Electrophysiology Comes to the Clinic

How clinical electrophysiology can improve your diagnosis and management of posterior segment disease.

Ron P. Gallemore, MD, PhD, Michael Baker, OD, Calvin K. Chou, BS, and Spencer M. Onishi, BS, Los Angeles

Electrophysiologic testing for the evaluation of posterior segment disorders is often underutilized. There are practical limitations, including the setup itself, as well as patient convenience. Many feel that such testing is often academic, rarely impacting patient care. Here we review the main electrophysiologic tests and the indications for their use, as well as some of their limitations in the diagnosis and management of patients with retinal and optic nerve disorders.

The Setup

Commercial systems are now available that require minimal setup and staff training and allow more consistent, standardized measurements. The signals recorded vary between systems due to differences in filtering, amplification, averaging, stimuli and other aspects, so temporal changes should be made using the same system.1 Here we review the main diagnostic tests, the techniques, and the signals recorded.

Multifocal ERG

The mfERG is an objective measure of cone-driven central retinal function.2 A hexagonally patterned array stimulates different areas in a pseudo-random pattern.2 The recorded signals are mathematically processed utilizing “binary m-sequences” to generate a topographic map of retinal function.2,3 Areas of retinal dysfunction are identified by spatially comparing variations in the topographic array of signals.

Data is displayed (See Figure 1) as a trace array, 3-D density plot, and regional average data in a 2-D plot or waveform tracing.
Figure 1. Multifocal ERG data illustrations recorded with the LKC EPIC-4000 system with CRT monitor (100 cd/m2). A) Trace array. B) 3-D response density topography plot. C) Average response density plots in both 2-D (left) and tracing (right) illustrations. D) Individual mfERG waveform is composed of an initial negative deflection (N1) followed by a positive deflection (P1) and subsequent N2 and P2 components. Measurements include the N1-P1 amplitude and the P1 implicit time. Note similarities to the dark-adapted a- and b-waves of the full-field ERG (right).
It is important to look at all of these ways of displaying the data, as it can enhance your interpretation of the results.

Trace arrays are composed of individual biphasic waveforms (See Figure 1D, left), which have some resemblance to the standard full-field ERG (ff-ERG), with an initial negative wave (N1) followed by a positive deflection (P1), similar to the a- and b-waves of the ff-ERG (See Figure 1D, right). While there is data to suggest that N1 represents the outer retinal activity associated with phototransduction (similar to the a-wave) and the P1 response contains signal activity from the inner retina (similar to the b-wave), the stimulus and mathematical signal processing as well as the spatial differences (full-field versus central) and lack of rod contribution make a direct correlation impossible. Hence, the mfERG cannot replace the information provided by the ff-ERG.

The mfERG can be recorded with varying numbers of traces, with or without signal averaging. Higher number arrays result in more precise data, but provide a lower signal-to-noise ratio, as well as longer testing time. The International Society for Clinical Electrophysiology of Vision (ISCEV) recommends 61 or 103 tracings.4

An mfERG abnormality (suppressed signal) usually correlates well with visual-field defects (See Figure 2). Cataracts may influence mfERG recordings due to light scattering. Refractive error and axial length should also be accounted for when analyzing mfERG signals.3

Clinical applications of mfERG. Drug toxicity is a leading indication for the mfERG, which is more sensitive than the ff-ERG in detecting cases of toxicity caused by drugs affecting the macula. These include the anti-malarial (anti-inflammatory) drugs chloroquine, hydroxychloroquine and quinine; anti-tuberculosis drugs including ethambutol; anti-epileptic drugs like vigabatrin; and antipsychotic medications including thiothixene. Other applications include detection of non-organic vision loss; dysfunction from inflammatory disease (especially birdshot chorioretinopathy); and dysfunction caused by vascular disease, including diabetes and retinal vein occlusion, presumably as the result of ischemia and sometimes out of proportion to the clinical findings.5 Retinal degenerations can be monitored with the mfERG; residual cone function is detected in retinitis pigmentosa and it is suppressed in X-linked retinoschisis. We have found a robust initial mfERG to be a predictor for improved retinal function after anti-vascular endothelial growth factor therapy in wet age-related macular degeneration (See Figure 3), though long-term sequential treatment with anti-VEGF drugs can be associated with an overall decrease in the mfERG even when vision appears relatively preserved.6 This may be a useful measure in assessing long-term benefits of other drugs such as the anti-platelet-derived growth factor inhibitor, Fovista.
Figure 2. Top) mfERG/30-2 threshold field overlay in a patient with Stargardt’s disease. Bottom) Late-phase fluorescein angiogram of the same patient.

Figure 3. Improvement in mfERG signals in an 82-year-old Caucasian female being treated for age-related macular degeneration with anti-vascular endothelial growth factor therapy, OS. A) Optical coherence tomography showing subretinal fluid and pigment epithelial detachment. B) Post-treatment with anti-VEGF therapy, demonstrating resolution of the subretinal fluid. C) Central and nasal suppressions noted on the trace array prior to treatment. D) Increased retinal electrical activity noted with recovery of the central and nasal response densities, post-treatment.

mfERG Tips: Improve the signal to noise ratio by dilating the pupil, increasing the stimulus intensity and reducing the trace array number. Make sure the patient maintains fixation so results are reproducible and 3-D plots are accurate. 

Full-field ERG

The ff-ERG is a measurement of the summed mass electrical response of the retina under maximally dilated photopic and scotopic conditions. The ISCEV protocol includes five components designed to isolate rod and cone function as shown in Figure 4. Dark-adapt for 20 minutes before the scotopic ERG is recorded and light-adapt with a Ganzfeld background illumination of 30 cd/m2 for 10 minutes before recording photopic signals. A bright flash elicits a biphasic response, the negative a-wave followed by the positive b-wave (See Figure 3B).

The two primary measures are the wave amplitude and implicit times (onset of flash to peak or trough of wave). The a- and b-waves originate primarily in the outer and inner retina, respectively. An abnormal ff-ERG result occurs when approximately 20 percent of the retina is compromised.7 The signal is recorded with alternate current rather than direct current amplification, allowing only fast ERG signals to be detected (a-waves and b-waves rather than slower c-waves, fast oscillation and light peak potentials).8-9

Clinical applications of ff-ERG. The most common use is detecting a hereditary degeneration and differentiating it from other causes. In RP the ff-ERG is often the definitive test and the scotopic a- and b-waves are generally extinguished early in autosomal recessive and X-linked RP.10 A suppressed but intact b-wave may be seen in autosomal dominant RP and the increased implicit time may be helpful in making the diagnosis (See Figure 5). Leber’s congenital amaurosis presents with an RP-like picture of the retina and is also associated with markedly reduced ff-ERG signals. Congenital stationary night blindness is identified with the ff-ERG—usually a negative signal with a-wave greater than b-wave—and accounts for 10 to 20 percent of blindness in children.11 Evaluation for unexplained vision loss with ff-ERG should be performed before initiating a costly workup. X-linked Juvenile Retinoschisis (XLRS) also manifests as a negative waveform ERG, and is the result of a mutation of the RS1 gene, causing microcystic changes in the macula.12 Cone degeneration can be detected and distinguished from Stargardt’s disease or other bull’s-eye maculopathies using the ISCEV test protocol. The b-wave is useful for predicting rubeosis in central retinal vein occlusion. An implicit time greater than 50 msec and inter-eye difference of greater than 8 msec is highly predictive.13,14 In such patients we initiate anti-VEGF therapy followed by panretinal photocoagulation laser treatment early in the course of the disease. The ff-ERG may also be particularly useful for identifying malingering associated with profound visual field loss (See Figure 6). Chemical vitrectomy with ocriplasmin was reported to cause dyschromatopsia in less than 5 percent of patients, with an associated profound suppression of the ff-ERG. We have also noted ERG suppression in the absence of dyschromatopsia in cases where the drug has been effective in the treatment of macular hole (See Figure 7). These effects appear reversible.

  Figure 5. Full-field ERG tracing of healthy normal female patient diagnosed with Usher’s syndrome (bottom). Scotopic response amplitude is decreased and implicit time increased (arrow) compared with aged-matched control (top) recorded on the same system.   Figure 6. Full-field ERG of patient complaining of unexplained vision loss acute and stable five years after exposure to an ammonium-based cleaning solution. Goldman fields (top) are markedly constricted, OD>OS while all five ERG signals were of normal amplitude in each eye. MRI of brain and orbits, VEP, mfERG and EOG were all normal and repeat field testing was highly variable and never consistent (not shown).
Figure 4. Normal ff-ERG tracings recorded from the right eye of a healthy 40-year-old female patient. This tracing shows normal scotopic and photopic responses. The ISCEV protocol includes five components designed to isolate rod and cone function: A) Dark-adapted 0.01 cd/m-2 ERG (rod response); B) Dark-adapted 3.0 cd/m-2 ERG (maximal combined rod-cone response); C) Dark-adapted 3.0 cd/m-2 oscillatory potentials; D) Light-adapted 3.0 cd/m-2 ERG (single flash cone response); and E) Light-adapted 3.0 cd/m2 flicker ERG (30-Hertz flicker). Dark-adapted recordings occur under background luminance of 0 cd/m-2 while light-adapted recordings occur under a Ganzfeld background illumination of 30 cd/m-2.          

ff-ERG tips: Electrode contact is key for good signals. Minimize 60Hz line noise to optimize oscillatory potential recording. Be consistent with exact dark adaptation time.

Pattern ERG

Figure 7. Left) A 63-year-old highly myopic Asian patient with cataracts showing decreased scotopic response but maintains normal photopic response three weeks status-post Ocriplasmin injection OS for a stage II macular hole. Decreased scotopic response indicates rod dysfunction. Patient has normal color vision, but decreased red cap sensitivity OS. Right) OCTs showing closing of macula hole three weeks s/p Ocriplasmin injection. Note small amount of subretinal fluid.
Figure 8. EOG recording of normal female patient. The Arden ratio (light/dark ratio) is the ratio between the light peak (LP) and dark trough (DT).  In this case, the Arden ratio in the right eye is 2.21 (red line) and the left eye is 2.28 (blue line).
The PERG is generated by an alternating checkerboard stimulus, which activates ganglion and amacrine cells, generating a small potential change recorded at the cornea.15 It is used primarily to assess retinal damage secondary to glaucoma but may also be useful in the diagnosis and/or monitoring of ocular hypertension, optic neuritis, optic atrophy and amblyopia.


The EOG is an indirect way to measure the slow electrical responses generated by the retinal pigment epithelium, which are selectively affected in some conditions. Under direct current of the ERG, a series of slower potentials can be measured following the fast a- and b-waves, but these are lost with standard alternate current ERG recordings. The EOG is used to measure these slower potentials (usually just the light peak and dark trough, but a fast oscillation can also be identified).16 Since the retinal pigment epithelium generates a resting potential across the eye, changes in that potential can be recorded by shifting the dipole—patients look side to side and the voltage is recorded during dark-adaptation followed by a light adaptation.16 Figure 8 shows a typical EOG measurement. The response reaches its lowest trough eight to 12 minutes into the dark phase, and reaches its highest peak six to nine minutes into the light phase. The EOG amplitude is reported as the Arden Ratio: the greatest amplitude in light divided by the lowest amplitude in the dark. The size of the light peak and dark trough should approximately be 2:1 or greater, respectively. A light/dark ratio less than 1.7 is considered abnormal.

Clinical applications. The EOG has classically been used to detect hydroxycholoquine toxicity and Best disease.16,17 In case of the former, we find other modalities may be more sensitive at early detection of toxicity, including a central 10-degree visual field with red target, autofluorescence (See Figure 9), mfERG and optical coherence tomography, demonstrating foveal atrophy. Toxicity may be progressive after discontinuation of the medication and continued monitoring is in order. In addition to Best disease, other RPE dystrophies, including pattern dystrophies and the fundus flavimaculatus variant of Stargardt’s, can be associated with a suppressed EOG with typically normal ff-ERG.18

Tip: Make sure saccades are consistent and do not overshoot and saturate the recording
system. This can underestimate the Arden ratio.

Visually Evoked Potential

The VEP measures the function of the optic nerve and its connection between the retina and brain. A VEP stimulus may be in the form of a pattern reversal (checkerboard) or pattern onset (flash). Pattern reversal is the preferred stimulus for most clinical purposes due to fewer variations in waveform and latency compared to the flash (See Figure 10). Pattern reversal stimuli are the best choice in cooperative patients with visual acuity of 20/200 or better, particularly when testing for possible effects of optic neuritis. Smaller check sizes subtending 10 to 20 degrees (minutes) of arc are best for evaluating foveal vision. Larger check sizes subtending 40 to 50 degrees of arc are better utilized for evaluating parafoveal vision.19 The higher-intensity Flash VEP is useful when poor optics, poor cooperation (nystagmus) or poor vision limit the use of pattern reversal VEP.

Figure 9. A) EOG Arden Ratio of patient diagnosed with plaquenil toxicity measured from time of plaquenil discontinuation (2/3/2011) and consecutively thereafter. Values begin in the normal range and subsequently decline over the next two years off plaquenil.  Values of <1.7 are considered abnormal. B) In contrast, the mfERG is clearly suppressed at the onset OS>OD (19 trace array). C) OCT studies highlight the macular atrophy associated with progression of the bull’s-eye, best seen on D) autoflourescence image documented at baseline (2/3/2011) and last follow-up (7/11/2013).
Figure 10. A) Pattern visually evoked potentials displaying normal latency and amplitude responses across stimuli ranging from Step 1 [100’ arc (8x8)] to step 5 [6’ arc (128x128)]. B) Pattern VEP affected by uncorrected refractive error. VA 20/20 OD (left), 20/200 OS (right).
Figure 11. VEP in traumatic optic neuropathy. A patient suspected of malingering after hitting his head on a turnstile. VA 20/20 OU. A) VEP amplitudes reduced OD, eye with purported vision loss. B) Fundus images show subtle temporal cupping, pallor and disc excavation OD (left) with c/d of 0.3 compared with OS where nerve is crowded, c/d 0.15.
Interpretation of the VEP includes analysis of amplitude and latency of each waveform, compared to age-related norms. Expected peak latency is about 100 msec using pattern reversal stimuli, and about 110 msec using flash stimuli for individuals below the age of 55. Beyond this age, VEPs change gradually, resulting in attenuation of amplitude and slowing of latency. A VEP finding that shows decreased latency/amplitude at all check sizes may indicate nerve damage.19 VEP findings which show decreased latency/amplitude at only smaller check sizes may indicate refractive error opposed to nerve damage (See Figure 10B). A common clinical referral is to determine whether a patient’s visual problems are due to retinal or visual pathway dysfunction. Recording both an ERG and VEP will usually help determine the cause of visual dysfunction.

Clinical applications.
The VEP is useful in assessing damage from glaucoma, retrobulbar optic neuritis, traumatic optic neuropathy (See Figure 11), compressive optic neuropathy and damage from meningitis.20 It is important to understand the limitations as noted above, but don’t underestimate the potential in complex cases where optic nerve dysfunction is difficult to confirm or quantify with other tests.

Tips: Make sure the patient is properly refracted and note level of best-corrected vision. If vision is <20/200, a flash rather than the standard pattern VEP may be indicated. Make sure the patient is fixating on the target screen during the test. 

Dark adaptometry/Scotopic sensitivity

Dark adaptometry is used to measure absolute cone and rod sensitivity. Sensitivity of the retina is measured over time, producing a biphasic curve, with a rod-cone break occurring within 5 to 10 minutes. Dark adaptometry is useful in the diagnosis and management of retinal degenerations, high myopia, vitamin A deficiency and other night blinding conditions. The two major parameters that are measured are the dark adaptometry curve and the final dark-adapted threshold.21 Fenretinide was found to slow the progression of geographic atrophy in Phase II studies. However, this drug also acted as a retinol-binding protein inhibitor, reducing dark adaptation kinetics and dark adaptometry was used as confirmation.22

In summary, a clinical electrophysiology unit can be established in any retina practice and will provide useful information in the diagnosis and management of specific disorders. It may alter the course of patient care and improve clinical outcomes. Something to consider as you evolve your practice towards optimal state-of-the-art diagnosis and care for your patients.  REVIEW

Dr. Gallemore is an assistant clinical professor at Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, and founder and director of the Retina Macula Institute and Research Center, Torrance, Calif.

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