Acta neurol. scandinav. 59, 96-107, 1979 State Hearing Center, Odense, and Neurological Institute, University Hospital, Odense, Denmark
Auditory double click evoked potentials in multiple sclerosis FINNMOGENSEN AND
OLE
KRISTENSEN
Brain stem electric responses (BSER), evoked by acoustic stimuli, were investigated in 29 patients with multiple sclerosis and compared with the responses in a control group of 26 young adults without neurological disease or hearing defect. The procedure included monaural and binaural stimulus presentation of single clicks and pairs of clicks. In the evaluations the vertex-positive Jewett I, I11 and V response components, and the vertexnegative “FFP7” peak were considered. In the assessment of the BSER components, the FFP, (the vertex-negative 7 ms far field potential following the Jewett, wave) proved to be the best single component with respect to reproducibility in normal subjects. In addition the FFP, was the single most consistently abnormal component in the patient group. Determination of the latency of the Jewett components and the interpeak conduction times, however, contributed further to the disclosure of the abnormal cases. Five of the patients whose hearing was impaired were :onsidered separately. Of the remaining 24 patients, 20 (83 %) had BSER abnormalities. Further analysis did not reveal a clear correlation between BSER abnormalities and clinical signs of brain stem dysfunction. Key words: Brain stem potentials - double click stimulation potentials - multiple sclerosis
-
evoked
The early auditory evoked responses, commonly referred to as the brain stem electric responses (BSER), are extremely small signals consisting of seven vertex-positive components evoked from the brain stem within the first 10 ms after sound stimulation (Figure la). In the last decade it has been possible, by averaging techniques, to extract these time-locked signals from the simultaneous “biological noise”, EEG and EMG signals, which are cancelled out by the averaging. In animal experiments with intracranial recordings and ablations, the approximate site of origin of the signals has been established. In humans these results have been correlated to surface recordings which have then been compared to surgical and autopsy findings (Sohmer & Feinmesser 1967, Lev & Sohmer 1972). According to Jewett (1970), Jewett & Williston (1971), Buchwald & Huang (1975), these signal generators of the first five components are thought to be:I) the acoustic nerve, 11) the cochlear nucleus, 111) the superior olive, 0001-6314/79/020096-12 $0.2.50/0 @ 1979 Munksgaard, Copenhagen
97
0.5p v
I Figure l a . Typical normal recordings. The components I-V and FFP, indicated. Vertexpositivity delineated downwards. Normal limits indicated with dotted lines.
IV) the lateral lemniscus, V) the inferior colliculus. The roman numerals indicate each vertex-positive peak. This may be an oversimplification of matters. The signals recorded from the surface are the algebraic sum of a series of generators. However, little doubt exists that the Jewett, (JI) is the response of the first neuron, the J,, is generated at the ponto-medullary junction, the J,,, originates in the pons, and that the Jv is derived from the mensencephalon (Stockard et al. 1977). The recording results depend on stimulus intensity. High stimulus intensity gives the most stable values of the signal, especially with respect to the latencies. A lowering of the intensity increases the latency and diminishes the amplitude. By this procedure Terkildsen (1974) traced the FFP," succeeding the Jv component, close to the subjective threshold and thereby pointed out the significance of this component for objective audiometry. In recent years the method of BSER recording has offered a unique possibility to evaluate the localization of brain stem lesions in patients with neuro-
* The FFP, is the vertex-negative component following the J, wave. The term was coined by Terkildsen et al. (1974): FFP for far field potential, 7 for the approximate latency of the component at higher stimulus levels. 7 Acta neurol. scandinav. 59:2/3
98 logical disorders, especially acoustic nerve tumors (Selters & Brackmann 1977) and multiple sclerosis (Stockard et al. 1977). Robinson & Rudge (1977) investigated patients with multiple sclerosis, using binaural stimulation with trains of single clicks and pairs of clicks, i.e. two clicks 5 ms apart. In their study a latency increase and/or an amplitude reduction of the Jv component were assessed as the sole measures of abnormality. In the present study we have compared the findings in a control group with a group of patients with multiple sclerosis in order to assess the value of monaural and binaural stimulation with double clicks. In addition we have evaluated, whether further information of brain stem dysfunction could be gained by including demonstration of a latency delay of other components than the Jv, especially the FFP,.
MATERIALS AND METHODS The control group consisted of 26 healthy volunteers (13 males and 13 females) with a median age of 23 years (range 18-26 years). They all went through standard otological examination, pure tone audiometry and stapedius reflex threshold determination. Their hearing was within the normal range (air conduction threshold equal to or better than 15 dB HL at the frequencies 250-8.000 Hz). The patient group included 29 cases, diagnosed according to the criteria of McAlpine (1972) as “definite” multiple sclerosis. There were 14 males and 15 females, median age 31 years (range 17-45 years). The median duration of the disease was 2 years (range 1-24 years). Twenty patients had had attacks of optic neuritis, and 25 had had spinal fluid electrophoretic patterns suggesting multiple sclerosis. All the patients went through neurological examination at the time of the neurophysiological procedure. During the recording sessions the persons rested comfortably in the supine position on a couch in a room, which was acoustically but not electrically shielded. Many of the subjects fell asleep during the procedure, which lasted about 1 hour. The acoustic stimuli were trains of unfiltered rarefaction clicks produced by activating the transducer by 0.2 ms square waves. The stimulus level was 116 dB peak equivalent SPL. Clicks were also presented in pairs, 5 ms apart. The stimulus rate employed was approximately 23 s-1. Stimulus presentation was monaural to each ear or binaural, by means of magnetically and electrically screened supraaura1 earphones (Krogh ei al., in preparation). The signals delivered by the earphones had broad frequency spectra with peak energy about 1.5 kHz. Before the objective measurements the subjective thresholds were established in all the subjects both for single clicks and pairs of clicks. placed The responses were picked up by self-adhesive electrodes (Medico-test A-15-8), on 1) the forehead in the midline just beneath the hair border, 2) each mastoid, 3) left side of the nose or cheek (ground). The electrode resistance was below 1.5 KOhm (DC measurement). The monaural recordings were made with a homolateral mastoid derivation. When binaural stimulation was used, the mastoid electrodes were linked. The electrodes were connected by shielded wires to a Madsen Electronics ERP 74 preamplifier, containing a 180-3.500 Hz band pass filter. The amplified and filtered signal was conveyed to a Madsen Electronics averaging computer ERC 74 with a 200 address memory. The sweep time was 10 ms. The averaged response was visualized on a
99 monitor and graphically recorded on a X-Y plotter (modified Hewlett Packard 7035). A total of 2,000 clicks (or pairs of clicks) comprised a single average, which was repeated three times to assess reproducibility of the responses. Vertex-positive deflections were delineated downwards. The latencies of the individual, reproducible peaks were measured from the onset of the electrical pulse driving the transducers to a mean of the three averaged potentials. The peak-to-peak amplitudes were measured from each vertex-positive peak to the following vertex-negative peak. I n five cases with clicks and two of these with double clicks, the J, showed two peaks. The assumption that this was a matter of interaction with cochlear microphonics was confirmed by the fact, that an additional average of 2,000 stimuli in 180" phase-inversion made the two peaks fuse into one peak, identical with that of the other ear.
RESULTS
Normal subjects The median subjective click threshold for each ear as determined by 5 dB attenuator steps was found to be 20 and 25 dB SPL, lower for double than single clicks. Thus the stimulus intensity was 90-95 dB HL. The JI, JIII and Jv, as well as the FFP7 were consistently reproduced both with single and double clicks. The latencies, amplitudes and interpeak conduction times for the individual components are shown in Tables 1, 2, and 3. The J,,, and the FFP, were found to be the overall best defined components. In some cases, in which the J I V and Jv appeared fused when using single click stimuli, double clicks enabled separation of the two components (Table 4). The normal range (mean 2 SD) of the right - left difference for the JV and the FFP7 was 0.4 ms. Comparing the mean JI, JIII, Jv and FFP, latencies between females and males, we found no statistically significant differences (all P > 0.1). The JII, JvI,and JYIIwere not present in all the recordings and were therefore omitted in the tables and evaluation of the patients. The
+
Table 1. Latency (ms) in 26 normal subjects to components I , I l l , V and FFP,, obtained with single or double click stimulation of right ( R ) ear, left (L) ear or binaurally (B) I
V
I11
FFP,
Component
,
R Single clicks Mean (ms) SD
L
B
R
L
B
R
L
B
,
R
L
B
1.58 1.60 1.56 3.83 3.84 3.79 5.69 5.62 5.47 6.53 6.49 6.42 0.13 0.14 0.13 0.14 0.17 0.15 0.17 0.19 0.24 0.17 0.20 0.18
Double clicks 1.62 1.62 1.65 3.92 3.93 3.90 5.86 5.84 5.81 6.59 6.59 6.62 Mean (ms) SD 0.14 0.15 0.11 0.13 0.15 0.14 0.21 0.21 0.22 0.18 0.14 0.20
'7
100 Table 2. Amplitude ( p V ) in 26 normal subjects of components I , III and V obtained with single or double click stimuIation of right (R) ear, Ieft (L) ear or binaurally (B)
I
V
I11
Component R
L
B
R
L
B
R
L
B
0.33 0.13
0.33 0.13
0.39 0.14
0.44 0.18
0.46 0.14
0.61 0.20
0.68 0.28
0.68 0.29
1.02 0.53
Double clicks MeanGV) 0.32 SD 0.11
0.34 0.13
0.35 0.14
0.47 0.19
0.47 0.19
0.64 0.26
0.61 0.26
0.65 0.29
0.90 0.43
Single clicks Mean (,uV) SD
Table 3. Interpeak conduction times (ms) in 26 normal subjects stimulated with single clicks or pairs of clicks. Right ( R ) ear, left ( L ) ear, binaurally ( B )
v-I
111-1
v-111
Component L
B
R
L
B
R
L
B
Single clicks Mean(ms) 2.25 SD 0.14
2.24 0.18
2.22 0.12
4.11 0.14
4.02 0.20
3.92 0.26
1.87 0.18
1.78 0.20
1.65 0.12
Double clicks 2.30 Mean(ms) SD 0.17
2.24 0.21
2.26 0.11
4.25 0.20
4.20 0.20
4.16 0.17
1.94 0.21
1.90 0.15
1.90 0.21
R
Table 4. Number of normal subjects in which .II, and J , were clearly separated comparing single click and double click stimulation. The number of cases with combined J,, and J , are in brackets
Right
Left
Binaural
Single clicks
11 (15)
7 (19)
6 (20)
Double clicks
18 (8)
18 (8)
22 (4)
amplitude measurements of the components showed great inter-subject variation, the lower limits of the normal range (mean k 2 SD) being close to zero. However, the Jv had a greater amplitude than Jr in all cases but one,
101
Patients The patients were divided into three groups, according to the following symptoms or signs of brain stem dysfunction, present at the time of the investigation or earlier: A. Pareses of the cranial nerves or internuclear ophtalmoplegia (13 cases) B. Circumduction ataxia or oculogyric instability of eye movements (10 cases) C. No clinical evidence of brain stem dysfunction (six cases).
Five of the patients with multiple sclerosis had abnormal pure tone audiometry, one had conductive and four had sensorineural hearing loss. They are therefore not included in the table, but considered separately. In the 24 patients with normal hearing the median subjective click threshold for each ear was 40 and 35 dB SPL for single and double clicks, respectively. This represented a significant increase (P< 0.001, Mann-Whitney test) compared to the control group. The abnormal BSER findings in the patients were either marked morphologic changes of the averaged potentials (Figures lb, c) with missing peaks, or icreased latencies (Figure Id) and interpeak conduction times (more than mean k 2 SD).
Figure l b . The recordings are well-defined and reproducible up to III, but severely abnormal in the later part of the response (patient of clinical group B).
102
The FFP, was the overall best defined component in the control group. The highest number of patients with abnormal findings was obtained by evaluation of this component (Table 5). Assessing other BSER components we found abnormalities in five and two extra cases during single click and double click stimulation, respectively. Abnormal findings were present in a total of 20 (83 %) of 24 normally hearing patients, judged from measurements of peak latencies and interpeak conduction times of potentials, evoked by stimulation with single and/or pairs of clicks (Figure 2). Comparing the proportions of cases with abnormal findings in clinical group A, B, and C (Table 5 and Figure 2) there seemed to be, however, a poor correlation between clinical indicators and types of BSER indicators of brain stem dysfunction. Four patients showed no BSER abnormalities, two in clinical group A and one in each of the clinical groups B and C. In theory brain stem dysfunction in some cases of multiple sclerosis could be monolateral and not detectable activating the acoustic system by binaural stimulation. We therefore compared the findings obtained by monaural and binaural stimulation. Monaural stimulus presentation with single and double clicks considered together yielded abnormalities in three cases, not found by binaural stimulation alone. Surprisingly, binaural stimulation showed abnormality in one case, not identified by monaural stimulation of each ear. The only abnormality in this patient was increased FFP, latency in binaural stimulation with double clicks. Five patients posed problems in interpretation of BSER, because in addi-
I
,
I
,
,
I
/
I
1
8
8
I
I
0
1
2
3
4
5
6
"
1
1
I
8 9 1 0
rns
Figure I c . N o recognizable peaks in recordings from a patient of clinical group A .
103
1 0 5 pv
I
Figure I d . Well-defined recordings with increased latency as the only abnormal finding (patient of clinical group C ) .
Table 5. Number of patients with normal hearing (24 cases), presenting abnormality of components (missing or delayed peaks), stimulated with single (*) clicks or pairs (**) of clicks compared to clinical (ABC) grouping. Results for right, left and binaural stimulation combined
Component
I11
Clinical group (n) A (10) B (8) C (6)
*/** 5/6 2/4 3/4
5/5 3/3
10/14
15/15
Total
(24)
V
v-I11
FFP,
*/**
*/**
*/**
717
5/6 4/3
8/7
4/4
5/6 2/5
13/13
15/18
tion to multiple sclerosis they had a moderate or slight hearing loss. These cases were excluded from the tables. One of the patients had a moderate conductive flat tone loss of approximately 35 dB in both ears and abnormality of all BSER components. Four patients had slight bilateral sensorineural
104 high tone losses, approximately 30 dB in frequencies higher than 2 kHz. The FFP7, the Jv, and the V-I11 interpeak conduction time was abnormal in all these cases. Three of the patients with impaired hearing were in clinical group A and two in clinical group B. N 10
4 2
n
. .. A
. .. B
. .. C
Figure 2 . Number of cases in clinical groups (ABC) showing one or more BSER abnormality(ies). Horizontal hatching showing recordings with missing peak(s) and latency increase(s). Vertical hatching representing delayed latency(ies). N o hatching, normal recordings. *: single click, **: double click stimulation.
DISCUSSION
Diagnostic difficulties may occur in early stages of multiple sclerosis, in cases presenting with clinical signs of only one demyelinating lesion in the central nervous system. Also, difficulties may be encountered in estimating the risk of subsequent development of multiple sclerosis in patients with optic neuritis of unknown etiology. This overall risk was found to be 40 % in the study of Compston et al. (1978), which showed that the risk was significantly higher in patients possessing the HLA antigen BT 101. However, the value of HLA typing in patients with optic neuritis in order to estimate the prognosis of the individual patient was judged to be of limited value. The introduction of the evoked potential procedures has made it possible to detect even subclinical demyelinating lesions by stimulation of the visual system (Halliduy et al. 1973), somatosensory system (Dorfman et al. 1978), and auditory system (Stockard et al. 1977), thus enabling the demonstration of a second lesion in cases posing diagnostic and prognostic difficulties. Using binaural 20 s-l single click stimulation Robinson & Rudge (1977) found Jv BSER abnormalities in 79 % of patients with, and in 51 % of those without, clinical evidence of brain stem lesion. In the present study we found comparable corresponding percentages of 83 % and 83 %, respec-
105 tively, thus confirming the high frequency of subclinical brain stem lesions in patients with multiple sclerosis. The impaired ability of demyelinated axons in the central nervous system to transmit trains of impulses led Robinson & Rudge (1977) to employ acoustic stimuli consisting of pairs of clicks. They thereby detected Jv abnormalities not disclosed by single clicks. The direct comparison of single click and double click stimulation in the present investigation did not reveal any sizeable difference between the two methods, when other components than the Jv were included in the evaluation of the patients with multiple sclerosis (Figure 2). It is, however, our impression, that double click stimuli should be preferred, since this mode of stimulation provides a better separation of JIv and Jv. We have attempted to improve the technique, replacing double clicks with trains of sine-waves (frequency following responses to tone bursts) (Mogensen & Kristensen, to be published). In some cases without a well-defined JIv the possibility that the Jv represents a fused JIv-Jv, conseiquently affecting the Jv latency, cannot be excluded. On the other hand it is necessary to use one of the last of the early components in order to evaluate the function also of the upper brain stem. In the present study we found the FFP-, to be a well-defined component in normal subjects and at the same time abnormal in the majority of patients. The BSER amplitudes with their wide normal ranges did not seem to be of value in our assessment of patients with multiple sclerosis. In the present study we found no significant difference in latency related to sex. Beagly & Sheldrake (1978) found latency differences between the sexes which was probably negligible in practical terms. In the same study, Beagly & Sheldrake (1978) excluded that there was, for practical purposes, a latency increase related to age. As opposed to the middle and late auditory evoked responses the early components are independent of consciousness and the majority of drugs. On the other hand they are dependent on the auditory stimulus parameters, filter settings, and electrode positions (Terkildsen et al. 1974). Therefore it is highly important in clinical work to take these factors into account. In addition these circumstances necessitate that each laboratory establish its own normal values. A hearing loss may influence the recording results to a marked degree. This holds true for sensorineural losses (MGller & Blegvad 1976, Coats & Martin 1977) as well as for conductive ones (Clemis & Mitchell 1977). Standard audiological examination should therefore be considered mandatory before evaluation of BSER. Rowe (1978) suggested the interpeak conduction time (V-111) to be the most stable BSER parameter, independent of hearing level, age, and sex. In the present study it was our impression that only in one of the five patients with impaired hearing could the abnormalities be explained by the hearing loss alone, since the abnormali-
ties in the four other cases included increased interpeak conduction time (V-111). An interesting finding in the present study is the significant elevation of the median subjective threshold to clicks, even in patients with normal hearing. This finding may indicate an impaired- temporal integration of acoustic energy as a reflection of brain stem dysfunction in multiple sclerosis. In one of our patients, a 32-year-old female in clinical group B, we had the opportunity to repeat BSER recording 1 month later, after a course of steroid treatment. Compared to the first recording we found a reduction in the latency of the Jv and FFP-, components. It is conceivable that BSER recording, in addition to providing diagnostic and prognostic information, may be employed as a longitudinal parameter in the assessment of treatment of the disease with different drugs.
ACKNOWLEDGMENT This investigation was supported by a grant from “Landsforeningen ti1 bekiempelse af dissemineret sclerose”. REFERENCES Beagly, H. A. & J. B. Sheldrake (1978): Differences in brain stem response latency with age and sex. Br. J. Audiol. 12, 69-77. Buchwald, J. S. & C. M. Huang (1975): Far-field acoustic response: origins in the cat. Science 189, 382-384. Clemis, J. D. & C. Mitchell (1977): Electrocochleography and brain stem responses used in the diagnosis of acoustic tumors. J. Otolaryngol. (Toronto) 6, 447-459. Coats, A. C. & J. L. Martin (1977): Human auditory nerve action potentials and brain stem evoked responses. Arch. Otolaryngol. 103, 605-622. Compston, D. A. S., J. R. Batchelor, C. J. Earl & W. I. McDonald (1978): Factors influencing the risk of multiple sclerosis developing in patients with optic neuritis. Brain 101, 495-511. Dorfman, L. J., T. M. Bosley & K. L. Cummins (1978): Electrophysiological localization of central somatosensory lesions in patients with multiple sclerosis. Electroenceph. Clin. Neurophysiol. 44, 742-753. Halliday, A. M., W. I. McDonald & J. Mushin (1973): Visual evoked responses in diagnosis of multiple sclerosis. Br. Med. J. 4, 661-664. Jewett, D. L. (1970): Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroenceph. Clin. Neurophysiol. 28, 609-618. Jewett, D. L. & J. S. Williston (1971): Auditory-evoked far fields averaged from the scalp of humans. Brain 94, 681-696. Krogh, H. J. & L. G. Chisnall: Magnetic screened electrodynamic earphones for measuring acoustic stimulated bioelectric signals evoked in the nerve system. In preparation. Lev, A. & H. Sohmer (1972): Sources of averaged neural responses recorded in animal and human subjects during cochlear audiometry (Electrocochleogram). Arch. Klin. Exp. 0hr.-, Nas.-, u. Kehlk. Heilk. 201, 79-90.
107 McAlpine, D. (1972): In: Multiple Sclerosis, A Reappraisal. ed. McAlpine, D., C. E. Lumsden & E. D. Acheson. Williams & Wilkins, Baltimore. Mogensen, F. & 0. Kristensen: Brain stem frequency following responses in multiple sclerosis. In preparation. Meller, K. & B. Blegvad (1976): Brain stem responses in patients with sensorineural hearing loss. Scand. Audiol. 5, 115-127. Robinson, K. & P. Rudge (1977): Abnormalities of the auditory-evoked potentials in patients with multiple sclerosis. Brain 100, 19-40, Rowe, M. J. I11 (1978): Normal variability of the brain stem auditory-evoked response in young and old adult subjects. Electroenceph. Clin. Neurophysiol. 44, 459-470. Selters, W. A. & D. E. Brackmann (1977): Acoustic tumor detection with brain stem electric response audiometry. Arch. Otolaryngol. 103, 181-187. Sohmer, H. & M. Feinmesser (1967): Cochlear action potentials recorded from the external ear in man. Ann. Otol. 76, 427-435. Stockard, J. J. & V. S. Rossiter (1977): Clinical and pathologic correlates of brain stem auditory response abnormalities. Neurol. 27, 316-325. Stockard, J. J., J. E. Stockard & F. W. Sharbrough (1977) Detection and localization of occult lesions with brain stem auditory responses. Mayo Clin. Proc. 52, 761-769. Terkildsen, K., P. Osterhammel & F. Huis in’t Veld (1974): Far field electrocochleography, electrode positions. Scand. Audiol. 3, 123-129. Received January 22, accepted February 14, 1979
F. Mogensen, M.D. Otological Department Holstebro Hospital DK-7500 Holstebro Denmark
Auditory double click evoked potentials in multiple sclerosis FINNMOGENSEN AND
OLE
KRISTENSEN
Brain stem electric responses (BSER), evoked by acoustic stimuli, were investigated in 29 patients with multiple sclerosis and compared with the responses in a control group of 26 young adults without neurological disease or hearing defect. The procedure included monaural and binaural stimulus presentation of single clicks and pairs of clicks. In the evaluations the vertex-positive Jewett I, I11 and V response components, and the vertexnegative “FFP7” peak were considered. In the assessment of the BSER components, the FFP, (the vertex-negative 7 ms far field potential following the Jewett, wave) proved to be the best single component with respect to reproducibility in normal subjects. In addition the FFP, was the single most consistently abnormal component in the patient group. Determination of the latency of the Jewett components and the interpeak conduction times, however, contributed further to the disclosure of the abnormal cases. Five of the patients whose hearing was impaired were :onsidered separately. Of the remaining 24 patients, 20 (83 %) had BSER abnormalities. Further analysis did not reveal a clear correlation between BSER abnormalities and clinical signs of brain stem dysfunction. Key words: Brain stem potentials - double click stimulation potentials - multiple sclerosis
-
evoked
The early auditory evoked responses, commonly referred to as the brain stem electric responses (BSER), are extremely small signals consisting of seven vertex-positive components evoked from the brain stem within the first 10 ms after sound stimulation (Figure la). In the last decade it has been possible, by averaging techniques, to extract these time-locked signals from the simultaneous “biological noise”, EEG and EMG signals, which are cancelled out by the averaging. In animal experiments with intracranial recordings and ablations, the approximate site of origin of the signals has been established. In humans these results have been correlated to surface recordings which have then been compared to surgical and autopsy findings (Sohmer & Feinmesser 1967, Lev & Sohmer 1972). According to Jewett (1970), Jewett & Williston (1971), Buchwald & Huang (1975), these signal generators of the first five components are thought to be:I) the acoustic nerve, 11) the cochlear nucleus, 111) the superior olive, 0001-6314/79/020096-12 $0.2.50/0 @ 1979 Munksgaard, Copenhagen
97
0.5p v
I Figure l a . Typical normal recordings. The components I-V and FFP, indicated. Vertexpositivity delineated downwards. Normal limits indicated with dotted lines.
IV) the lateral lemniscus, V) the inferior colliculus. The roman numerals indicate each vertex-positive peak. This may be an oversimplification of matters. The signals recorded from the surface are the algebraic sum of a series of generators. However, little doubt exists that the Jewett, (JI) is the response of the first neuron, the J,, is generated at the ponto-medullary junction, the J,,, originates in the pons, and that the Jv is derived from the mensencephalon (Stockard et al. 1977). The recording results depend on stimulus intensity. High stimulus intensity gives the most stable values of the signal, especially with respect to the latencies. A lowering of the intensity increases the latency and diminishes the amplitude. By this procedure Terkildsen (1974) traced the FFP," succeeding the Jv component, close to the subjective threshold and thereby pointed out the significance of this component for objective audiometry. In recent years the method of BSER recording has offered a unique possibility to evaluate the localization of brain stem lesions in patients with neuro-
* The FFP, is the vertex-negative component following the J, wave. The term was coined by Terkildsen et al. (1974): FFP for far field potential, 7 for the approximate latency of the component at higher stimulus levels. 7 Acta neurol. scandinav. 59:2/3
98 logical disorders, especially acoustic nerve tumors (Selters & Brackmann 1977) and multiple sclerosis (Stockard et al. 1977). Robinson & Rudge (1977) investigated patients with multiple sclerosis, using binaural stimulation with trains of single clicks and pairs of clicks, i.e. two clicks 5 ms apart. In their study a latency increase and/or an amplitude reduction of the Jv component were assessed as the sole measures of abnormality. In the present study we have compared the findings in a control group with a group of patients with multiple sclerosis in order to assess the value of monaural and binaural stimulation with double clicks. In addition we have evaluated, whether further information of brain stem dysfunction could be gained by including demonstration of a latency delay of other components than the Jv, especially the FFP,.
MATERIALS AND METHODS The control group consisted of 26 healthy volunteers (13 males and 13 females) with a median age of 23 years (range 18-26 years). They all went through standard otological examination, pure tone audiometry and stapedius reflex threshold determination. Their hearing was within the normal range (air conduction threshold equal to or better than 15 dB HL at the frequencies 250-8.000 Hz). The patient group included 29 cases, diagnosed according to the criteria of McAlpine (1972) as “definite” multiple sclerosis. There were 14 males and 15 females, median age 31 years (range 17-45 years). The median duration of the disease was 2 years (range 1-24 years). Twenty patients had had attacks of optic neuritis, and 25 had had spinal fluid electrophoretic patterns suggesting multiple sclerosis. All the patients went through neurological examination at the time of the neurophysiological procedure. During the recording sessions the persons rested comfortably in the supine position on a couch in a room, which was acoustically but not electrically shielded. Many of the subjects fell asleep during the procedure, which lasted about 1 hour. The acoustic stimuli were trains of unfiltered rarefaction clicks produced by activating the transducer by 0.2 ms square waves. The stimulus level was 116 dB peak equivalent SPL. Clicks were also presented in pairs, 5 ms apart. The stimulus rate employed was approximately 23 s-1. Stimulus presentation was monaural to each ear or binaural, by means of magnetically and electrically screened supraaura1 earphones (Krogh ei al., in preparation). The signals delivered by the earphones had broad frequency spectra with peak energy about 1.5 kHz. Before the objective measurements the subjective thresholds were established in all the subjects both for single clicks and pairs of clicks. placed The responses were picked up by self-adhesive electrodes (Medico-test A-15-8), on 1) the forehead in the midline just beneath the hair border, 2) each mastoid, 3) left side of the nose or cheek (ground). The electrode resistance was below 1.5 KOhm (DC measurement). The monaural recordings were made with a homolateral mastoid derivation. When binaural stimulation was used, the mastoid electrodes were linked. The electrodes were connected by shielded wires to a Madsen Electronics ERP 74 preamplifier, containing a 180-3.500 Hz band pass filter. The amplified and filtered signal was conveyed to a Madsen Electronics averaging computer ERC 74 with a 200 address memory. The sweep time was 10 ms. The averaged response was visualized on a
99 monitor and graphically recorded on a X-Y plotter (modified Hewlett Packard 7035). A total of 2,000 clicks (or pairs of clicks) comprised a single average, which was repeated three times to assess reproducibility of the responses. Vertex-positive deflections were delineated downwards. The latencies of the individual, reproducible peaks were measured from the onset of the electrical pulse driving the transducers to a mean of the three averaged potentials. The peak-to-peak amplitudes were measured from each vertex-positive peak to the following vertex-negative peak. I n five cases with clicks and two of these with double clicks, the J, showed two peaks. The assumption that this was a matter of interaction with cochlear microphonics was confirmed by the fact, that an additional average of 2,000 stimuli in 180" phase-inversion made the two peaks fuse into one peak, identical with that of the other ear.
RESULTS
Normal subjects The median subjective click threshold for each ear as determined by 5 dB attenuator steps was found to be 20 and 25 dB SPL, lower for double than single clicks. Thus the stimulus intensity was 90-95 dB HL. The JI, JIII and Jv, as well as the FFP7 were consistently reproduced both with single and double clicks. The latencies, amplitudes and interpeak conduction times for the individual components are shown in Tables 1, 2, and 3. The J,,, and the FFP, were found to be the overall best defined components. In some cases, in which the J I V and Jv appeared fused when using single click stimuli, double clicks enabled separation of the two components (Table 4). The normal range (mean 2 SD) of the right - left difference for the JV and the FFP7 was 0.4 ms. Comparing the mean JI, JIII, Jv and FFP, latencies between females and males, we found no statistically significant differences (all P > 0.1). The JII, JvI,and JYIIwere not present in all the recordings and were therefore omitted in the tables and evaluation of the patients. The
+
Table 1. Latency (ms) in 26 normal subjects to components I , I l l , V and FFP,, obtained with single or double click stimulation of right ( R ) ear, left (L) ear or binaurally (B) I
V
I11
FFP,
Component
,
R Single clicks Mean (ms) SD
L
B
R
L
B
R
L
B
,
R
L
B
1.58 1.60 1.56 3.83 3.84 3.79 5.69 5.62 5.47 6.53 6.49 6.42 0.13 0.14 0.13 0.14 0.17 0.15 0.17 0.19 0.24 0.17 0.20 0.18
Double clicks 1.62 1.62 1.65 3.92 3.93 3.90 5.86 5.84 5.81 6.59 6.59 6.62 Mean (ms) SD 0.14 0.15 0.11 0.13 0.15 0.14 0.21 0.21 0.22 0.18 0.14 0.20
'7
100 Table 2. Amplitude ( p V ) in 26 normal subjects of components I , III and V obtained with single or double click stimuIation of right (R) ear, Ieft (L) ear or binaurally (B)
I
V
I11
Component R
L
B
R
L
B
R
L
B
0.33 0.13
0.33 0.13
0.39 0.14
0.44 0.18
0.46 0.14
0.61 0.20
0.68 0.28
0.68 0.29
1.02 0.53
Double clicks MeanGV) 0.32 SD 0.11
0.34 0.13
0.35 0.14
0.47 0.19
0.47 0.19
0.64 0.26
0.61 0.26
0.65 0.29
0.90 0.43
Single clicks Mean (,uV) SD
Table 3. Interpeak conduction times (ms) in 26 normal subjects stimulated with single clicks or pairs of clicks. Right ( R ) ear, left ( L ) ear, binaurally ( B )
v-I
111-1
v-111
Component L
B
R
L
B
R
L
B
Single clicks Mean(ms) 2.25 SD 0.14
2.24 0.18
2.22 0.12
4.11 0.14
4.02 0.20
3.92 0.26
1.87 0.18
1.78 0.20
1.65 0.12
Double clicks 2.30 Mean(ms) SD 0.17
2.24 0.21
2.26 0.11
4.25 0.20
4.20 0.20
4.16 0.17
1.94 0.21
1.90 0.15
1.90 0.21
R
Table 4. Number of normal subjects in which .II, and J , were clearly separated comparing single click and double click stimulation. The number of cases with combined J,, and J , are in brackets
Right
Left
Binaural
Single clicks
11 (15)
7 (19)
6 (20)
Double clicks
18 (8)
18 (8)
22 (4)
amplitude measurements of the components showed great inter-subject variation, the lower limits of the normal range (mean k 2 SD) being close to zero. However, the Jv had a greater amplitude than Jr in all cases but one,
101
Patients The patients were divided into three groups, according to the following symptoms or signs of brain stem dysfunction, present at the time of the investigation or earlier: A. Pareses of the cranial nerves or internuclear ophtalmoplegia (13 cases) B. Circumduction ataxia or oculogyric instability of eye movements (10 cases) C. No clinical evidence of brain stem dysfunction (six cases).
Five of the patients with multiple sclerosis had abnormal pure tone audiometry, one had conductive and four had sensorineural hearing loss. They are therefore not included in the table, but considered separately. In the 24 patients with normal hearing the median subjective click threshold for each ear was 40 and 35 dB SPL for single and double clicks, respectively. This represented a significant increase (P< 0.001, Mann-Whitney test) compared to the control group. The abnormal BSER findings in the patients were either marked morphologic changes of the averaged potentials (Figures lb, c) with missing peaks, or icreased latencies (Figure Id) and interpeak conduction times (more than mean k 2 SD).
Figure l b . The recordings are well-defined and reproducible up to III, but severely abnormal in the later part of the response (patient of clinical group B).
102
The FFP, was the overall best defined component in the control group. The highest number of patients with abnormal findings was obtained by evaluation of this component (Table 5). Assessing other BSER components we found abnormalities in five and two extra cases during single click and double click stimulation, respectively. Abnormal findings were present in a total of 20 (83 %) of 24 normally hearing patients, judged from measurements of peak latencies and interpeak conduction times of potentials, evoked by stimulation with single and/or pairs of clicks (Figure 2). Comparing the proportions of cases with abnormal findings in clinical group A, B, and C (Table 5 and Figure 2) there seemed to be, however, a poor correlation between clinical indicators and types of BSER indicators of brain stem dysfunction. Four patients showed no BSER abnormalities, two in clinical group A and one in each of the clinical groups B and C. In theory brain stem dysfunction in some cases of multiple sclerosis could be monolateral and not detectable activating the acoustic system by binaural stimulation. We therefore compared the findings obtained by monaural and binaural stimulation. Monaural stimulus presentation with single and double clicks considered together yielded abnormalities in three cases, not found by binaural stimulation alone. Surprisingly, binaural stimulation showed abnormality in one case, not identified by monaural stimulation of each ear. The only abnormality in this patient was increased FFP, latency in binaural stimulation with double clicks. Five patients posed problems in interpretation of BSER, because in addi-
I
,
I
,
,
I
/
I
1
8
8
I
I
0
1
2
3
4
5
6
"
1
1
I
8 9 1 0
rns
Figure I c . N o recognizable peaks in recordings from a patient of clinical group A .
103
1 0 5 pv
I
Figure I d . Well-defined recordings with increased latency as the only abnormal finding (patient of clinical group C ) .
Table 5. Number of patients with normal hearing (24 cases), presenting abnormality of components (missing or delayed peaks), stimulated with single (*) clicks or pairs (**) of clicks compared to clinical (ABC) grouping. Results for right, left and binaural stimulation combined
Component
I11
Clinical group (n) A (10) B (8) C (6)
*/** 5/6 2/4 3/4
5/5 3/3
10/14
15/15
Total
(24)
V
v-I11
FFP,
*/**
*/**
*/**
717
5/6 4/3
8/7
4/4
5/6 2/5
13/13
15/18
tion to multiple sclerosis they had a moderate or slight hearing loss. These cases were excluded from the tables. One of the patients had a moderate conductive flat tone loss of approximately 35 dB in both ears and abnormality of all BSER components. Four patients had slight bilateral sensorineural
104 high tone losses, approximately 30 dB in frequencies higher than 2 kHz. The FFP7, the Jv, and the V-I11 interpeak conduction time was abnormal in all these cases. Three of the patients with impaired hearing were in clinical group A and two in clinical group B. N 10
4 2
n
. .. A
. .. B
. .. C
Figure 2 . Number of cases in clinical groups (ABC) showing one or more BSER abnormality(ies). Horizontal hatching showing recordings with missing peak(s) and latency increase(s). Vertical hatching representing delayed latency(ies). N o hatching, normal recordings. *: single click, **: double click stimulation.
DISCUSSION
Diagnostic difficulties may occur in early stages of multiple sclerosis, in cases presenting with clinical signs of only one demyelinating lesion in the central nervous system. Also, difficulties may be encountered in estimating the risk of subsequent development of multiple sclerosis in patients with optic neuritis of unknown etiology. This overall risk was found to be 40 % in the study of Compston et al. (1978), which showed that the risk was significantly higher in patients possessing the HLA antigen BT 101. However, the value of HLA typing in patients with optic neuritis in order to estimate the prognosis of the individual patient was judged to be of limited value. The introduction of the evoked potential procedures has made it possible to detect even subclinical demyelinating lesions by stimulation of the visual system (Halliduy et al. 1973), somatosensory system (Dorfman et al. 1978), and auditory system (Stockard et al. 1977), thus enabling the demonstration of a second lesion in cases posing diagnostic and prognostic difficulties. Using binaural 20 s-l single click stimulation Robinson & Rudge (1977) found Jv BSER abnormalities in 79 % of patients with, and in 51 % of those without, clinical evidence of brain stem lesion. In the present study we found comparable corresponding percentages of 83 % and 83 %, respec-
105 tively, thus confirming the high frequency of subclinical brain stem lesions in patients with multiple sclerosis. The impaired ability of demyelinated axons in the central nervous system to transmit trains of impulses led Robinson & Rudge (1977) to employ acoustic stimuli consisting of pairs of clicks. They thereby detected Jv abnormalities not disclosed by single clicks. The direct comparison of single click and double click stimulation in the present investigation did not reveal any sizeable difference between the two methods, when other components than the Jv were included in the evaluation of the patients with multiple sclerosis (Figure 2). It is, however, our impression, that double click stimuli should be preferred, since this mode of stimulation provides a better separation of JIv and Jv. We have attempted to improve the technique, replacing double clicks with trains of sine-waves (frequency following responses to tone bursts) (Mogensen & Kristensen, to be published). In some cases without a well-defined JIv the possibility that the Jv represents a fused JIv-Jv, conseiquently affecting the Jv latency, cannot be excluded. On the other hand it is necessary to use one of the last of the early components in order to evaluate the function also of the upper brain stem. In the present study we found the FFP-, to be a well-defined component in normal subjects and at the same time abnormal in the majority of patients. The BSER amplitudes with their wide normal ranges did not seem to be of value in our assessment of patients with multiple sclerosis. In the present study we found no significant difference in latency related to sex. Beagly & Sheldrake (1978) found latency differences between the sexes which was probably negligible in practical terms. In the same study, Beagly & Sheldrake (1978) excluded that there was, for practical purposes, a latency increase related to age. As opposed to the middle and late auditory evoked responses the early components are independent of consciousness and the majority of drugs. On the other hand they are dependent on the auditory stimulus parameters, filter settings, and electrode positions (Terkildsen et al. 1974). Therefore it is highly important in clinical work to take these factors into account. In addition these circumstances necessitate that each laboratory establish its own normal values. A hearing loss may influence the recording results to a marked degree. This holds true for sensorineural losses (MGller & Blegvad 1976, Coats & Martin 1977) as well as for conductive ones (Clemis & Mitchell 1977). Standard audiological examination should therefore be considered mandatory before evaluation of BSER. Rowe (1978) suggested the interpeak conduction time (V-111) to be the most stable BSER parameter, independent of hearing level, age, and sex. In the present study it was our impression that only in one of the five patients with impaired hearing could the abnormalities be explained by the hearing loss alone, since the abnormali-
ties in the four other cases included increased interpeak conduction time (V-111). An interesting finding in the present study is the significant elevation of the median subjective threshold to clicks, even in patients with normal hearing. This finding may indicate an impaired- temporal integration of acoustic energy as a reflection of brain stem dysfunction in multiple sclerosis. In one of our patients, a 32-year-old female in clinical group B, we had the opportunity to repeat BSER recording 1 month later, after a course of steroid treatment. Compared to the first recording we found a reduction in the latency of the Jv and FFP-, components. It is conceivable that BSER recording, in addition to providing diagnostic and prognostic information, may be employed as a longitudinal parameter in the assessment of treatment of the disease with different drugs.
ACKNOWLEDGMENT This investigation was supported by a grant from “Landsforeningen ti1 bekiempelse af dissemineret sclerose”. REFERENCES Beagly, H. A. & J. B. Sheldrake (1978): Differences in brain stem response latency with age and sex. Br. J. Audiol. 12, 69-77. Buchwald, J. S. & C. M. Huang (1975): Far-field acoustic response: origins in the cat. Science 189, 382-384. Clemis, J. D. & C. Mitchell (1977): Electrocochleography and brain stem responses used in the diagnosis of acoustic tumors. J. Otolaryngol. (Toronto) 6, 447-459. Coats, A. C. & J. L. Martin (1977): Human auditory nerve action potentials and brain stem evoked responses. Arch. Otolaryngol. 103, 605-622. Compston, D. A. S., J. R. Batchelor, C. J. Earl & W. I. McDonald (1978): Factors influencing the risk of multiple sclerosis developing in patients with optic neuritis. Brain 101, 495-511. Dorfman, L. J., T. M. Bosley & K. L. Cummins (1978): Electrophysiological localization of central somatosensory lesions in patients with multiple sclerosis. Electroenceph. Clin. Neurophysiol. 44, 742-753. Halliday, A. M., W. I. McDonald & J. Mushin (1973): Visual evoked responses in diagnosis of multiple sclerosis. Br. Med. J. 4, 661-664. Jewett, D. L. (1970): Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroenceph. Clin. Neurophysiol. 28, 609-618. Jewett, D. L. & J. S. Williston (1971): Auditory-evoked far fields averaged from the scalp of humans. Brain 94, 681-696. Krogh, H. J. & L. G. Chisnall: Magnetic screened electrodynamic earphones for measuring acoustic stimulated bioelectric signals evoked in the nerve system. In preparation. Lev, A. & H. Sohmer (1972): Sources of averaged neural responses recorded in animal and human subjects during cochlear audiometry (Electrocochleogram). Arch. Klin. Exp. 0hr.-, Nas.-, u. Kehlk. Heilk. 201, 79-90.
107 McAlpine, D. (1972): In: Multiple Sclerosis, A Reappraisal. ed. McAlpine, D., C. E. Lumsden & E. D. Acheson. Williams & Wilkins, Baltimore. Mogensen, F. & 0. Kristensen: Brain stem frequency following responses in multiple sclerosis. In preparation. Meller, K. & B. Blegvad (1976): Brain stem responses in patients with sensorineural hearing loss. Scand. Audiol. 5, 115-127. Robinson, K. & P. Rudge (1977): Abnormalities of the auditory-evoked potentials in patients with multiple sclerosis. Brain 100, 19-40, Rowe, M. J. I11 (1978): Normal variability of the brain stem auditory-evoked response in young and old adult subjects. Electroenceph. Clin. Neurophysiol. 44, 459-470. Selters, W. A. & D. E. Brackmann (1977): Acoustic tumor detection with brain stem electric response audiometry. Arch. Otolaryngol. 103, 181-187. Sohmer, H. & M. Feinmesser (1967): Cochlear action potentials recorded from the external ear in man. Ann. Otol. 76, 427-435. Stockard, J. J. & V. S. Rossiter (1977): Clinical and pathologic correlates of brain stem auditory response abnormalities. Neurol. 27, 316-325. Stockard, J. J., J. E. Stockard & F. W. Sharbrough (1977) Detection and localization of occult lesions with brain stem auditory responses. Mayo Clin. Proc. 52, 761-769. Terkildsen, K., P. Osterhammel & F. Huis in’t Veld (1974): Far field electrocochleography, electrode positions. Scand. Audiol. 3, 123-129. Received January 22, accepted February 14, 1979
F. Mogensen, M.D. Otological Department Holstebro Hospital DK-7500 Holstebro Denmark
