The rate of structural change: the confocal scanning laser ophthalmoscopy ancillary study to the ocular hypertension treatment study.

PURPOSE: To compare rates of topographic change in ocular hypertensive eyes that develop primary open-angle glaucoma (POAG) compared to eyes that do not, and to identify factors that influence the rate of change. DESIGN: Longitudinal, randomized clinical trial. METHODS: Four hundred forty-one participants (832 eyes) in the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study were included. POAG was defined as repeatable visual field, photography-based optic disc changes, or both. The rate of topographic change in the 52 participants (66 eyes) who developed POAG was compared with that of participants who did not develop POAG using multivariable mixed effects models. RESULTS: In both univariate and multivariate analyses, the rate of rim area loss was significantly faster in eyes in which POAG developed than in eyes in which it did not (univariate mean, -0.0131 mm(2)/year and -0.0026 mm(2)/year, respectively). The significantly faster rate of rim area loss in black persons found in the univariate analysis did not remain significant when baseline disc area was included in the model. In multivariate analyses, the rate of rim area loss and other topographic parameters also was significantly faster in eyes with worse baseline visual field pattern standard deviation and higher intraocular pressure during follow-up. Moreover, a significant rate of rim area loss was detected in eyes in which POAG did not develop (P < .0001). The rate of rim area loss in eyes with an optic disc POAG endpoint was significantly faster than in those with a visual field POAG endpoint. CONCLUSIONS: The rate of rim area loss is approximately 5 times faster in eyes in which POAG developed compared with eyes in which it did not. These results suggest that measuring the rate of structural change can provide important information for the clinical management of ocular hypertensive patients. Additional follow-up is needed to determine whether the statistically significant change in the eyes in which POAG did not develop represents normal aging or glaucomatous change not detected by conventional methods.

Predicting the onset of glaucoma: the confocal scanning laser ophthalmoscopy ancillary study to theOcular Hypertension Treatment Study.

OBJECTIVE: To evaluate the predictive ability of baseline confocal scanning laser ophthalmoscopy (CSLO) Glaucoma Probability Score (GPS) for the development of primary open-angle glaucoma (POAG) and to compare it with the Moorfields regression analysis (MRA) classification, other topographic optic disc parameters, and stereophotograph-based cup-to-disc ratio. DESIGN: Longitudinal, randomized clinical trial. PARTICIPANTS: We included 857 eyes of 438 participants in the CSLO Ancillary Study to the Ocular Hypertension Treatment Study (OHTS) with good quality baseline CSLO images. METHODS: The ability of baseline GPS, MRA, and optic disc parameters to predict the development of POAG was evaluated in univariate and multivariable proportional hazard ratio analyses. Likelihood ratios and positive and negative predictive values were compared. MAIN OUTCOME MEASURES: The POAG end point as determined by repeatable changes in the visual field or optic disc. RESULTS: Sixty-four eyes of 50 CSLO Ancillary Study participants developed POAG. Median time to reach a POAG end point was 72.3 months. The 93 eyes of 388 participants not reaching endpoint were followed for a median of 124.9 months. Baseline GPS identified many more eyes as outside normal limits than the MRA. In multivariable analyses, all regional and global baseline GPS indices were significantly associated with the development of POAG; hazard ratios (95% confidence interval) ranged from 2.92 to 3.74 for an outside normal limits result. The MRA indices were also significantly associated with the development of POAG in multivariable analyses. In addition, the predictive ability of baseline GPS, MRA and stereometric parameters were similar to the predictive ability of models using photograph-based horizontal cup-to-disc ratio. CONCLUSIONS: These results suggest that baseline GPS, MRA, and stereoparameters alone or when combined with baseline clinical and demographic factors can be used to predict the development of POAG end points in OHTS participants and are as effective as stereophotographs for estimating the risk of developing POAG in ocular hypertensive subjects.

MRI retinovascular studies in humans: research in patients with diabetes.

PURPOSE: To review existing applications of MRI for detecting blood-retinal barrier (BRB) damage and retinal oxygenation response abnormalities in patients with diabetes and highlight new information available from such applications. METHODS: BRB studies were accomplished using dynamic contrast-enhanced MRI, and the retinal oxygenation response studies were accomplished by monitoring changes in the MRI signal associated with hyperoxic provocation. Participants were patients with diabetes and macular edema, with either no detectable or mild to moderate background retinopathy, as well as non-diabetic individuals of similar age (controls). Single-slice FLASH images were obtained using a Siemens Sonata, 1.5 T together with a Siemens 'Loop Small' surface coil fixed in place over the eye. Time-dependent changes in image contrast in the pre-retinal vitreous were quantified, and differences between patients and controls were assessed statistically. RESULTS: The BRB breakdown studies showed a significant difference in the temporal evolution of the MRI signal enhancement post-contrast injection between the controls and the patients with diabetic macular edema. The retinal oxygenation studies revealed a supernormal oxygenation response in the pre-retinal vitreous in patients with diabetes who had no evidence of retinopathy, as well as in patients with background diabetic retinopathy. A nasal-temporal asymmetry in the evolution of retinal oxygenation response was found in patients with diabetes that was not present in healthy subjects. CONCLUSIONS: These studies show that subtle differences in retinovascular function between patients with diabetes and non-diabetic individuals, including changes that occur in advance of the clinical appearance of diabetic retinopathy, can be detected with MRI. These results, together with previous extensive preclinical data, establish MRI as a powerful non-invasive method for measuring spatial and temporal changes in the same key retinovascular metrics in both animals and humans. Wide application of these techniques for diagnosis and evaluation of treatment efficacy in a variety of human retinopathies, including diabetic retinopathy, is expected.

A new method for eyelid elevation in glaucoma patients with ptosis during automated perimetry testing.

PURPOSE: Ptosis is a well-recognized confounding factor when interpreting superior visual field defects. As the current technique for eyelid elevation during automated perimetry is cumbersome and inconsistent, we developed a new technique. To evaluate its efficacy and feasibility, we studied a group of glaucoma patients with ptosis and superior visual field defects that had been attributed to nerve fiber layer defects. PATIENTS AND METHODS: A 24-2 SITA-fast visual field was performed without eyelid elevation. Then, it was repeated either with elevation (group A, 14 eyes, 7 patients) or without (group B, 9 eyes, 5 patients). Elevation was achieved by the following method: a 4-0 silk suture (needle removed) was wrapped around a micropore strip, attached to the upper eyelid margin. Suture edges were pulled and attached to the forehead creating a slinglike elevation. Mean thresholds of upper and lower hemifields were calculated. Mean deviation and pattern standard deviation were recorded for each visual field. Results of the first and second tests were compared. RESULTS: Eyelid elevation resulted in significant improvement in mean thresholds for upper hemifield in group A: values increased by 28% in OD and 22% in OS. Lower hemifield values did not change. Significant improvement also was observed in mean deviation and pattern standard deviation. In group B, there were no significant differences between the 2 sets of tests. CONCLUSIONS: This new method of eyelid elevation significantly improves visual field testing by reducing the confounding effect of ptosis on interpretation of visual field defects in glaucoma patients.

Early supernormal retinal oxygenation response in patients with diabetes.

PURPOSE: To determine whether the human retinal oxygenation response (deltaPO2) to a hyperoxic provocation is abnormal in patients with type I diabetes. METHODS: Magnetic resonance imaging (MRI) was used to measure deltaPO2 during 100% oxygen breathing in patients with type I diabetes who had either no clinically detectable retinopathy (n = 5) or mild to moderate background diabetic retinopathy (BDR; n = 5) and in age-matched healthy control subjects (n = 7). RESULTS: Both the patients with diabetes and the control subjects exhibited a significant (P < 0.05) increase in the preretinal vitreous signal intensity on changing from room air breathing to oxygen inhalation (i.e., 5 minutes). However, only diabetic patients demonstrated significant (P < 0.05) increases in deltaPO2 between measurements made at 5 minutes of oxygen inhalation and measurements at longer durations of hyperoxia (15, 25, and 35 minutes). Furthermore, deltaPO2 was significantly (P < 0.05) greater in patients with diabetes than in control subjects, but there was no significant difference in deltaPO2 (P > 0.05) between patients with diabetes, with or without retinopathy. Age and deltaPO2 correlated significantly (P < 0.05) in control subjects but not in patients with diabetes. In control subjects, deltaPO2 was relatively uniform panretinally, whereas in the diabetic group, changes in oxygenation response were spatially inhomogeneous. CONCLUSIONS: These results demonstrate, for the first time, that MRI deltaPO2 detects a significant supernormal retinal oxygenation response in patients with type I diabetes, even before the appearance of retinopathy. This study raises the possibility of using MRI measurements of deltaPO2 to monitor therapeutic efficacy in human trials.

A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma.

OBJECTIVE: To examine resource consumption and the direct costs of treating glaucoma at different disease severity levels. DESIGN: Observational, retrospective cohort study based on medical record review. PARTICIPANTS: One hundred fifty-one records of patients with primary open-angle or normal-tension glaucoma, glaucoma suspect, or ocular hypertension (age > or =18 years) were randomly selected from 12 sites in the United States and stratified according to severity based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients had to have been followed up for a minimum of 5 years. Patients with concomitant ocular disease likely to affect glaucoma treatment-related resource consumption were excluded. METHODS: Glaucoma severity was assessed and assigned using a 6-stage glaucoma staging system, modified from the Bascom Palmer (Hodapp-Anderson-Parrish) system. Clinical and resource use data were collected from the medical record review. Resource consumption for low-vision care and vision rehabilitation was estimated for patients with end-stage disease based on specialist surveys. For each stage of disease, publicly available economic data were then applied to assign resource valuation and estimate patient-level direct costs from the payer perspective. MAIN OUTCOME MEASURES: Average annual resource use and estimated total annual direct cost of treatment were calculated at the patient level and stratified by stage of disease. Direct costs by specific resource types, including ophthalmology visits, glaucoma surgeries, medications, visual field examinations, and other glaucoma services, were also assessed. RESULTS: Direct ophthalmology-related resource use, including ophthalmology visits, glaucoma surgeries, and medication use, increased as disease severity worsened. Average direct cost of treatment ranged from $623 per patient per year for glaucoma suspects or patients with early-stage disease to $2511 per patient per year for patients with end-stage disease. Medication costs composed the largest proportion of total direct cost for all stages of disease (range, 24%-61%). CONCLUSIONS: The study results suggest that resource use and direct cost of glaucoma management increase with worsening disease severity. Based on these findings, a glaucoma treatment that delays the progression of disease could have the potential to significantly reduce the health economic burden of this chronic disease over many years.

Advances in imaging of the optic disc and retinal nerve fiber layer.

In the past decade, three technologies for imaging the optic disc and retinal nerve fiber layer have become commercially available: 1) confocal scanning laser tomography with the Heidelberg retinal tomograph; 2) confocal scanning laser polarimetry with the GDx VCC; and 3) optical coherence tomography with the Stratus OCT. Each uses different principles of physics. Understanding the merits and limitations of each of these technologies requires familiarity with the principles of operation of each device. This knowledge should be considered a prerequisite for the appropriate clinical utilization of these devices and for accurate interpretation of their results.

Dynamic contrast enhanced MRI in patients with diabetic macular edema: initial results.

To assess the ability of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to detect blood retinal barrier (BRB) damage in patients with diabetic macular edema (DME). DCE-MRI with 0.1 mmol Gd-DTPA was used to measure BRB permeability in 10 healthy and visually normal subjects and eight patients with DME, including five patients with non-clinically significant (NCS) DME and three patients with clinically significant (CS) DME. For each subject, the enhancement of the MRI signal intensity in the pre-macular vitreous was measured as a function of time following contrast injection. A linear regression analysis was performed on each subject and the slopes of the contrast enhancement functions were compared. The DCE-MRI procedure was well tolerated by all 18 subjects. However, in four subjects, excessive eye movements resulted in spurious results. Consequently, 78% (14/18) of the subjects provided usable data. The mean slope of the control group was not significantly (p>0.05) different from zero (i.e. signal intensity in the pre-macular vitreous space was constant as a function of time post-contrast injection). For the diabetic patients, the average slope of the contrast enhancement function was significantly greater than in the control group (p<0.01). Furthermore, for both diabetic sub-groups, the average slopes were greater (p<0.05) than that for the control group but not significantly (p>0.05) different from each other. This 'proof of concept' study demonstrated that DCE-MRI detects passive leakage through the BRB in diabetic patients with either NCS or CS macular edema. In future studies, DCE-MRI may be useful for early quantitative evaluation of drug treatment effects in patients with DME.

Retinal oxygenation response and retinopathy.

Oxygen supply and demand of the retina, one of the most metabolically active tissues in the body, must be dynamically balanced to insure the health of the tissue. The integrity of such active regulation can be assessed by measuring retinal oxygenation response (ROR) to a hyperoxic provocation. Over the last decade, we have developed an MRI-based technique to measure ROR as a change in vitreal oxygen level from room air breathing to a new hyperoxic condition (DeltaPO2). This review summarizes progress to-date in the development and application of MRI ROR measures in retinopathy with emphasis on the spatial and temporal association of subnormal ROR and non-proliferative and proliferative retinopathy, as well as examining the usefulness of ROR as a surrogate marker of drug treatment efficacy. Recent adaptation of the MRI technique has made measurement of human ROR routine raising the likelihood of clinical trials.

Beyond visual acuity: new and complementary tests of visual function.

Visual acuity is an essential component of the routine ophthalmic examination and the most common measure of visual function. There is increasing recognition, however, of the need to evaluate visual function beyond the limited extent afforded by visual acuity. The primary objective of this article is to introduce a variety of new and lesser-used techniques for measuring visual function that complement visual acuity assessment, each of which has been shown to detect visual dysfunction in patients with normal visual acuity.