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The stability of the auditory evoked potentials in normal man and patients with multiple sclerosis
Journal of the Neurological Sciences, 1978, 36: 147-156 © Elsevier/North-Holland Biomedical Press
147
T H E STABILITY OF T H E A U D I T O R Y EVOKED POTENTIALS IN N O R M A L M A N A N D PATIENTS W I T H M U L T I P L E SCLEROSIS
KATHLEEN ROBINSON and PETER RUDGE Department of Clinical Neurophysiology, and the MRC Hearing and Balance Unit, National Hospital, Queen Square, London WCI (Great Britain)
(Received 20 October, 1977) (Accepted 26 October, 1977)
SUMMARY Sequential records of the early and middle components of the auditory evoked potential in response to a click stimulus have been obtained over a period of 2.5 years in normal subjects and in patients with multiple sclerosis. The latencies of all the components were highly consistent in the control subjects and in the patients who were clinically stable throughout the period of study. In contrast, in some of the patients who had clinical relapses during the study there was variation in the latency and amplitude of some of the components. The significance of this variation is discussed and the poor correlation between the sites of the new lesions as determined clinically and the auditory evoked potential variability is emphasised.
INTRODUCTION The auditory evoked potential recorded from scalp electrodes in response to a click stimulus is complex and comprises a series of waves which have been classified by latency into early, middle and late components (Picton, Hillyard, Krausz and Galambos 1974) (Fig. 1). The early components, which are dependent upon brain stem structures, are frequently abnormal in patients with multiple sclerosis especially those with clinical evidence of a brain stem disorder, and component V is always affected in abnormal records (Robinson and Rudge 1977). Furthermore the middle latency components, which may be of cortical origin, are also often abnormal. Thus, while deafness is rare in multiple sclerosis, clinically silent plaques can be detected in the auditory system even in patients with no evidence of any brain stem disturbance on clinical examination. Such silent plaques can also be detected in the visual sensory system (Halliday, McDonald and Mushin 1973; Asselmann, Chadwick and Marsden 1975; Regan, Milner and Heron 1976) and spinal pathways (Small, Matthews and Small 1978).
148 EARLY
MII3OLE
LATE N2
0"1
0.3"-
2 ,
,
, ~ ....
~,
'~
,
,~, ....
m
~ ,
LATENCY ms
Fig. 1. Early, middle and late components of the auditory evoked potential induced by click stimulus. Horizontal axis, latency (ms); vertical axis, amplitude (pV). Note log scale.
Because of the understandable desire to have an "objective" measure of abnormality in patients with multiple sclerosis and because of the high proportion of abnormalities detected in the sensory systems by evoked potential techniques, these have been used to monitor the effects of treatment. It has been claimed that both the brain stem components of the auditory evoked potential and the spinal cord evoked potentials changed towards normal during a period of spinal cord stimulation (IUis, EINegamy, Sedgwick and Thornton 1978), and that clinical remission after a period of ACTH therapy was paralleled by a change towards normal of the brain stem components of the auditory evoked potential in a single case of multiple sclerosis (Stockard and Rossiter 1977). However, before any conclusions can be drawn it is important to determine, in a long term study, whether evoked potential abnormalities, once they have occurred, are constant, or whether they fluctuate spontaneously and whether any variation is related to the clinical state of the patient. It is to these questions that the present study is directed. METHODS
Early and middle components of the auditory evoked potential to a binaural 95 dBC click (0.5 ms duration) were averaged between the vertex and mastoid (for details see Robinson and Rudge 1977). The auditory evoked potential was classified as abnormal if: (1) The latency and/or amplitude of component V was more than 2 SD from the mean for normals. (2) The latency increase of component V to the first of a pair of clicks was abnormal. (3) The latency of any of the middle components Pa, Nb and P1 was more than 2 SD from the mean for normals. Because the amplitude variation between sequential records in normal subjects is much greater than the variation of latency, only the latency data are used to illustrate
149 this paper. However, the normality of any individual record was determined by the above criteria. Eighteen healthy controls, aged 20-56, and 27 patients with clinically diagnosed multiple sclerosis, aged 18-58 years, were studied. Records of the early and middle components of the auditory evoked potential were obtained on 2 or 3 occasions over a period of 9 months-3 years for the control subjects and on 2-9 occasions over a period of 9 months-2.5 years for the patients. All the patients, who were seen at regular intervals in an out-patient clinic, were examined clinically on each occasion prior to the auditory evoked potential recording to determine if a relapse had occurred or if there had been any change in their neurological status. None of the control subjects or patients was deaf on clinical examination. Different persons examined the patients neurologically and recorded the auditory evoked potential and the data from both were blind until the completion of the study. RESULTS Controls The remarkable consistency of the auditory evoked potentials in control subjects is illustrated in Fig. 2, where the latencies of the early and middle components obtained at the first recording session are plotted against the latencies at the second. If recordings were obtained on 3 occasions the latencies from the second record are plotted against those obtained from the third. Patients Of the 27 patients studied 16 had a clinical relapse during the trial (we have called this group "unstable patients") and 11 did not have relapses in the period of study ("stable patients"). Details of the clinical state of these 2 groups of patients are given
ms
5O d., Na
10 11
7.
3. I 1'1 10
ms 50
Fig. 2. Latencies of early and middle components at successive recording sessions, normal subjects. Continuous lines enclose all the points obtained for early components I, II, III and V and for middle components Na, Pa, Nb and P1. Axes, latency (ms). Note that axes are different for early and middle components. This same format applies to Figs. 3 and 5.
150 TABLE 1 CLINICAL DETAILS OF PATIENTS P = progressive disease; RBN = retrobulbar neuritis. Age
Sex
Number of relapses before the trial
Number of relapses during the trial
Duration of illness at time of trial (years)
Length of trial (years)
------------
4 6 3 3 5 1.25 5 34 2 3 10
0.75 0.75 2.25 0.75 2.5 1.75 2.25 1 1 1.5 1.5
2 6 4 1 2
0.5 2.25 1 0.5 4
2.5 2 1 1 1.5
Clinically stable 24 26 31 33 43 44 38 54 47 49 58
F F F M F F M F F M F
3 2 3 2 4 2 2+P 2+P P P P
Clinically unstable 18 20 22 22 24
F F F F M
24 24 25 26 31 34 34 35 36 38 43
F M M F F F F M M F F
1 1 5 3 10+, all RBN 2 1 2 3 4 2 4 2 3 1 3
2 1 2 1 1 1 1 3 2 1 1
3 4 2 5 3 2 9 10 9 2 17
2.5 2 0.75 1.5 1 0.75 1 2 2.5 2 l
in T a b l e 1. T h e p a t i e n t s in t h e 2 clinical g r o u p s are m a t c h e d f o r d u r a t i o n o f disease a n d f o r n u m b e r a n d f r e q u e n c y o f p r e v i o u s relapses. F i v e p a t i e n t s in the clinically s t a b l e g r o u p h a d p r o g r e s s i v e disease a n d w e r e o l d e r t h a n t h e others. I n t h e clinically u n s t a b l e g r o u p t h e r e w e r e 4 p a t i e n t s a g e d 18-22 years w h o w e r e y o u n g e r t h a n a n y o f t h e stable p a t i e n t s . T h e p r o p o r t i o n o f p a t i e n t s h a v i n g a b n o r m a l 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 t h e " c l i n i c a l l y u n s t a b l e " a n d t h e " c l i n i c a l l y s t a b l e " g r o u p s at t h e b e g i n n i n g o f t h e s t u d y w a s t h e same. H o w e v e r , in t h e ',clinically s t a b l e " g r o u p t h e a b n o r m a lity was m o r e o f t e n o f t h e m i d d l e c o m p o n e n t s a l o n e . T h e a u d i t o r y e v o k e d p o t e n t i a l s w e r e r e m a r k a b l y c o n s t a n t in t h e " c l i n i c a l l y s t a b l e " g r o u p o f p a t i e n t s w h e t h e r t h e y h a d p r o g r e s s i v e o r e p i s o d i c disease. T h i s is i l l u s t r a t e d in Fig. 3 w h e r e t h e l a t e n c y o f e a c h c o m p o n e n t is p l o t t e d a ~ n s t t h a t o b .
151 ms
50 ~-" Nb . ,-:?,, Pa "" Na
10 11
7V C~ ~:'_',~II III
3-
I '
~
'
,
11 10
,
, 5O
ms
Fig. 3. Latencies of early and middle components at successive recording sessions, clinically stable multiple sclerosis subjects. The vertical extension of the contour for component V is due to a variation in one patient. See Fig. 2 and text for further explanation. tained from the preceding record. This plot is similar to that obtained from the control subjects (compare Figs. 2 and 3). Only on one occasion was there a significant change in latency of any component (in component V). An example of abnormal records from one of the clinically stable patients is shown in Fig. 4 where it can be seen that the 2 recerds are similar. These results contrast sharply with those from patients who were "clinically unstable" during the study. The results from this group of patients are illustrated in Fig. 5. It is apparent that in some patients there is a marked variation in the latency of the various components, except component I, between consecutive recording sessions, component V being particularly affected, while in other patients the latencies are unchanged. An example of 2 records from a "clinically unstable" patient in which the laten-
WT 41175
[ o.4.v 576
0
6
12 m s
Fig. 4. Example of 2 records of the early components of the auditory evoked potential obtained from a clinically stable patient with multiple sclerosis at interval of 6 months. Component V and stimulus indicated. Horizontal axis, latency (ms); bar, 0.4/~V.
152 ms
50
P: • Nb
lO ,1
:3
'
7'
1'I
ms
10 Fig. 5. Latencies of the early and middle components obtained at successive recording sessions from clinically unstable patients with multiple sclerosis. Every value for components I, Iil, Na and Nb is shown by open circles and for components II, V, Pa and P1, shown by filled circles. VR
16776
[0"4uV 5 477
6'
' ~, ' ' 1 ~ m s
Fig. 6. Example of 2 records of the early component of the auditory evoked potential obtained at an interval of 9 months in a clinically unstable patient with multiple sclerosis. Component V and stimulus indicated. Horizontal axis, latency (ms): bar, 0.4 pV.
DP
~
2437,5
"ka~d
bs
6 476 9775 "
"~,~J'~
6 776
81275
~
~
.
1 377
3276
! 0.4uV 0
71276
6
12 ms
....... 0
6
12ms
Fig. 7. Example of 8 consecutive records of the early components of the auditozy evoked potential obtained from a clinically unstable patient with multiple sclerosis. Dates of i ~ i v ~ ! ~ d s i component V and sites of new lesions indicated. Horizontal axis, latency (ms); bar, 0;4 pV: See text for further explanation.
153 cies did not alter is shown in Fig. 6. The initial brain stem response from this patient has a delayed component V. A similar abnormality is seen in the next record obtained 9 months later, the patient having had an attack of retrobulbar neuritis in the intervening period. In contrast, a series of brain stem recordings from a clinically unstable patient in whom marked alterations of the auditory evoked potential occurred is shown in Fig. 7. It can be seen that there is considerable variation in the form of the brain stem auditory evoked potential but that the relationship to the apparent sites of the lesions determined by clinical assessment is poor. For example, the already small component V did decrease further in amplitude following the development of vertigo and gross nystagmus 2 weeks prior to obtaining a second record but this decrease was of doubtful significance. Later a definite delay of component V occurred (see third trace) which subsequently improved again. Three other patients whose initial brain stem auditory evoked potential was abnormal developed clinical signs of a brain stem lesion during the period of study and in these there was no consistent change in component V; indeed in one patient the auditory evoked potential improved following such an episode. Only one patient in this group had a normal auditory evoked potential initially and then developed clinical evidence of a brain stem lesion. Component V became abnormal in this patient. In these "clinically unstable" patients with fluctuating abnormalities the early and middle components changed independently in many cases. In some the middle components were unaffected by changes in the brain stem responses, in others the early components remained constant while changes occurred in the middle components, whilst in the remainder there were changes in both the early and middle components. An interesting finding in this study was that the consistency of the auditory evoked potential in the "clinically unstable" patients seemed to depend upon whether the initial auditory evoked potential was normal or not. Thus all the clinically unstable patients with a normal auditory evoked potential at the onset of the study had consistently normal records on subsequent recordings with the one exception mentioned above where a new lesion apparently developed in the brain stem. On the other hand, if the initial auditory evoked potential was abnormal subsequent recordings were often variable and this can be clearly seen in the records from the patient illustrated in Fig. 7. This patient and others had marked fluctuations in the early and middle components of the auditory evoked potential, while developing lesions at sites remote from the brain stem, e.g., optic nerve and spinal cord. In some of these patients the auditory evoked potential tended to become normal after exhibiting marked abnormalities as shown in Fig. 7. DISCUSSION The latencies of the early and middle components of the auditory evoked potential were remarkably constant in normal subjects over the 3 year period of this study. Some of the patients had similarly stable records. The majority of these patients had normal auditory evoked potentials at the onset and in those with abnormal records the abnormalities were unchanged. In contrast there were a number of patients in
154 whom the record did alter significantly, the majority of whom had an abnormality at the initial recording session, and, with one exception, these patients belonged to the group classified as "clinically unstable". It seems that the necessary requirements for a variable auditory evoked potential are an abnormal potential initially, with the addition of "active disease". The alteration observed could be either of increasing abnormality or the reverse, and some records became essentially normal at some time during the study. This is in marked contrast to the stability of the visual evoked potentials in which it has been claimed that once the latency has become abnormal, as a result of a demyelinating lesion, the abnormality will persist indefinitely (Halliday et al. 1973). This difference may be related to the source of the potentials, cortical with the visual stimulation and infracortical, at least for the early components, with auditory stimulation. In this connection it is of interest that certain brain stem reflexes, if abnormal, are sometimes labile in patients with multiple sclerosis (Kimura 1975). However, somatosensory evoked potentials, thought to arise from the cortex, can change towards normal latencies in the course of the disease (Namerow 1968) and in the present study the middle components of the auditory evoked potential, some of which are probably cortical in origin, did sometimes return to normal independently of the brain stem response. This may of course reflect alterations in conduction at a lower level, but does indicate that certain cortical potentials may be labile in patients with multiple sclerosis. It might be supposed that the abnormal form of the evoked potential recorded in a particular sensory system in patients with multiple sclerosis is due to conduction abnormalities in fibres passing through demyelinating lesions in that system. Furthermore, it would be reasonable to assume that a deterioration in the auditory evoked potential is the result of demyelination within the auditory pathways with alteration of conduction in these fibres. If these new plaques also involved more eloquent parts of the brain stem than the auditory pathways they would be clinically apparent, as happened in one of the patients in the present study when a clinically obvious brain stem lesion coincided with the development, for the first time, of an abnormal auditory evoked potential. However, it is difficult to account for the return to virtual normality of the auditory evoked potential on this basis. The actual mechanism by which conduction recovers in the central nervous system is far from clear especially as there is little evidence of remyelination in multiple sclerosis (McDonald 1974). Could there be any other mechar~sm to account for the lability of the auditory evoked potential in multiple sclerosis? Since it is known that temperature change and alteration of calcium and phosphate levels of body fluids can have profound effects upon conduction in the peripheral nervous system and alter the functioning of the central nervous system in multiple sclerosis (Becker, Michael and Davis 1974), it is conceivable that there is some general effect of activity of the disease upon conduction in the damaged central nervous system fibres. While it is conceded that such a hypothesis may be heretical and that one is merely seeing the effects of silent plaques upon the auditory system, it is surprising that within the group of patients having clinical relapses, those with an auditory evoked potential that was initially normal remained normal (with the one exception
155 above), while 7 of the 9 patients with abnormal auditory evoked potentials at the start of the study had marked changes in their response. This is remarkable since both subgroups had active disease, as judged by the number of clinical relapses occurring during the study, and there is no obvious reason why the auditory system of those with normal auditory evoked potentials at the start should have privileged immunity to attacks. It is, however, important to note that to some extent the sampling rate of the patients is critical in assessing the significance of the abnormalities shown and to reach a firm conclusion on whether silent plaques are occurring or not would require a much more frequent sampling rate and more prolonged study. Of more practical importance is the value of auditory evoked potential recording as an "objective" measure of the extent of demyelination, particularly the occurrence of new plaques, in patients subjected to therapeutic trials. In patients having frequent clinical relapses caution is necessary in attributing alteration of the auditory evoked potential to a particular therapeutic regime, particularly if the auditory evoked potential is abnormal initially. Even those patients with an apparently normal auditory evoked potential may in fact already have a lesion in the auditory system as it has been shown that the auditory evoked potential can become essentially normal after a prolonged period of derangement. In patients who are clinically stable the clinician is probably on safer ground in assuming that alterations observed are related to the therapy administered, provided that an initial baseline is obtained. A more prolonged study of clinically stable patients with initially abnormal auditory evoked potentials is needed to determine whether the auditory evoked potential may not also fluctuate spontaneously in this group. ACKNOWLEDGEMENTS We are grateful to Dr. D. G. Small and Dr. R. G. Willison for helpful advice and criticism, and to Dr. W. A. Cobb for his continuing support and encouragement.
REFERENCES Asselmann, R., D. W. Chadwick and C. D. Marsden (1975) Visual evoked responses in the diagnosis and management of patients suspected of multiple sclerosis, Brain, 98 : 261-282. Becker, F. O., J. A. Michael and F. A. Davis (1974) Acute effects of oral phosphate on visual function in multiple sclerosis, Neurology (Minneap.), 24" 601-607. Halliday, A. M., W. I. McDonald and J. Mushin (1973) Visual evoked responses in diagnosis of multiple sclerosis, Brit. med. J., 4: 661-664. Illis, L. S., E. E1-Negamy,E. M. Sedgwick and A. R. D. Thornton (1978)Dorsal column stimulation in the management of patients with multiple sclerosis, Electroenceph. clin. NeurophysioL, In press. Kimura, J. (1975) Electricallyelicited blink reflex in diagnosis of multiple sclerosis, Brain, 98 : 413-426. McDonald, W. I. (1974) Remyelination and clinical lesions of the central nervous system, Brit. reed. Bull., 30: 186-189. Namerow, J. S. (1968) Somatosensory evoked responses in multiple sclerosis patients with varying sensory loss, Neurology (Minneap.), 18 : 1197-1204. Picton, T. W., S. A. Hillyard, H. I. Krausz and R. Galambos (1974) Human auditory evoked potentials: evaluation of components, Electroenceph. clin. Neurophysiol., 36: 179-190. Regan, D., B. A. Milner and J. R. Heron (1976) Delayed visual perception and delayed visual evoked potentials in the spinal form of multiple sclerosis and in retrobulbar neuritis, Brain, 99: 43-66.
156 Robinson, K. and P. Rudge (1977) Abnormalities of the auditory evoked potentials in patients with multiple sclerosis, Brain, 100: 19-40. Small, D. G., W. B. Matthews and M. Small (1978) The cervical somatosensory evoked potential in the diagnosis of multiple sclerosis, J. neurol. Sci., 35 : 211-224. Stockard, J. J. and V. S. Rossiter (1977) Clinical and pathological correlates of brain stem auditory response abnormalities, Neurology (Minneap.), 27: 316-325.
147
T H E STABILITY OF T H E A U D I T O R Y EVOKED POTENTIALS IN N O R M A L M A N A N D PATIENTS W I T H M U L T I P L E SCLEROSIS
KATHLEEN ROBINSON and PETER RUDGE Department of Clinical Neurophysiology, and the MRC Hearing and Balance Unit, National Hospital, Queen Square, London WCI (Great Britain)
(Received 20 October, 1977) (Accepted 26 October, 1977)
SUMMARY Sequential records of the early and middle components of the auditory evoked potential in response to a click stimulus have been obtained over a period of 2.5 years in normal subjects and in patients with multiple sclerosis. The latencies of all the components were highly consistent in the control subjects and in the patients who were clinically stable throughout the period of study. In contrast, in some of the patients who had clinical relapses during the study there was variation in the latency and amplitude of some of the components. The significance of this variation is discussed and the poor correlation between the sites of the new lesions as determined clinically and the auditory evoked potential variability is emphasised.
INTRODUCTION The auditory evoked potential recorded from scalp electrodes in response to a click stimulus is complex and comprises a series of waves which have been classified by latency into early, middle and late components (Picton, Hillyard, Krausz and Galambos 1974) (Fig. 1). The early components, which are dependent upon brain stem structures, are frequently abnormal in patients with multiple sclerosis especially those with clinical evidence of a brain stem disorder, and component V is always affected in abnormal records (Robinson and Rudge 1977). Furthermore the middle latency components, which may be of cortical origin, are also often abnormal. Thus, while deafness is rare in multiple sclerosis, clinically silent plaques can be detected in the auditory system even in patients with no evidence of any brain stem disturbance on clinical examination. Such silent plaques can also be detected in the visual sensory system (Halliday, McDonald and Mushin 1973; Asselmann, Chadwick and Marsden 1975; Regan, Milner and Heron 1976) and spinal pathways (Small, Matthews and Small 1978).
148 EARLY
MII3OLE
LATE N2
0"1
0.3"-
2 ,
,
, ~ ....
~,
'~
,
,~, ....
m
~ ,
LATENCY ms
Fig. 1. Early, middle and late components of the auditory evoked potential induced by click stimulus. Horizontal axis, latency (ms); vertical axis, amplitude (pV). Note log scale.
Because of the understandable desire to have an "objective" measure of abnormality in patients with multiple sclerosis and because of the high proportion of abnormalities detected in the sensory systems by evoked potential techniques, these have been used to monitor the effects of treatment. It has been claimed that both the brain stem components of the auditory evoked potential and the spinal cord evoked potentials changed towards normal during a period of spinal cord stimulation (IUis, EINegamy, Sedgwick and Thornton 1978), and that clinical remission after a period of ACTH therapy was paralleled by a change towards normal of the brain stem components of the auditory evoked potential in a single case of multiple sclerosis (Stockard and Rossiter 1977). However, before any conclusions can be drawn it is important to determine, in a long term study, whether evoked potential abnormalities, once they have occurred, are constant, or whether they fluctuate spontaneously and whether any variation is related to the clinical state of the patient. It is to these questions that the present study is directed. METHODS
Early and middle components of the auditory evoked potential to a binaural 95 dBC click (0.5 ms duration) were averaged between the vertex and mastoid (for details see Robinson and Rudge 1977). The auditory evoked potential was classified as abnormal if: (1) The latency and/or amplitude of component V was more than 2 SD from the mean for normals. (2) The latency increase of component V to the first of a pair of clicks was abnormal. (3) The latency of any of the middle components Pa, Nb and P1 was more than 2 SD from the mean for normals. Because the amplitude variation between sequential records in normal subjects is much greater than the variation of latency, only the latency data are used to illustrate
149 this paper. However, the normality of any individual record was determined by the above criteria. Eighteen healthy controls, aged 20-56, and 27 patients with clinically diagnosed multiple sclerosis, aged 18-58 years, were studied. Records of the early and middle components of the auditory evoked potential were obtained on 2 or 3 occasions over a period of 9 months-3 years for the control subjects and on 2-9 occasions over a period of 9 months-2.5 years for the patients. All the patients, who were seen at regular intervals in an out-patient clinic, were examined clinically on each occasion prior to the auditory evoked potential recording to determine if a relapse had occurred or if there had been any change in their neurological status. None of the control subjects or patients was deaf on clinical examination. Different persons examined the patients neurologically and recorded the auditory evoked potential and the data from both were blind until the completion of the study. RESULTS Controls The remarkable consistency of the auditory evoked potentials in control subjects is illustrated in Fig. 2, where the latencies of the early and middle components obtained at the first recording session are plotted against the latencies at the second. If recordings were obtained on 3 occasions the latencies from the second record are plotted against those obtained from the third. Patients Of the 27 patients studied 16 had a clinical relapse during the trial (we have called this group "unstable patients") and 11 did not have relapses in the period of study ("stable patients"). Details of the clinical state of these 2 groups of patients are given
ms
5O d., Na
10 11
7.
3. I 1'1 10
ms 50
Fig. 2. Latencies of early and middle components at successive recording sessions, normal subjects. Continuous lines enclose all the points obtained for early components I, II, III and V and for middle components Na, Pa, Nb and P1. Axes, latency (ms). Note that axes are different for early and middle components. This same format applies to Figs. 3 and 5.
150 TABLE 1 CLINICAL DETAILS OF PATIENTS P = progressive disease; RBN = retrobulbar neuritis. Age
Sex
Number of relapses before the trial
Number of relapses during the trial
Duration of illness at time of trial (years)
Length of trial (years)
------------
4 6 3 3 5 1.25 5 34 2 3 10
0.75 0.75 2.25 0.75 2.5 1.75 2.25 1 1 1.5 1.5
2 6 4 1 2
0.5 2.25 1 0.5 4
2.5 2 1 1 1.5
Clinically stable 24 26 31 33 43 44 38 54 47 49 58
F F F M F F M F F M F
3 2 3 2 4 2 2+P 2+P P P P
Clinically unstable 18 20 22 22 24
F F F F M
24 24 25 26 31 34 34 35 36 38 43
F M M F F F F M M F F
1 1 5 3 10+, all RBN 2 1 2 3 4 2 4 2 3 1 3
2 1 2 1 1 1 1 3 2 1 1
3 4 2 5 3 2 9 10 9 2 17
2.5 2 0.75 1.5 1 0.75 1 2 2.5 2 l
in T a b l e 1. T h e p a t i e n t s in t h e 2 clinical g r o u p s are m a t c h e d f o r d u r a t i o n o f disease a n d f o r n u m b e r a n d f r e q u e n c y o f p r e v i o u s relapses. F i v e p a t i e n t s in the clinically s t a b l e g r o u p h a d p r o g r e s s i v e disease a n d w e r e o l d e r t h a n t h e others. I n t h e clinically u n s t a b l e g r o u p t h e r e w e r e 4 p a t i e n t s a g e d 18-22 years w h o w e r e y o u n g e r t h a n a n y o f t h e stable p a t i e n t s . T h e p r o p o r t i o n o f p a t i e n t s h a v i n g a b n o r m a l 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 t h e " c l i n i c a l l y u n s t a b l e " a n d t h e " c l i n i c a l l y s t a b l e " g r o u p s at t h e b e g i n n i n g o f t h e s t u d y w a s t h e same. H o w e v e r , in t h e ',clinically s t a b l e " g r o u p t h e a b n o r m a lity was m o r e o f t e n o f t h e m i d d l e c o m p o n e n t s a l o n e . T h e a u d i t o r y e v o k e d p o t e n t i a l s w e r e r e m a r k a b l y c o n s t a n t in t h e " c l i n i c a l l y s t a b l e " g r o u p o f p a t i e n t s w h e t h e r t h e y h a d p r o g r e s s i v e o r e p i s o d i c disease. T h i s is i l l u s t r a t e d in Fig. 3 w h e r e t h e l a t e n c y o f e a c h c o m p o n e n t is p l o t t e d a ~ n s t t h a t o b .
151 ms
50 ~-" Nb . ,-:?,, Pa "" Na
10 11
7V C~ ~:'_',~II III
3-
I '
~
'
,
11 10
,
, 5O
ms
Fig. 3. Latencies of early and middle components at successive recording sessions, clinically stable multiple sclerosis subjects. The vertical extension of the contour for component V is due to a variation in one patient. See Fig. 2 and text for further explanation. tained from the preceding record. This plot is similar to that obtained from the control subjects (compare Figs. 2 and 3). Only on one occasion was there a significant change in latency of any component (in component V). An example of abnormal records from one of the clinically stable patients is shown in Fig. 4 where it can be seen that the 2 recerds are similar. These results contrast sharply with those from patients who were "clinically unstable" during the study. The results from this group of patients are illustrated in Fig. 5. It is apparent that in some patients there is a marked variation in the latency of the various components, except component I, between consecutive recording sessions, component V being particularly affected, while in other patients the latencies are unchanged. An example of 2 records from a "clinically unstable" patient in which the laten-
WT 41175
[ o.4.v 576
0
6
12 m s
Fig. 4. Example of 2 records of the early components of the auditory evoked potential obtained from a clinically stable patient with multiple sclerosis at interval of 6 months. Component V and stimulus indicated. Horizontal axis, latency (ms); bar, 0.4/~V.
152 ms
50
P: • Nb
lO ,1
:3
'
7'
1'I
ms
10 Fig. 5. Latencies of the early and middle components obtained at successive recording sessions from clinically unstable patients with multiple sclerosis. Every value for components I, Iil, Na and Nb is shown by open circles and for components II, V, Pa and P1, shown by filled circles. VR
16776
[0"4uV 5 477
6'
' ~, ' ' 1 ~ m s
Fig. 6. Example of 2 records of the early component of the auditory evoked potential obtained at an interval of 9 months in a clinically unstable patient with multiple sclerosis. Component V and stimulus indicated. Horizontal axis, latency (ms): bar, 0.4 pV.
DP
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Fig. 7. Example of 8 consecutive records of the early components of the auditozy evoked potential obtained from a clinically unstable patient with multiple sclerosis. Dates of i ~ i v ~ ! ~ d s i component V and sites of new lesions indicated. Horizontal axis, latency (ms); bar, 0;4 pV: See text for further explanation.
153 cies did not alter is shown in Fig. 6. The initial brain stem response from this patient has a delayed component V. A similar abnormality is seen in the next record obtained 9 months later, the patient having had an attack of retrobulbar neuritis in the intervening period. In contrast, a series of brain stem recordings from a clinically unstable patient in whom marked alterations of the auditory evoked potential occurred is shown in Fig. 7. It can be seen that there is considerable variation in the form of the brain stem auditory evoked potential but that the relationship to the apparent sites of the lesions determined by clinical assessment is poor. For example, the already small component V did decrease further in amplitude following the development of vertigo and gross nystagmus 2 weeks prior to obtaining a second record but this decrease was of doubtful significance. Later a definite delay of component V occurred (see third trace) which subsequently improved again. Three other patients whose initial brain stem auditory evoked potential was abnormal developed clinical signs of a brain stem lesion during the period of study and in these there was no consistent change in component V; indeed in one patient the auditory evoked potential improved following such an episode. Only one patient in this group had a normal auditory evoked potential initially and then developed clinical evidence of a brain stem lesion. Component V became abnormal in this patient. In these "clinically unstable" patients with fluctuating abnormalities the early and middle components changed independently in many cases. In some the middle components were unaffected by changes in the brain stem responses, in others the early components remained constant while changes occurred in the middle components, whilst in the remainder there were changes in both the early and middle components. An interesting finding in this study was that the consistency of the auditory evoked potential in the "clinically unstable" patients seemed to depend upon whether the initial auditory evoked potential was normal or not. Thus all the clinically unstable patients with a normal auditory evoked potential at the onset of the study had consistently normal records on subsequent recordings with the one exception mentioned above where a new lesion apparently developed in the brain stem. On the other hand, if the initial auditory evoked potential was abnormal subsequent recordings were often variable and this can be clearly seen in the records from the patient illustrated in Fig. 7. This patient and others had marked fluctuations in the early and middle components of the auditory evoked potential, while developing lesions at sites remote from the brain stem, e.g., optic nerve and spinal cord. In some of these patients the auditory evoked potential tended to become normal after exhibiting marked abnormalities as shown in Fig. 7. DISCUSSION The latencies of the early and middle components of the auditory evoked potential were remarkably constant in normal subjects over the 3 year period of this study. Some of the patients had similarly stable records. The majority of these patients had normal auditory evoked potentials at the onset and in those with abnormal records the abnormalities were unchanged. In contrast there were a number of patients in
154 whom the record did alter significantly, the majority of whom had an abnormality at the initial recording session, and, with one exception, these patients belonged to the group classified as "clinically unstable". It seems that the necessary requirements for a variable auditory evoked potential are an abnormal potential initially, with the addition of "active disease". The alteration observed could be either of increasing abnormality or the reverse, and some records became essentially normal at some time during the study. This is in marked contrast to the stability of the visual evoked potentials in which it has been claimed that once the latency has become abnormal, as a result of a demyelinating lesion, the abnormality will persist indefinitely (Halliday et al. 1973). This difference may be related to the source of the potentials, cortical with the visual stimulation and infracortical, at least for the early components, with auditory stimulation. In this connection it is of interest that certain brain stem reflexes, if abnormal, are sometimes labile in patients with multiple sclerosis (Kimura 1975). However, somatosensory evoked potentials, thought to arise from the cortex, can change towards normal latencies in the course of the disease (Namerow 1968) and in the present study the middle components of the auditory evoked potential, some of which are probably cortical in origin, did sometimes return to normal independently of the brain stem response. This may of course reflect alterations in conduction at a lower level, but does indicate that certain cortical potentials may be labile in patients with multiple sclerosis. It might be supposed that the abnormal form of the evoked potential recorded in a particular sensory system in patients with multiple sclerosis is due to conduction abnormalities in fibres passing through demyelinating lesions in that system. Furthermore, it would be reasonable to assume that a deterioration in the auditory evoked potential is the result of demyelination within the auditory pathways with alteration of conduction in these fibres. If these new plaques also involved more eloquent parts of the brain stem than the auditory pathways they would be clinically apparent, as happened in one of the patients in the present study when a clinically obvious brain stem lesion coincided with the development, for the first time, of an abnormal auditory evoked potential. However, it is difficult to account for the return to virtual normality of the auditory evoked potential on this basis. The actual mechanism by which conduction recovers in the central nervous system is far from clear especially as there is little evidence of remyelination in multiple sclerosis (McDonald 1974). Could there be any other mechar~sm to account for the lability of the auditory evoked potential in multiple sclerosis? Since it is known that temperature change and alteration of calcium and phosphate levels of body fluids can have profound effects upon conduction in the peripheral nervous system and alter the functioning of the central nervous system in multiple sclerosis (Becker, Michael and Davis 1974), it is conceivable that there is some general effect of activity of the disease upon conduction in the damaged central nervous system fibres. While it is conceded that such a hypothesis may be heretical and that one is merely seeing the effects of silent plaques upon the auditory system, it is surprising that within the group of patients having clinical relapses, those with an auditory evoked potential that was initially normal remained normal (with the one exception
155 above), while 7 of the 9 patients with abnormal auditory evoked potentials at the start of the study had marked changes in their response. This is remarkable since both subgroups had active disease, as judged by the number of clinical relapses occurring during the study, and there is no obvious reason why the auditory system of those with normal auditory evoked potentials at the start should have privileged immunity to attacks. It is, however, important to note that to some extent the sampling rate of the patients is critical in assessing the significance of the abnormalities shown and to reach a firm conclusion on whether silent plaques are occurring or not would require a much more frequent sampling rate and more prolonged study. Of more practical importance is the value of auditory evoked potential recording as an "objective" measure of the extent of demyelination, particularly the occurrence of new plaques, in patients subjected to therapeutic trials. In patients having frequent clinical relapses caution is necessary in attributing alteration of the auditory evoked potential to a particular therapeutic regime, particularly if the auditory evoked potential is abnormal initially. Even those patients with an apparently normal auditory evoked potential may in fact already have a lesion in the auditory system as it has been shown that the auditory evoked potential can become essentially normal after a prolonged period of derangement. In patients who are clinically stable the clinician is probably on safer ground in assuming that alterations observed are related to the therapy administered, provided that an initial baseline is obtained. A more prolonged study of clinically stable patients with initially abnormal auditory evoked potentials is needed to determine whether the auditory evoked potential may not also fluctuate spontaneously in this group. ACKNOWLEDGEMENTS We are grateful to Dr. D. G. Small and Dr. R. G. Willison for helpful advice and criticism, and to Dr. W. A. Cobb for his continuing support and encouragement.
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156 Robinson, K. and P. Rudge (1977) Abnormalities of the auditory evoked potentials in patients with multiple sclerosis, Brain, 100: 19-40. Small, D. G., W. B. Matthews and M. Small (1978) The cervical somatosensory evoked potential in the diagnosis of multiple sclerosis, J. neurol. Sci., 35 : 211-224. Stockard, J. J. and V. S. Rossiter (1977) Clinical and pathological correlates of brain stem auditory response abnormalities, Neurology (Minneap.), 27: 316-325.