Donald C. Hood

A framework for comparing structural and functional measures of glaucomatous damage

While it is often said that structural damage due to glaucoma precedes functional damage, it is not always clear what this statement means. This review has two purposes: first, to show that a simple linear relationship describes the data relating a particular functional test (standard automated perimetry (SAP)) to a particular structural test (optical coherence tomography (OCT)); and, second, to propose a general framework for relating structural and functional damage, and for evaluating if one precedes the other. The specific functional and structural tests employed are described in Section 2. To compare SAP sensitivity loss to loss of the retinal nerve fiber layer (RNFL) requires a map that relates local field regions to local regions of the optic disc as described in Section 3. When RNFL thickness in the superior and inferior arcuate sectors of the disc are plotted against SAP sensitivity loss (dB units) in the corresponding arcuate regions of the visual field, RNFL thickness becomes asymptotic for sensitivity losses greater than about 10dB. These data are well described by a simple linear model presented in Section 4. The model assumes that the RNFL thickness measured with OCT has two components. One component is the axons of the retinal ganglion cells and the other, the residual, is everything else (e.g. glial cells, blood vessels). The axon portion is assumed to decrease in a linear fashion with losses in SAP sensitivity (in linear units); the residual portion is assumed to remain constant. Based upon severe SAP losses in anterior ischemic optic neuropathy (AION), the residual RNFL thickness in the arcuate regions is, on average, about one-third of the premorbid (normal) thickness of that region. The model also predicts that, to a first approximation, SAP sensitivity in control subjects does not depend upon RNFL thickness. The data (Section 6) are, in general, consistent with this prediction showing a very weak correlation between RNFL thickness and SAP sensitivity. In Section 7, the model is used to estimate the proportion of patients showing statistical abnormalities (worse than the 5th percentile) on the OCT RNFL test before they show abnormalities on the 24-2 SAP field test. Ignoring measurement error, the patients with a relatively thick RNFL, when healthy, will be more likely to show significant SAP sensitivity loss before statistically significant OCT RNFL loss, while the reverse will be true for those who start with an average or a relatively thin RNFL when healthy. Thus, it is important to understand the implications of the wide variation in RNFL thickness among control subjects. Section 8 describes two of the factors contributing to this variation, variations in the position of blood vessels and variations in the mapping of field regions to disc sectors. Finally, in Sections 7 and 9, the findings are related to the general debate in the literature about the relationship between structural and functional glaucomatous damage and a framework is proposed for understanding what is meant by the question, Does structural damage precede functional damage in glaucoma? An emphasis is placed upon the need to distinguish between statistical and relational meanings of this question.

Glaucomatous damage of the macula

There is a growing body of evidence that early glaucomatous damage involves the macula. The anatomical basis of this damage can be studied using frequency domain optical coherence tomography (fdOCT), by which the local thickness of the retinal nerve fiber layer (RNFL) and local retinal ganglion cell plus inner plexiform (RGC+) layer can be measured. Based upon averaged fdOCT results from healthy controls and patients, we show that: 1. For healthy controls, the average RGC+ layer thickness closely matches human histological data; 2. For glaucoma patients and suspects, the average RGC+ layer shows greater glaucomatous thinning in the inferior retina (superior visual field (VF)); and 3. The central test points of the 6° VF grid (24-2 test pattern) miss the region of greatest RGC+ thinning. Based upon fdOCT results from individual patients, we have learned that: 1. Local RGC+ loss is associated with local VF sensitivity loss as long as the displacement of RGCs from the foveal center is taken into consideration; and 2. Macular damage is typically arcuate in nature and often associated with local RNFL thinning in a narrow region of the disc, which we call the macular vulnerability zone (MVZ). According to our schematic model of macular damage, most of the inferior region of the macula projects to the MVZ, which is located largely in the inferior quadrant of the disc, a region that is particularly susceptible to glaucomatous damage. Axa0small (cecocentral) region of the inferior macula, and all of the superior macula (inferior VF), project to the temporal quadrant, a region that is less susceptible to damage. The overall message is clear; clinicians need to be aware that glaucomatous damage to the macula is common, can occur early in the disease, and can be missed and/or underestimated with standard VF tests that use a 6° grid, such as the 24-2 VF test.

Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma.

With the multifocal technique, visual evoked potentials (VEPs) can be recorded simultaneously from many regions of the visual field in a matter of minutes. Recently, the multifocal visual evoked potential technique (mfVEP) has generated considerable interest, especially among those seeking objective measures of glaucomatous damage. It is well accepted that significant ganglion cell damage can occur before functional deficits are detected with static automated achromatic perimetry, the gold standard for detecting and monitoring glaucomatous damage. In this article, we ask the following questions: What are the potential applications of the mfVEP technique? What are its limitations? To what extent will it replace or augment static automated achromatic perimetry? To answer these questions requires an understanding of the mfVEP technique, as well as techniques needed to relate its results to those of automated perimetry. describes how the mfVEP is elicited, recorded, derived and displayed. If both eyes of an individual are normal, then mfVEPs recorded for monocular stimulation of each eye are essentially identical. However, the amplitude and waveform of the mfVEP responses vary across individuals, as well as across the visual field within an individual. These variations in the normal mfVEPs are described in Section 3. In, these variations are related to cortical anatomy, and to the cortical sources contributing to the mfVEP. The mfVEP is predominantly generated in V1. Although there are undoubtedly extrastriate contributions, these contributions are probably smaller for the mfVEP than for the conventional VEP. The mfVEP is not a small version of the conventional VEP. To detect ganglion cell damage with the mfVEP requires methods for analyzing the responses and for displaying the results. In, a method for detecting ganglion cell damage is described. This method compares the monocular responses from the two eyes of an individual and produces a map of the defects. This map is in the form of a probability plot similar to the one used to display visual field defects measured with automated perimetry. Procedures are described for directly comparing these mfVEP probability plots to the probability plots for Humphrey visual fields (HVFs). The interocular mfVEP test described in will not be sensitive to bilateral damage. describes a test based upon monocular mfVEPs. The statistical basis of the monocular mfVEP test is relatively complex (see ). In any case, under many conditions the interocular test will be more sensitive and this is discussed in. summarizes a number of clinical applications of the mfVEP and concludes that the mfVEP has a place in the clinical management of glaucoma. To understand the limitations of the mfVEP, a signal-to-noise ratio (SNR) approach is described in. Using the techniques described in, the relationship between the amplitude of the mfVEP and the sensitivity loss of the HVF is discussed in. The evidence supports a simple model in which the amplitude of the signal portion, but not the noise portion, of the mfVEP response is proportional to HVF loss where HVF loss is expressed in linear, not dB, units. It is hypothesized that both the signal in the mfVEP, and the sensitivity of the HVF, are linearly related to ganglion cell loss. A theoretical approach, developed in, allows a direct comparison of the efficacy of the mfVEP and HVF in detecting glaucomatous damage. In short, when the mfVEP has a large SNR it will often be superior to the HVF in detecting damage. On the other hand, when the mfVEP has a small SNR, the HVF will probably be superior. summarizes the relative advantages of the HVF and the mfVEP. In summary, the mfVEP does have a place in the clinical management of glaucoma, although it is not likely to replace static automated achromatic perimetry in the near future. However, this is an evolving technology and the future will undoubtedly see major improvements in the mfVEP technique.

Human cone receptor activity: The leading edge of the a –wave and models of receptor activity

The leading edge of the a-wave of the electroretinogram (ERG) was evaluated as a measure of human cone photoreceptor activity. The amplitude of the cone a-wave elicited by flashes of different energy was compared to the predictions of a class of models from in vitro studies of cone photoreceptors. These models successfully describe the leading edge of the a-wave. Thus, the human cone a-wave can be used to test hypotheses about normal and abnormal cone receptors. The ability of the human cone to adjust its sensitivity in the presence of steady adapting lights was assessed by recording cone a-waves to flashes on adapting fields up to 3.9 log td in intensity and by comparing these responses to quantitative models of adaptation. The first 10 ms of the cones response is little affected by field intensities up to 2.9 log td. The 3.9 log td field reduced the response to weak flashes by about a factor of 2.5 (0.4 log unit). This relatively small reduction in sensitivity can be attributed to a combination of response compression, pigment bleaching, and an adaptation mechanism that changes the gain without changing the time course. We conclude that either the human cones show relatively little adaptation or that they have an adaptation mechanism that involves a time-course change. That is, as we are limited with the a-wave to the first 10 ms or so of the cones response, we cannot rule out a gain mechanism linked to a time-course change.

Initial Arcuate Defects within the Central 10 Degrees in Glaucoma

PURPOSEnTo better understand the relationship between the spatial patterns of functional (visual field [VF] loss) and structural (axon loss) abnormalities in patients with glaucomatous arcuate defects largely confined to the central 10° on achromatic perimetry.nnnMETHODSnEleven eyes (9 patients) with arcuate glaucomatous VF defects largely confined to the macula were selected from a larger group of patients with both 10-2 and 24-2 VF tests. Eyes were included if their 10-2 VF had an arcuate defect and if the 24-2 test was normal outside the central 10° (i.e., did not have a cluster of three contiguous points within a hemifield). For the structural analysis, plots of retinal nerve fiber layer (RNFL) thickness of the macula were obtained with frequency-domain optical coherence tomography (fdOCT). The optic disc locations of the RNFL defects were identified on peripapillary fdOCT scans.nnnRESULTSnThe VF arcuate defects extended to within 1° of fixation on the 10-2 test and were present in the superior hemifield in 10 of the 11 eyes. The arcuate RNFL damage, seen in the macular fdOCT scans of all 11 eyes, involved the temporal and inferior temporal portions of the disc on the peripapillary scans.nnnCONCLUSIONSnGlaucomatous arcuate defects of the maculas RNFL meet the disc temporal to the peak of the main arcuate bundles and produce a range of macular VF defects from clear arcuate scotomas to a papillofoveal horizontal step (pistol barrel scotoma). If RGC displacement is taken into consideration, the RNFL and VF defects can be compared directly.

A Test of a Linear Model of Glaucomatous Structure-Function Loss Reveals Sources of Variability in Retinal Nerve Fiber and Visual Field Measurements

PURPOSEnRetinal nerve fiber (RNFL) thickness and visual field loss data from patients with glaucoma were analyzed in the context of a model, to better understand individual variation in structure versus function.nnnMETHODSnOptical coherence tomography (OCT) RNFL thickness and standard automated perimetry (SAP) visual field loss were measured in the arcuate regions of one eye of 140 patients with glaucoma and 82 normal control subjects. An estimate of within-individual (measurement) error was obtained by repeat measures made on different days within a short period in 34 patients and 22 control subjects. A linear model, previously shown to describe the general characteristics of the structure-function data, was extended to predict the variability in the data.nnnRESULTSnFor normal control subjects, between-individual error (individual differences) accounted for 87% and 71% of the total variance in OCT and SAP measures, respectively. SAP within-individual error increased and then decreased with increased SAP loss, whereas OCT error remained constant. The linear model with variability (LMV) described much of the variability in the data. However, 12.5% of the patients points fell outside the 95% boundary. An examination of these points revealed factors that can contribute to the overall variability in the data. These factors include epiretinal membranes, edema, individual variation in field-to-disc mapping, and the location of blood vessels and degree to which they are included by the RNFL algorithm.nnnCONCLUSIONSnThe model and the partitioning of within- versus between-individual variability helped elucidate the factors contributing to the considerable variability in the structure-versus-function data.

Prevalence and Nature of Early Glaucomatous Defects in the Central 10° of the Visual Field

IMPORTANCEnThe macula is essential for visual functioning and is known to be affected even in early glaucoma. However, little is currently understood about the prevalence and nature of central vision loss in early glaucoma.nnnOBJECTIVEnTo determine the prevalence and characteristics of visual field (VF) defects in the central 10° in glaucoma suspects and patients with mild glaucoma using a prospective design.nnnDESIGN, SETTING, AND PARTICIPANTSnThis prospective observational cohort study was conducted at an outpatient glaucoma specialty clinic. One hundred eyes from 74 patients with glaucomatous optic neuropathy and a 24-2 VF with mean deviation better than -6 dB were prospectively studied and tested with a 10-2 test.nnnMAIN OUTCOMES AND MEASURESnReliable: VF hemifields were classified as abnormal based on a cluster criterion, and abnormal 10-2 VFs were categorized based on the pattern of abnormal points: arcuatelike, widespread, or other. In addition, at each point of the 10-2 VF, the total deviation values were averaged across eyes and the number of abnormal points with total deviation values below a specific criterion level were calculated. RESULTS There appeared to be as many abnormal 10-2 hemifields (53%) as abnormal 24-2 hemifields (59%). Of the eyes with normal 24-2 hemifields, 16% were classified as abnormal when the 10-2 test was used. Of the abnormal 10-2 hemifields, 68%, 8%, and 25% were arcuatelike, widespread, and other, respectively. The average total deviation values and number of abnormal points plots revealed superior VF defects that were deeper and closer to fixation than those in the inferior VF.nnnCONCLUSIONS AND RELEVANCEnThe 10-2 VF was abnormal in nearly as many hemifields as was the 24-2 VF, including some with normal 24-2 VF, suggesting that the 24-2 test is not optimal for detecting early damage of the macula. The pattern of the defects was in agreement with a recent model of macular damage.

Early glaucoma involves both deep local, and shallow widespread, retinal nerve fiber damage of the macular region.

PURPOSEnTo better understand the nature of early glaucomatous damage of the macula by comparing the results from 10-2 visual fields, optical coherence tomography (OCT) macular cube scans, and OCT circumpapillary circle scans.nnnMETHODSnOne eye of each of 66 glaucoma patients or suspects, with a mean deviation (MD) on the 24-2 visual field (VF) test of better than -6 decibels (dB), was prospectively tested with 10-2 VFs and OCT macular cube and circumpapillary circle scans. Thickness and probability maps of the retinal ganglion cell plus inner plexiform (RGC+) layers were generated. A hemifield was considered abnormal if both the macular RGC+ and the 10-2 probability plots were abnormal (cluster criteria). The thickness plots of the circumpapillary retinal nerve fiber layer (RNFL) were analyzed in the context of a model that predicted the region of the disc associated with macular damage.nnnRESULTSnTwenty-seven hemifields (20 eyes) had abnormal 10-2 and RGC+ probability plots: 7 in upper VF/inferior retina, 6 in lower VF/superior retina, and 7 in both hemifields. Both shallow widespread and deep local thinning of the circumpapillary RNFL were observed. The local defects were more common and closer to fixation in the upper VF/inferior retina as predicted.nnnCONCLUSIONSnA model of glaucomatous damage of the macula predicted the location of both the widespread and local defects in the temporal and inferior disc quadrants. Optical coherence tomography scans of the circumpapillary RNFL and the macular RGC+ layer can aid in the identification of these defects and help in the interpretation of 24-2 and 10-2 VF tests.

Method for deriving visual field boundaries from OCT scans of patients with retinitis pigmentosa.

The location of the loss of the inner segment (IS)/outer segment (OS) border, as seen with frequency domain optical coherence tomography (fdOCT), was determined on fdOCT scans from patients with retinitis pigmentosa. A comparison to visual field loss supported the hypothesis, based upon previous work, that the point at which the IS/OS border disappears provides a structural marker for the edge of the visual field. Repeat fdOCT measures showed good within day reproducibility, while data obtained on average 22.5 months later showed signs of progression. The IS/OS contour shows promise as a measure for following changes in patients undergoing treatment.

The Pupil Light Reflex in Leber's Hereditary Optic Neuropathy: Evidence for Preservation of Melanopsin-Expressing Retinal Ganglion Cells

PURPOSEnTo investigate the pupillary light reflex (PLR) of patients with severe loss of vision due to Lebers Hereditary Optic Neuropathy (LHON) in the context of a proposed preservation of melanopsin-expressing retinal ganglion cells (mRGCs).nnnMETHODSnTen LHON patients (7 males; 51.6 ± 14.1 years), with visual acuities ranging from 20/400 to hand motion perception and severe visual field losses, were tested and compared with 16 healthy subjects (7 males; 42.15 ± 15.4 years) tested as controls. PLR was measured with an eye tracker and the stimuli were controlled with a Ganzfeld system. Pupil responses were measured monocularly, to 1 second of blue (470 nm) and red (640 nm) flashes with 1, 10, 100, and 250 cd/m² luminances. The normalized amplitude of peak of the transient PLR and the amplitude of the sustained PLR at 6 seconds after the flash offset were measured. In addition, optical coherence topography (OCT) scans of the peripapillary retinal nerve fiber layer were obtained.nnnRESULTSnThe patients peak PLR responses were on average 15% smaller than controls (P < 0.05), but 5 out of 10 patients had amplitudes within the range of controls. The patients sustained PLRs were comparable with controls at lower flash intensities, but on average, 27% smaller to the 250 cd/m² blue light, although there was considerable overlap with the PLR amplitudes of control. All patients had severe visual field losses and the retinal nerve fiber layer thickness was reduced to a minimum around the optic disc in 8 of the 10 patients.nnnCONCLUSIONSnThe PLR is maintained overall in LHON patients despite the severity of optic atrophy. These results are consistent with previous evidence of selective preservation of mRGCs.