Objective detection of visual field defects with multifrequency VEPs.

PURPOSE: To correlate multifrequency pattern reversal VEPs in quadrants (QmfrVEPs) with perimetric field losses for objective detection of visual field losses. METHODS: QmfrVEP measurements were performed using four LED-based checkerboard stimulators to stimulate the four quadrants of the visual field. QmfrVEPs were measured monocularly in 5 normal subjects and in 5 glaucoma patients who showed losses in conventional Octopus perimetry. The pattern reversal frequency varied slightly between the stimulators: (11.92, 12.00, 12.08 and 12.16 reversals/sec). The responses to the different stimuli were identified by discrete Fourier analysis. VEPs were recorded using different electrode configurations, and the recording with the highest signal-to-noise ratio (SNR) was used for further analysis. RESULTS: QmfrVEP responses from the different quadrants can be reliably measured and separated using the 0.08 reversals/sec interstimulus reversal frequency differences. The signal-to-noise ratio in the four quadrants was significantly correlated with the equivalent visual field losses obtained with perimetry (Spearman rank correlation: P < 0.001). In the five glaucoma patients, the SNR was reduced in 15 out of the 16 quadrants with a perimetric defect, in comparison to the results in quadrants of healthy subjects. This confirms the sensitivity of the procedure. CONCLUSION: QmfrVEP responses can be measured reliably. This pilot study suggests that high SNR values exclude visual field defects and that focal defects can be identified in glaucoma patients. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . NCT00494923.

Pattern electroretinogram, blue-yellow visual evoked potentials and the risk of developing visual field defects in glaucoma suspects: a longitudinal "survival" analysis with a very long follow-up.

PURPOSE: Estimating glaucoma suspects' risk for visual field defects helps to avoid under- and over-treatment. In this retrospective, longitudinal cohort study with a very long follow-up, we studied whether pattern electroretinograms (PERG) amplitudes and blue-on-yellow visual evoked potential (BY-VEP) latencies can predict visual field defects. METHODS: Participants of the Erlangen Glaucoma Study were examined with PERG and BY-VEP between 9/1991 and 8/2001. Stimuli were created using an optical bench with Maxwellian view and consisted of vertical gratings (0,88 cpd) in a 32° field for both PERG and BY-VEP. Patients were treated according to clinical standards and performed standard automated perimetry (SAP) annually. Retrospectively, patients with normal SAP at baseline were selected. Primary endpoint was conversion to perimetric glaucoma. Predictive value was modeled using Kaplan-Meier analyses and a multivariate cox proportional hazards model with the continuous variables PERG amplitude, BY-VEP peak time and SAP square-root of loss variance (sLV) after stratification for Jonas classification of the optic discs. RESULTS: Of 412 patients (288: Jonas 0, 103: I, and 21: II; baseline age: 20-60 years), 65 converted to perimetric glaucoma during follow-up (0.5-23.3 years; median 5.5 years). Optic disc classification was a strong risk factor for conversion (log rank p < 0.0001), and patients with more advanced changes progressed earlier. In the multivariate analysis (log rank p = 0.005), only PERG amplitude remained an independent risk factor after stratification for optic disc morphology (p = 0.021), with a ~ 30% higher risk per µV amplitude decrease. CONCLUSIONS: PERG helps to estimate glaucoma suspects' risk for visual field defects.

Blue-Yellow VEP with Projector-Stimulation in Glaucoma.

BACKGROUND AND AIM: In the past, increased latencies of the blue-on-yellow pattern visually evoked potentials (BY-VEP), which predominantly originate in the koniocellular pathway, have proven to be a sensitive biomarker for early glaucoma. However, a complex experimental setup based on an optical bench was necessary to obtain these measurements because computer screens lack sufficient temporal, spatial, spectral, and luminance resolution. Here, we evaluated the diagnostic value of a novel setup based on a commercially available video projector. METHODS: BY-VEPs were recorded in 126 participants (42 healthy control participants, 12 patients with ocular hypertension, 17 with "preperimetric" glaucoma, and 55 with perimetric glaucoma). Stimuli were created with a video projector (DLP technology) by rear projection of a blue checkerboard pattern (460 nm) for 200 ms (onset) superimposed on a bright yellow background (574 nm), followed by an offset interval where only the background was active. Thus, predominantly S-cones were stimulated while L- and M-cone responses were suppressed by light adaptation. Times of stimulus onset to VEP onset-trough (N-peak time) and offset-peak (P-peak time) were analyzed after age-correction based on linear regression in the normal participants. RESULTS: The resulting BY-VEPs were quite similar to those obtained in the past with the optical bench: pattern-onset generated a negative deflection of the VEP, whereas the offset-response was dominated by a positive component. N-peak times were significantly increased in glaucoma patients (preperimetric 136.1 ± 10 ms, p < 0.05; perimetric 153.1 ± 17.8 ms, p < 0.001) compared with normal participants (123.6 ± 7.7 ms). Furthermore, they were significantly correlated with disease severity as determined by visual field losses retinal nerve fiber thinning (Spearman R = -0.7, p < 0.001). CONCLUSIONS: Video projectors can be used to create optical stimuli with high temporal and spatial resolution, thus potentially enabling sophisticated electrophysiological measurements in clinical practice. BY-VEPs based on such a projector had a high diagnostic value for detection of early glaucoma. Registration of study Registration site: www. CLINICALTRIALS: gov Trial registration number: NCT00494923.

Steady-state multifocal visual evoked potential (ssmfVEP) using dartboard stimulation as a possible tool for objective visual field assessment.

PURPOSE: To investigate whether a conventional, monitor-based multifocal visual evoked potential (mfVEP) system can be used to record steady-state mfVEP (ssmfVEP) in healthy subjects and to study the effects of temporal frequency, electrode configuration and alpha waves. METHODS: Multifocal pattern reversal VEP measurements were performed at 58 dartboard fields using VEP recording equipment. The responses were measured using m-sequences with four pattern reversals per m-step. Temporal frequencies were varied between 6 and 15 Hz. Recordings were obtained from nine normal subjects with a cross-shaped, four-electrode device (two additional channels were derived). Spectral analyses were performed on the responses at all locations. The signal to noise ratio (SNR) was computed for each response using the signal amplitude at the reversal frequency and the noise at the neighbouring frequencies. RESULTS: Most responses in the ssmfVEP were significantly above noise. The SNR was largest for an 8.6-Hz reversal frequency. The individual alpha electroencephalogram (EEG) did not strongly influence the results. The percentage of the records in which each of the 6 channels had the largest SNR was between 10.0 and 25.2 %. CONCLUSION: Our results in normal subjects indicate that reliable mfVEP responses can be achieved by steady-state stimulation using a conventional dartboard stimulator and multi-channel electrode device. The ssmfVEP may be useful for objective visual field assessment as spectrum analysis can be used for automated evaluation of responses. The optimal reversal frequency is 8.6 Hz. Alpha waves have only a minor influence on the analysis. Future studies must include comparisons with conventional mfVEP and psychophysical visual field tests.

Comparison of frequency doubling and flicker defined form perimetry in early glaucoma.

PURPOSE: To compare perimetric data based on the second-generation frequency doubling technology (FDT) and on flicker defined form (FDF) stimulation in early glaucoma patients. METHODS: Seventy-two experienced glaucoma patients and 50 healthy subjects of the Erlangen Glaucoma Registry participated in the study. The definition of glaucoma was solely based on optic disc appearance. All patients underwent FDF perimetry (HEP), FDT perimetry (Matrix), standard automated perimetry (SAP, Octopus), and peripapillar measurements of the RNFL thickness (Spectralis OCT). Exclusion criteria were: mean defect (MD) in SAP > 6 dB, eye diseases other than glaucoma, or non-reliable FDF or FDT measurements. Statistical analyses included comparison of the standard indices and correlations between methods. Venn-diagrams show the number of patients with abnormal results in HEP, Matrix, SAP, and mean RNFL thickness. RESULTS: Mean defect data from FDT and FDF perimetry were strongly correlated (R = -0.85, P <0.001). In this cohort of early glaucoma patients, the MD values were 6.1 ± 5.0 dB (FDF) and 4.5 ± 4.1 dB (FDT). Sensitivity in this patient group was 65 % for FDF-MD, 60 % for FDT-MD, and 60 % for RNFL-thickness, all at a specificity of 95 %. The correlation analysis between local RNFL thickness and corresponding visual defects revealed significant Spearman correlation coefficients for the arcuate bundles of the visual field (FDF-inferior: R = -0.65, FDF-superior: R = -0.74, FDT-inferior: R = -0.55, FDT-superior: R = -0.72). CONCLUSION: FDF and FDT stimulations can be used to detect patients with early glaucoma. Combined consideration of RNFL thickness and results from one of these perimetric tests can increase the total number of detected patients.

Flicker-defined form perimetry in glaucoma patients.

PURPOSE: To assess the potential of flicker-defined form (FDF) perimetry to detect functional loss in patient groups with beginning glaucoma, and to evaluate the dynamic range of the FDF stimulus in individual patients and at individual test positions. METHODS: FDF perimetry and standard automated perimetry (SAP) were performed at identical test locations (adapted G1 protocol) in 60 healthy subjects and 111 glaucoma patients. All patients showed glaucomatous optic disc appearance. Grouping within the glaucoma cohort was based on SAP-performance: 33 "preperimetric" open-angle glaucoma (OAG) patients, 28 "borderline" OAG (focal defects and SAP-mean defect (MD) <2 dB), 33 "early" OAG (SAP-MD < 5 dB), 17 "advanced" OAG. All participants were experienced in psychophysical and perimetric tests. Defect values and the areas under receiver operating characteristic curves (ROC) in patient groups were statistically compared. RESULTS: The values of FDF-MD in the preperimetric, borderline, and early OAG group were 2.7 ± 3.4 dB, 5.5 ± 2.6 dB, and 8.5 ± 3.4 dB respectively (all significantly above normal). The percentage of patients exceeding normal FDF-MD was 27.3 %, 60.7 %, and 87.9 % respectively. The age-adjusted FDF-mean defect (MD) of the G1X-protocol was not significantly correlated with refractive error, lens opacity, pupil size, or gender. Occurrence of ceiling effects (inability to detect targets at highest contrast) showed a high correlation with visual field losses (R = 0.72, p < 0.001). Local analysis indicates that SAP losses exceeding 5 dB could not be distinguished with the FDF technique. CONCLUSION: The FDF stimulus was able to detect beginning glaucoma damage. Patients with SAP-MD values exceeding 5 dB should be monitored with conventional perimetry because of its larger dynamic range.

Evidence for two types of lateral interactions in visual perception of temporal signals.

The aim of this work was to investigate the mechanisms of lateral interactions involved in flicker perception. Furthermore, the spatial properties of the monoptic and dichoptic components of these mechanisms were studied. We quantified the perceived flicker strength (PFS) in the center of a test stimulus, which was simultaneously modulated with a surround stimulus of variable size. The modulation depth of a separate stimulus, identical to the center test stimulus but without the surround, was determined using a two-alternative forced choice procedure. Using LCD goggles synchronized to the frame rate of a CRT screen, the center and surround of the test stimulus were presented either monoptically or dichoptically. In the monoptic condition, center-surround interactions have subcortical and cortical origins. In the dichoptic condition, center-surround interactions must have a cortical origin. The difference between the dichoptic and the monoptic data is an estimate of the contribution of the subcortical mechanisms. At each condition (surround stimulus size; monoptic or dichoptic presentation), the PFS was measured for phase differences between center and surround stimuli. The PFS changed systematically with phase difference. It also was observed that the PFS in the center stimulus changed merely be the presence of a surround stimulus independently of the center-surround phase difference. We propose that this is a phase-independent mechanism related to contrast adaptation owing to the presence of surround modulation. Our data suggest that both phase-dependent and -independent mechanisms have cortical and subcortical origins. There were no systematic differences between the spatial properties of subcortical and cortical components involved in PFS modulation.

Spectral characteristics of the PhNR in the full-field flash electroretinogram of normals and glaucoma patients.

Flash electroretinogram responses were measured in normal subjects to different chromatic combinations of flashes and backgrounds. The amplitudes of the flash response components were measured at different flash strengths and could be described by a generalized Naka-Rushton function. The measurements were repeated at different background luminances to study adaptation effects. It was found that when flash strength and background luminance were expressed in photometric terms (cd s/m² and cd/m², respectively), then the responses were very similar for all chromatic combinations with the exception of the condition in which blue (peak wavelength 458 nm) was flashed upon an orange (peak wavelength 591 nm) background. We propose that in this condition, a second (possibly S-cone or rod-driven) mechanism intrudes. The negative response after the b-wave (here called "photopic negative response" or PhNR for all conditions) is thought to reflect ganglion cell activity and was also largest at this condition. Responses were measured to the 458 nm flash on 591 nm background and the reversed combination in a population of 39 normal subjects and 49 glaucoma patients. It was found that the PhNR amplitude was affected by glaucoma in all conditions. Other component parameters, reflecting responses and adaptation dynamics, were not altered. The best stimulus condition among the conditions used to separate the PhNR amplitude of normals and patients was a 1 cd s/m² 458 nm flash on a 10 cd/m² 591 nm background.

On- and off-response ERGs elicited by sawtooth stimuli in normal subjects and glaucoma patients.

The aim of this study is to measure the on- and off-responses and their response asymmetries elicited by sawtooth stimuli in normal subjects and glaucoma patients. Furthermore, the correlation between the ERGs and other functional and structural parameters are investigated. Full-field stimuli were produced using a Ganzfeld bowl with Light Emitting Diodes (LEDs) as light sources. On- and off-response ERGs were recorded from 17 healthy subjects, 12 pre-perimetric and 15 perimetric glaucoma patients using 4-Hz luminance rapid-on and rapid-off sawtooth stimuli (white light; mean luminance 55 cd/m(2)) at 100% contrast. The on- and off-responses were added to study response asymmetries. In addition, flash ERGs were elicited by red stimuli (200 cd/m(2)) on a blue background (10 cd/m(2)). The mean deviations (MD) of the visual field defects were obtained by standard automated perimetry. The retinal nerve fibre layer thickness (RNFLT) was measured with Spectral Domain Optical Coherence Tomography (SOCT). We studied the correlation between ERG response amplitudes, visual field mean deviation (MDs) and RNFLT values. The on-responses showed an initial negative (N-on) followed by a positive (P-on), a late positive (LP-on) and a late negative responses (LN-on). The off-responses showed an initial positive (P-off) a late positive (LP-off) and a late negative response (LN-off). The addition of on- and off-responses revealed an initial positive (P-add) and a late negative response (LN-add). The on-response components (N-on, P-on and LN-on) in the glaucoma patients were relatively similar to those of the control subjects. However, the LP-on was significantly elevated (p = 0.03) in perimetric patients. The LP-off was significantly elevated (p < 0.001), and the amplitude of LN-off was significantly reduced in perimetric patients (p = 0.02). The LN-add amplitude was significantly reduced (p < 0.001) and delayed (p = 0.03) in perimetric patients. The amplitudes of the LN-off and LN-add ERG components were significantly correlated with the PhNR in the flash ERG (LN-off: p = 0.01; LN-add: p < 0.001) and with RNFLT (LN-off: p = 0.006; LN-add: p = 0.001). On- and off-response ERGs and their response asymmetries, elicited by sawtooth stimuli, are altered in the glaucoma patients. The late components are affected. Changes in the late negative components are correlated with structural and other functional changes.

On and off responses of the photopic fullfield ERG in normal subjects and glaucoma patients.

Recent studies suggest a diagnostic value of the photopic negative response (PhNR) with a long-duration stimulus. The aim of this study was to record the on and off responses of the photopic fullfield electroretinogram (ERG) in normal subjects and glaucoma patients. We focused on different waves of the responses after onset and offset of the long-duration stimulus ERG. Photopic fullfield ERGs were recorded in response to a white bright LED flash on a white 20 cd/m(2) background. Stimulus luminances were 40, 60 and 80 cd/m(2). Responses were averaged using a flash duration of 240 ms and an offset period of 500 ms. We examined 19 healthy subjects, 27 patients with glaucomatous optic disc atrophy and 7 ocular hypertensive patients. The amplitudes and implicit times of the on and off responses of the human ERG depended on flash luminance. Comparing patients with glaucoma and healthy subjects for the 60 cd/m² flash, there was a significant change in the PhNRs (at onset: P < 0.01, at offset: P < 0.001) of the d-wave and of the i-wave at offset (P < 0.01). No significant difference was found for peak times of the fullfield ERG and for a- and b-wave amplitudes. PhNR amplitudes were significantly correlated with mean thickness of retinal nerve fibre layer as measured with OCT. In comparison with the normal photopic long-flash ERG, glaucoma patients showed changes in the PhNR amplitude following stimulus onset and in waves following stimulus offset.

Responses of Postreceptoral Pathways Elicited by L- and M-Cone Isolating ON- and OFF-Electroretinograms in Glaucoma Patients.

Purpose: To compare the electroretinographical (ERG) responses elicited by L- and M-cone isolating ON- and OFF-sawtooth stimuli in normal subjects and glaucoma patients. Methods: Twenty-one normal subjects and 44 primary open-angle glaucoma patients participated in the study. L- and M-cone isolating (18% cone contrast; 284 cd/m2) rapid ON- and rapid OFF-sawtooth (4 Hz) stimuli with two stimulus sizes (full-field (FF) and central 70° diameter) were generated using the triple silent substitution technique. ON- and OFF-response asymmetries were studied by adding the two (to obtain L-add and M-add responses). The initial positive (P) and subsequent late negative (LN) components of the L-add and M-add ERGs were compared between the subject groups and correlated with retinal nerve fiber layer thickness (RNFLT) and pattern ERG responses. Results: The responses to L-ON and to M-OFF stimuli and vice versa resembled each other particularly with 70° stimuli. The PL-add amplitudes were not significantly different between the normal subjects and glaucoma patients, whereas the LNL-add amplitude was significantly (P < 0.01) smaller in the glaucoma patients. Both PM-add and LNM-add were not significantly different between the subject groups. The PERG amplitude with 0.8° check sizes and the 0.8°/16° amplitude ratio (PERG ratio) were significantly (P < 0.05) different between the subject groups. The 70° LNL-add amplitude and the 0.8° PERG amplitude were significantly correlated with RNFLT. Conclusions: The ERGs to 70° cone isolating sawtooth stimuli reflect cone opponency. The cone opponent ERG responses were not significantly different between glaucoma patients and normal subjects. Luminance driven L-add responses were significantly different, indicating that central luminance signals are mainly affected in glaucoma.

A new interpretation of components in the ERG signals to sine wave luminance stimuli at different temporal frequencies and contrasts.

Full-field electroretinograms were recorded from five normal human subjects using white light (mean luminance: 250 cd/m2) sine wave stimuli at different frequencies and contrasts. In agreement with previous studies, we found that the amplitude of the fundamental component displayed a dip at about 12 Hz, coinciding with a maximum in the second harmonic component, indicating frequency doubling of the responses. By including measurements at different contrasts, we were able to recognize two (sine-like and transient) response components. We found that the waveform of the transient response was relatively frequency independent. An algorithm to separate the two components was developed. The interaction between these two components can explain the frequency-doubled responses around 12 Hz. The sine-like component is more linear and prominent in the low-frequency region, whereas the transient seems to be more nonlinear and prominent in the high-frequency region.

GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization: interim results of a randomized phase II trial.

PURPOSE: Pathologic corneal neovascularization not only reduces corneal transparency and visual acuity, but also is one of the most significant preoperative and postoperative risk factors for graft rejection after corneal transplantation. The aim of this study was to test tolerability and efficacy of gene signal (GS)-101 eye drops, an antisense oligonucleotide against insulin receptor substrate-1, versus placebo on inhibition of progressive corneal neovascularization. DESIGN: Randomized, double-blind, multicenter, phase II clinical study. PARTICIPANTS AND CONTROLS: Interim analysis on 40 patients with progressive corneal neovascularization resulting from various underlying diseases being nonresponsive to conventional therapy. INTERVENTIONS: Four groups of 10 patients were treated for 3 months in this dose-finding study comparing 3 doses of GS-101 (eye drops twice daily; 43, 86, and 172 microg/day total) with placebo (10 patients per group). MAIN OUTCOME MEASURES: The primary end point was the area covered by pathologic corneal blood vessels, which was measured morphometrically on digitized slit-lamp pictures using image analysis techniques. RESULTS: GS-101 eye drops were well tolerated. All serious and 95% of all other adverse events were categorized by the investigators as unrelated. In 3 patients, there was a potentially related side effect of ocular surface discomfort. At a dose of 86 microg/day (43 microg/drop), GS-101 eye drops produced a significant inhibition and regression of corneal neovascularization (-2.04+/-1.57% of total corneal area; P = 0.0047), whereas the low dose tended to stabilize it (0.07+/-2.94%; P = 0.2088) compared with placebo (0.89+/-2.15%), where corneal neovascularization progressed in all patients. There was no apparent benefit to the higher dose (1.60+/-7.63%). CONCLUSIONS: The interim results of this phase II study suggest that GS-101 eye drops at an optimal dose of 86 microg/day are an effective and noninvasive approach specifically to inhibit and regress active corneal angiogenesis, a major risk factor for corneal graft transplantation and graft rejection. Safety concerns were not detected. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A comparison of the suitability of cathode ray tube (CRT) and liquid crystal display (LCD) monitors as visual stimulators in mfERG diagnostics.

The aim of this study was to determine up to which extent the specific characteristics of cathode ray tube (CRT) and liquid crystal display (LCD) monitors influence the retinal biosignal when used as stimulators in ocular electrophysiology. In a conventional CRT monitor, each pixel lights up only for a duration of a few milliseconds during each frame. In contrast, liquid crystal displays are quasi-static, i.e. each pixel has a constant luminance during the whole length of the frame, but lights up only with a certain delay after the trigger. These different display characteristics may affect the mfERG signal. The temporal and spatial luminance distributions of a CRT and an LCD monitor were measured in white flashes. The total amount of emitted light was calculated by integration of the intensity versus time curves. By means of an mfERG recording system (RETIsystem, Roland Consult, Brandenburg, Germany) first-order kernel (FOK) mfERG signals were computed and then analysed using customized MATLAB (TheMathWorks, Natick, MA, USA) software. With the two stimulator monitors, differences in the mfERG signal were observed. The latencies of mfERG responses recorded with the LCD monitor were significantly increased by 7.1 ms for N1 and 9.5 ms for P1 compared to the CRT. Due to a higher luminance, the N1 amplitude was significantly higher by approx. 2 dB in measurements with the LCD monitor while no significant difference could be detected with regard to the more contrast sensitive P1 amplitude. When using LCD monitors as stimulators the increase in latencies and differences in the luminance versus time profile must be taken into account. Prior to clinical application, the establishment of guidelines for the use of LCD monitors is recommended.

Tele-transmission of stereoscopic images of the optic nerve head in glaucoma via Internet.

The objective was to describe an inexpensive system to visualize stereoscopic photographs of the optic nerve head on computer displays and to transmit such images via the Internet for collaborative research or remote clinical diagnosis in glaucoma. Stereoscopic images of glaucoma patients were digitized and stored in a file format (joint photographic stereoimage [jps]) containing all three-dimensional information for both eyes on an Internet Web site (www.trizax.com). The size of jps files was between 0.4 to 1.4 MB (corresponding to a diagonal stereo image size between 900 and 1400 pixels) suitable for Internet protocols. A conventional personal computer system equipped with wireless stereoscopic LCD shutter glasses and a CRT-monitor with high refresh rate (120 Hz) can be used to obtain flicker-free stereo visualization of true-color images with high resolution. Modern thin-film transistor-LCD displays in combination with inexpensive red-cyan goggles achieve stereoscopic visualization with the same resolution but reduced color quality and contrast. The primary aim of our study was met to transmit stereoscopic images via the Internet. Additionally, we found that with both stereoscopic visualization techniques, cup depth, neuroretinal rim shape, and slope of the inner wall of the optic nerve head, can be qualitatively better perceived and interpreted than with monoscopic images. This study demonstrates high-quality and low-cost Internet transmission of stereoscopic images of the optic nerve head from glaucoma patients. The technique allows exchange of stereoscopic images and can be applied to tele-diagnostic and glaucoma research.

Steady-State Visually Evoked Potentials Elicited by Multifrequency Pattern-Reversal Stimulation.

PURPOSE: It has been shown that multifrequency stimulation with multifocal electroretinography can reduce recording time without a loss in signal-to-noise ratio. Here, we studied the applicability of multifrequency stimulations for steady-state visually evoked potential (VEP) recordings. METHODS: Multifrequency VEPs were recorded monocularly from 10 healthy subjects using pattern-reversal stimuli. The reversal frequency varied between 5 and 30 Hz. Pattern-reversal checkerboard stimuli were generated using four square arrays, each containing 100 light-emitting diodes (LEDs), positioned in four quadrants. Each array had a temporal frequency that differed slightly from the nominal frequency. The long duration of the data acquisition ensured that the slightly different stimulus frequencies in the four LED arrays can be resolved and that the responses to the stimulus in each array can be distinguished (e.g., with a frequency resolution: 0.011 Hz at 12 Hz). The best response from the four recording electrode configuration, defined as the recording with the maximal signal-to-noise ratio, was used for further analysis. Algorithmic latencies were calculated from the ratio of phase data and frequencies in a range of 4 and 20 Hz. RESULTS: Quadrant-VEPs with simultaneous pattern-reversal stimulation yielded a significant dependency on temporal frequency and stimulus location. The frequency range leading to the maximal response amplitude was between 10 and 12 Hz. Response phases decreased approximately linearly, with increasing temporal frequency suggesting a mean algorithmic latency between 112 and 126 ms. CONCLUSIONS: Multifrequency stimulation using LED arrays is an efficient method for recording pattern-reversal VEPs while all stimuli are presented at the same time. TRANSLATIONAL RELEVANCE: Simultaneously recorded VEPs as performed by the multi-frequency method can be used for objective measurements of visual field defects.

Predictive Factors for Visual Field Conversion: Comparison of Scanning Laser Polarimetry and Optical Coherence Tomography.

PURPOSE: The purpose of this study was to compare the ability of scanning laser polarimetry (SLP) and spectral-domain optical coherence tomography (SD-OCT) to predict future visual field conversion of subjects with ocular hypertension and early glaucoma. METHODS: All patients were recruited from the Erlangen glaucoma registry and examined using standard automated perimetry, 24-hour intraocular pressure profile, and optic disc photography. Peripapillary retinal nerve fiber layer thickness (RNFL) measurements were obtained by SLP (GDx-VCC) and SD-OCT (Spectralis OCT). Positive and negative predictive values (PPV, NPV) were calculated for morphologic parameters of SLP and SD-OCT. Kaplan-Meier survival curves were plotted and log-rank tests were performed to compare the survival distributions. Contingency tables and Venn-diagrams were calculated to compare the predictive ability. RESULTS: The study included 207 patients-75 with ocular hypertension, 85 with early glaucoma, and 47 controls. Median follow-up was 4.5 years. A total of 29 patients (14.0%) developed visual field conversion during follow-up. SLP temporal-inferior RNFL [0.667; 95% confidence interval (CI), 0.281-0.935] and SD-OCT temporal-inferior RNFL (0.571; 95% CI, 0.317-0.802) achieved the highest PPV; nerve fiber indicator (0.923; 95% CI, 0.876-0.957) and SD-OCT mean (0.898; 95% CI, 0.847-0.937) achieved the highest NPV of all investigated parameters. The Kaplan-Meier curves confirmed significantly higher survival for subjects within normal limits of measurements of both devices (P<0.001). Venn diagrams tested with McNemar test statistics showed no significant difference for PPV (P=0.219) or NPV (P=0.678). CONCLUSIONS: Both GDx-VCC and SD-OCT demonstrate comparable results in predicting future visual field conversion if taking typical scans for GDx-VCC. In addition, the likelihood ratios suggest that GDx-VCC's nerve fiber indicator<30 may be the most useful parameter to confirm future nonconversion. (http://www.ClinicalTrials.gov number, NTC00494923; Erlangen Glaucoma Registry).

Glaucoma detection with frequency doubling perimetry and short-wavelength perimetry.

PURPOSE: The aim of this analysis was to evaluate the diagnostic usefulness of frequency doubling technology (FDT) perimetry and short-wavelength perimetry (SWAP). Moreover, to study a combination of both methods using the machine-learning technique double-bagging, which was recently established in glaucoma research. METHODS: Forty-three patients with "preperimetric" open-angle glaucoma (glaucomatous optic disc atrophy and no visual field defect in standard perimetry), 26 patients with "perimetric" open angle glaucoma (glaucomatous optic disc atrophy and visual field defect in standard perimetry), and 40 control subjects had FDT screening (protocol: C-20-5) and SWAP (Octopus 101, G2). Criteria for exclusion were color vision abnormalities, media opacities, and an age below 31 years or above 63 years. Data of 1 eye of each patient and control subject entered the statistical evaluation. A point wise evaluation of the diagnostic power of SWAP values was performed to derive spatial patterns of visual field loss. A double-bagging machine-learning algorithm was used to train classification rules on the basis of a combination of FDT scores and nerve fiber related visual field losses in SWAP. The diagnostic power of the classifiers was compared regarding their misclassification error rates and area under the receiver-operating characteristic curve. RESULTS: The combination of FDT perimetry and SWAP yielded better diagnostic results compared with FDT or SWAP separately. The overall estimated misclassification error rate of the combined classifier was 24% compared with 28% for both SWAP and FDT perimetry. Regarding the estimated performance of classifier at high specificities (>80%) in control eyes as measured by the partial area under the receiver-operating characteristic curve, the combination of both instruments is also superior to the individual instruments. CONCLUSIONS: A combination of SWAP and FDT perimetry, each targeting different neuronal pathways, may improve early glaucoma detection.

Long-term reproducibility of screening for glaucoma with FDT-perimetry.

PURPOSE: Aim of this study was to evaluate the long-term reproducibility of frequency doubling technology (FDT) screening procedures. METHODS: Longitudinal data of 433 eyes of 294 patients with no progression of glaucomatous optic disc atrophy were retrospectively analyzed: 62 control eyes, 184 ocular hypertensive eyes, 104 preperimetric, and 83 perimetric open-angle glaucoma eyes. All subjects had annual tests with the FDT perimeter and a standardized ophthalmologic examination (ie, conventional perimetry, optic disc inspection, tonometry, lens opacity measurement for exclusion of cataract). The present analysis used a published overall screening score with case-wise recalculation of missed localized probability levels. We analyzed long-term variability by correlation analysis, sign tests, and limits of agreement (LoA) as introduced by Altman and Bland. All subjects had at least 2 annual tests. Three hundred twenty-six eyes had 2 annual tests with the C-20 procedure and at least 1 test with the N-30 protocol another year later. One hundred thirty-five eyes had 1 C-20 and 2 annual tests with the N-30 protocol. RESULTS: Analyses of repeated measurements revealed a significant learning effect (P<0.001, LoA: -4, 17) between the first and second examination but no significant difference between the second and following tests with the C-20 protocol (P>0.6, LoA: +/-9). In addition, there was no significant difference between second C-20 and N-30 tests (P>0.5, LoA: -12, 6). CONCLUSIONS: The study demonstrates the variability of FDT tests over several years. Longitudinal FDT-results in a clinical study showed a higher reproducibility if the first test was discarded. Reproducibility of screening with the N-30 protocol is comparable to the C-20 procedure if an overall score is considered.

Can Glaucomatous Visual Field Progression be Predicted by Structural and Functional Measures?

PURPOSE: The aim of this study was to compare the predictive value of retinal nerve fiber layer thickness (RNFLT) measurements obtained by optical coherence tomography (OCT), morphometric parameters of confocal scanning laser ophthalmoscopy (CSLO), and frequency-doubling technique perimetry to predict visual field conversion of normal individuals, ocular hypertensive subjects, and early preperimetric glaucoma patients as determined by standard automated perimetry (SAP). PATIENTS AND METHODS: This longitudinal single-center study included 107 eyes of 56 controls, 164 eyes of 98 patients with ocular hypertension, and 169 eyes of 110 patients with preperimetric glaucoma. At baseline, all patients and controls underwent OCT (Spectralis OCT), CSLO (Heidelberg Retina Tomograph) examination, optic disc photography, and frequency-doubling technique perimetry. At baseline SAP was normal in all participants. Univariate and multivariate hazard ratios (HRs) were measured to model the conversion-free survival including morphometric functional and clinical variables. RESULTS: The median follow-up period was 6.9 years. In total, 48 eyes (10.9%) demonstrated visual field conversion in the follow-up. RNFLT temporal-inferior outside normal limits demonstrated the highest HR with 1.2 (95% confidence interval, 1.1-1.4) per 10 µm loss for OCT, and Glaucoma probability score global outside normal limits demonstrated the highest HR with 1.3 (95 % confidence interval, 1.1-1.5) per 0.1 increase for CSLO in a multivariate model adjusted for photograph-based glaucoma staging, central corneal thickness, and SAP pattern SD. CONCLUSIONS: Both measurement of RNFLT by OCT and Glaucoma probability score by CSLO are highly predictive of future visual field conversion and provide independent predictive information beyond optic disc assessment, central corneal thickness, and SAP pattern SD.