Brain (1973) 98, 261-282
VISUAL EVOKED RESPONSES IN THE DIAGNOSIS AND MANAGEMENT OF PATIENTS SUSPECTED OF MULTIPLE SCLEROSIS BY
INTRODUCTION HALLIDAY, MCDONALD AND MUSHIN (1972 and 1973) discovered that the visual evoked potential produced by pattern reversal stimulation was often abnormal in patients with optic neuritis or multiple sclerosis. The latency to the peak of the first major positive potential recorded from the affected eye was delayed in 17 of 18 patients with optic neuritis, 16 of whom were studied in the acute phase. Such a delayed response could be recorded for up to five years after the acute episode of loss of vision, even when visual acuity had returned to normal. In a subsequent series of 51 patients with multiple sclerosis no less than 49 had significant delay in the pattern evoked response (in one eye in 14 cases, and both eyes in 35 cases). Only 24 of these patients gave a history suggestive of optic neuritis, and only 28 were found to have optic atrophy. In 8 patients with significant delay, full ophthalmological investigation did not detect any abnormality in the fields, fundi, pupils or acuity. Halliday, McDonald and Mushin concluded that "the latency of the pattern-evoked response is the single most reliable index of persisting damage to the visual pathways," and that this "is a valuable test in the early diagnosis of multiple sclerosis, particularly in cases presenting without signs of a lesion above the foramen magnum." We report here our own studies on visual potentials evoked by pattern reversal in 51 patients with multiple sclerosis, and in 55 patients with other neurological disorders. We have also found a high incidence of abnormality in the pattern-evoked responses in patients with multiple sclerosis, and in some other neurological diseases affecting the optic nerves. MATERIAL
Fifty-four control subjects aged 20 to 74 years (37 of whom were healthy and 17 of whom were patients with diseases not affecting the eyes); 51 patients with multiple sclerosis (aged 22 to 67) and 55 patients (aged 16 to 70) with other neurological diseases that might involve the visual apparatus were studied. All were assessed
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
P. ASSELMAN, D. W. CHADWICK AND C. D. MARSDEN {From the University Department of Neurology, Institute of Psychiatry, and King's College Hospital Medical School, London SE5)
262
P. ASSELMAN, D. W. CHADWICK AND C. D. MARSDEN
METHODS
The average visual-evoked response (VER) to pattern reversal stimuli was recorded in the dark from each eye separately in all patients. A slide of a black and white checkerboard-pattern was back-projected via a mirror mounted on a pen motor on to a translucent screen in front of the subject. The current delivered to the pen motor was modulated to cause the mirror to rotate through a small angle, producing side to side movements of the pattern on the screen. The amplitude of the movement was adjusted so that the pattern moved alternately one square to the right or left every 750 msec. The overall luminance of the field did not change. The luminance of individual white squares was 1,929 cd per sq m, that of the black squares was 122 cd per sq m. The pulse triggering each movement of the mirror was also used to trigger a PDP-12 computer to average the signals recorded from the subject's scalp for the succeeding 250 msec. There was a small delay of 1 msec between this pulse and the start of the mirror movement, and the mirror took 5 msec to complete a single rotation. 128 responses (64 pattern movements to the right and 64 pattern movements to the left) were averaged from each eye separately, and three such averages were subsequently
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
clinically; in particular the visual acuity (Snellen charts) with correction for refractive error, colour vision (lshihara charts), pupillary responses, visual fields (perimetry, Bjerrum screen and other techniques), and the state of the optic fundi were recorded. The diagnosis of multiple sclerosis was made on the basis of clinical assessment, examination of the cerebrospinal fluid and exclusion of other diseases by appropriate investigation including contrast radiography. The diagnostic criteria of Halliday, McDonald and Mushin (1973), which were based on those of McAlpine, Lumsden and Acheson (1972), were used to separate cases of multiple sclerosis into categories of: Definite diagnosis.—(a) 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, or (b) a gradual onset of paraplegia later followed by relapses and signs of disease in brain-stem, cerebrum or optic nerves. Probable diagnosis.—(a) During the original episode 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, or (b) 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. Possible diagnosis.—(a) A history similar to that described under probable, but with unusual features or few signs or insufficient follow-up information, or {b) 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 of progressive paraplegia.
VER IN MULTIPLE SCLEROSIS
263
100ms*c
Fio. 1.—Normal VERs recorded from one eye by an electrode 5 cm above the inion referred to electrodes 10 cm above the inion, the vertex, prefrontal and frontal sites, A, Average response to 384 pattern displacements, each square subtending 30 minutes at the eye. B, AS in A, but a pattern each square of which subtended fifty-seven minutes at the eye. Subject C. D. M. In this and all subsequent records, positivity is indicated by a downward deflection.
larger pattern evoked a slightly smaller response. When the central field was obliterated by black discs of increasing diameter it was found that the VER amplitude was reduced to 50 per cent of control values by occlusion of the central 5 or 6° for both patterns (fig. 2). In the initial studies in patients the larger pattern only was used, but subsequently we have employed both sizes of pattern. The VER was recorded from scalp electrodes fed into Devices 3021 pre-amplifiers with a frequency response 3 db down at 2-5 kHz and a time constant of one second. The optimum electrode placement was studied in preliminary experiments. Fig. 3A illustrates the VER recorded from a chain of five electrodes in the mid-line (at 5 and 10 cm above the inion, and at vertex, midfrontal and frontal sites), all referred to a common linked-ear reference and with a lateral frontal earth. A large positive wave was recorded from the electrode 5 cm above the inion with phase reversal at the vertex and frontal sites. Fig. 3B illustrates the VER recorded from the same electrodes linked
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
averaged to produce a final VER comprising the average of 384 individual responses. The subject sat 50 cm in front of the screen, the whole stimulating field subtending 18° at the eye. The subject wore appropriate spectacles if suffering from refractive error. He was instructed to fixate on a spot marked on the centre of the screen throughout each run. (Preliminary experiments indicated that even if the subject attempted to follow the pattern, this did not substantially alter the VER, nor was there any significant difference between responses recorded from movements of the pattern to the right compared with those obtained with movements to the left.) Preliminary experiments were undertaken to investigate the optimum size of individual black and white squares. Two pattern sizes were investigated, one with each square subtending fifty-seven minutes at the eye, the other thirty minutes at the eye. The responses recorded with the two patterns were similar (fig. 1) but the
264
P . ASSELMAN, D . W. CHADWICK AND C. D . MARSDEN A
B
1-3
100-
A
1 •
A nSiraJI tq>nn fmttm (301 • —Urs« aqos* pittam (570
80.
A 60.
X
•
#
•
20
6
•
10
AREA OF CENTRAL VISION OCCLUDED (Dagnat)
FIG. 2.—Effect of progressive occlusion of central vision on the VER of one eye recorded from an electrode 5 cm above the inion referred to the vertex, A, Representative recordings from subject FM. The area of central vision occluded by black circular discs is shown in degrees to the left of each record, B, Amplitude of major positive potential (measured from the apex of the preceding negative wave to the peak of the major positive wave) in relation to degree of occlusion of central vision. The amplitudes are expressed as a percentage of control values, and the averages of data for five experiments on 3 subjects are shown, for both the small square pattern (A) and the large square pattern (•).
as a bipolar chain. The maximum response was recorded between the electrodes 5 and 10 cm above the inion, with little or no response between the frontal electrodes. Thus, the linked-ear reference was not electrically silent but saw a significant positive potential, while no activity was detectable anteriorly. Fig. 3c illustrates the VER recorded from the electrode 5 cm above the inion referred in sequence to each of the other electrodes. The maximum response was seen between the 5 cm electrode and the vertex; this arrangement was finally adopted for all routine recordings. Fig. 4 shows that with this electrode placement the greater part of the VER recorded when the subject fixated the centre of the screen was due to pattern-stimulation of the lower half-fields with less contribution from upper field stimulation, as described by Michael and Halliday (1971). In summary, the VER to pattern stimulation was finally routinely recorded from an electrode placed in the mid-line 5 cm above the inion referred to an electrode on the vertex, in response to 384 movements (alternating right and left) of a
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
A 40'
265
VER IN MULTIPLE SCLEROSIS A
B
100 mno
Fio. 3.—Normal VERs recorded from one eye with varying electrode arrangements to .384 reversals of a pattern with squares subtending fifty-seven minutes at the eye. A, Each electrode referred to a linked-ear reference electrode, B, Bipolar chain recording, c, Recording from the electrode 5 cm above the inion referred to each of the other electrodes in sequence (as in fig. 1). Subject C. D. M.
100
loo
Fio. 4.—Normal VERs recorded from one eye as described in the legend to fig. 1. A, With the subject fixating the centre of the upper border of the pattern, so that the lower fields only were stimulated, B, Fixating the centre of the lower border of the pattern to stimulate the upper fields only. Subject C. D. M.
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
100c
266
P. ASSELMAN, D . W. CHADWICK AND C. D. MARSDEN
pattern, each square of which subtended fifty-seven minutes at the eye. The resulting average VER depended primarily on stimulation of the central 6° of vision and on stimulation of the lower half of that central field. RESULTS
Control Subjects Variations in the form of the VER in control subjects are illustrated in fig. 5. A large positive wave with a latency to the peak of some 80-100 sec was present in both eyes
100 nwc
100 m we
FIG. 5.—VERs recorded in 4 normal subjects (A-D) from left (L) and right (R) eyes. Each VER was recorded from an electrode 5 cm above inion referred to the vertex, to 384 reversals of a pattern with squares subtending fifty-seven minutes at the eye. Note the large positive wave recorded from both eyes in all subjects, the slight differences in shape of the wave form between subjects, but the similarity between the two eyes in each individual, and the presence of an earlier smaller positive wave in the records shown in A and c.
in all 54 subjects. The range of latency to this positive peak is shown in fig. 6 in relation to age. Peak latency was unaffected by age up until about 60 years, but thereafter there was a tendency for it to increase. In subjects under the age of 60, mean latency was 90-5 msec (SD ±4-3). Over the age of 60 mean peak latency was significantly longer at 97-2 msec (SD+41) (P
VISUAL EVOKED RESPONSES IN THE DIAGNOSIS AND MANAGEMENT OF PATIENTS SUSPECTED OF MULTIPLE SCLEROSIS BY
INTRODUCTION HALLIDAY, MCDONALD AND MUSHIN (1972 and 1973) discovered that the visual evoked potential produced by pattern reversal stimulation was often abnormal in patients with optic neuritis or multiple sclerosis. The latency to the peak of the first major positive potential recorded from the affected eye was delayed in 17 of 18 patients with optic neuritis, 16 of whom were studied in the acute phase. Such a delayed response could be recorded for up to five years after the acute episode of loss of vision, even when visual acuity had returned to normal. In a subsequent series of 51 patients with multiple sclerosis no less than 49 had significant delay in the pattern evoked response (in one eye in 14 cases, and both eyes in 35 cases). Only 24 of these patients gave a history suggestive of optic neuritis, and only 28 were found to have optic atrophy. In 8 patients with significant delay, full ophthalmological investigation did not detect any abnormality in the fields, fundi, pupils or acuity. Halliday, McDonald and Mushin concluded that "the latency of the pattern-evoked response is the single most reliable index of persisting damage to the visual pathways," and that this "is a valuable test in the early diagnosis of multiple sclerosis, particularly in cases presenting without signs of a lesion above the foramen magnum." We report here our own studies on visual potentials evoked by pattern reversal in 51 patients with multiple sclerosis, and in 55 patients with other neurological disorders. We have also found a high incidence of abnormality in the pattern-evoked responses in patients with multiple sclerosis, and in some other neurological diseases affecting the optic nerves. MATERIAL
Fifty-four control subjects aged 20 to 74 years (37 of whom were healthy and 17 of whom were patients with diseases not affecting the eyes); 51 patients with multiple sclerosis (aged 22 to 67) and 55 patients (aged 16 to 70) with other neurological diseases that might involve the visual apparatus were studied. All were assessed
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
P. ASSELMAN, D. W. CHADWICK AND C. D. MARSDEN {From the University Department of Neurology, Institute of Psychiatry, and King's College Hospital Medical School, London SE5)
262
P. ASSELMAN, D. W. CHADWICK AND C. D. MARSDEN
METHODS
The average visual-evoked response (VER) to pattern reversal stimuli was recorded in the dark from each eye separately in all patients. A slide of a black and white checkerboard-pattern was back-projected via a mirror mounted on a pen motor on to a translucent screen in front of the subject. The current delivered to the pen motor was modulated to cause the mirror to rotate through a small angle, producing side to side movements of the pattern on the screen. The amplitude of the movement was adjusted so that the pattern moved alternately one square to the right or left every 750 msec. The overall luminance of the field did not change. The luminance of individual white squares was 1,929 cd per sq m, that of the black squares was 122 cd per sq m. The pulse triggering each movement of the mirror was also used to trigger a PDP-12 computer to average the signals recorded from the subject's scalp for the succeeding 250 msec. There was a small delay of 1 msec between this pulse and the start of the mirror movement, and the mirror took 5 msec to complete a single rotation. 128 responses (64 pattern movements to the right and 64 pattern movements to the left) were averaged from each eye separately, and three such averages were subsequently
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
clinically; in particular the visual acuity (Snellen charts) with correction for refractive error, colour vision (lshihara charts), pupillary responses, visual fields (perimetry, Bjerrum screen and other techniques), and the state of the optic fundi were recorded. The diagnosis of multiple sclerosis was made on the basis of clinical assessment, examination of the cerebrospinal fluid and exclusion of other diseases by appropriate investigation including contrast radiography. The diagnostic criteria of Halliday, McDonald and Mushin (1973), which were based on those of McAlpine, Lumsden and Acheson (1972), were used to separate cases of multiple sclerosis into categories of: Definite diagnosis.—(a) 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, or (b) a gradual onset of paraplegia later followed by relapses and signs of disease in brain-stem, cerebrum or optic nerves. Probable diagnosis.—(a) During the original episode 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, or (b) 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. Possible diagnosis.—(a) A history similar to that described under probable, but with unusual features or few signs or insufficient follow-up information, or {b) 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 of progressive paraplegia.
VER IN MULTIPLE SCLEROSIS
263
100ms*c
Fio. 1.—Normal VERs recorded from one eye by an electrode 5 cm above the inion referred to electrodes 10 cm above the inion, the vertex, prefrontal and frontal sites, A, Average response to 384 pattern displacements, each square subtending 30 minutes at the eye. B, AS in A, but a pattern each square of which subtended fifty-seven minutes at the eye. Subject C. D. M. In this and all subsequent records, positivity is indicated by a downward deflection.
larger pattern evoked a slightly smaller response. When the central field was obliterated by black discs of increasing diameter it was found that the VER amplitude was reduced to 50 per cent of control values by occlusion of the central 5 or 6° for both patterns (fig. 2). In the initial studies in patients the larger pattern only was used, but subsequently we have employed both sizes of pattern. The VER was recorded from scalp electrodes fed into Devices 3021 pre-amplifiers with a frequency response 3 db down at 2-5 kHz and a time constant of one second. The optimum electrode placement was studied in preliminary experiments. Fig. 3A illustrates the VER recorded from a chain of five electrodes in the mid-line (at 5 and 10 cm above the inion, and at vertex, midfrontal and frontal sites), all referred to a common linked-ear reference and with a lateral frontal earth. A large positive wave was recorded from the electrode 5 cm above the inion with phase reversal at the vertex and frontal sites. Fig. 3B illustrates the VER recorded from the same electrodes linked
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
averaged to produce a final VER comprising the average of 384 individual responses. The subject sat 50 cm in front of the screen, the whole stimulating field subtending 18° at the eye. The subject wore appropriate spectacles if suffering from refractive error. He was instructed to fixate on a spot marked on the centre of the screen throughout each run. (Preliminary experiments indicated that even if the subject attempted to follow the pattern, this did not substantially alter the VER, nor was there any significant difference between responses recorded from movements of the pattern to the right compared with those obtained with movements to the left.) Preliminary experiments were undertaken to investigate the optimum size of individual black and white squares. Two pattern sizes were investigated, one with each square subtending fifty-seven minutes at the eye, the other thirty minutes at the eye. The responses recorded with the two patterns were similar (fig. 1) but the
264
P . ASSELMAN, D . W. CHADWICK AND C. D . MARSDEN A
B
1-3
100-
A
1 •
A nSiraJI tq>nn fmttm (301 • —Urs« aqos* pittam (570
80.
A 60.
X
•
#
•
20
6
•
10
AREA OF CENTRAL VISION OCCLUDED (Dagnat)
FIG. 2.—Effect of progressive occlusion of central vision on the VER of one eye recorded from an electrode 5 cm above the inion referred to the vertex, A, Representative recordings from subject FM. The area of central vision occluded by black circular discs is shown in degrees to the left of each record, B, Amplitude of major positive potential (measured from the apex of the preceding negative wave to the peak of the major positive wave) in relation to degree of occlusion of central vision. The amplitudes are expressed as a percentage of control values, and the averages of data for five experiments on 3 subjects are shown, for both the small square pattern (A) and the large square pattern (•).
as a bipolar chain. The maximum response was recorded between the electrodes 5 and 10 cm above the inion, with little or no response between the frontal electrodes. Thus, the linked-ear reference was not electrically silent but saw a significant positive potential, while no activity was detectable anteriorly. Fig. 3c illustrates the VER recorded from the electrode 5 cm above the inion referred in sequence to each of the other electrodes. The maximum response was seen between the 5 cm electrode and the vertex; this arrangement was finally adopted for all routine recordings. Fig. 4 shows that with this electrode placement the greater part of the VER recorded when the subject fixated the centre of the screen was due to pattern-stimulation of the lower half-fields with less contribution from upper field stimulation, as described by Michael and Halliday (1971). In summary, the VER to pattern stimulation was finally routinely recorded from an electrode placed in the mid-line 5 cm above the inion referred to an electrode on the vertex, in response to 384 movements (alternating right and left) of a
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
A 40'
265
VER IN MULTIPLE SCLEROSIS A
B
100 mno
Fio. 3.—Normal VERs recorded from one eye with varying electrode arrangements to .384 reversals of a pattern with squares subtending fifty-seven minutes at the eye. A, Each electrode referred to a linked-ear reference electrode, B, Bipolar chain recording, c, Recording from the electrode 5 cm above the inion referred to each of the other electrodes in sequence (as in fig. 1). Subject C. D. M.
100
loo
Fio. 4.—Normal VERs recorded from one eye as described in the legend to fig. 1. A, With the subject fixating the centre of the upper border of the pattern, so that the lower fields only were stimulated, B, Fixating the centre of the lower border of the pattern to stimulate the upper fields only. Subject C. D. M.
Downloaded from http://brain.oxfordjournals.org/ by guest on December 5, 2015
100c
266
P. ASSELMAN, D . W. CHADWICK AND C. D. MARSDEN
pattern, each square of which subtended fifty-seven minutes at the eye. The resulting average VER depended primarily on stimulation of the central 6° of vision and on stimulation of the lower half of that central field. RESULTS
Control Subjects Variations in the form of the VER in control subjects are illustrated in fig. 5. A large positive wave with a latency to the peak of some 80-100 sec was present in both eyes
100 nwc
100 m we
FIG. 5.—VERs recorded in 4 normal subjects (A-D) from left (L) and right (R) eyes. Each VER was recorded from an electrode 5 cm above inion referred to the vertex, to 384 reversals of a pattern with squares subtending fifty-seven minutes at the eye. Note the large positive wave recorded from both eyes in all subjects, the slight differences in shape of the wave form between subjects, but the similarity between the two eyes in each individual, and the presence of an earlier smaller positive wave in the records shown in A and c.
in all 54 subjects. The range of latency to this positive peak is shown in fig. 6 in relation to age. Peak latency was unaffected by age up until about 60 years, but thereafter there was a tendency for it to increase. In subjects under the age of 60, mean latency was 90-5 msec (SD ±4-3). Over the age of 60 mean peak latency was significantly longer at 97-2 msec (SD+41) (P
