From the Departments of Ophthalmology and Visual Sciences (JSW, DCM, LMN, NWK) and Epidemiology (DCM), University of Michigan, Ann Arbor, Michigan.
Supported in part by a departmental grant from Research to Prevent Blindness (RPB), Inc., New York, New York. Dr. Musch is a recipient of RPB’s Lew R. Wasserman Merit Award.
The authors have no financial or proprietary interest in the materials presented herein.
The authors thank Dr. Donald C. Hood and Dr. Xian Zhang for providing the Matlab multifocal VEP processing programs, Ms. Carol Pollock-Rundle for assistance with subject recruitment and data collection, and Peter Huebner for assistance with mfVEP data entry and analysis.
Address correspondence to Jennifer S. Weizer, MD, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: email@example.com
Standard automated perimetry (SAP) is considered the gold standard for measuring visual loss in primary open-angle glaucoma (POAG), but it is a subjective test that some patients are unable to perform reliably. Therefore, considerable interest has developed in finding objective measures of visual loss in glaucoma. Also, newer technologies such as short-wave automated perimetry (SWAP), frequency-doubling threshold perimetry (FDT), and nerve fiber layer optical coherence tomography (OCT) may help identify early glaucoma damage that is not yet detectable by SAP.1,2 Some of these testing methods are more easily performed by patients, who have been shown to prefer them over SAP.3,4
Studies have shown that multifocal visual evoked potentials (mfVEP) can detect glaucomatous damage in patients with glaucoma with established SAP defects.5–8 We hypothesize that mfVEP is useful in detecting early visual loss due to POAG in patients with normal SAP and that its results correspond with other testing modalities, namely SWAP, FDT, and OCT.
Patients and Methods
Institutional Review Board approval was obtained from the University of Michigan Medical School. Fifteen patients who were either patients with suspected glaucoma or had early POAG were prospectively recruited from the glaucoma clinic of the University of Michigan’s Kellogg Eye Center from 2006 to 2009. Inclusion criteria were diagnosis of suspected glaucoma or early POAG. Exclusion criteria were age younger than 18 years, secondary causes of glaucoma, narrow angles or angle-closure glaucoma, previous eye surgery besides cataract surgery, best-corrected visual acuity worse than 20/30 in either eye, or inability to reliably perform the testing described in this study. Patients with suspected glaucoma were defined as having glaucomatous optic nerve cupping in one or both eyes without documented progression, SAP defects, SWAP defects, or elevated intraocular pressure (IOP) history in either eye. Patients with POAG were defined as having optic nerve cupping in one or both eyes with documented progression of cupping, history of elevated IOP, or visual field defects on SAP or SWAP.
The following data were collected at a single study visit per study patient: age, sex, race, presence of diabetes mellitus or systemic hypertension by history, and family history of glaucoma. At the same study visit, the following examination data were collected per eye: glaucoma diagnosis, number of glaucoma medications prescribed, best-corrected Snellen visual acuity, spherical equivalent, IOP by Goldmann applanation, central corneal thickness by ultrasound pachymetry, and vertical and horizontal cup-to-disc ratios by stereoscopic slit-lamp biomicroscopy as measured by one physician (JSW). For central corneal thickness, the average of five readings per eye was used.
All patients underwent the following diagnostic testing per eye: SWAP, FDT, OCT, and mfVEP (all within 6 months of the study visit) and SAP (within 1 year of the study visit). For SAP, patients performed Humphrey Swedish Interactive Threshold Algorithm (SITA) standard 24-2 visual fields. For SWAP, patients performed Humphrey SITA-SWAP 24-2 visual fields. Mean deviation, pattern standard deviation, and glaucoma hemifield test results were recorded for each SAP and SWAP performed. Cluster defects on SAP were based on the total deviation probability plot and were defined as two or more adjacent points with a P value of less than .01 or three or more adjacent points with a P value of less than .05 in the superior or inferior hemifield.9 Mean deviation and pattern standard deviation were recorded for each FDT (FDT 710; Humphrey-Zeiss, Dublin, CA) performed.
Reliability criteria used for SAP, SWAP, and FDT were adapted from the Advanced Glaucoma Intervention Study investigators,10 where reliable fields had to have less than 20% fixation losses, 33% false-positive responses, or 33% false-negative responses. Nerve fiber layer OCT was performed through dilated pupils using the Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA) Fast RNFL protocol. We analyzed the average values of three clock-hour measurements per quadrant (superior, nasal, inferior, and temporal), the overall nerve fiber layer thickness averaged from all 12 clock-hours, and the class of nerve fiber layer thickness (ie, > 5%, between 1% and 5%, or < 1%) compared to the device’s normative age-matched distribution database. Abnormal nerve fiber layer thinning was defined as one quadrant with thickness less than the first percentile.
The mfVEP was performed using VERIS 5.1 software (Electro-Diagnostic Imaging, Redwood City, CA). The stimulus was a dartboard pattern comprising 60 sectors.11 Each sector consisted of a checkerboard pattern of eight white checks and eight black checks. The stimulus was presented on the FMSII refractor/camera stimulus display system (Electro-Diagnostic Imaging). We used the three-channel recording method using gold cup electrodes described by Thienprasiddhi et al.9 The electrode formation consisted of the active electrode at 4 cm above the inion, reference at the inion, and ground on the forehead. For the other two channels, the active electrode was placed 1 cm up and 4 cm lateral to the inion on either side. The ground and reference were the same as for the other two channels. The mfVEP responses were analyzed9,11 using the MATLAB program, which was provided to us by Dr. Donald C. Hood. Briefly, the program calculated the root-mean-square amplitude and the signal-to-noise ratio of each response from each eye at each of the 60 locations. The channel with the largest signal-to-noise ratio was selected for analysis.
For the monocular test, the signal-to-noise ratio for each response was considered. An interocular probability plot was derived by taking the ratio of the root-mean-square amplitude from corresponding locations in each eye. The log of the interocular ratio from the patient with glaucoma at each location was compared to the log of ratios obtained for control subjects. We used the cluster criteria of Hood et al.12 to determine when a subject’s responses could be considered abnormal. Significant clusters were those that had two or more adjacent points with P values of less than .01 or three or more points with a P value of less than .05, with at least one of these points with a P value of less than .01.
Nineteen age-matched normal control subjects were recruited from volunteers at the Kellogg Eye Center for the purpose of calibrating the mfVEP results. For these control subjects, visual acuity testing, IOP measurement by Goldmann applanation, and stereoscopic slit-lamp biomicroscopy were performed to ensure that none had suspected glaucoma, confirmed glaucoma, or any other significant eye disease. Control subjects with IOP greater than 21 mm Hg or cup-to-disc ratio of 0.6 or greater in either eye were excluded. All control subjects performed SAP and mfVEP testing.
Comparisons between groups involving continuous variables were made using independent t tests; for categorical variables, Fisher’s exact test was used. A P value of less than .05 was considered to be statistically significant. SAS 9.2 statistical software (SAS Institute, Cary, NC) was used for all analyses.
The mean age (± standard deviation) of the 15 study patients was 50.1 ± 9.1 years. Nine (60%) were male and all were white. For comparison, the mean age of the 19 control patients was 48.0 ± 8.0 years; 8 (42%) of the control patients were male, 17 (89%) were white, and 2 (11%) were Asian. Ten of the 15 study patients (67%) had suspected glaucoma and 5 (33%) had early POAG. Three (20%) study patients had a family history of glaucoma in a first-degree relative; 2 (13%) had systemic hypertension and none had diabetes mellitus.
All study patients contributed data from both eyes to the study. Per eye, mean Snellen visual acuity was 20/20. Average spherical equivalent was −2.33 ± 1.01 diopters. Three eyes (10%) were treated with IOP-lowering drops. Mean IOP was 14.5 ± 2.8 mm Hg, and mean central corneal thickness was 560 ± 37 microns. Mean vertical cup-to-disc ratio was 0.66 ± 0.12, and mean horizontal cup-to-disc ratio was 0.68 ± 0.12. Average mean deviation on SAP was −0.18 ± 0.90 dB.
The mfVEP traces and probability plots are shown in Figure 1 for a patient with suspected glaucoma and a normal control subject. The mfVEP detected more abnormal hemifields in the patients with suspected glaucoma and early POAG than in the normal control subjects. More abnormal hemifields were detected in the interocular test than in the monocular test (Table 1) for the patients with suspected glaucoma and early POAG. However, only 5 of these 15 subjects had mfVEP deficits by the monocular test and 7 of these 15 subjects had deficits by the interocular test. Three of these 15 subjects had deficits by both interocular and monocular tests.
Figure 1. Multifocal visual evoked potentials (mfVEP) traces and probability plots for patients with suspected glaucoma and a normal control subject. The mfVEP traces are shown in blue for the right eye and red for the left eye. (A) Traces for a patient with suspected glaucoma. (B) Interocular probability plot for the traces shown in A. The black squares indicate no significant difference between the two eyes and colored squares indicate a significant difference between eyes. The color depicts whether the right (blue) or the left (red) eye has significantly smaller mfVEP responses. Dark colored squares correspond to P values < .01 and light colored squares correspond to P values < .05. Clusters of adjacent abnormal points are within the ellipse. (C) The mfVEP traces for a control subject. (D) The corresponding interocular probability plot.
Table 1: No. of Hemifields With Abnormal Clusters From 15 Subjects With Suspected Glaucoma and Early Primary Open-Angle Glaucoma (30 Eyes, 60 Hemifields) and 19 Normal Control Subjects (38 Eyes, 76 Hemifields)
The presence of mfVEP cluster defects by monocular analysis corresponded with an increased pattern standard deviation on SAP: 1.32 ± 0.23 for eyes without mfVEP cluster defects and 1.72 ± 0.44 for eyes with mfVEP cluster defects (P = .0195). The presence of mfVEP cluster defects in either hemifield by interocular analysis corresponded with abnormal nerve fiber layer thinning in the superior quadrant by OCT analysis, where eyes without mfVEP cluster defects had no abnormal nerve fiber layer thinning, and 3 eyes with mfVEP cluster defects had abnormal nerve fiber layer thinning in the superior quadrant (P = .0152). Eyes with mfVEP cluster defects by interocular analysis had significantly greater mean deviation on SWAP (P = .0190). These eyes had an average mean deviation of −1.27 ± 2.68 on SWAP, whereas eyes without mfVEP cluster defects had an average mean deviation of −3.71 ± 2.69.
When analyzing the hemifield location of mfVEP cluster defects compared with the hemifield location of SAP cluster defects, the presence of mfVEP cluster defects in the superior hemifield agreed marginally with the presence of SAP cluster defects in the same hemifield, but this correspondence did not reach statistical significance (kappa = 0.1553; P = .0672). There were no other significant associations between presence of mfVEP cluster defects by interocular or monocular analysis and other SAP, SWAP, FDT, or OCT outcomes measures. Likewise, there were no significant associations between presence of mfVEP cluster defects and clinical examination parameters (such as IOP, central corneal thickness, or vertical or horizontal cup-to-disc ratios).
When comparing results of SAP, SWAP, and FDT among these three tests, there were significant associations by paired t tests between SAP mean deviation and SWAP mean deviation (P < .0001), and SWAP mean deviation and FDT mean deviation (P < .0001). The association of SAP mean deviation and FDT mean deviation approached but did not achieve statistical significance at .076. Also, the following were significantly associated by paired t tests: SAP pattern standard deviation and SWAP pattern standard deviation (P < .0001), SAP pattern deviation and FDT pattern standard deviation (P < .0001), and SWAP pattern standard deviation and FDT pattern standard deviation (P = .0016). SAP glaucoma hemifield test scores and SWAP glaucoma hemifield test results were not significantly associated (P = .2060).
In our study, we found that the presence of mfVEP cluster defects was associated with outcomes indicative of glaucomatous optic neuropathy, namely increased pattern standard deviation on SAP, superior nerve fiber layer thinning on OCT, and less negative mean deviation on SWAP. There were many other outcome variables measured by SAP, FDT, SWAP, and OCT that were not significantly related to the presence of mfVEP clusters. Agreement among SAP, FDT, and SWAP outcome variables was generally more significant than agreement of any of these outcomes with the presence of mfVEP clusters.
The mfVEP result has been shown to be variably abnormal in patients with suspected glaucoma or early glaucoma. Graham et al. noted that low-risk patients with suspected glaucoma had normal mfVEP results 92.2% of the time, whereas mfVEP testing showed 97.5% sensitivity for detecting glaucoma in patients with established glaucoma.13 However, Grippo et al. noted that few glaucomatous eyes and even fewer eyes with suspected glaucoma had abnormal mfVEP latencies compared to normal eyes.14
Several studies have shown that the mfVEP can demonstrate defects in the same areas of visual field loss as shown by SAP.5–8 In these studies, this finding was most reproducible in patients with moderate or significant SAP defects. In another study of patients with suspected glaucoma, mfVEP detected abnormal clusters in 20% of eyes that had normal SAP, although this was significantly higher than in normal control subjects.11 Similarly, Fortune et al. found that mfVEP cluster defects were found in 28% to 32% of eyes with early glaucoma, and this agreed with the presence of SAP defects in these eyes 80% of the time.15 Probably because our patients had either early POAG or suspected glaucoma, only increased pattern standard deviation and not mean deviation or location of SAP cluster defects corresponded to presence of mfVEP cluster defects by monocular analysis in our study.
Studies comparing mfVEP to structural optic nerve and nerve fiber layer imaging have shown mixed results. Although there are few studies in the literature comparing standard mfVEP to glaucomatous nerve fiber layer thinning by OCT, one study of patients with optic neuritis showed that mfVEP detected abnormalities in these eyes 89% of the time, compared to 62% by OCT.16 In moderate glaucoma, when mfVEP and SAP results agreed in detecting hemifield abnormalities (which occurred in 48% of patients), nerve fiber layer thinning as measured by OCT corresponded with these abnormalities 95% of the time.17 In patients with preperimetric glaucoma, blue-on-yellow mfVEP amplitude and latency defects corresponded with thinner nerve fiber layer measurements on OCT.18 Greenstein et al. noted that when mfVEP was compared to confocal scanning laser ophthalmoscopic testing in patients with open-angle glaucoma, both tests agreed on abnormalities detected 84.6% of the time.19 However, there were cases where the two tests disagreed. Likewise, Punjabi et al. also found good correlation between mfVEP amplitudes and select outcome measures on Heidelberg retinal tomography in patients with open-angle glaucoma.20 On the other hand, Balachandran et al. found limited correlation between Heidelberg retinal tomography and mfVEP results.7
To our knowledge, there are no other studies in the literature that directly compare mfVEP to SWAP in patients with glaucoma or suspected glaucoma. Although we hypothesized that mfVEP cluster defects would correspond with more negative mean deviation on SWAP, we actually found that eyes with mfVEP cluster defects by interocular analysis tended to have less negative mean deviation on SWAP (P = .0190). Therefore, mfVEP and SWAP did not seem to show clinically relevant correlations in our study. We also did not find any significant associations between the presence of mfVEP cluster defects and any FDT outcome parameters studied.
Our study was limited by a small number of patients in each of the suspected glaucoma and early POAG groups. We treated both eyes of each subject as independent, for purposes of statistical analysis. Also, patients with suspected glaucoma in our study were defined on the basis of optic nerve cupping without IOP elevation or defects on perimetry, which means that this group of subjects may include people who have merely physiologic cupping. Although the mfVEP can detect visual field defects in early glaucomatous damage before abnormalities can be detected by SAP,13 the reverse can also be true and the mfVEP may fail to detect visual field defects.8 Some of the drawbacks of the mfVEP include its dependence on the quality of recordings and inter-subject variability. We observed clusters in the central five degrees in two patients with glaucoma; however, they may be due to fixation losses because no associated defects were detected by other tests in these patients.
The mfVEP did relate to select outcomes measures on SAP, SWAP, and nerve fiber layer OCT testing of patients with suspected glaucoma and early POAG. However, there were many outcome measures on SAP, SWAP, FDT, and OCT testing that did not relate to mfVEP cluster defects, and SAP, SWAP, and FDT results tended to correlate more closely with each other than with mfVEP testing. More study is needed in the area of early glaucoma to determine whether mfVEP is a useful tool to detect preperimetric glaucoma damage.
- Ferreras A, Polo V, Larrosa JM, et al. Can frequency-doubling technology and short-wavelength automated perimetries detect visual field defects before standard automated perimetry in patients with preperimetric glaucoma?J Glaucoma. 2007;16:372–383. doi:10.1097/IJG.0b013e31803bbb17 [CrossRef]
- Nomoto H, Matsumoto C, Takada S, et al. Detectability of glaucomatous changes using SAP, FDT, flicker perimetry, and OCT. J Glaucoma. 2009;18:165–171. doi:10.1097/IJG.0b013e318179f7ca [CrossRef]
- Bjerre A, Grigg JR, Parry NR, Henson DB. Test-retest variability of multifocal visual evoked potential and SITA standard perimetry in glaucoma. Invest Ophthalmol Vis Sci. 2004;45:4035–4040. doi:10.1167/iovs.04-0099 [CrossRef]
- Gardiner SK, Demirel S. Assessment of patient opinions of different clinical tests used in the management of glaucoma. Ophthalmology. 2008;115:2127–2131. doi:10.1016/j.ophtha.2008.08.013 [CrossRef]
- Klistorner A, Graham SL. Objective perimetry in glaucoma. Ophthalmology. 2000;107:2283–2299. doi:10.1016/S0161-6420(00)00367-5 [CrossRef]
- Hood DC, Greenstein VC, Odel JG, et al. Visual field defects and multifocal visual evoked potentials. Arch Ophthalmol. 2002;120:1672–1681. doi:10.1001/archopht.120.12.1672 [CrossRef]
- Balachandran C, Graham SL, Klistorner A, Goldberg I. Comparison of objective diagnostic tests in glaucoma. J Glaucoma. 2006;15:110–116. doi:10.1097/00061198-200604000-00006 [CrossRef]
- Hood DC, Thienprasiddhi P, Greenstein VC, et al. Detecting early to mild glaucomatous damage: a comparison of the multifocal VEP and automated perimetry. Invest Ophthalmol Vis Sci. 2004;45:492–498. doi:10.1167/iovs.03-0602 [CrossRef]
- Thienprasiddhi P, Greenstein VC, Chen CS, Liebmann JM, Ritch R, Hood DC. Multifocal visual evoked potential responses in glaucoma patients with unilateral hemifield defects. Am J Ophthamol. 2003;136:34–40. doi:10.1016/S0002-9394(03)00080-1 [CrossRef]
- The Advanced Glaucoma Intervention Study Investigators. Advanced Glaucoma Intervention Study: 2. Visual field test scoring and reliability. Ophthalmology. 1994;101:1445–55.
- Thienprasiddhi P, Greenstein VC, Chu DH, et al. Detecting early functional damage in glaucoma suspect and ocular hypertensive patients with the multifocal VEP technique. J Glaucoma. 2006;15:321–327. doi:10.1097/01.ijg.0000212237.26466.0e [CrossRef]
- Hood DC, Greenstein VC. Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma. Prog Retin Eye Res. 2003;22:201–251. doi:10.1016/S1350-9462(02)00061-7 [CrossRef]
- Graham SL, Klistorner AI, Goldberg I. Clinical application of objective perimetry using multifocal visual evoked potentials in glaucoma practice. Arch Ophthalmol. 2005;123:729–739. doi:10.1001/archopht.123.6.729 [CrossRef]
- Grippo TM, Hood DC, Kanadani FN, et al. A comparison between multifocal and conventional VEP latency changes secondary to glaucomatous damage. Invest Ophthamol Vis Sci. 2006;47:5331–5336. doi:10.1167/iovs.06-0527 [CrossRef]
- Fortune B, Demirel S, Zhang X, et al. Comparing multifocal VEP and standard automated perimetry in high-risk ocular hypertension and early glaucoma. Invest Ophthalmol Vis Sci. 2007;48:1173–1180. doi:10.1167/iovs.06-0561 [CrossRef]
- Laron M, Cheng H, Zhang B, Schiffman JS, Tang RA, Frishman LJ. Comparison of multifocal visual evoked potential and optical coherence tomography in assessing visual pathway in multiple sclerosis patients. Mult Scler. 2010;16:412–426. doi:10.1177/1352458509359782 [CrossRef]
- Hood DC, Harizman N, Kanadani FN, et al. Retinal nerve fibre thickness measured with optical coherence tomography accurately detects confirmed glaucomatous damage. Br J Ophthalmol. 2007;91:905–907. doi:10.1136/bjo.2006.111252 [CrossRef]
- Arvind H, Graham S, Leaney J, et al. Identifying preperimetric functional loss in glaucoma: a blue-on-yellow multifocal visual evoked potentials study. Ophthalmology. 2009;116:1134–1141. doi:10.1016/j.ophtha.2008.12.041 [CrossRef]
- Greenstein VC, Thienprasiddhi P, Ritch R, Liebmann JM, Hood DC. A method for comparing electrophysiological, psychophysical, and structural measures of glaucomatous damage. Arch Ophthamol. 2004;122:1276–1284. doi:10.1001/archopht.122.9.1276 [CrossRef]
- Punjabi OS, Stamper RL, Bostrom AG, Han Y, Lin SC. Topographic comparison of the visual function on multifocal visual evoked potentials with optic nerve structure on Heidelberg retinal tomography. Ophthalmology. 2008;115:440–446. doi:10.1016/j.ophtha.2007.10.025 [CrossRef]
No. of Hemifields With Abnormal Clusters From 15 Subjects With Suspected Glaucoma and Early Primary Open-Angle Glaucoma (30 Eyes, 60 Hemifields) and 19 Normal Control Subjects (38 Eyes, 76 Hemifields)
|Monocular test only
|Interocular test only
|Clusters by both monocular and interocular tests