Quantifying biomarkers of axonal degeneration in early glaucoma to find the disc at risk.

To evaluate regional axonal-related parameters as a function of disease stage in primary open angle glaucoma (POAG) and visual field (VF) sensitivity. Spectral domain optical coherence tomography was used to acquire 20° scans of POAG (n = 117) or healthy control (n = 52) human optic nerve heads (ONHs). Region specific and mean nerve fibre layer (NFL) thicknesses, border NFL and peripapillary NFL, minimum rim width (MRW)/ area (MRA) and prelamina thickness; and volume were compared across POAG disease stages and with visual field sensitivity. Differences identified between early glaucoma (EG), preperimetric glaucoma (PG) and control (C) ONHs included thinner PG prelamina regions than in controls (p < 0.05). Mean border NFL was thinner in EG (p < 0.001) and PG (p = 0.049) compared to control eyes; and EG mean, and inferior and ST, border NFL was thinner than in PG (p < 0.01). Mean, superior and inferior PG peripapillary NFL were thinner than in controls (p < 0.05), and EG ST peripapillary NFL was thinner than in PG (p = 0.023). MRW differences included: PG SN and inferior less than in controls (p < 0.05); thinner EG mean regional, inferior, nasal, and ST MRW versus PG MRW (p < 0.05). Regional border NFL, peripapillary NFL, MRW, MRA, prelamina thickness (except centre, p = 0.127) and prelamina volume (p < 0.05) were significantly associated with VF mean deviation (MD). Novel axon-derived indices hold potential as biomarkers to detect early glaucoma and identify ONHs at risk.

The relationship between stimulus intensity and response amplitude for the photopic negative response of the flash electroretinogram.

The aim of this study was to investigate the relationship between stimulus intensity and response amplitude for the photopic negative response (PhNR) of the flash ERG. Specific aims were (i) to determine whether a generalized Naka-Rushton function provided a good fit to the intensity-response data and (ii) to determine the variability of the parameters of the best-fitting Naka-Rushton models. Electroretinograms were recorded in 18 participants, on two occasions, using both DTL fibre and skin active electrodes, in response to Ganzfeld red stimuli (Lee filter "terry red") ranging in stimulus strength from -1.30 to 0.53 log cd.s.m(-2) (0.28-2.11 log phot td.s) presented over a steady blue background (Schott glass filter BG28; 3.9 log scot td). PhNR amplitude was measured from b-wave peak and from pre-stimulus baseline. The Naka-Rushton function was fitted to all intensity-response data, and parameters, 'n', 'Vmax' and 'K' were obtained. Coefficients of variation (CoV), and inter-ocular and inter-session limits of agreement (LoA) were calculated for both Naka-Rushton parameters. A generalized Naka-Rushton function was found to provide a good fit to the intensity-response data, except at the highest stimulus intensity, where a reduction in amplitude occurred in many individuals. The 'Vmax' parameter was less variable than 'K' for all intensity-response data. Variability was lower for DTL than skin electrodes, and for peak-to-trough PhNR measurements, compared to baseline-to-trough. This study has demonstrated for the first time that the Naka-Rushton model provides a useful means of quantifying the intensity-response relationship of the PhNR.

Discrimination of glaucomatous optic neuropathy by digital stereoscopic analysis.

PURPOSE: To evaluate the diagnostic power of a novel digital stereoscopic imaging system in the diagnosis of glaucomatous optic neuropathy. DESIGN: Prospective cross-sectional analysis of the diagnostic accuracy of digital stereoscopic optic disc analysis in the diagnosis of glaucomatous optic neuropathy exhibiting mild to moderate field loss. PARTICIPANTS: Fifty-two patients with open-angle glaucoma and 54 normal individuals were recruited. The presence of a reproducible visual field loss characteristic of glaucoma was used as the reference standard for the presence of glaucoma independent of the optic nerve head appearance. Patients were excluded if the optic disc, fundus, or visual field indicated other disease. One eye from each patient and individual was included in the study, the eye with the least field loss and a randomly designated normal eye, respectively. METHODS: Simultaneous stereoscopic optic disc photography was performed on each specified eye. Three experienced observers viewed the resultant stereoscopic image of each nerve head using a Z screen, recorded a subjective clinical diagnosis, and undertook digital stereoscopic planimetry. Separate linear regression analysis was performed, post hoc, from the planimetric results for each observer of the logarithm of neuroretinal rim (NRR) against optic disc area derived from each normal eye. Eyes with NRR areas below the 95th prediction interval of the normal cohort were then classified as glaucomatous. MAIN OUTCOME MEASURES: Sensitivity and specificity for the detection of glaucomatous optic neuropathy. RESULTS: With subjective stereoscopic analysis, sensitivity for glaucoma detection among the 3 observers was 80.8%, 76.9%, and 90.4%, with respective specificities of 94.4%, 79.6%, and 79.6%. Regression analysis of the NRR in 30 degrees segments gave sensitivities between 69.2% and 80.8% and specificities between 83.3% and 90.7%. A combination of the subjective and quantitative analysis did not significantly improve discrimination. CONCLUSIONS: The subjective analysis of digital stereoscopic images provides a useful method for the discrimination of normal and glaucomatous optic nerves. Planimetric analysis does not significantly improve the diagnostic precision of this technique.

Digital imaging of the optic nerve head: monoscopic and stereoscopic analysis.

AIMS: To compare monoscopic and stereoscopic assessment of the optic disc using novel software for the digital stereoscopic analysis of optic disc stereopairs. METHODS: Software was developed for the stereoscopic display of digital optic disc images using an interlaced display method. Neuroretinal rim width was determined at 10 degree intervals around the optic disc using a custom (stereoscopic) cursor whose depth was adjusted to that of Elschnig's rim. Measurements were taken, first viewing the disc monoscopically and at a separate sitting, stereoscopically. RESULTS: Measurements were made in 35 eyes from 35 patients (1260 estimates for each observer) using three observers. The mean cup to disc ratio (CDR) ranged from 0.57 to 0.66 (SD 0.13-0.14) for monoscopic viewing compared with 0.64 to 0.69 (SD 0.12-0.14) for stereoscopic viewing. Stereoscopic assessments gave higher CDRs in temporal, superior, nasal, and inferior aspects of the optic disc (p<0.001, Mann-Whitney U test). Agreement between observers in estimating CDR was high for monoscopic assessment (intraclass correlation coefficient 0.74 (CI 0.72 to 0.76) increasing to 0.80 (0.78 to 0.82) for stereoscopic assessment. CONCLUSION: Digital stereoscopic optic disc assessment provides lower estimates of neuroretinal rim width and higher levels of interobserver agreement compared with monoscopic assessments.

Visual function in young IDDM patients over 8 years of age. A 4-year longitudinal study.

OBJECTIVE: To carry out a longitudinal study of visual functions in young patients over the age of 8 years with IDDM and to assess the impact of metabolic control on the presence of diabetic retinopathy. RESEARCH DESIGN AND METHODS: There were 37 young IDDM patients from the Paediatric and Adolescent Clinic at the University Hospital of Wales studied annually for 4 years, with a control group of 24 healthy subjects observed over a 2-year period. Assessment of visual functions included visual acuity, color vision, and contrast sensitivity. Ophthalmoscopy and retinal photography were used to determine the presence or absence of diabetic retinopathy. In addition, pubertal status and metabolic control (glycosylated hemoglobin) were determined at each visit. RESULTS: Patients with IDDM demonstrate abnormal color vision and contrast sensitivity compared with the control group (P < 0.05), but visual acuity was unaffected. Visual functions were not significantly different between those IDDM patients with and without retinopathy. After 4 years, diabetic retinopathy was present in 43% of the group and was related to diabetes duration and metabolic control (P < 0.05). CONCLUSIONS: Visual function testing could not distinguish between those IDDM patients with and without retinopathy, but the color vision and contrast sensitivity in those with IDDM were significantly impaired compared with the control group. The presence of retinopathy was related to the duration of diabetes and metabolic control. It is important to ensure that good glycemic control and regular attendance for retinopathy screening is encouraged in the adolescent patients.

The s-cone PHNR and pattern ERG in primary open angle glaucoma.

PURPOSE: To compare the sensitivity of the photopic negative response (PhNR) from the shortwave (S)-sensitive and the long (L)- and medium (M)-wave-sensitive cone electroretinograms (ERGs), with the pattern electroretinogram (PERG) in the early stages of primary open-angle glaucoma (POAG). METHODS: Eighteen patients under treatment for diagnosed POAG and 19 normal control subjects were investigated. S-cone ERGs were elicited using adaptation to 650-nm light to suppress L-cone activity, and substitution between 450 nm and 535 nm to silence M-cone response at luminances higher than rod saturation. PhNRs from the L&M-cone pathways were elicited by a 200-msec pulse of red light (650 nm) on a continuous blue (450 nm) background. PERGs were recorded in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standard. RESULTS: Each method showed a statistically significant difference in the two groups. The S-cone PhNR was the most sensitive test and provided the most statistically significant results, with the largest area enclosed by the receiver operating characteristic (ROC) curve. CONCLUSIONS: The findings indicate that all three types of ERG may be useful in glaucoma investigation. The L- and M-cone PhNRs may have a role in monitoring established glaucoma. The previously reported high sensitivity of the PERG was confirmed. Extensive diffuse damage to S-cone bipolar and bistratified ganglion cells appears to occur at a very early stage in POAG, owing to a pressure-related mechanism, and the S-cone PhNR was the most sensitive test. It may in future have an important role in diagnosis and monitoring of early glaucoma. Further investigation of this possibility is recommended.

The effects of astigmatism and working distance on optic nerve head images using a Heidelberg Retina Tomograph scanning laser ophthalmoscope.

PURPOSE: To determine effects of astigmatism and working distance on optic nerve head images in normal patients using the Heidelberg Retina Tomograph. METHODS: The optic disks of 51 normal healthy subjects, aged 19 to 44 years, were imaged through dilated pupils. Subjects with 0.75 DC or less of astigmatism were imaged without correction at a working distance of 15 mm. They were then re-imaged with a cylindrical correction of +3.00 DC at 90 degrees axis (n = 20). Naturally astigmatic subjects with more than 1.00 DC were imaged without correction and then re-imaged once this was neutralized with their appropriate spectacle prescription (n = 15). The effects of working distance were studied using subjects with 0.75 DC or less (n = 16). Two working distances were used, 15 and 25 mm. At each session the means of three topographic images were taken from which standard deviations and parameters were recorded. Parameters analyzed included cup shape measure, rim area, and inferior temporal rim volume. Z-profile full width at half maximum was calculated from one image per subject for each condition. RESULTS: No significant difference was found in the measured parameters of the optic disk for any astigmatic condition or changes in working distance (P >.05), (paired t test). Both the standard deviation of the mean topographic images and the Z-profile half-maximum width of the axial intensity profile were significantly greater with induced astigmatism of +3.00 DC (P values 0.3 and.00, respectively). CONCLUSIONS: Optic disk parameters are not significantly affected by uncorrected astigmatism (up to 2.50 DC) or working distance. The algorithm used by the Heidelberg Retina Tomograph to generate topographic maps is sufficiently robust that astigmatism up to 2.50 DC does not require correction.

Dark adaptation in diabetes mellitus.

The effect of diabetes mellitus on the normal dark adaptation curve is investigated. It has been found that diabetic patients take longer to adapt and that their absolute thresholds are raised. The degree of elevation in the final threshold correlates with the duration of diabetes.

Acutance, an objective measure of retinal nerve fibre image clarity.

BACKGROUND/AIMS: The interpretation of high contrast retinal nerve fibre layer (RNFL) images in glaucoma can be confounded by the presence of image blur; it can be difficult to discern diffuse axon loss in a poor quality image. One solution is to provide an objective measure of the image quality based on features in the image other than the RNFL. In this study the authors have developed an objective method to quantify the clarity of RNFL images, comparing it with a subjective image grading system. METHODS: Digitally acquired, monochrome retinal images were taken from 58 eyes (one image per eye) with a Topcon 50 IX retinal camera. Image resolution was 1320 x 1032 pixels at 8 bits per pixel. Image sharpness was subjectively graded by two masked experienced observers on a scale 1 to 5 relative to a reference set of RNFL images. Software algorithms were developed using Matlab (5.2) to calculate the acutance, an objective measure of the physical characteristics that underlie the subjective impression of sharpness in an image. RESULTS: Acutance values could be calculated for all the images. The Pearson correlation coefficients of the log of the acutance for each image and the subjective grades of observer 1 and observer 2 were 0.90 (p<0.001, n=58) and 0.84 (p<0.001, n=58) respectively. CONCLUSIONS: These data suggest that acutance may provide a useful objective measure of image quality, which correlates well with the subjective impression of the digital retinal image sharpness. Objective measures of image quality should help in the discrimination of diffuse retinal nerve fibre loss from image blur in patients with diffuse glaucomatous damage.

The Humphrey optical coherence tomography scanner: quantitative analysis and reproducibility study of the normal human retinal nerve fibre layer.

BACKGROUND/AIMS: To determine the reproducibility of the Humphrey optical coherence tomography scanner (OCT), software version 5.0, for measurement of retinal nerve fibre layer (RNFL) thickness in normal subjects and to compare OCT measurements with published histological thickness of the human RNFL. METHODS: Three independent measurements were obtained at each session for one eye from 15 normal subjects with a mean age of 30.8 (SD 10.9) years. Scans were taken in the peripapillary retina using the default setting (1.74 mm radius from centre of the optic disc) and were repeated 1 week later. Additional scans were obtained at the optic nerve head (ONH) margin overlying the scleral rim, for comparison with available histological data on the human RNFL. RESULTS: For the 1.74 mm circular scan, the mean coefficient of variation (COV) for the global RNFL thickness measurement was 5% (SD 3%). This increased to 8% (3%) for quadrant measurements and to 9% (3%) with further subdivision into 12 segments. Significant differences (p<0.05) between sessions were only found when the data were divided into segments. The mean RNFL thickness for the 1.74 mm scan was 127.87 (9.81) microm. The RNFL was maximal at the superior disc pole, 161.44 microm (14.8), and minimal at the temporal pole, 83.1 (12.8) microm. Peak thickness values occurred superior temporal and inferior temporal to the vertical axis. RNFL thickness for every sector of the disc was greatest at the margin of the optic disc (mean 185.79 microm; SD 32.61). Although the variation in RNFL thickness around the disc follows published histology data, the OCT underestimates RNFL thickness by an average of 37% (SD 11; range 21-48%). CONCLUSION: The OCT provides reproducible measurement of the retinal structures that are consistent with the properties of the RNFL. However, comparison with available studies of RNFL thickness in the human suggests that in its present form, the OCT underestimates RNFL thickness. Further refinement of this technology is required to improve the accuracy with which the OCT measures retinal nerve fibre layer thickness.

Quantitative comparison of static perimetric strategies in early glaucoma: test-retest variability.

PURPOSE: The aim of this study is to describe and compare test-retest variability of threshold-related suprathreshold and threshold examination strategies. METHODS: Threshold-related suprathreshold and FASTPAC threshold central visual field examinations were performed twice (test and retest) within a 4-week period on 322 subjects with early to moderate primary open-angle glaucoma and glaucoma suspects. For both strategies, defects were quantified by a count, or score, of the number of defective locations within the field as a whole and by hemifield, thereby providing a simple measure of defect extent. This quantification was obtained for the suprathreshold strategy at three suprathreshold increments (5, 8, and 12 dB) and for the full threshold strategy at two levels of pattern deviation probability, although absolute full threshold defect depth was not considered. Mean test-retest score differences and spread of score differences were used to describe variability. An index of relative variability was used to compare the two visual field examination strategies. RESULTS: Marked degrees of defect extent variability were found to exist in both suprathreshold and FASTPAC examination strategies. In general, the suprathreshold strategy exhibited lower test-retest variability of defect extent than the FASTPAC strategy. Suprathreshold test variability was dependent on the suprathreshold increment. FASTPAC examination variability was independent of defect depth when analyzed on the basis of pattern deviation probability values and was also found to be independent of the area of visual field loss. CONCLUSIONS: Suprathreshold examination techniques may provide a reliable perimetric alternative to thresholding strategies for monitoring individuals with early and moderate glaucoma, although they may not be suitable for individuals with advanced glaucomatous visual field loss.

Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis.

OBJECTIVES: To determine the incidence of any and referable diabetic retinopathy in people with type 2 diabetes mellitus attending an annual screening service for retinopathy and whose first screening episode indicated no evidence of retinopathy. DESIGN: Retrospective four year analysis. SETTING: Screenings at the community based Diabetic Retinopathy Screening Service for Wales, United Kingdom. PARTICIPANTS: 57,199 people with type 2 diabetes mellitus, who were diagnosed at age 30 years or older and who had no evidence of diabetic retinopathy at their first screening event between 2005 and 2009. 49,763 (87%) had at least one further screening event within the study period and were included in the analysis. MAIN OUTCOME MEASURES: Annual incidence and cumulative incidence after four years of any and referable diabetic retinopathy. Relations between available putative risk factors and the onset and progression of retinopathy. RESULTS: Cumulative incidence of any and referable retinopathy at four years was 360.27 and 11.64 per 1000 people, respectively. From the first to fourth year, the annual incidence of any retinopathy fell from 124.94 to 66.59 per 1000 people, compared with referable retinopathy, which increased slightly from 2.02 to 3.54 per 1000 people. Incidence of referable retinopathy was independently associated with known duration of diabetes, age at diagnosis, and use of insulin treatment. For participants needing insulin treatment with a duration of diabetes of 10 years or more, cumulative incidence of referable retinopathy at one and four years was 9.61 and 30.99 per 1000 people, respectively. CONCLUSIONS: Our analysis supports the extension of the screening interval for people with type 2 diabetes mellitus beyond the currently recommended 12 months, with the possible exception of those with diabetes duration of 10 years or more and on insulin treatment.

Evaluation of the high specificity Screening Program (C-20-1) of the Frequency Doubling Technology (FDT) perimeter in clinical practice.

AIMS: To compare the efficacy of the high specificity Frequency Doubling Technology (FDT) Perimeter Screening Program (C-20-1) to standard threshold automated perimetry in the diagnosis of open-angle glaucoma. METHODS: A total of 100 consecutively presenting patients attending a glaucoma clinic who volunteered for the study (approximately 30% of whom were attending for an initial visit) were examined with the FDT C-20-1 Screening Program and with the Humphrey Field Analyzer (HFA) SITA Fast algorithm and Program 24-2. RESULTS: Of the patients, 17 were excluded due to unreliable visual field results or non-glaucomatous ocular abnormalities. In all, 10 patients were diagnosed as normal, 54 with open-angle glaucoma, eight with ocular hypertension, and 11 as glaucoma suspects. Of the 54 glaucomatous patients, 45 exhibited high-tension glaucoma and nine normal tension glaucoma. Perimetry with the HFA gave a sensitivity of 81.5% for the combined category of glaucoma and glaucoma suspect and a specificity of 83.3% for the combined category of normal and ocular hypertension. Perimetry with the FDT gave a sensitivity of 74.5% and a specificity of 85.2% compared to that of the HFA. CONCLUSION: In the detection of glaucoma, Program C-20-1 of the FDT perimeter exhibits high specificity. It exhibits low sensitivity for the detection of mild loss but high sensitivity for advanced field loss relative to Program 24-2 and the SITA Fast algorithm of the HFA.

The relationship between the extent of visual field and driving performance--a review.

The effect of the extent of visual field upon driving performance has recently received a great deal of interest. With such a volume of traffic on the roads today, peripheral vision would seem to be essential for safe driving and yet past literature is inconclusive as to the relationship between the extent of visual field and driving performance. This paper reviews the research work and gives possible reasons for the lack of relationship reported in most of the studies. Until further research work does determine the minimum visual field required for safe driving, the role of the medical practitioner in advising patients when they are considered unsafe to drive is in question. The provision of a period of adaptation after complete loss of vision in a previously normal eye should also be considered, during which time the motorist is temporarily banned from driving.

Early ocular and non-ocular indications of diabetes mellitus.

This article aims to review the early indications of diabetes, both ocular and non-ocular. Epidemiological data is showing an increase in both non-insulin dependent and insulin dependent diabetes mellitus. It is therefore important that diabetes mellitus is detected early so that regular screening and good metabolic control can be encouraged. Strict glycaemic control is important in order to delay the onset or slow the progression of diabetic complications.

Effect of orthoptics upon the ability of patients to adapt to prism-induced heterophoria.

In a previous study we showed that subjects with abnormal binocular vision either lacked or had a deficient ability to adapt their oculomotor systems to a prism-induced heterophoria. In this study we report on the results of an experiment designed to establish whether the adaptation ability improves in patients who are successfully treated, by means of orthoptics, for convergence insufficiency. In all seven patients examined, we found an improved ability to adapt. Whereas at the beginning of the experiment only two patients fell within the 95% confidence limits of the norm, at the end five patients fell within these limits. These results demonstrate that the success of orthoptics in relieving symptoms is associated with an improved ability to adapt to prism-induced heterophoria.

Atropine occlusion in the treatment of strabismic amblyopia and its effect upon the non-amblyopic eye.

A total of 189 cases with amblyopia, where atropine sulphate 1% had been used as a method fo unilateral occlusion, were reviewed. The results show that after atropine had been appropriately applied, permanent reversal of amblyopia is rare, and unwanted side-effects are few and of minor nature. Pupil size, light reflex and accommodation of the atropinized eye appear to be unaffected. The angle of squint was unaffected and fixation of the amblyopic eye either remained unchanged or shifted to a more central point.

A review of the uses and adverse effects of topical administration of atropine.

Atropine is used widely in the treatment of a variety of ocular conditions. This article reviews the uses of atropine in children and any adverse ocular or systemic side effects that have been reported after topical instillation.

Vergence adaptive changes with varying magnitudes of prism-induced disparities and fusional amplitudes.

Vergence adaptation response monitored with various prism disparities demonstrated that the rates of adaptation decreased as the prismatic effect was increased. However, the amount adapted increased with the increase in the value of the prism until this value fell outside the fusional amplitude; the amount adapted then decreased. However, a large disparity can be adapted to with ease if the prismatic effect is increased gradually in small steps. The clinical implications of these results are discussed.

The effect of orthoptic treatment upon the vergence adaptation mechanism.

This paper is a review of the research work that has been carried out over the past few years investigating the ability of the oculomotor system to adapt to prism-induced heterophoria. Our results show that subjects with normal binocular vision can adapt to horizontal and vertical prism-induced heterophorias whether fixating at distance or near. Further studies have shown that subjects with symptomatic abnormal binocular vision have an abnormal adaptation mechanism. Finally, we have found that when orthoptic treatment results in relief from the symptoms, there is an associated improvement in the subjects' ability to adapt to prism-induced heterophoria.