Kathleen M. Brockie
February 20, 2002
Glaucoma is a degenerative disease which can be caused by high intraocular pressure (IOP) (Glaucoma, 2002). This IOP arises in the aqueous humor, the area between the cornea and the iris, where a drainage system allows the aqueous to drain from this area and recycle (Learn about Glaucoma, 2002). A specific balance of the production and removal of aqueous determines the IOP. Either malfunction or malformation of this drainage system can cause a rise in pressure. The elevated pressure causes irrevocable damage to the optic nerve and retinal fibers as well as damage to the other areas of the visual system, which leads to a gradual and permanent loss of vision if not treated (Glaucoma, 2002). Damage to the optic nerve causes loss of vision because this nerve, or group of ganglion axons, is responsible for transporting images to the brain from the eye. While there are other possible causes of glaucoma, such as variations of the myocilin gene, IOP is thought to be the main cause (Learn about Glaucoma, 2002). Treatment, especially with early detection, can slow or cease continued damage.
Types of Glaucoma
There are several types of glaucoma, the most prominent types being Open Angle, and Acute Angle Closure and the more infrequent types including Secondary Glaucoma, Congenital Glaucoma, Normal Tension Glaucoma (NTG), and Pigmentary Glaucoma. Open Angle Glaucoma (OAG), the most prevalent form of glaucoma (Glaucoma, 2002), is painless, and can go unnoticed without the help of an optometrist or ophthalmologist. Obstructed drainage channels, which develop over a period of time, characterize this type of glaucoma. These obstructions are not present at the openings of the channels, rather they occur inside the channels. The aqueous cannot recycle because of these obstructed channels, the IOP rises, and damage results (Learn about Glaucoma, 2002). Acute Angle Closure Glaucoma, however, is much more painful and results in rapid vision loss. In this case, the iris and cornea are not wide enough apart which can cause the edge of the iris to block the drainage channels (Learn about Glaucoma; and Glaucoma, 2002). Secondary Glaucoma results from other eye diseases or problems, such as diabetes, trauma, and tumors . Congenital Glaucoma is a rare glaucoma found in infants (Glaucoma, 2002). Normal Tension Glaucoma occurs in those with normal IOP’s but have damage to the optic nerve. Pigmentary Glaucoma results from parts of the pigment in the iris breaking off and slowly clogging the drainage channels.
Types of Electroretinograms
The continued discussion is focused on the use of Electroretinograms (ERGs) in early detection for Open Angle Glaucoma (OAG). Currently, the most common tests for OAG are the measurement of the IOP, assessment of the optic nerve health using ophthalmoscopy, measurement of peripheral vision using a visual field test, and inspection of the structures in the front of the eye with a gonioscopy (Glaucoma, 2002). Recently, however, studies have been investigating the use of an ERG as a way to test for glaucoma as well. There are several types of ERGs including Flash or Cone Mediated ERG (ERG) (Viswanathan, Frishman, Robson, Harwerth, and Smith, 1999; Colotto, Falsini, Salgarello, Iarossi, Galan, and Scullica, 2000), Pattern ERG (PERG) (Maddess, James, Goldberg, Wine, and Dobinson, 2000; Voswamatjam. Frosj,am. and Robsom, 2000) and the Multifocal ERG (mERG) (Hood, Greenstien, Holopigian, Bauer, Firoz, and Liebmann, 2000). In general, an ERG is a noninvasive measure used to clinically diagnose diseases of the retinal area (Viswanathan et al., 1999). The visual field test shows signs of degeneration of the ganglion cells already in progress while the benefit to ERGs is early detection. (Hood et al., 2000). However, scientists are still debating which is the most useful type of ERG.
Participants and Methods
Participants for ERG studies are mainly macaque monkeys and cats for invasive measures, and humans for the non-invasive measures. Glaucoma is experimentally induced in the non-humans by laser, which jeopardizes the ganglion cell performance to represent actual optic nerve damage (Viswanatha et al., 2000). An intraocular injection of tetrodotoxin (TTX) is also used to subdue the sodium action potentials of the ganglion cells and amacrine cells (Colotto et al., 2000). This lessening of the action potentials reduces spiking in the ERG of the amacrine cells, the ganglion cells and perhaps the interplexiform cells. Once the participants are prepared, through either experimental glaucoma or actual glaucoma, there are a variety of ERGs that can be performed.
Flash or Cone-Mediated ERG
Viswanathan et al. and Colotto et al. used the flash or cone-mediated ERG. One used macaque monkeys and normal human participants, and then generalized the results to the glaucomatous human population based on the idea that the anatomy and physiology of the eye, as well as visual capabilities, are similar between the two species (Viswanathan et al., 1999). The other study used glaucoma patients and ocular hypertension patients specifically (Colotto et al., 2000). The general purpose of the two studies was to use this ERG to measure glaucoma damage in either the monkeys (Viswanathan et al., 1999) or in an actual human glaucoma sample (Colotto et al., 2000). A photopic, or light adapted, ERG measured electrical activity to take advantage of the photopic state so that rods are saturated. This results in the cone receptors producing a-wave responses while bipolar and possibly Muller cells produce b-wave responses. Monkey ERG information was measured at the cornea, while the human ERG information was measured by an electrode placed on the lower eyelid (Viswanathan et al., 1999; Colotto et al., 2000). The ERG measured electrical activity originating from different groups of retinal cells using different stimuli for the separate populations. The illumination of a table-tennis ball with a red light flashing was the stimulus for the monkeys (Viswanathan, et al., 1999), whereas the human sample fixated on a green light in the center of a stimulating field, or specific area producing high neural activity for a particular group of cells, on a computer (Colotto et al. 2000). Early stages in retinal processing create the initial waves of activity recorded in the ERG, so damage to these areas would be easy to detect with this method. These responses are normally "negative-going", or PhNR (Photopic Negative Response) as the researchers simply referred to them, in both normal and glaucomatic eyes. Results show that in eyes with experimental and actual glaucoma the PhNR's were significantly reduced, indicating that the measured cells produced less activity (Viswanathan et al., 1999).
These studies found that using the flash ERG, which stimulates a larger area of the retina than that of normal perimetric testing, shows damage to the ganglion cells outside the central area measured by perimetry (Viswanathan et al., 1999). This is beneficial because damage due to glaucoma starts in the periphery. So, the further in the periphery tests can assess damage, the sooner glaucoma can be detected and subsequently treated. It is important to note, however, that PhNR was not as affected by glaucoma damage as responses on the pattern electroretinogram (Colotto et al., 2000).
Pattern Electroretinogram
In a follow up study to Viswanathan's 1999 study, comparisons were made between the Pattern electroretinogram (PERG) and the uniform field ERG, done perhaps because of the evidence that the PERG is the most prominent and sensitive electrodiagnostic test used for glaucoma detection (Viswanathan, 1999). The PERG measures voltage changes in response to "contrast reversals of pattern stimuli" at the cornea (Viswanathan et al., 2000). Again, macaque monkeys with experimental glaucoma and TTX injections were the participants, and a contact placed on the cornea measures retinal activity. The PERG manipulates grating patterns of uniform field or contrast reversal with square-wave luminance modulations to activate inner-retinal areas. The PERG measure found that the summation of responses is similar to that of the PhNR's in Viswanathan's previous study. However, these results also show that after there is a light-increment in the stimulus pattern there is a slow PhNR, but after the light-decrement the normal PhNR was positive indicating that the threshold was not met for an action potential. These results are equally true of eyes with actual glaucoma, but are significantly reduced. These results also show that glaucoma, or experimental glaucoma in this case, can be detected early due to effects on retinal ganglion cells.
Maddess et al. also conducted a study also utilizing the PERG, but tested a new visual stimulus rather than testing the ability of the ERG. The researchers found that previous studies failed to accurately represent the different ganglion cell sizes and density. It is important to note that "parasol cells project information onto the magnocellular layers of the dorsal lateral geniculate nucleus (dLGN) and so are frequently referred to as M cells." (Maddess et al., 2000). Additionally, in the M pathway there are two distinct parts, which in cats are the X and the Y cells, resulting in Mx and My cells. The My cells are much larger than the Mx, so damage to one My cell produces much more vision loss at that particular retinal location. The visual stimuli needed to be altered in the PERG to accurately measure My cells. These particular researchers found that an applicable stimulus to use is a spatial frequency-doubling (FD) illusion, where there were nine sections of stripes of gratings that alternate in coarseness and direction. This study found that responses to the FD illusion corresponded to My cell responses in the retinal area, thus also correlating with damage incurred by glaucoma in the retinal area. Since these My cells cover a large area, the sensitivity to glaucoma rises and early detection is also possible with this PERG stimulus relationship.
Multifocal Electroretinogram
The PERG however also has some problems, such as having small amplitudes, not correlating with visual field measures, and needing a large stimulus. Thus, the Mulitifocal ERG (mERG) was developed, which records multiple local retinal responses in a relatively short amount of time. Glaucoma blocks inner retinal activity so the action seen is solely from ganglion and amacrine cells. While the differences between normal eyes and glaucoma eyes is significant, and the mERG is able to distinguish between the two eyes in one participant, it has problems as well. For example, changes that appear in one participant may not appear in other participants, and in order for a measure to be reliable it has to be generalizable across populations. Thus, the conditions used for this particular experiment did not appear to produce enough change, due to damage in the ganglion cells, and therefore may not be useful in early detection of glaucoma.
Conclusion
Ultimately these studies have found that the ERG is useful in the early detection of glaucoma. However, there is still a need for more research. Alterations in the ERG functions need to be made since each one has problems which compromises their reliability. This summary has also shown that researchers need to continue to look for different stimuli for the actual research setting. Each study used different stimuli which shows that at this point that one stimulus is not necessarily better than another. Thus far, studies investigating the different types of ERGs useful in the detection of glaucoma have been limited, however their findings have been important in the study of glaucoma.
Colotto, A., Falsini, B, Salgarello, T., Iarossi, G., Galan, M.E., Scullica, L. (2000). Photopic negative rsponse of the human ERG: losses associated with glaucomatous damage. Investigative Ophthalmology and Visual Science, 41 (8), 2205-2211.
Hood, D.C., Greenstein, V.C., Holopigian, K., Bauer, R., Firoz, B., Liebmann, J.M., Odel, J.G., Ritch, R. (May, 2000). An attempt to detect glaucomatous damage to the inner retina with the multifocal ERG. Investigative Ophthalmology and Visual Science, 41 (6), 1570-1579.
Maddess, T., James, A.C., Goldberg, I., Wine, S., Dobinson, J. (November, 2000). A spatial frequency-doubling illusion-based pattern electroretinogram for glaucoma. Investigative Ophthalmology and Visual Science, 41 (12), 3818-3826.
Viswanathan, S, Frishman, L.J., Robson, J.G., Harwerth, R.S., Smith III, E.L. (May, 1999). The photopic negative response of the macaque electroretinogram: reduction by experimental glaucoma. Investigative Ophthalmology and Visual Science, 40 (6), 1124-1136.
Viswanathan, S., Frishman, L.J., Robson, J.G. (August, 2000). The uniform field and pattern ERG in macaques with experimental glaucoma: removal of spiking activity. Investigative Ophthalmology and Visual Science, 41 (9), 2797-2810.
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