Refined Frequency Doubling Perimetry Analysis Reaffirms Central Nervous System Control of Chronic Glaucomatous Neurodegeneration

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.

Keywords: frequency doubling; glaucoma; jigsaw effect; neurodegeneration; neuroprotection; perimetry; refined data analysis; visual fields.

Figure 1

Projection of human ocular dominance columns onto the VF. Top: The retinotopic map superimposed on the pattern of ocular dominance columns for a right visual cortex. Bottom left: The projection of the column pattern onto the visual hemifield. Bottom right: The central 16 degrees. Note that the amount of VF represented by the columns changes with eccentricity. Reproduced with permission from Adams, Sincich, and Horton, 2007.

Figure 2

Specimen VF pairs and analytical algorithm. Gray scale (above) and pairing algorithm (below) representations of FDT 30-2 VF plots. The four gray-scale VF plots show the paired right and left eye VFs of 4 of the 41 study subjects with clinically stable bilaterally advanced chronic glaucoma. Note the complementarity of the patterns of the focal areas of visual loss and visual conservation between the paired eyes, providing compensation when both eyes are used together to view the binocular VF. The pairing algorithm used matched each of the 69 loci in the left VF (lower left) with (α) the corresponding locus of the right VF (red), (β) any one randomly selected point from among those equidistant from central fixation (teal), and (χ) the precise mirror-image locus (orange).

Figure 3

Example of pairing algorithm outcomes and associated 3-D heat maps. Left and right FDT 30-2 VF pair for one subject (gray-scale 2-D, above) and associated set of heat maps (colored 3-D, below). Note that the lower left composite applying the better of each of the 69 loci (α) arising naturally for the two eyes has a much less pathologic binocular VF loss than the composite derived from isopterically equivalent randomly selected points (β) at the lower right. The probability that the mean logarithmic global light sensitivity threshold was the same for pairings (α) and (β) among all 41 subjects was < 10⁻⁹. The mean global threshold for (α) was 20.9 and for (β) 19.5 decibels.

Figure 4

Mean thresholds for monocular and paired VF outcomes. Histogram showing global mean FDT Matrix threshold values (n = 41) with associated SEMs for left (a) and right eye (b) FDT 30-2 VFs, and for both eyes overlying the higher of the 69 concomitant right and left eye using: (c) the pairings of each left eye locus with any alternate randomly selected co-isopteric right eye values (repeated for all 69 loci × 10,000 iterations for each of the 41 eyes), (d) for each left eye locus with its precise mirror-image symmetric locus, and (e) the natural concomitant right and left eye pairings. The actual observed fields provide the highest conjoint sensitivity.