obtained quickly from OCT measurements using an applet that we make freely available. These estimates may improve understanding of the eye sensitivity to IOP and assessment of patient risk for development or progression of glaucoma.

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Scan quality effect on glaucoma discrimination by glaucoma imaging devices.

AIM: To evaluate, within ocular imaging scans of acceptable quality as determined by manufacturers' guidelines, the effects of image quality on glaucoma discrimination capabilities. METHODS: One hundred and four healthy and 75 glaucomatous eyes from the Advanced Imaging in Glaucoma Study (AIGS) were imaged with GDx-VCC, HRT II and StratusOCT. Quality score (QS>/=8), pixel standard deviation (SD/=5) were used as quality parameter cut-offs, respectively. GDx nerve fibre indicator (NFI) and HRT Moorfields regression analysis (MRA) classifications and OCT mean retinal nerve fibre layer (RNFL) thickness were used as the discriminatory parameters. Logistic regression models were used to model the dichotomous clinical classification (healthy vs glaucoma) as a function of image-quality parameters and discriminatory parameters. RESULTS: Quality parameter covariates were statistically non-significant for GDx and HRT but had an inverse effect on OCT in predicting disease (a higher SS had a lower probability of glaucoma). Age was a significant covariate for GDx and HRT, but not OCT, while ethnicity and interaction between the image quality and the institute where scans were acquired were significant covariates in the OCT models. CONCLUSION: Scan quality within the range recommended as acceptable by the manufacturer of each imaging device does not affect the glaucoma discriminating ability of GDx or HRT but does affect Stratus OCT glaucoma discrimination.

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.

Imaging of the retinal nerve fibre layer for glaucoma.

BACKGROUND: Glaucoma is a group of diseases characterised by retinal ganglion cell dysfunction and death. Detection of glaucoma and its progression are based on identification of abnormalities or changes in the optic nerve head (ONH) or the retinal nerve fibre layer (RNFL), either functional or structural. This review will focus on the identification of structural abnormalities in the RNFL associated with glaucoma. DISCUSSION: A variety of new techniques have been created and developed to move beyond photography, which generally requires subjective interpretation, to quantitative retinal imaging to measure RNFL loss. Scanning laser polarimetry uses polarised light to measure the RNFL birefringence to estimate tissue thickness. Optical coherence tomography (OCT) uses low-coherence light to create high-resolution tomographic images of the retina from backscattered light in order to measure the tissue thickness of the retinal layers and intraretinal structures. Segmentation algorithms are used to measure the thickness of the retinal nerve fibre layer directly from the OCT images. In addition to these clinically available technologies, new techniques are in the research stages. Polarisation-sensitive OCT has been developed that combines the strengths of scanning laser polarimetry with those of OCT. Ultra-fast techniques for OCT have been created for research devices. The continued utilisation of imaging devices into the clinic is refining glaucoma assessment. In the past 20 years glaucoma has gone from a disease diagnosed and followed using highly subjective techniques to one measured quantitatively and increasingly objectively.

Sources of longitudinal variability in optical coherence tomography nerve-fibre layer measurements.

AIMS: The purpose of this study was to compare the day-to-day reproducibility of optical coherence tomography (OCT; StratusOCT, Carl Zeiss Meditec, Dublin, CA) measurements of retinal nerve-fibre layer (RNFL) measurements at time points 1 year apart. METHODS: One eye in each of 11 healthy subjects was examined using the StratusOCT fast RNFL scan protocol. Three fast RNFL scans with signal strength > or =7 were obtained on each of 3 days within a month. This protocol was repeated after 12 months. A linear mixed effects model fitted to the nested data was used to compute the variance components. RESULTS: The square root of the variance component that was attributed to the differences between subjects was 7.17 microm in 2005 and 7.28 microm in 2006. The square roots of the variance component due to differences between days within a single subject were 1.95 microm and 1.50 microm, respectively, and for within day within a single subject were 2.51 microm and 2.55 microm, respectively. There were no statistically significant differences for any variance component between the two testing occasions. CONCLUSIONS: Measurement error variance remains similar from year to year. Day and scan variance component values obtained in a cohort study may be safely applied for prediction of long-term reproducibility.

Heidelberg Retina Tomograph 3 machine learning classifiers for glaucoma detection.

AIMS: To assess performance of classifiers trained on Heidelberg Retina Tomograph 3 (HRT3) parameters for discriminating between healthy and glaucomatous eyes. METHODS: Classifiers were trained using HRT3 parameters from 60 healthy subjects and 140 glaucomatous subjects. The classifiers were trained on all 95 variables and smaller sets created with backward elimination. Seven types of classifiers, including Support Vector Machines with radial basis (SVM-radial), and Recursive Partitioning and Regression Trees (RPART), were trained on the parameters. The area under the ROC curve (AUC) was calculated for classifiers, individual parameters and HRT3 glaucoma probability scores (GPS). Classifier AUCs and leave-one-out accuracy were compared with the highest individual parameter and GPS AUCs and accuracies. RESULTS: The highest AUC and accuracy for an individual parameter were 0.848 and 0.79, for vertical cup/disc ratio (vC/D). For GPS, global GPS performed best with AUC 0.829 and accuracy 0.78. SVM-radial with all parameters showed significant improvement over global GPS and vC/D with AUC 0.916 and accuracy 0.85. RPART with all parameters provided significant improvement over global GPS with AUC 0.899 and significant improvement over global GPS and vC/D with accuracy 0.875. CONCLUSIONS: Machine learning classifiers of HRT3 data provide significant enhancement over current methods for detection of glaucoma.

A new quality assessment parameter for optical coherence tomography.

AIM: To create a new, automated method of evaluating the quality of optical coherence tomography (OCT) images and to compare its image quality discriminating ability with the quality assessment parameters signal to noise ratio (SNR) and signal strength (SS). METHODS: A new OCT image quality assessment parameter, quality index (QI), was created. OCT images (linear macular scan, peripapillary circular scan, and optic nerve head scan) were analysed using the latest StratusOCT system. SNR and SS were collected for each image. QI was calculated based on image histogram information using a software program of our own design. To evaluate the performance of these parameters, the results were compared with subjective three level grading (excellent, acceptable, and poor) performed by three OCT experts. RESULTS: 63 images of 21 subjects (seven each for normal, early/moderate, and advanced glaucoma) were enrolled in this study. Subjects were selected in a consecutive and retrospective fashion from our OCT imaging database. There were significant differences in SNR, SS, and QI between excellent and poor images (p = 0.04, p = 0.002, and p<0.001, respectively, Wilcoxon test) and between acceptable and poor images (p = 0.02, p<0.001, and p<0.001, respectively). Only QI showed significant difference between excellent and acceptable images (p = 0.001). Areas under the receiver operating characteristics (ROC) curve for discrimination of poor from excellent/acceptable images were 0.68 (SNR), 0.89 (IQP), and 0.99 (QI). CONCLUSION: A quality index such as QI may permit automated objective and quantitative assessment of OCT image quality that performs similarly to an expert human observer.

Glaucomatous optic disc changes in the contralateral eye of unilateral normal pressure glaucoma patients.

OBJECTIVE: To evaluate the optic disc for structural abnormalities in the contralateral eye of unilateral normal pressure glaucoma patients. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty-three unilateral normal pressure glaucoma patients. TESTING: Optic disc imaging with the Heidelberg Retina Tomograph (HRT). MAIN OUTCOME MEASURES: Optic disc structural parameters. RESULTS: Of the contralateral (normal visual field) eyes, 79.2% were found to have an abnormal optic disc by HRT analysis. Of the glaucomatous (abnormal visual field) eyes, 94.3% were found to have an abnormal disc. The patterns of disc abnormality were defined as marked or moderate diffuse thinning of the neuroretinal rim (NRR) or broad or narrow focal thinning of the NRR. The most common pattern in the contralateral eyes was moderate diffuse thinning of the NRR (45.2%). The most frequently abnormal segments were the nasal superior (73. 8%) followed by the nasal inferior and the global NRR parameter (both 54.8%). CONCLUSIONS: A high frequency of NRR thinning was found in the contralateral (normal visual field) eyes of unilateral normal pressure glaucoma patients by HRT analysis. Knowing whether these abnormalities predict future progression to the development of visual field abnormality must wait until longitudinal studies are completed. If a disc abnormality is shown to predict future field loss, then early identification will allow early treatment.

Identifying early glaucomatous changes. Comparison between expert clinical assessment of optic disc photographs and confocal scanning ophthalmoscopy.

OBJECTIVE: To compare the ability of expert clinicians, using qualitative assessment of stereoscopic optic disc photographs, and confocal scanning laser ophthalmoscope imaging to discriminate between healthy persons and patients with early glaucoma. DESIGN: Comparative instrument validation study. PARTICIPANTS: Seventy-two healthy persons and 51 patients with early glaucoma (average visual field mean deviation, -3.6 dB). Early glaucoma was defined as a history of ocular hypertension and a reproducible visual field defect scoring 5 or less in the Advanced Glaucoma Intervention Study classification, regardless of optic disc appearance. INTERVENTION: Stereoscopic optic nerve head (ONH) photography and Heidelberg Retina Tomograph (HRT) imaging, (Heidelberg Engineering GmbH, Dossenheim, Germany). MAIN OUTCOME MEASURES: Ability of clinical assessment of stereoscopic ONH photographs and analysis of HRT parameters, taking into account the optic disc size, to detect early glaucomatous optic disc changes. RESULTS: The specificity of the majority opinion of five observers to detect early glaucomatous optic disc changes was 94.4%, with a sensitivity of 70.6%. Using the HRT analysis, the specificity was 95.8% and the sensitivity was 84. 3%. CONCLUSIONS: Heidelberg Retina Tomograph image analysis that takes into account the optic disc size is more sensitive than clinical assessment of stereoscopic optic disc photographs in distinguishing between healthy persons and patients with early glaucoma.

Macular changes in type I Gaucher's disease.

The authors illustrate the spectrum of Gaucher's disease involving the eye in the case of a 51-year-old man suffering from Type I Gaucher's disease who presented with unusual macular changes. This is the first report of chronic adult non-neuronopathic disease (Type I) with a plaque-like mass at the fovea. Our hypothesis is that the lesion at the fovea is probably an aggregation of Gaucher's cells.

Inter- and intraobserver variation in the analysis of optic disc images: comparison of the Heidelberg retina tomograph and computer assisted planimetry.

AIMS: The development of imaging and measurement techniques has brought the prospect of greater objectivity in the measurement of optic disc features, and therefore better agreement between observers. The purpose of this study was to quantify and compare the variation between observers using two measurement devices. METHODS: Optic disc photographs and images from the Heidelberg retina tomograph (HRT) of 30 eyes of 30 subjects were presented to six observers for analysis, and to one observer on five separate occasions. Agreement between observers was studied by comparing the analysis of each observer with the median result of the other five, and expressed as the mean difference and standard deviation of differences between the observer and the median. Inter- and intraobserver variation was calculated as a coefficient of variation (mean SD/mean x 100). RESULTS: For planimetry, agreement between observers was dependent on observer experience, for the HRT it was independent. Agreement between observers (SD of differences as a percentage of the median) for optic disc area was 4.0% to 7.2% (planimetry) and 3.3% to 6.0% (HRT), for neuroretinal rim area it was 10.8% to 21.0% (planimetry) and 5.2% to 9.6% (HRT). The mean interobserver coefficient of variation for optic disc area was 8.1% (planimetry) and 4.4% (HRT), for neuroretinal rim area it was 16.3% (planimetry) and 8.1% (HRT), and (HRT only) for rim volume was 16.3%, and reference height 9.1%. HRT variability was greater for the software version 1.11 reference plane than for version 1.10. The intraobserver coefficient of variation for optic disc area was 1.5% (planimetry) and 2.4% (HRT), for neuroretinal rim area it was 4.0% (planimetry) and 4.5% (HRT). CONCLUSIONS: Variation between observers is greatly reduced by the HRT when compared with planimetry. However, levels of variation, which may be clinically significant, remain for variables that depend on the subjective drawing of the disc margin.

Identification of early glaucoma cases with the scanning laser ophthalmoscope.

PURPOSE: This study aimed to define the confocal laser scanning ophthalmoscope (Heidelberg Retina Tomograph [HRT]) parameters that best separate patients with early glaucoma from normal subjects. STUDY DESIGN: A cross-sectional study. PARTICIPANTS: A total of 80 normal subjects and 51 patients with early glaucoma participated (average visual field mean deviation = -3.6 dB). INTERVENTION: Imaging of the optic nerve head with the HRT and analysis using software version 1.11 were performed. MAIN OUTCOME MEASURES: The relation between neuroretinal rim area and optic disc area, and cup-disc area ratio and optic disc area, was defined by linear regression of data derived from the normal subjects. The normal ranges for these two parameters were defined by the 99% prediction intervals of the linear regression between the parameter and optic disc area, for the whole disc, and for each of the predefined segments. Normal subjects and patients were labeled as abnormal if the parameter for either the whole disc or any of the predefined segments was outside the normal range. The sensitivity and specificity values of the method were calculated. RESULTS: The highest specificity (96.3%) and sensitivity (84.3%) values to separate normal subjects and those patients with early glaucoma were obtained using the 99% prediction interval from the linear regression between the optic disc area and the log of the neuroretinal rim area. Similar specificity (97.5%) and lower sensitivity (74.5%) values were obtained with the 99% prediction interval derived from regression between the disc area and cup-disc area ratios. Poor separation between groups was obtained with the other parameters. CONCLUSIONS: The HRT, using the technique of linear regression to account for the relationship between optic disc size and rim area or cup-disc area ratio, provides good separation between control subjects and patients with early glaucoma in this population.

Aging changes of the optic nerve head in relation to open angle glaucoma.

AIMS: To determine the age related changes in optic nerve head structure in a group of normal subjects and assess the significance of any changes in relation to those found in open angle glaucoma. METHODS: A group of 88 white volunteers and friends and spouses of patients with a normal visual field and normal intraocular pressure was studied. Two different imaging and measurement devices were used (computer assisted planimetry and scanning laser ophthalmoscopy), and the results from each were compared. Measurements were made of the optic disc, optic cup, and neuroretinal rim areas, and the vertical optic disc diameter and cup/disc diameter ratio. RESULTS: Neuroretinal rim area declined at the rate of between 0.28% and 0.39% per year. Vertical optic cup diameter and optic cup area increased with age. The mean cup/disc diameter ratio increased by about 0.1 between the ages of 30 and 70 years. CONCLUSIONS: Age related changes are significant and measurable, and should be taken into account when assessing the glaucoma suspect, and when estimating the rate of progression of glaucomatous optic neuropathy in patients with established disease.