time than full-threshold SAP and seems to generate more repeatable fields.98,121 Reliability indices are similar to SAP.122 High-pass

resolution perimetry seems easier to perform and slightly more reliable­ than SAP in children.123

In summary, HRP shows great promise as a subjective test that is sensitive, specific, repeatable, short, and patient-friendly. It can be used for screening, diagnosis, and follow-up. Several studies have indicated that it may be superior to full-threshold automated perimetry clinically. Unfortunately, patent disputes have held up its commercialization in the United States. When and if the disputes can be settled, additional studies will be needed to determine its role in glaucoma diagnosis and management.

Motion detection perimetry

Several visual functions other than light sense are disturbed in glaucoma. One of these functions is motion detection. It has been known for some time that patients with glaucoma detected motion less well than age-matched normals.124 This is evident in kinetic perimetry. Motion detection perimetry probably isolates the magnocellular pathway.125 With the advent of computerized stimuli, it became possible to embed motion in a series of random dots among other sophisticated stimuli. Studies began appearing to test whether motion detection may be impaired at an earlier stage in glaucoma than SAP or some of the other tests noted above.While it is clear that motion detection is indeed impaired, with current testing capabilities, motion

detection does not do as well at picking up glaucomatous damage as FDT and SWAP.126,127 Motion detection perimetry was able to

successfully identify abnormal quadrants in glaucomatous eyes and in some glaucoma suspect eyes with normal SAP, but not any more reliably than SWAP.125 While motion detection perimetry does correlate well with other functional tests, it seems to detect a small subset of abnormal ocular hypertensive eyes that the other tests do not, but its sensitivity and specificity at this point make it less reliable as a test than either FDT or SWAP or both.

Electrophysiology

All psychophysical tests have some inherent disadvantages. They are subjective and their performance is subject to the physical and emotional status of the patient. Such conditions as fatigue, emotional upset, anxiety, physical discomfort, extraneous noise, and movement can all adversely affect the results. The search has been on for an objective test that can eliminate or reduce the effect of the above factors.Three approaches utilizing new adaptations of old technology are currently in the investigative stage, one of which has been approved by the US Food and Drug Administration (FDA) and has reached the marketplace. These techniques are pattern electroretinography (PERG), multifocal electroretinography (mfERG) and multifocal visual evoked potentials (mfVEP).

The electroretinogram (ERG)

The ERG has been a part of ophthalmic diagnosis for the past 50 or more years. The ERG uses electrodes on the cornea, usually held in place with a soft contact lens, to pick up the very faint electrical signals emitted by retinal cells following stimulation with light. Because the electrical signal is very faint, the best that could be done until recently has been to measure a mass response, that is, the response of the whole retina. The shape of the massed retinal electrical wave could be analyzed, and if missing one or more of its

components, some general conclusions could be made about the health of the retina as a whole. Most ophthalmologists are at least exposed to this technique during their residency as a diagnostic aid in generalized retinal diseases, such as the hereditary retinal dystrophies, and as a prognostic aid in major trauma to the eye. The faintness of the responses from small areas precluded detecting any merely local areas of retinal dysfunction.

The addition of the computer to this technique allowed rapid stimulation, randomization of location of stimuli, and averaging of the responses from many stimuli. By stimulating different parts of the retina in a random or semi-random sequence and by averaging the responses to several stimuli to a particular part of the retina, the computer can effectively (although only virtually) multiply the amplitude of the faint signal from one part of the retina so it can be detected by the corneal electrode.

The pattern electroretinogram (PERG)

The PERG is similar to the standard bright-flash ERG in that recordings are made from the entire retina; in this case, the stimulus, rather than being just a flash of light, is a reversing checkerboard pattern. The electrical signal from the retina is recorded using corneal electrodes which must be carefully constructed so as not to interfere optically with the image projected onto the central 15° of the retina by the checkerboard pattern.128 Using optically neutral corneal electrodes and proper technique, the variability can be minimized and a stable, reproducible series of wave forms generated.129 While the flash ERG generates an electrical signal from the retinal rods and/or cones, the signal derived from the PERG seems to come largely from the retinal ganglion cells, although other inner retinal cells such as amacrine and bipolar probably contribute to the signal.130 Most likely, based on studies of optic nerve disease, the negative (downward) part of the signal comes from the

ganglion cells and the positive (upward) part comes from the amacrine, bipolar and other inner retinal cells.131,132 Other mammals

besides humans seem to generate similar responses to the PERG.133 In fact, the changes in PERG correlate well with ganglion cell loss in hypertensive rats.134 The PERG probably is detecting early diffuse damage to the ganglion cells rather than focal damage.128

Early on in the studies of PERG in humans it was noted that the amplitude of the signal was reduced in glaucoma.135–137 Multiple

subsequent studies have confirmed a PERG abnormality in openangle glaucoma.128 Similar findings were observed in monkeys made glaucomatous with argon laser treatment to the trabecular meshwork.138 Reduced amplitude of the PERG has also been found in

some patients with ocular hypertension and in those with highly suspicious optic nerves (‘pre-perimetric glaucoma’).139,140 In one

retrospective study, amplitude (bottom of negative to top of positive) was reduced in 87% of confirmed open-angle glaucoma and in 57% of ocular hypertensive eyes.141 Abnormal PERG findings quantitatively correlated with neuroretinal rim area and retinal sensitivity as measured by threshold perimetry.142,143

In one study, over a 1–3 year period, 5 of 12 high-risk ocular hypertensive eyes with abnormal PERG at the beginning of the study developed glaucomatous visual field defects, while none of the eyes with normal PERGs showed any sign of progressing.144 Bayer and Erb, in a 5-year, prospective study of over 150 glaucomatous eyes, showed that combining PERG with SWAP had an 88% success in predicting future SAP visual field progression.145 Pattern electroretinography findings correlated well with mfVEP findings, optic nerve cupping and visual field loss in most patients with glaucoma.146 Abnormalities in the PERG correlate well in ocular hypertensives

with risk factors for the development of glaucoma such as thin ­corneas,African heritage, positive family history, etc.147

The PERG has been utilized to assess visual function in glaucoma following experimental treatments.148 Improvement of the PERG (as well as the mfVEP – see below) was used in one longitudinal, controlled study as an objective measure to assess the effect of citicoline treatment on glaucoma.149 In another study, comparing eyes with ocular hypertension or glaucoma who were treated with pressure-lowering drops to similar eyes without treatment, showed definite improvement of PERG parameters in many of the eyes in the treated group but not in the untreated group.150 Thus, PERG may be more sensitive than perimetry in detecting either deterioration or improvement and could be used in the future as an objective way to monitor the effects of treatment.

In summary, the pattern electroretinogram shows promise as an early warning system for glaucomatous damage and possibly to detect those eyes at high risk for progression. Also promising is the possibility that it can be used as an objective method to determine either progression or improvement of glaucomatous damage during treatment. Whether this test paradigm has superiority over any of the others in this chapter remains to be demonstrated.

The multifocal electroretinogram (mfERG)

Based on studies by Sutter, Hare was able to show that monkeys treated with laser to develop elevated intraocular pressure developed evidence on the mfERG of ganglion cell dysfunction which was confirmed by histopathologic correlation.151 Furthermore, this laboratory was able to show an effect of the neuroprotective agent, oral memantine, in protecting components of the mfERG as well as the mfVEP (see below) in monkeys with experimental glaucoma, establishing the usefulness of electrophysiology for monitoring ganglion cell and optic nerve damage in subhuman primates.152 Raz et al demonstrated that the mfERG is affected both by stimulus contrast

and by luminance in monkeys and that wave forms were generated by both inner and outer retinal elements.153,154

Furthermore, they were able to demonstrate a clear difference between normal and glaucomatous monkeys with the mfERG.

Other laboratories showed various defects in the mfERG associated with glaucoma in humans.155,156 Some of these findings correlate

with nerve fiber layer thickness.157 Although it may be tempting to ascribe the mfERG changes to the ganglion cell layer, some contribution from the inner plexiform layer is probably also present.158

The multifocal visual-evoked potential (mfVEP)

Like the electroretinogram, the visual evoked potential (VEP) has been around for a long time. The visual evoked potential is basically a localized electroencephalogram – reading the faint electrical signals from the visual cortex using skin electrodes over the back of the head. Like the ERG, the VEP can detect large-scale problems in the visual system from retina to visual cortex (Fig. 11-5). As a general rule, if the retina is at fault or if there is a major interruption in the visual system from optic nerve to visual cortex, the amplitude of the signal is reduced. If the problem is a malfunction of the optic nerve, such as demyelinating disease, the signal is delayed and, perhaps, prolonged causing a prolongation of signal latency. As with the ERG, improvements in stimuli and in averaging of the signals have allowed the stimulation of specific parts of the retina and representation of those specific parts of the retina in the signals measured from the visual cortex.

Klistorner and co-workers used pattern stimulation of different parts of the visual field using multifocal pseudorandomly alternated pattern stimuli that were scaled in size to match their respective

representation in the visual cortex, and were able to identify loss of signal in areas of scotomata as seen on standard automated perimetry.159 Correlation of histopathologic damage to ganglion cells with the mfVEP in ocular hypertensive monkeys was confirmed by Hare and co-workers.151 A similar correlation was found in humans, where a linear relationship was found between the degree of defect on the mfVEP and the depth and breadth of scotomata on SAP, with both correlating with estimated number of ganglion cells lost.160 Graham and co-workers stimulated up to 60 sites within the central 25° of visual field and found that defects seen on both amplitude and latency of the mfVEP did correspond with visual field defects in eyes with glaucoma.161 Graham and co-workers further refined their observations by applying asymmetry analysis of both amplitude and latency to improve the detection of early glaucomatous defects in eyes with asymmetrical glaucoma.162 Hood and co-workers had similar findings.163 However, in a recent study, latency delay was modest in proven glaucoma patients and proved less reliable as an indicator of damage than previous studies.164

In a larger study, Klistorner and Graham demonstrated that the mfVEP could be considered an objective visual field measurement in 60 patients with either suspected or actual glaucoma.165 Other studies have confirmed that the mfVEP can detect glaucomatous damage early, sometimes even before white-on-white threshold perimetry.166 The correlation with SAP is quite high – 95% in one study.167 However, not all studies found a good correlation; Bengsston found considerable overlap between glaucoma eyes and normals using aVEP probability map.168 Thienprasiddhi et al found that the mfVEP often identified defects in the perimetrically normal hemifield of glaucomatous eyes whose only SAP defect was in the alternate hemifield, suggesting that it does indeed identify some defects before SAP.169

While there appears to be good correlation between the mfVEP and SAP, in a minority of patients with early glaucoma, defects may appear on one and not the other suggesting that they may not measure exactly the same functions and that some functions may be differentially affected early in the disease.170 In one recent study, the sensitivity of mfVEP for all glaucoma was 97.5%, and for early glaucoma 95%, with specificity of 92% based on SAP; however, based on masked optic nerve analysis, the sensitivity was equal for SAP and mfVEP with mfVEP having the better specifi-

city.171 Correlation with structural abnormality as evidenced by Heidelberg retinal tomography has been variable.172,172b

Signal-to-noise ratios have been found to be a good proxy for reliability including false positives and negatives.173 The higher the signal-to-noise ratio, the more reliable the result. Repeatability has been shown to be at least as good and probably better than SAP in one study;174 however, in another study, the variability of mfVEP was slightly worse than SAP.175 Interpretation of the results can be tricky, especially with monocular testing, where not only do the waveforms vary between individuals but may vary across different

regions of the visual field; cluster analysis may be the most accurate way of determining defects.176,177 A cluster of three abnormal

points seems to be a strong indicator of glaucomatous damage.178 Electrode position is critical in obtaining good signals.179 The

Acumap (Heidelberg Engineering, Heidelberg, Germany) unit uses the inion as a reliable landmark to position the electrodes. Other sources of error include poor contact with the scalp, patient movement, lack of fixation, and significant refractive error (Box 11-2).180 Even small fixation instability, as little as 3°, may significantly reduce the amplitude of the signal.181 However, other than fixation, little