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The Electroretinogram and Electro-oculogram: Clinical Applications by Donnell J. Creel

Donnell J. Creel

1. Introduction

 

Electrophysiological testing of patients with retinal disease began in clinical departments in the late nineteen forties. Under the influence of the Swedish pioneers, Holmgren (1865) and Granit (1933), the electroretinogram was being dissected into component parts and early intraretinal electrode studies were beginning to tell which cells or cell layers gave rise to the various components. A detailed discussion of the electroretinogram, or ERG as it is commonly abbreviated, is found in the accompanying chapter by Ido Perlman. A little after the introduction of the ERG as a test of the state of the patient’s retina, another diagnostic test called the electrooculogram (EOG) was introduced to the clinic (Arden et al., 1962). The EOG had advantages over the ERG in that electrodes did not touch the surface of the eye. The changes in the standing potential across the eyeball were recorded by skin electrodes during simple eye movements and after exposure to periods of light and dark. Over the years ERG recording techniques have become progressively more sophisticated in the clinical setting. With the advent of perimetry, optical coherence tomography (OCT) and pattern ERG techniques, more precise mapping of dysfunctional areas of the retina is now possible. The most recent advance in ERG technology is the multifocal electroretinogram (mfERG). The mfERG provides a detailed assessment of the health of the central retina.

 

Where the previous chapter (The electroretinogram: ERG, Ido Perlman) presents the basic science behind the waveforms and components of the massed ERG response, in this chapter the intention is to show the clinical use of the various electrophysiological tests. The chapter is based on experience in the ERG clinic of the Moran Eye Center.

2. The electroretinogram ERG.

The global or full-field electroretinogram (ERG) is a mass electrical response of the retina to photic stimulation. The ERG is a test used worldwide to assess the status of the retina in eye diseases in human patients and in laboratory animals used as models of retinal disease.

The basic method of recording the electrical response known as the global or full-field ERG is by stimulating the eye with a bright light source such as a flash produced by LEDs or a strobe lamp. The flash of light elicits a biphasic waveform recordable at the cornea similar to that illustrated below (Fig 1). The two components that are most often measured are the a- and b-waves. The a-wave is the first large negative component, followed by the b-wave which is corneal positive and usually larger in amplitude.

Fig.1 The biphasic waveform of the typical normal patient

Two principal measures of the ERG waveform are taken: 1) The amplitude (a) from the baseline to the negative trough of the a-wave, and the amplitude of the b-wave measured from the trough of the a-wave to the following peak of the b-wave; and 2) the time (t) from flash onset to the trough of the a-wave and the time (t) from flash onset to the peak of the b-wave (Fig. 2). These times, reflecting peak latency, are referred to as “implicit times” in the jargon of electroretinography.

Fig.2 Amplitude and implicit time measurements of the ERG waveform

The a-wave, sometimes called the “late receptor potential,” reflects the general physiological health of the photoreceptors in the outer retina. In contrast, the b-wave reflects the health of the inner layers of the retina, including the ON bipolar cells and the Muller cells (Miller and Dowling, 1970). Two other waveforms that are sometimes recorded in the clinic are the c-wave originating in the pigment epithelium (Marmor and Hock, 1982) and the d-wave indicating activity of the OFF bipolar cells (see Figure 3). Later we shall discuss some wavelets that occur on the rising phase of the b-wave known as oscillitatory potentials (OPs). OPs are thought to reflect activity in amacrine cells (Fig. 3).

 

Fig.3 Cartoon of the retina to show where the major components of the ERG originate

The ERG of a normal full-term infant looks similar to a mature ERG. The ERG attains peak amplitude in adolescence and slowly declines in amplitude throughout life (Weleber, 1981). After age 55-60 years the amplitude of the ERG declines even more. Implicit times slow gradually from adolescence through old age as well. Below are two figures illustrating how the b-wave attenuates in amplitude with age and slows in its implicit time (Fig. 3a). There is considerable variation among individuals but the linear regression line in each figure indicates the trend of aging affects on the ERG.

 

 

Fig.3a Scatter plot of b-wave samplitudes and latencies with age with regression lines to show the aging effects

3. ERG recording electrodes.

The ERG can be recorded several ways. The pupil is usually dilated. There are a number of corneal ERG electrodes that are in common use. Some are speculum structures (Fig. 4) that hold the eye open and have a contact lens with a wire ring that “floats” on the cornea supported by a small spring. Some versions use carbon, wire or gold foil to record electrical activity. There are also cotton wick electrodes (Fig. 4).

Fig.4 Speculum or Burian type electrodes used to record the human ERG

There are yet other simpler ERG recording devices (Fig. 5) using gold Mylar tape that can be inserted between the lower lid and sclera/cornea. Most electrodes are monopolar, i.e., are referred to another electrode site most commonly on the forehead. Some are bipolar with the reference electrodes built into a metal surface on a speculum.

Fig. 5 Other simple types of electrode used to record the human ERG

Each of these electrodes record large voltage responses directly from the cornea or sclera and each have advantages and disadvantages. We use Burian speculum electrodes when possible. Sizes are available down to a size that fits in the eye of most full-term babies. When the eye is too small for speculum recording electrodes we use the ERG Jet type most of the time. When the eye is very small such as in some microphthalmic eyes or cases of trauma to tissue surrounding the eye, we use a carbon wick or gold Mylar tape.

The ERG can also be recorded using skin electrodes placed just above and below the eye, or below the eye and next to the lateral canthus. Since skin electrodes are not in direct contact with the eye there is significant attenuation in amplitude of the ERG, so a number of individual responses to flash stimulation are usually averaged by computer. Pictured in Figure 6 is a comparison of bright white flash ERGs recorded from the same person using three types of recording devices and an averaged ERG from skin electrodes.

 

Fig. 6 Typical ERGs as recorded with different electrodes

If electrodes are to be reused, they should be sterilized with a solution that neutralizes prion-transmitted diseases such as Creutzfeldt-Jakob disease (CJD). Follow sterilization recommended by the manufacturer. We use household clothing bleach (active ingredient sodium hypochlorite), diluted to a 10% solution with distilled water. Do not leave electrodes in this solution for more than a few minutes.

 

4. Light stimulation for ERGs.

There are also several methods of stimulating the eye. Some laboratories use a strobe lamp that is mobile and can be easily placed in front of a person whether sitting or reclining (Fig. 7). The mobility of a strobe lamp or an array of LEDs is a necessity in some situations such as at the hospital bedside or in the operating room.


Fig. 7. Portable strobe light source

Fig. 8. The Ganzfeld stimulation globe

 

For patients over 5 years of age most laboratories use a Ganzfeld (globe) with a chin rest and fixation points (Fig. 8). The Ganzfeld allows the best control of background illumination and stimulus flash intensity. Either strobe lamp or Ganzfeld methods of flash presentation can be used to record the ERG following a single flash or to average responses to several flashes with the aid of a computer. Clinical decisions can be made from ERGs generated by either methodology.

Testing infants for ERGs

Infants up to about 2 years of age can usually be tested without sedation by the parent holding them bundled in a blanket. It is difficult to convince a child less than 5 years of age to allow a contact lens or speculum recording electrode in their eye. Alternatively, the child is sedated or anesthetized.

ERG testing is also sometimes performed as part of a more extensive exam under anesthesia (EUA). Few laboratories have Ganzfeld stimulators that can be tilted and placed over the face of a sedated patient and it is difficult to use such equipment in the operating room. Thus flash stimuli with sedated patients are usually delivered with a strobe lamp (Fig. 7) or LED stimulators. Mesopic single flashes, oscillatory potentials and 30 Hz flicker can be used to evaluate retinal function.

It is difficult to completely darken the O.R. so abbreviated testing is accomplished under mesopic and photopic light conditions. Anesthesia affects the ERG varying with type and depth of anesthesia. Some anesthetics can attenuate b-wave amplitude as much as 50%. Light levels of anesthesia have little affect and most anesthetics do not affect a-waves or implicit times. Coordinate with anesthesiologists to attain a light level of anesthesia.

Separating rod and cone ERGs

Most disorders of the retina are detected by an attenuation of amplitude. Implicit times, of both a- and b-waves are also affected in some conditions. Implicit times and amplitudes vary depending upon whether the eye is dark adapted or not, and brightness and color of the light stimulus. These parameters allow separation of rod and cone activity in any duplex retina.

Rods and cones differ in number, peak color sensitivity, threshold and recovery. There are about 120 million rods in each retina and about 6-7 million cones (see Facts and Figures chapter). Because of sheer numbers, the ERG following a white flash is dominated by the mass response of the rods. By manipulating adaptation level and background illumination, flash intensity, color of the flash and rate of stimulation, rod and cone activity can be significantly isolated.

Using color stimuli

Peak wavelength sensitivity for rods is around 510 nm and the peak sensitivity of cones as a group is about 560 nm (Tennis ball yellow) (Fig. 9). By using color filters such as the Kodak Blue and Red Wratten series, or color flashes generated by LEDs (Figure 9a), you can isolate rod and cone ERGs using dim flash stimuli into photopic (cone)and scotopic (rod) signals as illustrated in Figure 9b. Dim red flashes stimulate both rod and cone function producing a small photopic component bx and larger rod b-wave. Rods are about three log units more sensitive than cones. However cones recover faster than rods.

Fig. 9a Filter conditions used to isolate rod and cone components of the ERG using dim scotopic flashes

 

Using different rates (flicker) of stimulus presentation also allows rod and cone contributions to the ERG to be separated. Even under ideal conditions rods cannot follow a flickering light up to 20 per second whereas cones can easily follow a 30 Hz flicker, which is the rate routinely used to test if a retina has good cone physiology (Fig. 9c).


Fig. 9b. Typical testing parameters used in our ERG recording set up

Fig. 9c. Typical 30 Hz flicker ERG recorded in our clinic

5. ERG recording methods.

 

There are many ways of recording ERGs from patients. I recommend reviewing ISCEV standards for recording ERGs (Marmor et al, 2009). Most procedures give similar results but vary mainly in sequence. Some laboratories record the light adapted state first and others dark-adapt first. Some laboratories use only white flashes and others included colored flashes. Many laboratories use a scotopic intensity series as well. Supplemental analysis such as Perlman’s (1983) relationship between the ratio of a- and b-wave amplitudes can be extracted from this intensity series. If only bright white flash stimuli are used subtle abnormalities will be missed.

Method at Moran Eye Center

1. Dark adapt patient for a set time of 30 minutes.

2. Attach electrodes using dim red illumination. We use an indirect headlamp with several Wratten 26 red filters so that it simulates a mobile dark room “safe” light.

3. Record ERG using single scotopically-balanced dim blue and red flashes, and bright white flashes as illustrated in sample ERGs of Figure 9b. Some laboratories average several responses.

4. Turn on moderately high background illumination of about 10 ftL for about 10 minutes and record ERGs using 30 Hertz flicker and bright white flashes (Fig. 9c). Responses recorded using moderately high background illumination accentuate the cone system by bleaching the rods and only cones can recover fast enough between flashes to accurately follow a flickering 30 Hertz light.

Recording scotopic ERGs

Thirty minutes or more in the dark produces a state of 98% dark adaptation in most individuals. Reducing flash intensity two or more log units and using deep blue color limit stimulation to the rods. “Scotopically balanced” blue and red flashes (Fig. 9b) mean that dim blue and red flashes with transmission spectra that do not overlap are matched through trial and error until the ERGs produce b-wave amplitudes of the same size (Fig. 9a). The purpose of this is to establish a standard so that differences between rod and cone physiology can be more easily detected. The scotopic dim blue ERG is most sensitive not only to rod disorders but also to systemic metabolic aberrations and retinal toxicity.

 

6. Oscillatory Potentials OPs.

Some laboratories also include recording oscillatory potentials. Oscillatory potentials (OPs) seen on the ascending limb of most b-waves in both scotopic and photopic bright flash ERG recordings were first described by Cobb and Morton (1954). By raising the low bandpass from the usual <1 Hz up to around 100 Hz the slower a- and b-wave components are filtered out leaving a burst of cone oscillatory potentials following a bright white flash between about 15 and 40 msec (Fig.10). Scotopic rod OPs produced by dim blue flash appear later between about 25 and 55 msec. Oscillatory potentials are thought to reflect activity initiated by amacrine cells in the inner retina (Wachtmeister and Dowling, 1978).

Fig. 10 Oscillatory potentials

This brings up an interesting clinical anecdote which also indicates the ERGs vulnerability to changes in retinal chemistry. Until recently for over 50 years the irrigating solution of choice when removing enlarged prostate glands was glycine. When the procedure took a long time or the surgeon cut deeply into the venous beds surrounding the prostate gland, an awake patient under spinal block anesthesia has said, “Why did you turn the lights off?” This can create considerable consternation among personnel in a brightly illuminated operating room. Glycine is an inhibitory transmitter in the retina particularly associated with amacrine cells. When the glycine reaches retinal circulation it short circuits the amacrine cell pathways in the retina and turns off the source of oscillatory potentials (Creel et al, 1987). Oscillatory potentials specifically disappear from the ascending limb of the b-wave. Oscillatory potentials and vision return to the patient over several hours as the glycine is metabolized (Fig. 11).

Fig. 11 Patient with glycine overload

Oscillatory potentials are significantly attenuated in various retinal degenerations amongst them are the following:

Retinitis pigmentosa

Central serous retinopathy

CSNB Type 2

Birdshot choroidopathy

Retinoschisis

Carriers of X-linked CSNB

Diabetic retinopathy

Hypertensive retinopathy

CRVO and CRAO

Takayasu’s (pulseless) disease

 

7. ERGs in retinitis pigmentosa-like diseases.

In all forms of retinal pathology there is considerable variability. There are no absolute rules. Genetic variation in penetrance and expression in combination with individual differences affects retinal electrophysiology.


Fig. 12a. Fundus photo of a normal human retina

Fig. 12b. Fundus photo of a patient with retinitis pigmentosa

 

ERGs recorded from a representative normal subject (Fig. 12a) and from a patient with retinitis pigmentosa (RP) (Fig. 12b) using the above methodology are illustrated in figure 13. The scotopic blue and red ERG traces are 200 milliseconds and the other traces are 100 milliseconds. The vertical calibration is 100 microvolts. The low bandpass limit was 0.1 Hz and the upper 1 KHz. When dim stimuli are used such as an intensity series starting with low intensity white or dim scotopic red and blue flashes it is important that the low bandpass be less than 1 Hz. The slow b-wave initiated by dim stimuli will be attenuated if a low bandpass is not used.

 

Fig. 13 ERG recordings in a normal patient and one with retinitis pigmentosa

The first two responses are scotopically matched blue and red ERGs. The blue flash was dim enough that no a-wave can be discerned in a normal patient leaving only the rod-dominated slower b-wave. The red flash is bright enough that photopic oscillations and bx component can be observed just after the a-wave (Fig. 13). The bx component appears in dim red scotopic ERGs at the time a photopic single flash b-wave would appear. Bright white flash in the dark produces the largest amplitude ERG. The 30 Hz flicker illustrates the response of the rapidly recovering cones, and the photopic response is representative of a normal response with the more sensitive rods bleached by background illumination. Oscillatory potentials on the ascending b-wave are seen in responses to moderate-high intensity white flashes and in response to red, yellow, and green flashes (Fig. 13).

This particular case of retinitis pigmentosa (RP) was selected because the individual was tested early in the onset of retinitis pigmentosa, as a young adult when she still had remnants of a cone ERG. As in most cases of retinitis pigmentosa, the rods are affected most severely as evidenced by the extinguished response to the blue flash. Although it may take some imagination, some of those “squiggles” in the first half of the response to red flashes are remnants of photopic cone physiology. There are also remnants of cone physiology in the responses to bright white flash in the dark, 30 Hz flicker and photopic white flash. In many individuals with RP the electrophysiological progression is more severe with all ERGs extinguished, similar in appearance to the response to scotopic dim blue flash. Both scotopic and photopic b-wave peak implicit times are usually prolonged. Almost always it is impossible to record oscillatory potentials.

Early in the clinical onset of RP, with the exception of severe expressions such as Leber’s congenital amaurosis or X-linked RP (Fig. 14), there are recordable ERGs at least to bright photopic stimuli. Some individuals with dominantly inherited RP maintain recordable ERGs throughout most of their lives. I have tested over 100 members of one extended family with dominantly inherited RP. Some of the affected members showed no usual ERG changes until their mid-teens. Expression of RP in all forms of inheritance varies considerably even between siblings. Female carriers of the X-linked form can show fundus changes and somewhat abnormal ERGs.


Fig. 14. Fundus photo of patient with carrier X-linked retinitis pigmentosa

Fig. 15. Fundus photo of a patient with paravenous retinitis pigmentosa

 

Atypical cases of RP are common. There are occasional cases of RP without the usual pigment changes in the fundus (retinitis pigmentosa sine pigmento). Often these cases represent early stages of the disease. Sector retinitis pigmentosa usually results in a subnormal ERG proportional to the area of retina involved. Paravenous retinitis pigmentosa (Fig. 15) is associated with a poor ERG most of the time but again, similar to sector RP, the ERG may be attenuated proportional to the extent of retinal involvement.

RP is seen as a component of a number of syndromes with variability in expression. A common syndrome is Usher’s. Usher’s syndrome is congenital deafness plus RP. Usher’s syndrome may comprise over 20% of RP cases not associated with other syndromes (Boughman and Fishman, 1983).

Myotonic dystrophy (MD) can show ocular changes similar to RP (Fig. 16). Even without fundus changes the ERG in MD patients is usually moderately affected like that seen in early dominantly inherited RP (Creel et al. 1985). It is interesting to note that minimally affected individuals without neurological symptoms usually have significant attenuation of their dim flash scotopic ERG b-wave amplitudes. Thus the ERG can be used to identify the minimally affected parent with MD (Fig. 16, the mother) in cases where neither parent of a child with myotonic dystrophy exhibits neurological symptoms.

 

Fig. 16 ERG of a family with a child with myotonic dystrophy

There are a number of central nervous system syndromes with RP-like ocular involvement. Prominent among these are the mucopolysaccharidoses such as the Hurler, Scheie and Hunter syndromes, which often have abnormal ERGs early in the disease. Another group is the neuronal ceroid lipofuscinoses such as Batten’s disease which have abnormal ERGs, usually attenuated b-waves.

There are syndromes that may include retinitis pigmentosa. The following list summarizes many of these syndromes:

Alagille syndrome: ERG normal or subnormal

Albers-Schonberg syndrome (osteopetrosis): ERG often abnormal

Alport’s syndrome: ERG normal or subnormal

Alstrom’s syndrome: ERG abnormal

Ataxia with isolated vitamin E deficiency (AVED) and RP: ERG abnormal

Bassen-Kornzweig syndrome (a-beta-lipoproteinemia): ERG abnormal

Cockayne’s syndrome: ERG often abnormal

Cystinosis: ERG abnormal in older children

Flynn-Ard syndrome: ERG sometimes abnormal

Friedreich’s ataxia: ERG sometimes abnormal

Hallervorden-Spatz syndrome: ERG often abnormal

Infantile phytanic acid storage disease: ERG usually abnormal

Jeune’s syndrome: ERG usually abnormal

Joubert’s syndrome: ERG abnormal

Kearn’s-Sayres syndrome: ERG some abnormal

Laurence-Moon-Bardet-Biedl syndrome: ERG usually abnormal

Methlmalonic aciduria with homocystinuria: ERG some abnormal

Mucopolysaccharidoses:Hurler; Scheie; Hunter: ERG often has b-wave attenuation

Myotonic dystrophy: ERG abnormal, dim scotopic ERGs

Neuronal ceroid lipofuscinosis:

Haltia-Sanavouri; Jansky-Bielschowsky; Batten’s: ERG often has b-wave attenuation

Neuropathy ataxia and retinitis pigmentosa (NARP): ERG abnormal

Refsum’s disease : ERG often abnormal

Saldino-Merzbacher syndrome: ERG usually abnormal

Senior-Loken syndrome: ERG usually abnormal

Spinocerebellar atrophy Type 7 (SPA7): ERG abnormal

Usher’s syndrome: ERG abnormal

Zellweger’s syndrome: ERG usually abnormal

In the differential diagnosis of retinitis pigmentosa there are a number of disorders in which the ERG can be used to distinguish the correct diagnosis. Pigment in the retina is prominent in many infectious diseases and may not solely be an indication of retinitis pigmentosa. Syphilis, particularly the congenital form, can mimic the fundus appearance of RP (Fig. 17 illustrates late-stage syphilis). In rubella and early stages of syphilis the ERG is usually normal or only slightly subnormal.


Fig. 17. Fundus photo of patient with syphilis

Fig. 18. Fundus photo of patient with rubella

 

Rubella and viral infections such as mumps, measles, and herpes can produce pigment changes in the retina (Fig. 18). These ERGs are usually normal.

Stationary rod dystrophies

Congenital stationary night blindness (CSNB) is found in several forms. Although rare, CSNB is more often seen in the form with a normal appearing retina and may be inherited in any fashion. Within this form are two types. Type 1 have an abnormal dim scotopic ERGs but the bright flash ERG maintains oscillatory potentials on the ascending limb of the b-wave. Type 2 (Fig. 19) has a very abnormal dim scotopic ERG and the bright flash scotopic ERG has a large a-wave and no b-wave (Fig. 20). Oscillatory potentials are also missing.


Fig. 19. Fundus photo of patient with CSNB Type 2

Fig. 20. ERGs in a patient with CSNB Type 2

 

CSNB with retinal lesions is quite rare. Oguchi’s disease is CSNB with an unusual golden to rust coloration of the fundus that is reversed with long dark adaptation. This is called Mizuo’s sign and requires 2-3 hours of dark adaptation. The ERG resembles CSNB Type 2 with no b-wave although cases have been reported that the ERG returns to normal after hours of dark adaptation. Another rare form of night blindness is stationary albipunctate degeneration also referred to as fundus albipunctata. This disorder includes stationary night blindness with white dots scattered throughout the fundus. The ERG b-wave is attenuated but returns to normal after long dark adaptation. A third form is Kandori’s syndrome characterized by large irregular hyperfluorescent flecks in the peripheral and central retina. In Nyctalopia the ERG is similarly affected as in stationary albipunctate degeneration.

Other retinal atrophies

The bright flash ERG b-wave is selectively attenuated in:

Juvenile retinoschisis

Coat’s disease

Central retinal vein occlusion and central retinal artery occlusion

Myotonic dystrophy

Congenital stationary night blindness Type 2

Oguchi’s disease

Lipopigment storage diseases (Batten’s disease)

Creutzfeldt-Jacob (CJD)

Choroideremia represents an X-linked diffuse atrophy of the choroid and pigment epithelium. In its mature form the fundus appearance is white to yellow-white with some small islands of choroid (Fig. 21). Carriers are asymptomatic except for more subtle peripheral fundus abnormalities (Fig. 22). ERGs are usually abnormal.


Fig. 21. Fundus photo of patient with Choroideremia

Fig. 22. Fundus photo of a patient with X-linked choroideremia carrier

 

Gyrate atrophy (Fig. 23) is a recessively inherited atrophy of the pigment epithelium and choroid caused by a deficient mitochondrial enzyme ornithine aminotransferase (OAT).

 

Fig. 23 Fundus photo of a patient with gyrate atrophy

Gyrate atrophy is less extensive than choroideremia and the fundus usually shows scalloped borders to degenerative areas (Fig. 23). ERGs are abnormal and progressly deteriorate according to the extent of degeneration of retinal pigment.

X-linked juvenile retinoschisis is a splitting or schisis in the central retina with a characteristic fundus appearance (Fig. 24). These patients have poor acuity. The ERG has a specific abnormality showing a normal a-wave but no b-wave. It is a negative ERG (Fig. 24). The picture is similar to that recorded in central retinal artery occlusion and Congenital Stationary Night Blindness Type 2. The splitting of the retina in retinoschisis can be seen in the OCT (Fig. 24a).

 

Fig. 24 Fundus photo and bright flash ERG of patient with retinoschisis

 

Fig24a

Fig. 24a Fundus photo of a patient with retinoschisis (above) and optical coherence tomography section of the same retina in the area of the green arrow (below). Notice the splitting of the retina at the inner nuclear layer

Patients with Creutzfeldt-Jakob disease (CJD) can also show selective loss of the b-wave (Katz et al. 2000) even in early stages. We have followed several patients with CJD that have shown unusual ERG waveforms. Similar in appearance to the ERGs of retinoschisis, the b-wave is greatly attenuated. In later stages the a-wave and oscillatory potentials are also affected. This pattern is seen in very few disorders, principally X-linked retinoschisis and congenital stationary night blindness type 2.

Except for some retinal dystrophies such as patients with severe retinitis pigmentosa or Leber’s congenital amaurosis, most retinal disorders produce reduced, “graded” amplitude attenuation of the ERG as we have seen in the above cases.

However, a few disorders result in a completely extinguished ERG. They include the following:

1) Leber’s congenital amaurosis

2) Severe retinitis pigmentosa

3) Retinal aplasia

4) Total detachment of retina

5) Ophthalmic artery occlusion

Leber’s congenital amaurosis unfortunately presents with significant visual loss in the first year after birth. The fundus usually has a salt and pepper appearance. The ERGs are usually unrecordable.

 

8. The ERG in cone dystrophies.

In contrast to retinitis pigmentosa, the ERGs of a patient with a cone dystrophy exhibit good rod b-waves that are just slower. However, the early “cone” portion (bx) of the scotopic red flash ERG is missing. The scotopic bright white ERG is fairly normal in appearance but with slow implicit times. The 30 Hz flicker and photopic white ERGs dependent upon cones are very poor. Cone dystrophies are inherited in all forms and include poor color vision and poor acuity. The most common fundus findings are a “bullseye” appearance or diffuse pigmentation in the macular area (Fig. 25). Many patients have nystagmus and photophobia. Cone-rod dystrophy appears to involve only cones early in the disease, later the ERGs usually show attenuated rod physiology. (Fig. 26).


Fig. 25. Fundus photo of patient with cone dystrophy

Fig. 26. ERGs in a patient with cone dystrophy

 

Other dystrophies are the flecked retina disorders, such as fundus flavimaculatus (Fig. 27) and Stargardt’s disease (Fig. 27b). The retinas display an abnormal accumulation of lipofuscin. Full-field ERGs in these disorders are normal except in very late stages where full-field ERGs may become slightly subnormal. Macular multifocal ERGs are dramatically abnormal.

Fig. 27 Fundus photo of patient with fundus flavimaculatus

Fig. 27b Fundus photo of patient with Stargardt’s disease

9. ERGs in retinal vascular disease.

Vascular occlusions such as central retinal artery thrombosis produce a characteristic avascular appearance to select areas of the fundus (Fig. 28a) and an ERG with no b-wave (Fig. 28b). Ophthalmic artery occlusions usually result in unrecordable ERGs.

Fig. 28a. Fundus photo of patient with central retinal artery occlusion
Fig. 28b. ERGs in a patient with central retinal artery occlusion

 

10. Foreign bodies and Trauma

The ERG is useful to assess cases of retinal foreign bodies and trauma to estimate the extent of retinal dysfunction. Foreign bodies affect retinal function depending on the extent of trauma to the retina, the location and composition of the object.

Fig. 29 Fundus photo of a patient with a hole in the retina caused by a metallic foreign body

A small piece of stainless steel or plastic outside the macula may have a minor affect on the retina. However a piece of copper or iron (Fig. 29) would likely have deleterious affects within a few weeks (Figs. 30a and 30b). In general if b-wave amplitudes are reduced 50% or greater compared to the fellow eye, it is unlikely that the retinal physiology will recover unless the foreign body is removed.


Fig. 30a. The effect of the foreign body on the ERG waveform

Fig. 30b. The effect of the foreign body on the ERG waveform some weeks later

 

The ERG can be used to estimate the extent of functional retina in cases of retinal detachment. An interesting case is shown in figures 31a and 31b. The patient had a small retinal detachment of the macular area in one eye (Fig. 31a, arrows point to circle of detachment). Viewing the retina using optical coherence tomography (OCT), which gives an optical image like a vertical section plane, the detached portion of the retina in the foveal and macular area can be clearly seen in comparison to the normal attached macular area in the fellow eye. In general ERG b-wave amplitudes correspond to the amount of attached healthy retina, although the detached retina may function for some time.


Fig. 31a. Fundus photo of a patient with a retinal detachment at the fovea and macula in one eye
DONFig31bFig. 31b. Optical coherence tomography (OCT) images of the patient’s normal macula and of the retina in the other eye with the macular detachment

 

11. Drug toxicities.

Several drugs taken in high doses or for long periods of time can cause retinal degeneration with pigmentary changes. Culprits include thioridazine (Mellaril; Novartis, withdrawn from market worldwide 2005), chlorpromazine (Thorazine; GlaxoSmithKline, and generic formulations), Vigabatrin (aka gamma-vinyl-GABA: Sabril; Lundbeck, and generic formulations), and chloroquine and hydroxychloroquine (Plaquenil; Sanofi, and generic formulations).

The effects of toxic medications can be detected and quantified using ERGs. Which type of ERG to apply depends on the mechanism and site of retinal toxicity.

Chloroquine retinopathy appears as a characteristic “bullseye” maculopathy (Fig. 32). The full-field ERGs may become abnormal in these cases (Fig. 33). The better substitute for chloroquine, Plaquenil, can also have macular effects noticeable by multifocal electroretinograms (see later section on mfERGs).

To detect chloroquine toxicity, the American Academy of Ophthalmology recommends performing fundus examinations, 10-2 automated visual fields, and at least one objective test: multifocal electroretinography, fundus autofluorescence imaging, or spectral-domain optical coherence tomography (SD-OCT) (Marmor et al., 2011). By contrast, Amsler grid testing, color vision testing, fluorescein angiography, full-field ERG, and electro-oculogram are not considered to be helpful (Michaelides et al., 2011; Costedoat-Chalumeau, et al., 2012).

The American Academy of Ophthalmology guidelines recommend a baseline examination for patients starting these drugs to serve as a reference point; and to rule out maculopathy an annual screening after 5 years of use unless there is suspicion of toxicity or presence of unusual risk factors. I recommend obtaining a screening mfERG within 4 to 6 months of starting medication to detect patients susceptible to toxicity, such as the patient’s mfERGs illustrated on left side of Figure 48. Consider that elderly patients can be more susceptible to toxicity, as can those with kidney or liver disease, and those with retinal disease.

Vigabatrin, a pediatric seizure medication, can be toxic to the retina. Attenuation of full-field ERG b-wave amplitudes can detect toxicity. Often the first indication of toxicity is reduced amplitude to 30 Hz flicker following.


Fig. 32. Fundus photo of patient with chloroquine retinopathy

Fig. 33. ERGs in a patient with chloroquine retinopathy

 

Hydroxychloroquine (Plaquenil) is usually less disruptive to the retina than chloroquine, but ERG changes can still occur. Other drugs can end up being accidentally toxic to the retina. Cis-platinum used to treat brain tumors sometimes reaches ophthalmic vascularization (Fig. 34) and causes a reduction in ERG waveform in the affected eye (OD in this case) (Fig. 35).

Fig. 34 Fundus photo of patient with OD cis-platinum toxicity

Fig. 35 ERGs in a patient with OD cis-platinum toxicity

An interesting case was seen in our clinic, where an intranasal steroid injection affected the retina of the patient’s right eye (OD) only. The fundus photo shows a cherry red spot in the macula (Fig. 36). The ERG response was diminished in size particularly following dim scotopic flashes (Fig. 37).


Fig. 36. Fundus photo of patient with steroid retinopathy

Fig. 37. ERGs in a patient with steroid retinopathy

 

Talc retinopathy is also seen occasionally (Fig. 38). Again the global ERG is attenuated in such cases (Fig. 39).


Fig. 38. Fundus photo of patient with talc retinopathy

Fig. 39. ERGs in a patient with talc retinopathy

 

12. Systemic disorders and the ERG.

Systemic metabolic disorders are reflected in retinal physiology. Liver and kidney disease and drugs that affect those organ systems, usually reduce ERG b-wave amplitudes, particularly in scotopic dim flash ERGs. For example, deferoxamine, an iron chelating drug used to reduce iron overload, can be toxic to the retina. This is reflected in reduced a- and b-waves of the ERG (Fig. 40).

Fig. 40. Deferoxamine toxity affects on the ERG

The estrogen antagonist Tamoxifen is primarily used in the management of metastatic breast adenocarcinoma. Toxicity in the form of retinal crystals may be asymptomatic or may cause mild central visual impairment along with dyschromatopsia. These latter visual symptoms generally occur secondary to development of cystoid macular edema (CME). Both full-field and multifocal ERGs suggest Tamoxifen is rarely toxic at low dose levels. Canthaxanthin is a carotenoid pigment used in vitiligo and photosensitivity disorders. Ocular abnormalities are rarely seen when canthaxanthin is used to treat these conditions. Toxicity is characterized by an asymptomatic ring of yellow-orange crystals in the macular region. Minor ERG changes have been reported but few long lasting visual effects.

An 80-year-old male experienced drop in acuity from 20/25 to 20/50 and poor night vision coincident with successful cataract removal and intraocular lens implantation. Ocular fundus exam was normal. The electroretinograms shown in Figure 40a reminded me of a past patient with failing liver and reduced small bowel. Further medical history revealed mystery patient has 130 cm of small bowel remaining, and coincidentally had stopped taking daily multiple vitamins. Patient Vitamin A level was 0.13 mg/L. After 30 days Vitamin A supplementation his ERGs returned to near normal for age (Fig. 40b) and acuity improved to 20/30.  Full-field ERGs especially the scotopic dim blue and red flash ERGs often reflect general metabolic health.

40a

Fig. 40a. Full-field electroretinograms (ERGs) recorded from 80 year old male with minimal small intestine.

40b

Fig. 40b. Full-field electroretinograms (ERGs) recorded from 80 year old male after 30 days Vitamin A supplementation.

Click here to download Quicktime movie (287MB) with Chinese subtitles on how to record multifocal electroretinograms (mfERG)

 

13. The multifocal ERG (mfERG).

A limitation of the traditional global or full-field ERG is that the recording is a massed potential from the whole retina. Unless 20% or more of the retina is affected with a diseased state the ERGs are usually normal. In other words a legally blind person with macular degeneration, enlarged blind spot or other small central scotomas will have a normal full-field ERG.

The most important development in ERGs is the multifocal ERG (mfERG). Erich Sutter adapted the mathematical sequences called binary m-sequences creating a program that can extract hundreds of focal ERGs from a single electrical signal. This system allows assessment of ERG activity in small areas of retina. With this method one can record mfERGs from hundreds of retinal areas in a several minutes (Sutter, 2010). ERG electrodes are used to record ERGs from the cornea from a dilated eye. Small scotomas in retina can be mapped and degree of retinal dysfunction quantified.

Below are the mfERGs of a patients tested at the Moran Eye Center. The first patient was an elderly woman with early macular degeneration. Figure 41 is the fundus photograph. In Figure 42 are 103 multifocal ERGs from approximately the central 40 degrees of retinal field. Figure 43 are the b-wave voltages from a patient with more severe expression of macular degeneration transformed into a color plot. Figure. 43 (lower right) shows a color plot of a normal person for comparison. The top color transformation is the difference between the patient’s multifocal ERGs and a normal group, which points out the worst areas of retinal function. Colors reflect standard deviations (S.D.) from average ERG amplitudes. These plots can be rotated from 3-D to 2-D so that they resemble visual field plots.



Fig. 41. Fundus photograph of a patient with age related macular degeneration

Fig. 42. Multifocal ERG recordings in a patient with early age related macular degeneration (AMD)
Fig. 43. Multifocal ERG recordings transformed into color maps of the macular area in a patient with AMD compared to a normal patient

 

One of the best uses of mfERGs is for distinguishing between retinal and central etiology of visual problems in patients with no apparent abnormalities in the ocular fundus.  These types of patients can include MEWDS (Multiple Evanescent White Dot Syndrome) and AZOOR (acute zonal occult outer retinopathy).  Figure 44 is example of 17-year-old male diagnosed with AZOOR associated with a viral prodrome.  The mfERGs are clearly showing the retinal abnormalities coincident with the visual field losses (Fig. 44).  In contrast, the only visible fundus abnormalities were small, easily overlooked pinpoint hyperfluorescent lesions in Indocyanine Green Chorioangiography (ICG).

 



Fig. 44. Multifocal ERGs (yellow) superimposed on Humphrey 24-2 visual field plot of the right eye in a patient with acute zonal occult outer retina.  mfERG abnormalities match the visual field loss very well

 

Most mfERG analyses are based on amplitude of the mathematical approximation of the “b-wave”. Implicit times can sometimes better describe progression of retinal diseases. An example is in retinal degeneration called birdshot retinochoroidopathy. Birdshot retinochoroidopathy is an uncommon disease usually seen in Caucasian females of northern European descent past the fourth decade of life (Vitale, 2013). Funduscopy reveals characteristic multifocal, hypopigmented, ovoid, cream-colored lesions (50-1500 µm) at the level of the choroid and RPE in the postequatorial fundus (Fig. 45, a). Typically lesions show a nasal and radial distribution, emanating from the optic nerve, and frequently they follow the underlying choroidal vessels (Fig. 45, a).

Fig. 45. Birdshot retinochoroidopathy. a) Fundoscopy reveals characteristic multifocal hypopigmented, ovoid, cream colored lesions at the level of the choroids and RPE in the fundus. b) Indocyanine green (ICG) angiography reveals multiple non-fluorescent spots corresponding with the birdshot lesions

Indocyanine green (ICG) angiography reveals multiple hypofluorescent spots corresponding with birdshot lesions (Figs. 45, b). Full-field ERGs usually show characteristic 30 HZ flicker attenuation and prolonged photopic b-wave and 30 Hz implicit times. Full-field scotopic-b wave amplitudes are useful parameter to quantify general severity of expression. Multifocal ERG implicit times map the distribution of slow implicit times across the retina (Fig. 46). Normal “b-wave” implicit times are about 30 milliseconds. Sequential mfERGs performed over period of several years show progression across the retina. Both photos and mfERG implicit times in Figures 45 and 46 are from the left eye of the same patient.

Fig. 46 Birdshot retinopathy. Multifocal ERG implicit times map the distribution of slow implicit times across the retina

A small number of medications can be toxic to the retina. Effects of toxic medications can be detected and quantified using electroretinography. Which type of electroretinogram to use depends on mechanism and site of retinal toxicity. Abnormalities associated with toxic drugs may be detected using appropriate electroretinographic stimuli. Choosing the appropriate visual stimuli will maximize detection of toxic effects. Quantifying retinal drug toxicity using multi-focal electroretinograms is a strong point of mfERGs.

Antimalarials chloroquine, a 4-aminoquinoline, and Plaquenil, hydroxychloroquine, which is also used to treat discoid or systemic lupus erythematosus and rheumatoid arthritis, dermatological disorders, and Sjogren’s syndrome can be toxic to the retina producing ring scotomas. Multifocal ERGs better quantify retinal toxicity than full-field ERGs. Below are mfERGs of several patients with Plaquenil toxicity. Plaquenil first affects small areas between 5-15 degrees from fovea eventually progressing to produce a ring scotoma.(Figs. 47 and 48).

 

 

Fig-47DonPlaquenil

Fig. 47. Autofluorescence of the macula area of a patient who has received Plaquenil treatment for years. Note the area of ring scotoma at the macula

Fig. 48. Amplitudes of mfERGs of two patients showing Planquenil toxicity displayed as a color scale. Patient with more severe expression on left shows evidence of a macular ring scotoma. The patient on right shows early areas of retinal toxicity

 

Ethambutol used to treat tuberculosis, and Navane a psychotropic agent can also produce macular toxicity detectable by mfERGs. Central macular mfERGs may be attenuated in amplitude.

I mentioned earlier in the full-field ERG section that flecked retina disorders, such as fundus flavimaculatus and Stargardt’s disease (Fig. 27b) show few ERG anomalies. However, mfERGs show significant central loss in patients with Stargardt’s disease (Fig. 49).

Fig. 49. Multifocal ERG recordings in a patient with Stargart’s disease

14. The Electrooculogram EOG.

The electrooculogram measures the potential that exists between the cornea and Bruch’s membrane at the back of the eye. The potential produces a dipole field with the cornea approximately 5 millivolts positive compared to the back of the eye, in a normally illuminated room. Although the origin of the EOG is the pigment epithelium of the retina, the light rise of the potential requires both a normal pigment epithelium and normal mid-retinal function. Elwin Marg described and named the electrooculogram in 1951 and Geoffrey Arden (Arden et al. 1962) developed the first clinical application. With the cornea constantly positive, movement of the eye produces a shift of this electrical potential. By attaching skin electrodes on both sides of an an eye (Fig. 50) the potential can be measured by having the subject move his or her eyes horizontally a set distance (Fig. 51). The eyes are usually dilated. Skin electrodes are attached near the lateral and medial canthus of each eye (Fig. 50). A ground electrode is attached usually to either the forehead or earlobe. It is helpful that the patient have a chin rest to reduce head movement. Usually inside a Ganzfeld, or on a screen in front of the patient, small red fixation lights are place 30 degrees apart (Fig. 52). The distance the lights are separated is not critical for routine testing. Any set distance subtending from 20-40 degrees of visual angle is satisfactory.

Fig. 50. Placement of the electrodes for recording an EOG
Fig. 51. How the EOG potential is measured as the eyes turn towards and away from the skin electrodes

 

The patient should be light adapted such as in an well-illuminated room, and eyes dilated. After the electrodes are attached the procedure is explained and the patient asked to practice several times while baseline data are recorded. The procedure is simple. The patient keeps his or her head still while moving the eyes back and forth alternating between the two red lights. The movement of the eyes produces a voltage swing of approximately 5 millivolts between the electrodes on each side of the eye, which is charted on graph paper or stored in the memory of a computer.

Fig. 52. Ganzfeld used for stimulating the EOG waveform

Below are 10-second periods of eye movement back and forth between two red LED lights placed 30 degrees apart inside a Ganzfeld (Fig. 53).

Fig. 53. Light adapted pre-EOG, dark adaption phase and light-rise phase

After training the patient in the eye movements, the lights are turned off. About every minute a sample of eye movement is taken as the patient is asked to look back and forth between the two lights (Fig. 52). Some laboratories have the patients move their eyes the entire testing period. After 15 minutes the lights are turned on and the patient is again asked about once a minute to move his or her eyes back and forth for about 10 seconds. Figure 53 shows segments of eye movement that have been cut from 10 second samples from a normal person. The chart (Fig. 54) graphs the change in voltage in the eye through 15 minutes of dark adaptation and 15 minutes of bright light. Typically the voltage becomes a little smaller in the dark reaching its lowest potential after about 8-12 minutes, the so-called “dark trough.” When the lights are turned on the potential rises, the light rise, reaching its peak in about 10 minutes. When the size of the “light peak” is compared to the “dark trough” the relative size should be about 2:1 or greater (Fig. 54). A light/dark ratio of less than about 1.7 is considered abnormal. Figure 55 shows an abnormal response recorded from a patient with Best’s disease.

Fig. 54. Normal EOG recording Fig. 55. EOG from a patient with Best’s disease

 

Retinal diseases producing an abnormal EOG will usually have an abnormal ERG too which is the better test for analysis of scotopic and photopic measures. However, a particularly good use for the EOG is in following the affects of high dosage treatment with antimalarials such as chloroquine and plaquenil over the course of treatment and before the ERG is affected (Arden, Friedman and Kolb, 1962). The most common use of the EOG nowadays is to confirm Best’s disease. Best’s vitelliform macular dystrophy and variants of this disease are usually identified by the appearance of a retinal lesion resembling an egg yolk early in the disease (Fig. 56). There is considerable variation in the fundus appearance in Best’s disease.

 

 


Fig. 56. Fundus photo in Best’s Disease
Fig.57DonVitellFig. 57. Fundus in adult vitelliform dystrophy

 

Vitelliform lesions represent the accumulation of lipofuscin in the macular area. Further effects of retinal pigment epithelium (RPE) dysfunction include accumulation of degenerated photoreceptor outer segments in the subretinal space. Using autofluorescence imaging (AF) the subretinal accumulation is seen as hyperautofluorescent, suggesting that the material is composed of retinoid fluorophores such as photoreceptor outer segment debris.

 

Fig. 58 shows the progression of adult vitelliform macular dystrophy (AVMD) in a 50-year-old female. Images are a series of ocular coherence tomograhic pictures. During the initial stage, similar to the first OCT dated August 25, 2011 is when the ocular fundus may have “sunny-side-up” egg yolk appearance. In later stages the lipofuscin disperses resulting in “scrambled egg” appearance with mottled pigmentation and RPE atrophy.

Fig. 58 shows the progression of adult vitelliform macular dystrophy (AVMD) in a 50-year-old female. During the initial stage similar to the first OCT dated August 25, 2011, is when the ocular fundus may have a “sunny-side-up” egg yolk appearance. In later stages the lipofuscin disperses resulting in a “scrambled egg” appearance with mottled pigmentation and RPE atrophy. In Best’s disease and in some with AVMD, a dysfunction of bestrophin results in abnormal fluid and ion transport by the retinal pigment epithelium (RPE). Bestrophins are a family of proteins that can function both as Cl(-) channels and as regulators of voltage-gated Ca(2+) channels. It is proposed that dysfunction of bestrophin results in abnormal fluid and ion transport by the RPE and this results in a weakened interface between the retinal pigment epithelium and photoreceptors. Human bestrophin-1 (hBest1), located on human chromosome 11q13, was identified as the VMD2 gene responsible for a dominantly inherited juvenile-onset form called Best’s vitelliform macular dystrophy. Mutations in hBest1 have also been associated with a small fraction of adult-onset vitelliform macular dystrophies (Hartzell et al., 2008). The inheritance pattern of adult-onset vitelliform macular dystrophy is uncertain. The appearance of the ocular fundus and progression of accumulation of lipofuscin within the RPE and sub-RPE space in the foveal area in adult vitelliform macular dystrophy can appear similar to Best disease. AVMD can be differentiated from Best’s disease based on clinical appearance, age of onset, and using OCT, autofluorescence imaging and electro-oculograms.

 

 

15. References.

Arden GB, Barrada A, Kelsy JH. New clinical test of retinal function based on the standing potential of the eye. Br J Ophthalmol. 1962;46:449–467.[PubMed]

Arden, GB, Friedman, A. and Kolb. H. (1962) Anticipation of chloroquine retinopathy. The Lancet, June 2, pp 1164-1165.

Boughman JA, Fishman GA. A genetic analysis of retinitis pigmentosa. Br J Ophthalmol. 1983;67:449–454. [PubMed] [Free Full text in PMC]

Creel DJ, Crandall AS, Ziter FA. Identification of minimal expression of myotonic dystrophy using electroretinography. Electroencephalogr Clin Neurophysiol.1985;61:229–235. [PubMed]

Creel DJ, Wang JM, Wong KC. Transient blindness associated with transurethral resection of the prostate. Arch Ophthalmol. 1987;105:1537–1539.[PubMed]

Cobb WA, Morton HB. A new component of the human electroretinogram. J Physiol. 1954;123:36P–37P.

Costedoat-Chalumeau N, Ingster-Moati I, Leroux G, et al. Critical review of the new recommendations on screening for hydroxychloroquine retinopathy [in French]. Rev Med Interne. 2012;33(5):265-267. [PubMed]

Granit R. The components of the retinal action potential in mammals and their relation to the discharge in the optic nerve. J Physiol. 1933;77:207–239.[PubMed]

Hartzell HC, Zhiqiang Q, Kuai Y, Xiao Q, and Chien LT (2008) Molecular physiology of bestrophins: multifunctional membrane proteins linked to Best Disease and other retinopathies. Physiol. Rev. 88: 639-672. [PubMed]

Holmgren F. Metod att objektivera effektenav ljusintryck pa retina. Upsala lakaref Forhandl. 1865;1:177–191.

Hood DC, Bach M, Brigell M, et al; International Society For Clinical Electrophysiology of Vision. ISCEV standard for clinical multifocal electroretinography (mfERG). Doc Ophthalmol. 2012;124(1):1-13. [PubMed]

Katz BJ, Warner JEA, Digre KB, Creel DJ. Selective loss of the electroretinogram b-wave in a patient with Creutzfeldt-Jakob disease. J Neuroophthalmol.2000;20:116–118. [PubMed]

Lawwill T, Burian HM. A modification of the Burian-Allen contact-lens electrode for human electroretinography. Am J Ophthalmol. 1966;61:1506–1509.[PubMed]

Marg E. Development of electro-oculography; standing potential of the eye in registration of eye movement. AMA Arch Ophthalmol. 1951;45:169–185.[PubMed]

Marmor MF, Brigell MG, McCulloch DL, Westall CA, Bach M; International Society for Clinical Electrophysiology of Vision. ISCEV standard for clinical electro-oculography (2010 update). Doc Ophthalmol. 2011 Feb;122(1):1-7. doi:10.1007/s10633-011-9259-0. Epub 2011 Feb 5. PubMed PMID: 21298321. [PubMed]

Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M; International Society for Clinical Electrophysiology of Vision. ISCEV Standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol. 2009 Feb;118(1):69-77. doi: 10.1007/s10633-008-9155-4. Epub 2008 Nov 22. PubMed PMID: 19030905. [PubMed]

Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):415-422. [PubMed]

Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol. 2011;129(1):30-39. [PubMed]

Miller RF, Dowling JE. Intracellular responses of the Muller (glial) cells of mudpuppy retina: their relation to the b-wave of the electroretinogram. J Neurophysiol. 1970;33:323–341. [PubMed]

Perlman I. Relationship between the amplitudes of the b wave and the a wave as a useful index for evaluating the electroretinogram. Br J Ophthalmol.1983;67:443–448. [PubMed] [Free Full text in PMC]

Sutter E E Noninvasive Testing Methods: Multifocal Electrophysiology. In: Darlene A. Dartt, editor. Encyclopedia of the Eye, Vol 3. Oxford: Academic Press; 2010. pp. 142-160.

Vitale AT. Birdshot chorioretinopathy. In: Foster CS, Vitale AT, editors. Diagnosis and Treatment of Uveitis, 2nd Ed., New Delhi: Jaypee Brothers Medical Publishers Ltd, 2013. p. 982-1005.

Wachtmeister L, Dowling JE. The oscillatory potentials of the mudpuppy retina. Invest Ophthalmol Vis Sci. 1978;17:1176–1188. [PubMed]

Weleber RG. The effect of age on human cone and rod ganzfeld electroretinograms. Invest Ophthalmol Vis Sci. 1981;20:392–399. [PubMed]

 

Acknowledgements: I thank John A. Moran Eye Center Imaging for the photographs in this chapter, especially James Gilman for contributing images from his library.

 Updated September 4th, 2014

The author

Dr. Donnell J. Creel was born in Kansas City, Missouri. He received his B.A and M.A. from the University of Missouri at Kansas City, and his Ph.D. from the University of Utah in 1969. In 1971 Don first made the connection that visual anomalies in Siamese cats was associated with albinism and hypothesized that all albino mammals likely have optic misrouting, and published first visual evoked potential studies in human albinos in 1974 and ocular albinos in 1978.  Don has been the Director of Clinical Electrophysiology at the Moran Eye Center since its inception in 1993. e-mail Don at donnell.creel@hsc.utah.edu

Comment Feed

66 Responses

  1. Hello, great article – just a small point. Fig 47 looks like an autofluorescence image rather than an FFA.

    Matthew RichardsonSeptember 16, 2011 @ 11:12 amReply
  2. Hi, I am as a DVM and resident of small animal surgery in Iran going to run ERG for pets here for the first time and this is so useful for me. It gives me great pleasure if Dr. Creel contact me for further information.

    Roozbeh MordipourSeptember 25, 2011 @ 1:49 pmReply
  3. thank you very much for such valuable information which are straight concise and clinical to a great extent. it is not common to find such info on Electrophysiological eye tests on line.
    thanks

    osama giasinOctober 8, 2011 @ 7:36 amReply
  4. Just had ERG testing and all results came back “flat”. No retinal response at all. I do have ok central vision but no useful peripheral. I did not see in the article this type of ERG response. Do you have any insight on this?

    • Hey Sandy,

      I’ve gotta reply with the standard disclaimer for the site here: “information on Webvision should be considered as research appropriate and not be construed as clinically relevant, or medical advice. Information provided here is informational only. Medically related questions should be addressed with your health care providers.”. Its hard to give any feedback on this without seeing the data and this is not really a forum for that anyhow. My guess though is that if you have vision in the central part of your retina, then there will be an ERG response and they either missed it or did not measure retinal response from the middle of the retina.

  5. I suggest you see an ophthalmologist that is a retinal specialist in your area.

    Don

    Don CreelMarch 12, 2012 @ 12:00 pmReply
  6. Thank you so much Dr. Creel, ur page really helped me with my lab report.

    Hope you keep updating your page.

  7. Hi Sir,

    What could you share in regard to GA atrophy?

    Thanks,
    Mehdi

  8. Dr Creel
    i am a retinal specialist in NY . Is it possible to have an extinguished MFERG for about 10- 15 degrees in central serous retinoapthy due to a serous RD documented on OCT. The RP defect is minimal. . No other findings.patient says he is bare CF. I think he has objectively about 20/100. this is a disablity case. also can you predict the vision with these findings of an extinguished MFERG for only 10 – 15 degrees and only in his right eye?. Is the serous RD enough to cause it ?> can amblyopia cause it ?He has had it for 2 years. are you able to get an accurate MFERG with CF vision or would the patient need better vision . Ypir prompt response would be appreciated since i maseeing him Monday . Thankyou
    Robert Berg MD ,

  9. Dr. Creel thank you for your work! It is valuable for maintaining sight!

    marcia kilpatrickMay 26, 2012 @ 7:36 pmReply
  10. I am looking for a good ERG book, any suggestions?

    ChristeneJune 20, 2012 @ 8:18 amReply
  11. Christene-

    The Academy of Ophthalmology has a book on Electrophysiology, and there is the Basic Clinical Sciences series that ophthalmology residents study, also published by the “Academy”, which includes electrophysiology.

    The 2 ISCEV articles re International Standards for ERGs (Marmor et al. 2009) and mfERGs (Hood et al. 2011) are good.

    Books by David Martin Regan are comprehensive but from a physicist’s point of view.

    Don CreelJune 21, 2012 @ 5:52 pmReply
  12. I’m from Saudi Arabia
    I have a son, now age three and half years old and another son and a half years with the disease in the retina
    This scheme retina

    1-ERG-VEP
    VEP > Definite responses with obvious latency

    ERG > normal rod responses.

    moderately diminished cone and flicker

    CONCLUSION > cone dysfunction for clinical correlation

    Are Amkaah in treatment?Are Amkaah in treatment?

    wseem55@hotmail.com

    alsaherJuly 28, 2012 @ 5:17 pmReply
  13. I had a 6-months old daughter with roving eye movement, poor vision noted and FVEP showed p100 145 ms; ERG revealed flat response all, is there any possibility to technician artificial error? No family Hx of poor vision.

  14. Dr. Creel thank you for this excellent very clear discussion. With your permission will share with my ophthalmology residents.

    Marybeth Grazko MDOctober 6, 2012 @ 10:18 amReply
  15. My now 10 months old son was diagnosed at 5 months with LCA based on an absent ERG test. His vision at the time seemed somewhat less than it should have been at that age and he also has nystagmus. However, his vision has been improving and he is now able to see small items in front of him (including very small bread crumbles). He does seem to be near sighted and this was confirmed by our ophtalmologist. The machine used to determine his nearsightedness showed a myopia of at least -5. His fundus seems normal at this stage. We did genetic testing and 18 of the LCA genes that were tested came back negative. My question is regarding his ERG: could it be that due to his high myopia his ERG was absent? I should also mention that there is a family history of high myopia (maternal uncle).
    Thank you very much for your time.

  16. High myopia can be associated with abnormal ERGs, BUT NOT absent ERG. Leber’s congenital amaurosis is usually associated with absent ERG.
    Your son’s visual behavior is encouraging. There is significant variation in expression of all genetic disorders. You will be the first to know your child’s visual abilities. Re appearance of fundus, 10 months is young for fundus changes. Ocular fundus changes usually begin with subtle mottled appearance of pigment in peripheral retina.

    Donnell CreelDecember 6, 2012 @ 8:12 amReply
  17. Thank you very much for your reply. How possible it is for a technical error to occur during an ERG test?also is it difficult to interpret? I suppose I am
    still hoping that it is actually not LCA and that an error could have occured in view of the negative genetic testing and my son’s current visual behaviour…I forgot to mention that his nystagmus has also significantly decreased and that he does not have any of the other symptoms of LCA i.e.: eye rubbing/poking, photophobia and he is otherwise developing normally (even above average) from a neurodevelopmental perspective…walking held by one hand since the age of 8.5 months, also displays very good co ordination skills for his current age. Thank you

  18. As I mentioned there is considerable variation in expression of ocular disorders. Maybe your son got lucky.

    It is impossible for me to judge quality of the ERG recording, but as I tell patients, electrophysiology is not rocket science.

    Nystagmus often dampens as visual system matures.

    Donnell CreelDecember 6, 2012 @ 1:14 pmReply
  19. Thank you very much for your time and patience.

    Kind regards,

    Michelle

  20. hi thanks, it was really comprehensive.
    may i ask you to help me about the electrical circuit of retinogram if you have it?i will appreciate you if you send for me its circuit.i couldn’t find it on internet.
    thanks in advance

  21. My son is now 3.5 years old. His VA is about 20/100. He developed nystagmus since he was 7 weeks old. He has normal development and no obvious photophobia. The ERG(skin electrode) result showed marked decrease cone response and subnormal rod response,from less than 30 minutes dark adaptation. His doctor said the differential diagnosis are achromatopsia, blue cone monochromatism and cone-rod dystrophy. We have to repeat ERG again. I’m quite concern for cone-rod dystrophy because it can progress, but the doctor said the onset of cone-rod dystrophy is usually about 7-8 yrs old. What do you think about this clinical setting and onset? Is it possible that the subnormal rod response come from not enough dark adapted time?
    Thank you so much.

  22. It is possible that decreased rod ERG is due to insufficient dark adaptation, but most people are fairly well dark adapted in 20-30 minutes. On the up side, sometimes the rod dysfunction does not progress to extent of cone dysfunction. All the cone/rod, cone, rod/cone dystrophies vary extensively in both expression and underlying genetic mutations.

    Donnell CreelDecember 11, 2012 @ 1:53 pmReply
  23. Hi again Dr Creel,

    I was asking in December about my son`s absent ERG at 5 months old. He had a repeat ERG at 12 months which showed normal scotopic responses and abnormal?absent fotopic responses. I am now very confused as I am being told that the diagnosis is not LCA but cone dystrophy. May I please ask your opinion on the ERG? Is it possible to have an absent erg for both scotopic and fotopic responses and to then have a normal scotopic response? Thank you, Michelle

  24. Sorry I forgot to mention that his vision has continued to improve since December . He has a myopia of -3 at the moment.

    Michelle

  25. If you record no ERG in scotopic (dark) condition, then get a recordable scotopic ERG later usually something was wrong 1st recording. There is very remote chance that at 5 months the rod system was not developed enough, but so remote I have never seen it.

    The good news is he now has scotopic (rod) ERGs. Cone dystrophies can be expressed as either a pure cone dystrophy or a cone-rod dystrophy with variable degree of rod dysfunction. The rod dysfunction can develop at a later time.

    His acuity can be estimated with a test called a Teller Acuity Test, which you can “Google” to see what is involved.

    Donnell CreelFebruary 25, 2013 @ 12:50 pmReply
  26. Thank you for your answer. The acuity was tested and it eas 20/200-20/300 not corrected (myopia of -3). My hope is that glasses can improve that to some extent. Have you ever seen improvement in photopic responses on the ERG over time or that would be too hopeful? thank you

  27. Dr. Creel.

    I am a student studying and conducting research into sensory homogenised conditions such as the ganzfeld effects of sensory flooding and flicker light induced experiments using EEG. I have found this page particularly useful in building my knowledge and understanding of ERG and its clinical implications as well as relating the information provided here for my project to further theorise and hypothesise the top down and bottom up processing models of sensory input to the cortical areas of the striate, primary visual cortical layers such as the higher processing units (V1-V5 and LGN). Many thanks and Best wishes!

  28. Thank you for your support. If questions arise please email.

    Don Creel

    Don CreelMarch 14, 2013 @ 9:08 pmReply
  29. Dear Dr. Creel,
    how does Pattern Electroretinogram (perg) differ in testing than ERG test

    Charles PritchardApril 11, 2013 @ 8:23 amReply
  30. Pattern ERGs stimulate localized areas of the retina with patterns instead of a global flash, which makes them great for mapping local dysfunction in retina such as macular degeneration, enlarged blind spot, and mapping scotomas. However, pattern ERGs are not as informative when a “whole retina” disorder is involved such as retinitis pigmentosa or a cone-rod, or cone dystrophy.

    Donnell CreelApril 12, 2013 @ 8:38 amReply
  31. Hi,thank you very much for this article.could you send me a raw data of eog signal(with right and left movements)?
    thank you

  32. Thank you so much for this very interesting and useful article. It had just the right amount of technical language. I work as a research assistant and I needed some background on ERG – this filled me in perfectly.

    Danielle MasurskyJune 11, 2013 @ 8:53 amReply
  33. Very important information is given by this article and it has helped me a lot for the preparation of my Seminar on the topic EOG.
    Thank u very much…!!!
    -Sushant Nakod,
    Final yr BE student,
    SSGM college of engg.,
    Shegaon, maharastra, India.

    Sushant NakodSeptember 4, 2013 @ 2:00 pmReply
  34. Hi, I found your article to be very enlightening.Could I have person to use some of your images in my dissertation for a communication system I am developing for an mfERG.
    Medical Electronics student

    Faith MansonOctober 31, 2013 @ 3:30 amReply
    • Faith, please see the About/FAQ page: http://webvision.med.utah.edu/aboutfaq/

      Q: Can I use images and/or content from Webvision? What is the copyright? A: All copyright for chapters belongs to the individual authors who created them. However, for non-commercial, academic purposes, images and content from the chapters portion of Webvision may be used with a non-exclusive rights under a Attribution, Noncommercial, No Derivative Works Creative Commons license. Cite Webvision, http://webvision.med.utah.edu/ as the source. Commercial applications need to obtain license permission from the administrator of Webvision and are generally declined unless the copyright owner can/wants to donate or license material. Use online should be accompanied by a link back to the original source of the material. All imagery or content associated with blog posts belong to the authors of said posts, except where otherwise noted.

      For your dissertation purposes, we would be happy to grant permission under the above terms.

  35. Hi, I’ve been involved in car accident , however after been referred to 6 different specialist and all the test they only found small evedence that’s actually showing up. I am not happy and wanted a proper answer apart from I’ve only got 10% left vision the left and 25% on the right. I have recently got my test from multificol Arg and it’s showing normal, it makes me angry because I know nothing has change on my vision. Is it possible for not to show the damage that it’s left in my condition. All the other specialist says that it’s normal to leave damages but cannot appear on the test..the nerves cells of the retina.

  36. Misty –

    Webvision is not a site for medical advice. We cannot address medical management.

    Donnell CreelNovember 8, 2013 @ 12:10 pmReply
  37. Hello I am a veterinarian from peru interested in purchasing an ERG which one you recommend me? Or where can I find one?
    Thanks

  38. I am not certain which companies market ERG equipment in Peru. If there is a University ophthalmology program nearby you could phone and ask if they have ERG equipment. One American company that markets ERG systems in Peru is http://www.diagnosysllc.com. Email: brenda@diagnosysllc.com. A German company that might is Roland Consult. Email: j.finger@roland-consult.de. Another American company to contact is LKC Technologies. Email: jdatovech@lkc.com. You will need a hand-held stimulator for testing animals, not the Ganzfeld used for humans such as Fig 8 of chapter.

    Donnell CreelNovember 22, 2013 @ 7:59 amReply
  39. dr. creel, my wife is going to have an erg 12/31 /13. my question is, she is epilepsy. no seizure activity for 14 years. on meds,doing very well with that.will the erg flicker lights possible to induce a seizure? have you ever run across this? thanks so much for your posts.

  40. Dr creel, my post was removed for some reason. i will redirect in it different way. erg test done on people with epilepsy. is it possible to induce seizure . any feed back from others welcome. tim

  41. Inducing a seizure during recording an ERG is very, very unlikely. Seizures driven by flickering light are usually produced by the flicker rate synchronizing with the EEG rate of the subject.

    Most ERG stimuli are single flashes except 30 Hz, which is used to quantitate if cones are functioning normally. In 40 years of recording ERGs I have never witnessed a seizure induced by photic stimuli.

  42. Hi Doc Creel:
    I recently had cataract surgery. And after a few days there appeared some serious Macular edema. I was prescribed NASID and seriod eye drops. The macular edma is very slowly receding. My concern is will I get a better vision after the macular edema returns to normal fovea configuration.

    And some good references to macular edema cures.
    Thanks
    John

  43. Apologies, but we cannot give medical advice. I recommend you do what I would in this case: search Internet on this topic.

  44. Thank you Dr. Donnell J. Creel. I am a PhD in Biomedical Engineering. This chapter also covers some aspects of the technology site which helped me as well. The pictures helped my students to understand how the test is done and what is the morphology of the ERG waveform in normal and abnormal conditions.

    Thanks again.

    Dr. ShafiqueMarch 20, 2014 @ 2:50 amReply
  45. hello
    i am student biomedical from iran and i’m intressting reserch about bionic eye but unfortunatly due to iran sanction , i have not article about bionic eye
    can you help me?
    Thank you

  46. I need an article about electrical circuit artificial retinas. can you help me?



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