T

Pearl

For macular diseases, however, the multifocal ERG (see below) is a particularly valuable diagnostic test.

Evaluation of the Flash ERG

During the flash ERG, the following values are recorded:

■ The amplitude of the a-wave, measured from the electrical baseline to the negative peak recorded just before the appearance of the b-wave

■ The amplitude of the b-wave, measured from the valley of the a-wave to the positive peak of the b-wave

■ The implicit times, meaning the time from the flash stimulus to the peak of the corresponding ERG peak

Reductions in amplitude or increases in implicit time are considered pathological when they deviate significantly from age-corrected normal ranges.

Indications for Flash ERG Testing

Given the above explanation of the physiologic and anatomic determinates of the ERG, the following are good indications of the need for ERG testing:

■ Inherited retinal dystrophies. This group of disorders is the primary indication for flash ERG testing. These disorders cause a diffuse type of damage to the photore-ceptor layer of the retina, with a consequent reduction in or complete loss of the amplitudes of both the a- and b-waves.

■ Nyctalopia. Patients with night blindness commonly have associated and diverse hereditary and/or acquired diseases that contribute to a marked variation in prognosis. The ERG is a decisively helpful test when the differential diagnosis of a visual disorder includes heredofamilial retinopathies (see ■ Table 7.2).

■ Congenital nystagmus. Nystagmus during infancy is frequently sensory in origin, meaning it is caused by a disturbance of retinal and/or retrobulbar disease of the afferent visual pathway. Retinal dystrophies as different from one another as achromatopsia, congenital stationary night blindness, and Leber's congenital amaurosis can be disguised by the presence of what appears to be a congenital nystagmus. The ERG plays a central role in determining the diagnosis, since each of these diseases produces a characteristic change in the flash ERG.

■ Toxic disorders. Siderosis bulbi, caused by a retained ferrous-metal foreign body, can be diagnosed in its early stages, typically by showing a reduction in the b-wave of the flash ERG. If the foreign body can be identified and removed from the eye, a remission in, or even reversal of, the visual loss may occur. Drug side effects, such as those of the phenothiazine group of agents, e.g., chlorpromazine or thioridazine), and the antimalarial drugs, e.g., chloroquine, can cause a depression of both a- and b-wave tracings in the flash ERG responses.

■ Chorioretinitides. In this class of disorders, the ERG often shows little change. This aids in the ruling out of retinitis pigmentosa (RP) when inflammatory diseases mimic its fundoscopic appearance (so-called pheno-copies of RP; see ■ Table 7.2).

■ Vascular diseases. Ischemia in the retinal vascular tree depresses the oscillatory potentials of the ERG. In severe cases, ischemia can evoke a b-wave reduction with depression of the b/a amplitude ratios and a prolongation of the cone implicit times. ERG changes can be associated with various causes of retinal hypoperfusion, including diabetic retinopathy, central retinal vein occlusion or any of the occlusive inflammatory vasculopa-thies, such as Behcet's disease.

■ Clouding of the optic media. In some cases where there is a loss of media clarity, whether by cataract or clouding of the vitreous, an ERG may be part of a preopera-tive evaluation, when interventional surgery is being considered. While it cannot establish a precise visual prognosis, it can give a coarse estimate of the preservation or loss of retinal function, ruling out a central retinal artery occlusion for instance.

Multifocal ERG

The multifocal ERG (mfERG), as developed by Sutter and Tran, has made it possible to derive simultaneously a local photopic ERG at each of a number of locations in the central visual field. This allows a topographic determination of ERG function within the central radius of 25 to 30° of the fundus. The summed potentials of the conventional flash ERG, by contrast, do not permit a localization of retinal disease. The stimulus used for the multifocal ERG consists of an array of hexagonal zones that interlock with one another and increase in size as the periphery of the central field is approached. The fields can be black or white and are positioned on a monitor or similar device, the center of which provides the patient with a fixation point. During the test, each of the hexagonal zones, independent of one another, change from black to white or vice versa. This is done in a pseudorandom sequence in which with each change of one of the test stimuli from black to white, a local retinal response is evoked. The recorded data are analyzed by means of a computed cross-correlation between the sequence of stimuli and the summed responses, and a calculation of the responses corresponding to each of the various stimulus areas is calculated. The measurements are recorded with conventional ERG electrodes. The amplitude of the local potentials can be plotted per unit area of the retina, i.e., they are displayed as a "response density" (■ Fig. 7.3 a). In this three-dimensional representation, the fovea with its high level of photoreceptor density is also the location with the greatest response density. At the left border of the display, the physiologic blind spot is seen as a local depression in the response density. Other choices exist for representing the local responses ("trace array" in ■ Fig. 7.3 c) or grouping and averaging of the responses according to their eccentricities relative to the fovea center. A final type of representation permits determination of the amplitudes and implicit times for each of the response groups during routine clinical use of the test.

Indications for the mfERG

The mfERG is particularly useful and indicated in cases where help is needed in the detection of retinal disorders confined to the macular and perimacular regions. It is a big diagnostic help at the very early stages of a macular dystrophy, such as Stargardt's disease (■ Fig. 7.3). In such early stages, there is often a significant discrepancy between a marked reduction in central visual function and a largely unremarkable appearance of the macula and optic disc. In addition, in cases of retinitis pigmentosa in its more advanced stages, when responses to the flash ERG are no longer detectable, the mfERG will often detect intact retinal function in a small area at the center of the visual field. This gives the physician an objective method for continued monitoring of foveal and perifoveal macular function.

Pearl

The mfERG is also useful for the topical classification of visual field defects of unexplained origin. If there is a suspicion that a prior choroidal infarct might have damaged the outer layers of the retina (which commonly causes no change in the fundus appearance), the mfERG can detect local zones of lost retinal function that correspond to the visual field defects.

Fig. 7.3. Multifocal ERG (mfERG) of the left eye in a normal person (a, c) and a patient with Stargardt's macular dystrophy (b, d). a and b show three-dimensional and color-coded plots of responses. The patient with macular disease (b) shows an absence of foveal responses, the expected peak being replaced by a central depression of responses. c and d show the local response tracings in which the case of macular disease (d) shows an increasing depression of local b 0123456799 10 nV/dcgnZ

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response tracings that reaches a maximum at the foveal center. (Apfelstedt-Sylla, E., Gal, A. und Weber B.H.F.: Molekulare Grundlagen erblicher Netzhautdegenerationen: Retinitis pigmentosa, Zapfen- und Makuladystrophien. In: Handbuch der Molekularen Medizin [Eds.: Ganten, D., Ruckpaul, K.]. Springer, Berlin Heidelberg New York 2000)

Normal responses Stargardt's disease

Normal responses Stargardt's disease

Fig. 7.3. Multifocal ERG (mfERG) of the left eye in a normal person (a, c) and a patient with Stargardt's macular dystrophy (b, d). a and b show three-dimensional and color-coded plots of responses. The patient with macular disease (b) shows an absence of foveal responses, the expected peak being replaced by a central depression of responses. c and d show the local response tracings in which the case of macular disease (d) shows an increasing depression of local

Pattern ERG | Definition

The pattern ERG (PERG) measures retinal potentials that are responses to changes in a pattern reversal stimulus. The stimulus is most often a checkerboard pattern of black and white, displayed on a video monitor. The pattern is reversed (black squares become white and white squares become black) at a steady pace. The average luminance of the video monitor remains constant. The retinal responses are not to changes in total luminance, but to changes in the luminance of each square element in the pattern, so the retinal responses being recorded are contrast specific. The size of the squares can be changed, allowing the use of both coarse and fine patterns.

Measurements are made with fiber or foil electrodes, with the eye in an undilated state (normal pupil size and accommodation). For reversal frequencies of 4 Hz or less, the responses are said to be those of a transient PERG, while for frequencies of 5 Hz or higher, the responses are those of a steady-state PERG. The transient type of PERG forms a tracing initiated at each reversal of the pattern that has negative deflection at about 35 ms, a positive peak at about 50 ms, and another negative deflection that is maximal at about 95 ms (called the N95). The tracings of the steady-state PERG are similar in appearance to sine waves. The N95 values and the steady-state responses are thought to be contrast specific components of the PERG. Animal experiments have indicated that these responses are linked to events in the inner plexiform layer and the ganglion cell layer.

Indications for PERG Testing

The PERG is essentially suited to the detection of disorders that damage the ganglion cell layer of the retina, i.e., glaucoma and other optic neuropathies. It is ideal for the differentiation between the manifest visual loss of primary open-angle glaucoma on one hand, and ocular hypertension without visual damage on the other; its use has been adopted for many long-term clinical studies of glaucoma. From a clinically practical point of view, this method is too difficult to use in most office environments. Particularly for the very small patterns, reliable and reproducible PERG responses are difficult to obtain. This has made it impractical for every day clinical use.

Visually Evoked Potentials

The visual data processed by the neural network of the retina are passed on to the retrobulbar visual pathways through the axons of the ganglion cells, which form the optic nerve. The data are received by the neurons whose somas are located in the lateral geniculate body (LGB) and are passed on again in the axons of the LGB, which course through the deep white matter of the cerebral hemisphere, arriving at the primary visual cortex (also called the striate cortex, area striata, or Brodmann area 17) in the occipital lobe.

Definition

The VEP test measures field potentials that originate during cortical processing of the visual data received from the afferent visual pathway. On one hand, this electrical activity reflects the events of visual processing in the primary visual cortex, but on the other hand, it also reflects the integrity of all neural structures in the afferent pathway from the photoreceptor layer of the retina to the cortex of the occipital lobe.

The visual data originate essentially in the retinal cone system, because the VEP is conducted under photopic conditions of retinal light adaptation, and also because about one half of the visual cortex is devoted to processing data originating in the cone dominated region of the macula. The visual cortex is also located on the surface of the occipital lobe at the occipital pole, so that its activity makes up most of the responses recorded by the VEP.

The VEP can be elicited by simple flash stimuli (flash VEP), which is the method of choice for cases in which the patient is not cooperative. Most often, however, a pattern reversal stimulus is used, which is essentially identical to that described above for use in the PERG test. The patient fixes a visual target on the center of the pattern and an age-appropriate optical correction for near is used; the same as is used in threshold perimetry. The potentials originating in the occipital cortex are picked up by surface electrodes fixed to the scalp, relative to a reference electrode mounted on the brow or the vertex. The measured potentials are very small and are masked by much larger potentials that originate in the muscles of the scalp, and which are not related to visual function at all. Consequently, the same stimulus must be used 100 times or more, while summing the response tracings to produce a computation of average transients that have been generated mostly by events in the occipital cortex.

As in the use of ERG data, the VEP responses of importance are the amplitudes and implicit times of the recorded potentials. (Implicit time is measured from stimulus onset to the peak of a response.)

Depending on the stimulus configuration, various VEP tracings are recorded (■ Fig. 7.4):

■ The flash VEP consists of a series of negative and positive peaks, whose amplitudes and latencies vary considerably between individuals. There is also an age-dependent effect. The latencies found in premature babies and infants are prolonged as compared with adults, and normalize with the maturation of the myelin sheaths of the visual pathway, completing the process at about school age. Frequently relevant response components include a positive peak at about 100 ms and a negative peak at about 150 ms (■ Fig. 7.4).

■ In response to a patterned stimulus the VEP has a negative (N75), a positive (P100), and another negative (N135) component, where the number in the name is the average latency of the corresponding response peak. In routine clinical tests the P100 amplitude relative to the N75 valley and the latency of the P100 peak are determined.

The amplitude of the VEP in test subjects falls with a reduction in the size of the pattern elements (the squares of a checkerboard pattern) to a threshold value below which no responses can be detected. This threshold correlates well with the clinical values of visual acuity measured in the same subjects.

The pattern VEP amplitude as a function of a series of pattern element sizes can be used as an objective estimate of visual acuity.

Measures of the P100 latency are most frequently used, since it is a measure of retinocortical latency (■ Table 7.3).

Fig. 7.4. Normal visually evoked potential (VEP) findings. Left A flash VEP tracing. N1-N4 mark the sequence of negative potential fluctuations. P1-P3 mark the positive peaks. Right A pattern-reversal VEP tracing with the clinically relevant P100 peak and both negative peaks N75 and N135 (modified from Harding GFA, Odom JV, Spileers W, Spekreijse H (1996) Standard for visual evoked potentials. Vision Res 36: 3567-3572)

Fig. 7.4. Normal visually evoked potential (VEP) findings. Left A flash VEP tracing. N1-N4 mark the sequence of negative potential fluctuations. P1-P3 mark the positive peaks. Right A pattern-reversal VEP tracing with the clinically relevant P100 peak and both negative peaks N75 and N135 (modified from Harding GFA, Odom JV, Spileers W, Spekreijse H (1996) Standard for visual evoked potentials. Vision Res 36: 3567-3572)

Table 7.3. VEP signs in various disease categories

Disease

Amplitude

Latency

Optic neuritis

Normal to reduced

Markedly prolonged

Optic nerve compression

Minimally reduced

Moderately prolonged

Anterior ischemic optic neuropathy (AION)

Moderately reduced

Minimally prolonged

Leber's hereditary optic neuropathy

Reduced

Minimally prolonged

Dominantly inherited optic neuropathy

Minimally reduced

Normal or minimally prolonged

Papilledema

Normal or minimally reduced

Normal or minimally prolonged

Toxic optic neuropathies

Minimally reduced

Normal or minimally prolonged

Vitamin B12 deficiency

Normal

Minimally prolonged

Glaucoma

Normal or minimally reduced

Normal

Amblyopia

Normal or reduced

Normal or minimally prolonged

Most Important Clinical Uses of the Pattern VEP

Optic Neuritis

In optic neuritis, there is a destruction (demyelination) of the myelin sheaths of the ganglion cell axons, which causes a significant retardation in the velocity of neural conduction. Consequently, the P100 latency of the pattern VEP will, as a rule, be prolonged by 20 ms or more. The VEP is helpful when the clinical picture of an optic neuropathy is atypical for optic neuritis or the history and subjective findings are limited by poor cooperation, making the diagnosis uncertain.

In addition, the etiologic source of an existing optic atrophy can be retrospectively clarified. After (always partial) remyelination of a nerve damaged by optic neuritis, the prolonged latency will remain demonstrable for months or years. The VEP can also contribute to a diagnosis of multiple sclerosis in cases where a history of optic neuritis is lacking, since the majority of patients demonstrate prolonged VEP latencies, caused by asymptomatic demyelin-ation, i.e., an episode of demyelination that was unnoticed.

Optic Nerve Compression

Compressive optic neuropathies can produce pathologic changes in the VEP in the form of diminished amplitudes of responses and prolonged latencies of responses. The VEP can thereby support the clinical suspicion of optic nerve compression, whether by tumors or by nontumorous space-occupying disorders such as in dysthyroid ophthalmopathy, during which swelling of the rectus muscles in the limited space of the orbital apex causes a compressive ischemia.

Objective Acuity Testing

As mentioned above, the response amplitudes and spatial frequencies of the pattern VEP, i.e., the objective resolving power of the visual system, correlates well with conventional, subjective measures of visual acuity. The pattern VEP can therefore objectively confirm an optical or neurosensory loss of visual acuity. Diminished pattern VEP amplitude, especially for small pattern sizes, can indicate the presence of developmental amblyopia.

Since the visual acuity of an amblyopic eye, as measured by grating resolution with the VEP, can be significantly better than that measured by subjective reading of optotypes, the VEP has been used for monitoring the clinical response to occlusion therapy only in cases where conventional measures are not possible. This can be the case in children with poor cognitive development for example. The objective estimation of acuity with the pattern VEP can also yield a higher value for acuity than that suggested by the patient's verbal responses. A measure of the "acuity VEP" can be in some cases of use during a certifying examination to measure the vision, when feigned or exaggerated loss of acuity is suspected. Similarly, purely functional reductions in acuity can be quickly identified in the setting of an outpatient clinic.

Indications for Use of the Flash VEP

The flash VEP requires neither cooperation nor steady fixation of the part of the patient. It can be used for infants and small children with uncertain visual function in order to test the intactness of the retinocortical sensory pathway. For example, it can be used to rule out or to confirm evidence of blindness in children with brain damage. In addition, it can be used to monitor visual development in small children.

In the setting of preoperative evaluation of media opacities, such as dense cataracts or vitreous hemorrhages, the flash VEP amplitude and latency are correlated with the maximal attainable acuity after surgical correction. The flash VEP findings can therefore be used to confirm the indications for surgery and the prognosis for successful improvement of vision.

Albinism

The afferent visual pathways of patients with oculocutaneous and ocular forms of albinism have a distinctive anatomic feature: A large majority of the fibers passing through the chiasm decussates to the contralateral side. This phenomenon can be detected with VEP testing through a comparison of the potentials evoked by monocular stimulation. The responses recorded over the contralateral occipital lobe are significantly larger than those generated by the ipsilateral lobe are. Given the usually distinct clinical picture of ocular and oculocutaneous albinism, the VEP is needed only in those few cases for which there exists significant uncertainty about the correct diagnosis.

Conclusion

The EOG measures the slow, light-dependent changes of the ocular resting potential. It tests the collective function of the pigment epithelium-photoreceptor complex. The most significant parameter is the Arden quotient. The most important indications for its use are in the diagnostic confirmation of Best's vitelliform macular degeneration and the monitoring of vision during long-term therapy with chloroquine.

The ERG measures the layer-specific summed potential of the retina and detects generalized or widespread retinal dysfunction. Changes in the a-wave mark disturbances of the photoreceptor layer; changes in the b-wave (with a normal a-wave) suggest a disorder in the region of the bipolar cell layer and in Muller's cells.

Oscillatory potentials are a sensitive detector of the function of the inner plexiform layer of the retina. The sco-topic ERG measures primarily the intactness of rod function, and the photopic ERG isolates the function of the cone system. Important indications for use of the ERG include heredofamilial retinal degenerations, suspicion of a toxic retinopathy, inflammatory or vascular retinopathies, and retinal function testing in eyes with opaque media. In addition, the ERG is often decisive in the differential diagnosis of congenital nystagmus and nyctalopia (night blindness).

The VEP reflects the functioning of the cone-fed channel of the afferent visual system. Its most important clinical values are the amplitude and latency of the P100 response in the pattern VEP. In addition to providing an objective estimate of visual acuity, demyelinating, and compressive disorders of the optic nerve, testing of visual function and development in infants and small children, and suspicion of albinism are also indications for its use.

Further Reading

Arden GB, Barrada A, Kelsey JH (1962) New clinical test of retinal function, based upon the standing potential of the eye. Br J Ophthalmol 46: 449-467

Bach M, Pfeiffer N, Birkner-Binder D (1992) Pattern-electroretinogram reflects diffuse retinal damage in early glaucoma. Clin Vis Sci 7: 335-340

Hajek A, Zrenner E (1988) Verbesserte objektive Visusprüfung mit visuell evozierten corticalen Potentialen durch schnelle Reizmustersequenzen unterschiedlicher Raumfrequenz. Fortschr Ophthal-mol 85: 550-554

Heckenlively JR, Arden GB (2006) (eds) Principles and practice of clinical electrophysiology of vision. MIT Press, Cambridge. Mass.

Lam BL (2005) Electrophysiology of vision: clincial testing and applications. Taylor & Francis, Boca Raton

Miyake Y (2006) Electrodiagnosis of retinal diseases. Springer, Berlin

Heidelberg New York Odom JV, Hobson R, Coldran JT et al (1987) 10-Hz flash visual evoked potentials predict post-cataract extraction visual acuity. Doc Oph-thalmol 66: 291-299 Scherfig E, Edmund J, Tinning S et al (1984) Flash visual evoked potential as a prognostic factor for vitreous operations in diabetic eyes. Ophthalmology 91: 1475-1479 Seeliger MW, Kretschmann U, Apfelstedt-Sylla E et al (1998) Multifocal

ERG in retinitis pigmentosa: Am J Ophthalmol 125: 214-226 Sutter EE, Tran D (1992) The field topography of ERG components in man-I. The photopic luminance response. Vision Res 32: 433-446 Zrenner E (1990) The physiological basis of the pattern electroretino-gram. Prog Retin Eye Res 9: 427-464

Chapter 8

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