Abstract
Purpose::
Refined analysis of frequency doubling perimetric data was performed to assess binocular visual field conservation in patients with comparable degrees of bilateral glaucomatous damage, to determine whether unilateral visual field loss is random, anatomically symmetric, or non-random in relation to the fellow eye.
Methods::
Case control study of 41 consecutive patients with bilaterally mild to severe glaucoma; each right eye visual field locus was paired with randomly-selected co-isopteric left eye loci, performing 690,000 (10,000 complete sets of 69 loci) such iterations per subject. The potential role of anatomic symmetry in bilateral visual field conservation was also assessed by pairing mirror-image loci of the right- and left-eye fields. The mean values of the random co-isopteric and the symmetric mirror pairings were compared with natural point-for-point pairings of the two eyes by paired t-test.
Results::
Mean unilateral Matrix threshold across the entire 30-degree visual field were 17.0 dB left and 18.4 dB right (average 17.7). The better of the naturally paired concomitant loci yielded binocular equivalent mean bilateral Matrix threshold of 20.9 dB, 1.6 dB higher than the population mean of the 690,000 coisopteric pairings (t = −10.4; P < 10-12). Thus, a remarkable natural tendency for conservation of the binocular Matrix visual field was confirmed, far stronger than explicable by random chance. Symmetric pairings of precise mirror-image loci also produced values higher than random co-isopteric pairings (Δ 1.1 dB; t = −4.0; P = 0.0004).
Conclusions::
Refined data analysis of paired Matrix visual fields confirms the existence of a natural optimization of binocular visual function in severe bilateral glaucoma via interlocking fields that could only be created by CNS involvement. The disparity of paired Matrix threshold values at mirror-image loci was also highly nonrandom and quantitatively inverse from the expected if anatomic symmetry factors were merely passively contributing systematically to the compensatory binocular Matrix effect.
Translational Relevance::
The paired eyes and brain are reaffirmed to function as a unified system in the progressive age-related neurodegenerative condition chronic open angle glaucoma, maximizing the binocular visual field. Given the extensive homology of this disorder with other age-related neurodegenerations, it is reasonable to assume that the brain will similarly resist simultaneous bilateral loss of paired functional zones in both hemispheres in diseases like Alzheimer's and Parkinson's disease. Glaucomatous eyes at all stages of the disease appear to provide a highly accessible paired-organ study model for developing therapeutics to optimize conservation of function in neurodegenerative disorders.
Institutional review board (IRB)/ethics committee approval was obtained for this Health Insurance Portability and Accountability Act (HIPAA)-compliant cross-sectional study, which was fully adherent to the tenets of the Declaration of Helsinki. All available records for patients with bilateral chronic progressive glaucoma in the IRB-sanctioned San Antonio, Texas, glaucoma subspecialty clinic were assessed, and all patients meeting the inclusion criteria are included in this analysis. Inclusion criteria were: (1) perimetric experience (two or more prior VFs) and reliability (false-positive and false-negative rates both <25%) with comparable degrees of mild, moderate, or severe VF loss in both eyes using Matrix (Carl Zeiss Meditec; Dublin, CA) Frequency Doubling Technology (FDT) perimetry. The FDT Matrix pattern employs 69 (17 loci per quadrant and one central locus) 5° × 5° square targets across a 30-degree central VF reversing sinusoidal contrast gratings of spatial frequency of 0.5 cycles/degree at a counterphase flicker temporal frequency of 18 Hz. These produce the FD percept across the field.
16 A Bayesian threshold estimation strategy is applied to provide thresholds with normal attenuation values numerically comparable to those attained using standard forms of static perimetry.
17 VF loss is typically seen at an earlier clinical stage with Matrix than with more traditional automated static perimetry that utilize focal light stimuli flashed for 0.2 seconds in an illuminated bowl (as used in our prior study). Included in this study were all patients meeting reliability criteria exhibiting comparable degrees of VF loss in both eyes (using previously published full-threshold scoring criteria; see below),
18–20 (2) visual acuity ≥ 20/80 in both eyes, (3) with moderate to severe excavatory optic neuropathy (cup/disc ratio ≥0.5 in both eyes), and (4) bilaterally stable intraocular pressure in both eyes in the range 6 to 16 mmHg.
Briefly outlined, the study design is as follows:
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Objective scoring of bilaterally reliable stable glaucoma patient VFs into mild, moderate, and severe Humphrey Visual Field Analyser (HVFA) II VF chart data screening confirmed reliable for paired eyes with bilateral defects within the same grading category or within one step thereof;
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Criteria met: Document bilateral VF data mean deviation (MD) and pattern standard deviation (PSD) oculus uterque (both eyes; OU) and calculate maximal concomitant threshold values OU;
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Perform refined data analysis with 10,000 iterations of optionally equivalent bilateral co-isopteric outcomes for each subject;
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Perform bilateral absolute symmetry analysis for each of the 69 points on the FDT analyses OU; and
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Calculate the paired t-test P values for all comparisons (i.e., mean right and left eye versus computed and actual bilateral binocular VF values).
Details of each step are described further below.
A majority of participants had both FDT and Humphrey VFA II VFs, and when both were available glaucoma severity was defined using the latter. In those with only FDT fields an adapted version of a previously published algorithm
19 intended to produce concordance between HVFA II and Matrix FDT pathologic categories was applied. Severe VF loss was defined as Humphrey MD worse than −12 dB, and/or 37 or more points depressed at or below 5%, and or 20 or more below 1%, and/or a glaucomatous scotoma with one or more pericentral loci at 0 dB or two such loci at or below 15 dB. Moderate VF loss was defined as having a MD between −12 and −6 dB, and/or 18 to 36 points depressed at or below 5%, and/or 10 to 19 points depressed at or below 1%, and no points in the central 5 degrees at 0 dB, and no pericentral hemifield pairs at or below 15 dB. Mild VF loss was defined as having MD > −6 dB and between 7 and 17 points depressed below 5%, and 10 or fewer points depressed at or below 1%, and no points in the central 5 degrees at 0 dB, and no hemifield pairs in the central 5 degrees at or below 15 dB.
All eyes were tested with best refractive lens correction in place during a single perimetric session. All patients with evidence of ptosis underwent perimetric testing with the upper lid taped to the brow to avoid lid artifact. Prior work demonstrated the predictability of the binocular VF via pairing of directly corresponding (concomitant) loci of the individual right and left eye VFs.
21 For the present statistical analysis, to assess the randomness of the contribution of each eye to binocular visual function, each left eye Matrix 30-2 VF locus was paired with (α) its actual corresponding (concomitant) right eye locus, or (β) multiple random co-isopteric right eye loci having equal eccentricity from fixation (
Fig. 2). This was performed in a sequential manner choosing one random co-isopteric left eye locus for each right eye locus until all 69 were paired, repeating this process 10,000 times for all 41 paired VFs. The per-locus maximum light-sensitivity threshold values for all 69 loci within the central 30 degrees for all subjects were then generated, for measured contralateral concomitant pairings and for physiologically balanced alternative pairings, using combinations α and β, above. As an additional exercise to estimate the optimal field pairing that could be obtained from the two eyes, the maximum field mean of all 10,000 randomized binocular fields was also determined for each of the 41 subjects. Mean and maximum light attenuation threshold results were then compiled for each subject to provide means of each for all 41 subjects
. The results for each patient were fitted with an extreme value probability density function. Composite means for the study population were then compared by paired
t-test.
4
Additional comparisons were made pairing each left eye VF locus with its horizontal mirror-image locus from the right eye (χ) to determine the potential contribution of anatomic symmetry. To identify the extent of any such passive anatomic compensation, probability distribution comparisons were performed to determine to what extent passive bilateral symmetry might account for any observed optimization of binocular visual function. Heat maps of the higher paired threshold value projected binocular VF were created for all subjects for combinations α, β, and χ, to compare with one another and with their associated individual right and left eye 3-D projections. All computations were carried out using MATLAB version 7.13 (The Mathworks, Inc.; Natick, MA) in the University of Texas at San Antonio Department of Biomedical Engineering. It should be emphasized that all probability values presented are the result of comparisons of the final refined data compilations of each of the 41 individuals in the study, and there is no statistical retreatment of any nonindependent variables in this analysis.
An additional analysis was applied to the central VF to identify cortical effects in preserving the central binocular field. Loci located within a central, vertically oriented ellipse with major radius 15° and minor radius 10° from fixation were compared using the same tests for randomization and mirror-like anatomical symmetry as above. This analysis was also repeated for points outside this central ellipse.
All authors contributed significantly to the preparation of this manuscript. William Eric Sponsel devised the concept for the paper. Analaura Villarreal gathered the visual fields and Analaura Villarreal, William Eric Sponsel, and Matthew A. Reilly all input the data. Matthew A. Reilly ran the statistical analysis of the field data. Matthew A. Reilly, William Eric Sponsel, and Analaura Villarreal created the graphs and figures. The draft manuscript was written by William Eric Sponsel and Matthew A. Reilly, with subsequent additions, revisions, and editing by all the co-authors. Ted Maddess and William Eric Sponsel performed literature searches.
William Eric Sponsel is a Primary Investigator in the Australian Research Council Centre of Excellence in Visual Sciences, of which co-author Ted Maddess is Director.
Disclosure: M.A. Reilly, None; A. Villarreal, None; T. Maddess, previously received royalities for sale of the FDT/Matrix perimeters (Carl Zeiss Meditec AG) and holds patents on the device mentioned in the references 48 and 49 (nuCoria Pty Ltd); W.E. Sponsel, None