Retinal ganglion cell and inner plexiform layer thickness measurements in regions of severe visual field sensitivity loss in patients with glaucoma.

PURPOSE: To better understand the effects of severe glaucoma on the thickness of the retinal ganglion cell (RGC) and inner plexiform (IP) layers measured with frequency-domain optical coherence tomography. METHODS: In experiment 1, macular cube scans were obtained in 11 patients with glaucoma and the thickness of both the RGC and IP layers were measured at locations corresponding to 3, 5, and 7° eccentricity. For patients, only locations with total deviation losses of -15 dB or worse on perimetry were included. In experiment 2, higher resolution, horizontal midline scans were obtained from 30 controls in order to obtain a precise measure of the thickness of the RGC and IP layers of the healthy retina. RESULTS: In regions of severe field loss (experiment 1), glaucoma decreased the thickness of both layers, leaving a residual layer. The residual thickness of the IP layer was larger than the residual thickness of the RGC layer. In healthy controls (experiment 2), the RGC layer was about 57% of the RGC+IP layer thickness at 3° as compared with only 36% at 10°, in agreement with a recent histological study. CONCLUSION: Glaucomatous optic neuropathy, with severe losses in visual field sensitivity, decreases the thickness of both the RGC and IP layers, but leaves a residual thickness of both. The IP layer contributes slightly more than the RGC to this residual, even just outside the center of the fovea where the RGC layer thickness exceeds the IP layer thickness in controls.

Eccentricity-dependent changes in local onset and offset responses in patients with progressive cone dystrophy.

Shinoda and colleagues hypothesized that patients with cone dystrophy (CD) might suffer from a selective ON-system deficit, based on the local nature of the disease [Shinoda, K, Ohde, H, Inoue, R, Ishida, S, Mashima, Y, & Oguchi, Y (2002). ON-pathway disturbance in two siblings. Acta Ophthalmologica Scandinavica, 80, 219-223]. The purpose of the current study was to test this hypothesis by examining onset and offset responses as a function of eccentricity in a group of patients with CD using long-duration LED stimuli. Nine patients with CD participated in this study (mean age of 36.1 years and visual acuity 20/200). For this study, the following measures were obtained: Humphrey threshold visual fields, standard multifocal ERGs (mfERGs) as well as mfERGs to long duration stimuli recorded using the Retiscan stimulator (Roland Instruments). This display contained 61 scaled hexagons and the LEDs were on for 100ms (180cd/m(2)) and off for 100ms. In addition, standard full-field photopic and flicker ERGs using Ganzfeld stimulation were obtained. For the control subjects, the onset responses were larger than the offset responses at all eccentricities; whereas for the patients, there was overlap between the amplitudes of the onset and offset responses. For the patients, the amplitude ratios (relative to the control data) indicated that the difference between the onset and offset responses was greatest for the central-most ring and this difference decreased with increasing eccentricity. For the onset responses, Humphrey thresholds and mfERG amplitudes, performance was poorest for the center ring and best for the most peripheral ring; for the offset responses, the opposite pattern of results was obtained. The differences in the pattern of results in the long duration mfERG data are consistent with a selective loss of the onset responses in our patient population.

Retinal nerve fibre thickness measured with optical coherence tomography accurately detects confirmed glaucomatous damage.

AIM: To assess the accuracy of optical coherence tomography (OCT) in detecting damage to a hemifield, patients with hemifield defects confirmed on both static automated perimetry (SAP) and multifocal visual evoked potentials (mfVEP) were studied. METHODS: Eyes of 40 patients with concomitant SAP and mfVEP glaucomatous loss and 25 controls underwent OCT retinal nerve fibre layer (RNFL), mfVEP and 24-2 SAP tests. For the mfVEP and 24-2 SAP, a hemifield was defined as abnormal based upon cluster criteria. On OCT, a hemifield was considered abnormal if one of the five clock hour sectors (3 and 9 o'clock excluded) was at <1% (red) or two were at <5% (yellow). RESULTS: Seventy seven (43%) of the hemifields were abnormal on both mfVEP and SAP tests. The OCT was abnormal for 73 (95%) of these. Only 1 (1%) of the 100 hemifields of the controls was abnormal on OCT. Sensitivity/specificity (one eye per person) was 95/98%. CONCLUSIONS: The OCT RNFL test accurately detects abnormal hemifields confirmed on both subjective and objective functional tests. Identifying abnormal hemifields with a criterion of 1 red (1%) or 2 yellow (5%) clock hours may prove useful in clinical practice.

Structural and functional assessment of the macular region in patients with glaucoma.

PURPOSE: To investigate the correlation of a structural measure of the macular area (optical coherence tomography (OCT)) with two functional measures (10-2 Humphrey visual field (HVF) and multifocal visual evoked potential (mfVEP)) of macular function. METHODS: 55 eyes with open-angle glaucoma were enrolled. The 10-2 HVF was defined as abnormal if clusters of > or =3 points with p<5%, one of which had p<1%, were present. The mfVEP was abnormal if probability plots had > or =2 adjacent points with p<1%, or > or =3 adjacent points with p<5% and at least one of these points with p<1%. Two criteria were used for the macular OCT: (I) > or =2 sectors with p<5% or 1 sector with p<1% and (II) 1 sector with p<5%. RESULTS: 54 of the 55 eyes showed an abnormal 10-2 HVF and 50 had central mfVEP defects. The two OCT criteria resulted in sensitivities of 85% and 91%. When both functional tests showed a defect (in 49 eyes), the OCT was abnormal in 45. For the OCT the outer and inner inferior regions were the most likely to be abnormal, and both functional techniques were most abnormal in the superior hemifield. CONCLUSIONS: Good agreement exists between macular thickness and functional defects in patients with glaucoma. Study of the macular region may provide a quantitative measure for disease staging and monitoring.

The effects of glaucoma on the latency of the multifocal visual evoked potential.

AIMS: To determine the effect of glaucomatous damage on the latency of the multifocal visual evoked potential (mfVEP). METHODS: Monocular mfVEPs were recorded from a glaucoma group (n = 50) defined by a glaucomatous disc and an abnormal visual field and a control group (n = 47). 25 patients were characterised as normal tension glaucoma (NTG) and 25 as high tension glaucoma (HTG). Monocular and interocular latency analyses of the more affected eye were obtained using custom software. RESULTS: On interocular analysis, both the HTG and NTG groups showed a statistically significant increase in mean mfVEP latency with average relative latencies and percentage of points with significant delays of 1.7 ms and 10.3% (HTG) and 1.3 ms and 8.2% (NTG) compared to -0.3 ms and 2.7% (controls). On monocular analysis, only the HTG group showed a significant increase in latency with measures of 5.7 ms and 14.6% (HTG) compared to 3.2 ms and 10.6% (NTG) and 2.1 ms and 9.6% (controls). Using the 95th percentile of a normative group as the cut off, the sensitivity ranged from 20% to 38% and the specificity from 87% to 100% with the interocular analysis providing the best discrimination, CONCLUSION: Although up to 40% of patients showed delays in the mfVEP latency, these delays were modest, on average a few milliseconds. These results differ markedly from those of a recent conventional VEP study, which reported 100% sensitivity, 100% specificity, and an average delay that exceeded 25 ms.

Multifocal visual evoked potentials to cone specific stimuli in patients with retinitis pigmentosa.

Our aim was to determine whether patients with retinitis pigmentosa show differences in L- and M-cone multifocal visual evoked potential (mfVEP) responses that are eccentricity dependent, as has been shown for control subjects. Second, we compared the losses for mfVEPs to losses on achromatic visual field and multifocal electroretinogram (mfERG) measures in the patients. Monocular mfVEPs were recorded to a pattern reversing display that modulated only the L- or M-cones. Also, standard automated achromatic visual fields and mfERGs were obtained. For the control subjects, the ratio of L-cone to M-cone mfVEP amplitudes increased as a function of retinal eccentricity. For the patients, the ratio did not vary with eccentricity. For all measures, responses were least affected for the first ring (central 2.4 degrees ) and most affected for the third ring (11.6 degrees - 44.4 degrees ). For the first ring, mfERG amplitudes were more impaired than were the mfVEPs or the visual field thresholds. For most of the patients, there was local response correspondence among our measures of visual function.

Interpreting the multifocal visual evoked potential: the effects of refractive errors, cataracts, and fixation errors.

AIM: To understand how refractive errors, cataracts, and fixation errors affect multifocal visual evoked potential (mfVEP) responses. METHODS: Monocular mfVEP responses were obtained using a pattern reversal dartboard display. For the control condition, visual acuity was corrected to > or =20/20 and foveal fixation was maintained. The right eye was tested under the following conditions: simulated refractive error, simulated cataract, steady eccentric fixation, and unsteady fixation. RESULTS: No subject demonstrated significant abnormalities under control conditions. For the simulated refractive error condition, significant centrally located abnormalities were seen for all subjects. For the simulated cataract condition, significant abnormalities were found for three subjects. The steady eccentric fixation condition yielded abnormalities in both eyes for all subjects while the unsteady fixation condition yielded significant central abnormalities in the tested eye. With eccentric and unsteady fixation conditions, all subjects had at least one sector with a waveform polarity reversal. CONCLUSIONS: While the mfVEP is a useful tool for identifying local optic nerve damage or ruling out non-organic aetiology of visual field defects, factors such as uncorrected refractive errors, cataract, eccentric fixation, and unsteady fixation can produce apparent field defects on the mfVEP. With care, these problems can be correctly identified.

Atypical multifocal ERG responses in patients with diseases affecting the photoreceptors.

The purpose of this study was to investigate atypical multifocal ERG (mfERG) responses for patients with diseases that can affect the photoreceptors. MfERGS were obtained from seven patients with retinitis pigmentosa (RP), three with progressive cone dystrophy (CD) and eight with diabetic retinopathy (DR). Both first- and second-order kernel responses were analyzed. The amplitudes and implicit times of the first-order responses were compared to those obtained from age-similar controls. For the first slice of the second-order response, the root-mean-square (RMS) and the signal-to-noise ratio (SNR) of each response were calculated. Achromatic visual fields were also obtained from each subject. For the three groups of patients, first-order responses with relatively large amplitudes, broad-shaped waveforms and markedly increased implicit times had non-measurable second-order responses. These responses were associated with areas of decreased visual field sensitivity. As RP, CD and DR affect the outer retina, the results are consistent with damage to the outer plexiform layer rather than damage to the inner retina.

The optic nerve head component of the monkey's (Macaca mulatta) multifocal electroretinogram (mERG).

To search for an optic nerve head component (ONHC) in the monkey's (Macaca mulatta) multifocal electroretinogram (mERG), mERGs from three animals were recorded with different electrode configurations. A component with a latency that varied with distance from the optic nerve head was easily identified by eye in recordings from the speculum of a Burian-Allen electrode referenced to a DTL on the unstimulated eye. This component was reasonably well isolated by subtracting a weighted version of a Burian-Allen bipolar recording or by employing the extraction algorithm of Sutter and Bearse (1999, Vision Research, 39, 419-436). The waveform of this component resembles the ONHC reported for the human mERG.

Local cone and rod system function in patients with retinitis pigmentosa.

PURPOSE: To compare local cone and rod system function in patients with retinitis pigmentosa (RP) using electrophysiological and psychophysical techniques. METHODS: Cone-mediated multifocal electroretinograms (M-ERGs), cone system threshold visual fields, rod-mediated M-ERGs, and rod system threshold visual fields were measured in seven patients with RP. RESULTS: All the patients had normal cone system visual field thresholds and normal cone-mediated M-ERG implicit times within the central 5 degrees. Both cone-mediated responses were abnormal at some peripheral retinal locations. There were significant correlations among cone system amplitude, timing, and visual field loss. All the patients had some retinal areas where the rod-mediated M-ERG amplitudes were not measurable. In areas where they were measurable, these rod-mediated M-ERG responses were often within normal limits for amplitude and timing. In contrast to the cone system data, there were no significant relationships between rod-mediated M-ERG measures and rod system threshold elevations. The cone and rod system psychophysical thresholds showed regional correspondence; the amplitude-scale and time-scale measures of the M-ERG did not. CONCLUSIONS: The results indicate that there was better local correspondence between psychophysical and electrophysiological measures in the cone system than in the rod system in patients with RP. In addition, the psychophysical measures of cone and rod system function showed better correspondence than did the electrophysiological measures.

Tracking the recovery of local optic nerve function after optic neuritis: a multifocal VEP study.

PURPOSE: To explore the multifocal visual evoked potential (mVEP) as a technique for tracking local optic nerve damage after unilateral optic neuritis (ON). METHODS: Humphrey visual fields and mVEP recordings were obtained from three patients within 7 days of an episode of ON. Patients were retested during the recovery phase, approximately 4 to 7 weeks later. The multi-input procedure of Sutter was used to obtain 60 local VEP responses (the mVEP) to a scaled checkerboard pattern. The mVEPs were recorded separately for monocular stimulation of both eyes. RESULTS: Initially, all three patients had extensive visual field defects, reduced visual acuity, and depressed mVEP amplitude in regions of poor visual field sensitivity. By 4 to 7 weeks, the fields recovered to near normal sensitivity in most locations, and visual acuity returned to 20/20. The mVEP recovered to nearly full amplitude in all regions, but substantial delays were present in many locations. The delayed responses were associated with regions of visual field loss documented during the acute phase. CONCLUSIONS: The mVEP can be used to track local optic nerve damage after unilateral ON. This technique should be useful in observing the effects of treatments as well as in testing hypotheses about the mechanisms underlying both the acute loss of vision and the subsequent recovery.

The nature and extent of retinal dysfunction associated with diabetic macular edema.

PURPOSE: To evaluate the nature and extent of retinal dysfunction in the macular and surrounding areas that occurs in patients with diabetes with clinically significant macular edema (CSME). METHODS: Eleven patients were evaluated before focal laser treatment. Multifocal electroretinogram (ERG) and full-field ERG techniques were used to assess the effects of diabetic retinopathy and CSME on macular, paramacular, and peripheral retinal function. A modified visual field technique was used to obtain local threshold fields. The relationship between local sensitivity changes and local ERG changes was determined. RESULTS: Local ERG responses were significantly delayed and decreased in amplitude, and timing changes were observed in a larger area of the retina than amplitude changes. Visual field deficits were similarly widespread with marked sensitivity losses occurring in retinal areas with normal ERG amplitudes and in areas that appeared to be free of fundus abnormalities. Despite this similarity and the finding that retinal areas with elevated thresholds have timing delays, timing delays were not good predictors of the degree of threshold elevation. CONCLUSIONS: The results demonstrate the widespread nature of timing deficits and visual field deficits that are associated with CSME.

Retinal function in diabetic macular edema after focal laser photocoagulation.

PURPOSE: To assess the effects of focal photocoagulation on retinal function in the macular and perimacular areas in patients with diabetes who have clinically significant macular edema. METHODS: Eleven patients were assessed after focal laser treatment. Multifocal electroretinogram (ERG) and full-field ERG techniques were used to evaluate the effects of treatment on macular, paramacular, and peripheral retinal function. A modified visual field technique was used to obtain local threshold fields. The posttreatment results were compared with pretreatment results. Changes in local ERG response amplitudes and implicit times were calculated for each patient and presented as difference fields. The changes in local ERG responses were compared with the changes in local field sensitivity. RESULTS: After treatment, the results of the psychophysical tests suggested little or no change in visual function, but changes in retinal function were observed with the multifocal ERG technique. Local ERG responses showed increases in implicit time and decreases in amplitude, compared with pretreatment values. Timing was affected more than amplitude. CONCLUSIONS: The results suggest that focal treatment produces changes in retinal function, and these changes are not restricted to the treated macular area.

Functional bitemporal quadrantopia and the multifocal visual evoked potential.

Cases of functional bitemporal hemianopia rarely have been reported. The authors describe the case of a patient with dense bilateral inferotemporal quadrantic field defects on a functional basis that was confirmed by multifocal visual evoked potential. The normality of the multifocal visual evoked potential provides evidence of the functional basis of the field defects.

Assessing retinal function with the multifocal technique.

With the multifocal technique, as developed by Erich Sutter and colleagues, scores of focal electroretinogram (ERG) responses can be obtained in a matter of minutes. Although this technique is relatively new, it has already provided insights into the mechanisms of retinal disease. However, because it is new, there also remain questions about how it works and what it measures. This chapter considers some of these insights and some of these questions. The first part (Section 2) describes how the multifocal ERG (mERG) is recorded and considers its relationship to the full-field ERG. The mERG responses are shown to be from relatively local regions of the retina and are comprised of the same components as the full-field ERG. The diagnostic advantage of the mERG as compared to the full-field ERG is also illustrated. In Section 3, the effects of damage to different cell layers of the retina are shown to affect the mERG differently, and these changes are summarized within a conceptual framework. It is argued, for example, that when diseases of the receptor outer segment, like retinitis pigmentosa, result in small, depressed mERG responses, then the damage is, as expected, at the outer segment. However, when these diseases result in mERG responses that are reasonably large but very delayed, then the damage is beyond the outer segment, probably in the outer plexiform layer. The implicit time of the mERG, not amplitude, is the more sensitive measure of damage in degenerative diseases of the receptors. On the other hand, diseases, like glaucoma, which act on the ganglion axon, do not result in easily identified changes to the mERG unless inner retinal damage is involved as well. Inner retinal damage changes the waveform of the mERG and decreases the naso-temporal variation normally observed. Finally, diseases, like diabetes, that act on more than one layer of the retina can have a range of effects. In Section 4, recent work with the monkey mERG is reviewed, with emphasis on the relevance to human diseases. For example, blocking the sodium-based action potentials produced by ganglion and amacrine cells eliminates the naso-temporal variation in the monkey mERG and these altered mERG responses resemble those from some patients with diabetes or glaucoma. Finally, in Section 5 the second-order kernel is described. The presence of a second-order kernel has important implications for understanding the shape of the mERG response (first-order kernel). Full-field simulations of the mERG paradigm illustrate that the first-order kernel is comprised of responses with different waveforms. Further, it is argued that the nonlinear, adaptive mechanisms that produce the second-order kernel are involved in shaping the time course of the response. Patients with large, but abnormally delayed mERG responses (first-order kernel), do not have a detectable second-order kernel. It is speculated that a markedly diminished second-order kernel is diagnostic of outer plexiform layer damage, not inner plexiform layer damage as is commonly assumed.

An attempt to detect glaucomatous damage to the inner retina with the multifocal ERG.

PURPOSE: To detect glaucomatous damage to the inner retina using the multifocal electroretinogram (mERG). METHODS: The stimulus array consisted of 103 hexagons with a mean luminance of 100 cd/m2 and a contrast of 50%. The mERG was recorded from 13 control subjects, 18 patients with open-angle glaucoma (OAG), 4 glaucoma suspects, and one patient with ischemic optic neuropathy (ION). Individual responses, as well as responses summed within quadrants or across the entire array, were measured in a number of ways. Humphrey visual fields were obtained for all patients, and the mean total deviation (MD) values for the 18 patients with OAG ranged from -2.2 to -18.2 with a mean (SD) of -7.3 (4.5). RESULTS: The mERG measure that best discriminated between the patients and the control subjects was the ratio of the amplitude at 8 msec after the peak response to the amplitude at the peak. Although the value of this ratio fell below the median of the control group for 16 of the 18 OAG patients, only 6 of these patients had ratios that fell below the normal range. Other measures of first- and second-order kernels did not do as well. Both within and across patients, the correlation between local field loss and the mERG ratio measure was poor. Furthermore, although in some patients the mERG waveform is clearly different from normal, in other patients (including the patient with ION) the waveform approximates the normal even in visual field areas with substantial sensitivity loss. CONCLUSIONS: Because glaucomatous damage is known to affect the ganglion cell axon, these data suggest that damage to ganglion cell axons is not a sufficient condition to produce changes in the mERG as measured here and that in patients with clear changes in mERG waveforms, these changes do not appear to be well localized and local waveforms are poorly correlated with local changes in field sensitivity.

An interocular comparison of the multifocal VEP: a possible technique for detecting local damage to the optic nerve.

PURPOSE: To develop a quantitative measure of local damage to the ganglion cells/optic nerve based on an interocular comparison of multifocal visual evoked potentials (mVEP). METHODS: Multifocal VEPs were recorded from both eyes of six normal subjects and four patients; each eye was stimulated separately. Two of the patients had glaucoma, one had ischemic optic neuropathy, and one had unilateral optic neuritis. All four patients had considerably more damage in one eye than in the other, as indicated by their Humphrey visual fields. The multi-input procedure of Sutter was used to obtain 60 VEP responses to a scaled checkerboard pattern. The amplitude in each response was obtained using a root mean square measure of response magnitude. For each of the 60 pairs of responses, a ratio between the amplitude of the responses from the two eyes was obtained as a measure of the relative health of one eye compared with the other. The mean and SD of this ratio measure for the control group were used to specify confidence intervals for each of the 60 locations. All patients had Humphrey 24-2 visual fields performed. To allow a comparison of the mVEPs to the visual fields, a procedure was developed for displaying the results of both tests on a common set of coordinates. RESULTS: Except for a small interocular difference in timing attributable to nasotemporal retinal differences, the pairs of mVEP responses from the two eyes of the control subjects were essentially identical. Many of the pairs of responses from the patients were significantly different. In general, there was reasonably good agreement with the Humphrey 24-2 visual field data. Although some regions with visual field defects were not detected in the mVEP due to small responses from the better eye, other abnormalities were detected that were hard to discern in the visual fields. CONCLUSIONS: Local monocular damage to the ganglion cell/optic nerve can be quantitatively measured by an interocular comparison of the mVEP.

Electrophysiologic assessment of photoreceptor function in patients with primary open-angle glaucoma.

PURPOSE: Electroretinograms to high-intensity flashes were obtained to determine the extent of rod and cone photoreceptor and postreceptor dysfunction in patients with primary open-angle glaucoma. METHODS: Full-field flash electroretinograms were obtained using brief high-intensity flashes. Dark-adapted (rod-dominated) and light-adapted (cone-dominated) electroretinogram responses were recorded to a "white" light as a function of flash intensity. The a-wave data were fitted with a model based on photopigment transduction to obtain values for the parameters of log Rmax (the maximum response) and log S (sensitivity). Oscillatory potentials were measured to the cone-dominated high-intensity flashes. Standard clinical 30 Hz flicker electroretinogram responses were recorded using a Grass photostimulator. RESULTS: Analysis of rod and cone a-wave data showed that log Rmax and log S values were within the normal range in nearly all of the patients. For some patients, oscillatory potentials were delayed beyond the normal range. CONCLUSION: Our results provide little evidence for widespread photoreceptor abnormalities in primary open-angle glaucoma.

Multifocal ERG and VEP responses and visual fields: comparing disease-related changes.

Static visual perimetry and the multifocal technique both measure the local effects of diseases of the retina and optic tract. The purpose here is to relate the measures obtained from each technique and to describe this relationship in some diseases. It is important to measure both the implicit time and amplitude of the multifocal ERG (mERG) or multifocal VEP (mVEP) responses. Some diseases affect one measure of the responses but not the other. The comparison of either measure to local sensitivity changes measured with static perimetry (e.g. the Humphrey 24-2 and 30-2) presents a problem. Different stimulus displays are employed. Further, the multifocal responses are displayed with arbitrary spacing between the responses. One approach is to measure the amplitude and implicit time of the multifocal responses and display these values on the same coordinates as in the visual field plots. This allows a qualitative comparison of fields and multifocal responses on the same scale. A second approach involves modifying the Humphrey perimeter software so that the test spots are placed in the centers of the multifocal stimuli (e.g. the center of each hexagon of the mERG display). A third approach involves estimating the thresholds for the regions of the multifocal display by interpolating from values at the standard Humphrey locations. The second and third approaches produce a one-to-one mapping of the multifocal and field measures and allow a quantitative comparison between the two. The relationship between visual fields and multifocal responses, determined through one or more of these approaches, is different depending upon whether the disease primarily affects the outer retina (retinitis pigmentosa), ganglion cell (glaucoma), or optic nerve (ischemic optic neuropathy and optic neuritis).