International Jounal of Pediatric Otorhinolaryngology, @ Elsevier/North-Holland Biomedical Press
1 (1979)
255-264
255
AUDITORY BRAIN STEM RESPONSES OF KERNICTERUS INFANTS
KIMITAKA KAGA, EIJI KITAZUMI and KAZUO KODAMA Department of Otolaryngology, Teikyo University School of Medicine, Kaga, 2-1 l-1, Itabashi-ku, Tokyo 173, and (E.K. and K. Kod.) Department of Pediatrics, Tokyo Seishi Ryogoen, Komone, l-l-10, Itabashi-ku, Tokyo 170 (Japan) (Received August 28th, 1979) (Accepted October lst, 1979)
SUMMARY
Auditory brainstem evoked responses ( ABRs) and behavioral audiometry in 25 infants with kernicterus were studied to determine the level of the lesion causing their hearing disorders. ABR thresholds, peak latencies of wave I and V, and interwave latency of wave V-I were measured; behavioral audiometric thresholds were determined through conditioned orientation reflex audiometry (COR). Eighty-eight per cent of infants with kernicterus who showed ABR threshold elevation with respect to age-matched normals, were found to show ABR abnormalities associated with peripheral hearing loss, and 84% of these were found to have COR threshold elevation. The ABR abnormalities were threshold elevation of wave V, prolonged latency of wave I and V, and the absence of ABRs. However, no brainstem lesion pattern was found in our cases. Our results suggested that at least some lesions which produce hearing disorders in kemicterus occur in the cochlea or auditory nerve.
INTRODUCTION
Kernicterus is caused by serious neonatal jaundice arising from fetalKemicterus patients usually develop maternal blood incompatibility. extrapyramidal motor signs such as choreoathetosis [ 6,17,19]. Pathological studies reveal that besides the basal ganglia there can be cerebellar and brainstem involvement as well [13,17]. The brainstem symptomatology includes impaired vertical gaze [17,19]. The critical bilirubin level for auditory involvement seems to be about 20 mg% where several percent of the patients will develop hearing difficulties [ 141. Although the association of athetosis and auditory dysfunction in kemicterus has been known more than three decades [9], the identification of the
256
lesion location has remained problematic. Currently it is believed that either the cochlea [1,7,12,16,18,20], the brainstem [2,5,8,10,13,17], or both, are lesion sites [23]. There are a variety of reasons to account for the difficulty in establishing an auditory lesion location for kernicterus of infants and children. One is that hearing involvement itself seems to be a rather variable component of kernicterus. Another reason is that until recently there have been no reliable and objective means of testing hearing in infants - especially infants with psychomotor dysfunctions. The auditory brainstem response (ABR) could provide a way to overcome the hearing measurement problem in kernicterus infants. This response consists of 5-7 vertex positive waves, each believed to come from different levels of the auditory pathway from the cochlea to inferior colliculus [3,15]. The problem of dissociating peripheral from central pathology can be accomplished by determining which wave in this series in the first to show abnormalities. This dissociation is the aim of the present study. SUBJECTS
AND METHODS
Subjects Con tro1group There was a total of 112 normal subjects consisting of 78 infants (l-18 months), 24 children (2-5 years) and 10 adults (18-22 years). Each month and age group consisted of 5 or 6 subjects. Kernicterus group Twenty-five infants and children (ranging in age from 11 months to 5 years) with kemicterus, mainly due to ABO incompatibility, were studied. For treatment of neonate jaundice, exchange transfusion for 15 cases and phototherapy for 5 cases were performed, but others were not treated. Neurologically, 23 cases developed cerebral palsy of the athetosis type and one case showed spastic rigidity. Only one case did not develop cerebral palsy. Methods For the purpose of investigating auditory dysfunction in kemicterus, both behavioral audiometry and auditory brainstem response audiometry were performed. Behavioral audiometry (1) Control group. Appropriate tests of conventional behavioral audiometry for each age group were chosen because of differences in development. The following tests were employed. (a) Neonates to 3 months. The behavioral threshold for 500,1000,2000
257
and 4000 Hz tones was determined by taking the lowest threshold for eliciting either auropalpebral reflex, startle reflex and the Moro reflex for each frequency [ 251. (b) 4 months to 2 years. Conditioned orientation reflex audiometry [ 241. The child’s orientation responses to auditory stimuli, moving their head or eyes toward one of two sound sources are reinforced by illuminating toy animals placed near the source producing the stimulus. An estimate of hearing sensitivity can be obtained by varying the intensity of the pure tones with subsequent presentations until the lowest level at which the child will respond, is found. (c) 3-4 years. Play audiometry. (d) 5 years to adult. Standard pure tone audiometry. (2) Kernicterus group. Condition orientation reflex audiometry was employed because patients ranged in age from 11 months to 5 years and had motor dysfunction. In both the control and kemicterus groups, mean thresholds of behavioral audiometry were calculated at 1 and 2 kHz for a comparison with ABR thresholds. Auditory brainstem responses audiometry Both control and kemicterus groups were tested in a supine position inside of an electrically shielded and sound attenuating room. Data were recorded with silver disc electrodes from the forehead referenced to the test ear mastoid. The opposite mastoid was grounded. (1) Stimuli. Auditory stimuli were clicks (one cycle of a 3 kHz sine wave) produced by a signal generator (Dana Japan DA-502A) delivered through TDH-39 earphones. Clicks were given monoaurally at intensities up to 85 dB HL. Two thousands clicks were given to the subjects at a rate of 10 clicks/set at each intensity level tested. (2) Procedure. Recordings were made at each intensity level beginning with the high intensities and then successively reducing the level. Both ears were tested. Replicate records were made to assess reliability. During the recording sessions, the patient was usually sedated with trichloryl chloride. However, the EEG was continuously monitored for movement artifacts. When they occurred, recording was interrupted. (3) Recording. ABR data were differentially amplified (Nihon-Kohden RB-5; time constant 0.003 set; high-cut filter 1 kHz). The amplified data were averaged and displayed by an on-line computer (Nihon-Kohden ATAC201) and graphically recorded on an XY plotter. (4) Thresholds and peak latencies measurement. ABR thresholds were estimated by wave V. The peak latencies of wave I and wave V were measured at 85 dB HL and interwave latency between wave I and V was also measured. When peak latencies did not replicate, the intensity was considered subthreshold.
258 RESULTS
Control group The threshold changes-age function from behavioral audiometry is shown in Fig. 1 (open circle and solid line) and that from ABR audiometry is illustrated in Fig. 2 (black circle and dotted line). Mean peak latencies of wave I, wave V and mean interwave latencies of wave V-I are summarized in Table I. Kernic terus group (1) Thresholds of behavioral audiometry Behavioral thresholds of the 25 patients (in Table II) are plotted with those of normal infants and adults in Fig. 1. Four groups of patients were constructed: (A) normal threshold group (O-20 dB) (Nos. 2,11, 12,15); (B) mild threshold elevation group (20-60 dB) (Nos. 3, 9, 14, 17, 18, 19, 22, 23, 25); (C) severe threshold elevation group (above 60 dB-95 dB) (Nos. 1, 4, 5, 6, 8, 10, 13, 16, 21); and (D) most severe threshold elevation group (above 95 dB), two cases (Nos. 7, 20). Over all groups 84% of the patients showed threshold elevation. (2) Thresholds of ABRs, peak latencies of wave I and wave V, and interwave latencies of wave V-I Wave V thresholds of 25 patients are plotted with those of normal infants and adults in Fig. 2; ABR wave forms at 85 dB HL are shown in Fig. 3. For each group determined with ABR audiometry the following observation were noted: (A) normal threshold group (O-20 dB) (Nos. 2, 22). The wave V latencies, the wave V-I interwave latencies, and the configuration of TABLE
I
IN CONTROL GROUP, MEANS AND STANDARD V PEAK LATENCIES AND WAVE V-I INTERWAVE Peak latency
DEVIATIONS LATENCIES
OF WAVE
I, WAVE
Age
@=ec)
Month 1
2
3
4
5
6
7
8
Wave I
X S.D.
1.61 0.08
1.61 0.10
1.59 0.20
1.49 0.12
1.48 0.08
1.47 0.09
1.39 0.08
1.42 0.06
Wave V
X S.D.
6.65 0.37
6.48 0.35
6.53 0.21
6.37 0.23
6.35 0.15
6.06 0.24
6.10 0.16
5.94 0.20
Wave V-I
X S.D.
5.04 0.32
4.87 0.34
4.94 0.15
4.88 0.21
4.87 0.14
4.59 0.25
4.71 0.12
4.52 0.13
259 YEAR
MONTH 1234567~g101112..1.52345
,.ACUT.
Fig. 1. Behavioral audiometry thresholds of the 25 kemicterus patients (open squares) are plotted with those of normal infants and adults which appear as open circles and solid lines. The thresholds are categorized into 4 groups: (A) normal threshold group (O-20 dB); (B) mild threshold elevation group (20-60 dB); (C) severe threshold elevation group (above 60 dB and below 95 dB); and (D) most severe threshold elevation group (above 95 dB).
those were normal; (B) mild threshold elevation group (20-60 dB) (Nos. 1, 9, 11-15, 17-19, 23). In the case of No. 15, wave V at 85 dB HL showed normal latencies but in other cases, prolonged latencies of wave V and wave I were found. The wave V-I interwave latencies in 13 and 15, of which wave I was present, were within the normal range; (C) severe threshold elevation group (60-85 dB) (Nos. 3, 8, 10, 24). All cases showed greatly prolonged latencies of wave V with no appearance of wave I; and (D) most severe threshold elevation group (above 85 dB) (Nos. 4-7, 16, 20, 21, 25). No components of ABRs were observed in these cases.
Adult Year 9
10
11
12
1.5
2
3
4
5
1.36 0.07
1.46 0.02
1.44 0.05
1.42 0.06
1.41 0.09
1.41 0.04
1.45 0.04
1.41 0.07
1.39 0.09
1.39 0.07
6.00 0.35
6.12 0.15
5.94 0.25
5.93 0.10
5.92 0.23
5.57 0.12
5.66 0.08
5.43 0.10
5.49 0.15
5.42 0.25
4.64
4.66 0.2
4.5 0.35
4.51 0.13
4.51 0.19
4.16 0.10
4.21 0.11
4.02 0.14
4.12 0.16
4.03 0.31
0.38
Age, sex
9mM 1lmM 11 mM 1ylmM ly2mM ly3mM ly4mM ly5mM ly6mM 1yllmM 2yOmM 2y4mM 2y4mM 2y4mM 2y6mF 2y6mF 2y7mM 2y7mF 2y8mF 3ylmF 3y8mM 3yllmM 4ylOmF 5yllmF 5yllmM
No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
A&et&is No sign Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis
Athetosis Athetosis Athetosis Athetosis
Type of cerebral palsy
90 45 70 95 75 80 95 80 50 90 35 25 70 50 30 90 45 50 50 95 80 50 50 60 35
dB dB dB dB dB dB dB< dB dB dB dB dB dB dB dB dB dB dB dB dB< dB dB dB dB dB
COR threshold
- = absence of wave I or V peak latencies and wave V-I
85 25 85 85< 85< 85: 85~ 85 75 85 85 55 55 45 45 85~ 55 75 85 85~ 85< 15 75 85 85~
R dB
ABR threshold
75 25 85 85< 85< 85< 85~ 85~ 75 85< 55 45 45 45 55 85~ 55 75 75 85< 85~ 15 65 85 85~
L dB
;I;
(-) (-) (-) (-) 1.73 (-) 1.55 (-) (-) (-) (-) (-) (-) 1.59 (-)
;I;
1.55 (-) (-) (-) (-)
t-1
Wave I
5.91 5.91 7.45 (-)
;z;
(-) 4.32
;I;
I-; 4.09 (-) 4.0 (-) (-) (-)
;I;
(-)
Is;
‘(1; 7.00 6.57 7.09 6.82 5.71 5.82 5.64 5.55 (-) 5.9 7.00 6.36
4.27 (-) (-) (-)
t-1
Wave I-V
7.18 5.82 7.64 (-) (-)
Wave V
ABR latency (msec)
interwave latencies
Phototherapy No treatment Exchange transfusion Exchange transfusion Exchange transfusion Exchange transfusion Exchange transfusion Phototherapy Exchange transfusion No treatment Exchange transfusion Phototherapy Phototherapy Phototherapy Exchange transfusion Exchange transfusion Exchange transfusion Exchange transfusion No treatment Exchange transfusion Exchange transfusion No treatment No treatment Exchange transfusion Exchange transfusion
Treatment
IN INFANTS WITH KERNICTERUS, AGE, TYPES OF CEREBRAL PALSY, BEHAVIORAL AUDIOMETRY THRESHOLD, ARR..c .-___ ERI. THRESHOLDS, WAVE I, WAVE V LATENCY, WAVE V-I INTERWAVE LATENCIES AND KINDS OF TREATMENT FOR S__._ OUS NEONATE JAUNDICE ARE SUMMARIZED.
TABLE II
o
%i
263 MONTH 1234dT789101112,.1.52345
YEAR ,.ADULT
0 10 20 30 40
). 4. *
4, +
4. f. .?.--Is
) t
dB50 60 70 80 90 100
Fig. 2. Black squares indicating ABR thresholds of kernicterus patients are plotted with those of normal infants and adults, which are shown with black circles and dotted lines.
These ABR data revealed that wave V threshold elevation occurred in 88% of the cases, among which about 12% showed normal wave forms at 85 dB HL but others showed the abnormal configurations, with prolonged latencies of waves I and V, prolonged latency of wave V and no appearance of wave I,
A: NORMAL HEARING (D-2068)
6: MODERATE HEARING LOSS
(20-SOdB)
c: SEVERE HEARING LOSS (5045dB)
0: MOST SEVERE HEARING LOSS (Abovc85dB)
Fig. 3. ABRs of 25 kernicterus cases at 85 dB HL, which are categorized into 4 groups: (A) normal threshold group (O-20 dB); (B) mild threshold elevation group (20-60 dB); (C) severe threshold elevation group (60-85 dB); and (D) most severe threshold elevation group (above 85 dB).
262
or the absence of all ABR components. In all cases with wave I and wave V at 85 dB HL, wave V-I peak intervals were within the normal range and no brainstem lesion pattern of ABRs was observed. DISCUSSION
Our data indicate that kernicterus children who suffer from hearing impairment are likely to have peripheral auditory lesions. In our patients (except for two) wave I, which is primarily an auditory nerve response [3,15], was either delayed or absent altogether. This finding is positive evidence that the auditory pathology was outside the brainstem in either the cochlea or auditory nerve. A number of reports support these results [4,21,22,26]. Some audiometric studies have reported positive evidence for sensorineural hearing losses in cases of kernicterus [1,7,12,14,20]. Recruitment and temporary threshold shifts [ 1,7], both of which are signs of peripheral involvement, have also been associated with kemicterus. Cochlear pathology has been discovered as well. Keleman [16] observed a collapsed cochlear duct with fibrinosis in a 3dayold kemicterus infant. This infant showed no brain abnormalities. The present study cannot rule out the possibility of brainstem pathology. The fact that V-I interwave latency was within normal limits in our patients supports the claim that the brainstem section of the auditory pathway was functioning normally. In addition, the ABR pattern usually associated with brainstem involvement (i.e. normal wave I and abnormal later components) was never observed. These negative findings do not preclude the possibility that along with peripheral pathology there was accompanying brainstem damage. The pathological peripheral responses could mask brainstem abnormalities. Histological findings suggest that the brainstem could well be involved in these hearing losses. Gerrard [8] observed destruction of ventral and dorsal cochlear nuclei in a kemicterus patient, for example. Cortical damage may also be a component of deafness associated with kernicterus. Cortical involvement could be mainfested as cortical deafness, auditory agnosia or receptive aphasia [10,11,19]. Since the ABR cannot be used to assess cortical function, the present data cannot resolve this issue. However, the ABR might be useful in ruling out peripheral deafness as a diagnostic possibility. The conclusion that the deafness of kernicterus is mainly peripheral gives hope that early detection and treatment would prevent later speech impairments. In this respect, the ABR is well-suited as a means of early detection. Not only is the ABR a completely objective measure, but also it has been found to be a highly reliable test. For cases of suspected kernicterus in infants the ABR is perhaps the simplest and so the best way of assessing auditory involvement.
263 ACKNOWLEDGEMENTS
We thank Dr. R. Hink for reading and criticizing the paper. We also thank Miss K. Shimodaira and Y. Kaneko for their assistance. REFERENCES
5 6
7 8 9 10 11
12 13
14
15
16 17 18 19
Blakeley, R.W., Erythrohlastosis and perceptive hearing loss: response of athetoids to tests of cochlear function, J. Speech Hear. Res., 1 (1959) 5-15. Carhart, R., Probable mechanisms underlying kernicteric hearing loss, Acta otolaryng. (Stockh.), Suppl. 221, 1967. Buchwald, J.S. and Huang, C., Far field acoustic response: origins in the cat, Science, 189 (1975) 282-284. Coats, A.C. and Martin, J.L., Human auditory nerve action potentials and brain stem evoked responses: effects of audiogram shape and lesion location, Arch. Otolaryng., 103 (1977) 605-622. Dublin, W., Neurological lesions in erythroblastosis fetalis in relation to nuclear deafness, Amer. J. clin, Pathol., 21 (1951) 935-938. Farmer, T.W., Disorders of basal ganglia, cerebellum, brain stem and cranial nerves. In R.W. Farmer (Ed.), Pediatric Neurology, Harper and Row, Hager&own, 1975, pp. 390-424. Flottorp, G., Morley, D.E. and Skatvedt, M., The localization of hearing impairment in athetoids, Acta otolayng. (Stockh.), 48 (1957) 404-414. Gerrard, T.W., Kernicterus, Brain, 75 (1952) 526-570. Goodhill, V., Nuclear deafness and the nerve deaf child: the importance of the Rh factor, Trans. Amer. Acad. Ophthal. Otolaryng., 54 (1950) 671-687. Goodhill, V., The child: deaf or “aphasic”?: I. Clinical pathological aspects of kernicteric nuclear deafness, J. Speech Hear., Dis., 21 (1956) 407-410. Hardy, W.G., Auditory deficits of the kernicterus child. In C.A. Swinyard (Ed.), Kernicterus and Its importance in Cerebral Palsy, Charles C Thomas, Springfield, 1962, pp. 255-266. Hervei, S., Bodlnszky, H., Miriszlai, E. and Csapo, S., Untersuchungen der Gel&- und Vestibular funktion nach Icterus gravis, Mschr. Kinderheilk., 125 (1977) 168-170. Haymaker, W., Margoles, C., Pentschew, A., Jacob, H., Lindenberg, R., Arrow, L.S., Stochdorph, 0. and Stowens, D., Pathology of kernicterus and posticteric encephalopathy. in C.A. Swinyard (Ed.), Kernicterus and Its Importance in Cerebral Palsy, Charles C. Thomas, Springfield, 1962, pp. 21-228. Hyman, C.B., Keaster, J., Hanson, V., Harris, I., Sedgwick, R., Wursten, H. and Wright, A.R., CNS abnormalities after neonatal hemolytic disease or hyperbilirubinemia , Amer. J. Dis. Child., 117 (1969) 395-405. Jewett, D.L., Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat, Electroenceph. clin. Neurophysiol., 28 (1970) 609-618. Kelemen, G., Erythroblastosis fetalis. Pathologic report of the hearing organs of a newborn infant, Arch. Otolaryng., 63 (1956) 392-398. Larroche, J. Cl., Kernicterus. In P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 6, North-Holland, Amsterdam, 1969, pp. 491-515. Markle, D.M. and M.H. Miller, Nature of deafness in athetoid cerebral palsy, Arch. Otolaryng., 78 (1963) 794-796. Menkes, J.H., Toxic disorders and neurologic manifestations of diseases arising outside the nervous system. In J.S. Menkes (Ed.), Textbook of Child Neurology, Lea and Febiger, Philadelphia, 1974, pp. 339-379.
264 20 Schuknecht, H.F., Deafness caused by noxious prenatal influences. In H.F. Schuknecht (Ed.), Pathology of the Ear, Harvard University Press, Cambridge, 1974, pp. 189-183. 21 Starr, A. and Achor, L.J., Auditory brain stem responses in neurological disease, Arch. Neurol. (Chic), 32 (1975) 761-768. 22 Stockard, M.M. and Rossiter, V.S., Clinical and pathologic correlates of brain stem auditory response abnormalities, Neurology (Minneap.), 27 (1977) 316-325. 23 Suga, F., Kiuchi, M., Hisanaga, S. and Takashima, Y., Kernicterus and deafness, Otologia (Fukuoka), 20 (1974) 22-26. 24 Suzuki, T. and Ogiba, Y., Conditioned orientation reflex audiometry. Arch. Otolaryng., 74 (1961) 192-198. 25 Wedenberg, E., Objective audiometry tests on non-cooperative children, Acta otolaryng., (Stockh.), Suppl. 175 (1963). 26 Yamada, O., Kodera, K., Yagi, T. and Yamane, H., Cochlear process affecting wave V latency of the auditory evoked response: a study of patients with sensory hearing loss, Stand. Audiol., 8 (1979) 67-70.
1 (1979)
255-264
255
AUDITORY BRAIN STEM RESPONSES OF KERNICTERUS INFANTS
KIMITAKA KAGA, EIJI KITAZUMI and KAZUO KODAMA Department of Otolaryngology, Teikyo University School of Medicine, Kaga, 2-1 l-1, Itabashi-ku, Tokyo 173, and (E.K. and K. Kod.) Department of Pediatrics, Tokyo Seishi Ryogoen, Komone, l-l-10, Itabashi-ku, Tokyo 170 (Japan) (Received August 28th, 1979) (Accepted October lst, 1979)
SUMMARY
Auditory brainstem evoked responses ( ABRs) and behavioral audiometry in 25 infants with kernicterus were studied to determine the level of the lesion causing their hearing disorders. ABR thresholds, peak latencies of wave I and V, and interwave latency of wave V-I were measured; behavioral audiometric thresholds were determined through conditioned orientation reflex audiometry (COR). Eighty-eight per cent of infants with kernicterus who showed ABR threshold elevation with respect to age-matched normals, were found to show ABR abnormalities associated with peripheral hearing loss, and 84% of these were found to have COR threshold elevation. The ABR abnormalities were threshold elevation of wave V, prolonged latency of wave I and V, and the absence of ABRs. However, no brainstem lesion pattern was found in our cases. Our results suggested that at least some lesions which produce hearing disorders in kemicterus occur in the cochlea or auditory nerve.
INTRODUCTION
Kernicterus is caused by serious neonatal jaundice arising from fetalKemicterus patients usually develop maternal blood incompatibility. extrapyramidal motor signs such as choreoathetosis [ 6,17,19]. Pathological studies reveal that besides the basal ganglia there can be cerebellar and brainstem involvement as well [13,17]. The brainstem symptomatology includes impaired vertical gaze [17,19]. The critical bilirubin level for auditory involvement seems to be about 20 mg% where several percent of the patients will develop hearing difficulties [ 141. Although the association of athetosis and auditory dysfunction in kemicterus has been known more than three decades [9], the identification of the
256
lesion location has remained problematic. Currently it is believed that either the cochlea [1,7,12,16,18,20], the brainstem [2,5,8,10,13,17], or both, are lesion sites [23]. There are a variety of reasons to account for the difficulty in establishing an auditory lesion location for kernicterus of infants and children. One is that hearing involvement itself seems to be a rather variable component of kernicterus. Another reason is that until recently there have been no reliable and objective means of testing hearing in infants - especially infants with psychomotor dysfunctions. The auditory brainstem response (ABR) could provide a way to overcome the hearing measurement problem in kernicterus infants. This response consists of 5-7 vertex positive waves, each believed to come from different levels of the auditory pathway from the cochlea to inferior colliculus [3,15]. The problem of dissociating peripheral from central pathology can be accomplished by determining which wave in this series in the first to show abnormalities. This dissociation is the aim of the present study. SUBJECTS
AND METHODS
Subjects Con tro1group There was a total of 112 normal subjects consisting of 78 infants (l-18 months), 24 children (2-5 years) and 10 adults (18-22 years). Each month and age group consisted of 5 or 6 subjects. Kernicterus group Twenty-five infants and children (ranging in age from 11 months to 5 years) with kemicterus, mainly due to ABO incompatibility, were studied. For treatment of neonate jaundice, exchange transfusion for 15 cases and phototherapy for 5 cases were performed, but others were not treated. Neurologically, 23 cases developed cerebral palsy of the athetosis type and one case showed spastic rigidity. Only one case did not develop cerebral palsy. Methods For the purpose of investigating auditory dysfunction in kemicterus, both behavioral audiometry and auditory brainstem response audiometry were performed. Behavioral audiometry (1) Control group. Appropriate tests of conventional behavioral audiometry for each age group were chosen because of differences in development. The following tests were employed. (a) Neonates to 3 months. The behavioral threshold for 500,1000,2000
257
and 4000 Hz tones was determined by taking the lowest threshold for eliciting either auropalpebral reflex, startle reflex and the Moro reflex for each frequency [ 251. (b) 4 months to 2 years. Conditioned orientation reflex audiometry [ 241. The child’s orientation responses to auditory stimuli, moving their head or eyes toward one of two sound sources are reinforced by illuminating toy animals placed near the source producing the stimulus. An estimate of hearing sensitivity can be obtained by varying the intensity of the pure tones with subsequent presentations until the lowest level at which the child will respond, is found. (c) 3-4 years. Play audiometry. (d) 5 years to adult. Standard pure tone audiometry. (2) Kernicterus group. Condition orientation reflex audiometry was employed because patients ranged in age from 11 months to 5 years and had motor dysfunction. In both the control and kemicterus groups, mean thresholds of behavioral audiometry were calculated at 1 and 2 kHz for a comparison with ABR thresholds. Auditory brainstem responses audiometry Both control and kemicterus groups were tested in a supine position inside of an electrically shielded and sound attenuating room. Data were recorded with silver disc electrodes from the forehead referenced to the test ear mastoid. The opposite mastoid was grounded. (1) Stimuli. Auditory stimuli were clicks (one cycle of a 3 kHz sine wave) produced by a signal generator (Dana Japan DA-502A) delivered through TDH-39 earphones. Clicks were given monoaurally at intensities up to 85 dB HL. Two thousands clicks were given to the subjects at a rate of 10 clicks/set at each intensity level tested. (2) Procedure. Recordings were made at each intensity level beginning with the high intensities and then successively reducing the level. Both ears were tested. Replicate records were made to assess reliability. During the recording sessions, the patient was usually sedated with trichloryl chloride. However, the EEG was continuously monitored for movement artifacts. When they occurred, recording was interrupted. (3) Recording. ABR data were differentially amplified (Nihon-Kohden RB-5; time constant 0.003 set; high-cut filter 1 kHz). The amplified data were averaged and displayed by an on-line computer (Nihon-Kohden ATAC201) and graphically recorded on an XY plotter. (4) Thresholds and peak latencies measurement. ABR thresholds were estimated by wave V. The peak latencies of wave I and wave V were measured at 85 dB HL and interwave latency between wave I and V was also measured. When peak latencies did not replicate, the intensity was considered subthreshold.
258 RESULTS
Control group The threshold changes-age function from behavioral audiometry is shown in Fig. 1 (open circle and solid line) and that from ABR audiometry is illustrated in Fig. 2 (black circle and dotted line). Mean peak latencies of wave I, wave V and mean interwave latencies of wave V-I are summarized in Table I. Kernic terus group (1) Thresholds of behavioral audiometry Behavioral thresholds of the 25 patients (in Table II) are plotted with those of normal infants and adults in Fig. 1. Four groups of patients were constructed: (A) normal threshold group (O-20 dB) (Nos. 2,11, 12,15); (B) mild threshold elevation group (20-60 dB) (Nos. 3, 9, 14, 17, 18, 19, 22, 23, 25); (C) severe threshold elevation group (above 60 dB-95 dB) (Nos. 1, 4, 5, 6, 8, 10, 13, 16, 21); and (D) most severe threshold elevation group (above 95 dB), two cases (Nos. 7, 20). Over all groups 84% of the patients showed threshold elevation. (2) Thresholds of ABRs, peak latencies of wave I and wave V, and interwave latencies of wave V-I Wave V thresholds of 25 patients are plotted with those of normal infants and adults in Fig. 2; ABR wave forms at 85 dB HL are shown in Fig. 3. For each group determined with ABR audiometry the following observation were noted: (A) normal threshold group (O-20 dB) (Nos. 2, 22). The wave V latencies, the wave V-I interwave latencies, and the configuration of TABLE
I
IN CONTROL GROUP, MEANS AND STANDARD V PEAK LATENCIES AND WAVE V-I INTERWAVE Peak latency
DEVIATIONS LATENCIES
OF WAVE
I, WAVE
Age
@=ec)
Month 1
2
3
4
5
6
7
8
Wave I
X S.D.
1.61 0.08
1.61 0.10
1.59 0.20
1.49 0.12
1.48 0.08
1.47 0.09
1.39 0.08
1.42 0.06
Wave V
X S.D.
6.65 0.37
6.48 0.35
6.53 0.21
6.37 0.23
6.35 0.15
6.06 0.24
6.10 0.16
5.94 0.20
Wave V-I
X S.D.
5.04 0.32
4.87 0.34
4.94 0.15
4.88 0.21
4.87 0.14
4.59 0.25
4.71 0.12
4.52 0.13
259 YEAR
MONTH 1234567~g101112..1.52345
,.ACUT.
Fig. 1. Behavioral audiometry thresholds of the 25 kemicterus patients (open squares) are plotted with those of normal infants and adults which appear as open circles and solid lines. The thresholds are categorized into 4 groups: (A) normal threshold group (O-20 dB); (B) mild threshold elevation group (20-60 dB); (C) severe threshold elevation group (above 60 dB and below 95 dB); and (D) most severe threshold elevation group (above 95 dB).
those were normal; (B) mild threshold elevation group (20-60 dB) (Nos. 1, 9, 11-15, 17-19, 23). In the case of No. 15, wave V at 85 dB HL showed normal latencies but in other cases, prolonged latencies of wave V and wave I were found. The wave V-I interwave latencies in 13 and 15, of which wave I was present, were within the normal range; (C) severe threshold elevation group (60-85 dB) (Nos. 3, 8, 10, 24). All cases showed greatly prolonged latencies of wave V with no appearance of wave I; and (D) most severe threshold elevation group (above 85 dB) (Nos. 4-7, 16, 20, 21, 25). No components of ABRs were observed in these cases.
Adult Year 9
10
11
12
1.5
2
3
4
5
1.36 0.07
1.46 0.02
1.44 0.05
1.42 0.06
1.41 0.09
1.41 0.04
1.45 0.04
1.41 0.07
1.39 0.09
1.39 0.07
6.00 0.35
6.12 0.15
5.94 0.25
5.93 0.10
5.92 0.23
5.57 0.12
5.66 0.08
5.43 0.10
5.49 0.15
5.42 0.25
4.64
4.66 0.2
4.5 0.35
4.51 0.13
4.51 0.19
4.16 0.10
4.21 0.11
4.02 0.14
4.12 0.16
4.03 0.31
0.38
Age, sex
9mM 1lmM 11 mM 1ylmM ly2mM ly3mM ly4mM ly5mM ly6mM 1yllmM 2yOmM 2y4mM 2y4mM 2y4mM 2y6mF 2y6mF 2y7mM 2y7mF 2y8mF 3ylmF 3y8mM 3yllmM 4ylOmF 5yllmF 5yllmM
No.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
A&et&is No sign Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis Athetosis
Athetosis Athetosis Athetosis Athetosis
Type of cerebral palsy
90 45 70 95 75 80 95 80 50 90 35 25 70 50 30 90 45 50 50 95 80 50 50 60 35
dB dB dB dB dB dB dB< dB dB dB dB dB dB dB dB dB dB dB dB dB< dB dB dB dB dB
COR threshold
- = absence of wave I or V peak latencies and wave V-I
85 25 85 85< 85< 85: 85~ 85 75 85 85 55 55 45 45 85~ 55 75 85 85~ 85< 15 75 85 85~
R dB
ABR threshold
75 25 85 85< 85< 85< 85~ 85~ 75 85< 55 45 45 45 55 85~ 55 75 75 85< 85~ 15 65 85 85~
L dB
;I;
(-) (-) (-) (-) 1.73 (-) 1.55 (-) (-) (-) (-) (-) (-) 1.59 (-)
;I;
1.55 (-) (-) (-) (-)
t-1
Wave I
5.91 5.91 7.45 (-)
;z;
(-) 4.32
;I;
I-; 4.09 (-) 4.0 (-) (-) (-)
;I;
(-)
Is;
‘(1; 7.00 6.57 7.09 6.82 5.71 5.82 5.64 5.55 (-) 5.9 7.00 6.36
4.27 (-) (-) (-)
t-1
Wave I-V
7.18 5.82 7.64 (-) (-)
Wave V
ABR latency (msec)
interwave latencies
Phototherapy No treatment Exchange transfusion Exchange transfusion Exchange transfusion Exchange transfusion Exchange transfusion Phototherapy Exchange transfusion No treatment Exchange transfusion Phototherapy Phototherapy Phototherapy Exchange transfusion Exchange transfusion Exchange transfusion Exchange transfusion No treatment Exchange transfusion Exchange transfusion No treatment No treatment Exchange transfusion Exchange transfusion
Treatment
IN INFANTS WITH KERNICTERUS, AGE, TYPES OF CEREBRAL PALSY, BEHAVIORAL AUDIOMETRY THRESHOLD, ARR..c .-___ ERI. THRESHOLDS, WAVE I, WAVE V LATENCY, WAVE V-I INTERWAVE LATENCIES AND KINDS OF TREATMENT FOR S__._ OUS NEONATE JAUNDICE ARE SUMMARIZED.
TABLE II
o
%i
263 MONTH 1234dT789101112,.1.52345
YEAR ,.ADULT
0 10 20 30 40
). 4. *
4, +
4. f. .?.--Is
) t
dB50 60 70 80 90 100
Fig. 2. Black squares indicating ABR thresholds of kernicterus patients are plotted with those of normal infants and adults, which are shown with black circles and dotted lines.
These ABR data revealed that wave V threshold elevation occurred in 88% of the cases, among which about 12% showed normal wave forms at 85 dB HL but others showed the abnormal configurations, with prolonged latencies of waves I and V, prolonged latency of wave V and no appearance of wave I,
A: NORMAL HEARING (D-2068)
6: MODERATE HEARING LOSS
(20-SOdB)
c: SEVERE HEARING LOSS (5045dB)
0: MOST SEVERE HEARING LOSS (Abovc85dB)
Fig. 3. ABRs of 25 kernicterus cases at 85 dB HL, which are categorized into 4 groups: (A) normal threshold group (O-20 dB); (B) mild threshold elevation group (20-60 dB); (C) severe threshold elevation group (60-85 dB); and (D) most severe threshold elevation group (above 85 dB).
262
or the absence of all ABR components. In all cases with wave I and wave V at 85 dB HL, wave V-I peak intervals were within the normal range and no brainstem lesion pattern of ABRs was observed. DISCUSSION
Our data indicate that kernicterus children who suffer from hearing impairment are likely to have peripheral auditory lesions. In our patients (except for two) wave I, which is primarily an auditory nerve response [3,15], was either delayed or absent altogether. This finding is positive evidence that the auditory pathology was outside the brainstem in either the cochlea or auditory nerve. A number of reports support these results [4,21,22,26]. Some audiometric studies have reported positive evidence for sensorineural hearing losses in cases of kernicterus [1,7,12,14,20]. Recruitment and temporary threshold shifts [ 1,7], both of which are signs of peripheral involvement, have also been associated with kemicterus. Cochlear pathology has been discovered as well. Keleman [16] observed a collapsed cochlear duct with fibrinosis in a 3dayold kemicterus infant. This infant showed no brain abnormalities. The present study cannot rule out the possibility of brainstem pathology. The fact that V-I interwave latency was within normal limits in our patients supports the claim that the brainstem section of the auditory pathway was functioning normally. In addition, the ABR pattern usually associated with brainstem involvement (i.e. normal wave I and abnormal later components) was never observed. These negative findings do not preclude the possibility that along with peripheral pathology there was accompanying brainstem damage. The pathological peripheral responses could mask brainstem abnormalities. Histological findings suggest that the brainstem could well be involved in these hearing losses. Gerrard [8] observed destruction of ventral and dorsal cochlear nuclei in a kemicterus patient, for example. Cortical damage may also be a component of deafness associated with kernicterus. Cortical involvement could be mainfested as cortical deafness, auditory agnosia or receptive aphasia [10,11,19]. Since the ABR cannot be used to assess cortical function, the present data cannot resolve this issue. However, the ABR might be useful in ruling out peripheral deafness as a diagnostic possibility. The conclusion that the deafness of kernicterus is mainly peripheral gives hope that early detection and treatment would prevent later speech impairments. In this respect, the ABR is well-suited as a means of early detection. Not only is the ABR a completely objective measure, but also it has been found to be a highly reliable test. For cases of suspected kernicterus in infants the ABR is perhaps the simplest and so the best way of assessing auditory involvement.
263 ACKNOWLEDGEMENTS
We thank Dr. R. Hink for reading and criticizing the paper. We also thank Miss K. Shimodaira and Y. Kaneko for their assistance. REFERENCES
5 6
7 8 9 10 11
12 13
14
15
16 17 18 19
Blakeley, R.W., Erythrohlastosis and perceptive hearing loss: response of athetoids to tests of cochlear function, J. Speech Hear. Res., 1 (1959) 5-15. Carhart, R., Probable mechanisms underlying kernicteric hearing loss, Acta otolaryng. (Stockh.), Suppl. 221, 1967. Buchwald, J.S. and Huang, C., Far field acoustic response: origins in the cat, Science, 189 (1975) 282-284. Coats, A.C. and Martin, J.L., Human auditory nerve action potentials and brain stem evoked responses: effects of audiogram shape and lesion location, Arch. Otolaryng., 103 (1977) 605-622. Dublin, W., Neurological lesions in erythroblastosis fetalis in relation to nuclear deafness, Amer. J. clin, Pathol., 21 (1951) 935-938. Farmer, T.W., Disorders of basal ganglia, cerebellum, brain stem and cranial nerves. In R.W. Farmer (Ed.), Pediatric Neurology, Harper and Row, Hager&own, 1975, pp. 390-424. Flottorp, G., Morley, D.E. and Skatvedt, M., The localization of hearing impairment in athetoids, Acta otolayng. (Stockh.), 48 (1957) 404-414. Gerrard, T.W., Kernicterus, Brain, 75 (1952) 526-570. Goodhill, V., Nuclear deafness and the nerve deaf child: the importance of the Rh factor, Trans. Amer. Acad. Ophthal. Otolaryng., 54 (1950) 671-687. Goodhill, V., The child: deaf or “aphasic”?: I. Clinical pathological aspects of kernicteric nuclear deafness, J. Speech Hear., Dis., 21 (1956) 407-410. Hardy, W.G., Auditory deficits of the kernicterus child. In C.A. Swinyard (Ed.), Kernicterus and Its importance in Cerebral Palsy, Charles C Thomas, Springfield, 1962, pp. 255-266. Hervei, S., Bodlnszky, H., Miriszlai, E. and Csapo, S., Untersuchungen der Gel&- und Vestibular funktion nach Icterus gravis, Mschr. Kinderheilk., 125 (1977) 168-170. Haymaker, W., Margoles, C., Pentschew, A., Jacob, H., Lindenberg, R., Arrow, L.S., Stochdorph, 0. and Stowens, D., Pathology of kernicterus and posticteric encephalopathy. in C.A. Swinyard (Ed.), Kernicterus and Its Importance in Cerebral Palsy, Charles C. Thomas, Springfield, 1962, pp. 21-228. Hyman, C.B., Keaster, J., Hanson, V., Harris, I., Sedgwick, R., Wursten, H. and Wright, A.R., CNS abnormalities after neonatal hemolytic disease or hyperbilirubinemia , Amer. J. Dis. Child., 117 (1969) 395-405. Jewett, D.L., Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat, Electroenceph. clin. Neurophysiol., 28 (1970) 609-618. Kelemen, G., Erythroblastosis fetalis. Pathologic report of the hearing organs of a newborn infant, Arch. Otolaryng., 63 (1956) 392-398. Larroche, J. Cl., Kernicterus. In P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 6, North-Holland, Amsterdam, 1969, pp. 491-515. Markle, D.M. and M.H. Miller, Nature of deafness in athetoid cerebral palsy, Arch. Otolaryng., 78 (1963) 794-796. Menkes, J.H., Toxic disorders and neurologic manifestations of diseases arising outside the nervous system. In J.S. Menkes (Ed.), Textbook of Child Neurology, Lea and Febiger, Philadelphia, 1974, pp. 339-379.
264 20 Schuknecht, H.F., Deafness caused by noxious prenatal influences. In H.F. Schuknecht (Ed.), Pathology of the Ear, Harvard University Press, Cambridge, 1974, pp. 189-183. 21 Starr, A. and Achor, L.J., Auditory brain stem responses in neurological disease, Arch. Neurol. (Chic), 32 (1975) 761-768. 22 Stockard, M.M. and Rossiter, V.S., Clinical and pathologic correlates of brain stem auditory response abnormalities, Neurology (Minneap.), 27 (1977) 316-325. 23 Suga, F., Kiuchi, M., Hisanaga, S. and Takashima, Y., Kernicterus and deafness, Otologia (Fukuoka), 20 (1974) 22-26. 24 Suzuki, T. and Ogiba, Y., Conditioned orientation reflex audiometry. Arch. Otolaryng., 74 (1961) 192-198. 25 Wedenberg, E., Objective audiometry tests on non-cooperative children, Acta otolaryng., (Stockh.), Suppl. 175 (1963). 26 Yamada, O., Kodera, K., Yagi, T. and Yamane, H., Cochlear process affecting wave V latency of the auditory evoked response: a study of patients with sensory hearing loss, Stand. Audiol., 8 (1979) 67-70.
