The objective assessment of visual function remainsa primary goal in glaucoma research dueto the limitations of subjective tests. To date, themultifocal pattern visual evoked potential(mfVEP) is the only electrophysiological test capable oftopographically mapping glaucomatous visual field defects.1 Although the pattern electroretinogram (PERG)has been extensively studied and certainly reflects ganglioncellular loss, it tests only the central visual field anddoes not provide any topographic information. The photopicnegative response has also recently been shown tobe reduced in glaucoma, but it also provides only a singlewaveform for analysis.2 For the mfVEP, employing corticallyscaled pattern stimuli with appropriate electrode positionsand multiple channels enables visual evoked potential(VEP) responses to be recorded from small areas ofthe field as far as 26° eccentricity. Many investigators havenow verified this capability using different recording systemsand techniques, and they have shown good correlationwith subjective perimetric defects.3-7
The mfVEP technique has been refined during the last15 years, with the addition of multiple channels, adjustedfilter settings, electrode positions, different types ofstimuli, and analysis of resulting waveforms. The goal hasbeen to maximize signals and improve interpretation.Bipolar electrodes, placed near or straddling the inion,allow a larger response to be recorded than the conventionalfronto-occipital electrode placements (where theupper hemifield responses are consistently smaller).Adding at least one pair of electrodes oriented at 90°(ie, horizontally) from the first pair allows detection ofadditional signals that are otherwise very small for thevertically oriented pair. Conventional VEPs have previouslyshown variable results in glaucoma patients, dependingon the distribution of the field loss. An upperfield defect, for example, may not produce a significantchange in the signal on a conventional VEP2 but is readilyidentified on a multichannel mfVEP.
RECORDING SYSTEMS
The electrophysiological method used is now similar inmost systems. Investigators have used the VERIS Scientificsystem (Electro-Diagnostic Imaging, Redwood City, CA),the AccuMap (ObjectiVision, Sydney, Australia; no longeravailable commercially), the Retiscan system (RolandInstruments, Wiesbaden, Germany), MetroVision(MetroVision, Perenchies, France), or the SHIL MultifocalImager (Scottish Health Innovations, Ltd., Glasgow,Scotland, United Kingdom). The visual stimulus is usuallygenerated on a CRT screen (eg, 22-inch high-resolutiondisplay), but with faster refreshing rates, flat screens (LCDand plasma) can now be used. The most common stimulusconsists of a dartboard pattern of 60 close-packedsegments, the sizes of which are cortically scaled witheccentricity to stimulate approximately equal areas ofcortical (striate) surface.8 The scaling would therefore beexpected to produce a signal of a similar order of amplitudefrom each stimulating segment. I consider it essentialto include in the analysis a means for removing theeffects of alpha rhythm on the signal-to-noise ratio andto adjust for interindividual variability. Otherwise, specificityis reduced.
SENSITIVITY/PERFORMANCE
Sensitivity of the mfVEP in established glaucoma hasbeen reported to be greater than 90%, depending on thecriteria used to define abnormality and the degree of theglaucoma's severity.4,6,9-13 Signal amplitude is reduced inglaucoma, but mfVEP latency shows only minimalchanges. Inter-eye asymmetry analysis is a useful techniquefor detecting early changes.9,14 The close proximityin the striate cortex of the signal generators for the rightand left eyes' visual fields means that the signals are normallyalmost identical for the two eyes, assuming noother pathology or amblyopia. Interocular asymmetryanalysis will not be reliable, however, in patients wheresymmetric field loss occurs between both eyes or for detecting damage in the less affected eye when one eyehas more advanced loss. It is therefore necessary to examineboth the monocular amplitude deviation and theinterocular asymmetry in combination.
In a study by Fortune et al using the VERIS system15 of185 individuals with high-risk ocular hypertension orearly glaucoma (average standard automated perimetry[SAP] mean deviation, +0.3 ±2.1 dB; average point standarddeviation, 2.3 ±1.9 dB), the diagnostic performanceof mfVEP was similar to that of SAP. This was truewhether the diagnostic standard was a masked evaluationof stereo optic disc photographs or the HRTMoorfields Regression Analysis (Heidelberg EngineeringGmbH, Heidelberg, Germany). SAP and mfVEP agreedin only approximately 80% of eyes, however, suggestingthat these testing strategies may detect slightly differentfunctional deficits.
Currently, the between-test amplitude variability ofthe mfVEP is 10% to 16%, and it is greatest in the zoneswith smaller signals. This limits the application of thedata to progression analysis. Improved signal-to-noiseratios are needed to enable better reproducibility andthe potential for serial analysis. Several studies are lookingat repeatability, and they have implications for thetechnique's ability to be used in some form of progressionanalysis.16,17
The mfVEP is not invasive, with only scalp electrodesrequired. No pupillary dilation, light adaptation, orshielding is required. Testing time is around 8 minutes pereye, with additional setup time for the electrodes' application.Cataract and visual blur can reduce central amplitudes,18 whereas the more peripheral points remain unaffected.As for the PERG, the resultant mfVEP signal canbe affected by other pathology, and an exclusion of retinalpathology is therefore needed. Clinicians must rememberthe mfVEP is not a specific test for glaucoma; itis effectively a field test with latency information.
NEW STIMULI FOR MFVEP
The possibility of simultaneous binocular (dichoptic)mfVEPs was recently realized using virtual reality goggles19or with twin LCD screens split by 45° mirrors.20 Theadvantage of a simultaneous binocular technique is thatinter-eye comparisons are more valuable due to the identicalrecording and noise conditions for each eye. Limitationswill remain, however, with patients who have underlyingstrabismus or another disparity in the fixationangle between their eyes. The use of a spatially sparsestimulation21 pattern has the potential to provide bettersignal-to-noise ratios, at least in the central field, and possiblygreater sensitivity to early glaucoma.
Along with our colleagues, we recently reported on ahigh-resolution stimulus recording with 120 test zones of3 X 3 checks arranged in eight rings (vs 4 X 4 checks infive rings for conventional mfVEP).22 The recordingsshowed slightly reduced variability across the field andimproved scotoma definition (but not initial detection).Figure 1 shows a high-resolution mfVEP recording. Wewere pleased to find no loss of sensitivity despite thelower signal-to-noise ratio with small testing zones. Thetesting time was longer, however, so this technique maybe reserved for eyes with small focal or paracentraldefects due to its much better topographic definition.
A blue-on-yellow mfVEP has also been described using a sparse blue pattern-onset stimulus (instead of patternreversal) on a yellow-adapting background. The goal wasto target the koniocellular pathway. This approachshowed good sensitivity and displayed more extensivescotomata than the conventional black-white mfVEP(92.2% sensitivity), and it correlated well with SAP.23,24The advantage of the blue-on-yellow stimulus over standardmfVEP, however, was probably more likely related tothe fact that the pattern-onset stimulus was spatiallysparse25 (likely due to less lateral inhibition) and was oflow luminance, both of which we have demonstratedmay increase sensitivity.26
CLINICAL APPLICATION
Unfortunately, no international standards are yetdefined for the mfVEP (nor for any other forms of VEPother than transient flash and pattern). Moreover, arecent review somewhat negatively stated that themfVEP “is perhaps best regarded as a promisingresearch tool.”27 We have been using the mfVEP regularlyin our clinic for the last 8 years, however, andalthough it does not replace SAP in routine testing, themodality has several useful roles. Figure 2 provides anexample of an inferior field defect that is confirmed onmfVEP testing.
In clinical assessment, the mfVEP supports the subjectivefield findings and is most helpful in equivocal orvariable cases. It helps to rule out excessive field loss inpatients who have trouble with perimetric testing(false positives). In some early or high-risk glaucomacases, mfVEP may detect functional damage earlierthan other measures. Less commonly but very importantly,when the results of both subjective and objectivetests are out of proportion to changes in the opticdisc, alternative pathology may be at play. The physicianshould therefore consider obtaining magnetic resonanceimaging. The mfVEP is very helpful in nonorganicvision loss and medicolegal cases. It can also beextremely useful in other optic neuropathies such asoptic neuritis,28-31 where the test has been used tomonitor outcomes and the likelihood of progression tomultiple sclerosis.
The mfVEP is easy for patients to perform, even thefirst time, and it has a high level of acceptance amongpatients. It is likely that mfVEP testing will continue toevolve in the future as an objective means of monitoringindividuals with glaucoma. With improved signal detection,greater reproducibility, and shortened testing times,mfVEP will provide clinicians with a valuable adjunct forassessing visual function in glaucoma.
Stuart L. Graham, MBBS, PhD, MS, FRANZCO,is a professor of ophthalmology and visual scienceat the Australian School AdvancedMedicine, Macquarie University, and the SaveSight Institute, Sydney University. He holdspatents for technology licensed to Objectivision Pty Ltd.Dr. Graham may be reached at +61 2 98123933;stuart.graham@asam.mq.edu.au.
Alexander Klistorner, MD, PhD, is an associate professor ofvisual science at the Australian School Advanced Medicine,Macquarie University, and the Save Sight Institute, SydneyUniversity. He holds patents for technology licensed toObjectivision Pty Ltd.
