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Standards, Recommendations and Guidelines

Standard for Clinical Electro-oculography



Michael F. Marmor, M.D.1 and Eberhart Zrenner, M.D.2 for the International Society for Clinical Electrophysiology of Vision3

Documenta Ophthalmologica 1993;85:115-124
Published by Kluwer academic publishers, reproduced with kind permission

1Department of Ophthalmology, Stanford University School of Medicine, Stanford CA
(Chairman, ISCEV Standardization Committee)

2Department of Pathophysiology of Vision and Neuro-ophthalmology, University Eye
Hospital of Tübingen, Tübingen, Germany (President, ISCEV).

3This document was approved by the International Society for Electrophysiology of Vision on May 22, 1992, in Vienna, Austria. The Society acknowledges the special efforts of many of its members who read and contributed to drafts of the Standard. The Standard was originally published in Archives of Ophthalmology, and is reprinted by kind permission of the American Medical Association.


Corresponding author: Michael F. Marmor, M.D., Department of Ophthalmology,
Room A-157, Stanford University School of Medicine, Stanford, CA 94305-5308.
Telephone: (415) 723-5517
FAX: (415) 723-7918



Key Words: Electro-oculogram, Electrophysiology, Retina, Retinal pigment, epithelium.



Abstract

The electro-oculogram (EOG) is a widely used electrophysiological test, but recording techniques vary among different laboratories. This Standard, approved by the International Society for Clinical Electrophysiology of Vision (ISCEV), describes simple technical procedures that will allow reproducible and comparable EOGs to be recorded under a few defined conditions. The document is intended to improve the comparability of EOG data obtained throughout the world by guiding both clinicians and manufacturers, and ISCEV recommends that future published reports indicate whether the recording technique meets the International Standard.

Introduction

The eye has a standing electrical potential or charge across it, like a weak battery, with the front of the globe positive and the back negative. This resting or "standing potential" is generated largely by the transepithelial potential across retinal pigment epithelium. It varies from one to several millivolts, depending upon the state of ambient retinal illumination, because light leads to a polarization of the basal pigment epithelial membrane that translates into changes in the transepithelial potential. Retinal illumination causes an initial rapid fall in the standing potential over 60-75 sec (the "fast oscillation") followed by a slow rise over 7-14 min (the "light response" or "slow oscillation"). The clinical electro-oculogram (EOG) measures the amplitude of the standing potential and light response.
In the EOG, the standing potential is measured indirectly, using the fact that the spatial orientation of a polarized eye is detected by skin electrodes placed nasal and temporal to the eye. Patients follow an alternating fixation target to generate consistent saccades (which means that infants, small children and uncooperative subjects cannot be tested with this method). This technique can also be used to measure standing potential changes other than the light response such as the fast oscillation (see addendum) and non-photic responses to pharmacologic agents.
The EOG is a widely used electrophysiological test, and the members and Standardization Committee of the International Society for Clinical Electrophysiology of Vision (ISCEV), have worked on the proposition of a basic recording protocol so that clinical EOG responses can be compared throughout the world. ISCEV proposes standards for two alternative methods for recording the EOG: 1) The ratio of light peak to dark trough (Arden ratio); or 2) the ratio of light peak to a dark-adapted baseline. While this document is intended as a guide to practice, and will assist in the interpretation of EOGs, ISCEV recognizes that certain laboratories may choose to use additional conditions or measure additional parameters. The standard describes simple technical procedures that will allow relatively reproducible EOGs to be recorded under a few defined conditions. It will be incumbent on users of alternative techniques to demonstrate that their procedures do, in fact, produce signals that are equivalent in amplitude and physiological significance to the standard.
The intention of ISCEV is that the standard method and responses be used widely. However, because physiological knowledge and technology may change, these standards will be reviewed every four years. It is hoped that the standard will not only guide clinicians but also manufacturers in the production of commercial recording equipment. Note that this document is not a safety standard and does not mandate the use of any particular procedure for individual patients.

I. Basic Technology

1. Light stimulation.
a. Stimulus field: It is strongly recommended that full field (Ganzfeld) dome stimulation of the retina should be used. With more focal light sources, such as a light box, the area of retinal illumination is uneven and the extent of responding retina is unknown. Since the EOG is a mass retinal response, it is important for standardization that the entire visual field be evenly illuminated.
b. Fixation targets: The diffusing sphere should have fixation targets that induce eye movements of approximately 30° visual angle in the horizontal meridian. These are most typically constructed from red LEDs that are illuminated sufficiently to be visible during the dark and light phases of the test.

2. Skin electrodes.
a. Construction: Electrodes should be made of relatively non-polarizable material such as silver-silver chloride or gold.
b. Resistance: Impedance of the applied electrode should measure <10 k Ohms over a frequency range that includes 30 to 200 Hz.
c. Electrode application: The skin should be cleansed of oils with alcohol or a commercial skin-preparing material. The electrodes should be applied with a conductive paste.
d. Cleaning: If non-disposable electrodes are used, they should be suitably cleaned after each use to prevent transmission of infectious agents. The cleaning protocol should follow current standards for devices that contact the skin.

3. Light Source.
a. Luminance: Illumination may be provided by one or several lamps, but they should produce visibly white light, and be situated so that the full-field diffusing sphere is evenly illuminated from the vantage point of the patient. Areas of focal intensity ("hot spots") or shadows should be avoided.
b. Adjustment: The light source should be adjustable by the use of filters or other means, to allow for calibration of the unit. Large variation in stimulus intensity will need to be available if patients with both dilated and undilated pupils are to be studied.
c. Calibration: The luminance produced by the full-field stimulator should be measured in cd/m2 with a photometer that meets international standards for photometric measurements based on the photopic luminosity curve. ISCEV recommends that in the future, manufacturers of stimulators provide a suitable photometer as a part of the equipment. Since light output may vary with time, from changes in light bulbs or filters, it is important that the luminance be periodically recalibrated. Self-calibrating units are to be encouraged.

4. Electronic recording equipment.
a. Basis of measurement of the standing potential: Because of the dipole effect of the eye, with the cornea positive to the back of the globe, saccadic eye movements result in current flows around the orbit that are proportional to the magnitude of the standing potential of each eye. These voltage changes can be measured from skin electrodes placed at the nasal and temporal canthal regions of the eye.
b. Amplification systems: Direct current (DC) amplification most faithfully reproduces the square wave voltage changes that occur when a subject looks back and forth. However, for practical purposes the use of alternating current (AC) recording systems is easier since the problems of drift and stability are minimized. In general, it is recommended that an AC system with a low frequency cutoff at 0.1 Hz or lower, and a high frequency cutoff no lower than 20 Hz (but preferably below 50 or 60 Hz to minimize interference). DC recording may be utilized by experienced laboratories, but will usually require some type of electronic baseline compensation to avoid drift.
c. Display system: It is very important that the original waveforms be displayed during the recording of the EOG. This allows the individual performing the test to judge whether the signals are stable, and to observe artifacts, jerky saccades, unacceptable overshoot, etc., which might necessitate re-application of electrodes, re-instruction of the patient, or an altered interpretation of the results. In systems which automatically measure the amplitude of collections (epoches) of waveforms, and plot the values, it is important that the raw data be displayed transiently as it is gathered, to allow for these judgments.
d. Patient isolation: It is recommended that the amplifiers be electrically isolated from the patient, according to current standards for safety of biological recording systems used clinically.


II. CLINICAL PROTOCOL

1. Pupillary dilatation.
EOGs may be performed with pupils either dilated or undilated. Pupillary dilatation provides better control of illumination levels, but adds time to the test and may make the test somewhat more uncomfortable for certain patients. The critical parameter in producing a light response of the standing potential is the level of retinal illumination. Thus, the light levels which are used to perform the test (see below) will be different according to the state of the pupil.

2. Electrode placement.
Two skin electrodes should be used for each eye, placed as close to each canthus as possible. Avoid large size electrodes that fit poorly and increase the distance of separation. A ground electrode should be attached to the middle of the forehead, or some other neutral site.

3. Saccades.
Saccades are typically induced by illuminating the fixation lights alternately, but patients could be instructed by other means to look back and forth at a steady rate between fixation targets. ISCEV suggests that the eyes alternate direction every 1 to 2.5 seconds (equivalent to a complete back and forth cycle every 2-5 seconds). Faster alterations become uncomfortable and unstable, whereas alternations at the slow end make it more difficult for subjects to maintain a steady alternating rhythm. Since continuous saccadic movement becomes tiresome, it is recommended that a set number of saccades (minimum of 10) be recorded once per minute throughout the test. Testing at least once per minute is necessary to recognize the relevant peaks and troughs.

4. Pre-adaptation.
Patients should be in ordinary room light, or be pre-adapted to room light levels, for at least 15 minutes prior to the dark phase of testing. This pre-adaptation phase light should measure between 35 and 70 lux looking ahead (not at the ceiling or close to a white wall). Dimmer pre-adaptation light levels may fail to suppress rod function and will diminish the size of the dark trough (although they would be acceptable for the baseline method of recording described below). Stronger light levels or sudden changes in illumination may excessively stimulate the dark trough and slow oscillations, and they will make it more difficult to reach a steady baseline. Unusual bright light exposure such as sunlight, ophthalmoscopy or fluorescein angiography should be avoided within 60 minutes of EOG testing.

5. Dark phase.
The protocol for the dark adaptation phase differs between the two alternative methods of EOG recording. Use one or the other of the following protocols.
a. For the ratio of light peak to dark trough (Arden ratio): To record a dark trough, the room light should be turned off and EOG values recorded for 15 minutes in darkness. The minimum amplitude during this period will be designated as the dark trough. This occurs most often between 11 and 12 minutes, but may appear earlier or later.
b. For the ratio of light peak to dark-adapted baseline: Dark adaptation for at least 40 minutes is required to establish a stable baseline. It is not necessary to record the EOG throughout this period, but testing should begin at least 5 minutes before the light phase to establish a baseline and insure its stability. Note that testing time may be conserved by putting on the electrodes during the dark adaptation period, using dim red illumination; clinical dark adaptometry may also be performed during this period.

6. Light response.
The light stimulus should be turned on, and the EOG recorded, until the light peak has occurred and the signal amplitudes have clearly begun to descend (at which point the recording can be stopped). If there is no clear light peak, then recording should continue for at least 20 minutes to insure that a delayed light peak is not missed. The choice of luminance levels for the stimulus will depend on whether the pupil is dilated.
a. Dilated pupils: The stimulus intensity should be a fixed value (for each laboratory) within the range of 50 and 100 cd/m2.
b. Undilated pupils: The stimulus intensity should be a fixed value (for each laboratory) within the range of 400 and 600 cd/m2.
c. Technical note: These ranges of illumination are recommended to accommodate the typical range of dilated or undilated pupil sizes. Technically speaking, the EOG would be better standardized by the use of trolands (cd/m2 x mm2 of pupillary area) which would insure similar levels of retinal illumination regardless of pupil size. ISCEV considers the range of 1000 to 3000 trolands (3 to 3.5 log trolands) to be optimal. For practical purposes, however, it is difficult to measure pupillary diameter during the test, while the patient is looking into the diffusing sphere, and most commercial stimulus units do not have the capability of finely adjusting the luminance of the sphere. Thus, the Standard recommends separate fixed light intensities for dilated and undilated pupils, as the best compromise between an adjustable light level and the reality of clinical testing.


Figure 1 Appearance of EOG saccadic recordings with DC (top) or AC (bottom) amplification. Measurement of saccade amplitude (brackets) should avoid the artifact of overshoot.

7. Measurement of the EOG.
a. Saccadic amplitudes: The measurement of EOG oscillations must take into account the potential artifacts of overshoot (positive or negative) and falloff (Figure 1). Overshoot occurs when subjects look beyond the fixation target and then return to a stable position. Falloff occurs during AC recording, as the amplitude fades from its maximal value. Sharp overshoots can be ignored and the stable amplitude level used for measurement. If there is significant falloff from AC filtering of the signal, we recommend measurement of the leading edge, or at least the initial stable value.
b. The ratio of light peak to dark trough (Arden ratio): Measurement of the lowest dark-adapted point (dark trough) and highest light point (light peak) should be made. However, examiners should be aware that there is often some random variation in these values, and the curves should be visually or otherwise "smoothed" to identify the true trough and peak points (Figure 2).
c. The ratio of light peak to dark baseline: The average stable baseline value in the dark is determined. The light peak is determined as in the preceding section. The value of the light peak to dark baseline ratio will typically be lower than the Arden ratio.
d. Latency (implicit time) of the light peak: The latency is the time between the onset of the light phase and the peak of the light response. It can be of clinical relevance in addition to the Arden- or baseline-ratios.
e. Amplitude of dark trough or dark baseline: It is important to measure the standing potential amplitude in microvolts at either the bottom of the dark trough (if the Arden ratio method is used) or at the dark-adapted baseline, since low values may have clinical significance and may lead to the calculation of ratios of uncertain physiologic meaning. (These baseline amplitudes should be normalized to microvolts per degree if a visual angle other than the standard 30° is used).


Figure 2 Examples of an idealized (top) and a practical (bottom) EOG record of saccadic amplitude versus time. The points often must be "smoothed" visually or mathematically to accurately estimate the dark trough and light peak.

8. Normal values.
 ISCEV recommends that each laboratory establish or confirm normal values for its own equipment and patient population, and that EOG reporting (whether for local records or publication) include normal values. Some manufacturers may choose to distribute norms for their standard protocols. An effort will be underway to establish world-wide norms.
Although normal values for the Arden ratio may be larger than those for the light peak vs. dark baseline method, the two methods are roughly comparable in terms of variability of the response (in the range of 10% variance about the mean for repeated testing on an experienced subject). Norms from one method cannot and must not be used for the other.

9. Reporting the EOG.
ISCEV recommends that reports or communications of EOG data state clearly whether the ratio of light peak to dark trough (Arden ratio), or light peak to dark baseline, method has been used. EOG reports should include the latency of the light peak and the amplitude of the dark trough or dark baseline in microvolts per degree of visual cycle. Published clinical reports should indicate whether the recording technique meets the International Standard. Research reports should indicate pupil size, spatial arrangement and measured intensity of the light stimulus, conditions of pre-and dark-adaptation, time intervals of stimulation and filter characteristics of the recording equipment.


Addendum

Fast oscillation (FO)
This signal represents a hyperpolarization of the basal RPE membrane within 30 to 40 seconds of illumination. Investigators are beginning to use the FO to gather normative data and look for disease correlations. The acquisition of knowledge about the FO will be facilitated if laboratories use consistent methodology.

The Standardization Committee suggests the following test procedures:
For FO recording, the same amplification equipment, electrode placement, saccadic frequency, and stimulus light intensity (adjusted for pupillary status) should be used as for the EOG. Pre-adaptation is not ordinarily critical except insofar as one would prefer not to have the FO superimposed on slow oscillations. The major difference in FO recording is the light/dark cycle time. Alternating light and dark periods of 60 to 80 sec each are recommended, for a minimum of 6 complete light/dark cycles. Because each cycle is short, continuous recording of saccades throughout the test is ideal. Rest periods may miss a response peak or trough.
The FO may be recorded as an independent test or as the initial component of EOG testing (between pre-adaptation and the dark phase). It is the experience of many investigators that Arden ratios are not significantly altered by recording the FO prior to the dark phase. For light peak to baseline recording, an undisturbed dark adaptation period would still be necessary.
Reports should include the average peak to trough ratio, and an average latency or phase shift of the peaks. The absolute magnitude of the standing potential in the troughs (in microvolts per degree of visual angle) should also be noted.
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