Purpose
To present and evaluate a new method of estimating rates of retinal ganglion cell (RGC) loss in glaucoma by combining structural and functional measurements.
Design
Observational cohort study.
Methods
The study included 213 eyes of 213 glaucoma patients followed up for an average of 4.5 ± 0.8 years with standard automated perimetry visual fields and optical coherence tomography. A control group of 33 eyes of 33 glaucoma patients underwent repeated tests over a short period to test the specificity of the method. An additional group of 52 eyes from 52 healthy subjects followed up for an average of 4.0 ± 0.7 years was used to estimate age-related losses of RGCs. Estimates of RGC counts were obtained from standard automated perimetry and optical coherence tomography, and a weighted average was used to obtain a final estimate of the number of RGCs for each eye. The rate of RGC loss was calculated for each eye using linear regression. Progression was defined by a statistically significant slope faster than the age-expected loss of RGCs.
Results
From the 213 eyes, 47 (22.1%) showed rates of RGC loss that were faster than the age-expected decline. A larger proportion of glaucomatous eyes showed progression based on rates of RGC loss rather than based on isolated parameters from standard automated perimetry (8.5%) or optical coherence tomography (14.6%; P < .01), while maintaining similar specificities in the stable group.
Conclusions
The rate of RGC loss estimated from combining structure and function performed better than either isolated structural or functional measures for detecting progressive glaucomatous damage.
Glaucoma is an optic neuropathy characterized by progressive neuroretinal rim thinning, excavation of the optic nerve head, and loss of the retinal nerve fibers. These structural changes usually are accompanied by functional losses, which ultimately may result in significant decrease in vision-related quality of life. Although both the characteristic structural and functional changes seen in the disease ultimately are related to the pathologic loss of retinal ganglion cell (RGC) somas and axons, the measurements of structural and functional change are somewhat variable and have an imperfect relationship to one another, both for recognizing damage and for detecting disease progression over time. Standard automated perimetry (SAP) remains the usual method for monitoring functional changes in the disease. However, patients may demonstrate structural changes in the optic nerve or retinal nerve fiber layer (RNFL) before changes are detected with SAP. Nevertheless, several patients have shown evidence of functional deterioration without measurable changes in currently available structural tests.
The imperfect relationship between structural and functional measurements of the disease seems to be derived largely from the different algorithms and measurement scales, as well as the different variability characteristics of the tests commonly used to assess structural and functional losses. In fact, Harwerth and associates demonstrated that structural and functional tests are in agreement as long as one uses appropriate measurement scales for neural and sensitivity losses and considers factors such as the effect of aging and eccentricity on estimates of neural losses. In a series of investigations, they demonstrated that estimates of RGC losses obtained from clinical perimetry agreed closely with estimates of RGC losses obtained from RNFL assessment by optical coherence tomography (OCT). The results of their model provided a common domain for expressing results of structural and functional tests, that is, the estimates of RGC losses, opening the possibility of combining these different tests to improve the reliability and accuracy of estimates of the amount of neural losses in glaucoma.
In the current study, we combined measurements of structural and functional tests to provide an estimate of the rate of RGC loss in glaucoma patients followed up over time. We showed that the calculated estimates of the rate of RGC loss performed significantly better than isolated measures of structure or of function to detect disease progression over time.
Methods
This was an observational study. Participants from this study were included in 2 prospective longitudinal studies designed to evaluate optic nerve structure and visual function in glaucoma: the African Descent and Glaucoma Evaluation Study and the Diagnostic Innovations in Glaucoma Study. The 3-site African Descent and Glaucoma Evaluation Study collaboration included the Hamilton Glaucoma Center at the Department of Ophthalmology, University of California, San Diego (data coordinating center); the New York Eye and Ear Infirmary; and the Department of Ophthalmology, University of Alabama, Birmingham. Although the Diagnostic Innovations in Glaucoma Study includes only patients recruited at University of California, San Diego, the protocols of the 2 studies are identical. Methodologic details have been described previously.
At each visit during follow-up, subjects underwent a comprehensive ophthalmologic examination, including review of medical history, best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, gonioscopy, dilated funduscopic examination, stereoscopic optic disc photography, and automated perimetry using the Swedish interactive threshold Algorithm standard 24–2. Only subjects with open angles on gonioscopy were included. Subjects were excluded if they had a best-corrected visual acuity of less than 20/40, spherical refraction outside ± 5.0 diopters, cylinder correction outside 3.0 diopters, or a combination thereof; or any other ocular or systemic disease that could affect the optic nerve or the visual field.
Participants
The study included 3 groups of participants. The main study group was composed of 213 eyes of 213 glaucoma patients from the Diagnostic Innovations in Glaucoma Study/African Descent and Glaucoma Evaluation Study cohort followed up for an average of 4.5 ± 0.8 years. Eyes were classified as glaucomatous if they had evidence of glaucomatous optic neuropathy based on masked grading of optic disc stereophotographs, repeatable abnormal visual field test results, or both on the baseline visit. Glaucomatous optic neuropathy was diagnosed based on the presence of neuroretinal rim thinning, excavation, or RNFL defects. Abnormal visual fields were defined as a pattern standard deviation (PSD) outside of the 95% normal confidence limits, or glaucoma hemifield test results outside normal limits. All eyes were followed up at approximately annual intervals with SAP and OCT testing and were required to have a minimum of 5 SAP and 5 OCT images during follow-up.
A control group of 33 eyes from 33 stable glaucoma patients was used to evaluate the specificity of our method. This set consisted of eyes with 5 serial visual fields and OCT examination results collected under an institutional review board-approved protocol within a maximum period of 8 weeks from individuals seen at the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida. All participating subjects were fully informed, and each signed a consent form. All participants had previous experience with visual field testing. Each eye also had to have evidence of glaucoma at baseline based on ocular examination and the presence of repeated visual field loss as defined above. Mean mean deviation (MD) and PSD values at the first visit were −7.4 dB and 8.4 dB, respectively. There was a wide range of disease severity in these eyes, with MD values ranging from −30.43 to 0.91 dB. The assumption was made that the disease was not progressing in these eyes over such a short time and that any change noted would be the result of the variability in the visual fields or OCT measurements in stable glaucoma. Therefore, the order of testing would be exchangeable, and a permutation technique was used to provide a larger data set to evaluate specificity. We generated all possible permutations of the order of the tests so that 3960 different sequences were obtained. For evaluation of rates of change in these eyes, the visits were annualized.
An additional group of 52 eyes from 52 healthy subjects followed up for an average of 4.0 ± 0.7 years was used to evaluate the effect of aging on the rate of RGC loss. All eyes were followed up at approximately annual intervals with SAP and OCT testing and had an average of 4.4 ± 0.6 tests acquired during follow-up. These subjects were recruited from the general population and were required to have normal ophthalmologic examination results, IOP less than 22 mm Hg in both eyes, and normal visual field test results. Normal visual fields were defined as MD and PSD with P > .05 and glaucoma hemifield test results within normal limits.
Visual Field Testing
All patients underwent SAP testing using Swedish interactive threshold algorithm standard 24–2 strategy fewer than 6 months apart from imaging. All visual fields were evaluated by the University of California, San Diego, Visual Field Assessment Center. Visual fields with more than 33% fixation losses, false-negative errors, or more than 15% false-positive errors were excluded. The only exception was the inclusion of visual fields with false-negative errors of more than 33% when the field showed advanced disease (MD lower than −12 dB). Visual fields exhibiting a learning effect (ie, initial tests showing consistent improvement on visual field indexes) also were excluded. Visual fields were reviewed further for the following artifacts: lid and rim artifacts, fatigue effects, inappropriate fixation, evidence that the visual field results were the result of a disease other than glaucoma (such as homonymous hemianopia), and inattention. The University of California, San Diego, Visual Field Assessment Center requested repeats of unreliable visual field test results, and these were obtained whenever possible.
Optical Coherence Tomography
Subjects underwent ocular imaging with dilated pupils using the optical coherence tomograph StratusOCT (Carl Zeiss Meditec, Inc, Dublin, California, USA). Quality assessment of StratusOCT scans was evaluated by an experienced examiner masked to the subject’s results of the other tests. Good-quality scans had to have focused images from the ocular fundus, signal strength of more than 7, and presence of a centered circular ring around the optic disc. The fast RNFL algorithm was used to obtain RNFL thickness measurements with the StratusOCT. Three images were acquired from each subject, with each image consisting of 256 A-scans along a 3.4-mm diameter circular ring around the optic disc. The average parapapillary RNFL thickness (360-degree measure) was calculated automatically by the software and was used in the study. RNFL scans also were evaluated as to the adequacy of the algorithm for detection of the RNFL. Only scans without overt algorithm failure in detecting the retinal borders were included in the study.
Combined Structure and Function Estimate of Retinal Ganglion Cell Counts
The development of the combined structure and function estimate of RGC counts was based on previous work by Harwerth and associates on the development and validation of a model linking structure and function in glaucoma. Based on experimental studies in monkeys, the authors first derived an empirical model relating sensitivity measurements in SAP to histologic RGC counts as a function of retinal eccentricities. The experimental results then were translated to clinical perimetry in humans. The following formulas were proposed to estimate the number of RGC somas in an area of the retina corresponding to a specific SAP test field location at eccentricity ec with sensitivity s in decibels:
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