Acta neurol. scandinav. 60, 231-242, 1979 Neurological Labolratolry, Department o'f Neurology, Arhus Kommunehospital, DK-8000 Arhus C, Denmark
Evaluation and graduation of brain stem auditory evoked potentials in patients with neurological diseases MOGENSKJBR Based on normative data from 40 subjects, criteria for evaluating brain stem auditory evoked potentials have been elaborated. This system contained six grades from normal t o diffusely abnormal, and was used in evaluating recordings from 142 patients, including 38 patients with definite and 48 with probable and possible multiple sclerosis, 18 patients with brain stem infarctions, six patients with other organic brain stem lesions, six patients with a postcornmotional syndrome and 26 patients without any brain stem involvement. A statistically significant difference was found between normal persons and patients without evidence of brain stem lesions versus patients with such evidence, as well as between subgroups of slightly and severely affected patients. The system was found useful as a way of describing recordings, in comparing groups of patients and in a follow up of a few patients. Key words: Auditory evoked potentials - brain stem - brain stem infarctions - evaluation - graduation - multiple sclerosis
Brain stem auditory evoked potentials (BAEP) are the electrical events in the brain stem in the first 10 msec following a very short auditory stimulus. Usually seven vertex-positive waves are described in the human scalp recorded BAEP. The neural substrate of the first five of these waves has, from cat experiments (Jewett 1970, Buchwald & Huang 1975) and from recordings in humans with localized brain stem lesions (Sohmer et al. 1974, Starr & Hamilton 1976, Stockard & Rositter 1977), been suggested to be: I, the acoustic nerve, 11, the cochlear nuclei, 111, the superior olives, IV, the lateral lemniscus and V, the inferior colliculi. VI and VII are usually not present in animal recordings, but are supposed to reflect more rostra1 relays in the auditory pathways. As BAEP recording is a noninvasive procedure and abnormalities of the waves are supposed to indicate a localization, it has been suggested as a method of examining brain stem lesions (Sohmer et al. 1974, Starr & Achor 1975, Duly et al. 1977, Starr 1977, Rosenhammer 1977, Terkildsen et al. 1977) including patients with multiple sclerosis (Robinson & Rudge 1975, 1977a, b, Zoellner et al. 1976, Mogensen & Kristensen 1979). The abnor0001-6314/79/100231-12 $0.2.50/0 @ 1979 Munksgaard, Copenhagen
232
malities recorded have been complete absence, prolonged latencies or a combination of prolonged latencies and decreased amplitudes of one or more waves, as well as a difference in latencies between the two sides (Selters & Brackmann 1977, Gerull et al. 1977), but no standardized criteria have been formed to evaluate degrees of abnormality. In analogy with evaluation of an EEG, the described abnormalities are comparable with focal abnormalities. As other abnormal EEG findings have diagnostic value, it seems reasonable to describe other forms of abnormalities in the BAEP, being a special form of EEG, in order to enlarge the diagnostic value of the recordings, especially when other diagnostic tools may be more harmful or fail to show any abnormal findings. The purpose of this paper is to form a set of criteria for graduation of BAEP abnormalities from findings in a normal material and to apply this code to groups of patients as an attempt to assess the value of this graduation. MATERIAL AND METHODS The methods and normal material have been described earlier (KjLer 1979) and shall be only summarized. All patients and normal subjects were lying comfmtably supine in a quiet room. Auditory clicks 75 dBHL were delivered through earphones energized by an audiometer receiving 0.1 msec square waves randomly with an interstimulus interval about 250 msec. EEG disc-electrodes were attached t o the scalp with electrode paste after cleaning the skin with alcohol. Electrode impedance was kept below 2 kileohms. Activity was recorded between vertex (C,),inverting, and the ipsilateral mastoid process, noninverting. An EEG electrode attached t o the glabella was groanded. The signal was amplified 400,OMI times by an EMG amplifier with a filter bandpass of 50-5000 d se c and summated in an averager; 1024 stimuli were averaged in every recording. The output was written out by a X-Y plotter. All ware examined on both sides. If a recording was abnormal, duplicate recordings were made. No medication was given t o normal subjects and patients were not given any extra medicine or sedation during the recording. Forty normal subjects, 21 females and 19 males, aged 13-48 years, with no history of neurological disease and with normal hearing, were examined. Patients A total of 142 patients, who all had a normal or only slightly impaired hearing, were examined. They were divided into the following groups: A. Definite multiple sclerosis. Thirty-eight patients aged 24 to 65 years had definite multiple sclerosis (MS) according t o the criteria given by McAZpine (1972). They all had a pathological cerebrospinal fluid protein, either found as an abnormal gammafraction by elforesis or as an abnormal IgG-ratio. These patients were subdivided into: A,: 12 patients aged 24-59 years with only a few attacks and a few symptoms. A,: Seven patients aged 36-49 years who were atactic, but not severely disabled. In the groups A, and A, the duration of the history varied from a few to several years.
233 A,: 19 patients aged 28-65 years who had a long history and were severelly affected including mental and brain stem (BS) invo’lvement. B. ProbabZe and possible multiple sclerosis. Forty-eight patients aged 23-61 years. This group included seven patients, who clinically belonged to the “definite” group, but who had normal cerebrospinal protein findings. In the total B-group, the cerebrospinal gamma fraction was definitely abnormal in 24, normal in 15 and of a borderline abnormality in 9. The patients were subdivided into: B,: 17 patients aged 28-61 years with n 0 history or sign of BS involvement. B,: 10 patients aged 24-38 years with a history, but no actual signs of BS involvement. B,: 21 patients aged 24-61 years with clinical signs of BS involvement. C. Brain stem infarction. Eighteen patients aged 25 to 59 years had a history and signs indicating an infarction in the brain stem. The lesion was visualized by a CT-scan in eight patients. D. Other brain stem lesions. Six patients aged 32-70 years had a lesion in the brain stem (tumor, syringobulbia, hereditary ataxia).
E. Postcommotional syndrome. Six male patients aged 15-49 years had a preceding cranial trauma but were without any actual signs of BS involvement. F. N o brain stem involvement. Twenty-six patients aged 16-58 years were initially suspected of having a lesion of the group B to D type, but subsequent examinations failed t o confirm these diagnoses. Four patients had a paresis 04 one of the extraocular muscles as an isolated finding, seven patients had a spinal tumor, disc prolapse or spinal arachnoiditis, three patients had an infarction in one of the hemispheres, and 12 patients had vertigo as their main complaint, but no sign of BS involvement.
RESULTS
Graduation of BAEP recordings The normative data have previously been published ( K j m 1979). The central conduction latencies for the different waves are seen in Table 1. For both latencies and amplitudes, different values were found for the two sexes. The difference in latencies in normal subjects between the waves recorded from the two ears was below 0.3 msec. Based on the normative data the following graduation system was elaborated: Grade 1 . Normal recording. All the latencies had to be within the normal limits. Only one could be a borderline value. The side difference was within the 0.3 msec limit. The amplitude of waves IV-V had to be greater than 0.4 pV for women, 0.3 pV for men, and at least for two of the waves I, I1 and I11 greater than 0.25 pV for women and 0.2 pV for men.
234 Table 1. Mean and limits of normal values for latencies in msec of BAEP waves Wave
Males
Females
Mean
Limits
Mean
Limits
1.25-1.75 0.9 -1.4 1.85-2.4 3.05-3.6 3.8 -4.25 5.15-5.8 6.35-7.75
1.50 1.10 2.20 3.45 4.25 5.75 7.50
1.2 -1.85 0.9 -1.4 1.95-2.4 3.05-3.7 3.9 -4.6 5.2 -6.2 6.9 -8.3
~
I 11-1 111-1 IV-I v-I VI-I VII-I
1.50 1.10 2.15 3.30 4.05 5.50 7.10
Grade 2. Borderline abnormality. One latency outside the limits or two borderline values, and/or the amplitudes slightly less than for Grade 1. Grade 3. Moderately abnormal. Two latencies outside the limits. The amplitudes might vary. Grade 4. Severely abnormal. The latency of wave V was prolonged. Grade 5. Focal abnormality. Normal waves were followed either by absence of one or more waves or by waves significantly delayed. Grade 6. Diausely abnormal. The amplitudes of the waves varied so much that no definite measure of latencies could be made. The recording was poorly reproduced. For Grade 1-4 at least waves I, I11 and V should be easily recognizable. Isolated abnormalities of wave I1 and VI would give only a Grade 2 or 3 abnormality. All latencies were measured as central conduction latencies. In the normal material all pairs of recordings were of Grade 1 (33, 17 female and 16 male) or Grade 2 (seven, four female and three male). In the different groups of patients Grade 1 and 2 was thus considered normal, Grades 3-6 abnormal in the calculation of abnormality percentages.
Reliability of graduation As an attempt to test the reliability of the graduation the first 131 recordings were evaluated without clinical information on three different occasions. Concordant graduation in all three evaluations was found in 79 % of the readings. In all instances of non-concordant graduations two of the evaluations were similar. Divergent graduation between Grades 1 and 2 occurred
235 Table 2. Graduation of BAEP recordings in the MS groups
Groups A, A2 A3
A Total B, B2 B3
B Total
N
1
2
12 4 3 7 0 1 19 1 0 38 5 4 17 5 2 10 5 4 2 1 4 4 48 14 10
Grade 3 4 5
1 1 3 1 5 1 0 0 1 3 4 4 5 0 1 0
6
Abnormal %
95 % confidence limits
42 86
15-72 42-100 74-100 60-89 33-82 0-45 38-82 35-65
1 3 1 3 1 1 4 3 2 0 2 7 0 0 2 4 4 11
95
76 59 10 62 50
Table 3. Graduation in group B correlated to findings in the cerebrospinal fluid protein Spinal protein Definitely abnormal Bolrderline abnormality NoIrma1
N
1
2
Grade 3 4
5
24 8 3 2 2 1 9 2 3 2 1 1 1 5 4 4 0 2 2
6 8 0 3
Abnormal % 54 44 47
in 13 %, between Grades 2 and 3 in 4 % and between Grades 3 and 5 in 4 %. The reasons for divergent evaluations between Grades 1, 2 and 3 were minor insecurity in measuring the amplitudes and latencies, a borderline value becoming significant. The Grades 3 to 5 difference was due to insecurity of determining whether a minor deflection in the curve was a proper wave or not. MS patients The graduation of the recordings from the MS patients was plotted out in Table 2. In patients with definite MS only one of 19 of the most severely affected patients, and one of seven of the atactic patients had a normal recording. In group B, patients with clinical evidence of brain stem involvement had a much higher incidence of abnormal recordings than patients with a history but no signs of lesions in this location. In 10 of the 17 patients who clinically had only spinal involvement, the recording was abnormal, indicating that the lesion was not in fact limited to the spinal cord. This subgroup contained many patients with a long standing progressive paraplegia. Patients with definite MS had more abnormal recordings than patients
236
Figure I . Brain stem auditory evoked potentials recorded after stimulation o f the ipsilateral ear. Upper curve from a normal person, following curves from three patients suffering f r o m multiple sclerosis o f increasing severity. Upper curve: Grade I , all parameters are normal. Second curve: Grade 4, waves V and V I are delayed. Third curve: Grade 5, only waves I and I1 are normal. Fourth curve: Grade 6, n o definite waves can be recognized. Calibration: x = 2 msec, y = 0.25 pV.
with probable and possible MS. This was not related to the fact that all patients in group A had abnormal cerebro-spinal protein findings, and patients in group B not necessarily so. Table 3 shows that patients in group B with a borderline abnormality or a normal spinal fluid protein had almost the same degree of abnormality in BAEP recordings as patients with an abnormal spinal fluid protein. In 11 patients with a normal spinal protein BAEP recordings were abnormal so that 73 % of patients in the B group had either an abnormal spinal protein or an abnormal BAEP. Table 4 illustrates that patients with a prolonged duration (more than 40 seconds) of post-rotational nystagmus had an incidence of abnormal BAEP recordings twice as high, as patients with a duration below 30 sec-
237 Table 4. Graduation in groups A and B correlated to duration of post-rotational nystagmus
Duration in sec
> 40 30-40 < 30
N
Grade 2 3 4
1
Abnormal 5
6
%
7 7 4
83 67 44
1 2 2 0 0 3 0 12 2 2 0 0 1 25 6 8 1 4 2
Table 5. Graduation of BAEP recordings in patients with brain stem infarction
CT scan Positive Negative or nolt performed Total group
N
1
2
Grade 3 4
5
6
%
8 10 18
1 3 4
0 3 3
1 0 1
0 0 0
3 3 6
88 40 61
3 1 4
Abnormal
onds, thus indicating a high correlation between the two methods of examination. BAEP recording was found to be the most sensitive of the methods, as it revealed an abnormality in 59 % of patients examined in both ways, compared to 24 % abnormal values found by the post-rotational nystagmus examination. Other patients with clinical evidence of BS involvement or preceding cranial trauma Table 5 shows a high correlation between CT-scan and BAEP abnormality in patients with BS infarctions. All group D patients with clinical BS lesions had an abnormal BAEP as seen in Table 6. In the patients with a preceding trauma to the skull, one-third had a Grade 3 abnormality. Patients without any evidence of BS involvement Table 6 illustrates a high correlation between negative evidence of BS involvement based on clinical versus BAEP findings among patients in group F. None of the patients with lesions in the hemispheres or in the spinal canal of a non-MS type had an abnormal BAEP. The BAEP recording supported the clinical impression that the eyemuscle paresis in group F patients was an isolated phenomenon, and that the vertigo felt by group F patients was not due to a BS lesion.
238 DISCUSSION
The criteria for abnormalities vary from laboratory to laboratory. This variation is partly due to differences in stimulus and recording techniques, but may also reflect that many works have been based on very small normal material, or on normal subjects much younger than patients. Some authors consider absence or prolonged latencies of any of the waves I-VII to be an abnormality. As shown in Table 7, all the waves are not recognized in some bigger normal materials. Chiappa et al. (1979) suggest that absence of waves VI and VII cannot be considered abnormal, and Rowe (1978) finds only waves I, I11 and V to be stable enough to mark abnormalities. Mogensen & Kristensen (1979) in addition to waves I, I11 and V, use the “FFP7”, that is the vertex-negative component following wave V, described by Terkildsen et al. (1974), in the evaluation of the recordings. Robinson & Rudge (1977a)
Figure 2. Right and left recordings from two patients. Two upper curves: Grade 2. Right 111-1 latency prolonged. Side difference in latencies o f 111-1 and Vl-I. Two lower curves: Grade 3. Variation in amplitudes. Only waves I , 111 and V can be easily identified. Both V-I and right 111-1 latencies are borderline. Calibration: x = 2 msec, y = 0.25 p V .
Table 6. Summary of findings in the differentgroups
Normal subjects A B C D E F
40 38 48 1 6 6 26
33 7 0 5 4 1 14 10 4 8 4 3 1 0 0 1 2 2 2 18 8 0
0 0 5 3 2 0 5 4 11 4 0 6 0 1 4 0 0 0 0 0 0
0 - 9 60- 89 35- 65 36- 83 54-1W 4- 78 0- 13
0 76 50 61 100 33 0
0
Table 7. Frequency of recognizability of individual waves in normal subjects, %
Waves Robinson & Rudge (1977) Rowe (1978) Chiappa et al. (1979) K i m (1979)
I
I1
93 97 97 100
82 80 96 98
I11
IV
v
v1
VII
93
60 67 88 95
100 100 1001 100
80 100 84 94
60 89
100 100 100
?
60
in their normal material find only wave V to be recorded in all subjects, and thus the only component reliable to detect abnormalities in patients, but their technique uses binaural 20 clicks/sec, which favors wave V on behalf of the smaller waves, and average only 512 responses. They define wave V as the most prominent component in the first 5-10 msec. Selters & Brackmann (1977) consider it abnormal for wave V to be smaller than wave IV. In other materials wave V is not the wave with the highest amplitude in the 5-10 msec period. Chiappa et al. (1979) in only 62 % find V bigger than wave IV. In the normal subjects of this material, this was found in 56 %, and in a few instances even wave VI was of higher amplitude than wave V. The criteria for abnormality used in this paper are mainly based on waves I, 11, I11 and V. It includes objective data based on the findings in normal subjects, but subjective judgment remains, especially in recordings from patients, when the waves are difficult to identify, or when the maximum of a wave is flat or double. The criteria for separation of Grade 3 versus 5 and Grade 4 versus 6 recordings also may include subjective judgment. Some recordings in Grade 4 may be grouped as a localized abnormality, that is if the preceding waves are normal, but as waves IV-V are
240 the most prominent waves of the recordings, and some authors only describe abnormalities of these waves, a special grade for this abnormality has been chosen. When Grades 1 and 2 are considered normal, all normal subjects have normal recordings, and the reliability in the triple evaluation gives only divergent graduation between normality and abnormality in 4 %. In comparing groups of subjects this distinction gives a significant separation between normal subjects and patients without clinical signs of brain stem involvement (group F) versus groups of patients suspected for BS lesions (groups A, B, C and D). A significant difference is also found between slightly and severely affected MS patients, and suggested between other groups and subgroups of patients as shown in the tables. The present evaluation system with six different grades may seem too elaborate, especially in comparing groups of patients. Differences in the relative occurrence of the varying degrees of abnormality may reflect differences between groups and subgroups, however. In evaluating the individual recordings, a differentiated graduation may be valuable, especially when recordings have been obtained in the same patient in different states of the disease. In the present material BAEPs have been made in seven patients at different times, and a shift between grades of abnormality has been observed in three instances, reflecting changes in the clinical state. Three of the remaining patients had Grade 6 recordings at both examinations. The graduation system thus seems suitable when recordings are used as a longitudinal parameter in the individual patient. Furthermore, repeated recordings may elucidate the way the BAEP changes from normal to abnormal. The graduation system offers a practical advantage, as it is so elaborate, as a further detailed description of the abnormality in most instances is superfluous. If a non-graded system of evaluation is used, such a description of the abnormality is required. The grade of abnormality most often found in this study is Grade 6. It is difficult or even impossible to describe this abnormality in a system based on latencies and amplitudes of individual ways. The finding of recordin8s with poorly defined waves and poor reproducibility in MS patients has also been emphasized by Nodar (1978) and Mogensen & Kristensen (1979). The reduced stability of these abnormal BAEP recordings may partly be due to the fact that the BAEP waves, although having maximum activity at definite locations, probably reflect a temporal conglomerate of electrical events from several sources (Jewett 1970, Starr & Hamilton 1976, Elberling 1978). Furthermore, it is probable, that although the normal BAEP is not influenced by fatigueability, the pathological neurons giving an abnormal BAEP may indeed be so (Robinson & Rudge 1977a).
24 1 The system af evaluating and graduating BAEP recordings presented in this paper has thus been found useful in comparing groups of patients, in a longitudinal follow up of a few patients and as a practical way of describing degrees of normality and abnormality. ACKNOWLEDGMENTS This work was suppo'rted by grants from the Danish Lelague against Multiple Sclerosis. REFERENCES Buchwald, J. S. & C. M. Huang (1975): Far-field acoustic response: origins in the cat. Science, New York 189, 382-384. Chiappa, K. H., K. J. Gladstone & R. R. Young (1979): Brain stem auditory evoked responses. Studies of waveform variations in 50 normal human subjects. Arch. Neurol. Chicago 36, 81-87. Daly, D. M., R. J. Roeser, M. H. Aung & D. D.Daly (1977): Early evoked potentials in patients with acoustic neuroma. Electroenceph. Clin. Neurophysiol. 43, 151-159. Elberling, C. (1978): Compound impulse response for the brain stem derived through combinations of cochlear and brain stem recordings. Scand. Audiol. 7, 147-157. Gerull, G., M. Giesen, D. Mrowinski & R. Kniipling (1977): Untersuchung von Schadigungen der Horbahn im Bereich des Hirnstammes durch Registrierung friiher akustisch evozierter Potentiale. Laryng. Rhinol. 56, 76-80. 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. Kjaer,M. (1979): Differences of latencies and amplitudes of brain stem evoked potentials in subgroups of a normal material. Acta Neurol. Scandinav. 59, 72-79. McAlpine, D. (1972): Course and prognosis. In: Multiple sclerosis, a reappraisal. Ed. McAlpine, D., C. E. Lumsden & E. D. Acheson. Churchill Livingstone, London, pp. 197-223. Mogensen, F. & 0.Kristensen (1979): Auditory double click evoked potentials in multiple sclerosis. Acta Neurol. Scandinav. 59, 96-107. Nodar, R. H. (1978): Brain stem auditory evoked potentials on individuals with multiple sclerosis. In: International evoked potentials symposium. The Biological Engineering Society, Nottingham, U.K. Robinson, K. & P. Rudge (1975): Auditory evoked responses in multiple sclerosis. Lancet i, 1164-1166. Robinson, K. & P. Rudge (1977a): Abnormalities of the auditory evoked potentials in patients with multiple sclerosis. Brain 100, 19-40. Robinson, K. & P. Rudge (1977b): The early components of the auditory evoked potentials in multiple sclerosis. In: Auditory evoked potentials in man. Ed. Desmedt, J. E. S. Karger, Basel, pp. 58-67. Rosenhammer, H. J. (1977): Observations on electric brain-stem responses in retrocochlear hearing loss. Scand. Audiol. 6, 179-196. Rowe, M. J., 111 (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 & G. Szabo (1974): Sources of electrocochleographic responses as studied in patients with brain damage. Electroenceph. Clin. Neurophysiol. 37, 663-669. 16 Acta neurol. scandinav. 60:4
242 Starr, A. & L. J. Achor (1975): Auditory brain stem responses in neurological disease. Arch. Neurol., Chicago, 32, 761-768. Starr, A. & A. E. Hamilton (1976): Correlation between confirmed sites of neurological lesions and abnormalities of far-field auditory brainstem responses. Electroenceph. Clin. Neurophysiol. 41, 595-608. Starr,A. (1977): Clinical relevance of brain stem auditory evoked potentials in man. In: Auditory evoked potentials in man. Ed. Desmedt, J. E. S. Karger, Basel, pp. 45-57. Stockard, J. J. & V. S. Rossiter (1977): Clinical and pathologic correlates of brain stem auditory response abnormalities. Neurol. (Minneap.) 27, 316-325. Terkildsen, K., P. Osterhammel & F. Huis in’t Veld (1974): Far-field electrocochleography. Electrode positions. Scand. Audid. 3, 123-129. Terkildsen, K., F. Huis in’t Veld & P. Osterhammel (1977): Auditory brain stem responses in the diagnosis of cerebellopmtine angle tumours. Scand. Audio]. 6, 43-47. Zoellner, C., G. Stange & D. Marquetand (1976): Tcpodiagnostische ERA Befunde einer Patientin mit Hirnstamm M. S. Laryng. Rhinol. Otol. Grenzgeb. 55, 755-760.
Received July 5, accepted August 23, 1979
Mogens Kjcer, M.D. Neurologisk afdeling Kommunehospitalet DK-8000 Arhus C Denmark
Evaluation and graduation of brain stem auditory evoked potentials in patients with neurological diseases MOGENSKJBR Based on normative data from 40 subjects, criteria for evaluating brain stem auditory evoked potentials have been elaborated. This system contained six grades from normal t o diffusely abnormal, and was used in evaluating recordings from 142 patients, including 38 patients with definite and 48 with probable and possible multiple sclerosis, 18 patients with brain stem infarctions, six patients with other organic brain stem lesions, six patients with a postcornmotional syndrome and 26 patients without any brain stem involvement. A statistically significant difference was found between normal persons and patients without evidence of brain stem lesions versus patients with such evidence, as well as between subgroups of slightly and severely affected patients. The system was found useful as a way of describing recordings, in comparing groups of patients and in a follow up of a few patients. Key words: Auditory evoked potentials - brain stem - brain stem infarctions - evaluation - graduation - multiple sclerosis
Brain stem auditory evoked potentials (BAEP) are the electrical events in the brain stem in the first 10 msec following a very short auditory stimulus. Usually seven vertex-positive waves are described in the human scalp recorded BAEP. The neural substrate of the first five of these waves has, from cat experiments (Jewett 1970, Buchwald & Huang 1975) and from recordings in humans with localized brain stem lesions (Sohmer et al. 1974, Starr & Hamilton 1976, Stockard & Rositter 1977), been suggested to be: I, the acoustic nerve, 11, the cochlear nuclei, 111, the superior olives, IV, the lateral lemniscus and V, the inferior colliculi. VI and VII are usually not present in animal recordings, but are supposed to reflect more rostra1 relays in the auditory pathways. As BAEP recording is a noninvasive procedure and abnormalities of the waves are supposed to indicate a localization, it has been suggested as a method of examining brain stem lesions (Sohmer et al. 1974, Starr & Achor 1975, Duly et al. 1977, Starr 1977, Rosenhammer 1977, Terkildsen et al. 1977) including patients with multiple sclerosis (Robinson & Rudge 1975, 1977a, b, Zoellner et al. 1976, Mogensen & Kristensen 1979). The abnor0001-6314/79/100231-12 $0.2.50/0 @ 1979 Munksgaard, Copenhagen
232
malities recorded have been complete absence, prolonged latencies or a combination of prolonged latencies and decreased amplitudes of one or more waves, as well as a difference in latencies between the two sides (Selters & Brackmann 1977, Gerull et al. 1977), but no standardized criteria have been formed to evaluate degrees of abnormality. In analogy with evaluation of an EEG, the described abnormalities are comparable with focal abnormalities. As other abnormal EEG findings have diagnostic value, it seems reasonable to describe other forms of abnormalities in the BAEP, being a special form of EEG, in order to enlarge the diagnostic value of the recordings, especially when other diagnostic tools may be more harmful or fail to show any abnormal findings. The purpose of this paper is to form a set of criteria for graduation of BAEP abnormalities from findings in a normal material and to apply this code to groups of patients as an attempt to assess the value of this graduation. MATERIAL AND METHODS The methods and normal material have been described earlier (KjLer 1979) and shall be only summarized. All patients and normal subjects were lying comfmtably supine in a quiet room. Auditory clicks 75 dBHL were delivered through earphones energized by an audiometer receiving 0.1 msec square waves randomly with an interstimulus interval about 250 msec. EEG disc-electrodes were attached t o the scalp with electrode paste after cleaning the skin with alcohol. Electrode impedance was kept below 2 kileohms. Activity was recorded between vertex (C,),inverting, and the ipsilateral mastoid process, noninverting. An EEG electrode attached t o the glabella was groanded. The signal was amplified 400,OMI times by an EMG amplifier with a filter bandpass of 50-5000 d se c and summated in an averager; 1024 stimuli were averaged in every recording. The output was written out by a X-Y plotter. All ware examined on both sides. If a recording was abnormal, duplicate recordings were made. No medication was given t o normal subjects and patients were not given any extra medicine or sedation during the recording. Forty normal subjects, 21 females and 19 males, aged 13-48 years, with no history of neurological disease and with normal hearing, were examined. Patients A total of 142 patients, who all had a normal or only slightly impaired hearing, were examined. They were divided into the following groups: A. Definite multiple sclerosis. Thirty-eight patients aged 24 to 65 years had definite multiple sclerosis (MS) according t o the criteria given by McAZpine (1972). They all had a pathological cerebrospinal fluid protein, either found as an abnormal gammafraction by elforesis or as an abnormal IgG-ratio. These patients were subdivided into: A,: 12 patients aged 24-59 years with only a few attacks and a few symptoms. A,: Seven patients aged 36-49 years who were atactic, but not severely disabled. In the groups A, and A, the duration of the history varied from a few to several years.
233 A,: 19 patients aged 28-65 years who had a long history and were severelly affected including mental and brain stem (BS) invo’lvement. B. ProbabZe and possible multiple sclerosis. Forty-eight patients aged 23-61 years. This group included seven patients, who clinically belonged to the “definite” group, but who had normal cerebrospinal protein findings. In the total B-group, the cerebrospinal gamma fraction was definitely abnormal in 24, normal in 15 and of a borderline abnormality in 9. The patients were subdivided into: B,: 17 patients aged 28-61 years with n 0 history or sign of BS involvement. B,: 10 patients aged 24-38 years with a history, but no actual signs of BS involvement. B,: 21 patients aged 24-61 years with clinical signs of BS involvement. C. Brain stem infarction. Eighteen patients aged 25 to 59 years had a history and signs indicating an infarction in the brain stem. The lesion was visualized by a CT-scan in eight patients. D. Other brain stem lesions. Six patients aged 32-70 years had a lesion in the brain stem (tumor, syringobulbia, hereditary ataxia).
E. Postcommotional syndrome. Six male patients aged 15-49 years had a preceding cranial trauma but were without any actual signs of BS involvement. F. N o brain stem involvement. Twenty-six patients aged 16-58 years were initially suspected of having a lesion of the group B to D type, but subsequent examinations failed t o confirm these diagnoses. Four patients had a paresis 04 one of the extraocular muscles as an isolated finding, seven patients had a spinal tumor, disc prolapse or spinal arachnoiditis, three patients had an infarction in one of the hemispheres, and 12 patients had vertigo as their main complaint, but no sign of BS involvement.
RESULTS
Graduation of BAEP recordings The normative data have previously been published ( K j m 1979). The central conduction latencies for the different waves are seen in Table 1. For both latencies and amplitudes, different values were found for the two sexes. The difference in latencies in normal subjects between the waves recorded from the two ears was below 0.3 msec. Based on the normative data the following graduation system was elaborated: Grade 1 . Normal recording. All the latencies had to be within the normal limits. Only one could be a borderline value. The side difference was within the 0.3 msec limit. The amplitude of waves IV-V had to be greater than 0.4 pV for women, 0.3 pV for men, and at least for two of the waves I, I1 and I11 greater than 0.25 pV for women and 0.2 pV for men.
234 Table 1. Mean and limits of normal values for latencies in msec of BAEP waves Wave
Males
Females
Mean
Limits
Mean
Limits
1.25-1.75 0.9 -1.4 1.85-2.4 3.05-3.6 3.8 -4.25 5.15-5.8 6.35-7.75
1.50 1.10 2.20 3.45 4.25 5.75 7.50
1.2 -1.85 0.9 -1.4 1.95-2.4 3.05-3.7 3.9 -4.6 5.2 -6.2 6.9 -8.3
~
I 11-1 111-1 IV-I v-I VI-I VII-I
1.50 1.10 2.15 3.30 4.05 5.50 7.10
Grade 2. Borderline abnormality. One latency outside the limits or two borderline values, and/or the amplitudes slightly less than for Grade 1. Grade 3. Moderately abnormal. Two latencies outside the limits. The amplitudes might vary. Grade 4. Severely abnormal. The latency of wave V was prolonged. Grade 5. Focal abnormality. Normal waves were followed either by absence of one or more waves or by waves significantly delayed. Grade 6. Diausely abnormal. The amplitudes of the waves varied so much that no definite measure of latencies could be made. The recording was poorly reproduced. For Grade 1-4 at least waves I, I11 and V should be easily recognizable. Isolated abnormalities of wave I1 and VI would give only a Grade 2 or 3 abnormality. All latencies were measured as central conduction latencies. In the normal material all pairs of recordings were of Grade 1 (33, 17 female and 16 male) or Grade 2 (seven, four female and three male). In the different groups of patients Grade 1 and 2 was thus considered normal, Grades 3-6 abnormal in the calculation of abnormality percentages.
Reliability of graduation As an attempt to test the reliability of the graduation the first 131 recordings were evaluated without clinical information on three different occasions. Concordant graduation in all three evaluations was found in 79 % of the readings. In all instances of non-concordant graduations two of the evaluations were similar. Divergent graduation between Grades 1 and 2 occurred
235 Table 2. Graduation of BAEP recordings in the MS groups
Groups A, A2 A3
A Total B, B2 B3
B Total
N
1
2
12 4 3 7 0 1 19 1 0 38 5 4 17 5 2 10 5 4 2 1 4 4 48 14 10
Grade 3 4 5
1 1 3 1 5 1 0 0 1 3 4 4 5 0 1 0
6
Abnormal %
95 % confidence limits
42 86
15-72 42-100 74-100 60-89 33-82 0-45 38-82 35-65
1 3 1 3 1 1 4 3 2 0 2 7 0 0 2 4 4 11
95
76 59 10 62 50
Table 3. Graduation in group B correlated to findings in the cerebrospinal fluid protein Spinal protein Definitely abnormal Bolrderline abnormality NoIrma1
N
1
2
Grade 3 4
5
24 8 3 2 2 1 9 2 3 2 1 1 1 5 4 4 0 2 2
6 8 0 3
Abnormal % 54 44 47
in 13 %, between Grades 2 and 3 in 4 % and between Grades 3 and 5 in 4 %. The reasons for divergent evaluations between Grades 1, 2 and 3 were minor insecurity in measuring the amplitudes and latencies, a borderline value becoming significant. The Grades 3 to 5 difference was due to insecurity of determining whether a minor deflection in the curve was a proper wave or not. MS patients The graduation of the recordings from the MS patients was plotted out in Table 2. In patients with definite MS only one of 19 of the most severely affected patients, and one of seven of the atactic patients had a normal recording. In group B, patients with clinical evidence of brain stem involvement had a much higher incidence of abnormal recordings than patients with a history but no signs of lesions in this location. In 10 of the 17 patients who clinically had only spinal involvement, the recording was abnormal, indicating that the lesion was not in fact limited to the spinal cord. This subgroup contained many patients with a long standing progressive paraplegia. Patients with definite MS had more abnormal recordings than patients
236
Figure I . Brain stem auditory evoked potentials recorded after stimulation o f the ipsilateral ear. Upper curve from a normal person, following curves from three patients suffering f r o m multiple sclerosis o f increasing severity. Upper curve: Grade I , all parameters are normal. Second curve: Grade 4, waves V and V I are delayed. Third curve: Grade 5, only waves I and I1 are normal. Fourth curve: Grade 6, n o definite waves can be recognized. Calibration: x = 2 msec, y = 0.25 pV.
with probable and possible MS. This was not related to the fact that all patients in group A had abnormal cerebro-spinal protein findings, and patients in group B not necessarily so. Table 3 shows that patients in group B with a borderline abnormality or a normal spinal fluid protein had almost the same degree of abnormality in BAEP recordings as patients with an abnormal spinal fluid protein. In 11 patients with a normal spinal protein BAEP recordings were abnormal so that 73 % of patients in the B group had either an abnormal spinal protein or an abnormal BAEP. Table 4 illustrates that patients with a prolonged duration (more than 40 seconds) of post-rotational nystagmus had an incidence of abnormal BAEP recordings twice as high, as patients with a duration below 30 sec-
237 Table 4. Graduation in groups A and B correlated to duration of post-rotational nystagmus
Duration in sec
> 40 30-40 < 30
N
Grade 2 3 4
1
Abnormal 5
6
%
7 7 4
83 67 44
1 2 2 0 0 3 0 12 2 2 0 0 1 25 6 8 1 4 2
Table 5. Graduation of BAEP recordings in patients with brain stem infarction
CT scan Positive Negative or nolt performed Total group
N
1
2
Grade 3 4
5
6
%
8 10 18
1 3 4
0 3 3
1 0 1
0 0 0
3 3 6
88 40 61
3 1 4
Abnormal
onds, thus indicating a high correlation between the two methods of examination. BAEP recording was found to be the most sensitive of the methods, as it revealed an abnormality in 59 % of patients examined in both ways, compared to 24 % abnormal values found by the post-rotational nystagmus examination. Other patients with clinical evidence of BS involvement or preceding cranial trauma Table 5 shows a high correlation between CT-scan and BAEP abnormality in patients with BS infarctions. All group D patients with clinical BS lesions had an abnormal BAEP as seen in Table 6. In the patients with a preceding trauma to the skull, one-third had a Grade 3 abnormality. Patients without any evidence of BS involvement Table 6 illustrates a high correlation between negative evidence of BS involvement based on clinical versus BAEP findings among patients in group F. None of the patients with lesions in the hemispheres or in the spinal canal of a non-MS type had an abnormal BAEP. The BAEP recording supported the clinical impression that the eyemuscle paresis in group F patients was an isolated phenomenon, and that the vertigo felt by group F patients was not due to a BS lesion.
238 DISCUSSION
The criteria for abnormalities vary from laboratory to laboratory. This variation is partly due to differences in stimulus and recording techniques, but may also reflect that many works have been based on very small normal material, or on normal subjects much younger than patients. Some authors consider absence or prolonged latencies of any of the waves I-VII to be an abnormality. As shown in Table 7, all the waves are not recognized in some bigger normal materials. Chiappa et al. (1979) suggest that absence of waves VI and VII cannot be considered abnormal, and Rowe (1978) finds only waves I, I11 and V to be stable enough to mark abnormalities. Mogensen & Kristensen (1979) in addition to waves I, I11 and V, use the “FFP7”, that is the vertex-negative component following wave V, described by Terkildsen et al. (1974), in the evaluation of the recordings. Robinson & Rudge (1977a)
Figure 2. Right and left recordings from two patients. Two upper curves: Grade 2. Right 111-1 latency prolonged. Side difference in latencies o f 111-1 and Vl-I. Two lower curves: Grade 3. Variation in amplitudes. Only waves I , 111 and V can be easily identified. Both V-I and right 111-1 latencies are borderline. Calibration: x = 2 msec, y = 0.25 p V .
Table 6. Summary of findings in the differentgroups
Normal subjects A B C D E F
40 38 48 1 6 6 26
33 7 0 5 4 1 14 10 4 8 4 3 1 0 0 1 2 2 2 18 8 0
0 0 5 3 2 0 5 4 11 4 0 6 0 1 4 0 0 0 0 0 0
0 - 9 60- 89 35- 65 36- 83 54-1W 4- 78 0- 13
0 76 50 61 100 33 0
0
Table 7. Frequency of recognizability of individual waves in normal subjects, %
Waves Robinson & Rudge (1977) Rowe (1978) Chiappa et al. (1979) K i m (1979)
I
I1
93 97 97 100
82 80 96 98
I11
IV
v
v1
VII
93
60 67 88 95
100 100 1001 100
80 100 84 94
60 89
100 100 100
?
60
in their normal material find only wave V to be recorded in all subjects, and thus the only component reliable to detect abnormalities in patients, but their technique uses binaural 20 clicks/sec, which favors wave V on behalf of the smaller waves, and average only 512 responses. They define wave V as the most prominent component in the first 5-10 msec. Selters & Brackmann (1977) consider it abnormal for wave V to be smaller than wave IV. In other materials wave V is not the wave with the highest amplitude in the 5-10 msec period. Chiappa et al. (1979) in only 62 % find V bigger than wave IV. In the normal subjects of this material, this was found in 56 %, and in a few instances even wave VI was of higher amplitude than wave V. The criteria for abnormality used in this paper are mainly based on waves I, 11, I11 and V. It includes objective data based on the findings in normal subjects, but subjective judgment remains, especially in recordings from patients, when the waves are difficult to identify, or when the maximum of a wave is flat or double. The criteria for separation of Grade 3 versus 5 and Grade 4 versus 6 recordings also may include subjective judgment. Some recordings in Grade 4 may be grouped as a localized abnormality, that is if the preceding waves are normal, but as waves IV-V are
240 the most prominent waves of the recordings, and some authors only describe abnormalities of these waves, a special grade for this abnormality has been chosen. When Grades 1 and 2 are considered normal, all normal subjects have normal recordings, and the reliability in the triple evaluation gives only divergent graduation between normality and abnormality in 4 %. In comparing groups of subjects this distinction gives a significant separation between normal subjects and patients without clinical signs of brain stem involvement (group F) versus groups of patients suspected for BS lesions (groups A, B, C and D). A significant difference is also found between slightly and severely affected MS patients, and suggested between other groups and subgroups of patients as shown in the tables. The present evaluation system with six different grades may seem too elaborate, especially in comparing groups of patients. Differences in the relative occurrence of the varying degrees of abnormality may reflect differences between groups and subgroups, however. In evaluating the individual recordings, a differentiated graduation may be valuable, especially when recordings have been obtained in the same patient in different states of the disease. In the present material BAEPs have been made in seven patients at different times, and a shift between grades of abnormality has been observed in three instances, reflecting changes in the clinical state. Three of the remaining patients had Grade 6 recordings at both examinations. The graduation system thus seems suitable when recordings are used as a longitudinal parameter in the individual patient. Furthermore, repeated recordings may elucidate the way the BAEP changes from normal to abnormal. The graduation system offers a practical advantage, as it is so elaborate, as a further detailed description of the abnormality in most instances is superfluous. If a non-graded system of evaluation is used, such a description of the abnormality is required. The grade of abnormality most often found in this study is Grade 6. It is difficult or even impossible to describe this abnormality in a system based on latencies and amplitudes of individual ways. The finding of recordin8s with poorly defined waves and poor reproducibility in MS patients has also been emphasized by Nodar (1978) and Mogensen & Kristensen (1979). The reduced stability of these abnormal BAEP recordings may partly be due to the fact that the BAEP waves, although having maximum activity at definite locations, probably reflect a temporal conglomerate of electrical events from several sources (Jewett 1970, Starr & Hamilton 1976, Elberling 1978). Furthermore, it is probable, that although the normal BAEP is not influenced by fatigueability, the pathological neurons giving an abnormal BAEP may indeed be so (Robinson & Rudge 1977a).
24 1 The system af evaluating and graduating BAEP recordings presented in this paper has thus been found useful in comparing groups of patients, in a longitudinal follow up of a few patients and as a practical way of describing degrees of normality and abnormality. ACKNOWLEDGMENTS This work was suppo'rted by grants from the Danish Lelague against Multiple Sclerosis. REFERENCES Buchwald, J. S. & C. M. Huang (1975): Far-field acoustic response: origins in the cat. Science, New York 189, 382-384. Chiappa, K. H., K. J. Gladstone & R. R. Young (1979): Brain stem auditory evoked responses. Studies of waveform variations in 50 normal human subjects. Arch. Neurol. Chicago 36, 81-87. Daly, D. M., R. J. Roeser, M. H. Aung & D. D.Daly (1977): Early evoked potentials in patients with acoustic neuroma. Electroenceph. Clin. Neurophysiol. 43, 151-159. Elberling, C. (1978): Compound impulse response for the brain stem derived through combinations of cochlear and brain stem recordings. Scand. Audiol. 7, 147-157. Gerull, G., M. Giesen, D. Mrowinski & R. Kniipling (1977): Untersuchung von Schadigungen der Horbahn im Bereich des Hirnstammes durch Registrierung friiher akustisch evozierter Potentiale. Laryng. Rhinol. 56, 76-80. 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. Kjaer,M. (1979): Differences of latencies and amplitudes of brain stem evoked potentials in subgroups of a normal material. Acta Neurol. Scandinav. 59, 72-79. McAlpine, D. (1972): Course and prognosis. In: Multiple sclerosis, a reappraisal. Ed. McAlpine, D., C. E. Lumsden & E. D. Acheson. Churchill Livingstone, London, pp. 197-223. Mogensen, F. & 0.Kristensen (1979): Auditory double click evoked potentials in multiple sclerosis. Acta Neurol. Scandinav. 59, 96-107. Nodar, R. H. (1978): Brain stem auditory evoked potentials on individuals with multiple sclerosis. In: International evoked potentials symposium. The Biological Engineering Society, Nottingham, U.K. Robinson, K. & P. Rudge (1975): Auditory evoked responses in multiple sclerosis. Lancet i, 1164-1166. Robinson, K. & P. Rudge (1977a): Abnormalities of the auditory evoked potentials in patients with multiple sclerosis. Brain 100, 19-40. Robinson, K. & P. Rudge (1977b): The early components of the auditory evoked potentials in multiple sclerosis. In: Auditory evoked potentials in man. Ed. Desmedt, J. E. S. Karger, Basel, pp. 58-67. Rosenhammer, H. J. (1977): Observations on electric brain-stem responses in retrocochlear hearing loss. Scand. Audiol. 6, 179-196. Rowe, M. J., 111 (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 & G. Szabo (1974): Sources of electrocochleographic responses as studied in patients with brain damage. Electroenceph. Clin. Neurophysiol. 37, 663-669. 16 Acta neurol. scandinav. 60:4
242 Starr, A. & L. J. Achor (1975): Auditory brain stem responses in neurological disease. Arch. Neurol., Chicago, 32, 761-768. Starr, A. & A. E. Hamilton (1976): Correlation between confirmed sites of neurological lesions and abnormalities of far-field auditory brainstem responses. Electroenceph. Clin. Neurophysiol. 41, 595-608. Starr,A. (1977): Clinical relevance of brain stem auditory evoked potentials in man. In: Auditory evoked potentials in man. Ed. Desmedt, J. E. S. Karger, Basel, pp. 45-57. Stockard, J. J. & V. S. Rossiter (1977): Clinical and pathologic correlates of brain stem auditory response abnormalities. Neurol. (Minneap.) 27, 316-325. Terkildsen, K., P. Osterhammel & F. Huis in’t Veld (1974): Far-field electrocochleography. Electrode positions. Scand. Audid. 3, 123-129. Terkildsen, K., F. Huis in’t Veld & P. Osterhammel (1977): Auditory brain stem responses in the diagnosis of cerebellopmtine angle tumours. Scand. Audio]. 6, 43-47. Zoellner, C., G. Stange & D. Marquetand (1976): Tcpodiagnostische ERA Befunde einer Patientin mit Hirnstamm M. S. Laryng. Rhinol. Otol. Grenzgeb. 55, 755-760.
Received July 5, accepted August 23, 1979
Mogens Kjcer, M.D. Neurologisk afdeling Kommunehospitalet DK-8000 Arhus C Denmark
