Auditory Brain Stem Responses in Neurological Disease Arnold
Starr, MD, L. Joseph Achor,
MD
• A sequence of seven low-amplitude (nanovolt) potentials that occur in the ini¬ tial 10 msec following click signals can be recorded from scalp electrodes in hu¬ man subjects using computer averaging techniques. The potentials, termed audi¬ tory brain stem responses, are thought to
be the far-field reflection of electrical events originating in the auditory pathway during its course through the brain stem. We have studied auditory brain stem re¬ sponses in a variety of neurological dis¬ orders and found them to be of assistance in evaluating the mechanisms of coma, the localization of midbrain and brain stem tumors, the localization of demyeli¬ nation of the brain stem, and the presence of diminished brain stem circulation. (Arch Neurol 32:761 -768, 1975)
for publication Jan 29, 1975. From the Division of Neurology and the De¬ partment of Psychobiology, University of Cali¬ fornia, Irvine. Read in part before the 26th meeting of the American Academy of Neurology, April 24,1974. Reprint requests to Division of Neurology, University of California, Irvine, Orange County Medical Center, 101 City Drive South, Orange, CA 92668 (Dr Starr).
Accepted
brain stem responses are of electrical events generated along the auditory path¬ way that can be recorded from the scalp by far-field averaging methods. The technique was first described by Jewett in 1970.'2 He employed a com¬ puter to extract the auditory brain stem responses from background electroencephalogram activity. Jew¬ ett defined a series of seven deflec¬ tions of submicrovolt amplitude (now colloquially referred to as "Jewett bumps") during the initial 10 msec following a click. He suggested that these responses represent the farfield reflection of electrical events generated deep within the brain stem.1 Subsequent studies have de¬ fined some of the stimulus and record¬ ing characteristics of auditory brain stem responses4: (1) the responses are independent of level of arousal or at¬ tention5; (2) their latency varies sys¬ tematically with signal intensity«; (3) they are present at birth and their la¬ tency changes with maturation68; and (4) they can be abolished by le¬ sions of the auditory pathway.9 It seemed to us that measures of the auditory brain stem response could be a useful technique for objec¬ tively assessing brain stem function in neurological diseases of man. This article describes a procedure
Auditory
il measures
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that
can be applied at the bedside to provide information rapidly about the status of the auditory brain stem pathways in man. We have employed the technique in over 100 patients and
have defined clinical conditions in which the response measure appears to be useful. Quantitative and qual-
Fig 1.—Auditory brain stem responses from normal subject in response to monaural click signals, 65 dB SL, pre¬ sented at 10/sec. Clicks were presented to right ear and recordings derived from vertex and right earlobe electrodes (CzA2). Total of 2,048 click trials were used to form each of two averages presented. Ro¬ man numerals, I through VII, designate se¬ quence of upward peaks comprising re¬ sponse. Note that amplitude calibration is in submicrovolt range and sweep duration is 10 msec. In this and all subsequent fig¬ ures, positivity at vertex (Cz) electrode is in upward direction.
-
-1VII
VI
.ß..
" & ...,_
"·:">.. r.
"· ...".«... -' - ..
IV""»·
'.
*
" -._C .«.
Ill
.OL..
II
Fig 2.—Auditory brain stem responses in normal subject as func¬ tion of signal intensity (65 to —5 dB SL) with monaural (left) or binaural (right) presentation. Calibration is in microvolts and mil¬ liseconds. _L
Fig 3.—Latency measures of seven components (I to VII) and IV-V complex of auditory brain stem response as function of signal in¬ tensity. Data are means of measures from six subjects with nor¬ mal hearing in response to monaural click signals as presented in
5
_L
15
_L
25
35
_L
45 dB SL
55
X
65
75
Table 2.
itati ve data from normal subjects served as guidelines for establishing abnormalities in the response mea¬
ferential
sures.
Acoustic transients (clicks) were gener¬ ated by passing square wave pulses, 0.2 msec in duration, through an attenuator for regulation of intensity, and amplified before presentation to the subject by ear¬ phones. The pulse polarity was reversed al¬ ternately to decrease the amplitude of stimulus artifact during the averaging process. An extra shielding wire was also placed around the earphone cable to fur¬ ther reduce the amplitude of the stimulus artifact created by capacitive pick-up. This arrangement permitted binaural presenta¬ tion of equal intensity click signals. Monaural stimulation was achieved by simply disconnecting the input to one of the earphones. The click rate used in these studies was 10/sec. The intensity of the signal will be noted in decibels referenced against the mean threshold of six subjects with normal hearing (for instance, 35 dB sensation level [SL]).
METHODS The procedure can be divided into four sections: (1) response amplification, (2) acoustic signal generation, (3) auditory brain stem response processing, and (4) measurement.
Response Amplification Auditory brain stem responses
were
recorded with conventional EEG disk elec¬ trodes placed on the skin at the vertex (Cz) and earlobes (Al, A2), using parlodion for mechanical coupling and electrode jelly as the conductive medium. The skin under¬ lying the electrodes was abraded with a blunt needle to reduce interelectrode re¬ sistance to less than 5,000 ohms. Differ¬ ential amplification (Cz to Al or A2) of 1,000,000 (1X10«) times was accomplished by two amplifiers linked in series. The am¬ plifier band-pass was between 100 hertz and 3 kilohertz (3 dB down points) to achieve resolution of high-frequency com¬ ponents of the auditory brain stem re¬ sponse. Patient grounding was through the earlobe electrode not employed in the dif-
recordings. Acoustic
clicks/sec, only four minutes were re¬ quired to obtain one averaged response. The time base was 10 msec and comprised 500 points. Each point was sampled at a 20/isec interval to allow resolution of highfrequency spectral components. Theoret¬ ically an 83µ8ß sampling would have suf¬ at 10
Signals
Evoked
Response Averaging output of the amplifiers was con¬
The nected to the averaging computer. The computer time base was triggered by each click for a total of 2,048 click trials. Thus,
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ficed to define the 3-kHz components comprising the upper limit of our response system. (Upper frequency resolution in hertz 1/4 x sampling interval). A perma¬ nent record of the averaged response was obtained by an XY plot of the contents of the averager's memory. Figure 1 is an ex¬ ample of two sets of auditory brain stem responses derived from a normal subject in response to monaural click signals at 65 dB SL. The components, designated I through VII, are consistent and easy to define. The click-generating equipment, the averager, and the XY plotter were con¬ tained on a small cart, which was wheeled to the patient's bedside. The amplifiers were placed on the bed and the electrodes and earphones attached in place. The clini¬ cal protocol used binaural presentation of clicks at 65, 45, and 25 dB SL, and monau¬ ral presentations at 65 dB SL. Two sets of averaged responses were obtained at each intensity and plotted over one another to define response consistency. In those pa¬ tients in whom auditory brain stem re=
sponses were either difficult to define or abnormal in latency or amplitude of the various components, additional monaural and binaural testing at 75 and 85 dB SL was also carried out. The most serious problem encountered in recording these small potentials at the patient's bedside was the presence of un¬
Table 1.—Effect of Electrode Array on Amplitude of Auditory Brain Stem Responses Right Monaural Stimulation (65 dB SL)*
Wave I
generated by the acoustic equipment, patient movements, or bed¬ side monitoring equipment. The single most important factor for minimizing
Measurement
Latency and amplitude data were ob¬ tained from six individuals with normal hearing (ages 25 to 30 years) in response to monaural and binaural click presentations at varying intensities. All the subjects had hearing thresholds that were within 5 dB of one another. Latency was easy to mea¬ sure when there was a sharp rise and fall of the component of interest. However, when the wave forms were broad, as oc¬ curred with low-intensity signals, latency was defined at the point of bisection of lines drawn over the ascending and de¬ scending slopes. Measures of components IV and V were often obscured by their tendency to blend together to form a single complex. An additional measure of the IV and V waves as a complex was also made in all subjects. For all conditions, latency measures were carried out to 0.1 msec. The amplitude of the components was mea¬ sured from the positive peak to the subse¬ quent negative trough.
VI VII *
SD
Mean 0.28 0.16 0.26 0.11 0.36 0.30 0.16
III IV IV-V
wanted artifacts
these artifacts was the reduction of elec¬ trode resistance. The detection of the elec¬ trical pulse used for click generation was reduced by shielding the earphone cables and by alternating the polarity of the pulses applied to the earphones. Line fre¬ quency and high-frequency pick-up could occur by radiation from adjacent equip¬ ment or from grounding loops introduced through monitoring devices. It was some¬ times necessary to turn off these in¬ struments to obtain satisfactory results. Patient movements produced recording difficulty through generation of electromyelogram (EMG) activity and electrome¬ chanical potentials. It was sometimes nec¬ essary to sedate the actively moving patient with diazepam (5 mg given in¬ travenously or intramuscularly) to obtain satisfactory recordings. In other patients, positioning of the head could often reduce muscle artifact. The only complaints expressed by pa¬ tients about the procedure were that the scratching of the scalp to reduce electrode resistance was uncomfortable and that the acoustic signals were monotonous.
Vertex-Left Earlobe, uv
Vertex-Right Earlobe, µ
Mean 0.13
0.08 0.09 0.07 0.10 0.05 0.06 0.06
Mean of ten normal subjects; values not significant at = .05.
t NS,
0.18 0.11 0.16 0.37 0.28 0.17
SD 0.03 0.09 0.05 0.10 0.09 0.06 0.10
t
testf .01 NS .01 NS NS NS NS
given in microvolts.
Table 2.—Latency of Auditory Brain Stem
Responses*
Latency, dB SL
Mon¬ aural Wave
75 1.4 2.6 3.7 4.6 5.2 5.4 6.9 8.7 0.2
I
III IV IV-V
VI VII
SDf
65 1.6
2.8 3.8 4.8 5.2 5.5 7.1 9.0 0.2
55 1.8 3.0 3.9 5.0 5.6 5.8 7.5 9.0 0.2
45 2.2 3.3 4.3 5.4 5.9 6.0 7.8 9.6 0.3
35 2.7 3.6 4.7 5.8 6.4 6.6 8.4
25 2.9 3.8 5.1 6.6 7.0 7.1 9.2
0.3
0.4
15
5.9 7.7 7.7 9.5 0.4
0.4
response detected,
*Mean of six normal subjects; values given in milliseconds; t Values represent largest SD for any of components at each intensity. ...,
In the clinical tests using monaural sig¬ nals, recordings were always made between the vertex and the earlobe ipsilateral to
With binaural tests the routinely made between vertex (Cz) and the right earlobe (A2). This arrangement is necessary because ampli¬ tude, but not latency, is affected by the choice of electrode array. During monaural stimulation, components I and III are sig¬ stimulation.
recordings
were
nificantly larger if recordings are made be¬ tween vertex and the
ear stimulated than if recordings are made between vertex and the contralateral ear. In contrast, the am¬ plitudes of waves II, IV, V, and VI are no different in the two recording conditions. Table 1 contains amplitude measures of the various waves from ten normal sub¬ jects as a function of the recording condi¬ tion.
RESULTS Normal Subjects
brain stem responses de¬ in amplitude and become longer in latency as signal intensity is reduced (Fig 2). Moreover, binaural stimulation (Fig 2, right) evokes larger amplitude responses than does
Auditory
crease
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no
monaural stimulation (Fig 2, left). Tables 2 and 3 contain the means of latency and amplitude for the seven waves and the IV-V complex as a function of signal intensity for six normal subjects. Only the latency measures to monaural stimulation are included as there were no substantial differences between monaural and binaural presentations. Latency can provide an accurate estimate of the extent of a peripheral hearing loss be¬ cause there is an orderly change in the timing of all of the waves with changes of intensity as is shown in Fig 3. For instance, the normal la¬ tencies of waves I and the IV-V com¬ plex at 65 dB SL are 1.6 and 5.2 msec, respectively. A middle ear conductive hearing loss of 20 dB would be associ¬ ated with an increase in latency of these waves to 2.2 msec (wave I) and 5.9 msec (IV-V complex). However, the finding of a normal latency for wave I and a delayed latency for the later components would be suggestive of a conduction delay in the central
auditory pathway. Measures of amplitude varied con¬ siderably between subjects. In gen¬ eral, waves I, II, and III could not be distinguished consistently until sig¬
nal intensities were 25 to 35 dB above hearing threshold. Wave I increased gradually in amplitude up to 55 dB SL and then grew much more rapidly with further increments of intensity. In contrast, the IV-V complex was evident at 5 dB SL in all of the sub¬ jects and increased in a fairly linear fashion with intensity. Although the amplitudes of the in¬ dividual components could vary be¬ tween subjects, there were several features of the amplitude measures that appeared sufficiently consistent to justify their use as guidelines for distinguishing abnormalities in the clinical situation. The ratio of the am¬ plitudes of the IV-V complex to wave I, (IV-V)/I, was always greater than 1.0 in response to binaural signals from 5 to 75 dB SL. With monaural stimulation the ratio was also always greater than 1.0 from 5 to 55 dB SL. At 65 dB SL the ratio was still greater than 1.0 in 45 of the 50 nor¬ mal individuals tested, and between 0.5 and 1.0 in the other five subjects. In three of the individuals in the group the (IV-V)/I ratio was less than 1.0 because wave I was unusu¬ ally large ( >0.35µ ) whereas the IVV complex was of average amplitude for that intensity (>0.30µ ). In the two other normal subjects with (IVV)/I ratios less than 1.0, wave I was of normal amplitude (0.25µ , 0.33µ ) but the IV-V complex was unusually small (0.18µ , 0.14µ ). Thus, we sug¬ gest that (1) a (IV-V)/I ratio of less than 1.0 should be considered abnor¬ mal in response to binaural stimula¬ tion at all intensities if both ears are functioning normally, and that (2) with monaural stimulation at 65 dB SL or below a (IV-V)/I ratio of less than 0.5 is abnormal and a ratio be¬ tween 0.5 and 1.0 is suggestive of cen¬ tral auditory pathway dysfunction. Patients
Coma.—When coma was due to toxic or metabolic factors, auditory brain stem responses were usually normal with regard to latency and
amplitude of all of the components. The following tabulation shows the various causes of the coma in patients tested with auditory brain stem re¬ sponses:
Drug overdose, 9 (two patients more than one drug) Barbiturates, 4 Diazepam, 3 Glutethimide, 1 Amitryptyline hydrochloride, 1 Imipramine hydrochloride, 1 Propoxyphene, 1 Perphenazine, 1 Hypoxia, 7 Metabolic, 5 Diabetic ketoacidosis, 2 Uremia, 2 Hepatic failure, 1 Status epilepticus, 2 Traumatic, 9 Concussion, 5 Contusion, 4 Subarachnoid hemorrhage, 4 Bacterial meningitis, 1
consumed
abnormalities in latency that found in these patients usually persisted when the individual recov¬
Any
were
ered, signifying an underlying sensorineural or conductive hearing loss. The only exceptions to this statement
in five of the 37 comatose pa¬ tients in whom the latency of the IVV complex was 0.1 to 0.6 msec longer in coma than in the waking state. An example of an individual in coma due to a combination of barbiturate and glutethimide overdose is shown in were
Fig 4, left. The patient
was
a
21-year-old
admitted in coma on Aug 20, 1973. She was unresponsive to nociceptive stimuli, had depressed respi¬ rations, and required assistance to maintain adequate ventilation. The pupils reacted sluggishly to light. Cold caloric stimulation of the ears and oculocephalic reflexes did not elic¬ it eye movements. The patient was flaccid, without deep tendon reflexes, and there were no responses to nociceptive stimulation of the plantar surface of the feet. The blood level of short-acting barbiturates was 2.3 mg/ 100 ml and of glutethimide 1.6 mg/ 100 ml. The EEG contained a mixture of diffuse delta activity and barbitu¬ woman
rate
spindles.
Five days later when the patient recovered and was alert, additional
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brain stem responses were obtained (Fig 4, right). There is no substantial difference between the responses recorded when this patient was deeply comatose and when she was alert. In our experience, the finding of normal brain stem responses in a comatose patient suggests that the cause of coma is due to (1) a metabolic or toxic cause or (2) a diffuse cortical process in which the brain stem has been spared. It should be stressed that in some patients with metabolic or toxic causes of coma, auditory brain stem responses were normal at a time when the customary clinical measures of brain stem function, such as spontaneous respiration, cold ca¬ loric responses, and oculocephalic re¬ flexes, were absent or depressed. Tumor.—The anatomical localiza¬ tion of tumors to the midbrain and brain stem was verified by auditory brain stem recordings. Five patients with tumors in this region were stud¬ ied. The tumors included a pinealoma, a brain stem glioma, a glioma associ¬ ated with tuberous sclerosis, a metas¬ tasis from the breast, and an acoustic neuroma. Auditory brain stem re¬ sponses were abnormal in all. The clinical details of two of these pa¬ tients are presented below. An 18-year-old man had a fourmonth history of progressive head¬
ache, diplopia, personality changes,
and left-sided numbness and weak¬ ness. Examination in June 1973 re¬ vealed an alert, young man with bi¬ lateral papilledema, paralysis of upward gaze, and pupils that did not react to light or accommodation. There was a slight left-sided hemi¬ paresis and hemisensory deficit. Deep tendon reflexes were slightly more ac¬ tive on the left side and plantar stim¬ ulation elicited left extensor and right flexor responses. Diagnostic studies, including arteriography and ventriculography, revealed dilated lateral and third ventricles with a mass impinging on the third ventricle and elevating the aqueduct of Syl¬ vius. The presumptive diagnosis was brain stem glioma. The patient dete¬ riorated over the next few months and became unresponsive with decor¬ ticate posturing. Cold caloric testing
of eye movement functions was com¬ patible with a medial longitudinal fasciculus (MLF) syndrome: there was nystagmus of the abducting eye and no movement of the adducting
Table
brain stem responses were recorded in both July and Sep¬ tember. The latter recording was made just ten days before the pa¬ tient's death, with essentially similar findings (Fig 5, top). There was ab¬ sence of all components after wave III and waves II and III were de¬ layed. The patient's responses (Fig 5, top) can be compared to the normal pattern in Fig 5, bottom. At post¬
Auditory
pinealoma was found to have entirely destroyed the midbrain and compressed the dor¬ sal portion of the pons, but to have spared the VIII nerves and cochlear examination,
sponses.
Auditory
brain
III
IVt IV-V
Vf VI VII
stem
responses
Responses*
75
65
55
0.20 0.16 0.18 0.10 0.34 0.25 0.12 0.09
0.19 0.11 0.16 0.09 0.28 0.23 0.13 0.08
0.09 0.07 0.12 0.09 0.25 0.18 0.10 0.05
0.30 0.23 0.26 0.30 0.58 0.42 0.14 0.09
0.28 0.16 0.21 0.22 0.52 0.34 0.12 0.09
0.17 0.15 0.16 0.15 0.46 0.32 0.11 0.10
45 Monaural 0.09 0.05 0.10 0.05 0.23 0.17 0.07
35
25
0.08 0.06 0.10 0.03 0.18 0.17 0.04
0.05
0.11 0.03 0.08 0.09 0.38 0.29 0.05
15
0.07
0.04
0.08
0.17 0.18 0.06
0.14 0.11 0.08
0.12 0.11
0.08 0.03 0.05
0.05 0.02 0.05
0.33 0.33 0.04
0.24 0.29
Binaural
III
IVt IV-V
a
nuclei. The second patient was an 8-yearold boy with a brain stem glioma. The patient developed diplopia and a change in behavior two years earlier. Six months after the onset of the ill¬ ness he was reported to have lost vi¬ sion and shortly thereafter he had a generalized seizure. The diagnosis of Schilder disease was made and the patient was sent to an institution for the care of patients with chronic neu¬ rological diseases. A routine skull xray film six months later demon¬ strated widening of the sutures and the patient was transferred to Or¬ ange County Medical Center for eval¬ uation. Examination revealed a boy with bilateral decorticate postures, who was unresponsive except to nociceptive stimuli. The pupils were 4 mm in diameter and unreactive to light. The ciliospinal reflex was present. There was bilateral papilledema. Oculocephalic reflexes were intact only on turning the head to the left. Cold caloric stimulation of the right ear caused slow tonic deviation of the eyes to the right with failure of the right eye to fully abduct. Cold caloric stimulation of the left ear was with¬ out effect. There was spasticity bilat¬ erally. The deep tendon reflexes could not be elicited and clonus was absent. There were bilateral Babinski re¬
Brain Stem
Latency, dB SL Wave
eye.
mortem
3.—Amplitude of Auditory
vt VI VII
0.13 0.08 0.14 0.15 0.43 0.26 0.07
0.17 0.34 0.02
no response detected. Mean of six normal subjects; values given in microvolts; f Because of tendency of waves IV and V to fuse into single peak, amplitudes of these waves could only be obtained for two of six normal subjects. *
..,
.
absent to stimulation of the and showed only the initial right wave I to stimulation of the left ear (Fig 6). The results were compatible with absent cochlear function on the right and blockage of the central auditory pathway close to the cochlea on the left. Contrast studies revealed an ob¬ struction of the aqueduct of Sylvius with pronounced enlargement of the lateral and third ventricles. A circum¬ scribed mass was noted to extend into the lateral ventricles. A ventriculoatrial shunt was placed and the diagnosis of a thalamic or midbrain tumor made. The patient died four months later. Additional neurological and brain stem response recordings were made one month before death and were un¬ changed from the earlier studies. Postmortem examination demon¬ strated enlargement of the brain stem and midbrain. Microscopic sec¬ tions showed the enlargement to be due to an astrocytoma that had infil¬ trated from the posterior thalamus to the medulla. Both cochlear nuclei were infiltrated by the tumor with considerably more involvement on the right than on the left. The measurement of auditory brain stem responses did not substantially were
ear
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affect the clinical management of the cases. However, the definition of abnormalities in auditory brain stem responses in these two cases raises the possibility that the measure may be of use early in the evaluation of patients with suspected tumors in this region. two
Demyelinating
Diseases
We have not systematically exam¬ ined auditory brain stem responses in patients with the diagnosis of mul¬ tiple sclerosis but rather studied four patients in whom the clinical findings of nystagmus, MLF syndrome, dysar¬ thria, and ataxia clearly localized the pathologic findings to brain stem structures. The clinical history of one of the patients follows. A 35-year-old woman has had an 11-year history of progressive neuro¬ logical disability marked by sudden exacerbation with minimal improve¬ ment. On examination the patient's affect was labile. Cranial nerve exam¬ ination showed normal disks and no central scotomata. There was rota¬ tory nystagmus both at rest and on lateral and vertical gaze. Hearing was intact bilaterally to whispered speech. There was paraplegia in flex¬ ion with flexor spasms. A severe in¬ tention tremor was present in the up-
Fig 4.—Auditory brain
stem responses recorded from patient in due to barbiturate overdose (left) and again five days later after regaining consciousness (right). Binaural click signals were presented at varying intensities (25 to 75 dB SL). Note remark¬ able similarity of responses in regard to amplitude and latency in two conditions. coma
Fig 5.—Auditory brain stem responses recorded from patient with tumor that destroyed midbrain (top) compared with normal sub¬ ject's responses (bottom). In patient, note (1) almost total loss of all components after third upward deflection and (2) prolonged latency of both second and third peaks compared to normal sub¬ ject. Calibrations are 0.25µ and 2 msec. Click signals were pre¬ sented monaurally at 65 dB SL (with regard to normal). per extremities. The
deep tendon exaggerated and there bilateral extensor plantar re¬
reflexes were
were
sponses. The sensory examination showed absent vibration sense to the iliac crests with a slight decrease of response to pin prick and touch in the legs but no sensory level.
In the four
patients, auditory brain
were abnormal. In three of the patients the abnormality took the form of a reduction in the amplitude of all components except wave I as is shown in Fig 7. In the other patient the components were normal except that wave V was ab¬ sent on stimulation of one ear but present on stimulation of the other ear. It would be of interest to mea¬ sure auditory brain stem responses in other patients with multiple sclerosis in whom brain stem or midbrain dys¬ function was less apparent. The brain stem responses could be determined before and after elevation of body temperature to enhance the detection of demyelinated areas involving the brain stem auditory pathways.
stem responses
Brain Stem Encephalomalacia.—In another individual seen with unex¬ plained coma, the auditory brain stem responses were abnormal because of
their poor definition and small ampli¬ tudes, particularly those of the IV-V
complex (Fig 8). A 21-year-old man was known to use intravenously injected narcotics.
He was found at home unconscious and taken to the nearest emergency room where he was reported to have been without heart beat. He was re¬ suscitated by external cardiac mas¬ sage. On transfer to Orange County Medical Center he was unconscious with irregular respirations. The pu¬ pils were miotic and nonreactive to light. The oculocephalic, caloric, and ciliospinal reflexes were absent. He made no spontaneous movements. During the next few days the pupils gradually dilated and were unrespon¬ sive except for hippus noted on his second hospital day. Two EEGs showed suppression of cerebral activ¬ ity with diffuse low-voltage fast ac¬ tivity. There were no organic bases detected in the urine and the results of a screen for hypnotic drugs were negative. The cerebrospinal fluid two days after admission was clear with a protein level of 44 mg/100 ml, glucose level of 156 mg/100 ml, and 37 white blood cells per cubic millimeter, 82% of which were polymorphonuclear leu-
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Fig 6.—Auditory brain stem responses from patient with brain stem glioma that had infiltrated in rostral-caudal manner from midbrain to pons. Records are in re¬ sponse to monaural click signals (left [top] and right [bottom] at 75 dB SL [with re¬ gard to normal]). Note absence of re¬ sponse to monaural right stimulation and presence of only component I in response to monaural left stimulation. Calibrations are 0.25µ and 2 msec.
kocytes. On the fifth hospital day, the patient's blood pressure dropped and he died the following day. At post¬ mortem examination, the brain stem appeared grossly normal but on mi¬ croscopic examination there were many patches of encephalomalacia of
the midbrain and pons.
Brain Death.—Auditory brain stem responses have been recorded in the evaluation of brain death. In 20 indi¬
viduals with isoelectric EEGs, re¬ sponses have either been absent or have only shown the presence of wave I, which also subsequently dis¬ appeared. An example of the re¬ sponses from one of the patients is
shown in Fig 9. A 21-year-old woman with sus¬ pected heroin overdose was brought to the Orange County Medical Center unconscious without pulse or respira¬ tion. The patient was resuscitated with return of heart beat and blood pressure to 80/60 mm Hg. She was in deep coma with absent spontaneous respirations, negative caloric or oculo¬ cephalic reflexes, and dilated and fixed pupils. Auditory brain stem responses two hours later (Fig 9, top) showed a wave I of slightly prolonged latency (1.8 msec) and no other components. Shortly thereafter the patient had a cardiac arrest and wave I also dis¬
appeared (Fig 9, bottom). The failure to detect auditory brain stem response should not be equated
Fig 7.—Auditory brain stem response from patient with multiple sclerosis with clinical
involvement of brain stem structures. Records are in response to monaural click signals (left [top] and right [bottom] at 75 dB SL [with regard to normal]). Note that both left-sided and right-sided stimulation evoked wave I of normal latency (1.7 msec) but that remainder of records are reduced in amplitude and deviate substan¬ tially from normal (Fig 1). Calibration is in microvolts and milliseconds.
Fig 8.—Auditory brain
stem responses stem encepha¬ lomalacia in response to binaural clicks at 75 dB SL (with regard to normal). Compo¬ nents are of normal latency but poorly de¬ veloped in amplitude. Calibrations are 0.25µ and 2 msec. from
patient with brain
with brain death since responses could also be absent in an individual who was totally deaf. However, the demonstration of a wave I provides assurance that the cochlea and VIII nerve are indeed functional while the absence of the latter components is evidence of impairment of the central
auditory pathway.
COMMENT
Auditory brain stem responses can help in evaluating the condition of patients with neurological diseases. In particular, structural damage of the auditory brain stem pathways due to tumors, demyelination, or loss Fig 9.—Auditory brain stem responses patient with isoelectric EEG before (top) and after (bottom) cardiac arrest. Note that in top, wave I is only component detected, which then disappears in bot¬
from
tom.
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of circulation can be reflected in ab¬ normalities of amplitude and latency of the various components. In con¬ trast, the responses are normal in toxic and metabolic conditions when the structural integrity of the brain stem is not compromised. It was par¬ ticularly impressive to define normal responses in individuals in coma due to drug ingestion at a time when the usual clinical measures of brain stem function (respiration, oculocephalic, and vestibular reflexes) were absent. The measurement of auditory brain stem responses is a relatively simple procedure. The equipment required for the test is commercially available and can be placed together in a por¬ table system. An EEG technician can quickly learn to operate the equip¬ ment and the electrodes and their ap¬ plication are similar to those used in EEG. A major advantage of the tech¬ nique is that it can be performed at the bedside on acutely ill individuals with the results being available in a few minutes. Quantitative measures of latency and amplitude of the com¬ ponents provide information as to the portion of the brain stem that may be abnormal. The location of generators contrib¬ uting to the auditory brain stem re¬ sponse has been analyzed both in ex¬ periments in animals1 ·· and in the clinical pathological studies presented in this article. First, the latencies of the various components of the audi¬ tory brain stem response can be cor¬ related with latencies of sound evoked potentials recorded directly from the various nuclei comprising the auditory pathway. Thus, wave I occurs coincident with activity in VIII nerve; wave II occurs coincident with activity in cochlear nucleus; wave III occurs coincident with activ¬ ity in superior olive; waves IV and V occur coincident with activity in the inferior colliculus. Moreover, as one lowers an electrode through the brain while recording auditory brain stem responses, the amplitudes of par¬ ticular components grow when the electrode reaches the region of the auditory pathway. The particular component affected depends on the electrode location with the results
supporting the data obtained from the latency measures. Finally, lesion experiments in animals" and the clinicopathological observations made by
have shown that waves IV and V depend on the structural integrity of the midbrain. Waves VI and VII are not consistently detected in animal experiments and no good correlations have been made as to the cortical or subcortical generators of these com¬ us
ponents. We consider the data to be consist¬ ent with the idea that each of the
components of the auditory brain stem response arises from
activity in located close the nu¬ to generators clear stations comprising the auditory pathway. The precise dimensions of these generators need to be defined in additional experiments. Acoustic signal characteristics such as frequency also need investigation
in neurological disease as it may be possible to utilize the frequency fol¬ lowing response of the auditory path¬ way to low-frequency tones as an
additional function.10
measure
of brain stem
Auditory brain stem responses have certain advantages for the eval¬ uation of the anatomical basis of neu¬ rological disease over the more classic cortical evoked responses. Cortical evoked responses depend in part on levels of attention, arousal, and ex¬ pectation, while auditory brain stem responses are not affected by these variables.4-5 Furthermore, latency and amplitude can be rigorously defined in the brain stem responses, whereas these measures are variable with cor¬ tical evoked responses. A major technical limitation in recording auditory brain stem re¬ sponses relates to their small-ampli-
tude and high-frequency components. Both of these factors can result in the unwanted detection of artifacts.
However,
that
our
experience suggests
skilled EEG technician can lo¬ cate and eliminate the source of these artifacts in the same manner as when recording the EEG. Auditory brain stem responses of¬ fer a new method of objective mea¬ surement of the deep structures of the brain that can complement the clinical evaluation. Furthermore, the concept of far-field recordings raises the possibility that measures of activ¬ ity arising in other sensory or motor pathways traversing the brain stem can also be developed. a
This investigation was supported in part by grant PHS/NS 11876-01 from the National Insti¬
Neurological Diseases and Stroke. Keith Manahan gave technical assistance.
tute of
References 1. Jewett DL: Volume conducted potentials in response to auditory stimuli as detected by aver¬ aging in the cat. Electroencephalogr Clin Neu¬ rophysiol 28:609-618, 1970. 2. Jewett DL, Romano MN, Williston JS: Hu¬ man auditory evoked potentials: Possible brain¬ stem components detected on the scalp. Science 167:1517-1518, 1970. 3. Jewett DL, Williston JS: Auditory evoked far-fields averaged from the scalp of humans. Brain 94:681-696, 1971. 4. Picton TW, Hillyard SA, Krausz HI, et al: Human auditory evoked potentials: I. Evaluation
Electroencephalogr Clin Neu¬ rophysiol 36:179-190, 1974. 5. Picton TW, Hillyard S: Human auditory evoked potentials: II. Effects of attention. Elec¬ troencephalogr Clin Neurophysiol 36:191-200, of components.
1974. 6. Hecox K, Galambos R: Brainstem auditory evoked responses in human infants and adults. Arch Otolaryngol 99:30-33, 1974. 7. Jewett DL, Romano M: Neonatal develop¬ ment of auditory system potentials averaged from the scalp of rat and cat. Brain Res 36:101115, 1972.
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8. Liberman A, Sohmer H, Szabo G: Cochlear audiometry (electrocochleography) during the neonatal period. Dev Med Child Neurol 15:8-13,
1973. 9. Lev A, Sohmer H: Sources of averaged neu¬ ral responses recorded in animal and human subjects during cochlear audiometry (electrocochleogram). Arch Klin Exp Ohren Nasen Kehlkopfheilkd 201:79-90, 1972. 10. Moushegian G, Rupert AL, Stillman RD: Scalp-recorded early responses in man to fre¬ quencies in the speech range. Electroencephalogr Clin Neurophysiol 35:665-667, 1973.
Starr, MD, L. Joseph Achor,
MD
• A sequence of seven low-amplitude (nanovolt) potentials that occur in the ini¬ tial 10 msec following click signals can be recorded from scalp electrodes in hu¬ man subjects using computer averaging techniques. The potentials, termed audi¬ tory brain stem responses, are thought to
be the far-field reflection of electrical events originating in the auditory pathway during its course through the brain stem. We have studied auditory brain stem re¬ sponses in a variety of neurological dis¬ orders and found them to be of assistance in evaluating the mechanisms of coma, the localization of midbrain and brain stem tumors, the localization of demyeli¬ nation of the brain stem, and the presence of diminished brain stem circulation. (Arch Neurol 32:761 -768, 1975)
for publication Jan 29, 1975. From the Division of Neurology and the De¬ partment of Psychobiology, University of Cali¬ fornia, Irvine. Read in part before the 26th meeting of the American Academy of Neurology, April 24,1974. Reprint requests to Division of Neurology, University of California, Irvine, Orange County Medical Center, 101 City Drive South, Orange, CA 92668 (Dr Starr).
Accepted
brain stem responses are of electrical events generated along the auditory path¬ way that can be recorded from the scalp by far-field averaging methods. The technique was first described by Jewett in 1970.'2 He employed a com¬ puter to extract the auditory brain stem responses from background electroencephalogram activity. Jew¬ ett defined a series of seven deflec¬ tions of submicrovolt amplitude (now colloquially referred to as "Jewett bumps") during the initial 10 msec following a click. He suggested that these responses represent the farfield reflection of electrical events generated deep within the brain stem.1 Subsequent studies have de¬ fined some of the stimulus and record¬ ing characteristics of auditory brain stem responses4: (1) the responses are independent of level of arousal or at¬ tention5; (2) their latency varies sys¬ tematically with signal intensity«; (3) they are present at birth and their la¬ tency changes with maturation68; and (4) they can be abolished by le¬ sions of the auditory pathway.9 It seemed to us that measures of the auditory brain stem response could be a useful technique for objec¬ tively assessing brain stem function in neurological diseases of man. This article describes a procedure
Auditory
il measures
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that
can be applied at the bedside to provide information rapidly about the status of the auditory brain stem pathways in man. We have employed the technique in over 100 patients and
have defined clinical conditions in which the response measure appears to be useful. Quantitative and qual-
Fig 1.—Auditory brain stem responses from normal subject in response to monaural click signals, 65 dB SL, pre¬ sented at 10/sec. Clicks were presented to right ear and recordings derived from vertex and right earlobe electrodes (CzA2). Total of 2,048 click trials were used to form each of two averages presented. Ro¬ man numerals, I through VII, designate se¬ quence of upward peaks comprising re¬ sponse. Note that amplitude calibration is in submicrovolt range and sweep duration is 10 msec. In this and all subsequent fig¬ ures, positivity at vertex (Cz) electrode is in upward direction.
-
-1VII
VI
.ß..
" & ...,_
"·:">.. r.
"· ...".«... -' - ..
IV""»·
'.
*
" -._C .«.
Ill
.OL..
II
Fig 2.—Auditory brain stem responses in normal subject as func¬ tion of signal intensity (65 to —5 dB SL) with monaural (left) or binaural (right) presentation. Calibration is in microvolts and mil¬ liseconds. _L
Fig 3.—Latency measures of seven components (I to VII) and IV-V complex of auditory brain stem response as function of signal in¬ tensity. Data are means of measures from six subjects with nor¬ mal hearing in response to monaural click signals as presented in
5
_L
15
_L
25
35
_L
45 dB SL
55
X
65
75
Table 2.
itati ve data from normal subjects served as guidelines for establishing abnormalities in the response mea¬
ferential
sures.
Acoustic transients (clicks) were gener¬ ated by passing square wave pulses, 0.2 msec in duration, through an attenuator for regulation of intensity, and amplified before presentation to the subject by ear¬ phones. The pulse polarity was reversed al¬ ternately to decrease the amplitude of stimulus artifact during the averaging process. An extra shielding wire was also placed around the earphone cable to fur¬ ther reduce the amplitude of the stimulus artifact created by capacitive pick-up. This arrangement permitted binaural presenta¬ tion of equal intensity click signals. Monaural stimulation was achieved by simply disconnecting the input to one of the earphones. The click rate used in these studies was 10/sec. The intensity of the signal will be noted in decibels referenced against the mean threshold of six subjects with normal hearing (for instance, 35 dB sensation level [SL]).
METHODS The procedure can be divided into four sections: (1) response amplification, (2) acoustic signal generation, (3) auditory brain stem response processing, and (4) measurement.
Response Amplification Auditory brain stem responses
were
recorded with conventional EEG disk elec¬ trodes placed on the skin at the vertex (Cz) and earlobes (Al, A2), using parlodion for mechanical coupling and electrode jelly as the conductive medium. The skin under¬ lying the electrodes was abraded with a blunt needle to reduce interelectrode re¬ sistance to less than 5,000 ohms. Differ¬ ential amplification (Cz to Al or A2) of 1,000,000 (1X10«) times was accomplished by two amplifiers linked in series. The am¬ plifier band-pass was between 100 hertz and 3 kilohertz (3 dB down points) to achieve resolution of high-frequency com¬ ponents of the auditory brain stem re¬ sponse. Patient grounding was through the earlobe electrode not employed in the dif-
recordings. Acoustic
clicks/sec, only four minutes were re¬ quired to obtain one averaged response. The time base was 10 msec and comprised 500 points. Each point was sampled at a 20/isec interval to allow resolution of highfrequency spectral components. Theoret¬ ically an 83µ8ß sampling would have suf¬ at 10
Signals
Evoked
Response Averaging output of the amplifiers was con¬
The nected to the averaging computer. The computer time base was triggered by each click for a total of 2,048 click trials. Thus,
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ficed to define the 3-kHz components comprising the upper limit of our response system. (Upper frequency resolution in hertz 1/4 x sampling interval). A perma¬ nent record of the averaged response was obtained by an XY plot of the contents of the averager's memory. Figure 1 is an ex¬ ample of two sets of auditory brain stem responses derived from a normal subject in response to monaural click signals at 65 dB SL. The components, designated I through VII, are consistent and easy to define. The click-generating equipment, the averager, and the XY plotter were con¬ tained on a small cart, which was wheeled to the patient's bedside. The amplifiers were placed on the bed and the electrodes and earphones attached in place. The clini¬ cal protocol used binaural presentation of clicks at 65, 45, and 25 dB SL, and monau¬ ral presentations at 65 dB SL. Two sets of averaged responses were obtained at each intensity and plotted over one another to define response consistency. In those pa¬ tients in whom auditory brain stem re=
sponses were either difficult to define or abnormal in latency or amplitude of the various components, additional monaural and binaural testing at 75 and 85 dB SL was also carried out. The most serious problem encountered in recording these small potentials at the patient's bedside was the presence of un¬
Table 1.—Effect of Electrode Array on Amplitude of Auditory Brain Stem Responses Right Monaural Stimulation (65 dB SL)*
Wave I
generated by the acoustic equipment, patient movements, or bed¬ side monitoring equipment. The single most important factor for minimizing
Measurement
Latency and amplitude data were ob¬ tained from six individuals with normal hearing (ages 25 to 30 years) in response to monaural and binaural click presentations at varying intensities. All the subjects had hearing thresholds that were within 5 dB of one another. Latency was easy to mea¬ sure when there was a sharp rise and fall of the component of interest. However, when the wave forms were broad, as oc¬ curred with low-intensity signals, latency was defined at the point of bisection of lines drawn over the ascending and de¬ scending slopes. Measures of components IV and V were often obscured by their tendency to blend together to form a single complex. An additional measure of the IV and V waves as a complex was also made in all subjects. For all conditions, latency measures were carried out to 0.1 msec. The amplitude of the components was mea¬ sured from the positive peak to the subse¬ quent negative trough.
VI VII *
SD
Mean 0.28 0.16 0.26 0.11 0.36 0.30 0.16
III IV IV-V
wanted artifacts
these artifacts was the reduction of elec¬ trode resistance. The detection of the elec¬ trical pulse used for click generation was reduced by shielding the earphone cables and by alternating the polarity of the pulses applied to the earphones. Line fre¬ quency and high-frequency pick-up could occur by radiation from adjacent equip¬ ment or from grounding loops introduced through monitoring devices. It was some¬ times necessary to turn off these in¬ struments to obtain satisfactory results. Patient movements produced recording difficulty through generation of electromyelogram (EMG) activity and electrome¬ chanical potentials. It was sometimes nec¬ essary to sedate the actively moving patient with diazepam (5 mg given in¬ travenously or intramuscularly) to obtain satisfactory recordings. In other patients, positioning of the head could often reduce muscle artifact. The only complaints expressed by pa¬ tients about the procedure were that the scratching of the scalp to reduce electrode resistance was uncomfortable and that the acoustic signals were monotonous.
Vertex-Left Earlobe, uv
Vertex-Right Earlobe, µ
Mean 0.13
0.08 0.09 0.07 0.10 0.05 0.06 0.06
Mean of ten normal subjects; values not significant at = .05.
t NS,
0.18 0.11 0.16 0.37 0.28 0.17
SD 0.03 0.09 0.05 0.10 0.09 0.06 0.10
t
testf .01 NS .01 NS NS NS NS
given in microvolts.
Table 2.—Latency of Auditory Brain Stem
Responses*
Latency, dB SL
Mon¬ aural Wave
75 1.4 2.6 3.7 4.6 5.2 5.4 6.9 8.7 0.2
I
III IV IV-V
VI VII
SDf
65 1.6
2.8 3.8 4.8 5.2 5.5 7.1 9.0 0.2
55 1.8 3.0 3.9 5.0 5.6 5.8 7.5 9.0 0.2
45 2.2 3.3 4.3 5.4 5.9 6.0 7.8 9.6 0.3
35 2.7 3.6 4.7 5.8 6.4 6.6 8.4
25 2.9 3.8 5.1 6.6 7.0 7.1 9.2
0.3
0.4
15
5.9 7.7 7.7 9.5 0.4
0.4
response detected,
*Mean of six normal subjects; values given in milliseconds; t Values represent largest SD for any of components at each intensity. ...,
In the clinical tests using monaural sig¬ nals, recordings were always made between the vertex and the earlobe ipsilateral to
With binaural tests the routinely made between vertex (Cz) and the right earlobe (A2). This arrangement is necessary because ampli¬ tude, but not latency, is affected by the choice of electrode array. During monaural stimulation, components I and III are sig¬ stimulation.
recordings
were
nificantly larger if recordings are made be¬ tween vertex and the
ear stimulated than if recordings are made between vertex and the contralateral ear. In contrast, the am¬ plitudes of waves II, IV, V, and VI are no different in the two recording conditions. Table 1 contains amplitude measures of the various waves from ten normal sub¬ jects as a function of the recording condi¬ tion.
RESULTS Normal Subjects
brain stem responses de¬ in amplitude and become longer in latency as signal intensity is reduced (Fig 2). Moreover, binaural stimulation (Fig 2, right) evokes larger amplitude responses than does
Auditory
crease
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no
monaural stimulation (Fig 2, left). Tables 2 and 3 contain the means of latency and amplitude for the seven waves and the IV-V complex as a function of signal intensity for six normal subjects. Only the latency measures to monaural stimulation are included as there were no substantial differences between monaural and binaural presentations. Latency can provide an accurate estimate of the extent of a peripheral hearing loss be¬ cause there is an orderly change in the timing of all of the waves with changes of intensity as is shown in Fig 3. For instance, the normal la¬ tencies of waves I and the IV-V com¬ plex at 65 dB SL are 1.6 and 5.2 msec, respectively. A middle ear conductive hearing loss of 20 dB would be associ¬ ated with an increase in latency of these waves to 2.2 msec (wave I) and 5.9 msec (IV-V complex). However, the finding of a normal latency for wave I and a delayed latency for the later components would be suggestive of a conduction delay in the central
auditory pathway. Measures of amplitude varied con¬ siderably between subjects. In gen¬ eral, waves I, II, and III could not be distinguished consistently until sig¬
nal intensities were 25 to 35 dB above hearing threshold. Wave I increased gradually in amplitude up to 55 dB SL and then grew much more rapidly with further increments of intensity. In contrast, the IV-V complex was evident at 5 dB SL in all of the sub¬ jects and increased in a fairly linear fashion with intensity. Although the amplitudes of the in¬ dividual components could vary be¬ tween subjects, there were several features of the amplitude measures that appeared sufficiently consistent to justify their use as guidelines for distinguishing abnormalities in the clinical situation. The ratio of the am¬ plitudes of the IV-V complex to wave I, (IV-V)/I, was always greater than 1.0 in response to binaural signals from 5 to 75 dB SL. With monaural stimulation the ratio was also always greater than 1.0 from 5 to 55 dB SL. At 65 dB SL the ratio was still greater than 1.0 in 45 of the 50 nor¬ mal individuals tested, and between 0.5 and 1.0 in the other five subjects. In three of the individuals in the group the (IV-V)/I ratio was less than 1.0 because wave I was unusu¬ ally large ( >0.35µ ) whereas the IVV complex was of average amplitude for that intensity (>0.30µ ). In the two other normal subjects with (IVV)/I ratios less than 1.0, wave I was of normal amplitude (0.25µ , 0.33µ ) but the IV-V complex was unusually small (0.18µ , 0.14µ ). Thus, we sug¬ gest that (1) a (IV-V)/I ratio of less than 1.0 should be considered abnor¬ mal in response to binaural stimula¬ tion at all intensities if both ears are functioning normally, and that (2) with monaural stimulation at 65 dB SL or below a (IV-V)/I ratio of less than 0.5 is abnormal and a ratio be¬ tween 0.5 and 1.0 is suggestive of cen¬ tral auditory pathway dysfunction. Patients
Coma.—When coma was due to toxic or metabolic factors, auditory brain stem responses were usually normal with regard to latency and
amplitude of all of the components. The following tabulation shows the various causes of the coma in patients tested with auditory brain stem re¬ sponses:
Drug overdose, 9 (two patients more than one drug) Barbiturates, 4 Diazepam, 3 Glutethimide, 1 Amitryptyline hydrochloride, 1 Imipramine hydrochloride, 1 Propoxyphene, 1 Perphenazine, 1 Hypoxia, 7 Metabolic, 5 Diabetic ketoacidosis, 2 Uremia, 2 Hepatic failure, 1 Status epilepticus, 2 Traumatic, 9 Concussion, 5 Contusion, 4 Subarachnoid hemorrhage, 4 Bacterial meningitis, 1
consumed
abnormalities in latency that found in these patients usually persisted when the individual recov¬
Any
were
ered, signifying an underlying sensorineural or conductive hearing loss. The only exceptions to this statement
in five of the 37 comatose pa¬ tients in whom the latency of the IVV complex was 0.1 to 0.6 msec longer in coma than in the waking state. An example of an individual in coma due to a combination of barbiturate and glutethimide overdose is shown in were
Fig 4, left. The patient
was
a
21-year-old
admitted in coma on Aug 20, 1973. She was unresponsive to nociceptive stimuli, had depressed respi¬ rations, and required assistance to maintain adequate ventilation. The pupils reacted sluggishly to light. Cold caloric stimulation of the ears and oculocephalic reflexes did not elic¬ it eye movements. The patient was flaccid, without deep tendon reflexes, and there were no responses to nociceptive stimulation of the plantar surface of the feet. The blood level of short-acting barbiturates was 2.3 mg/ 100 ml and of glutethimide 1.6 mg/ 100 ml. The EEG contained a mixture of diffuse delta activity and barbitu¬ woman
rate
spindles.
Five days later when the patient recovered and was alert, additional
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brain stem responses were obtained (Fig 4, right). There is no substantial difference between the responses recorded when this patient was deeply comatose and when she was alert. In our experience, the finding of normal brain stem responses in a comatose patient suggests that the cause of coma is due to (1) a metabolic or toxic cause or (2) a diffuse cortical process in which the brain stem has been spared. It should be stressed that in some patients with metabolic or toxic causes of coma, auditory brain stem responses were normal at a time when the customary clinical measures of brain stem function, such as spontaneous respiration, cold ca¬ loric responses, and oculocephalic re¬ flexes, were absent or depressed. Tumor.—The anatomical localiza¬ tion of tumors to the midbrain and brain stem was verified by auditory brain stem recordings. Five patients with tumors in this region were stud¬ ied. The tumors included a pinealoma, a brain stem glioma, a glioma associ¬ ated with tuberous sclerosis, a metas¬ tasis from the breast, and an acoustic neuroma. Auditory brain stem re¬ sponses were abnormal in all. The clinical details of two of these pa¬ tients are presented below. An 18-year-old man had a fourmonth history of progressive head¬
ache, diplopia, personality changes,
and left-sided numbness and weak¬ ness. Examination in June 1973 re¬ vealed an alert, young man with bi¬ lateral papilledema, paralysis of upward gaze, and pupils that did not react to light or accommodation. There was a slight left-sided hemi¬ paresis and hemisensory deficit. Deep tendon reflexes were slightly more ac¬ tive on the left side and plantar stim¬ ulation elicited left extensor and right flexor responses. Diagnostic studies, including arteriography and ventriculography, revealed dilated lateral and third ventricles with a mass impinging on the third ventricle and elevating the aqueduct of Syl¬ vius. The presumptive diagnosis was brain stem glioma. The patient dete¬ riorated over the next few months and became unresponsive with decor¬ ticate posturing. Cold caloric testing
of eye movement functions was com¬ patible with a medial longitudinal fasciculus (MLF) syndrome: there was nystagmus of the abducting eye and no movement of the adducting
Table
brain stem responses were recorded in both July and Sep¬ tember. The latter recording was made just ten days before the pa¬ tient's death, with essentially similar findings (Fig 5, top). There was ab¬ sence of all components after wave III and waves II and III were de¬ layed. The patient's responses (Fig 5, top) can be compared to the normal pattern in Fig 5, bottom. At post¬
Auditory
pinealoma was found to have entirely destroyed the midbrain and compressed the dor¬ sal portion of the pons, but to have spared the VIII nerves and cochlear examination,
sponses.
Auditory
brain
III
IVt IV-V
Vf VI VII
stem
responses
Responses*
75
65
55
0.20 0.16 0.18 0.10 0.34 0.25 0.12 0.09
0.19 0.11 0.16 0.09 0.28 0.23 0.13 0.08
0.09 0.07 0.12 0.09 0.25 0.18 0.10 0.05
0.30 0.23 0.26 0.30 0.58 0.42 0.14 0.09
0.28 0.16 0.21 0.22 0.52 0.34 0.12 0.09
0.17 0.15 0.16 0.15 0.46 0.32 0.11 0.10
45 Monaural 0.09 0.05 0.10 0.05 0.23 0.17 0.07
35
25
0.08 0.06 0.10 0.03 0.18 0.17 0.04
0.05
0.11 0.03 0.08 0.09 0.38 0.29 0.05
15
0.07
0.04
0.08
0.17 0.18 0.06
0.14 0.11 0.08
0.12 0.11
0.08 0.03 0.05
0.05 0.02 0.05
0.33 0.33 0.04
0.24 0.29
Binaural
III
IVt IV-V
a
nuclei. The second patient was an 8-yearold boy with a brain stem glioma. The patient developed diplopia and a change in behavior two years earlier. Six months after the onset of the ill¬ ness he was reported to have lost vi¬ sion and shortly thereafter he had a generalized seizure. The diagnosis of Schilder disease was made and the patient was sent to an institution for the care of patients with chronic neu¬ rological diseases. A routine skull xray film six months later demon¬ strated widening of the sutures and the patient was transferred to Or¬ ange County Medical Center for eval¬ uation. Examination revealed a boy with bilateral decorticate postures, who was unresponsive except to nociceptive stimuli. The pupils were 4 mm in diameter and unreactive to light. The ciliospinal reflex was present. There was bilateral papilledema. Oculocephalic reflexes were intact only on turning the head to the left. Cold caloric stimulation of the right ear caused slow tonic deviation of the eyes to the right with failure of the right eye to fully abduct. Cold caloric stimulation of the left ear was with¬ out effect. There was spasticity bilat¬ erally. The deep tendon reflexes could not be elicited and clonus was absent. There were bilateral Babinski re¬
Brain Stem
Latency, dB SL Wave
eye.
mortem
3.—Amplitude of Auditory
vt VI VII
0.13 0.08 0.14 0.15 0.43 0.26 0.07
0.17 0.34 0.02
no response detected. Mean of six normal subjects; values given in microvolts; f Because of tendency of waves IV and V to fuse into single peak, amplitudes of these waves could only be obtained for two of six normal subjects. *
..,
.
absent to stimulation of the and showed only the initial right wave I to stimulation of the left ear (Fig 6). The results were compatible with absent cochlear function on the right and blockage of the central auditory pathway close to the cochlea on the left. Contrast studies revealed an ob¬ struction of the aqueduct of Sylvius with pronounced enlargement of the lateral and third ventricles. A circum¬ scribed mass was noted to extend into the lateral ventricles. A ventriculoatrial shunt was placed and the diagnosis of a thalamic or midbrain tumor made. The patient died four months later. Additional neurological and brain stem response recordings were made one month before death and were un¬ changed from the earlier studies. Postmortem examination demon¬ strated enlargement of the brain stem and midbrain. Microscopic sec¬ tions showed the enlargement to be due to an astrocytoma that had infil¬ trated from the posterior thalamus to the medulla. Both cochlear nuclei were infiltrated by the tumor with considerably more involvement on the right than on the left. The measurement of auditory brain stem responses did not substantially were
ear
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affect the clinical management of the cases. However, the definition of abnormalities in auditory brain stem responses in these two cases raises the possibility that the measure may be of use early in the evaluation of patients with suspected tumors in this region. two
Demyelinating
Diseases
We have not systematically exam¬ ined auditory brain stem responses in patients with the diagnosis of mul¬ tiple sclerosis but rather studied four patients in whom the clinical findings of nystagmus, MLF syndrome, dysar¬ thria, and ataxia clearly localized the pathologic findings to brain stem structures. The clinical history of one of the patients follows. A 35-year-old woman has had an 11-year history of progressive neuro¬ logical disability marked by sudden exacerbation with minimal improve¬ ment. On examination the patient's affect was labile. Cranial nerve exam¬ ination showed normal disks and no central scotomata. There was rota¬ tory nystagmus both at rest and on lateral and vertical gaze. Hearing was intact bilaterally to whispered speech. There was paraplegia in flex¬ ion with flexor spasms. A severe in¬ tention tremor was present in the up-
Fig 4.—Auditory brain
stem responses recorded from patient in due to barbiturate overdose (left) and again five days later after regaining consciousness (right). Binaural click signals were presented at varying intensities (25 to 75 dB SL). Note remark¬ able similarity of responses in regard to amplitude and latency in two conditions. coma
Fig 5.—Auditory brain stem responses recorded from patient with tumor that destroyed midbrain (top) compared with normal sub¬ ject's responses (bottom). In patient, note (1) almost total loss of all components after third upward deflection and (2) prolonged latency of both second and third peaks compared to normal sub¬ ject. Calibrations are 0.25µ and 2 msec. Click signals were pre¬ sented monaurally at 65 dB SL (with regard to normal). per extremities. The
deep tendon exaggerated and there bilateral extensor plantar re¬
reflexes were
were
sponses. The sensory examination showed absent vibration sense to the iliac crests with a slight decrease of response to pin prick and touch in the legs but no sensory level.
In the four
patients, auditory brain
were abnormal. In three of the patients the abnormality took the form of a reduction in the amplitude of all components except wave I as is shown in Fig 7. In the other patient the components were normal except that wave V was ab¬ sent on stimulation of one ear but present on stimulation of the other ear. It would be of interest to mea¬ sure auditory brain stem responses in other patients with multiple sclerosis in whom brain stem or midbrain dys¬ function was less apparent. The brain stem responses could be determined before and after elevation of body temperature to enhance the detection of demyelinated areas involving the brain stem auditory pathways.
stem responses
Brain Stem Encephalomalacia.—In another individual seen with unex¬ plained coma, the auditory brain stem responses were abnormal because of
their poor definition and small ampli¬ tudes, particularly those of the IV-V
complex (Fig 8). A 21-year-old man was known to use intravenously injected narcotics.
He was found at home unconscious and taken to the nearest emergency room where he was reported to have been without heart beat. He was re¬ suscitated by external cardiac mas¬ sage. On transfer to Orange County Medical Center he was unconscious with irregular respirations. The pu¬ pils were miotic and nonreactive to light. The oculocephalic, caloric, and ciliospinal reflexes were absent. He made no spontaneous movements. During the next few days the pupils gradually dilated and were unrespon¬ sive except for hippus noted on his second hospital day. Two EEGs showed suppression of cerebral activ¬ ity with diffuse low-voltage fast ac¬ tivity. There were no organic bases detected in the urine and the results of a screen for hypnotic drugs were negative. The cerebrospinal fluid two days after admission was clear with a protein level of 44 mg/100 ml, glucose level of 156 mg/100 ml, and 37 white blood cells per cubic millimeter, 82% of which were polymorphonuclear leu-
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Fig 6.—Auditory brain stem responses from patient with brain stem glioma that had infiltrated in rostral-caudal manner from midbrain to pons. Records are in re¬ sponse to monaural click signals (left [top] and right [bottom] at 75 dB SL [with re¬ gard to normal]). Note absence of re¬ sponse to monaural right stimulation and presence of only component I in response to monaural left stimulation. Calibrations are 0.25µ and 2 msec.
kocytes. On the fifth hospital day, the patient's blood pressure dropped and he died the following day. At post¬ mortem examination, the brain stem appeared grossly normal but on mi¬ croscopic examination there were many patches of encephalomalacia of
the midbrain and pons.
Brain Death.—Auditory brain stem responses have been recorded in the evaluation of brain death. In 20 indi¬
viduals with isoelectric EEGs, re¬ sponses have either been absent or have only shown the presence of wave I, which also subsequently dis¬ appeared. An example of the re¬ sponses from one of the patients is
shown in Fig 9. A 21-year-old woman with sus¬ pected heroin overdose was brought to the Orange County Medical Center unconscious without pulse or respira¬ tion. The patient was resuscitated with return of heart beat and blood pressure to 80/60 mm Hg. She was in deep coma with absent spontaneous respirations, negative caloric or oculo¬ cephalic reflexes, and dilated and fixed pupils. Auditory brain stem responses two hours later (Fig 9, top) showed a wave I of slightly prolonged latency (1.8 msec) and no other components. Shortly thereafter the patient had a cardiac arrest and wave I also dis¬
appeared (Fig 9, bottom). The failure to detect auditory brain stem response should not be equated
Fig 7.—Auditory brain stem response from patient with multiple sclerosis with clinical
involvement of brain stem structures. Records are in response to monaural click signals (left [top] and right [bottom] at 75 dB SL [with regard to normal]). Note that both left-sided and right-sided stimulation evoked wave I of normal latency (1.7 msec) but that remainder of records are reduced in amplitude and deviate substan¬ tially from normal (Fig 1). Calibration is in microvolts and milliseconds.
Fig 8.—Auditory brain
stem responses stem encepha¬ lomalacia in response to binaural clicks at 75 dB SL (with regard to normal). Compo¬ nents are of normal latency but poorly de¬ veloped in amplitude. Calibrations are 0.25µ and 2 msec. from
patient with brain
with brain death since responses could also be absent in an individual who was totally deaf. However, the demonstration of a wave I provides assurance that the cochlea and VIII nerve are indeed functional while the absence of the latter components is evidence of impairment of the central
auditory pathway.
COMMENT
Auditory brain stem responses can help in evaluating the condition of patients with neurological diseases. In particular, structural damage of the auditory brain stem pathways due to tumors, demyelination, or loss Fig 9.—Auditory brain stem responses patient with isoelectric EEG before (top) and after (bottom) cardiac arrest. Note that in top, wave I is only component detected, which then disappears in bot¬
from
tom.
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of circulation can be reflected in ab¬ normalities of amplitude and latency of the various components. In con¬ trast, the responses are normal in toxic and metabolic conditions when the structural integrity of the brain stem is not compromised. It was par¬ ticularly impressive to define normal responses in individuals in coma due to drug ingestion at a time when the usual clinical measures of brain stem function (respiration, oculocephalic, and vestibular reflexes) were absent. The measurement of auditory brain stem responses is a relatively simple procedure. The equipment required for the test is commercially available and can be placed together in a por¬ table system. An EEG technician can quickly learn to operate the equip¬ ment and the electrodes and their ap¬ plication are similar to those used in EEG. A major advantage of the tech¬ nique is that it can be performed at the bedside on acutely ill individuals with the results being available in a few minutes. Quantitative measures of latency and amplitude of the com¬ ponents provide information as to the portion of the brain stem that may be abnormal. The location of generators contrib¬ uting to the auditory brain stem re¬ sponse has been analyzed both in ex¬ periments in animals1 ·· and in the clinical pathological studies presented in this article. First, the latencies of the various components of the audi¬ tory brain stem response can be cor¬ related with latencies of sound evoked potentials recorded directly from the various nuclei comprising the auditory pathway. Thus, wave I occurs coincident with activity in VIII nerve; wave II occurs coincident with activity in cochlear nucleus; wave III occurs coincident with activ¬ ity in superior olive; waves IV and V occur coincident with activity in the inferior colliculus. Moreover, as one lowers an electrode through the brain while recording auditory brain stem responses, the amplitudes of par¬ ticular components grow when the electrode reaches the region of the auditory pathway. The particular component affected depends on the electrode location with the results
supporting the data obtained from the latency measures. Finally, lesion experiments in animals" and the clinicopathological observations made by
have shown that waves IV and V depend on the structural integrity of the midbrain. Waves VI and VII are not consistently detected in animal experiments and no good correlations have been made as to the cortical or subcortical generators of these com¬ us
ponents. We consider the data to be consist¬ ent with the idea that each of the
components of the auditory brain stem response arises from
activity in located close the nu¬ to generators clear stations comprising the auditory pathway. The precise dimensions of these generators need to be defined in additional experiments. Acoustic signal characteristics such as frequency also need investigation
in neurological disease as it may be possible to utilize the frequency fol¬ lowing response of the auditory path¬ way to low-frequency tones as an
additional function.10
measure
of brain stem
Auditory brain stem responses have certain advantages for the eval¬ uation of the anatomical basis of neu¬ rological disease over the more classic cortical evoked responses. Cortical evoked responses depend in part on levels of attention, arousal, and ex¬ pectation, while auditory brain stem responses are not affected by these variables.4-5 Furthermore, latency and amplitude can be rigorously defined in the brain stem responses, whereas these measures are variable with cor¬ tical evoked responses. A major technical limitation in recording auditory brain stem re¬ sponses relates to their small-ampli-
tude and high-frequency components. Both of these factors can result in the unwanted detection of artifacts.
However,
that
our
experience suggests
skilled EEG technician can lo¬ cate and eliminate the source of these artifacts in the same manner as when recording the EEG. Auditory brain stem responses of¬ fer a new method of objective mea¬ surement of the deep structures of the brain that can complement the clinical evaluation. Furthermore, the concept of far-field recordings raises the possibility that measures of activ¬ ity arising in other sensory or motor pathways traversing the brain stem can also be developed. a
This investigation was supported in part by grant PHS/NS 11876-01 from the National Insti¬
Neurological Diseases and Stroke. Keith Manahan gave technical assistance.
tute of
References 1. Jewett DL: Volume conducted potentials in response to auditory stimuli as detected by aver¬ aging in the cat. Electroencephalogr Clin Neu¬ rophysiol 28:609-618, 1970. 2. Jewett DL, Romano MN, Williston JS: Hu¬ man auditory evoked potentials: Possible brain¬ stem components detected on the scalp. Science 167:1517-1518, 1970. 3. Jewett DL, Williston JS: Auditory evoked far-fields averaged from the scalp of humans. Brain 94:681-696, 1971. 4. Picton TW, Hillyard SA, Krausz HI, et al: Human auditory evoked potentials: I. Evaluation
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8. Liberman A, Sohmer H, Szabo G: Cochlear audiometry (electrocochleography) during the neonatal period. Dev Med Child Neurol 15:8-13,
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