In vivo oximetry of human bulbar conjunctival and episcleral microvasculature using snapshot multispectral imaging.

Multispectral imaging (MSI) is a well-established technique for non-invasive oximetry of retinal blood vessels, which has contributed to the understanding of a variety of retinal conditions, including glaucoma, diabetes, vessel occlusion, and retinal auto-regulation. We report the first study to use snapshot multi-spectral imaging (SMSI) for oximetry of the bulbar conjunctival and episcleral microvasculature in the anterior segment of the eye. We report the oxygen dynamics of the bulbar conjunctival and episcleral microvasculature at normoxia and at acute mild hypoxia conditions. A retinal-fundus camera fitted with a custom Image-Replicating Imaging Spectrometer was used to image the bulbar conjunctival and episcleral microvasculature in ten healthy human subjects at normoxia (21% Fraction of Inspired Oxygen [FiO2]) and acute mild hypoxia (15% FiO2) conditions. Eyelid closure was used to control oxygen diffusion between ambient air and the sclera surface. Four subjects were imaged for 30 seconds immediately following eyelid opening. Vessel diameter and Optical Density Ratio (ODR: a direct proxy for oxygen saturation) of vessels was computed automatically. Oximetry capability was validated using a simple phantom that mimicked the scleral vasculature. Acute mild hypoxia resulted in a decrease in blood oxygen saturation (SO2) (i.e. an increase in ODR) when compared with normoxia in both bulbar conjunctival (p < 0.001) and episcleral vessels (p = 0.03). Average episcleral diameter increased from 78.9 ± 8.7 µm (mean ± standard deviation) at normoxia to 97.6 ± 14.3 µm at hypoxia (p = 0.02). Diameters of bulbar conjunctival vessels showed no significant change from 80.1 ± 7.6 µm at normoxia to 80.6 ± 7.0 µm at hypoxia (p = 0.89). When exposed to ambient air, hypoxic bulbar conjunctival vessels rapidly reoxygenated due to oxygen diffusion from ambient air. Reoxygenation occured in an exponential manner, and SO2 reached normoxia baseline levels. The average ½ time to full reoxygenation was 3.4 ± 1.4 s. As a consequence of oxygen diffusion, bulbar conjunctival vessels will be highly oxygenated (i.e. close to 100% SO2) when exposed to ambient air. Episcleral vessels were not observed to undergo any significant oxygen diffusion, instead behaving similarly to pulse oximetry measurements. This is the first study to the image oxygen dynamics of bulbar conjunctival and episcleral microvasculature, and consequently, the first study to directly observe the rapid reoxygenation of hypoxic bulbar conjunctival vessels when exposed to ambient air. Oximetry of bulbar conjunctival vessels could potentially provide insight into conditions where oxygen dynamics of the microvasculature are not fully understood, such as diabetes, sickle-cell diseases, and dry-eye syndrome. Oximetry in the bulbar conjunctival and episcleral microvasculature could be complimentary or alternative to retinal oximetry.

Oxygen saturation measurements of the retinal vasculature in treated asymmetrical primary open-angle glaucoma using hyperspectral imaging.

PURPOSE: To determine whether there are differences in retinal vascular oxygen saturation measurements, estimated using a hyperspectral fundus camera, between normal eyes and treated eyes of subjects with asymmetrical primary open-angle glaucoma (POAG). METHODS: A noninvasive hyperspectral fundus camera was used to acquire spectral images of the retina at wavelengths between 556 and 650 nm in 2-nm increments. In total, 14 normal eyes and both eyes of 11 treated POAG subjects were imaged and analyzed using algorithms that use the spectral variation of the optical densities of blood vessels to estimate the oxygen saturation of blood within the retinal vasculature. In the treated POAG group, each of the eyes were categorized, based on the mean deviation of the Humphrey visual-field analyzer result, as either more-advanced or less-advanced, glaucomatous eyes. Unpaired t-tests (two-tailed) with Welch's correction were used to compare the mean oxygen saturation between the normal subjects and the treated POAG subgroups. RESULTS: In less-advanced and more-advanced-treated POAG eyes, mean retinal venular oxygen saturations (48.2±21.6% and 42.6±18.8%, respectively) were significantly higher than in normal eyes (27.9±9.9%; P=0.03 and 0.01, respectively). Arteriolar oxygen saturation was not significantly different between normal eyes and treated POAG eyes. CONCLUSIONS: The increased oxygen saturation of the retinal venules in advanced-treated POAG eyes may indicate reduced metabolic consumption of oxygen in the inner retinal tissues.

Portsmouth visual field database: an audit of glaucoma progression.

AIM: To explore visual field (VF) progression in a cohort of secondary care-treated glaucoma and ocular hypertensive (OHT) patients. METHODS: We extracted VFs from our database drawn from our normal clinical practice. VF series from 4177 eyes from 2208 patients who had five or more VFs were obtained, the 'better' eye was selected and the rate of VF progression was calculated using mean deviation (MD) data. RESULTS: The median rate of progression for the whole sample was -0.1 dB/year (interquartile range (IQR) -4 to 0 dB/year) over a median of 6.7 years (IQR 4.9-8.7). Of 2208 patients, 477 (21.2%) progressed at > -0.5 dB/year; 46 (2.1%) progressed at >-2.0 dB/year. Of those with a 'final MD' of worse than -10 dB (N=244) in their better eye; 14.0% were 'fast progressors' (>-2 dB/year), 33.7% 'moderate progressors' (-1 to -2 dB/year), and 28.8% 'slow progressors' (-0.3 dB to -1 dB/year). Of those with 'initial MD' better than -3 dB and those with worse than -3 dB, 31/1679 (1.8%) and 213/529 (40.3%) respectively, had a final MD of worse than -10 dB. CONCLUSION: Fast progressors, while important, are relatively rare. Moderate and slow progressors make up the majority of the progressing population within this data set. The risk of significant visual loss is much higher in those with initial damage. With increasing life expectancy, moderate and slow progressors may become increasingly clinically important.

Spectral imaging of the retina.

INTRODUCTION: The work described here involved the use of a modified fundus camera to obtain sequential hyperspectral images of the retina in 14 normal volunteers and in 1 illustrative patient with a retinal vascular occlusion. METHODS: The paper describes analysis techniques, which allow oximetry within retinal vessels; these results are presented as retinal oximetry maps. RESULTS: Using spectral images, with wavelengths between 556 and 650 nm, the mean oxygen saturation (OS) value in temporal retinal arterioles in normal volunteers was 104.3 (± 16.7), and in normal temporal retinal venules was 34.8 (± 17.8). These values are comparable to those quoted in the literature, although, the venular saturations are slightly lower than those values found by other authors; explanations are offered for these differences. DISCUSSION: The described imaging and analysis techniques produce a clinically useful map of retinal oximetric values. The results from normal volunteers and from one illustrative patient are presented. Further developments, including the recent development of a 'snapshot' spectral camera, promises enhanced non-invasive retinal vessel oximetry mapping.

Interobserver agreement on visual field progression in glaucoma: a comparison of methods.

AIM: To examine the level of agreement between clinicians in assessing progressive deterioration in visual field series using two different methods of analysis. METHODS: Each visual field series satisfied the following criteria: more than 19 reliable fields, patient age over 40 years, macular threshold at least 30 dB. The first three fields in each series were excluded to minimise learning effects: the following 16 were studied. Five expert clinicians assessed the progression status of each series using both standard Humphrey printouts and pointwise linear regression (PROGRESSOR). The level of agreement between the clinicians was evaluated using a weighted kappa statistic. RESULTS: A total of 432 tests comprising 27 visual field series of 16 tests each were assessed by the clinicians. The level of agreement on progression status between the clinicians was always higher when they used PROGRESSOR (median kappa = 0.59) than when they used Humphrey printouts (median kappa = 0.32). This was statistically significant (p = 0.006, Wilcoxon matched pairs signed rank sum test). CONCLUSIONS: Agreement between expert clinicians about visual field progression status is poor when standard Humphrey printouts are used, even when the field series studied are long and consist solely of reliable fields. Under these ideal conditions, clinicians agree more closely about patients' visual field progression status when using PROGRESSOR than when inspecting series of Humphrey printouts.

Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). DESIGN: Cross-sectional genetic study. PARTICIPANTS: Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. METHODS: Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the eight pedigrees, 29 Gln368STOP mutation-carrying individuals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 individuals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these individuals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more individuals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. CONCLUSIONS: The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.

Accuracy and implications of a reported family history of glaucoma: experience from the Glaucoma Inheritance Study in Tasmania.

OBJECTIVES: To ascertain the prevalence of previously undiagnosed primary open-angle glaucoma (POAG) within 5 large POAG pedigrees and to evaluate the reliability of a reported family history of glaucoma within these pedigrees. METHODS: The Glaucoma Inheritance Study in Tasmania (GIST) identified several large adult POAG pedigrees. Intraocular pressure (IOP), optic disc stereophotography, and automated perimetry were performed on all adult pedigree members. Participants were classified as normal (IOP <22 mm Hg and normal optic disc and field); glaucoma suspect (normal field, but an IOP >/=22 mm Hg and/or suspicious optic disc); or POAG (field defect and glaucomatous optic disc). Some individuals with POAG had been previously diagnosed by their local ophthalmologist; others were diagnosed as a result of the GIST project. Family members with a prior diagnosis of POAG were asked to report if they were aware of any relatives with POAG. This reported family history was then directly compared with the actual pedigree (before the diagnosis of new cases) to calculate agreement. MAIN OUTCOME MEASURE: The rate of glaucoma in pedigrees and percentage of previously diagnosed glaucoma cases who were aware of the positive family history of POAG. RESULTS: Four hundred forty-two subjects (mean age, 54 years [range, 13-97 years]) from 5 pedigrees were examined: 316 subjects (71%) were normal, 47 (11%) were previously diagnosed with POAG, and 8 (2%) were previously diagnosed glaucoma suspects; 30 cases (7%) of POAG and 41 suspects (9%) were newly diagnosed as a direct result of the GIST examination. Of the 47 previously diagnosed POAG cases, 41 were questioned about their prior knowledge of any family history and 11 (27%) were unaware of their family history of POAG. CONCLUSIONS: Examination of all adult subjects from POAG families yields new cases. Even in large POAG pedigrees, 27% of previously diagnosed POAG patients were unaware of their positive family history. These findings suggest that a higher percentage of adult POAG may be inherited than hitherto reported. Arch Ophthalmol. 2000;118:900-904

Severity and stability of glaucoma: patient perception compared with objective measurement.

OBJECTIVE: To elucidate the relationship between the subjective assessment in patients with glaucoma of (1) the severity of their visual loss, and (2) any deterioration in their visual function and their objective visual fields as measured by computed perimetry. DESIGN: First, patients completed a questionnaire relating to perceived visual disability and underwent binocular visual field testing. Second, a separate group of patients answered a question about perceived visual deterioration: their monocular visual field tests were analyzed retrospectively by pointwise linear regression to establish stability or deterioration. SETTING: The Glaucoma Service of a specialist eye hospital, which is a tertiary referral center and serves the local community. SUBJECTS: One hundred twenty-three patients with glaucoma including 62 for the severity arm of the study and 61 for the progression arm. MAIN OUTCOME MEASURES: Questionnaire responses, Esterman binocular disability score, and objective visual field deterioration. RESULTS: Questions strongly associated with Esterman binocular disability scores related to bumping into things, problems with stairs, and finding things that have been dropped. There was a strong association between perceived visual deterioration and measured bilateral visual field deterioration (P<.01). CONCLUSIONS: There is a strong association between some types of perceived visual disability and the severity of binocular field loss. A patient who notices gradual visual deterioration is twice as likely to have bilateral visual field deterioration as not. The findings in this sample of patients with mild-to-moderate glaucoma challenge the belief that glaucoma is an insidious process in which the symptoms do not appear until the end stage of the disease.

Simulating binocular visual field status in glaucoma.

AIMS: To simulate the central binocular visual field using results from merged left and right monocular Humphrey fields. To assess the agreement between the simulation and the binocular Humphrey Esterman visual field test (EVFT). METHOD: 59 consecutive patients with bilateral glaucoma each recorded Humphrey 24-2 fields for both eyes and binocular EVFT on the same visit. EVFT results were used to identify patients exhibiting at least one defect (< 10 dB) within the central 20 degrees of the binocular field. This criterion is relevant to a patient's legal fitness to drive in the UK. Individual sensitivity values from monocular fields are merged to generate a simulated central binocular field. Results are displayed as a grey scale and as symbols representing defects at the < 10 dB level. Agreement between patients failing the criterion using the simulation and the EVFT was evaluated. RESULTS: Substantial agreement was observed between the methods in classifying patients with at least one defect (< 10 dB) within the central binocular field (kappa 0.81; SE 0.09). Patients failing this criterion using the EVFT results were identified by the binocular simulation with high levels of sensitivity (100%) and specificity (86%). CONCLUSIONS: Excellent agreement exists between the simulated binocular results and EVFT in classifying glaucomatous patients with central binocular defects. A rapid estimate of a patient's central binocular field and visual functional capacity can be ascertained without extra perimetric examination.

High spatial resolution automated perimetry in glaucoma.

BACKGROUND: Automated perimetry is of fundamental importance in assessing visual function in glaucoma. A technique was evaluated to perform high spatial resolution automated perimetry to allow a more detailed assessment of the luminance sensitivity in selected regions of the visual field than is possible with conventional perimetry. METHOD: High spatial resolution perimetry was performed using a Humphrey automated perimeter by measuring luminance sensitivity across a 9 by 9 degree custom grid of 100 test locations with a separation between adjacent locations of 1 degree. Quantitative analysis of the raw and Gaussian filtered thresholds was performed to assess the repeatability of the technique in normals, glaucoma suspects, and glaucoma patients. RESULTS: The testing protocol was well tolerated by all subjects. High spatial resolution perimetry in glaucomatous eyes demonstrated fine luminance sensitivity loss not suspected with conventional perimetry. High spatial resolution perimetry also demonstrated reproducible areas of sensitivity loss in some glaucomatous eyes in areas of the visual field which appear normal with conventional programmes. The repeatability of the technique correlated with mean threshold sensitivity and was substantially improved to clinically acceptable levels by Gaussian filtering the thresholds. CONCLUSION: This technique of high spatial resolution perimetry allows the practical assessment of selected regions of the visual field at higher resolution than conventional perimetry, and may be clinically useful in glaucoma.

Improving the prediction of visual field progression in glaucoma using spatial processing.

PURPOSE: The authors show how the predictive performance of a method for determining glaucomatous progression in a series of visual fields can be improved by first subjecting the data to a spatial processing technique. METHOD: Thirty patients with normal-tension glaucoma, each with at least ten Humphrey fields and 3.5 years of follow-up, were included. A linear regression model of sensitivity against time of follow-up determined rates of change at individual test locations over the first five fields (mean follow-up 1.46 years; standard deviation = 0.08) in each field series. Predictions of sensitivity at each location of the field nearest to 1 and 2 years after the fifth field were generated using these rates of change. Predictive performance was evaluated by the difference between the predicted and measured sensitivity values. The analysis was repeated using the same field data subjected to a spatial filtering technique used in image processing. RESULTS: Using linear modeling of the unprocessed field series, at 1 year after the fifth field, 72% of all predicted values were within +/- 5 dB of the corresponding measured threshold. This prediction precision improved to 83% using the processed data. At the 2-year follow-up field, the predictive performance improved from 56% to 73% with respect to the +/- 5 dB criterion. CONCLUSIONS: Predictions of visual field progression using a pointwise linear model can be improved by spatial processing without increased cost or patient time. These methods have clinical potential for accurately detecting and forecasting visual field deterioration in the follow-up of glaucoma.

Visual field progression: comparison of Humphrey Statpac2 and pointwise linear regression analysis.

BACKGROUND: Humphrey Statpac2 "glaucoma change probability analysis' is a widely available analysis technique to aid the clinician in the diagnosis of glaucomatous visual field deterioration. A comparison of this technique with the more recently described pointwise linear regression analysis (PROGRESSOR) is given. METHODS: Series of visual field data from a group of nine eyes of nine patients with normal-tension glaucoma were selected. Each series had 16 fields with mean follow-up of 5.7 years (SD 0.6 years). Statpac2 "glaucoma change probability analysis' was used to define test locations that had unequivocally deteriorated in the last three fields of each series. The accuracy of both Statpac2 and PROGRESSOR in providing early detection of these deteriorated locations was assessed. RESULTS: The sensitivity and specificity of the two techniques in predicting deteriorated locations were similar when a rate of luminance sensitivity loss of faster than 1 dB/year (2 dB/year for outer locations beyond 15 deg of eccentricity) with a slope significance of P < 0.10 was used as the regression definition of deterioration. The difficulties of comparing two techniques in the early diagnosis of field progression without a true external standard for field loss are illustrated. CONCLUSIONS: PROGRESSOR closely emulates the performance of Statpac2 in detecting sensitivity deterioration at individual test locations. This new technique, which uses all available data in a field series and gives the rate of sensitivity loss at each location, may provide a clinically useful method for detecting field progression in glaucoma.

Analysis of visual field progression in glaucoma.

BACKGROUND: Despite the widespread use of computerised perimetry the diagnosis of visual field deterioration in following glaucoma patients over time remains particularly difficult. A new method of analysis using a novel graphical display of longitudinal field data is presented. METHODS: A linear regression model of the luminance sensitivity at each stimulus location against time of follow up transforms the quantitative data from a series of fields into a colour coded form which illustrates the spatial configuration of change to aid the interpretation of field loss. The method of analysis and the developed computer software (PROGRESSOR) is described. Comparison with STATPAC-2 glaucoma change probability analysis is given including levels of agreement between the techniques using series of fields of 10 eyes from patients with normal tension glaucoma. RESULTS: Examples of this new method compare well with STATPAC-2 analysis. The level of agreement between the techniques to separate progressing from stable retinal locations is good (kappa = 0.62; SE = 0.04). CONCLUSIONS: This new technique, which combines the change in perimetric sensitivity over time with colour coding of significant change into one image may provide an efficient method to detect true progression in glaucomatous field loss.

Modelling series of visual fields to detect progression in normal-tension glaucoma.

BACKGROUND: Use of statistical modelling techniques to identify models that both describe glaucomatous sensitivity decay and allow predictions of future field status. METHOD: Twelve initially normal fellow eyes of untreated patients with confirmed normal tension glaucoma were studied. All had in excess of 15 Humphrey fields (mean follow-up 5.7 years). From this cohort individual field locations were selected for analysis if they demonstrated unequivocal deterioration at the final two fields. Forty-seven locations from five eyes satisfied this criterion and were analysed using curve-fitting software which automatically applies 221 different models to sensitivity (y) against time of follow up (x). Curve-fitting was then repeated on the first five fields, followed by projection to the date of the final field to generate a predicted threshold which was compared to the actual threshold. Competing models were therefore assessed on their performance at adequately fitting the data (R2) and their potential to predict future field status. RESULTS: Models that provide the best fit to the data were all complex polynomial expressions (median R2 0.93). Other simple expressions fitted fewer locations and exhibited lower R2 values. However, accuracy in predicting future deterioration was superior with these less complex models. In this group a linear expression demonstrated an adequate fit to the majority of the data and generated the most accurate predictions of future field status. CONCLUSIONS: A linear model of the pointwise sensitivity values against time of follow-up can provide a framework for detecting and forecasting glaucomatous field progression. Linear modelling allows the clinically important rate of sensitivity loss to be estimated.

Clinical comparison of semiconductor diode versus neodymium: YAG non-contact cyclo photocoagulation.

AIMS: The advent of diode lasers has allowed their use in transscleral cyclo photocoagulation for refractory glaucoma. A trial was performed to compare the ocular hypotensive and inflammatory effects of cyclo photocoagulation using a continuous wave diode (810 nm) and a free running neodymium:yttrium aluminium garnet (Nd:YAG) laser (1064 nm). METHODS: Forty patients with refractory glaucoma were randomised to receive either diode or Nd:YAG therapy. The intraocular pressure (IOP) and inflammatory response to treatment were monitored over 3 months. RESULTS: There was no significant laser related difference in the effect on IOP after one treatment. There was, however, a difference in effect in retreatments with the IOP lowering effect significantly less, but equally sustained in diode retreatment patients. Severe postoperative complications such as hyphaema or fibrinous anterior uveitis only occurred in the Nd:YAG group. CONCLUSION: The degree and duration of the ocular hypotensive response to cyclo photocoagulation appears to be related to the available power output of the system used, and the extent of tissue damage.

Image processing of computerised visual field data.

BACKGROUND: Computerised perimetry is of fundamental importance in assessing visual function. However, visual fields are subject to patient response variability which limits the detection of true visual loss. METHODS: A method of improving the repeatability of visual field data was demonstrated by applying techniques used in image processing. An illustrative sample of nine normals and nine patients with field loss was used. Two successive Humphrey fields were selected for each subject. Repeatability was defined as the standard deviation of the pointwise differences between sensitivity values of the reference field and repeat field. The field data were then separately subjected to Gaussian and median image processing filters and the repeatability was compared with the unprocessed field results. RESULTS: Improvement in repeatability, by a factor of approximately 2, was demonstrated by both processes. CONCLUSION: These techniques may improve the reliable detection of loss of visual function using computerised perimetry.

New approach to estimating variability in visual field data using an image processing technique.

AIMS: A new framework for evaluating pointwise sensitivity variation in computerised visual field data is demonstrated. METHODS: A measure of local spatial variability (LSV) is generated using an image processing technique. Fifty five eyes from a sample of normal and glaucomatous subjects, examined on the Humphrey field analyser (HFA), were used to illustrate the method. RESULTS: Significant correlation between LSV and conventional estimates--namely, HFA pattern standard deviation and short term fluctuation, were found. CONCLUSION: LSV is not dependent on normals' reference data or repeated threshold determinations, thus potentially reducing test time. Also, the illustrated pointwise maps of LSV could provide a method for identifying areas of fluctuation commonly found in early glaucomatous field loss.

Motion detection threshold and field progression in normal tension glaucoma.

Psychophysical tests may demonstrate abnormalities of visual function before the appearance of conventional visual field loss in glaucoma. Motion detection thresholds (MDT) were measured in the normal fellow eye of 51 patients with confirmed normal tension glaucoma and initially unilateral field loss. Humphrey visual fields from the initially normal eye covering a mean follow up of 3.4 years were assessed using pointwise linear regression analysis. In 22 of the 51 eyes with normal visual fields at presentation, field deterioration occurred at one or more Humphrey locations within a mean of 1.7 (SD 1.6) years. An initially abnormal MDT test showed a sensitivity of 73% and a specificity of 90% in predicting field deterioration within the cluster of four Humphrey locations closest to the original MDT test site. Sensitivity was lower (40%) in predicting progression at retinal locations distant from the MDT test site, though specificity remained high (90%).