Visual field defects and neural losses from experimental glaucoma
Introduction
Clinical glaucoma is usually described as a multi-factorial disease or as a constellation of diseases because there is not an identifiable single etiology (Quigley, 1993; Epstein, 1997). It is well known, however, that there are epidemiological risk factors that are associated with an increased likelihood of having the disease (Quigley, 1993; Gramer and Tausch, 1995) and there are cellular-level risk factors leading to pathologic injury and death of retinal ganglion cells (Schumer and Podos, 1994; Nickells, 1996; Quigley, 1998a). In the final analysis, all of the etiological factors lead to a single manifestation of glaucoma, the death of retinal ganglion cells, which can be observed in patients by a cupping of the optic nerve head, a loss of retinal nerve fiber layer, and functional visual field defects (Anderson, 1989; Alexander, 1991). Consequently, clinical procedures for the diagnosis and assessment of the progression of glaucoma are based on quantification of these characteristics of optic neuropathy and, thus, it is important to know how well the diagnostic techniques provide a true representation of the extent of ganglion cell death. For this purpose, we have investigated the functional and structural effects of glaucomatous optic neuropathy in an experimental monkey-model of glaucoma. The present report will describe investigations that were designed to study: (1) the relationship between the depth of visual field defects and the loss of retinal ganglion cells from glaucoma, (2) the relative effects of glaucoma on neurons in the magnocellular and parvocellular afferent visual pathways, and (3) the use of the electroretinogram (ERG) for objective measurements of retinal neural losses from glaucoma.
Section snippets
Structure–function relationships for clinical perimetry
In modern clinics, the standard for assessment of functional vision defects is visual field testing by computer-automated perimetry, using white-light test targets superimposed on a white background (Heijl, 1985a; Johnson, 1996). In general, the depth and extent of functional defects are diagnosed by a sensitivity map of the visual field that is derived from light-sense thresholds measured at a number of locations across the retina (Anderson, 1987). The visual field defects from glaucoma are
Experimental glaucoma
Gaasterland and Kupfer (1974) introduced the model of experimentally elevated intraocular pressure (IOP) in monkeys, which has become the model of choice for anatomical and physiological investigations of glaucoma. In current use, experimental glaucoma is produced by a unilateral elevation of intraocular pressure by Argon laser treatment of the trabecular meshwork, using energy levels that destroy the trabecular meshwork and obliterate Schlemm's canal in the vicinity of the laser burn (Pederson
Behavioral perimetry
Static threshold perimetry has become the clinical standard for the assessment of the visual effects of glaucoma (Johnson, 1996). The sophisticated methodology and statistical analyses of perimetry data that have been developed for human patients can be also applied to experimental glaucoma through behavioral training and testing of the monkey subjects (Harwerth et al., 1993a). For these measurements, a standard clinical instrument, the Humphrey Field Analyzer, was attached to a primate-testing
Retinal ganglion cell counts
Within a few days after the final visual field test, the monkeys were deeply anesthetized, their eyes were enucleated, and the posterior segments of the eyes were fixed by an immersion overnight in 2% paraformaldehyde and 2% glutaraldehyde at 4°C. The eyes were then transferred and stored at 4°C in phosphate buffered 4% paraformaldehyde (pH 7.3).
Tissue samples from specific perimetry test sites were taken from comparable retinal locations in the control and treated eyes (a total of 132 samples
Sensitivity vs. neural losses from experimental glaucoma
The relationship for the reduction of visual sensitivity as a function of the losses of retinal ganglion cells, for clinical perimetry using the standard Goldmann III test stimulus on a 31.5 asb adapting background, is presented in Fig. 3A. Each of the data points represents the sensitivity loss (i.e., the difference, in decibel (dB) units, between the thresholds for the control and treated eyes at a given test field location) as a function of ganglion cell loss (i.e., the percentage difference
Probability summation and visual field defects
By any model of neuronal to perceptual events, the relation between a psychophysical measurement of sensitivity and the neural mechanisms responsible for the level of sensitivity must involve interactions among the detection mechanisms over time and space. The statistical description for detection of a stimulus that is imaged on a retinal area with multiple detectors is probability summation (Pirenne, 1943; Nachmias, 1981; Robson and Graham, 1981). Probability summation is a well-established
Spatial summation for perimetry thresholds
Probability summation involves interactions among receptive fields and the predicted reduction of sensitivity is based on the reduced number of independent detection mechanisms, rather than the specific retinal location or type of perimetry stimulus. In contrast, spatial summation within the individual receptive fields of detection mechanisms may be more dependent on these factors (Bartlett, 1966). The interdependence of stimulus size and intensity for visual thresholds, known as Ricco's law,
Contrast sensitivity perimetry
Spatial contrast sensitivity functions provide an excellent description of the response properties of the visual system because the spatial response profiles of the receptive fields that are the most sensitive to a given stimulus will match the spatial frequency characteristics of the stimulus. Therefore, a stimulus that is composed of a narrow band of spatial frequencies and is restricted in its spatial size has many desirable properties for clinical perimetry (Atkin et al., 1979; Lundh and
Effects of experimental glaucoma in the afferent visual pathways
By the time patients complain of vision loss, a very high percentage of ganglion cells have already become non-functional or have died and, thus, the detection and assessment of glaucomatous visual dysfunction relies on clinical perimetry. In primary open angle glaucoma, the first appearance of a glaucomatous scotoma is typically in the mid-peripheral nasal field, which is the area of the retina served by the ganglion cells whose arching axons enter the dorsal and ventral aspects of the optic
Cytochrome oxidase and neuronal metabolism
The effects of experimental glaucoma in the afferent visual pathways were assessed by quantification of cytochrome oxidase activity to identify changes in the energy metabolism required for neural activity. Information transmission in a neuron expends energy, which in the main, is derived from the reduction of adenosine triphosphate (ATP) within the membranes of the cell's mitochrondria. Cytochrome oxidase (CO) is an essential enzyme in this process and the concentration of CO within the
Cytochrome oxidase reactivity in experimental glaucoma—lateral geniculate nucleus
The alterations in metabolic activity in the lateral geniculate nucleus were investigated in monkeys with behaviorally measured visual field defects from unilateral experimental glaucoma (Harwerth et al (1997), Harwerth et al. (1999a)). The monkeys’ brains were perfused, in situ, with paraformaldehyde fixatives, and then removed, dissected, dehydrated and sectioned (35 μm sections). Frozen sections were processed according to the protocol of Wong-Riley (1979), Wong-Riley (1989) to visualize
Cytochrome oxidase reactivity in experimental glaucoma—visual cortex
Additional evidence on the neural effects of experimental glaucoma and the relationship between visual function and metabolic defects along the parallel information processing streams can be gathered from investigations of CO reactivity in the input layer 4C of the primary visual cortex. The projections of the M- and P-cell pathways remain segregated into the visual cortex and terminate in separate sub-laminae of input layer 4C. The upper portion, layer 4Cα, receives the projection from the
Electroretinographic measures of neural loss from glaucoma
Although subjective measures of visual function seem to be a direct, valid assessment of the clinical stage of visual impairment caused by glaucoma, there are degrees of inaccuracy and imprecision in the underlying structure–function relationship for standard automated perimetry that limit the interpretation of stage of neural loss. Alternative approaches with objective measures of glaucomatous neuropathy that do not rely on psycho-physiological linking have been developed in recent years. One
Effects of experimental glaucoma on the scotopic flash ERG (STR)
The full-field flash ERG has been used widely to assess the function of photoreceptors and bipolar cells. The standard scotopic ERG response to brief intense flashes has an initial, negative a-wave that originates primarily from rod photoreceptors (Penn and Hagins, 1969), which is followed by the prominent positive b-wave that originates from rod-driven (On) bipolar cells with some contribution from the Müller (glial) cells (Miller and Dowling, 1970; Newman and Odette, 1984; Stockton and
Effects of experimental glaucoma on the photopic flash ERG (PhNR)
The photopic ERG is a complicated response, which probably represents contributions from each class of neurons in the retina. For example, fully photopic ERGs that are elicited by full-field red (630 nm) stimuli superimposed on a rod-saturating blue (450 nm) background, are composed of the standard a-waves, b-waves, and d-waves, and additional slow negative potentials, the photopic negative response, that are not ordinarily recorded in clinical ERGs. The cellular origins of the standard ERG
The PhNR in humans with primary open angle glaucoma
Laser-induced experimental glaucoma in macaque monkeys provides a valid model of the cellular and functional effects of ganglion cell death in glaucoma, but differences in the levels of intraocular pressure and in the time course of neural loss may affect the clinical application of some structure–function relationships (Osborne et al., 1999). It is, therefore, important to determine whether the experimental measures can be replicated in a clinical population of glaucoma patients (Colotto et
The effect of experimental glaucoma on the multifocal ERG
A limitation of the use of full field stimuli for flash ERGs or large fields for pattern ERGs is that these stimuli do not allow measurements of localized functional losses that are the hallmark of perimetric measurements (Anderson, 1987; Quigley, 1993). One alternative would be to record focal ERGs, but the amplitudes of responses to focal stimuli are small and the testing of multiple sites would be very time consuming. A potentially more effective procedure is the multifocal (mf) ERG that has
Summary and conclusions
The functional effects of ganglion cell death in glaucoma have been studied by diverse methods with converging results. Each of the studies used a common method of behavioral perimetry to assess the clinical stage of visual field loss from experimental glaucoma to relate the separate investigations of the structure–function relationship. The principal studies addressed: (1) the psycho-physiological links between ganglion cell loss and the depth of visual field defects, (2) the relative
Uncited References
Quigley et al., 1977.
Acknowledgements
This study was supported in part by a research grant from Alcon Research, Ltd., Fort Worth, TX, and National Institutes of Health/National Eye Institute grants RO1 EY01139, RO1 EY03611, EY06671 and P30 EY0551 to the University of Houston and grants RO1 EY07751, RO1 EY11545, and P30 EY10608 to the University of Texas–Houston. Additional support was provided by the University of Houston from John and Rebecca Moores Professorships (RSH & LJF) and the Greeman-Petty Professorship (ELS), and by the
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Present address: School of Optometry, Indiana University, Bloomington, IN 47405-3880, USA.