Glaucoma diagnosis and monitoring require assessments of both structure and function of the optic nerve and ganglion cell layer. The traditional tests of these parameters for the past half century or more have been structurally through ophthalmoscopy or photography and functionally by white light perimetry – either kinetic and, more recently, threshold static. Over the last few decades, these tests have been improved via computerized automation and/or laser-assisted quantitative structural analysis. Yet, the testing of both structure and function leave something to be desired. The assessment of structure by ophthalmoscopy and by stereo photography is subjective and varies greatly even among experts. Newer modalities of evaluating the optic nerve and ganglion cell layer using lasers and computerized analysis have greatly improved the subjectivity of this type of testing (see Ch. 14 ).
The ‘gold standard’ of modern functional assessment is automated threshold white-on-white perimetry (see Ch. 9 , Ch. 10 ). While this type of testing is a big improvement in sensitivity, specificity, and repeatability compared to kinetic perimetry, significant problems are still present. Problems with this modality include tediousness for the patient, a significant learning curve, great variability even in experienced subjects from test to test, difficulty with interpretation, and difficulty detecting both early damage and early progression ( Box 11-1 ).
Not all patients can perform reliably
Difficult for very young and for elderly
Instructions may be difficult for those not speaking the same language
Device not portable
Requires darkened and secluded environment
Not suitable for mass screening
Variability from test to test
Significant learning curve
Not sensitive to early glaucoma
Difficult to detect progression
Cataract or other media opacity may confound results
One of the biggest problems with standard automated white-on-white threshold perimetry (SAP) is that it often does not show an abnormality until between 25% and 50% of the ganglion cells have been lost. In trained glaucomatous monkeys, about 50% ganglion cell loss must occur before significant white-on-white perimetric loss is seen. Thus, sensitivity of SAP to early glaucomatous damage is fair to poor. For some time now, researchers have been attempting to identify visual functions that may be more sensitive to early damage, either because the tests would be inherently more sensitive or because they target a subset of ganglion cells that by being fewer in number may have their specific function disturbed earlier than the more general functions of the total mass of ganglion cells.
There are several types of ganglion cells. Initially, it was thought that certain ganglion cells are damaged earlier in the glaucomatous process than other types. However, more recent studies suggest that all ganglion cells are damaged or killed by glaucoma but that some types of ganglion cells have less redundancy (fewer partner cells to cover for them if they become injured). Therefore, if a test can be targeted at ganglion cell functions that have little redundancy, the hope is that these functions will be affected early in the process. Short-wavelength automated perimetry (SWAP) and frequency-doubling technology (FDT) are two such tests ( Fig. 11-1 ).
Another strategy is to find tests that have less noise (more reliable first tests with less variability between tests) than white-on-white (monochromatic) automated threshold perimetry. High-pass resolution perimetry and FDT are examples of this approach. Finally, attempts are being made using modern computer algorithms to either reduce the noise and variability or to better interpret from the standard test what is real and what is noise. The Swedish Interactive Test Algorithm (SITA) is one example of the former; neural network interpretation and the Glaucoma Progression Analysis (GPA) (Zeiss-Meditec, Dublin, CA) are examples of the latter. This chapter will discuss the most developed of these technologies, including SWAP, FDT, high-pass resolution perimetry, multifocal visual-evoked potential and multifocal electroretinogram. For a discussion of SITA and GPA, see the preceding chapters.
COLOR VISION AND SHORT-WAVELENGTH AUTOMATED PERIMETRY
As understanding of the differential functions of the several types of ganglion cells became known, tests began to be developed that were targeted at specific ganglion cell functions that might have less redundancy than white-on-white perimetry. That color vision is affected in the glaucomatous process has been known for many decades. Acquired optic nerve disease affects the blue-yellow end of the spectrum as well as the red-green, whereas inherited defects tend to be limited to the red-green. So tests that include the blue-yellow end of the spectrum will be more specific for glaucomatous damage.
While cones are scattered throughout the retina, most are concentrated in the macula and surrounding area. Clinical color vision tests, either by design or accident, usually involve only the central cone-concentrated portion of the retina. The most commonly used color vision test is the Ishihara which does not effectively test the blue-yellow spectrum. Color vision tests that have been associated with early glaucomatous damage do evaluate, at least to some degree, that end of the spectrum and include the anomaloscope, Hardy-Ritter-Rand color plates, Farnsworth D-100, and Farnsworth D-15. Several studies have shown that color vision defects as demonstrated by these tests appear early in glaucoma, and may even precede defects seen on white-on-white perimetry which has been considered the gold standard for glaucoma diagnosis. Unfortunately for the clinical usefulness of color vision tests, these instruments are insensitive, non-specific, too time-consuming or too difficult to interpret.
It has been known for more than 80 years that the defects associated with acquired optic nerve disease such as glaucoma could be amplified on the tangent screen by using colored test objects as compared to the standard white test objects. However, tangent screen color testing was even more variable and dependent on ambient illumination, technical skill, and cleanliness of the test objects than white-on-black tangent screen testing. So, even though color vision is largely a central retinal function, enough color perception remains in the periphery to allow color perimetry. The Goldmann perimeter allowed for testing using colored test objects, but because of the technical skills required was rarely utilized.
The advent of computerized visual field testing gave us the possibility of eliminating or markedly reducing many of the variables that plagued manual perimetry. Early studies with SWAP determined that abnormalities detected by SWAP were predictive of ultimate white-on-white perimetry defects and that SWAP actually detected glaucomatous progression earlier than SAP. Abnormal SWAP results were found in ocular hypertensive eyes without white-on-white perimetry abnormalities that were at high risk for developing glaucoma, suggesting that the sensitivity of SWAP to early glaucoma defects was higher than white-on-white perimetry. Abnormalities found on SWAP in early glaucoma mapped well to abnormalities found in the structure of the optic nerve or nerve fiber layer. Eyes with normal SAP but with SWAP abnormalities were likely to have thin corneas and glaucomatous optic nerve appearance. Clearly, a characteristic glaucomatous abnormality on a SWAP test is likely to be correlated with glaucomatous optic neuropathy, abnormalities on laser scanning of the optic nerve and nerve fiber layer, and with thin corneas and, therefore, indicative of early glaucoma.
Early concerns that yellowing of the crystalline lens nucleus with age would reduce the function and require an age or lens color correction factor did not materialize. Fortunately, these observations made it possible to eliminate lens density testing and shorten the test to a clinically acceptable duration.
Short-wavelength automated perimetry tests the blue-cone mechanisms and the small bistratified ganglion (konio) cells that carry this information (SWS system). Several theories have been proposed for why SWAP should work. One is that the blue cones themselves, or their partner ganglion cells, are preferentially damaged in glaucoma; however, this is very unlikely since the patterns of ganglion cell loss are in the arcuate areas which do not correspond to the distribution of the blue cones or their ganglion cell partners. More likely is the fact that the K (konio-) ganglion cells that carry the information from the blue-cone system only represent a small proportion of the total ganglion cells (≈20%) and loss of even a few of these cells would interfere with the total function since there is little functional overlap or cross-coverage.
In the actual test performed on an optionally equipped Humphrey or similar automated perimeter, a blue-violet (440 nm), Goldmann-size V stimulus is projected onto a bright yellow (500 nm) background ( Fig. 11-2 ). Note that the stimulus size is significantly larger than that usually used in white-on-white threshold perimetry (Goldmann size III). The brightness is gradually increased in randomly spaced trials until the stimulus is seen approximately 50% of the time. The determination of threshold in the standard SWAP test is the same as used in the full-threshold SAP. As of the writing of this chapter, the SITA, used so effectively in SAP, has been adapted to the SWAP test, allowing much shorter test times with less fatigue and less threshold variability. Since this algorithm is only a few months old as of this writing, experience is limited and little has been published, so most of this section, unless otherwise indicated, will be devoted to what is known about the standard, full-threshold SWAP. The output of the SWAP test is similar to the output of SAP ( Fig. 11-3 ). STATPAC is available for SWAP with a normative database that can indicate the probability of abnormality at each tested point. Probably the most useful parameter for detecting early glaucoma with SWAP is the glaucoma hemifield test; it seems to be a sensitive and specific indicator of glaucoma-like damage.
Several independent, longitudinal studies have demonstrated the superiority of SWAP compared to SAP, both in early detection of abnormalities and in earlier detection of progression.
Not all studies have shown that SWAP is more sensitive than SAP. On the other hand, abnormal SWAP results correlate with optic nerve abnormalities even when the SAP is normal.
Short-wavelength automated perimetry tests produce lots of noise, especially in naïve subjects, and a learning curve similar but actually longer than that seen for SAP has been demonstrated. Long-term fluctuation is greater with SWAP than with SAP. Defects seen on SWAP tend to be steeper and larger than those seen on either SAP or frequency-doubled perimetry.
Patients with migraine also may show defects on SWAP testing; whether this represents a manifestation of independent nerve damage caused by the migrainous process or an association of migraine with glaucoma remains to be determined. Tamoxifen may induce abnormalities in SWAP (but not frequency-doubled perimetry) well before abnormalities are seen on SAP or in the retina.
For interpretation, a SWAP can be considered abnormal if, on at least two exams, a pattern standard deviation is abnormal at worse than the 1% level, the glaucoma hemifield test is outside normal limits, there is one hemifield cluster with sensitivity below the 1% level, there are two hemifield clusters below the 5% level, there are four abnormal (<0.05%) points, or there are five abnormal (<0.05%) points on the pattern deviation plot. However, large variations are seen in ocular hypertensives examined with SWAP, and with different definitions of abnormality, large variations in who has abnormalities will be seen, suggesting that we do not yet have the right combination of diagnostic sensitivity and specificity to completely rely at least on a single SWAP test to determine if a true abnormality exists.
In summary, SWAP is likely to detect functional glaucomatous damage and progression before SAP. However, problems with media opacities, length of test, fatigue, tediousness, high long-term fluctuation, and repeatability compared to SAP limit its usefulness, especially in the elderly ( Table 11-1 ). It may be most useful in relatively young glaucoma suspects with good concentration for whom finding the earliest functional defect may play a role in determining management. As with any test, correlation of the results with other clinical findings is required to determine if the results of any single test or series of tests in a patient are reasonable and fit the clinical picture. The advent of SITA SWAP may reduce the tediousness, duration, and noise level of SWAP, but this remains to be independently verified.
|Detects glaucoma defects early||Tedious|
|Can track progression||Takes 20–30 minutes per eye|
|Most perimeters can be modified to perform||Affected by lens opacities |
Affected by refractive error
|Familiar format on results|
|SITA may make it more user friendly|
Frequency-doubling perimetry or technology (FDP, FDT) targets the function of a subset of ganglion cells – the M magnocellular ganglion cells that carry temporal information such as flicker and motion. These cells comprise only 10–15% of the total ganglion cells. There is little redundancy in this subset of cells and it would be expected that malfunction would be relatively easy to detect. In fact, studies have shown that abnormalities in FDP, like those seen with SWAP, often precede those seen in SAP by several years. In this test, a low-frequency sinusoidal grating (0.25 cycles per degree) undergoes rapid reversal of light bars to dark 50 times per second (25 Hertz). The gratings are projected into different parts of the visual field and, at each location, projected at different levels of contrast between the light and dark bars ( Fig. 11-4 ). The lower the contrast at which the grating is seen as a grating, the better is the sensitivity. Although the rapid reversal gives an optical illusion that the number of light and dark bars are twice as many in the same space as are actually present (doubled frequency – hence the name), it is not known if this optical illusion has anything to do with the diagnostic ability of the test; in fact, the mechanism seems similar to that which detects any flickering stimulus. The original device tested 17 sectors of the central 30°. Subsequent studies showed that even better sensitivity for glaucomatous defects was obtained with smaller gratings that were projected in a pattern similar to the 24-2 and 30–2 of the Humphrey automated perimeter. This latter observation formed the basis for the Humphrey Matrix (Carl Zeiss-Meditec, Dublin, CA) which is the newer, more versatile model. The 24–2 FDP testing strategy performs similarly to the 24–2 SAP in patients suspected of having glaucoma although the correlation is not one to one. Defects may be present on SAP that are not detected by FDP and vice versa.
There are two general algorithms for testing similar to SAP. The screening mode is a threshold-related suprathreshold test. It is fast (1–2 minutes per eye) but not very useful for a monitoring baseline. The other algorithm is full threshold which takes closer to 10 minutes per eye. It is still faster than full-threshold SAP but no longer practical for screening. New algorithms such as the Zest program, which uses Bayesian logic, can cut the testing time in half without significantly affecting the accuracy. The ZEST program is available with the Matrix device and has made the threshold program with FDP quite practical and useful. The 20–1 threshold program of the FDP takes one-quarter to one-half the time of a SITA SAP without loss of specificity or sensitivity.
In general, the FDP appears to be more sensitive and specific. Frequency-doubling perimetry has less test–retest variability than SAP, which might make it, theoretically at least, more sensitive at detecting changes over time. As noted above, defects on FDP may precede defects detected by SAP by several years. Furthermore, the defects on FDP in eyes with normal SAP relatively accurately predict the location of future SAP defects. Longitudinal studies do suggest that FDP is sensitive at detecting glaucomatous progression; however, the SAP and FDP do not always identify the same subset of patients, suggesting that patients may progress in different ways.
Frequency-doubling perimetry has a faster learning curve than SAP ( Table 11-2 ); furthermore, since the test is faster and the patients more comfortable with identifying the flickering target, fatigue is less of a factor. In the authors’ experience, patients overwhelmingly prefer the FDP to the SAP. While the learning curve is faster with FDP, the first attempt should not be relied upon in naïve subjects; however, the second attempt is usually accurate and stable. With the threshold programs, immediate retesting should be avoided as fatigue can be a factor after immediate repeat testing. However, in screening situations where the 2–minute screening program has been used, immediate repeat testing may help to significantly reduce false positives.
Frequency-doubling perimetry can be used reliably in children after 8 years of age but reasonable results may be obtained as young as 5 years of age with proper training and preparation.
From the beginning, it was shown that FDP was sensitive for glaucoma defects. The results of FDP correlate well with SAP in both high-tension and low-tension glaucoma. Sensitivity and specificity for all glaucoma defects are at about 90% compared to other visual tests for glaucoma. In particular, the sensitivity and specificity for moderate to advanced glaucomatous defects are above 97%, which is an enviable record indeed. For early glaucoma, the sensitivity is 85% and the specificity is 90%. Comparisons with SWAP and SAP are quite favorable for the FDP.
Defects on FDP correlate with thin corneas in ocular hypertensive eyes, adding more evidence that both these parameters may be risk factors for ultimate development of glaucoma as defined by SAP. Frequency-doubling perimetry also correlates well with structural abnormalities as defined by laser scanning devices such as the Heidelberg Retinal Tomography (HRT), Ocular Coherence Technology (OCT) and scanning polarimetry. However, the correlation is not perfect suggesting that the structure–function damage is not uniform from patient to patient.
As happens with SAP, the screening programs which forego the careful evaluation of the thresholds are going to be less sensitive at detecting early glaucomatous visual field defects than the threshold strategies. With FDP, the 54–stimulus 24° field similar to the 20–2 of the Humphrey SAP perimeter (now included with the Matrix version) is somewhat more sensitive than the original 17–stimulus field. However, the 24–2 seems to be as sensitive as the 30–2 pattern so there is little gain in performing the longer test.
Unlike SAP, FDP is relatively insensitive to refractive errors with up to about 6 diopters of spherical error having little effect on the results. Nevertheless, for most accurate results, refractive errors should be corrected where possible. Frequency-doubling perimetry seems to be affected only a little bit by aging; the small aging effects are incorporated as part of the normative database included with both models of the device. The normative database allows for similar analysis as seen with SAP, including mean deviation, pattern deviation, glaucoma hemifield test and reliability indices. Also, the second eye tested is less sensitive than the first eye tested, and this is also incorporated into the analysis procedures.
As with SAP, the presence of media opacities or pupil constriction which reduces retinal illumination may confound the results of FDP, causing the expected reduction in mean deviation but also possibly masking some local abnormalities. Removing a cataract generally improves the mean deviation with little effect on the pattern deviation, although, at least in one study, the pattern deviation worsened after cataract surgery suggesting that media opacity may mask some localizing defects.
Because of its relative small size, making it the most portable of threshold devices, FDP has been found to be a very useful device for community screening for glaucoma. In an English-speaking population, the screening C-20 program has only a modest learning effect. The screening algorithm of the FDP has acceptable sensitivity compared to SAP to justify its use in a mass screening to detect moderate to advanced glaucoma. The FDP in screening mode is superior to the Damato campimeter in both sensitivity and specificity. However, in a non-English speaking developing country, FDP may not be relied upon as the sole screening device since it has relatively low sensitivity when compared to expert optic nerve evaluation, although specificity can be improved by repeat testing. Children with learning disabilities have significant difficulty with FDP; however, adults with relatively mild reading disabilities have no greater problems performing reliable FDPs than adults without reading disabilities. The preceding study used college students, so it is unkown whether adults who had reading disabilities that interfered with their ability to attend college would have enough difficulty with FDP that other screening methods for glaucoma would be more effective in this particular population.
While progression of some defects has been shown with FDP, its ability to detect progression as a routine monitoring tool has not been demonstrated.
While no single test has been shown to detect all glaucoma, FDP has become a most useful screening tool for finding glaucoma and detecting it in its relatively early phases. Careful studies have suggested that each of the functional tests detect a subset of early glaucomatous changes and that some combination of functional tests (such as SWAP and FDP) may be better than any single functional test at finding the earliest functional changes in glaucoma. Usually, structural changes precede the functional ones, and these structural changes, when they finally correlate with functional ones, may affect different ganglion cell populations in different patients.
OTHER PSYCHOPHYSICAL TESTS
HIGH-PASS RESOLUTION PERIMETRY
High-pass resolution perimetry (HRP) was first described by Frisen in 1987 and is the measurement of resolution over the extent of the visual field. It appears to be measuring the function of the ganglion cells. In this technique, rings with a bright core and a dark border of various sizes (although other target types have been used) are projected onto the visual field while the subject fixates on a central target and the subject indicates when the ring is perceived. The process is a modification of acuity perimetry first described by Johnson et al in 1979 and later by Phelps in the 1980s. The smaller the ring that can be perceived at a given location, the higher is the resolution of that part of the retina. While contrast could be varied, in the test described by Frisen, contrast is held constant and the size of the target is varied. As one gets further from fixation, as might be expected, the rings need to be larger in order to be perceived. Furthermore, the bowl screen is only 167 mm away at the center but has a convex curve so that the more peripheral targets are actually further away than the central fixation target. Compare this to SAP where the bowl is at 330 mm and is curved in a concave way so that, in general, the test targets are all equidistant from the retina. The computer, therefore, needs to adjust the targets for both size and shape to maintain constancy of angular size.
The typical test involves 50 locations within the central 30° where the majority of ganglion cells lie and, in that way, is similar to the 30–2 of light-sense perimetry. Because of the close distance, a six diopter optical correction must be added to the distance correction. The test is easier on subjects because it is quicker and discriminations are more positive than standard automated perimetry, but it is still a subjective test and may be susceptible to many of the errors of any psychophysical test. High-pass resolution perimetry has less variability than SAP. The HRP probably depends on the parvocellular channels, since that appears to be the only system within the ganglion cell family that carries resolution information; parvocellular ganglion cells are the largest group of ganglion cells representing about 80% of the total population. Another study showed a good relationship between HRP and the number of midget ganglion cells, although the number of patients was quite small. However, not all studies support the selective action of HRP.
The technique is not affected by anti-glaucoma medications and seems suitable for both diagnosis and monitoring.
Like SAP, the response to HRP declines with age, but, unlike SAP, this decline is proportional to the ‘normal’ age-related loss of ganglion cells with a direct correlation with the known age-related ganglion cell loss. In addition to glaucoma, defects are found in intracranial hypertension, optic neuritis, and other neuro-ophthalmologic conditions that affect the visual fields. Also like SAP, HRP is affected by media opacities.
High-pass resolution perimetry is most useful in ocular hypertension and glaucoma. There is an overall general reduction in sensitivity as well as location-specific defects. Sensitivity for glaucomatous defects is probably slightly better than or similar to full-threshold SAP. Using age-related probability plots, sensitivity and specificity for early glaucoma were about 85%. High-pass resolution perimetry also seems useful in monitoring glaucoma eyes over time. In fact, one prospective and one cross-sectional study suggested that HRP can detect progression before it is evident on SAP. In another study, the sensitivity and specificity of HRP correlated well with that obtained with FDT. High-pass resolution perimetry may be more sensitive to intraocular pressure-induced damage than SAP.
The location of defects correlates well with SAP. Abnormalities on HRP correlate well with neuroretinal rim area as well as with other measures of optic nerve structure. High-pass resolution perimetry also correlates well with nerve fiber layer thickness measurements, although there appears better correlation with the higher pressure forms of glaucoma. The test takes about one-third less time than full-threshold SAP and seems to generate more repeatable fields. Reliability indices are similar to SAP. High-pass resolution perimetry seems easier to perform and slightly more reliable than SAP in children.
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. This is evident in kinetic perimetry. Motion detection perimetry probably isolates the magnocellular pathway. 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. 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. 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.
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. Using optically neutral corneal electrodes and proper technique, the variability can be minimized and a stable, reproducible series of wave forms generated. 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. 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. Other mammals besides humans seem to generate similar responses to the PERG. In fact, the changes in PERG correlate well with ganglion cell loss in hypertensive rats. The PERG probably is detecting early diffuse damage to the ganglion cells rather than focal damage.
Early on in the studies of PERG in humans it was noted that the amplitude of the signal was reduced in glaucoma. Multiple subsequent studies have confirmed a PERG abnormality in open-angle glaucoma. Similar findings were observed in monkeys made glaucomatous with argon laser treatment to the trabecular meshwork. 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’). 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. Abnormal PERG findings quantitatively correlated with neuroretinal rim area and retinal sensitivity as measured by threshold perimetry.
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. 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. Pattern electroretinography findings correlated well with mfVEP findings, optic nerve cupping and visual field loss in most patients with glaucoma. 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.
The PERG has been utilized to assess visual function in glaucoma following experimental treatments. 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. 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. 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. 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. 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.
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. Some of these findings correlate with nerve fiber layer thickness. 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.
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.