Brain (1977), 100, 119-136

THE COMPARISON OF SMALL-SIZE

RECTANGLE AND CHECKERBOARD
STIMULATION FOR THE EVALUATION OF
DELAYED VISUAL EVOKED RESPONSES IN
PATIENTS SUSPECTED OF MULTIPLE
SCLEROSIS

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by M. HENNERICI, D. WENZEL and H.-J. FREUND
(From the Department of Neurology, University of Freiburg, D-7800 Freiburg i. Br., West Germany)

INTRODUCTION

THE visual evoked response (VER) evoked by checkerboard pattern reversal was
first described to be abnormal in patients with optic neuritis by Halliday, McDonald
and Mushin in 1972. Recordings of the response to the peak of the first major
positive potential showed a marked delay of the latency from the affected eye.
The optic nerve is one of the most common sites for plaques in multiple sclerosis
(Lumsden, 1970) and subsequent studies of patients with multiple sclerosis
(Halliday, McDonald and Mushin, 1973a; Asselman, Chadwick and Marsden,
1975) established the high incidence of delayed VERs indicating optic nerve
lesions even in the absence of a history of visual impairment or visual abnormalities
seen in full ophthalmological investigation. Recording pattern evoked responses
was therefore suggested to provide a sensitive index of persisting optic nerve
damage.
Quantitative analysis of these investigations, however, showed that a delay of
the major positive potential could not generally be detected in a more slight and
chronic course of the disease: according to the diagnostic criteria of McAlpine,
Lumsden and Acheson (1972), the latency of pattern-evoked potentials was
significantly prolonged in 84 per cent of patients with 'definite' but only 21 per
cent of those with 'possible' multiple sclerosis (Asselman, Chadwick and Marsden,
1975).
The question thus arises whether the cases with normal latencies have no
involvement of the optic nerve or whether the sensitivity of the method is not
adequate to show them. We have tried to approach this problem by using a
small-size rectangle stimulus placed in the visual axis to elicit the VER and to
120 M. H E N N E R I C I , D. WENZEL A N D H.-J. F R E U N D

compare the results with those obtained by conventional checkerboard pattern

stimulation. This was done because theoretical considerations suggest that small
demyelinating lesions mainly affecting optic nerve fibres originating from
foveal ganglion cells cannot be detected by large visual angle checkerboard
stimulation. In this case normal conducting axons arising from the peripheral
retina could possibly preserve the normal latency of the potential under
consideration.
The results show that the incidence of delayed VERs is significantly higher for
foveal small-size rectangle stimulation, but that the number of false-positive
findings was not different in the two groups. Foveal stimulation is therefore more
sensitive but equally reliable. This indicates that demyelination of foveal fibres is
very common.

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PATIENTS

Forty-five normal control subjects ranging between 15 and 65 years of age

were studied; 35 of them were healthy and 10 were patients with diseases not
affecting the eyes. Fifty-seven patients (aged from 15 to 69) were examined
because of a suspected diagnosis of multiple sclerosis. The diagnosis of multiple
sclerosis was made by clinical, nystagmographical and cerebrospinal fluid
examination and exclusion of other diseases by appropriate investigations.
In 14 patients the diagnosis remained unclear at the time of investigation.
Additionally 12 patients were examined with diseases suspected to affect the
visual pathways.
Neuro-ophthalmological examination was routinely performed (measurement
of visual acuity and intraocular pressure, pupillary response, visualfieldperimetry,
colour discrimination (Ishihara) and examination of the optic fundi). According
to the diagnostic criteria of McAlpine et al. (1972) three classes of multiple sclerosis
were differentiated: (a) definite diagnosis (n = 16), (b) probable diagnosis (n = 18)
and (c) possible diagnosis (n = 23).
Definite. (1) A history of an acute neurological episode with improvement but
one or more relapses in association with other signs indicating multiple lesions in
the central nervous system.
(2) A gradual onset of paraplegia later followed by relapses and signs indicating
brain-stem, cerebral or optic nerve disease.
Probable. (1) During the original attack clinical evidence of multiple lesions
followed by a good recovery. During a lengthy follow-up no clear-cut relapses but
with a tendency to variability in the original signs or the occasional late appearance
of new signs.
(2) A history of one or more attacks of acute optic neuritis accompanied or
followed by other signs, usually mild, with no clinical evidence of subsequent
relapse.
 VER ELICITED BY FOVEAL STIMULATION 121

Possible. (1) A history similar to that described under Probable (1) but with
unusual features, few signs or insufficient follow-up information.
(2) A history of progressive paraplegia without evidence of relapse or remission
or of a lesion outside the spinal cord, appropriate investigation, including
myelography, having excluded other causes.

METHODS

For two different stimulus conditions the average visual-evoked responses were recorded in an
evenly dimmed room. Refractive errors were corrected by using appropriate spectacles. A television
screen (Philips) producing 625 lines and 50 fields per second was placed 150 cm in front of the patient
who was instructed to fixate a spot marked on the centre of the monitor throughout each run. One
hundred and twenty-eight responses were averaged from each eye for two series successively.
In a first series (A) a black-and-white checkerboard pattern was produced on the monitor which

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routinely subtended 20° of the visual field. Reversals of the checkerboard were performed by a time-
pulse generator. At intervals of 800 ms the black squares became white and the white black. This resulted
in a rectangular pattern moving one square to the right or left alternately. The pulse triggering each
movement was also used to trigger a Nicolet computer to average the EEG recorded from the scalp
during the following 800 ms. The over-all luminance did not change. The luminance of the white squares
was 51-39 cd/m2, that of the black ones was 0-3426 cd/m2. Check size was 1° 10 min.
In a second series (B) a bright small-size rectangle (130 cd/m2) was applied on a diffuse monitor
illumination providing a background luminance of about 31 cd/m2.
This stimulus was placed in the visual axis subtending 45 min of the patient's central visual area
( = foveal stimulation). Triggered by a time-pulse generator this spot lasted for 700 ms. The interval
between two successive spot displays was 300 ms.
In a few control experiments, eye movements were observed by an infra-red detector and the EOG.
Routinely, fixation was controlled by continuously observing the summating VER; incorrect fixation
immediately leads to lack of the continuous increase of the amplitude of the VER. As shown in fig. 1,
the amplitude of the averaged EP decreases with increasing eccentricity of the stimulus from the visual
axis. This finding is in agreement with the observation of De Voe, Ripps and Vaughan (1968) who
showed that a 1° stimulus spot located at 5° eccentricity evoked a response which was minute
in comparison with a response evoked by the same spot centrally fixed.
The VER recorded from scalp electrodes was high pass filtered (a second order filter with asymptotic
break points at 1-5 and 300 Hz). The optimum electrode placement was studied in preliminary
experiments as shown in fig. 2: VERs were recorded from a chain of 3 electrodes in the mid-line (at
3, 6 and 9 cm above inion all referred to a common linked ear reference). The major positive potential
could best be recorded from the electrode 6 cm above the inion and this position was finally adopted
for all routine recordings. The EEG and the averaged signals were continuously monitored. This could
be displayed on to a storage oscilloscope or an x-y plotter. Each point of the curve could be digitally
analysed in amplitude and latency with a time resolution of 1 ms. Latencies refer to the time from
stimulus onset to the peak of the major positive potential.

RESULTS

(A) Normal Subjects

Checkerboard pattern-evoked responses were recorded monocularly in 35
healthy control subjects. A large positive wave with a peak latency of 90-110 ms
could generally be seen from both eyes. The mean peak latency was unaffected
122 M. HENNERICI, D. WENZEL AND H.-J. FREUND

by age up to about 65 years. For children up to 15 years the latency seemed to be

slightly increased (Weinmann, Creutzfeldt and Heyde, 1965), but further studies
are necessary to establish this observation (in preparation). In subjects between
15 and 65 years the mean latency was 102-5 ms (SD±2-92) for checkerboard
stimulation.

100 - •

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B 60-

40-

3.8

4.8°

I I I I I
1 2 3 4 5
distance between stimulus and fixation point (degrees)

FIG. 1. Changes of the averaged VER by successive application of a bright small-size rectangle (1° diameter)
at areas of increasing eccentricity, A, monocular recordings from a normal subject. The distance between the
fixation point and the small bright square stimulus (cf. Methods) is indicated in degrees on the left of each record.
B, decrease of amplitude of the major positive potential (measured from the peak of the preceding negative wave
to the peak of the major positive wave) with increasing eccentricity of the stimulus from the visual axis. The
amplitudes are expressed as a percentage of the values obtained by foveal stimulation. Each point represents the
mean of eight experiments.

Subsequently, evoked responses elicited by foveal small-size rectangle stimulation

were recorded from the same control group. For both methods, the shape of the
evoked potentials was similar, but they differed in amplitude and latency (fig. 3).
For foveal stimulation the amplitude of the VER was generally smaller and the
latency of the major positive potential was always longer, with a mean latency of
120 ms(SD± 3-46).
 VER ELICITED BY FOVEAL STIMULATION 123

v-.v ' .

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3|jV

100 msec
FIG. 2. Normal VERs to checkerboard pattern reversals: recorded monocularly with a chain of three different
electrode positions along the mid-line, 3 cm (upper row), 6 cm (middle row) and 9 cm above inion (lower row).
Each electrode was referred to a common linked ear reference.

From these experiments the upper limit of normal for the latency of the major
positive potential in the VER was defined as the mean + 3 S D = 112 ms for
checkerboard pattern and 130 ms for foveal small-size rectangle stimulation. This
latency was not exceeded in any of the 35 control subjects or in the 10 patients with
diseases not affecting the visual system.
Fig. 4 summarizes the results of the normal control group: each point indicates
the value of the major positive peak-latency for both eyes separately. Open circles
represent foveal small-size rectangle and dark circles checkerboard pattern
stimulation. Only 2 eyes out of a total of 70 eyes showed a latency of more than
107 ms for checkerboard pattern stimulation and only 3 eyes exceeded a latency
of 125 ms for foveal small-size rectangle stimulation respectively.
Both groups are clearly separated and did not vary remarkably as opposed to
large field-bright and flash stimulation (Richey, Kooi and Tourtelotte, 1971).
The standard deviation for foveal small-size rectangle stimulation was slightly
higher than that for checkerboard pattern stimulation.
124 M. HENNERICI, D. WENZEL AND H.-J. FREUND

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FIG. 3. Normal VERs elicited from the left and right eye by checkerboard pattern reversal (A) and bright small-
size rectangle stimulation (B). The vertical lines illustrate the latencies of the peak of the major positive potential.
Note the differences in shape and amplitude as well as the latency of the VERs for the two stimulation procedures.
Calibrations: 1 ^V and 100 ms.

1301

o
oo o
o o
oo
o
o 0
J 120- o O O
o oo o
o o
o°
o o 0 o
o oo
oo
•3
o o o
o

. 110-
* .a.
••
•• •• •
•
• •
•• ••
. 100-
• • r• •
•
100 110 120 130
latency to peak ol major positive potential I msec)
- right eye -

FIG. 4. Comparison of the latencies of the major positive potential from 35 control subjects between checker-
board pattern reversal (dark circles) and bright small-size rectangle stimulation (open circles). Each symbol
represents the value of the left (ordinate) and right eye (abscissa) of a normal subject. Note the strong separation
but similar variance of each group.
 VER ELICITED BY FOVEAL STIMULATION 12S

No significant difference between the latencies of the two eyes could be detected
for both stimulation procedures; the mean difference of the sample was 3-25 ms
(SD±l-9) for checkerboard pattern and 315 ms (SD±l-8) for foveal small-size
rectangle stimulation. The upper limit for differences in latency between the two
eyes are defined as mean + 3 SD (about 9 ms for the two normal populations).
The shape and amplitude of the VER showed considerable variation between
subjects, even if electrode and recording parameters and visual acuity were carefully
controlled. These are the factors which contribute most to changes of shape and
amplitude (Halliday, McDonald and Mushin, 19736). The reliability of the
latency and amplitude of a usually small preceding and of a following wave in
reference to the major positive potential was not considered in the present paper.

(B) Multiple Sclerosis Subjects

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Incidence of Abnormal Latencies in Response to Checkerboard Pattern and Foveal
Small-size Rectangle Stimulation
Investigations were performed in 57 patients suspected of multiple sclerosis.
According to the classification of McAlpine et al. (1972) patients were grouped
into a definite (n = 16), probable (n = 18) or possible multiple sclerosis (n = 23).

100 - i n=16 n= 18

80-

60-

40-

20-

0-1
probable possible
MS MS undiagnosed

FIG. 5. Percentage of prolonged latencies of the major positive potential after checkerboard reversal (black
column) and foveal small-size rectangle stimulation (white column) in patients with definite, probable, possible
multiple sclerosis and sample of undiagnosed patients.

Delayed latencies to the major positive potential could be seen in 35 cases (61 per
cent) examined by checkerboard pattern stimulation, and in 50 patients (88 per
cent) examined by foveal small-size rectangle stimuli. Thus the over-all incidence
of significantly delayed VER is clearly higher for the latter. The comparison of the
three different categories and of a group of undiagnosed cases is shown infig.5.
126 M. HENNERICI, D. WENZEL AND H.-J. FREUND

In definite cases of multiple sclerosis 81 per cent of the checkerboard pattern

evoked and 94 per cent of the foveal small-size rectangle evoked responses showed
a clear delay in latencies of the major positive potential. Fig. 6 shows typical VER
abnormalities for a patient of that group with a history of optic neuritis of the
right eye. The latency of the major positive potential of the right eye for checker-
board stimulation is increased by 62 ms (A) and for foveal small-size rectangle
stimulation (B) by 107 ms. Another common abnormality is the broadening and
splitting of the major positive potential.

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RIGHT EYE

FIG. 6. Typical VER recordings of a patient suffering from 'definite' multiple sclerosis with a history of optic
neuritis of the right eye. There is a delay and distortion of the major positive potential. Calibrations: 1 ^V and
100 ms.

For probable multiple sclerosis 67 per cent (checkerboard pattern-evoked

responses) and 94 per cent (foveal small-size rectangle evoked responses) showed
a clear delay. For the third group {possible disease), the proportion was 43 per
cent for the checkerboard pattern evoked, and 78 per cent for the foveal
small-size rectangle response. It appears that the difference in the number of
delayed responses evoked by the two methods is greatest in the two uncertain
groups.
 VER ELICITED BY FOVEAL STIMULATION 127

Fig. 7 gives an example of a typical VER of a patient with possible multiple

sclerosis, suffering from spastic paraplegia without any signs of other lesions at
the time of recording. Whereas for checkerboard stimulation the VERs of both
eyes were normal, the latency was increased for foveal small-size rectangle
stimulation of the left eye (35 ms). In addition, the major positive potential was
broadened.

RIGHT EYE

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FIG. 7. Typical VER recordings of a patient suffering from 'possible' multiple sclerosis with only spinal symptoms
but no signs of an involvement of the visual system. Note the delay and broadening of the major positive potential
of the left eye after foveal small-size rectangle stimulation. Checkerboard reversal produced normal VERs from
both eyes as in the case of foveal small-size rectangle stimulation of the right eye. Calibrations: 1 >xV and 100 ms.

The higher sensitivity of foveal small-size rectangle stimulation for the detection
of small demyelinating lesions in the optic nerve has already been suggested (fig. 5).
It is further supported by the separate evaluation of the results obtained in patients
with and without a history or ophthalmological signs of optic neuritis. As shown
in Table 1, all patients with a positive history of optic neuritis had delayed responses
to both kinds of stimulation. But in the patients without a positive history
a delay was much more frequently found by foveal small-size rectangle
stimulation.
128 M. HENNERICI, D. WENZEL AND H.-J. FREUND

TABLE 1. PERCENTAGE OF DELAYED VER ELICITED BY CHECKERBOARD REVERSAL (ch)

AND FOVEAL (f) SMALL-SIZE RECTANGLE STIMULATION IN 57 PATIENTS WITH MULTIPLE
SCLEROSIS.

Definite MS Probable MS Possible MS

ch f ch f ch f
History of optic neuritis and/or 100% 100% 100% 100% 100% 100%
optic atrophy
No optic neuritis 57 86 57 93 35 75
The patients were grouped into two classes, one with and one without a history or findings indicating
previous optic neuritis.

The distribution of the actual latencies of the peak of the major positive

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component is shown in fig. 8 for both methods. The hatched area represents the
values falling within the normal latency limits. It appears that the probability of
patients with multiple sclerosis having normal latencies is clearly lower for foveal
small-size rectangle than for checkerboard pattern stimulation. This is true for all
three groups. For the normal population, the distribution of the foveal small-size
rectangle stimulation group is broader and therefore the confidence limit for
pathological values is further from the mean. But there are no false positive
results.

poltern - evoked-responses

120 IU) 1E0 130 2C0

control subjects
l?0 "0 160 ISO 200
lotency lo peak of major positive potential (msec)

FIG. 8. Comparison of the latencies of the major positive potential elicited by checkerboard pattern reversal
(upper part) and foveal small-size rectangle stimulation (lower part). The plot represents the values from each
eye of patients with definite, probable and possible multiple sclerosis and a normal control group. The range of
normal latencies is indicated by hatched lines.
 V E R E L I C I T E D BY F O V E A L S T I M U L A T I O N 129

Proportion of Monocular Delays

From the 35 patients with a delayed VER in response to checkerboard
stimulation, 10 (29 per cent) showed delays only from one eye, whereas 25 (71 per
cent) had delayed responses from both eyes. From the 50 patients with abnormal
latencies in response to foveal small-size rectangle stimulation, 13 patients (26 per
cent) had monocular and 37 (74 per cent) binocular delays. The proportion is
therefore similar for both methods of stimulation.

(C) Abnormal Latencies in Other Diseases

The specifity of the two methods with respect to optic nerve lesions is about
equally good. Delayed responses are obtained either in patients suspected of having
multiple sclerosis or other lesions affecting the primary visual pathways. This is
shown in Table 2, where, except in the patients with suspected multiple sclerosis,

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those patients with papillitis and ischaemic optic neuropathies have delayed
responses for both methods of stimulation.

TABLE 2. INCIDENCE OF DELAYED VER IN DIFFERENT CLINICAL GROUPS

No. of delayed VER

No. of cases ch f
A. Progressive spastic paraparesis in
(a) definite MS with multiple signs 5 5 5
(b) definite MS with small signs 2 1 1
(c) probable MS 6 4 6
(d) possible MS 7 3 4
(e) undiagnosed 14 5 6
B. Isolated brain-stem lesion 4 2 3
C. Ischxmic optic neuropathy 5 5 5
Optic nerve compression 1 0 1
Papillitis 2 2 2
Congenital nystagmus 2 0 2
Tumours of posterior fossa 2 2 0
ch = checkerboard stimulation. f = foveal small-size rectangle stimulation.

There are two exceptions pointing to false-positive results obtained with one of
the two methods of stimulation. Using foveal small-size rectangle stimulation
2 cases with congenital nystagmus had slightly prolonged latencies. In contrast,
the latencies in response to checkerboard pattern stimulation were normal. In
these cases with false-positive results after foveal small-size rectangle stimulation
the amplitudes of the major positive potentials were significantly diminished, but
the shape of the potential was normal. The discrepancy between the small delay
and the remarkable reduction of the amplitude of the major positive potential
without characteristic changes in shape is quite uncommon. These findings differ
i
130 M. HENNERICI, D. WENZEL AND H.-J. FREUND

markedly from VER abnormalities seen so far in cases indicating optic nerve
lesion by abnormal foveal small-size rectangle but normal checkerboard pattern-
evoked responses.
False-positive results of checkerboard pattern stimulation were seen in 2 cases.
Both were patients with a tumour of the posterior fossa. Fig. 9 shows the left eye
checkerboard pattern-evoked responses and foveal small-size rectangle evoked
responses of a 41-year-old patient suffering from an astrocytoma of the medulla
oblongata with a cyst of the left cerebellar hemisphere. The responses of the
right eye were similar to those shown in this figure. Neuro-ophthalmological
investigations were normal except for slight papilloedema in both fundi. The
tumour led to a distortion and dislocation of the brain-stem near the tentorium.
The latency of the checkerboard pattern-evoked VER was clearly lengthened
above the 3 SD limit, whereas the foveal small-size rectangle evoked responses

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were normal (upper row). After surgical treatment the latency of the response to
checkerboard stimulation turned to the normal (lower row).

FIG. 9. VER recordings of the left eye of a patient suffering from an astrocytoma of the medulla oblongata
before (upper row) and after surgical treatment (lower row). For foveal small-size rectangle stimulation (right)
no abnormalities of the VER can be seen in both records. The latency of the major positive potential elicited by
checkerboard reversal was clearly delayed before surgery and returned to normal afterwards. In this case no
relevant change of the shape of the potential can be observed. Calibrations: 1 fiV and 100 ms.
 VER ELICITED BY FOVEAL STIMULATION 131

The complementary use of both methods seems to be the safest way to avoid
false-positive findings of one method. Therefore, in cases of doubt, the combined
application of foveal small-size rectangle and checkerboard stimulation is the
suggested approach.

DISCUSSION
Our results confirm the recent findings of Halliday, McDonald and Mushin
(1973a, b), Asselman, Chadwick and Marsden (1975) and Lehmann and Mir
(1976) that the technique of recording visual evoked responses to checkerboard
pattern reversal stimulation is a useful way of detecting optic nerve damage even
in the absence of clinical visual impairment. A delay of the latency to the major
positive potential was found in 81 per cent of 'definite' and 67 per cent of 'probable'

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cases of multiple sclerosis. These results are in agreement with those reported by
Asselmann et al. (1975) and differ only slightly from the data reported by Halliday
etal. (1973a).
Delayed VERs are frequently obtained in patients without any abnormal
neuro-ophthalmological findings even when the improved method of fundoscopy
applied by Feinsod and Hoyt (1975), and Hoyt, Frisen and Newman (1973) is
used. Small-size rectangle stimulation of the fovea has been shown to further
improve the sensitivity of the method. This is particularly true for patients with
spinal multiple sclerosis (cf. Table 2) where the incidence of delayed VER was
more than 90 per cent. In spite of the small sample (n = 20) examined so far, this
figure is higher than that obtained by the combined use of several stimulation
methods (Regan, Milner and Heron, 1976). In contrast, for patients suffering from
symptoms of unknown aetiology without clinical evidence of multiple sclerosis
(e.g. 'undiagnosed' spastic paraplegia) about 40 per cent showed lengthened
latencies for both stimulation procedures. In addition, there were no false positive
results in the normal group for both kinds of stimulation. The higher incidence of
abnormal latencies after foveal small-size rectangle stimulation is therefore
unlikely to be due to a greater number of false positive results. For both methods
the same significance criteria as to 'normal' or 'pathological' were assessed:
(1) lengthening of the latency beyond the normal upper limit (mean + 3 SD),
(2) excessive difference in latency between the 2 eyes if combined with a monocular
delay of not yet significantly pathological value, (3) amplitude and shape difference
of the VER were only taken into account with abnormalities of the former groups.
Delayed VERs are not specific to multiple sclerosis. In accordance with recent
investigations additional examination of other neurological disorders showed
that delays could be observed in many disorders involving the primary afferent
visual pathways. They have been reported for some cases of spino-cerebellar
atrophy with optic atrophy, of compressive lesions to the optic nerve, hereditary
isolated optic atrophy and glaucoma (Cappin and Nissim, 1975). Ischaemic optic
neuropathy also leads to delayed VERs (Table 2). Small delays and characteristic
132 M. H E N N E R I C I , D. W E N Z E L A N D H.-J. F R E U N D

alterations in wave form and distribution have been reported recently in patients
suffering from tumours with compression of the anterior visual pathways (Halliday,
Halliday, Kriss, McDonald and Mushin, 1976). In our results false-positive
abnormal latencies were found in two cases without optic nerve lesions with both
kinds of stimuli. Using foveal small-size rectangle stimulation 2 patients with
congenital nystagmus had prolonged latencies. With checkerboard stimulation,
2 patients with tumours of the posterior fossa had delayed responses. The reason for
this is unknown. Whether there is an indirect pressure effect on the visual path-
ways in the latter patients remains an open question.
The quantitative comparison of latencies elicited by different methods of
stimulation or even between different laboratories is of very limited value. The
mean and the confidence limits of the normal distribution have to be established
for the particular stimulus condition used in each laboratory. Not only differences

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of stimulus luminance, size and contrast but also fixation influences the actual
latencies. Lehmann and Mir (1976) have recently shown that the latency of the
major positive potential elicited by checkerboard inversion in the upper retina is
on the average 22 ms shorter than that evoked by the same stimulus in the lower
retina.
Are the Two Modes of Stimulation Testing Different Parts of the Optic Nerve?
The actual site where the major positive potential of the VER is generated is
unknown. Investigations of the development of the field potentials after visual
stimulation showed that this potential appears first over the occipital cortex
(Lehmann, Meles and Mir, 1976). The time delay between thefirstparts of the VER
and the major positive potential indicates that the latter is not reflecting
the primary afferent input to the cortex but later processes. Whatever its nature,
the latency of this complex does depend on the same two factors determining the
latencies of the cells along the primary afferent visual pathway: stimulus magnitude
(for reference see Kuhnt, 1967) and axonal conduction velocity (McDonald,
1976). The dependence on conduction velocity is the basis for the diagnostic
application of the method.
If the latency of the potential depends on conduction velocity, then the latencies
should be different for stimulation of the foveal and peripheral parts of the retina.
Both morphological and physiological evidence from the cat (Stone and Freeman,
1971; Stone and Hollander, 1971), monkey (Ogden and Miller, 1966) and the
morphological data from human optic nerves (Chako, 1948, Polyak, 1957;
van Buren, 1963) indicate that the axons from foveal ganglion cells are much
smaller than those from the periphery, the conduction velocity of the former being
only about one-half that of the latter. Since fast conducting optic nerve fibres
synapse on the large geniculate relay cells with large axons, the relationship remains
preserved for the postgeniculate projection.
Stimulating the periphery and the fovea simultaneously should therefore result
in sequential arrival of the volleys giving rise to the potential under consideration.
 VER ELICITED BY FOVEAL STIMULATION 133

The latency of the potential should then represent the contribution of the faster
conducting axons arising from the retinal periphery. In cases of selective lesions of
fovealfibres,no change in latency should be observed. This assumption is supported
by the result that some of the patients had abnormal latencies only after foveal
stimulation. In such cases the potentials generated from the fovea would be
hidden by the potentials generated by the faster conducting peripheral fibres when
a checkerboard stimulus is used.
Rietveld, Tordoir, Hagenouw, Lubbers and Spoor (1967) showed that for
stimulation of large retinal areas roughly 30 per cent of the early major VER
amplitude is due to stimulation outside the central 3°, if a particularly small
check-size of 15' in diameter is used. The macular region was therefore suggested
to be the prime generating area of the VER. On the other hand, Halliday and
Michael (1970) using greater check-sizes of 50' in diameter reported that checker-

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board pattern reversal evoked potentials elicited by a stimulus falling on to the
central area of about 4° in diameter were of similar amplitudes to those recorded
to a stimulus falling within an annular region whose internal diameter was 4° and
external diameter 16°. Their results are in accordance with Harter's observation
(1971). He showed that the check size eliciting the largest visual evoked potentials
grows progressively with eccentricity of the stimulus. Checks of 30'-60' may be
optimal for stimuli of 4-5°-7-5° eccentricity, whereas checks of 7-5'-30-0' gave
the largest responses for central foveal stimulation. For the clinical measurements
reported so far check sizes were of about 1° in diameter, and hence the amplitudes
of the early components of the visual evoked potentials are probably not due to
stimulation of the central 3°-4° of the visual field but rather of extrafoveal regions
(Halliday, McDonald and Mushin, 1972, 1973a, b\ Asselman, Chadwick and
Marsden, 1975; Lehman and Mir, 1976).
If checkerboard stimulation reveals the conduction of the peripheral fibres,
a certain proportion of patients should show normal latencies after foveal small-
size rectangle and abnormal latencies after pattern checkerboard stimulation
indicating demyelination in peripheral fibres but not in foveal ones. This could not,
however, be observed. Whether this simply indicates that there is almost always
involvement of the axons originating from the area centralis is unclear. The large
number of these fibres and their extended cortical representation caused by the
central magnification factor could account for this result.
Whereas the principal relationship between the latency, even of the late major
positive potential and slowing of conduction in the optic nerve is well established,
the nature of these changes is in no way clear. In addition to the known difficulties
of attributing the latencies of the peaks of these composite evoked potentials to
the underlying neuronal mechanisms (for discussion see MacKay and Jeffreys,
1973), the delayed VERs in patients with only partial demyelinating optic nerve
lesions are difficult to understand. At least some of the patients with delayed
VERs have only restricted demyelinating optic nerve lesions according to
ophthalmological and patho-anatomical evidence. However, the remaining intact
134 M. H E N N E R I C I , D. WENZEL A N D H.-J. F R E U N D

fibres should certainly be sufficient to preserve normal conduction and thereby

latencies. McDonald (1976) has discussed the origin of the delay in the visual
evoked potential and concludes that it is unlikely that local slowing in
demyelinated fibres is the whole explanation. The problem of delayed VERs, if
a large part of the faster conducting axons are unaffected, raises an interesting
question about the neuronal mechanisms producing these potentials. Complex
interactions between different parts of the afferent input seem then to play a role
even for the timing of the evoked responses.

SUMMARY
The use of foveal small-size rectangle stimulation to elicit visual evoked responses

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was compared with VERs elicited by the standard checkerboard pattern. Foveal
stimulation achieved a significantly better discrimination of optic nerve lesions in
the early diagnosis of multiple sclerosis. Sources of misdiagnosis due to different
neurological disorders are discussed.

ACKNOWLEDGEMENTS

We thank Ing. H. Kapp for valuable technical assistance. We are indebted to Professor W.I. McDonald
and Dr. Lehmann for helpful comments on the manuscript. This work was supported by the Deutsche
Forschungsgemeinschaft, SFB 70.

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{Received July 13, 1976)

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