Brain (1977), 100, 19-40
ABNORMALITIES OF THE AUDITORY EVOKED POTENTIALS IN PATIENTS WITH MULTIPLE SCLEROSIS by KATHLEEN ROBINSON and PETER RUDGE (From the Department of Clinical Neurophysiology, and the Medical Research Council, Hearing and Balance Unit, Institute of Neurology, National Hospital, Queen Square, London WC1N 3BG)
INTRODUCTION
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M U L T I P L E SCLEROSIS is a disease characterized by multiple areas of demyelination in the central nervous system and the clinical diagnosis depends upon the demonstration of two or more such lesions. A major problem occurs in the early stages of the disease when the patient presents with a single lesion. Until recently the only methods for detecting other sites of demyelination were clinical and patients often underwent unpleasant and potentially hazardous investigations to exclude other pathologies; for instance myelography was performed in patients with an apparently isolated spinal cord lesion. Any method that demonstrates multiple sites of demyelination in such patients would obviously be of great value. With the development of averaging techniques it has been possible to record, through scalp electrodes, cortical potentials evoked by sensory stimuli. Initial studies of the visual system showed that the cortical potentials evoked by flash stimuli were abnormal in multiple sclerosis patients as a group, but the difference was not sufficient to separate individual patients from normal subjects (Richey, Kooi and Tourtellotte, 1971). This difficulty was overcome by using a reversing pattern checkerboard as the visual stimulus, when there is minimal overlap in the latency of the evoked potential between patients with optic neuritis and normal subjects. Furthermore the latency was abnormal not only in patients with clinical optic neuritis but also in a high proportion of those with apparently normal visual pathways (Halliday, McDonald and Mushin, 1973; Asselmann, Chadwick and Marsden, 1975; Regan, Milner and Heron, 1976). Although clinical deafness is rare in multiple sclerosis we were encouraged by the ability of evoked potential studies to detect silent lesions in the optic nerve and have investigated the auditory system. In the auditory system fifteen components of the auditory evoked potential occur within 300 ms of a click stimulus. These components have been classified by
20
KATHLEEN ROBINSON AND PETER RUDGE
METHODS 1. The Auditory Evoked Potential Two channels of the electro-encephalogram were averaged simultaneously from surface electrodes on each mastoid and a common electrode at the vertex. The electrodes were connected so that a positivegoing potential at the vertex, relative to the mastoid, caused a down-going deflection. Averaged responses were collected with a signal averager (Biomac 1000, i.e. 1000 words of store, Data Laboratories Ltd., Mitcham, UK). In all cases the result was the average of 512 individual responses. Each average response was punched on to paper tape which was fed into a PDP12 computer and stored on magnetic tape for further analysis. As the auditory evoked potential recorded from both channels was highly superimposable for all the components, measurements were made for one channel only. The auditory stimulus was a click of 0-5 ms duration, 95-7 dBC sound pressure level re 2-10~5 Pa (approx. 75 dB sensation level) which was presented binaurally to the subject through earphones. (a) Early components. Two distinct types of wave form for the early components have been described (compare Picton, Hillyard, Krausz and Galambos, 1974 with Lieberman, Sohmer and Szabo, 1973). As it was suspected that the difference between wave forms is due to the varying amounts of filtering used at the low-frequency end of the spectrum, a preliminary study of the low-frequency filter was undertaken. The effect of the low-frequency filter can be simulated by digital methods. Various filter settings were simulated using the same original record, and it was confirmed that the low-frequency filter does indeed cause alterations in the wave form of the early components (fig. 1). It will be noted that with a low-frequency filter of 0-8 Hz there is a marked change in the shape of component V due
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latency into early (0-8 ms), middle (8-50 ms) and late (more than 50 ms) components (Picton, Hillyard, Krausz and Galambos, 1974). The late components represent the vertex response and probably arise from cortical structures. The generators for the middle components are unknown. Reflex muscle responses have been reported at a similar latency (Kiang, Christ, French and Edwards, 1963; Cody and Bickford, 1969) and it has been suggested that the two are related (Thornton, 1975). Extensive work in the cat has shown that the early components depend upon the integrity of the eighth nerve and the brain-stem (Jewett, 1970; Buchwald and Huang, 1975). Since demyelination is common in the brain-stem of patients with multiple sclerosis it was thought that alteration of the early components of the auditory evoked potential might occur. Preliminary studies showed that this was indeed the case, and, moreover, that the abnormalities were not confined to latency (Robinson and Rudge, 1975). A larger sample of patients with clinically definite multiple sclerosis (McAlpine, Lumsden and Acheson, 1972) has now been studied with the following aims. First, to confirm the preliminary findings for the auditory evoked potential with particular emphasis on the use of amplitude as well as latency as a valid measure of abnormality. Secondly, to extend the investigation to all the components of the auditory evoked potential. Thirdly, an attempt has been made to stress the auditory system by presenting click stimuli in pairs. We have also studied the reflex response of muscles to the click in normal subjects to assess its contribution to the middle latency components.
AUDITORY EVOKED POTENTIALS IN MS
21
to the superimposition of a slower wave at this latency. This filter setting was used in the present study since the inclusion of the lower frequencies facilitated the identification of component V. For the early components the electro-encephalogram was amplified using a low-frequency cut off at 0-8 Hz (3 dB point, with a slope 6 dB Oct- 1 ) and high-frequency cut off at 2-5 kHz (slope —6 dB Oct- 1 ). The sweep duration of the averager was 40 ms. The auditory evoked potential was smoothed digitally using a three point moving averagefilter.The latency was measured from the onset of the click to the downgoing peak of each component and could be estimated to within 80 f*.s. The amplitudes of components II, III, VI and VII were measured to the preceding upgoing peak, and that of component V to the upgoing peak preceding component IV. The amplitude of component I was measured to the baseline as estimated from the prestimulus level.
B
I
10 ms
FIG. 1. Simulation of effect of the low-frequency filter upon early components of the auditory evoked potential. Original record shown in A, low-frequency filter = 0-8 Hz (slope — 6 dB Oct- 1 ). B, low-frequency filter = 100 Hz (slope - 6 d B Oct- 1 ). c, low-frequency filter = 250 Hz (slope - 6 dB Oct- 1 ). D, low-frequency filter = 250 Hz (slope —12 dB Oct- 1 ). Component V indicated. Horizontal scale, time in ms. Bar 0-5 jtV. Stimulus starts at
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[O-5JUV
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KATHLEEN ROBINSON AND PETER RUDGE
Pairs of clicks. The early components were also recorded when the stimulus was a pair of clicks, 5 ms apart, each of 0-5 ms duration, presented binaurally at an intensity of 95-7 dBC sound pressure level re 2-10"5 Pa. The recording and measurement of these early components was identical to that for a single click stimulus. Stimulus rate. The early components in normal subjects were compared at stimulus rates of 20 s -1 and 2-5 s~*. The patients were studied with clicks presented at the faster rate. (b) Middle and late components. The electro-encephalogram was amplified using a low frequency cut off at 0-8 Hz (3 dB point, with a slope 6 dB Oct- 1 ) high frequency cut off at 250 Hz (slope —6 dB Oct" 1 ). The sweep duration of the averager was 320 ms. The latency could be estimated to within 0-64 ms. Amplitude was measured from peak to peak. The clicks were presented at a rate of 2-5 s~'.
2. Muscle Components The stimulus was a click of 0-5 ms duration, presented binaurally at an intensity of 95-7 dBC sound pressure level re 210" 5 Pa.
(b) Post-auricular muscle. A fine coaxial needle electrode (Disa 13158) was inserted into the postauricular muscle and the response to a click was recorded. One channel of electro-encephalogram was averaged from between the shaft of this needle and a surface electrode at the vertex.
N O R M A L SUBJECTS Forty-five subjects, 25 males and 20 females, mean age 35 years ( ± 11 years), without any known hearing or neurological deficit, were studied.
PATIENTS Eighty-eight patients, 36 males and 52 females, mean age 39 years ( ± 12 years), were studied. All the patients had a history of a relapsing and remitting illness, with signs of two or more lesions in the central nervous system on clinical examination, that is, they had clinically definite multiple sclerosis (McAlpine, Lumsden and Acheson, 1972). The majority of these patients came from two out-patient clinics. Every patient who attended these clinics and who had definite multiple sclerosis was studied. Evoked potential studies of the visual and spinal system were not used to classify these patients. The duration of the illness ranged from one year to twenty-five years. Most of the patients were ambulant.
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(a) Posterior cervical, temporalis and frontalis muscles. One channel of electro-encephalogram was averaged from electrodes at the vertex and the left mastoid. Electrical activity from the muscles under investigation was recorded on a second channel through appropriately placed surface electrodes. This electromyogram was rectified and integrated on a third channel to give an indication of the amount of muscle activity being monitored. The temporalis muscles were activated by jaw clenching, the posterior cervical muscles by neck traction and the frontalis muscles by raising the forehead.
AUDITORY EVOKED POTENTIALS IN MS
23
RESULTS NORMAL SUBJECTS
Early Components It was thought that patients with demyelination would be more likely to have abnormal early responses at fast stimulation rates (McDonald and Sears, 1970). Thus we performed an initial study on 19 normal subjects to see if reliable records could be obtained with fast stimulation rates. Reproducible records were obtained at a stimulation rate of 20 s -1 . The effect of altering the rate from 2-5 s"1 to 20 s'1 is shown in Table 1. Forty-five normal subjects were then studied at the faster stimulation rate. The average of all the records is shown infig.2 (component VII is not indicated in this figure since, in some subjects, this component falls in the latency range of the reflex response from the post-auricular muscle) and values of amplitude and latency are given in Table 2. As the latency and amplitude measurements of the early components of the AEP are dependent upon a variety of factors including stimulus parameters and methods of recording, comparison of data between different laboratories should be made with caution (see Picton et ai, 1974).
Latency (ms) 2-5 Hz 20 Hz
Component I II III V
N/S N/S X X X
N/S
207 3-35 410 601
210 3-40 4-26 603
Amplitude (jxV) 2-5 Hz 20 Hz N/S X X X
X
N/S
0159 0-475 0-408 1158
0157 0-302 0-321 1090
x x x = / > < 0 0 0 1 . x = P < 005. N/S = not significant.
Moreover, many reports of normative data are based upon small groups of young subjects whereas in the present study a wide age range (20-56 years, mean 35 years) has been studied. It will be noted that component V, identified as the most negativegoing component in the first 5-10 ms, was the only one to be recorded in all normal subjects, one or more of the other components being absent in some subjects. Thus component V was the only component that could be reliably used to detect abnormalities in patients. Moreover, it has the greatest amplitude, showed the least relative variation of both amplitude and latency and was easily identified even when some of the earlier components were missing. Latency and amplitude values of component V for all normal subjects are shown infig.3. The 95 per cent confidence intervals for the bivariate distribution are indicated by the dotted line.
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TABLE 1. EFFECTS OF STIMULUS RATE ON LATENCY AND AMPLITUDE OF EARLY COMPONENTS IN 19 NORMAL SUBJECTS (ANALYSED USING A MIXED MODEL ONE WAY ANALYSIS OF VARIANCE)
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TABLE 2. LATENCY AND AMPLITUDE OF EARLY, MIDDLE AND LATE COMPONENTS OF THE AUDITORY EVOKED POTENTIAL IN NORMAL SUBJECTS EARLY
Double click stimulus
SingL'. click stimulus Component
I 42
•**n
Latency ms
37
III 42
IV 27
V 45
VI 36
VII 27
Va 32
Vb 24
LATE
(Stimulus rate 2'5 s~')
Single click stimulus Pa
Nb
PI
34
32
35
35
200
3-24
411
5-20
600
7-41
9-45
619
616
30-26
40-76
52-53
83-68
Standard deviation
018
0-21
0 19
0-24
0-24
0-40
0-60
0-24
0-25
3-58
4-82
4-67
Coefficient of variation (%)
9
6
5
5
4
5
6
4
4
12
9
II*
III*
IV
VI*
VII*
Vb
Pa-Nb
Nb-Pl
36
—
31
23
32
35
! •**n
P2
Nl
Mean
Component
Amplitude ^V
II
MIDDLE
(Stimulus rate 2-5 s~J)
35
i
N2 35
m m Z JO
147-23
276-60
O
1107
16-89
25-86
13
11
11
Pl-Nl
N1-P2
P2-N2
z on z z a
35
35
35
CD
I* 35
31
V 45
• Va
32
24
12
Mean
012
017
0-26
—
0-97
013
008
0-81
0-33
111
1-27
2-68
2-07
2-31
Standard deviation
008
019
019
—
0-23
006
004
0-20
017
0-61
1-06
1-25
0-99
1 29
Coefficient of variation (%)
KATHI
(Stimulus rate 20 s~l)
67
111
73
—
24
46
50
25
52
55
* Allowance for missing values, see Saw, J. G., 1961. *• N = total number of subjects. *•* n = number of subjects in which relevant component was identified.
83
47
48
56
•13
tfl
m C
a a
m
AUDITORY EVOKED POTENTIALS IN MS
25
0-5JJV
f
2
4
6
8
10 ms
FIG. 2. Average of early components from 45 normal subjects. Components I-VI indicated; component VII omitted. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0Downloaded from by guest on June 24, 2015
0)
5 6 Latency (ms)
8
10
FIG. 3. Distribution of amplitude and latency of component V for 45 normal subjects. Ninety-five per cent confidence limits indicated by broken line. Horizontal axis, latency in ms. Vertical axis, amplitude ^V.
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KATHLEEN ROBINSON AND PETER RUDGE
Middle Components In this study No, Po, Na, Pa, Nb and PI were classified as middle components. In some other studies PI has been classified as a late component (Picton et ai, 1974). The middle components were studied in 35 of the normal controls. The average of all the records is shown infig.4. Components No, Po and Na as described by Picton et al. (1974) are not indicated in this figure since they occur within the latency range of the reflex response from the post-auricular muscle. Values of amplitude and latency are given in Table 2. These values did not always have a Gaussian distribution and thus the 95 per cent normal ranges were estimated by a percentile method. The amplitude and latency of the middle components were not affected by the age or sex of the subjects.
O-5JJV
40
60
80 ms
FIG. 4. Average of middle components from 35 normal subjects. Components Pa, Nb and PI indicated; components No, Po and Na omitted. Component V of early group also indicated. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-5 /*V.
Muscle Components Interpretation of the middle components is complicated by the occurrence of the reflex response of muscles to the click at a similar latency. Such reflex responses have been reported to arise from posterior cervical muscles, frontalis muscles, temporalis muscles (Cody and Bickford, 1969) and the post-auricular muscles (Kiang, Christ, French and Edwards, 1963) in response to high-intensity clicks. The effect of these reflex EMG responses on the middle components of the auditory evoked potential was investigated. (1) Temporalis, frontalis and posterior cervical muscles. With simultaneous recording of muscle activity and the auditory evoked potential {see Methods) it can be seen (fig. 5B) that the middle components were obscured by the reflex
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r
20
AUDITORY EVOKED POTENTIALS IN MS
27
EMG response when the muscle was under sufficient tension. However, when the muscle was relaxed (fig. 5A) no reflex EMG response could be recorded, yet the full complement of middle components was present. It is thus unlikely that these muscles contribute to the middle components observed in this study. A
B
f
80ms ms|
I
I
i
40
I
l
80 ms
FIG. 5. Effect of contraction of temporalis muscles upon middle components of the auditory evoked potential. Middle components of the auditory evoked potential (above) whilst muscles are relaxed (A) and contracted (B). Average surface electromyogram shown below whilst muscles relaxed (A) and contracted (B). Onset of stimulus at arrow. Horizontal axis, time in ms. Bar 2 ^V.
(2) Post-auricular muscles. The post-auricular muscle reflex is a triphasic response occurring at a similar latency to components No, Po and Na, and is commonly seen even in the relaxed subject. Component No, Po and Na could be an attenuated form of this reflex muscle response, and it was therefore decided to omit these components in the classification of the records, and not to use the amplitude measurement of Na-Pa which depends upon the size of the postauricular muscle response. In contrast, components Pa, Nb and PI were not thought to be reflex muscle responses for several reasons. First, if the post-auricular muscle is recorded through a coaxial needle electrode and the auditory evoked potential between the shaft of the same needle and the vertex, the components Pa, Nb and PI occur after the reflex activity of the muscle has ceased (fig. 6). Secondly, in 15 per cent of normal subjects the response, which is recorded on the ipsilateral
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1
40
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KATHLEEN ROBINSON AND PETER RUDGE
mastoid electrode, was absent on one side yet Pa, Nb and PI were identical from the two sides. Thirdly, the response was bilaterally absent in 40 per cent of subjects. EMG Channel 1
80ms
Channel 2
40
2JJV
80ms
FIG. 6. Post-auricular muscle reflex and middle components of the auditory evoked potential. Electromyogram of post-auricular muscle recorded with coaxial needle electrode shown top left (EMG). Channel 1, three separate averages of reflex response recorded through coaxial needle electrode. Channel 2, simultaneous middle latency components recorded between shaft of coaxial needle electrode and vertex. Stimulus starts at arrow. Horizontal axis, time in ms. Note change in gain between Channels 1 and 2.
Late Components The late components comprise a series of three components, Nl, P2 and N2, which occur between 60-300 ms after the click stimulus (fig. 7); component Nl occasionally has a double peak. The values of amplitude and latency for these components are given in Table 2. The amplitude and latency of the late components were not affected by the age or sex of the subject. PATIENTS
Early Components Eighty-eight patients with clinically definite multiple sclerosis were studied. A record was classified as abnormal if the combined measure of amplitude and latency of component V was outside the 95 per cent limits constructed for normal subjects. Sixty-five per cent of all records fulfilled this criterion (fig. 8). The 99 per cent confidence intervals for normal subjects are also shown. It can be seen that the latency of component V, if abnormal, was usually beyond the 99 per cent limit.
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40
[2juV
A U D I T O R Y E V O K E D P O T E N T I A L S IN MS
29
0-5JJV
T
50
150
250 ms
In contrast, abnormalities of amplitude were of a lesser degree and values often lay between the 95 and 99 per cent limits. Thus latency was a more reliable discriminator of abnormality than amplitude. Component 1 was always normal but in some patients other components were abnormal. Since the other early components were not always recorded in normal subjects, no systematic analysis of them was undertaken. If any of these components was abnormal in latency, however, component V was always abnormal; moreover, component V was the only abnormality in 71 per cent of patients who had abnormalities of the early components of the AEP. Examples of four abnormal records are illustrated in fig. 9. The patients were subdivided into three groups on clinical assessment of brainstem function to see if there was any correlation between this and the abnormalities of the early components. The three groups were: (a) Evidence of a definite brain-stem lesion, for example, internuclear ophthalmoplegia, sixth or seventh nerve palsy. (b) Evidence suggestive of a brain-stem lesion in the form of bilateral horizontal or vertical nystagmus. (c) No clinical evidence of a brain-stem disorder.
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FIG. 7. Average of late components of the auditory evoked potential from 35 normal subjects. Components N l , P2 and N2 indicated. Middle components and component V also shown. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-5 /u.V.
30
KATHLEEN ROBINSON AND PETER RUDGE VII
VI
i 1
I f0 8 10 5 6 7 Latency (ms) FIG. 8. Distribution of amplitude and latency of component V for 88 patients with multiple sclerosis. Ninety-five per cent and 99 per cent confidence intervals indicated by concentric circles. Normal limits (± 1 standard deviation) for latency of components VI and VII indicated by vertical broken lines. Horizontal axis, time in ms. Vertical axis amplitude ^V.
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B
0-5JJV
T
2
6
10 ms
FIG. 9. Example of abnormal records of early components of the auditory evoked potential from 4 patients (B, C, D, E) compared with a record from a normal subject (A). Component V indicated. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-
AUDITORY EVOKED POTENTIALS IN MS
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A correlation between these clinical signs and the auditory evoked potential was found. Eighty-two per cent of group A, 76 per cent of group B and 51 per cent of group C were abnormal. The amplitude and latency of component V for all the patients studied, in relation to their group classification, are shown in fig. 10A-C. Middle Components Sixty-six of the patients were studied. A record was classified as abnormal if the amplitude or latency of any of the components (apart from No, Po, Na and amplitude Na-Pa) were outside the normal range (more than two standard deviations from the mean). Examples of four abnormal records are shown in fig. 11. Forty-five per cent of the records had abnormal middle latency components. When the patients were subdivided on clinical evidence of brain-stem involvement, 69 per cent of group A, 60 per cent of group B and 29 per cent of group C were abnormal. In all cases the abnormalities were confined to increase in latency and in none was amplitude abnormal. Furthermore, the patients as a group were not significantly different from the controls on any of the measures of amplitude used.
TABLE 3. PROPORTION OF ABNORMALITIES OF EARLY AND MIDDLE COMPONENTS OF AUDITORY EVOKED POTENTIAL IN 88 PATIENTS WITH MULTIPLE SCLEROSIS MIDDLE
E A R _) >•
Normal Abnormal
Normal
Abnormal
/o
/o
o/ /o
23 32
12 33 45
65
Early, Middle and Late Components Combined An abnormality of one or more of the early components did not invariably mean that there was an abnormality of the middle components. The highest proportion of abnormalities was detected in the early components. An additional 12 per cent of abnormalities was detected by recording the middle components (Table 3). The late components were abnormal in only 3 of the patients, and in these the middle components were also abnormal.
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Late Components Sixty-six of the patients were studied. A record was classified as abnormal if the amplitude or latency of any of the components were outside the normal range (more than two standard deviations from the mean). Only three records could be classified as abnormal. In each case the only abnormality was delay of component Nl. The patients as a group were not significantly different from the controls in latency or amplitude.
KATHLEEN ROBINSON AND PETER RUDGE
32
3 o
1
I oh < 5 6 Latency (ms)
K)
B
"5. < 5 6 Latency (ms)
10
5 6 Latency (ms)
10
FIG. 10. Distribution of amplitude and latency of component V in patients with multiple sclerosis, A, patients with definite clinical evidence of brain-stem lesion; B, patients with nystagmus; c, patients with no clinical evidence of brain-stem lesion. Broken circle 95 per cent confidence limits for normal subjects. Horizontal axis, time in ms. Vertical axis, amplitude pV.
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4)
AUDITORY EVOKED POTENTIALS IN MS
33
B
[0-5JJV
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20
40
60
80 ms
FIG. 11. Example of abnormal records of middle components of the auditory evoked potential from 4 patients (B, C, D, E) compared with record from a normal subject (A). Components Pa, Na and PI indicated in A. Component V also shown. Component PI in abnormal records indicated*. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-5 ;xV.
Pairs of Clicks Normal subjects. When normal subjects are given a pair of clicks, 5 ms apart, at a rate of 2-5 s"1 the latency and amplitude of all the components to the first click of the pair were unchanged compared to those for a single click; but when the pair of clicks was presented at a repetition rate of 20 s -1 there was a significant increase in the latency of components II, III and V to the^zm click of the pair compared to that observed for a single click, although the latency of component I remained unchanged.
34
K A T H L E E N ROBINSON AND PETER R U D G E
The early components evoked by the second click can also be recorded. They are of smaller amplitude than those evoked by the first click although they occur at the same latency. In some subjects, however, the early components to the second click of the pair can be difficult to identify because of their superimposition upon the post-auricular muscle response to the first click. The average of the records from 24 normal subjects with a pair of clicks as the stimulus is shown infig.12.
Vb
8
10 12 14 ms
FIG. 12. Average of early components to pairs of clicks from-24 normal subjects. Clicks start at arrows a and b. Components I, III and V to first click indicated by suffix a; components III and V to second click indicated by suffix b. Horizontal axis, time in ms. Bar 0-
Patients. Sixty of the patients were investigated with pairs of clicks presented at the faster stimulus rate of 20 s"1 and the increase in latency of component V to the first click of the pair compared to that observed for a single click was measured. The patients were divided into three groups: (i) Patients with an abnormal latency of component V (more than two standard deviations above the mean) to a single click. The amplitude of component V was normal in some of these. (ii) Patients with abnormal amplitude (more than two standard deviations below the mean) but normal latency of component V to a single click. (iii) Patients with normal early components to a single click. The results are shown in fig. 13. Fifty-five per cent of group (i) and 57 per cent of group (ii) had an abnormal increase in latency of component V to thefirstclick of the pair. In group (iii) only one patient had an abnormal increase in latency. Although this patient was normal to a single click when amplitude and latency
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PI
6
A U D I T O R Y E V O K E D P O T E N T I A L S IN MS
35
were considered separately, component V lay outside the 95 per cent confidence limits when both parameters were considered together. Two other patients in group (iii) failed to respond to the second click of the pair although the auditory evoked potential was normal in all other respects. However, no systematic analysis of the response to the second click of the pair was undertaken because of the difficulty of identifying the components in those subjects who had abnormal latency of component V even to a single click.
i
i
B
: ...:: i
: .
. :
•
i
i
c •
• i
0
1
2
ms
Latency increase
FIG. 13. Increase of latency of component V to first of a pair of clicks, A, control subjects; B, patients with abnormal latency of component V to single click; c, patients with abnormal amplitude but normal latency of component V to single click; D, patients with normal component V to single click. Each point represents one subject. Horizontal axis, increase of latency, time in ms.
DISCUSSION
Symptomatic deafness is rare in patients with multiple sclerosis although occasionally a lesion in the region of the cochlear nucleus can cause severe unilateral hearing loss (Dix, 1965). It has been claimed that multiple sclerosis patients as a group do have impaired hearing (Dayal and Swisher, 1967) but routine audiometry is of no value for the detection of plaques in the auditory system of individual patients. The present results do, however, show that the auditory system does not have a privileged immunity to demyelination and suggests that the auditory evoked potential is a more sensitive method than audiometry for detecting such lesions. It is known from both pathological and clinical studies that the brain-stem is a common site of demyelination. Such lesions frequently cause abnormalities of eye movements, for example, internuclear ophthalmoplegia, cranial nerve palsies and nystagmus. It is therefore to be expected that patients with such clinically apparent lesions would also have the greatest chance of involvement of the auditory
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••
36
KATHLEEN ROBINSON AND PETER RUDGE
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pathways within the brain-stem since the various fibre tracts are compressed into a small area and demyelinating plaques do not respect boundaries between different fibre systems. Concerning the early components of the auditory evoked potential, there is evidence in the present study that this is indeed the case. Components II, III, IV and V are known to depend upon the integrity of the cochlear nuclei, superior olivary nuclei, lateral lemniscus and inferior colliculus respectively (Jewett, 1970; Buchwald and Huang, 1975). In the patients with independent evidence of involvement of the brain-stem, for example eye movement disorders, 79 per cent have abnormalities of these brain-stem components. In contrast, only 51 per cent of patients in whom there was no other evidence of a brain-stem lesion had abnormal early components of the auditory evoked potential. This suggests that clinically silent areas of demyelination occur frequently and accords with evoked potential studies of the visual (Halliday, McDonald and Mushin, 1973, and Asselmann, Chadwick and Marsden, 1975) and spinal (Small, Beauchamp and Matthews, 1977) sensory systems. It could be argued that the abnormalities of the auditory evoked potential are the result of a small decrease in hearing threshold due to a peripheral deficit. Such a decrease would in effect be equivalent to a lowering of the intensity of the click stimulus. Since it is known that the early components of the auditory evoked potential are dependent upon the intensity of the stimulus, alteration of these components would be expected. This is unlikely, however, to be the explanation for the abnormalities detected. First, in all cases the latency of component I was normal implying that the input to the brain-stem was not reduced. Secondly, in normal subjects the latency and amplitude of the components change concurrently as the intensity of the click stimulus is reduced, whereas the abnormalities of the auditory evoked potential in patients with multiple sclerosis may be of either amplitude or latency alone. Furthermore, component V may be abnormal in the presence of normal earlier components. Finally, there is no correlation between abnormalities of the audiogram and abnormalities of the auditory evoked potential; a patient with a normal audiogram may show gross abnormalities of the auditory evoked potential. For these reasons it was concluded that the abnormalities of the early components of the auditory evoked potential are not due to a diminished input of the click stimulus and that they are the consequence of a more central lesion. The origin of the middle components is obscure. The experiments in which muscle activity has been sampled indicate that components Pa, Nb and PI are not reflex muscle responses to the click from the posterior cervical, temporalis, frontalis or post-auricular muscles sampled. It is, however, possible, although unlikely, that some other muscles give rise to them. No definitive conclusion concerning the components No, Po and Na can be made, as both the post-auricular muscle and component VII occur at a similar latency. Whatever the source of the middle components, additional information is obtained by studying them as in 12 per cent of patients who had normal early components of the auditory evoked potentials, these middle components were abnormal. Although this proportion
A U D I T O R Y E V O K E D P O T E N T I A L S I N MS
37
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is small it is significant clinically since it was the only evidence of demyelination within the auditory system in 6 patients (i.e. 6 patients in Group C). In contrast, studies of the late components does not increase the proportion of patients in whom abnormalities were detected. In only 3 patients were the late components abnormal and in all 3 the earlier components were also abnormal. This may in fact be due to the greater variation of the late components which are markedly affected by the state of arousal in normal subjects. The early and middle components are not affected by such changes. Any attempt to quantify the delays of the various components of the auditory evoked potential in terms of altered conduction velocity must be made with caution. In animal studies the effect of demyelination on conduction can be measured directly for single fibres. In contrast, in man, whilst the altered form of the evoked potential probably reflects changes of conduction within central nervous system fibres, no absolute measure of the change can be made. Estimates of amplitude and latency are made at the turning-points of the evoked potential wave form which merely reflect the point of maximum synchronization of many interacting fibres. The effect of demyelination of any of these fibres can be variable. It would be misleading to calculate conduction velocity from the wave form of the evoked potential. For example, selective slowing of the fastest conducting fibres could increase the amplitude of a component without altering peak latency. A particular problem with such extrapolations from the auditory evoked potential is the complexity of the wave form. If the early components represent electrical events in a sequential system, interaction between these components would be expected if a delay occurred in a part of that system. Two common features of the abnormalities of component V suggest that this does indeed occur. First, there was a marked tendency for component V to be recorded at the latency of components VI and VII (fig. 8). Secondly, there are frequently small additional waves on the down-going slope of the component V in abnormal records. These might be the result of selective alteration of conduction within the auditory system but could equally well be explained by interaction between various components. In this study, component V was identified as the most negative peak to occur within the first 5 to 10 ms and measurements of amplitude and latency were made at this point. This is a relatively crude way of assessing abnormality. A more sensitive method would be to compare the shape of the entire wave form if suitable templates for pattern recognition could be developed. Of more relevance to the present study is the impaired ability of demyelinated axons in the central nervous system to transmit trains of impulses (McDonald and Sears, 1970). This is due to an increase in the refractory period of transmission of the axons. It was for this reason that closely paired stimuli were administered to patients to stress the auditory system. For large demyelinated central nervous system axons in animals it is known that the refractory period of transmission can be as much as 4-3 ms although in general it is less than 2-5 ms. It was not possible to administer pairs of clicks at intervals of less than 5 ms since the analysis of the
38
KATHLEEN ROBINSON AND PETER R U D G E
SUMMARY
Fifteen components of the auditory evoked potential can be recorded within 300 ms of a click stimulus and these can be classified by latency into early (0-8 ms), middle (8-60 ms) and late (>60 ms) components. Following a click stimulus of high intensity these components have been studied in 45 normal subjects and in 88 patients with definite multiple sclerosis. Component V, thought to arise from brain-stem structures, was the most consistently abnormal in patients and there was a correlation between the abnormalities and clinical evidence of a brain-stem lesion. Thus in 79 per cent of patients with definite evidence of a brain-stem lesion
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wave form of the evoked potential becomes unreliable. In spite of this long interval there was a significant increase of latency of component V to even the first click of the pair in normal subjects indicating that such a stimulus did stress the auditory system. This was not due to adaptation at the end organ, as component I from the eighth nerve was not affected. Neither was it due to the fortuitous superimposition of earlier components upon component V as the latency change only occurred when pairs of clicks were given at the faster stimulation rate of 20/s. It is possible that the interaction of the high repetition rate with the added stress of a double click is sufficient to cause the delays seen. In the case of patients with multiple sclerosis this increase in latency is greater than in normals. This could be explained by the observation in single nerve fibre studies that there is a progressive reduction of conduction velocity when trains of impulses are transmitted through demyelinated axons in the central nervous system (McDonald and Sears, 1970). Whatever the cause, the technique of giving pairs of clicks validated the use of amplitude as well as latency in detecting abnormalities in the auditory pathways. In those patients in whom component V was of normal latency but reduced amplitude to a single click, 57 per cent developed an abnormal increase of latency of this component to a pair of clicks (fig. 13c). This suggests that the mechanism of the reduction in amplitude and increase in latency are similar and that it is justified to use amplitude as well as latency changes to detect demyelination. The present work demonstrates that evoked potential techniques are of value in detecting demyelinating lesions in the auditory system of patients with multiple sclerosis. This applies not only to the 90 per cent of patients with evidence, on other grounds, of a brain-stem lesion, but also to the 60 per cent of those with no such abnormality when data from early and middle components are combined. None of the patients had clinical deafness. There is thus a striking parallel between these patients and those in whom the visual evoked responses were abnormal and yet there was no clinical evidence of optic neuritis (Halliday, McDonald and Mushin, 1973; Asselmann, Chadwick and Marsden, 1975). As with all evoked potential studies, however, it remains to be seen if abnormalities that are clinically silent in patients with possible or probable multiple sclerosis will predict the subsequent diagnosis of definite multiple sclerosis at a later date.
A U D I T O R Y E V O K E D P O T E N T I A L S I N MS.
39
and in 51 per cent of those without clinical signs related to the brain-stem, component V was abnormal. Abnormalities were also detected for components Pa, Nb and PI of the middle components, and in 12 per cent of these the early components were normal. The late components were normal in all but 3 patients. Evidence is presented to show that pairs of click stimuli, 5 ms apart, presented at a fast stimulus rate, stress the auditory system in normal subjects. Using this technique abnormalities of component V in patients became more marked and the proportion of abnormalities detected was increased. The contribution of the reflex muscle responses to the click to the middle components of the auditory evoked potential has also been studied. It is concluded that components Pa, Nb and PI are independent of these reflexes. ACKNOWLEDGEMENTS We wish to thank Mr. H. B. Morton without whose help this work could not have been carried out. We thank also Drs. W. A. Cobb, J. D. Hood, P. A. Merton and Professor T. A. Sears for their helpful advice and criticism; and Dr. Hugh Bostock for the use of his CALCPLOT programme.
ASSELMANN, R., CHADWICK, D. W., and MARSDEN, C. D. (1975) Visual evoked responses in the diagnosis
and management of patients suspected of multiple sclerosis. Brain, 98, 261-282. BUCHWALD, J. S., and HUANG, C. M. (1975) Far-field acoustic response: origins in the cat. Science, 189,382-384. . CODY, D. T., and BICKFORD, R. G. (1969) Averaged evoked myogenic responses in normal man. Laryngoscope, St. Louis, 79, 400-416. DAYAL, V. S., and SWISHER, L. P. (1967) Pure tone thresholds in multiple sclerosis. Laryngoscope, St. Louis, 77, 2169-2177. Dix, M. R. (1965) Observations upon the nerve fibre deafness of multiple sclerosis with particular reference to the phenomenon of loudness recruitment. Journal of Laryngology and Otology, 79, 695-706. HALLIDAY, A. M., MCDONALD, W. I., and MUSHIN, J. (1973) Visual evoked responses in diagnosis of
multiple sclerosis. British Medical Journal, 4, 661-664. JEWETT, D. L. (1970) Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroencephalography and Clinical Neurophysiology, 28, 609-618. KIANG, N. Y. S., CHRIST, A. H., FRENCH, M. A., and EDWARDS, A. G. (1963) Post-auricular electric
response to acoustic stimuli in humans. Quarterly Progress Report, Research Laboratory of Electronics, Massachusetts Institute of Technology, 68, 218-225. LIEBERMAN, A., SOHMER, H., and SZABO, H. (1973) Standard values of amplitude and latency of cochlear
audiometry (electro-cochleography). Responses in different age groups. Archiv fur Ohren-, Nasen-, und Kehlkopfheilkunde, 203, 267-273. MCALPINE, D., LUMSDEN, C. E., and ACHESON, E. D. (1972) Multiple Sclerosis: A Reappraisal. Edin-
burgh: Livingstone, p. 202. MCDONALD, W. I., and SEARS, T. A. (1970) The effects of experimental demyelination on conduction in the central nervous system. Brain, 93, 583-598.
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REFERENCES
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KATHLEEN ROBINSON AND PETER RUDGE
PICTON, T. W., HILLYARD, S. A., KRAUSZ, H. I., and GALAMBOS, R. (1974) Human auditory evoked
potentials: evaluation of components. Electroencephalography and Clinical Neurophysiology, 36, 179-190. REGAN, D., MILNER, B. A., and HERON, J. R. (1976) Delayed visual perception and delayed visual evoked potentials in the spinal form of multiple sclerosis and in retrobulbar neuritis. Brain, 99, 43-66. RICHEY, E. T., Kooi, K. A., and TOURTELLOTTE, W. W. (1971) Visual evoked responses in multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry, 34, 275-280. ROBINSON, K., and RUDGE, P. (1975) Auditory evoked responses in multiple sclerosis. Lancet i, 11641166. SAW, J. G. (1961) Estimation of the normal population parameters given a type 1 censured sample. Biometrika, 48, 367-374. SMALL, D. G., BEAUCHAMP, M., and MATTHEWS, W. B. (1977) Spinal evoked potentials in multiple sclerosis. (To be published.) THORNTON, A. R. D. (1975) Distortion of averaged post-auricular muscle responses due to system bandwidth limits. Electroencephalography and Clinical Neurophysiology, 39, 195-197. {Received May 19, 1976) Downloaded from by guest on June 24, 2015
ABNORMALITIES OF THE AUDITORY EVOKED POTENTIALS IN PATIENTS WITH MULTIPLE SCLEROSIS by KATHLEEN ROBINSON and PETER RUDGE (From the Department of Clinical Neurophysiology, and the Medical Research Council, Hearing and Balance Unit, Institute of Neurology, National Hospital, Queen Square, London WC1N 3BG)
INTRODUCTION
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M U L T I P L E SCLEROSIS is a disease characterized by multiple areas of demyelination in the central nervous system and the clinical diagnosis depends upon the demonstration of two or more such lesions. A major problem occurs in the early stages of the disease when the patient presents with a single lesion. Until recently the only methods for detecting other sites of demyelination were clinical and patients often underwent unpleasant and potentially hazardous investigations to exclude other pathologies; for instance myelography was performed in patients with an apparently isolated spinal cord lesion. Any method that demonstrates multiple sites of demyelination in such patients would obviously be of great value. With the development of averaging techniques it has been possible to record, through scalp electrodes, cortical potentials evoked by sensory stimuli. Initial studies of the visual system showed that the cortical potentials evoked by flash stimuli were abnormal in multiple sclerosis patients as a group, but the difference was not sufficient to separate individual patients from normal subjects (Richey, Kooi and Tourtellotte, 1971). This difficulty was overcome by using a reversing pattern checkerboard as the visual stimulus, when there is minimal overlap in the latency of the evoked potential between patients with optic neuritis and normal subjects. Furthermore the latency was abnormal not only in patients with clinical optic neuritis but also in a high proportion of those with apparently normal visual pathways (Halliday, McDonald and Mushin, 1973; Asselmann, Chadwick and Marsden, 1975; Regan, Milner and Heron, 1976). Although clinical deafness is rare in multiple sclerosis we were encouraged by the ability of evoked potential studies to detect silent lesions in the optic nerve and have investigated the auditory system. In the auditory system fifteen components of the auditory evoked potential occur within 300 ms of a click stimulus. These components have been classified by
20
KATHLEEN ROBINSON AND PETER RUDGE
METHODS 1. The Auditory Evoked Potential Two channels of the electro-encephalogram were averaged simultaneously from surface electrodes on each mastoid and a common electrode at the vertex. The electrodes were connected so that a positivegoing potential at the vertex, relative to the mastoid, caused a down-going deflection. Averaged responses were collected with a signal averager (Biomac 1000, i.e. 1000 words of store, Data Laboratories Ltd., Mitcham, UK). In all cases the result was the average of 512 individual responses. Each average response was punched on to paper tape which was fed into a PDP12 computer and stored on magnetic tape for further analysis. As the auditory evoked potential recorded from both channels was highly superimposable for all the components, measurements were made for one channel only. The auditory stimulus was a click of 0-5 ms duration, 95-7 dBC sound pressure level re 2-10~5 Pa (approx. 75 dB sensation level) which was presented binaurally to the subject through earphones. (a) Early components. Two distinct types of wave form for the early components have been described (compare Picton, Hillyard, Krausz and Galambos, 1974 with Lieberman, Sohmer and Szabo, 1973). As it was suspected that the difference between wave forms is due to the varying amounts of filtering used at the low-frequency end of the spectrum, a preliminary study of the low-frequency filter was undertaken. The effect of the low-frequency filter can be simulated by digital methods. Various filter settings were simulated using the same original record, and it was confirmed that the low-frequency filter does indeed cause alterations in the wave form of the early components (fig. 1). It will be noted that with a low-frequency filter of 0-8 Hz there is a marked change in the shape of component V due
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latency into early (0-8 ms), middle (8-50 ms) and late (more than 50 ms) components (Picton, Hillyard, Krausz and Galambos, 1974). The late components represent the vertex response and probably arise from cortical structures. The generators for the middle components are unknown. Reflex muscle responses have been reported at a similar latency (Kiang, Christ, French and Edwards, 1963; Cody and Bickford, 1969) and it has been suggested that the two are related (Thornton, 1975). Extensive work in the cat has shown that the early components depend upon the integrity of the eighth nerve and the brain-stem (Jewett, 1970; Buchwald and Huang, 1975). Since demyelination is common in the brain-stem of patients with multiple sclerosis it was thought that alteration of the early components of the auditory evoked potential might occur. Preliminary studies showed that this was indeed the case, and, moreover, that the abnormalities were not confined to latency (Robinson and Rudge, 1975). A larger sample of patients with clinically definite multiple sclerosis (McAlpine, Lumsden and Acheson, 1972) has now been studied with the following aims. First, to confirm the preliminary findings for the auditory evoked potential with particular emphasis on the use of amplitude as well as latency as a valid measure of abnormality. Secondly, to extend the investigation to all the components of the auditory evoked potential. Thirdly, an attempt has been made to stress the auditory system by presenting click stimuli in pairs. We have also studied the reflex response of muscles to the click in normal subjects to assess its contribution to the middle latency components.
AUDITORY EVOKED POTENTIALS IN MS
21
to the superimposition of a slower wave at this latency. This filter setting was used in the present study since the inclusion of the lower frequencies facilitated the identification of component V. For the early components the electro-encephalogram was amplified using a low-frequency cut off at 0-8 Hz (3 dB point, with a slope 6 dB Oct- 1 ) and high-frequency cut off at 2-5 kHz (slope —6 dB Oct- 1 ). The sweep duration of the averager was 40 ms. The auditory evoked potential was smoothed digitally using a three point moving averagefilter.The latency was measured from the onset of the click to the downgoing peak of each component and could be estimated to within 80 f*.s. The amplitudes of components II, III, VI and VII were measured to the preceding upgoing peak, and that of component V to the upgoing peak preceding component IV. The amplitude of component I was measured to the baseline as estimated from the prestimulus level.
B
I
10 ms
FIG. 1. Simulation of effect of the low-frequency filter upon early components of the auditory evoked potential. Original record shown in A, low-frequency filter = 0-8 Hz (slope — 6 dB Oct- 1 ). B, low-frequency filter = 100 Hz (slope - 6 d B Oct- 1 ). c, low-frequency filter = 250 Hz (slope - 6 dB Oct- 1 ). D, low-frequency filter = 250 Hz (slope —12 dB Oct- 1 ). Component V indicated. Horizontal scale, time in ms. Bar 0-5 jtV. Stimulus starts at
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[O-5JUV
22
KATHLEEN ROBINSON AND PETER RUDGE
Pairs of clicks. The early components were also recorded when the stimulus was a pair of clicks, 5 ms apart, each of 0-5 ms duration, presented binaurally at an intensity of 95-7 dBC sound pressure level re 2-10"5 Pa. The recording and measurement of these early components was identical to that for a single click stimulus. Stimulus rate. The early components in normal subjects were compared at stimulus rates of 20 s -1 and 2-5 s~*. The patients were studied with clicks presented at the faster rate. (b) Middle and late components. The electro-encephalogram was amplified using a low frequency cut off at 0-8 Hz (3 dB point, with a slope 6 dB Oct- 1 ) high frequency cut off at 250 Hz (slope —6 dB Oct" 1 ). The sweep duration of the averager was 320 ms. The latency could be estimated to within 0-64 ms. Amplitude was measured from peak to peak. The clicks were presented at a rate of 2-5 s~'.
2. Muscle Components The stimulus was a click of 0-5 ms duration, presented binaurally at an intensity of 95-7 dBC sound pressure level re 210" 5 Pa.
(b) Post-auricular muscle. A fine coaxial needle electrode (Disa 13158) was inserted into the postauricular muscle and the response to a click was recorded. One channel of electro-encephalogram was averaged from between the shaft of this needle and a surface electrode at the vertex.
N O R M A L SUBJECTS Forty-five subjects, 25 males and 20 females, mean age 35 years ( ± 11 years), without any known hearing or neurological deficit, were studied.
PATIENTS Eighty-eight patients, 36 males and 52 females, mean age 39 years ( ± 12 years), were studied. All the patients had a history of a relapsing and remitting illness, with signs of two or more lesions in the central nervous system on clinical examination, that is, they had clinically definite multiple sclerosis (McAlpine, Lumsden and Acheson, 1972). The majority of these patients came from two out-patient clinics. Every patient who attended these clinics and who had definite multiple sclerosis was studied. Evoked potential studies of the visual and spinal system were not used to classify these patients. The duration of the illness ranged from one year to twenty-five years. Most of the patients were ambulant.
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(a) Posterior cervical, temporalis and frontalis muscles. One channel of electro-encephalogram was averaged from electrodes at the vertex and the left mastoid. Electrical activity from the muscles under investigation was recorded on a second channel through appropriately placed surface electrodes. This electromyogram was rectified and integrated on a third channel to give an indication of the amount of muscle activity being monitored. The temporalis muscles were activated by jaw clenching, the posterior cervical muscles by neck traction and the frontalis muscles by raising the forehead.
AUDITORY EVOKED POTENTIALS IN MS
23
RESULTS NORMAL SUBJECTS
Early Components It was thought that patients with demyelination would be more likely to have abnormal early responses at fast stimulation rates (McDonald and Sears, 1970). Thus we performed an initial study on 19 normal subjects to see if reliable records could be obtained with fast stimulation rates. Reproducible records were obtained at a stimulation rate of 20 s -1 . The effect of altering the rate from 2-5 s"1 to 20 s'1 is shown in Table 1. Forty-five normal subjects were then studied at the faster stimulation rate. The average of all the records is shown infig.2 (component VII is not indicated in this figure since, in some subjects, this component falls in the latency range of the reflex response from the post-auricular muscle) and values of amplitude and latency are given in Table 2. As the latency and amplitude measurements of the early components of the AEP are dependent upon a variety of factors including stimulus parameters and methods of recording, comparison of data between different laboratories should be made with caution (see Picton et ai, 1974).
Latency (ms) 2-5 Hz 20 Hz
Component I II III V
N/S N/S X X X
N/S
207 3-35 410 601
210 3-40 4-26 603
Amplitude (jxV) 2-5 Hz 20 Hz N/S X X X
X
N/S
0159 0-475 0-408 1158
0157 0-302 0-321 1090
x x x = / > < 0 0 0 1 . x = P < 005. N/S = not significant.
Moreover, many reports of normative data are based upon small groups of young subjects whereas in the present study a wide age range (20-56 years, mean 35 years) has been studied. It will be noted that component V, identified as the most negativegoing component in the first 5-10 ms, was the only one to be recorded in all normal subjects, one or more of the other components being absent in some subjects. Thus component V was the only component that could be reliably used to detect abnormalities in patients. Moreover, it has the greatest amplitude, showed the least relative variation of both amplitude and latency and was easily identified even when some of the earlier components were missing. Latency and amplitude values of component V for all normal subjects are shown infig.3. The 95 per cent confidence intervals for the bivariate distribution are indicated by the dotted line.
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TABLE 1. EFFECTS OF STIMULUS RATE ON LATENCY AND AMPLITUDE OF EARLY COMPONENTS IN 19 NORMAL SUBJECTS (ANALYSED USING A MIXED MODEL ONE WAY ANALYSIS OF VARIANCE)
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TABLE 2. LATENCY AND AMPLITUDE OF EARLY, MIDDLE AND LATE COMPONENTS OF THE AUDITORY EVOKED POTENTIAL IN NORMAL SUBJECTS EARLY
Double click stimulus
SingL'. click stimulus Component
I 42
•**n
Latency ms
37
III 42
IV 27
V 45
VI 36
VII 27
Va 32
Vb 24
LATE
(Stimulus rate 2'5 s~')
Single click stimulus Pa
Nb
PI
34
32
35
35
200
3-24
411
5-20
600
7-41
9-45
619
616
30-26
40-76
52-53
83-68
Standard deviation
018
0-21
0 19
0-24
0-24
0-40
0-60
0-24
0-25
3-58
4-82
4-67
Coefficient of variation (%)
9
6
5
5
4
5
6
4
4
12
9
II*
III*
IV
VI*
VII*
Vb
Pa-Nb
Nb-Pl
36
—
31
23
32
35
! •**n
P2
Nl
Mean
Component
Amplitude ^V
II
MIDDLE
(Stimulus rate 2-5 s~J)
35
i
N2 35
m m Z JO
147-23
276-60
O
1107
16-89
25-86
13
11
11
Pl-Nl
N1-P2
P2-N2
z on z z a
35
35
35
CD
I* 35
31
V 45
• Va
32
24
12
Mean
012
017
0-26
—
0-97
013
008
0-81
0-33
111
1-27
2-68
2-07
2-31
Standard deviation
008
019
019
—
0-23
006
004
0-20
017
0-61
1-06
1-25
0-99
1 29
Coefficient of variation (%)
KATHI
(Stimulus rate 20 s~l)
67
111
73
—
24
46
50
25
52
55
* Allowance for missing values, see Saw, J. G., 1961. *• N = total number of subjects. *•* n = number of subjects in which relevant component was identified.
83
47
48
56
•13
tfl
m C
a a
m
AUDITORY EVOKED POTENTIALS IN MS
25
0-5JJV
f
2
4
6
8
10 ms
FIG. 2. Average of early components from 45 normal subjects. Components I-VI indicated; component VII omitted. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0Downloaded from by guest on June 24, 2015
0)
5 6 Latency (ms)
8
10
FIG. 3. Distribution of amplitude and latency of component V for 45 normal subjects. Ninety-five per cent confidence limits indicated by broken line. Horizontal axis, latency in ms. Vertical axis, amplitude ^V.
26
KATHLEEN ROBINSON AND PETER RUDGE
Middle Components In this study No, Po, Na, Pa, Nb and PI were classified as middle components. In some other studies PI has been classified as a late component (Picton et ai, 1974). The middle components were studied in 35 of the normal controls. The average of all the records is shown infig.4. Components No, Po and Na as described by Picton et al. (1974) are not indicated in this figure since they occur within the latency range of the reflex response from the post-auricular muscle. Values of amplitude and latency are given in Table 2. These values did not always have a Gaussian distribution and thus the 95 per cent normal ranges were estimated by a percentile method. The amplitude and latency of the middle components were not affected by the age or sex of the subjects.
O-5JJV
40
60
80 ms
FIG. 4. Average of middle components from 35 normal subjects. Components Pa, Nb and PI indicated; components No, Po and Na omitted. Component V of early group also indicated. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-5 /*V.
Muscle Components Interpretation of the middle components is complicated by the occurrence of the reflex response of muscles to the click at a similar latency. Such reflex responses have been reported to arise from posterior cervical muscles, frontalis muscles, temporalis muscles (Cody and Bickford, 1969) and the post-auricular muscles (Kiang, Christ, French and Edwards, 1963) in response to high-intensity clicks. The effect of these reflex EMG responses on the middle components of the auditory evoked potential was investigated. (1) Temporalis, frontalis and posterior cervical muscles. With simultaneous recording of muscle activity and the auditory evoked potential {see Methods) it can be seen (fig. 5B) that the middle components were obscured by the reflex
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r
20
AUDITORY EVOKED POTENTIALS IN MS
27
EMG response when the muscle was under sufficient tension. However, when the muscle was relaxed (fig. 5A) no reflex EMG response could be recorded, yet the full complement of middle components was present. It is thus unlikely that these muscles contribute to the middle components observed in this study. A
B
f
80ms ms|
I
I
i
40
I
l
80 ms
FIG. 5. Effect of contraction of temporalis muscles upon middle components of the auditory evoked potential. Middle components of the auditory evoked potential (above) whilst muscles are relaxed (A) and contracted (B). Average surface electromyogram shown below whilst muscles relaxed (A) and contracted (B). Onset of stimulus at arrow. Horizontal axis, time in ms. Bar 2 ^V.
(2) Post-auricular muscles. The post-auricular muscle reflex is a triphasic response occurring at a similar latency to components No, Po and Na, and is commonly seen even in the relaxed subject. Component No, Po and Na could be an attenuated form of this reflex muscle response, and it was therefore decided to omit these components in the classification of the records, and not to use the amplitude measurement of Na-Pa which depends upon the size of the postauricular muscle response. In contrast, components Pa, Nb and PI were not thought to be reflex muscle responses for several reasons. First, if the post-auricular muscle is recorded through a coaxial needle electrode and the auditory evoked potential between the shaft of the same needle and the vertex, the components Pa, Nb and PI occur after the reflex activity of the muscle has ceased (fig. 6). Secondly, in 15 per cent of normal subjects the response, which is recorded on the ipsilateral
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1
40
28
KATHLEEN ROBINSON AND PETER RUDGE
mastoid electrode, was absent on one side yet Pa, Nb and PI were identical from the two sides. Thirdly, the response was bilaterally absent in 40 per cent of subjects. EMG Channel 1
80ms
Channel 2
40
2JJV
80ms
FIG. 6. Post-auricular muscle reflex and middle components of the auditory evoked potential. Electromyogram of post-auricular muscle recorded with coaxial needle electrode shown top left (EMG). Channel 1, three separate averages of reflex response recorded through coaxial needle electrode. Channel 2, simultaneous middle latency components recorded between shaft of coaxial needle electrode and vertex. Stimulus starts at arrow. Horizontal axis, time in ms. Note change in gain between Channels 1 and 2.
Late Components The late components comprise a series of three components, Nl, P2 and N2, which occur between 60-300 ms after the click stimulus (fig. 7); component Nl occasionally has a double peak. The values of amplitude and latency for these components are given in Table 2. The amplitude and latency of the late components were not affected by the age or sex of the subject. PATIENTS
Early Components Eighty-eight patients with clinically definite multiple sclerosis were studied. A record was classified as abnormal if the combined measure of amplitude and latency of component V was outside the 95 per cent limits constructed for normal subjects. Sixty-five per cent of all records fulfilled this criterion (fig. 8). The 99 per cent confidence intervals for normal subjects are also shown. It can be seen that the latency of component V, if abnormal, was usually beyond the 99 per cent limit.
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[2juV
A U D I T O R Y E V O K E D P O T E N T I A L S IN MS
29
0-5JJV
T
50
150
250 ms
In contrast, abnormalities of amplitude were of a lesser degree and values often lay between the 95 and 99 per cent limits. Thus latency was a more reliable discriminator of abnormality than amplitude. Component 1 was always normal but in some patients other components were abnormal. Since the other early components were not always recorded in normal subjects, no systematic analysis of them was undertaken. If any of these components was abnormal in latency, however, component V was always abnormal; moreover, component V was the only abnormality in 71 per cent of patients who had abnormalities of the early components of the AEP. Examples of four abnormal records are illustrated in fig. 9. The patients were subdivided into three groups on clinical assessment of brainstem function to see if there was any correlation between this and the abnormalities of the early components. The three groups were: (a) Evidence of a definite brain-stem lesion, for example, internuclear ophthalmoplegia, sixth or seventh nerve palsy. (b) Evidence suggestive of a brain-stem lesion in the form of bilateral horizontal or vertical nystagmus. (c) No clinical evidence of a brain-stem disorder.
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FIG. 7. Average of late components of the auditory evoked potential from 35 normal subjects. Components N l , P2 and N2 indicated. Middle components and component V also shown. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-5 /u.V.
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KATHLEEN ROBINSON AND PETER RUDGE VII
VI
i 1
I f0 8 10 5 6 7 Latency (ms) FIG. 8. Distribution of amplitude and latency of component V for 88 patients with multiple sclerosis. Ninety-five per cent and 99 per cent confidence intervals indicated by concentric circles. Normal limits (± 1 standard deviation) for latency of components VI and VII indicated by vertical broken lines. Horizontal axis, time in ms. Vertical axis amplitude ^V.
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B
0-5JJV
T
2
6
10 ms
FIG. 9. Example of abnormal records of early components of the auditory evoked potential from 4 patients (B, C, D, E) compared with a record from a normal subject (A). Component V indicated. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-
AUDITORY EVOKED POTENTIALS IN MS
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A correlation between these clinical signs and the auditory evoked potential was found. Eighty-two per cent of group A, 76 per cent of group B and 51 per cent of group C were abnormal. The amplitude and latency of component V for all the patients studied, in relation to their group classification, are shown in fig. 10A-C. Middle Components Sixty-six of the patients were studied. A record was classified as abnormal if the amplitude or latency of any of the components (apart from No, Po, Na and amplitude Na-Pa) were outside the normal range (more than two standard deviations from the mean). Examples of four abnormal records are shown in fig. 11. Forty-five per cent of the records had abnormal middle latency components. When the patients were subdivided on clinical evidence of brain-stem involvement, 69 per cent of group A, 60 per cent of group B and 29 per cent of group C were abnormal. In all cases the abnormalities were confined to increase in latency and in none was amplitude abnormal. Furthermore, the patients as a group were not significantly different from the controls on any of the measures of amplitude used.
TABLE 3. PROPORTION OF ABNORMALITIES OF EARLY AND MIDDLE COMPONENTS OF AUDITORY EVOKED POTENTIAL IN 88 PATIENTS WITH MULTIPLE SCLEROSIS MIDDLE
E A R _) >•
Normal Abnormal
Normal
Abnormal
/o
/o
o/ /o
23 32
12 33 45
65
Early, Middle and Late Components Combined An abnormality of one or more of the early components did not invariably mean that there was an abnormality of the middle components. The highest proportion of abnormalities was detected in the early components. An additional 12 per cent of abnormalities was detected by recording the middle components (Table 3). The late components were abnormal in only 3 of the patients, and in these the middle components were also abnormal.
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Late Components Sixty-six of the patients were studied. A record was classified as abnormal if the amplitude or latency of any of the components were outside the normal range (more than two standard deviations from the mean). Only three records could be classified as abnormal. In each case the only abnormality was delay of component Nl. The patients as a group were not significantly different from the controls in latency or amplitude.
KATHLEEN ROBINSON AND PETER RUDGE
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3 o
1
I oh < 5 6 Latency (ms)
K)
B
"5. < 5 6 Latency (ms)
10
5 6 Latency (ms)
10
FIG. 10. Distribution of amplitude and latency of component V in patients with multiple sclerosis, A, patients with definite clinical evidence of brain-stem lesion; B, patients with nystagmus; c, patients with no clinical evidence of brain-stem lesion. Broken circle 95 per cent confidence limits for normal subjects. Horizontal axis, time in ms. Vertical axis, amplitude pV.
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4)
AUDITORY EVOKED POTENTIALS IN MS
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B
[0-5JJV
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20
40
60
80 ms
FIG. 11. Example of abnormal records of middle components of the auditory evoked potential from 4 patients (B, C, D, E) compared with record from a normal subject (A). Components Pa, Na and PI indicated in A. Component V also shown. Component PI in abnormal records indicated*. Stimulus starts at arrow. Horizontal axis, time in ms. Bar 0-5 ;xV.
Pairs of Clicks Normal subjects. When normal subjects are given a pair of clicks, 5 ms apart, at a rate of 2-5 s"1 the latency and amplitude of all the components to the first click of the pair were unchanged compared to those for a single click; but when the pair of clicks was presented at a repetition rate of 20 s -1 there was a significant increase in the latency of components II, III and V to the^zm click of the pair compared to that observed for a single click, although the latency of component I remained unchanged.
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K A T H L E E N ROBINSON AND PETER R U D G E
The early components evoked by the second click can also be recorded. They are of smaller amplitude than those evoked by the first click although they occur at the same latency. In some subjects, however, the early components to the second click of the pair can be difficult to identify because of their superimposition upon the post-auricular muscle response to the first click. The average of the records from 24 normal subjects with a pair of clicks as the stimulus is shown infig.12.
Vb
8
10 12 14 ms
FIG. 12. Average of early components to pairs of clicks from-24 normal subjects. Clicks start at arrows a and b. Components I, III and V to first click indicated by suffix a; components III and V to second click indicated by suffix b. Horizontal axis, time in ms. Bar 0-
Patients. Sixty of the patients were investigated with pairs of clicks presented at the faster stimulus rate of 20 s"1 and the increase in latency of component V to the first click of the pair compared to that observed for a single click was measured. The patients were divided into three groups: (i) Patients with an abnormal latency of component V (more than two standard deviations above the mean) to a single click. The amplitude of component V was normal in some of these. (ii) Patients with abnormal amplitude (more than two standard deviations below the mean) but normal latency of component V to a single click. (iii) Patients with normal early components to a single click. The results are shown in fig. 13. Fifty-five per cent of group (i) and 57 per cent of group (ii) had an abnormal increase in latency of component V to thefirstclick of the pair. In group (iii) only one patient had an abnormal increase in latency. Although this patient was normal to a single click when amplitude and latency
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PI
6
A U D I T O R Y E V O K E D P O T E N T I A L S IN MS
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were considered separately, component V lay outside the 95 per cent confidence limits when both parameters were considered together. Two other patients in group (iii) failed to respond to the second click of the pair although the auditory evoked potential was normal in all other respects. However, no systematic analysis of the response to the second click of the pair was undertaken because of the difficulty of identifying the components in those subjects who had abnormal latency of component V even to a single click.
i
i
B
: ...:: i
: .
. :
•
i
i
c •
• i
0
1
2
ms
Latency increase
FIG. 13. Increase of latency of component V to first of a pair of clicks, A, control subjects; B, patients with abnormal latency of component V to single click; c, patients with abnormal amplitude but normal latency of component V to single click; D, patients with normal component V to single click. Each point represents one subject. Horizontal axis, increase of latency, time in ms.
DISCUSSION
Symptomatic deafness is rare in patients with multiple sclerosis although occasionally a lesion in the region of the cochlear nucleus can cause severe unilateral hearing loss (Dix, 1965). It has been claimed that multiple sclerosis patients as a group do have impaired hearing (Dayal and Swisher, 1967) but routine audiometry is of no value for the detection of plaques in the auditory system of individual patients. The present results do, however, show that the auditory system does not have a privileged immunity to demyelination and suggests that the auditory evoked potential is a more sensitive method than audiometry for detecting such lesions. It is known from both pathological and clinical studies that the brain-stem is a common site of demyelination. Such lesions frequently cause abnormalities of eye movements, for example, internuclear ophthalmoplegia, cranial nerve palsies and nystagmus. It is therefore to be expected that patients with such clinically apparent lesions would also have the greatest chance of involvement of the auditory
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••
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KATHLEEN ROBINSON AND PETER RUDGE
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pathways within the brain-stem since the various fibre tracts are compressed into a small area and demyelinating plaques do not respect boundaries between different fibre systems. Concerning the early components of the auditory evoked potential, there is evidence in the present study that this is indeed the case. Components II, III, IV and V are known to depend upon the integrity of the cochlear nuclei, superior olivary nuclei, lateral lemniscus and inferior colliculus respectively (Jewett, 1970; Buchwald and Huang, 1975). In the patients with independent evidence of involvement of the brain-stem, for example eye movement disorders, 79 per cent have abnormalities of these brain-stem components. In contrast, only 51 per cent of patients in whom there was no other evidence of a brain-stem lesion had abnormal early components of the auditory evoked potential. This suggests that clinically silent areas of demyelination occur frequently and accords with evoked potential studies of the visual (Halliday, McDonald and Mushin, 1973, and Asselmann, Chadwick and Marsden, 1975) and spinal (Small, Beauchamp and Matthews, 1977) sensory systems. It could be argued that the abnormalities of the auditory evoked potential are the result of a small decrease in hearing threshold due to a peripheral deficit. Such a decrease would in effect be equivalent to a lowering of the intensity of the click stimulus. Since it is known that the early components of the auditory evoked potential are dependent upon the intensity of the stimulus, alteration of these components would be expected. This is unlikely, however, to be the explanation for the abnormalities detected. First, in all cases the latency of component I was normal implying that the input to the brain-stem was not reduced. Secondly, in normal subjects the latency and amplitude of the components change concurrently as the intensity of the click stimulus is reduced, whereas the abnormalities of the auditory evoked potential in patients with multiple sclerosis may be of either amplitude or latency alone. Furthermore, component V may be abnormal in the presence of normal earlier components. Finally, there is no correlation between abnormalities of the audiogram and abnormalities of the auditory evoked potential; a patient with a normal audiogram may show gross abnormalities of the auditory evoked potential. For these reasons it was concluded that the abnormalities of the early components of the auditory evoked potential are not due to a diminished input of the click stimulus and that they are the consequence of a more central lesion. The origin of the middle components is obscure. The experiments in which muscle activity has been sampled indicate that components Pa, Nb and PI are not reflex muscle responses to the click from the posterior cervical, temporalis, frontalis or post-auricular muscles sampled. It is, however, possible, although unlikely, that some other muscles give rise to them. No definitive conclusion concerning the components No, Po and Na can be made, as both the post-auricular muscle and component VII occur at a similar latency. Whatever the source of the middle components, additional information is obtained by studying them as in 12 per cent of patients who had normal early components of the auditory evoked potentials, these middle components were abnormal. Although this proportion
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is small it is significant clinically since it was the only evidence of demyelination within the auditory system in 6 patients (i.e. 6 patients in Group C). In contrast, studies of the late components does not increase the proportion of patients in whom abnormalities were detected. In only 3 patients were the late components abnormal and in all 3 the earlier components were also abnormal. This may in fact be due to the greater variation of the late components which are markedly affected by the state of arousal in normal subjects. The early and middle components are not affected by such changes. Any attempt to quantify the delays of the various components of the auditory evoked potential in terms of altered conduction velocity must be made with caution. In animal studies the effect of demyelination on conduction can be measured directly for single fibres. In contrast, in man, whilst the altered form of the evoked potential probably reflects changes of conduction within central nervous system fibres, no absolute measure of the change can be made. Estimates of amplitude and latency are made at the turning-points of the evoked potential wave form which merely reflect the point of maximum synchronization of many interacting fibres. The effect of demyelination of any of these fibres can be variable. It would be misleading to calculate conduction velocity from the wave form of the evoked potential. For example, selective slowing of the fastest conducting fibres could increase the amplitude of a component without altering peak latency. A particular problem with such extrapolations from the auditory evoked potential is the complexity of the wave form. If the early components represent electrical events in a sequential system, interaction between these components would be expected if a delay occurred in a part of that system. Two common features of the abnormalities of component V suggest that this does indeed occur. First, there was a marked tendency for component V to be recorded at the latency of components VI and VII (fig. 8). Secondly, there are frequently small additional waves on the down-going slope of the component V in abnormal records. These might be the result of selective alteration of conduction within the auditory system but could equally well be explained by interaction between various components. In this study, component V was identified as the most negative peak to occur within the first 5 to 10 ms and measurements of amplitude and latency were made at this point. This is a relatively crude way of assessing abnormality. A more sensitive method would be to compare the shape of the entire wave form if suitable templates for pattern recognition could be developed. Of more relevance to the present study is the impaired ability of demyelinated axons in the central nervous system to transmit trains of impulses (McDonald and Sears, 1970). This is due to an increase in the refractory period of transmission of the axons. It was for this reason that closely paired stimuli were administered to patients to stress the auditory system. For large demyelinated central nervous system axons in animals it is known that the refractory period of transmission can be as much as 4-3 ms although in general it is less than 2-5 ms. It was not possible to administer pairs of clicks at intervals of less than 5 ms since the analysis of the
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KATHLEEN ROBINSON AND PETER R U D G E
SUMMARY
Fifteen components of the auditory evoked potential can be recorded within 300 ms of a click stimulus and these can be classified by latency into early (0-8 ms), middle (8-60 ms) and late (>60 ms) components. Following a click stimulus of high intensity these components have been studied in 45 normal subjects and in 88 patients with definite multiple sclerosis. Component V, thought to arise from brain-stem structures, was the most consistently abnormal in patients and there was a correlation between the abnormalities and clinical evidence of a brain-stem lesion. Thus in 79 per cent of patients with definite evidence of a brain-stem lesion
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wave form of the evoked potential becomes unreliable. In spite of this long interval there was a significant increase of latency of component V to even the first click of the pair in normal subjects indicating that such a stimulus did stress the auditory system. This was not due to adaptation at the end organ, as component I from the eighth nerve was not affected. Neither was it due to the fortuitous superimposition of earlier components upon component V as the latency change only occurred when pairs of clicks were given at the faster stimulation rate of 20/s. It is possible that the interaction of the high repetition rate with the added stress of a double click is sufficient to cause the delays seen. In the case of patients with multiple sclerosis this increase in latency is greater than in normals. This could be explained by the observation in single nerve fibre studies that there is a progressive reduction of conduction velocity when trains of impulses are transmitted through demyelinated axons in the central nervous system (McDonald and Sears, 1970). Whatever the cause, the technique of giving pairs of clicks validated the use of amplitude as well as latency in detecting abnormalities in the auditory pathways. In those patients in whom component V was of normal latency but reduced amplitude to a single click, 57 per cent developed an abnormal increase of latency of this component to a pair of clicks (fig. 13c). This suggests that the mechanism of the reduction in amplitude and increase in latency are similar and that it is justified to use amplitude as well as latency changes to detect demyelination. The present work demonstrates that evoked potential techniques are of value in detecting demyelinating lesions in the auditory system of patients with multiple sclerosis. This applies not only to the 90 per cent of patients with evidence, on other grounds, of a brain-stem lesion, but also to the 60 per cent of those with no such abnormality when data from early and middle components are combined. None of the patients had clinical deafness. There is thus a striking parallel between these patients and those in whom the visual evoked responses were abnormal and yet there was no clinical evidence of optic neuritis (Halliday, McDonald and Mushin, 1973; Asselmann, Chadwick and Marsden, 1975). As with all evoked potential studies, however, it remains to be seen if abnormalities that are clinically silent in patients with possible or probable multiple sclerosis will predict the subsequent diagnosis of definite multiple sclerosis at a later date.
A U D I T O R Y E V O K E D P O T E N T I A L S I N MS.
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and in 51 per cent of those without clinical signs related to the brain-stem, component V was abnormal. Abnormalities were also detected for components Pa, Nb and PI of the middle components, and in 12 per cent of these the early components were normal. The late components were normal in all but 3 patients. Evidence is presented to show that pairs of click stimuli, 5 ms apart, presented at a fast stimulus rate, stress the auditory system in normal subjects. Using this technique abnormalities of component V in patients became more marked and the proportion of abnormalities detected was increased. The contribution of the reflex muscle responses to the click to the middle components of the auditory evoked potential has also been studied. It is concluded that components Pa, Nb and PI are independent of these reflexes. ACKNOWLEDGEMENTS We wish to thank Mr. H. B. Morton without whose help this work could not have been carried out. We thank also Drs. W. A. Cobb, J. D. Hood, P. A. Merton and Professor T. A. Sears for their helpful advice and criticism; and Dr. Hugh Bostock for the use of his CALCPLOT programme.
ASSELMANN, R., CHADWICK, D. W., and MARSDEN, C. D. (1975) Visual evoked responses in the diagnosis
and management of patients suspected of multiple sclerosis. Brain, 98, 261-282. BUCHWALD, J. S., and HUANG, C. M. (1975) Far-field acoustic response: origins in the cat. Science, 189,382-384. . CODY, D. T., and BICKFORD, R. G. (1969) Averaged evoked myogenic responses in normal man. Laryngoscope, St. Louis, 79, 400-416. DAYAL, V. S., and SWISHER, L. P. (1967) Pure tone thresholds in multiple sclerosis. Laryngoscope, St. Louis, 77, 2169-2177. Dix, M. R. (1965) Observations upon the nerve fibre deafness of multiple sclerosis with particular reference to the phenomenon of loudness recruitment. Journal of Laryngology and Otology, 79, 695-706. HALLIDAY, A. M., MCDONALD, W. I., and MUSHIN, J. (1973) Visual evoked responses in diagnosis of
multiple sclerosis. British Medical Journal, 4, 661-664. JEWETT, D. L. (1970) Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroencephalography and Clinical Neurophysiology, 28, 609-618. KIANG, N. Y. S., CHRIST, A. H., FRENCH, M. A., and EDWARDS, A. G. (1963) Post-auricular electric
response to acoustic stimuli in humans. Quarterly Progress Report, Research Laboratory of Electronics, Massachusetts Institute of Technology, 68, 218-225. LIEBERMAN, A., SOHMER, H., and SZABO, H. (1973) Standard values of amplitude and latency of cochlear
audiometry (electro-cochleography). Responses in different age groups. Archiv fur Ohren-, Nasen-, und Kehlkopfheilkunde, 203, 267-273. MCALPINE, D., LUMSDEN, C. E., and ACHESON, E. D. (1972) Multiple Sclerosis: A Reappraisal. Edin-
burgh: Livingstone, p. 202. MCDONALD, W. I., and SEARS, T. A. (1970) The effects of experimental demyelination on conduction in the central nervous system. Brain, 93, 583-598.
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REFERENCES
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PICTON, T. W., HILLYARD, S. A., KRAUSZ, H. I., and GALAMBOS, R. (1974) Human auditory evoked
potentials: evaluation of components. Electroencephalography and Clinical Neurophysiology, 36, 179-190. REGAN, D., MILNER, B. A., and HERON, J. R. (1976) Delayed visual perception and delayed visual evoked potentials in the spinal form of multiple sclerosis and in retrobulbar neuritis. Brain, 99, 43-66. RICHEY, E. T., Kooi, K. A., and TOURTELLOTTE, W. W. (1971) Visual evoked responses in multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry, 34, 275-280. ROBINSON, K., and RUDGE, P. (1975) Auditory evoked responses in multiple sclerosis. Lancet i, 11641166. SAW, J. G. (1961) Estimation of the normal population parameters given a type 1 censured sample. Biometrika, 48, 367-374. SMALL, D. G., BEAUCHAMP, M., and MATTHEWS, W. B. (1977) Spinal evoked potentials in multiple sclerosis. (To be published.) THORNTON, A. R. D. (1975) Distortion of averaged post-auricular muscle responses due to system bandwidth limits. Electroencephalography and Clinical Neurophysiology, 39, 195-197. {Received May 19, 1976) Downloaded from by guest on June 24, 2015
