Electrophysiological Tests for Visual Function Assessment 279

Visual Electrophysiology Tests

of Berlin discovered standing potential of 6

Visual electrophysiology is an extremely powerful

millivolts in excised fish eyes and found that

corneawaspositivewithrespecttoposteriorpole

tool to assess functional integrity of the visual

of the eye in 1849. He thought that these signals

pathway. Visual pathway starts from the photo-

originate in optic nerve. Holmgren showed

receptor and retinal pigment epithelial layer,

electrical responses to light in excised frog and

proceeds through inner retinal layers, ganglion

demonstratedthatthesetooriginateintheretina.

cell layer and then via optic nerve through the

Dewar and McKendrick showed that

chiasma to the optic radiations in the brain, finally

electrical potentials could be recorded from intact

ending at the occipital cortex. This chapter aims

animal eyes on illumination of the retina. In 1877,

to introduce some basic concepts of visual

Dewar succeeded in recording ERG from the

electrophysiological tests (VET) with the help

human eye but the resulting curves were not

of some representative clinical cases.

published. The first human ERG was published

Visual electrophysiological tests include the

by Kahn and Lowenstein.

various types of electroretinogram (ERG),

Between 1933 and 1947 Ragnar Granit in

electrooculogram (EOG) and visual evoked

Oxford did extensive studies with various

potential (VEP). A patient may need some tests

chemical agents to analyze the origins of various

to ascertain the abnormality. Before ordering the

phases of the ERG. American psychologist Lorrin

tests a clear understanding of the nature of each

Riggs, and Gosta Karpe at the Karolinska Institute

of these is absolutely essential to derive a valid

designed a contact lens electrode independently.

interpretation. A thorough clinical evaluation is

The credit for taking the science of ERG from

a prerequisite before ordering any visual

the laboratory to the clinic goes to Gosta Karpe

electrophysiological test.

who invited ophthalmologists to visit his clinic

History

where routine diagnostic ERG was introduced.

Before ordering and interpreting these tests,

To understand how visual electrophysiological

a thorough understanding of the nature and

tests reached its present status, some of the

limitations of each of test is a essential to arrive

milestonesaredescribedhere.DuBois-Reymond

at a valid interpretation and diagnosis.

Electrophysiological Tests for Visual Function Assessment

281

Skin electrodes are placed at the medial and

amplified and displayed on a computer data

lateral canthi to detect the amplitude of the signal

acquisition system (Fig. 18.2). The changes in

between these two points. A ground electrode

this indirectly measured potential, from darkness

is fixed to the forehead. Pupils are dilated. A

to light is the light-induced rise of the resting

Ganzfeld is used to illuminate whole retina

potential.3 In the dark, the resting potential

uniformly. Eye should not be exposed to too bright

decreases while it slowly rises to a peak (Slow

or too dim lights before EOG. After an initial

oscillation of EOG) after the lights are switched

6 minutes of light adaptation, test is started. The

on (Fig. 18.2). The amplitude of the signal is

patient makes fixed 30-degree lateral eye

recorded at its minimum during dark adaptation

movements (using diode fixation lights) during

(the dark trough) and at its maximum during

a period of 20 minutes of dark adaptation, and

light adaptation (the light peak). The ISCEV has

then during a 12-15 minute period of light

laid down standards for EOG testing.4The

adaptation. The eye movements are made every

normal light peak occurs in conditions of

1-2 seconds for approximately 15 seconds and

normally functioning photoreceptors in contact

a pause of 45 seconds, every minute. The dipole

with a normally functioning RPE, and is caused

generated by the resting potential induces current

by progressive depolarization of the RPE basal

flow in the skin electrodes upon shift of the eye

membrane. The EOG is quantified by calculating

position (Fig. 18.1).The changes in voltage are

the amplitude of the light peak in relation to

the dark trough as a percentage, the Arden

years, Arden et al.7 have shown that after intake

index.3A normal index would be > 185% (Fig.

of low doses of ethanol an EOG peak similar

18.2).

to the light-induced EOG peak can be recorded.

This could test RPE layer function independent

Clinical Uses

of its interaction with the photoreceptors.7

A normal ERG and abnormal EOG are classically

Limitations of EOG Recording

seen in Bests’ vitelliform macular dystrophy5 (Fig.

18.3) even in very early stages of the disease

Patient cooperation and central fixation limit the

with minimal fundus changes and in asympto-

clinical recording of EOG. Patients with poor

matic carriers. EOG abnormality is also seen in

central fixation or variable eccentric fixation,

a variety of RPE and rod-photoreceptor disorders

children, infants and uncooperative adults can-

such as retinitis pigmentosa, choroideremia and

not be tested satisfactorily. Many testing variables

age-related macular degeneration. EOG is also

such as media opacities and illumination levels

abnormal in choroidal melanomas and could

can influence the voltages. Therefore, borderline

be an adjunct tool to differentiate melanoma from

EOG abnormalities need to be interpreted with

nevi.6 EOG is normal in isolated inner retinal

caution and test may have to be repeated for

cell dysfunction such as in congenital stationary

confirmation.1

night blindness (CSNB) where RPE and photo-

receptors are normal. EOG can be used to study

Fast Oscillations of EOG

drug toxicity against RPE. One must remember

that because light is used to provoke the voltage

It was reported by Kolder and colleagues8 that

change in EOG, this test cannot separate the

the EOG responses could be slow or fast, if the

photoreceptor and RPE dysfunction. In recent

frequency of the light and dark periods for

stimulation were altered. They found the ‘slow’

movement of especially sodium and potassium

oscillations were greatest with repeated light and

ions, making the cells hyperpolarized, that is,

dark periods of 12.5 minutes each, whereas, the

they become more negative to the extra cellular

greatest amplitude of ‘fast’ oscillations of EOG

space than in the dark. These voltage changes

were seen when the light and dark cycles were

are reflected in various ERG components.

of 1.1 minute each. The amplitude of ‘fast’

Various techniques are in clinical use to

oscillations increased in dark phase and reduced

assess the electrical response of retinal cells to

in light phase. The clinical value of these fast

light. The most common of these is the Full-field

oscillations needs further study.

Flash ERG. Others are Pattern ERG, Focal ERG

and Multifocal ERG (Table 18.1).

The Flash ERG is the mass response of the

neural and nonneural retinal cells to a full field

Electroretinogram (ERG)

luminance stimulation. The test reflects the

Due to selective transport of ions, the inside of

function of the photoreceptors and inner nuclear

the photoreceptor cells is more negative than the

layers of the retina in response to light stimu-

outside resulting in a standing membrane

lation. It is recorded by using stimuli delivered

potential in the dark. Once light falls on the retina,

by an integrating sphere, called Ganzfeld, which

it induces a change in the transmembrane

provides a uniform whole field illumination to

discomfort besides rare possibility of corneal

The recording electrodes, bipolar or non-

abrasion. The advantage, however, is that higher

bipolar are placed on the cornea. Topical

amplitudes are recordable due to proximity to

anesthesia is necessary for contact lens electrodes

the cornea. All reusable electrodes should be

but may not be required for other types of corneal

cleaned and sterilized after each use to prevent

and conjunctival electrodes. It is important to

disease transmission.

learn the technical requirements of a chosen

The non-corneal electrodes include gold foil,

electrode, to ensure good ocular contact, to ensure

the DTL-fiber (Dawson-Trick-Litzkow) and our

proper electrode impedance, to ensure that

own devised LVP-Zari electrode.12-14 The LVP-

waveforms are comparable to standard

Zari electrode is disposable, inexpensive, rigid

responses, and to define both normal values and

variability (which may be different with different

and reliable and made from locally available

electrodes) for their own laboratory.9,10 Skin

Zari-embroidery thread. It has a core of nylon

electrodes are in general not recommended as

(traditionally had cotton thread core) covered

active ERG recording electrodes.

with layers of silver, copper and gold, making

it a good conductor of electric currents. Due to

Reference electrodes: Reference electrodes may be

its nylon core, and multiple metallic coatings,

incorporated into the contact lens-speculum

the movement of the fiber across the limbus is

assembly as in Burian-Allen (Fig. 18.5) or can

minimal, making the recordings very reliable.

be placed near each ipsilateral outer canthus

Electrophysiological Tests for Visual Function Assessment

287

in steps of no more than 0.3 log unit. This

into the interface box at the other end, sending

attenuation should not change the wavelength.

the retinal signals into the amplifiers and

It is essential to periodically calibrate the stimulus

computer analyzers. Patients are encouraged to

and background illumination by integrated and

fixate at the central target to reduce eye movement

nonintegrated photometers to achieve standard

and artifacts.

test conditions.11

The ISCEV standard describes9,10 a minimum

The bandpass of the amplifier and

of 5 basic ERG response recordings, three in dark

preamplifier should include at least the range

adapted or scotopic conditions and two in light-

of 0.3 to 300 Hertz and should be adjustable

adapted or photopic state. These basic ERG wave-

for oscillatory potential recordings and other

forms are a mass response of the photoreceptors

specialized requirements. Amplifiers are

and inner retinal cells. The retinal ganglion cells

generally AC (alternating current) coupled.

do not contribute to the flash ERG. Various ERG

The recording equipment should be able to

responses (Fig. 18.7) are described below.

represent the full amplifier bandpass without

attenuation. The computer digitizers should

Isolated Rod Response

sample responses at the rate of 1000 Hertz or

To isolate the signals from the rod system of

higher. The observer should be able to watch

the displays so as to monitor and make

photoreceptors, a dim white flash of strength

adjustments to get clean and less noisy recording.

2.5 log units below the white SF is used. Serial

The computerized digitizers are usually capable

responses are recorded with a minimum of 2

of averaging multiple responses so as to remove

second interval between the flashes to allow the

some of the artifacts.

rods to return to dark-adapted state in between

the flashes. A blue stimulus is equally

Clinical Protocol9,10

appropriate if equated to the white standard.

At this low intensity level, the cones are

ERG is recorded after full pupillary dilatation

insensitive to the stimulus. The isolated rod

so that all parts of retina get illuminated. Avoid

response has almost no a-wave and a slowly

any extra illumination (as in fluorescein

rising, broad-peaked, b-wave. The b-wave in the

angiography or fundus photography) but if these

isolated rod-response waveform is a post-receptor

examinations have been performed, a period of

phenomenon, i.e. inner retinal cell response that

dark adaptation of at least one hour is needed

is driven by only the rod photoreceptors. At this

before scotopic recording.

low luminance a-wave is not recordable due to

The subject is placed in a completely dark

poor photoactivation. There is progressive

room for 30 minutes. Next, the subject with

appearance and increasing amplitude of the a-

electrodes in place is seated comfortably with

wave as stimulus intensity is increased from low

the chin on the chin rest and eyes open with

level to the higher level of the standard flash

the face inside the Ganzfeld bowl (Fig. 18.6). The

(intensity response curve). As the a-wave starts

height of patient should be adjusted so that the

appearing with increasing intensity of stimulus,

neck and back muscles are not in a tensed-up

it represents activity of the rod photoreceptors

position as this can induce muscle-generated

but with maximum flash intensity, the cones also

artifacts. The cable from junction box is fixed

start contributing to the a-wave as is seen in

to the shoulder at the subject’s end and plugged

the maximal combined response.

Maximal Combined Response

on the ascending limb of the b-wave of the

The maximal response is dominated by rod

maximal combined response.

These are extracted and amplified to present

responses but also has a small component of

the oscillatory potentials as seen in Figure 18.7.

cone activity. The initial negative a-wave is

They are generated in relation to amacrine cell

generated by the photoreceptors, i.e. both rods

activityinthemiddleandinnerretinalcelllayers.

and cones. The positive b-wave is generated post-

Under scotopic condition and using standard

receptoraly in relation to depolarization of the

flash intensity as a stimulus, other wavelets are

ON-bipolar cells.15 Under scotopic conditions,

removedbyresettingofthefilters.Thehigh-pass

flash ERG is obtained using the Standard white

filtermustberesetfromtheusual0.3Hzto75Hz,

flash which is 0 decibel attenuated. A sharp a-

so that an overall bandpass of 75 at high end and

wave and a much larger, rapidly rising peaked

300Hzatlowendisachieved.Theresponsevaries

b-wave which comes to baseline very slowly,

withstimulusrepetitionrateandchangesafterthe

are characteristic of this response. Duration

firststimulus.Flashesshouldbegiven15seconds

between two flashes should be at least 10 seconds

aparttothedark-adaptedeyes(1.5secondsapart

to remove effect of bleach of photoreceptors by

to light-adapted eyes), and only the second or

the bright flash of light.

subsequent responses should be retained or

Oscillatory Potentials

averaged.9,10 Normalresponseischaracterizedby

3 major peaks followed by 1-2 smaller peaks.

The oscillatory potentials (Ops pronounced as

Comparison with normal individual laboratory

opees) are small but high frequency oscillations

valuesisoftenadequatetoassessanyabnormality.

Electrophysiological Tests for Visual Function Assessment

289

Single-Flash Cone Response

amplitude of the initial cornea negative a-wave

To record the photopic responses, the retina is

is measured from baseline to the trough, while

b-wave amplitude is from the trough of a-wave

exposed to 10 minutes of light adaptation by

to peak of cornea positive b-wave. Latency of

using the background light in the dome of

each wave is measured from stimulus onset,

17-34 candelas per meter square of luminance

marked by a vertical line across the baseline,

(that saturates rods and makes them unrespon-

to peak of the response (Fig. 18.8). Both amplitude

sive). After this the retina is exposed to a standard

and implicit time should be measured for each

flash (SF) to obtain the photopic single flash (PSF)

component of the waveform. For practical

cone response. Inter-stimulus intervals should

purposes, the variables most often measured are

not be less than 0.5 seconds. This cone response

the b-wave amplitudes of the isolated rod

is characterized by a small a-wave and a very

response, maximal combined response and of

sharply rising b-wave that rapidly returns to

single flash cone response. The time-to peak of

the baseline. Better localization of cone functions

the single flash 30 Hz flicker response and b-

is seen with the single flash cone response than

wave latency of maximal combined response is

with the flicker response. The photopic cone a-

measured. Amplitudes and appearance of the

wave has contribution from the hyperpolarizing

oscillatory potentials9,10 are highly dependent

(OFF) bipolar cells and also cone photorecep-

upon stimulus conditions, adaptation and

tors.16 The cone b-wave probably reflects post-

amplifier filter characteristics, but most authors

phototransduction activity. Separation of the cone

describe three major peaks often followed by a

ON (depolarizing bipolar cells) and OFF

fourth smaller one. Comparison of the response

(hyperpolarizing bipolar cells) pathways is done

to the laboratory normative wavelets may be

by using a long duration stimulus with a photopic

adequate for many clinical purposes at our

background.17

present state of knowledge. An overall index of

30 Hz Flicker Cone Response

oscillatory potential amplitude can be obtained

Under the photopic condition repetitive standard

by adding up measurements of the three major

peaks, preferably from lines spanning the bases

flashes are presented at a frequency of 30 stimuli

per second. Rods are suppressed by the photopic

condition and are incapable of responding to

the highly repetitive stimuli. The amplitude is

measured from trough to peak of each response.

The latency is measured as the distance between

stimulus onset and time-to-peak. A vertical line

in the trace should indicate the time of onset

of the stimulus. The 30 Hz response is a sensitive

measure of cone dysfunction, but is generated

at an inner retinal level.18 The response is affected

in inner retinal ischemic states.

ERG Measurements and Recording

A typical flash ERG record is a double peak

Fig. 18.8: Methodology of ERG amplitudes and

waveform. According to current convention the

latency measurements (see text for details)

Electrophysiological Tests for Visual Function Assessment

291

electroretinogram (PERG) and multifocal ERG.

from the cortically generated VEP. Binocular

Pattern ERG is a contrast response driven by

stimulation and recording is usually preferred,

macular photoreceptors but originates in the

except in cases of squint, so the better eye can

ganglion cell layer of retina. It allows both a

maintain fixation and accommodation. It is a

measure of central retinal function, and retinal

small response and may be difficult to record

ganglion cell function. It is the only electrophysio-

without stringent controls. Diurnal variation and

logical test that can provide direct assessment

test-retest variability may be important in

of the ganglion cells. PERG helps in improved

longitudinal studies.

interpretation of VEP abnormalities and helps

PERG is measured as the electrical response

to differentiate optic nerve pathology from the

to a pattern reversal checkerboard stimulus where

macular pathology.19

the overall luminance is unchanged during

pattern reversal. A high contrast (near 100%)

Recording Parameters and Measurement

black and white checkerboard pattern of 15 and

30 minute check size with pattern reversal

The PERG is recorded (Fig. 18.9) with refractive

method is recommended. Field size of stimulus

correction in place, without mydriasis, using non-

should be between 10 and 16 degrees, and the

contact lens electrodes.12,13,19 Reference electrodes

frame rate of the Cathode rate tube should be

are placed on ipsilateral outer canthus, and not

a minimum of 75 Hz or above. Stimulus strength

on forehead or ear, to avoid the contamination

of the white checks should be 80 cd m-2. Steady

Electrophysiological Tests for Visual Function Assessment

293

optic nerve dysfunction, macular diseases can

The standard flash used in ERG recording can

cause delayed VEP latency. PERG P50 defects

be used for Flash VEP also. The pattern stimulus

associated with or without VEP abnormalities,

consists of an isoluminant checkerboard or

point to macular dysfunction. Normal or a defect

grating of various spatial frequencies. Skin

of only N95 component of PERG with an

electrodes used are silver-silver chloride or gold-

abnormal VEP suggests optic nerve/ ganglion

disk electrode (Fig. 18.5). Good contact of the

cell dysfunction.19

electrodes using conducting paste and thorough

cleaning of skin, help in obtaining clean and

Limitations of PERG

reliable recordings. The electrodes are placed on

the scalp relative to bony landmarks in relation

1. The PERG amplitudes are very small and

to the head size as per the international

due to technical demands, not all laborato-

10/20 system23 (Fig. 18.10). The anteroposterior

ries record PERG as a routine. Stringent

midline measurements are based on the distance

controls are required to avoid artifacts. The

between the nasion, inion and vertex. The active

ISCEV standards are available for PERG

electrode is placed on the midline over the visual

recordings.20

occipital cortex (OZ) while reference electrode

2. Patient cooperation is essential in recording

at the frontal pole (FZ). The ground electrode

the PERG.

is at the forehead or earlobe.

3. All equipments for ocular electrophysiology

Recordings are done with refractive correction

do not have the capability to perform PERG.

without mydriasis using monocular stimulation.

4. In eyes with hazy media where the pattern

Prechiasmal lesions are reliably detected by

stimulus cannot be projected on the macula,

pattern-reversal stimulation while flash stimulus

results can be erroneous.

is used in difficult and uncooperative patients

Visual Evoked Potential

or those with dense media opacities and very

poor vision. Pattern-onset/offset stimulus is

Visual evoked potential (VEP) is a sensitive

especially useful in malingerers and patients with

nystagmus, due to short stimulus duration and

indicator of optic nerve function. It is an evoked

inability of the subject to consciously defocus

electrophysiological signal that is recorded at

this stimulus. For chiasmal and postchiasmal

the scalp in response to visual stimuli. The

lesions, multichannel recordings are required as

responses are much smaller than the full-field

a single midline channel with active electrode

flash ERG responses, typically measuring only

only over the occipital cortex can miss lesions.

5-10 microvolts in amplitude, which lie buried

The VEP traces (two reproducible records of each)

in the electroencephalographic (EEG) noise of

can be presented as positive upwards (Fig. 18.11)

50 microvolts or greater. Averaging of the

or negative upwards. The polarity convention

recorded signals over a given time period after

and stimulus parameters used should be

repeated stimulation can help in extraction of

indicated in the report besides the amplitude

VEP from the background EEG activity.

and latency. Latency is measured from the

Recording and Measurement

stimulus onset to peak of the component

measured. It must be remembered that interocular

The visual stimuli used to elicit VEP are of three

difference in the pattern-reversal VEP indicates

types: flash, pattern-reversal and pattern-onset.22

dysfunction of the entire prechiasmal pathway

Electrophysiological Tests for Visual Function Assessment

295

and includes ocular, retinal and optic nerve

TABLE 18.2: SPECIALIZED TYPES OF VEP

causes.

NOT COVERED BY THE ISCEV STANDARD22

1.

Steady state VEP

Normal Waveforms22

2.

Sweep VEP

3.

Motion VEP

1. Flash VEP: It consists of a series of positive

4.

Chromatic

(color) VEP

5.

Binocular

VEP

and negative peaks that are designated in

6.

Stereo-electro VEP

numerical sequence. Commonest components

7.

Multichannel VEP

8.

Hemifield VEP

recorded are N2 and P2 at 90 and 120 msec,

9.

Multifocal

VEP

respectively (Fig. 18.11).

10.

Multifrequency VEP

2. Pattern-reversal VEP: The peaks are named

11.

LED goggles VEP

as negative or positive followed by the latency.

Commonest wave used for clinical cases is

investigational tools (Table 18.2). Knowledge

the P100 component, (positive peak at 100

in these areas is still evolving.

msec) since it is a very robust measure with

minimal interocular and inter-subject

measurement variation (Fig. 18.11).

Clinical Uses of Visual

3. Pattern-onset/offset VEP: Three components

Electrophysiological Tests

described are C1 (positive at 75 msec), C2

(negative at 125 msec) and C3 (positive at

A number of ocular disorders may require visual

150 msec). With a stimulated hemifield, the

electrophysiology testing for proper diagnosis

response will appear contralateral to the

(Tables 18.3 and 18.4). It must be remembered

hemifield stimulated.

that ERG needs to be interpreted in the context

of other clinical features and investigative reports

Limitations of VEP

to arrive at the correct diagnosis. One can be

way off the true diagnosis if it is based on ERG

VEP has following limitations:

recording alone.

1. Age, refractive error, inattention and

conscious defocusing of the pattern affect the

Photoreceptor Dysfunction

VEP latency.

2. Stimulus parameters such as contrast,

In widespread genetic retinal photoreceptor

luminance, check size and field size are

disorders like retinitis pigmentosa (RP) or

important determinants of the waveform

choroideremia, a profound reduction of ERG is

(Fig. 18.11) and it is essential for each

seen even when retina looks apparently normal.

laboratory to establish their own normal

The diagnosis of RP is often obvious in patients

controls.

with history of night blindness, progressive

3. Since the amplitudes of VEP are very small,

peripheral field constriction and typical retinal

surrounding noise can easily contaminate

changes including equatorial pigment migration,

them and, therefore, strict vigil has to be kept

arterial attenuation, RPE atrophy and disk pallor

on the recording equipment, recording

as seen in a 40 years male with visual acuity

technique and the stimulus parameters used.

of 20/50 and residual visual fields of 10 degrees

4. Numerous specialized types of VEP22 are

centrally (Fig. 18.12A, top). ERG has a limited

being assessed and these are still used as

role in diagnosis but helps to assess residual

macular photoreceptor function. In the test ERG

change, whereas diffuse or generalized disease

may not be recordable with routine testing using

is usually associated with abnormal implicit

standard flash. With extensive filtering and

time.24,25

averaging (Fig. 18.12B, bottom), response (arrow)

can be elicited identifying residual cone function.

Localized Photoreceptor Loss with

PERG is a more reliable method of eliciting

Pigmentary Retinal Dystrophy

residual central macular function (Fig. 18.13).

In atypical retinal pigmentary dystrophies, ERG

Fields are also important in such cases to define

legal blindness and functional disability in the

may help to confirm the diagnosis and

patient. ERG, however, is essential in research

differentiate various conditions. For example in

studies to demonstrate diffuse, severe photorecep-

a 65 years old female patient with BCVA of

tor dysfunction that characterizes even early

20/80 in each eye, there was no history of night

stages of RP. A normal ERG recorded beyond

blindness or reduced dark adaptation but

6 years of age practically rules out possibility

gradual progressive loss for reading since 5 years.

of developing RP in future. ERG helps to diagnose

Posterior pole showed RPE atrophy and mild

patients with atypical findings and also in carrier

pigment migration while the rest of the retina

detection. Flash ERG in RP (Figs 18.12 to 18.14)

was normal (Fig. 18.15). Retinal arteries showed

can be either extinguished, or show a rod-cone

attenuation and disk had temporal pallor. ERG

or rarely a cone-rod or even a negative type of

was not extinguished or severely affected,

ERG dysfunction. All such types usually point

excluding the diagnosis of typical RP. However,

to a progressive disease especially if implicit time

both scotopic and photopic responses showed

abnormalities are present. True sector or localized

20-40% reduction in amplitudes with only mild

central (restricted) disease (Fig. 18.15) may give

increase in latency. The condition can be interpre-

amplitude reduction with no implicit time

ted as an Inverse RP / Central RP26 or central

Electrophysiological Tests for Visual Function Assessment

297

TABLE 18.4: INDICATIONS OF ELECTROPHYSIOLOGY TESTS IN SPECIFIC DISEASES

A. Retinal and Choroidal Disorders

(c)

Kearns-Sayre syndrome [mitochondrial myo-

1.

Congenital and infantile forms of blindness

pathy, chronic progressive external ophthalmo-

(a)

Leber congenital amourosis (LCA)

plegia (CPEO), RP, heart block]

(b)

Stationary congenital retinal dysfunction

(d)

Chronic progressive external ophthalmoplegia

(1)

Congenital

achromatopsia (complete

plus

(CPEO+)

blue cone

monochromatacy)

D. Bruch’s

membrane

disorders

(2)

Congenital stationary night blindness

(a)

Angioid

streaks

(PXE)

(incomplete and complete CSNB)

(b)

Dominant drusen

(3)

Fundus

albipunctatus

E. Hereditary vitreoretinal disorders

(4)

Oguchi

disease

(a)

X-linked juvenile retinoschisis

(c)

Blindness as part of a pediatric neurologic

(b)

Goldmann-Favre

syndrome

syndrome

(c)

Enhanced S-cone syndrome (ESCS)

(1)

Infantile Refsum syndrome, Zelweger

F. Inflammatory

conditions

syndrome

(retinal

degeneration

(a)

Multiple evanescent white dot syndrome

associated

with

generalized

(MEWDS)

peroxisomal disease)

(b)

Birdshot

retinochoroidopathy

(2)

Neuronal

ceroid

lipofuscinoses

(c)

Pars planitis

(infantile, late

infantile, juvenile)

(d)

Syphilis

(3)

Mucolipidosis

type IV

(e)

Pigmented paravenous retinochoroidal atrophy

(4)

Hallervorden-Spatz syndrome (iron

(PPRCA)

storage in basal ganglia, mental

(f)

Diffuse

unilateral subacute

neuroretinitis

retardation,

spasticity, RP)

(DUSN)

(5)

Senior-Loken syndrome (LCA or

(g)

Rubella

severe early-onset RP with renal

G. Vascular disorders

failure)

(a)

Sickle-cell retinopathy

(6)

Joubert

syndrome

(retinal aplasia,

(b)

Ophthalmic artery occlusion

cerebellar

hypoplasia,

neonatal

(c)

Central

retinal

artery occlusion

tachypnea)

(d)

Central

retinal

vein occlusion

2.

Rod-cone photoreceptor dystrophy/degenera-

(e)

Carotid

insufficiency

(ocular ischemic

tion

(hereditary

dystrophies)

syndrome)

(i)

Rod and rod-cone dystrophy/degeneration

(f)

Diabetic

retinopathy

(retinitis pigmentosa)

H. Toxic disorders

(1)

Autosomal

dominant,

autosomal

(a)

Chloroquine and

hydroxychloroquine

recessive,

X-linked

(b)

Quinine

(2)

RP with slightly greater cone loss

(c)

Digoxin

(3)

RP with

electronegative

ERG

(d)

Thioridazine

(ii) Cone and cone-rod dystrophies

(e)

Chloropromazine

3.

Macular

Dystrophies

(f)

Indomethacin

(a)

Peripherin/Retinal degeneration slow type

(g)

Methanol

(RDS)

I. Miscellaneous

(b)

X-linked (juvenile) retinoschisis

(a)

Albinism

(c)

Stargardts macular dystrophy

(b)

High myopia

(d)

Bests macular

dystrophy

(c)

Acquired retinal

dysfunction/degeneration

(e)

Pattern dystrophy

(i)

Vitamin A

deficiency (malabsorption

B. Choroidal dystrophies

syndromes)

(a)

Choroidal atrophy

(ii) Autoimmune retinopathy, including cancer-

(b)

Gyrate atrophy of the choroid and retina

associated

retinopathy

(CAR) and

(c)

Choroideremia – patients and carriers

melanoma-associated retinopathy (MAR)

(d)

Central areolar choroidal atrophy

(d)

Retinal (cone-rod) dystrophy with supernormal

C. Retinal dystrophies associated with other diseases

and

delayed rod ERG

b-waves

(arrow)

with normal rod response suggestive of an early adult-onset cone dystrophy. The photopic single flash

is not

depicted

Causes of negative ERG28 include congenital

TABLE 18.5: CONDITIONS ASSOCIATED WITH

stationary night blindness (CSNB, complete and

ELECTRONEGATIVE ERG

incomplete), fundus albipunctatus, Oguchi's

(i)

CSNB/Oguchi

disease (Figs 18.18 to 18.20),29 X-linked retinoschi-

sis,30 quinine toxicity, melanoma associated

(ii)

Juvenile

retinoschisis

(iii)

CRAO,

CRVO

retinopathy (MAR),31 Battens disease, and

(iv)

Familial

optic atrophy

occasionally in cone-rod dystrophy (Table 18.5).

(v)

Siderosis bulbi

(vi)

Quinine

Carcinoma associated retinopathy (CAR) does

(vii)

Some forms of RP and cone-rod dystrophy

not usually give a “negative” ERG but profound

(viii)

Melanoma associated retinopathy, CAR

global ERG reduction in keeping with dysfunc-

tion at the level of the photoreceptor.31 It occurs

angiography or fundus appearance may not

due to damage from circulating antibodies.

Central retinal artery obstruction (CRAO) also

detect the true extent of retinal ischemia.32,33 ERG

has a negative ERG (vide infra). In patient of

is an indispensable and extremely powerful but

Oguchi’s disease an increased amplitudes of

unfortunately underutilized tool to differentiate

responses in PERG and single flash cone ERG

ischemic from non-ischemic obstruction of the

(Fig. 18.19) may occur after prolonged dark

central retinal vein (Figs 18.21 and 18.22).

adaptation that also changes the golden metallic

Reduced b-wave amplitude has 80-90%

color of retina to a relatively normal color.

sensitivity and 70-80% specificity to detect inner

retinal ischemia. An absolute increase of more

Ischemic Vascular Retinal Disorders

than 37 msec in latency of the flicker ERG

responses or a difference of more than 7 msec

ERG changes are profoundly helpful to detect

between affected and normal eye are almost

inner retinal ischemia since fundus fluorescein

pathognomic of ischemic type of CRVO in a given

A

B

A1

B1

clinical setting. Reliable information from FFA

the double blood supply of the retina. The RPE/

may be available only in 50-60% cases of CRVO

photoreceptors (a wave) are spared as they are

due to media haze, extensive hemorrhages, poor

supplied via choroidal circulation, but bipolar

quality photographs and inability to visualize

cells and amacrine cells (b-wave and oscillatory

peripheral retina. ERG circumvents all these

potentials) are affected as they are supplied via

limitations as it is a global response from the

central retinal artery. In ophthalmic artery

whole retina and is not too much affected by

obstruction where both retinal and choroidal

media haze.

circulation are affected, the ERG is unrecordable

Other conditions like ocular ischemic

as all retinal cell layers are involved.35

syndrome34 (Fig. 18.23), central retinal artery

In ocular ischemic syndrome ERG is

occlusion (Fig. 18.24) and ophthalmic artery

extremely useful since clinical presentation of

occlusion(extinguishedERG)35 arealsoverywell

this under diagnosed clinical entity is variable.36

detected on ERG. The “negative” ERG in central

In diabetic retinopathy37progressive abnorma-

retinal artery occlusion (CRAO) 35 occurs due to

lities in ERG are seen with progression of the

retinopathy. The oscillatory potentials show

are markedly affected and white flecks may be

profound reduction in case of disk new vessels

seen in the retina. Visual acuity is unaffected.

(NVD). The ERG can be subnormal even before

Similarly, ERG abnormalities can be seen in drug

clinical retinopathy, possibly due to metabolic

toxicity especially with hydroxychloroquine,38

effects on the retinal cells. ERG, however, cannot

chloroquine, quinine and thioridazine. VEP is

predict accurately the presence of PDR and is,

useful to detect ethambutol toxicity (Fig. 18.25).

therefore, not used clinically for monitoring

ERG can detect and prognosticate siderotic

diabetic retinopathy.

changes in eyes with retained iron IOFB.31 Initially

ERG has a subnormal b-wave on maximal

Drug Toxicity and Monitoring Health

combined scotopic response that can progress

to a negative ERG with time and ultimately

of Retina25

become extinguished. Removal of IOFB in eyes

ERG helps to differentiate nyctalopia due to

with recordable ERG, may lead to improvement

vitamin A deficiency from CSNB and RP. ERG

in ERG changes and a stable outcome. In

is indicated particularly in adults such as those

advanced siderosis, removal of IOFB will not

with alcoholic liver disease, chronic pancreatitis,

stop progressive visual loss and sometimes

or malabsorption syndromes. The rod responses

phthisis bulbi develops.

Pediatric Visual Impairment39

fication of an underlying systemic disease such

ERG is indispensable in evaluating the cause

as abetalipoproteinemia, neuronal ceroid

lipofuscinosis, mucopolysccharidoses and

of poor vision in children. Commonly seen condi-

cystinosis.

tions include Lebers congenital amaurosis

(LCA), rod monochromatism (Fig. 18.26),

Carrier Stage Detection

Stargardt’s macular dystrophy, ocular albinism

and delayed visual maturation. Correct

ERG can be helpful in detection of the carrier

identification of the underlying dysfunction helps

stage of certain X-linked conditions such as

in proper counseling as regards risks to relatives,

X-linked RP,40 blue-cone monochromatism,41 and

long-term prognosis and sometimes identi-

X-linked cone dystrophy.

Optic Nerve and Visual Pathway

3. Anterior ischemic optic neuropathy: In anterior

Optic nerve and visual dysfunction42 include

ischemic optic neuropathy (AION) the PERG

shows normal P50 amplitude and latency,

following conditions:

elevation of N95, normal flash ERG and

1. Optic nerve demyelination: The pattern VEP

reduced amplitude with normal P100 latency

(PVEP) latency (P100) is usually delayed in

in VEP (Fig. 18.27). Using multichannel VEP

optic nerve demyelination and the delay may

recordings, the chiasmal lesions, such as

be subclinical, i.e. it may occur with no signs

pituitary tumors, show a “crossed asym-

or symptoms of optic nerve involvement.43,44

metry” where there is an abnormal distribu-

This may significantly affect clinical manage-

tion over the two hemispheres which is in

ment in a patient with spinal cord disease

an opposite direction for the two eyes.45

and possible multiple sclerosis (MS). The VEP

Stimulus parameters are crucial for accurate

is almost invariably delayed following

localization. In general, use of a large field,

symptomatic optic nerve involvement in MS,

large check stimulus gives paradoxical

even when vision has returned to normal.

lateralization45 whereas a small field,

2. Papilledema: In papilledema the VEP is normal

small check stimulus gives anatomical

unless secondary optic atrophy occurs.

lateralization. Retrochiasmal lesions give an

“uncrossed” asymmetry where there is an

of albinism, where the majority of optic nerve

abnormal distribution that is the same for

fibers from each eye do not decussate to the

the two eyes. Serial VEP recordings can help

contralateral hemisphere, is readily demon-

detect recurrences or non-responsiveness to

strated by multichannel VEP. Abnormalities

medical therapy as VEP abnormalities can

may occur in response to either pattern

occur before visual fields or visual acuity

appearance or diffuse flash stimulation, but

become abnormal.

the flash VEP appears to be more effective

4. Ocular albinism: In some cases of ocular

in infants and the pattern appearance VEP

albinism, the condition may not be apparent

in adults.

in the absence of typical phenotypic expres-

5. Visual acuity assessment: Objective assessment

sion of skin or iris, but child can have nystag-

of visual acuity is performed with pattern

mus and poor vision due to an albino

appearance stimulation using a very brief

genotype. All albinos, irrespective of genotype

appearance time in order to minimize the

or phenotype exhibit misrouting. Heterozy-

possibility of voluntary closure or defocusing.

gote carriers do not demonstrate misrouting.

6. Other optic nerve diseases: Lebers hereditary

The diagnosis of the intracranial misrouting

optic neuropathy (LHON), toxic and nutri-

tional optic neuropathies and traumatic optic

technique as subjects cannot voluntarily blur

neuropathy show variable changes in

this stimulus.

amplitude and latency of VEP depending on

extent of involvement.

7. Visual loss assessment in infants and children:

Recent Advances in Multifocal

VEP is a useful tool along with ERG and

ERG and Multifocal VEP

other clinical assessments to differentiate

Multifocal ERG (mfERG) technique developed

various conditions such as cortical visual

initially by Bearse and Sutter46 allows local ERG

impairment, delayed visual maturation, and

responses to be recorded simultaneously from

amblyopia.

many regions of the retina. The response is

8. Malingering: Along with other tests, VEP helps

thought to originate from outer retina with rela-

to differentiate malingering from visual

tively little contribution from the ganglion cells.47

pathway lesions. Pattern onset is a useful

Responses are recorded to a scaled hexagonal

aspects. In mfERG the recording, ground and

pattern-reversal stimulus in photopic conditions

reference electrodes and their placement close to

(Fig. 18.28) although some laboratories are

or on the cornea, lateral canthus and ear lobe are

attempting to record scotopic mfERG also. MfERG

similar to the routine ERG. Recording is

helps to distinguish between diseases of the outer

done with dilated pupils with subject placed in

retina and ganglion cells or optic nerves. Along

ordinaryroomlightfor15minutesbeforetesting.

with multifocal VEP (mfVEP),48 the mfERG helps

to differentiate organic and non-organic causes

Effect of Stimulus on mfERG 46,47

of visual loss.

Therearesomelimitationsofthesetechniques.

Stimulus can be delivered by a cathode ray tube

Since it is an evolving technology the recording

(CRT), i.e. monitor LCD projectors, LED arrays

parametersandinterpretationarestillnotstanda-

or scanning laser ophthalmoscope. The com-

rdized,thoughguidelineshavebeenformulated.49

monest frame frequency of the CRT is 75 Hz

The techniques are still not widely available. Full

and should never be 50 or 60 Hz as this is similar

field ERG helps to evaluate the function of the

to the line current frequency which interferes

retina as a whole. However, it cannot detect focal

as noise with the recordings. Stable fixation is

areas of abnormal function. Multifocal ERG is a

essential to get reliable mfERG recordings and

new technique. It allows analysis of local ERG

various fixation targets and monitoring devices

responses to assess focal retinal function. Basic

may be used that do not interfere with the

technology is similar to full-field ERG in some

recordings.

is designed in such a way that the overall

the focal ERG signal associated with each

luminance of the screen over the time of recording

element is calculated. The data obtained can be

is relatively stable, i.e. equiluminant. The overall

displayed in various ways; commonly as a

stimulus pattern should subtend a visual angle

topographic array, a three-dimensional plot or

of 20-30 degrees on either side of fixation. The

as group averages (Fig. 18.28). The trace arrays

stimulus region can be divided into different

are essential to display as they not only show

numbers of hexagons such as 61, 103 or 241.

the topographical variations due to focal

Duration of recording varies from 4-8 minutes

pathology but also demonstrate the quality of

depending on whether 61 or 103 elements are

the records. It is important to remember that the

used. Various artifacts in mfERG recordings

tracings of mfERG are not responses in the sense

include electrical noise, movement errors due to

of direct electrical signals from a local region

fixation losses, eccentric fixation, shadowing

of the retina. The mfERG waveforms are a

errors due to edge of refraction lenses, and errors

mathematical extraction of signals that correlate

due to too much averaging.

with the time that one portion of the screen is

illuminated. The signals are hence influenced

Multifocal ERG Responses

by adaptation effects from previous stimuli and

by scattered light from other fundus areas.

By correlating the continuous ERG signal with

The typical waveform of the primary mfERG

the on or off phases of each stimulus element,

(first order or first order kernel K1) is a biphasic

315

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stain

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stain

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