Long-term effect of perinatal and postnatal asphyxia on developing human auditory brainstem responses: brainstem impairment

INTERNATiOW JOURNALOF

International Journal of Pediatric Otorhinolaryngology 34 (1996) Ill-127

ELSEVIER

Long-term effect of perinatal and postnatal asphyxia on developing human auditory brainstem responses: brainstem impairment Ze D. Jianga,b, Travis S. Tierney” “Department of Physiology, University of Oxford, Parks Rd, OX1 3PT, Oxford, England bDepartment of Child Health, Children’s Hospital, Shanghai Medical University, Shanghai, People’s Republic of China Received 4 April

1995; revision received 10 July 1995; accepted 16 July 1995

Abstract Long-term effect of perinatal and postnatal asphyxia on the developing auditory brainstem was investigated in children, particularly those who exhibited residual neurodevelopmental deficits, by analyzing the central components of brainstem auditory evoked responses (BAER). The major abnormalities in the BAER were a reduction of wave V amplitude, followed by a decrease in V/I amplitude ratio, while abnormalities in interpeak intervals were relatively rare. These findings suggest that asphyxia could result in residual neural dysfunction of the brainstem but does not appear to exert any major long-term effect on neuronal transmission. BAER abnormalities occurred more frequently in the children with residual neurodevelopmental deficits than those without these deficits after perinatal asphyxia. The occurrence of BAER abnormalities was related to the duration as well as the degree of asphyxia. No significant difference was found in the abnormalities of the central BAER components between the children after perinatal asphyxia and those after postnatal asphyxia, suggesting that perinatal and postnatal asphyxia exerts a similar long-term effect on the developing central nervous system.

Keywords: Neurodevelopment; Asphyxia; Children

* Corresponding

Auditory

development;

Brainstem auditory evoked response;

author, Fax.: + 44 1865 272469.

0165.5876/96/$09.50 0 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165.5876(95)OE1261-Z

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1. Introduction Brainstem auditory evoked response (BAER) test has been shown to play a significant role in the assessment of functional status of the brain following neonatal asphyxia and in the management of hypoxic encephalopathy [ 1,5,11,19,30,32,50,53].Shortly after the episode of neonatal asphyxia, the infants often show some abnormalities in the BAER such as prolonged wave latency and interpeak interval, reduced wave amplitude as well as increased response threshold [5,11,19,30,32,53]. Kileny et al. [30] noted that prolonged latency and interpeak interval was common in the asphyxiated neonates [30]. Hecox and Cone [19] reported that among the asphyxiated infants they studied, nearly 15% had prolonged interpeak intervals and 17% had decreased V/I amplitude ratio [19]. Yasuhara et al. [53] described as many as 89% of the asphyxiated neonates, demonstrated some abnormalities in the BAER [53]. Most of the previous studies were carried out shortly after the asphyxia episode. Little information is available with respect to whether there is any long-term effect of asphyxia occurring in early life upon the developing auditory brainstem. Furthermore, whether there is any difference between the long-term effects of perinatal and postnatal asphyxia on neural function of the developing brainstem remains to be investigated. In view of these questions, we examined the BAER in children who suffered perinatal or postnatal asphyxia, in particular those with residual neurodevelopmental deficits. BAER recording was undertaken more than 6 months following the episode of asphyxia. In the preceding report we addressed the long-term effect of asphyxia on peripheral hearing [22]. The present paper is devoted to the long-term effect of asphyxia on the central nervous system, in particular the auditory brainstem, by analyzing central BAER components. The following questions are addressed. Firstly, is there any residual abnormality in the developing auditory brainstem long after the episode of asphyxia? Secondly, if so, do BAER abnormalities occur more frequently in the children with clinically determined residual neurodevelopmental deficits compared to those without the deficits long after perinatal asphyxia? Thirdly, do long-term BAER findings correlate with the degree and duration of perinatal asphyxia? Finally, is there any difference between the long-term effects of severe perinatal and postnatal asphyxia on the developing brainstem in the affected children with residual neurodevelopmental deficits? 2. Subjects and methods 2.1. Subjects

A total of 103 children who suffered perinatal or postnatal asphyxia were studied. The children following perinatal asphyxia were those who had a 1-min Apgar score less than 8 and clinical evidence of perinatal asphyxia, including frequent depression and failure of breathing spontaneously at birth, hypotonia or hypertonia during ensuring hours and signs of hypoxic-ischemic encephalopathy such as pallor, cyanosis, apnoea, slow heart rate, seizure and unresponsiveness to stimulation.

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Peripheral hearing loss is known to affect the measurement of central BAER components, resulting in amplitude reduction and latency prolongation. If there is a high frequency hearing loss I-V interpeak interval could be shortened due to a shift in the relative contributions of different regions of the cochlea to the click response, from the normally dominant high frequency region (2-4 kHz) to lower frequency regions of the cochlea associated with longer latencies [3,8,9,14,49]. In view of these potential effects, detailed analysis of the BAER results were performed only in those children who did not show any evidence of peripheral hearing loss in an effort to avoid these effects and to assessthe central BAER components more accurately. In the pi-eceding paper, we have reported that ten of the 89 children following perinatal asphyxia exhibited residual peripheral hearing loss and none in the 14 children following postnatal asphyxia showed any evidence for peripheral hearing loss [22]. Thus, the remaining 79 children with normal peripheral hearing following perinatal asphyxia and all of the 14 children following postnatal asphyxia were analyzed in this study. A detailed description of the subjects have been given in the preceding report [22]. In brief, the age at the time of testing ranged between 6 months and 6 years (corrected age for gestation if the child was born prematurely) when the episode of asphyxia occurred more than 6 months ago. The gestational ageswere 34-42 weeks in the children following perinatal asphyxia and 38-41 weeks in those following postnatal asphyxia. Subjects were excluded from this study if he or she had a small birth weight for the gestation to preclude any possible influence of intra-uterine growth retardation on the BAER [20,24,28]. None had documented congenital diseases.All of these children had a negative history for hearing loss in their family and no history for administration of ototoxic drugs. We also excluded those who had postnatal disorders or conditions, which could damage the auditory pathways or other central nervous systemsand result in hearing loss and neurodevelopmental deficits, except those produced by, or relevant to, asphyxia. Neurodevelopmental outcome were determined according to clinical neurological examination and developmental screening tests (Denver Developmental Screening Test or DDST and Peabody Picture Vocabulary Test or PPVT). Neurodevelopmental deficits included cerebral palsy (non-progressive disorders of movement and posture) and developmental delay which was determined on the basis of either abnormal results in DDST or an IQ less than 70 in PPVT. Due to the physical handicaps which made the tests inappropriate, children with cerebral palsy did not take these developmental screening tests. In the children following perinatal asphyxia l- and 5-min Apgar scores are given in Table 1. Apgar score was also recorded at lo- and 20-min in some of those who did not achieve a score of 8 or higher at 5-min. Asphyxia was classified as severe (Apgar scores O-3) or mild (Apgar scores 4-7). According to clinically determined neurodevelopmental outcome, the children following perinatal asphyxia were divided into two groups. Perinatal asphyxia group A: children did not exhibit any evidence for neurodevelopmental deficits (n = 45). Based on I-min Apgar scores, 20 suffered severe asphyxia and 25 suffered mild asphyxia. At 5-min, asphyxia was severe in 8 cases, mild in 23 and recovered in the remainder. Perinatal asphyxia

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group B: children exhibited residual neurodevelopmental deficits (n = 34). Twentytwo had cerebral palsy, most being spastic quadriparesis, and the remaining 12 had developmental delay. These children usually suffered a prolonged period of asphyxia based on 20-min Apgar scores and/or clinical signs. Asphyxia was severe in 23 casesand mild in 11 at 1-min. At 5-min there were 20 with severe asphyxia, 11 with mild asphyxia and 3 recovered. In postnatal asphyxia group, there were 14 children who survived severe, prolonged asphyxia and all exhibited residual neurodevelopmental deficits (9 cerebral palsy and 5 developmental delay). The asphyxia occurred between 3 months and 1 year of age. The aetiology included pneumonia with severe hypoxia and respiratory failure (7 cases), aspiration of foreign bodies with severe hypoxia for more than 20 min (4 cases) and drowning (3 cases). One hundred and thirty-eight healthy children, selected from those reported previously [28,29] were used as the normal control group. They were divided into five age groups: 6 and 9 months; and 1, 2-3 and 4-6 years, with each group having 14 to 44 children. 2.2. Recording of the BAER The basic instrumentation and procedures for BAER recording have been described previously [22,26]. In brief, BAER recording was carried out in a sound-isolated and electrically shielded room and with the consent of the parents. Subjects lay supine on a soft bed and were tested during sedated sleep with oral chloral hydrate (40 mg/kg). Three Ag-AgCl disc electrodes were placed respectively, at the highest point of the forehead in the midline ( + ), the earlobe ipsilateral to acoustic stimuli ( - ) and the contralateral earlobe (ground). Rarefaction clicks with 100~,US duration were used as acoustic stimuli. The clicks with a repetition rate of 10/s and intensity of 90-O dB hearing level (HL, relative to the average threshold of 21 normal adults) were delivered monaurally through TDH 39 earphones. The contralateral ear was masked with white noise in an intensity level 40 dB less than that of the ipsilateral click stimuli. The recording signals were preamplified ( x 105), Table 1 Statistical comparison of BAER results between children following mild perinatal asphyxia and those following severe perinatal asphyxia n

BAER results Abnormal

I-min Apgar scores 4-l o-3 5-min Apgar scores 8-10 467 O-3

2

P

2.28

0.20

8.11

0.02

Normal

36

5 (13.9%)

31

43

I2 (27.9%)

31

I7 34 28

2 (I 1.8%) 4 (11.8%) I I (39.3%)

I5 30 I7

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bandpassed between 100 and 2000 Hz and processed by an averaging computer. Brain responses to 1024 clicks were recorded for each run. An automatic artifact rejection was used to reduce the inclusion of high-amplitude muscular activity in the averaged responses.The ongoing filtered EEG and the running averaged BAER were carefully monitored while averaging. Sampling was discontinued whenever there were excessivemuscle artifacts on the monitoring oscilloscope. Analysis of central BAER components were based on those obtained at 70 dB HL clicks. The main BAER measures analyzed included interpeak intervals and wave amplitudes which were determined from the positive peak of a BAER component to the immediately following negative trough [22]. 2.3. Normative criteria and data analysis

The normative criteria for various BAER measures at different ages were defined on the basis of the data obtained from the age-matched normals [27,29]. For I-V interpeak interval, 2.5 standard deviations above the means at various age groups were determined as the normative upper limits [27]. The 5th percentiles of the amplitude values seen in the normals were determined as the lower limits for wave amplitudes [29]. Normative lower limit for V/I amplitude ratio was set as 0.45 and 0.40 for 6 months to less than 2 years and 2 to 6 years respectively. BAER results were compared between various groups using Chi-squared test. Probabilities less than 0.05 were considered significant. 3. Results 3.1. BAER findings and the patterns of‘ abnormal waceforms

In general, the majority of the children who survived asphyxia whether it occurred perinatally or postnatally and whether its degree was mild or severe, presented normal BAER waveforms. Only a small proportion of the children showed some abnormal BAER results. The major abnormality was a reduction of wave V amplitude, followed by a decreasein V/I amplitude ratio and a prolongation of I-V interval. Abnormalities in I-III and III-V intervals, III-V/I-III interval ratio were rare. No significant amplitude reduction was observed in the BAER waves prior to wave V. In perinatal asphyxia group B and postnatal asphyxia group, the I-V, III-V intervals and III-V/I-III interval ratio in most children were greater than the means of the age-matched controls, while the amplitude of wave V and the V/I amplitude ratio tended to be smaller than the medians of age-matched controls [27,29] The raw data of the three major BAER measures, i.e. I-V interval, wave V amplitude and V/I amplitude ratio, in various asphyxia groups are plotted in Figs. 1-3, respectively. The degree of asphyxia mentioned in the following text was based on 1-min Apgdr score, unless stated otherwise. The abnormal BAER results could be categorized into five patterns. Representative recordings are shown in Fig. 4. Patterns A (combined wave V amplitude reduction and V/I amplitude ratio decrease) and B (combined wave V amplitude reduction and/or V/I amplitude ratio decreaseand I-V interval prolongation) were the most frequently seen abnormalities. As a whole, patterns A-E were found in

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0

MILD PERI. A

l

SEVEREPERLA

. .

MILDPERI. B SEVEREPEW. FXTNATAJ.

n

Q :

40

20

0

AGE

60

60

(months)

Fig. I. Distribution of 1-V interval in individual children in various asphyxia groups. The horizontal lines represent the upper limits (mean + 2.5 SD) in the normal controls at different ages (Jiang et al. [27]). Abbreviations: mild perinatal A, children who suffered mild asphyxia in perinatal group A; severe perinatal A, children who suffered severe asphyxia in perinatal group A; mild perinatal B, children who suffered mild asphyxia in perinatal group B; severe perinatal B children who suffered severe asphyxia in perinatal group B; postnatal, children who suffered postnatal asphyxia with residual neurodevelopmental deficits.

eight, eight, three, one and two casesrespectively. Thus, the most frequently seen BAER abnormality was wave V amplitude reduction, often accompanied by decreased V/I amplitude ratio or prolonged 1-V interval. The prevalence of prolonged I-V interval was about half of that of wave V amplitude reduction.

s 2

D.6-

0 . . A ”

MILD PER1.L. A SEVERE PERI. A MILD PERI. B SEVERE PERI. 6 FCS-INATAL o

AGE

.

(months)

Fig. 2. Distribution of wave V amplitude in individual children in various asphyxia groups. The horizontal lines represent the lower limits (5th percentiles) in the normal controls at different ages (Jiang et al. [29]). Abbreviations: as in Fig. I, In general, wave V amplitude in the children with neurodevelopmental deficits tends to be smaller than in those without neurodevelopmental deficits, and the amplitude in the children surviving severe asphyxia tends to be smaller than in those suffering mild asphyxia.

Z.D. Jiang, T.S. Tierne):i Int. J. Pediatr. Otorhinolaryngol.34 (1996)I II-127 0 l

A . *

AGE

117

MILD PERI. A SEVERE PERI. A MILD PEAI. B SEVERE PERI. S PosTNATAL

(months)

Fig. 3. Distribution of V/I amplitude ratio in individual children in various asphyxia groups. The horizontal lines represent the lower limits in the normal controls at different ages (Jiang et al. [29]). Abbreviations: as in Fig. I.

In perinatal asphyxia group A, abnormal BAER was seen in two of the 25 children following mild asphyxia (8.0%) with one in each of patterns B and D. The abnormality was slightly higher in the children following severe asphyxia (15.0%, 3/20 cases), with one case in each of patterns A, B and E. As a result BAER abnormality in this group was 11.1% (6/45 cases). By contrast, abnormal BAER waveforms were seen much more frequently in perinatal asphyxia group B (35.3%, 12/34 cases). Three of the 11 children following mild asphyxia showed abnormal BAER (27.30/o),with one in each of patterns A, B and C. The prevalence of BAER abnormalities in the children following severe asphyxia in group B was 39.1% (9/23 cases).Of the nine children whose BAER was abnormal, four exhibited pattern A, three pattern B, one pattern C and one pattern E. The children with abnormal BAER results often, though not always, suffered a prolonged period of asphyxia, based on 20-min Apgar scores and/or clinical signs. They tended to exhibit particularly or universally poor neurodevelopmental deficits, including persistent vegetative state, spastic quadriparesis, or severe developmental delay. The characteristics and prevalence of the central BAER abnormalities in postnatal asphyxia group were similar to those in perinatal asphyxia group B. Amplitude abnormalities occurred more frequently than prolonged I-V interval. Abnormal BAER results were seen in five cases(35.7%) including two pattern A, two pattern B and one pattern C. Similar to the observations in perinatal asphyxia group B, the children with abnormal BAER results following postnatal asphyxia often displayed particularly or universally poor neurodevelopmental deficits. 3.2. Comparison of BAER abnormalities between various groups and between mild and severe asphyxia

In the children following perinatal asphyxia, the prevalence of BAER abnormalities in perinatal asphyxia group B (35.3%, 12134cases)was significantly higher than that in perinataf asphyxia group A (1 l.l%, 5145 cases) (x2 = 6.71, P < 0.01). In

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terms of the degree of perinatal asphyxia, these children were regrouped into mild and severe asphyxia, regardless neurodevelopmental outcome. The BAER abnormalities were much higher in the children following severe asphyxia than in those following mild asphyxia. Statistical analysis showed that BAER results did not correlate significantly with I-min Apgar scores, but correlated significantly with 5-min Apgar scores (Table 1). The BAER results in postnatal asphyxia group were compared statistically with those following severe asphyxia in perinatal asphyxia group B. No significant difference was found between the two populations in the overall BAER abnormality (Table 2). In order to explore any possible differences in individual BAER measures between the two patient populations each of the major BAER measures

I

III

v

A

24 M

24 M

60 M

6M

II

11

0

2

11

1

4 6 TIME (ms)

I

I

6

I1

10

Fig. 4. Representative recordings of abnormal patterns of the central BAER components from right ears in children after asphyxia. The dashed traces are the age-matched controls. A. Combined wave V amplitude reduction and V/I amplitude ratio decrease: B. Combined wave V amplitude reduction and/or Vi1 amplitude ratio decrease and 1-V interval prolongation; C. Wave V amplitude reduction only: D. V/l amplitude ratio decrease only; E. I-V interval prolongation only.

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Table 2 Statistical comparison of BAER results between children with neurodevelopmental deficits following severe perinatal and those following postnatal asphyxia n

BAER results Abnormal

Normal

Perinatal asphyxia

23

9 (39.I’%:,)

14

Postnatal asphyxia

14

5 (35.7%)

9

z2

P

0.04

0.70

Table 3 Statistical comparison of I-V interval between children with neurodevelopmental deficits following severe perinatal and those following postnatal asphyxia n

I V interval

z2

Prolonged

Normal

Perinatal asphyxia

23

4 (17.4%)

19

Postnatal asphyxia

14

2 (14.3%)

12

0.13

P

0.80

Table 4 Statistical comparison of wave V amplitude between children with neurodevelopmental deficits following severe perinatal and those following postnatal asphyxia n

Wave V amplitude

z2

Reduced

Normal

Perinatal asphyxia

23

8 (34.8%)

15

Postnatal asphyxia -

14

5 (35.7%)

9

0.003

P

0.98

was compared individually. No statistically significant difference was found in any of these measures (Tables 3-5). 3.3. Follow-up

BAER testing in some of the children was repeated several months to 2 years later. Except for further maturational changes, BAER abnormalities observed at the initial test often showed little improvement or deterioration during the followup recordings (Fig. 5). This was comparable with our observations on the clinically determined neurodevelopmental outcome in these children. There was often no significant improvement or progress for neurodevelopmental deficits in most of these children during the follow-up assessment.

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Tierney 1 Int. J. Pediatr. Otorhinolaryngol.

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Table 5 Statistical comparison of V/I amplitude between children with neurodevelopmental deficits following severe perinatal and those following postnatal asphyxia n

V/I amplitude ratio Decreased

Normal

Perinatal asphyxia

23

6 (23.1%)

17

Postnatal asphyxia

14

3 (21.4%)

11

x2

P

0.10

0.80

4. Discussion 4.1. Characteristics of the BAER long following

asphyxia and their implications

Shortly after the episode of asphyxia, the major abnormality in central BAER measures is usually a prolonged I-V interval, followed by reduced V/I amplitude ratio. This is also the case in our BAER observations in asphyxiated neonates. In this study, however, the major abnormality was a reduction of wave V amplitude, followed by a decreasein V/I amplitude ratio, while the abnormality in interpeak intervals was relatively rare. These findings suggest that the prolonged I-V interval recovers more quickly than the reduced wave amplitude. It seemsthat asphyxia is unlikely to exert any major long-term effect on nerve conduction and synaptic transmission or myelination along brainstem auditory pathway. The reduction of wave V amplitude may be indicative of residual neural dysfunction in the rostra1 part of the brainstem following hypoxic-ischemic encephalopathies. Reduction of BAER wave amplitude may result from fewer generating neurons, fewer fibres conducting the volley and/or desynchronization of the volley secondary to widely different conduction velocities (demyelination causing very slow conduction). In this study abnormality in interpeak intervals was relatively rare, suggesting that there is no major defect in brain myelination and synchronization of the volley. The major underlying mechanism for the persistent reduction of wave V amplitude is therefore most likely to be fewer generating neurons and/or fewer fibres conducting the volley in the generators of BAER wave V following hypoxic-ischemic insults. Histopathologic studies have shown that following perinatal asphyxia there are discrete brainstem lesions involving auditory centres, including loss of neurons with gliosis or ischemic cell changes in the inferior colliculus and superior olivary complex [31]. In fetal primates asphyxic injury of the inferior colliculus was found to be one of the earliest effects of acute total asphyxia [44]. There are two possible interpretations for the amplitude reduction occurring in wave V, rather than in the earlier BAER waves, following asphyxia. One is that the generators of wave V may be particularly vulnerable to hypoxia. Animal experiments and human pathological studies have shown that specific auditory nuclei, including the cochlear nuclei, superior olive and inferior colliculus, in the brainstem

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Post. Asphym 1 111 v

I 0

I 2

I I I 4 6 8 TIME (Ins,

JO’“” I 10

0

2

4 6 TIME (Ills)

8

10

Fig. 5. Follow-up tests of the BAER in representative children with BAER abnormalities following asphyxia. Perinatal asphyxia A: decreased V/I amplitude ratio with normal wave V amplitude and 1-V interval (pattern D). Perinatal asphyxia B: wave V amplitude reduction, decreased Vi1 amplitude ratio and prolonged 1-V interval (pattern B). Postnatal asphyxia: wave V amplitude reduction and decreased WI amplitude ratio (pattern A).

have a selective vulnerability to hypoxic-ischemic insults [7,15,16,31,39,41,44,45,511. The inferior colliculus has very high metabolic rates [38,40]. The alternative interpretation is that compared to BAER waves I-IV, wave V has its origin in the most rostra1 part of the auditory brainstem. It has been shown that the later BAER components, generated by the auditory nuclei which are located rostrally in the brainstem, are more vulnerable to asphyxia than the earlier components, generated by the nuclei which lie relatively caudally in the brainstem. Animal experiments have demonstrated that following severe asphyxia, wave amplitude reduction or loss begins with later BAER components and progresses to the earlier components [47,48]. The persistent reduction of wave V amplitude revealed by the present study indicates that compared to the more caudal regions of the brainstem, the damage of asphyxia to the rostra1 brainstem is more profound and/or that the recovery of the damaged neurons in the rostra1 brainstem is more incomplete or retarded.

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Increasing evidence has shown that wave V originates in the high pons or low midbrain, most likely in the lateral lemniscus [10,34-373 and less likely in the inferior colliculus [17,18]. By recording click-evoked responses from the cochlear nucleus in humans, Moller et al. (1994) found that the sharp tip of BAER wave V is generated by the termination of the lateral lemniscus in the inferior colliculus [37]. Some recent studies have suggested that wave V depends on the integrity of neurons in the lateral subdivision and the medial nucleus of the trapezoid body of the superior olivary complex [54,55]. Because these nuclei are so close to one another anatomically, in terms of clinical interpretation, there is no significant difference among these auditory relay nuclei as the origin of wave V. In the preceding paper we reported that the long-term effect of perinatal asphyxia on peripheral hearing did not correlate well with its effect on the central nervous system [22]. The present study demonstrated that the central BAER components correlated significantly with the neurodevelopmental outcome. BAER abnormalities were seen more frequently in the children with neurodevelopmental deficits than those without the deficits. Thus, the abnormalities in the central BAER components, especially amplitude reduction of wave V reflect, to a substantial extent, the unfavourable outcome of the central nervous system following asphyxia. 4.2. BAER abnormality and the degree of asphyxia As reported by many others, we have observed that BAER results in asphyxiated neonates are closely related to the degree of asphyxia (unpublished data). The present study demonstrated that long after the episode of perinatal asphyxia, although BAER abnormalities occurred more frequently in the children following severe asphyxia than those following mild one, BAER results did not correlate strongly with the degree of asphyxia. BAER abnormalities were seen not only in those following severe asphyxia but also in those following mild asphyxia. Many children following severe asphyxia did not demonstrate any evidence for BAER abnormalities. These BAER findings are consistent with the clinical observations that long-term neurological outcome following asphyxia is not closely related to the degree of asphyxia or destructive brain injury. Although severe asphyxia increases the risk for neurologic sequelae, some children following mild asphyxia may have a certain degree of neurological deficits whereas many children following severe asphyxia may recover without any apparent neurological sequelae. These observations are essentially consistent with those reported by many others [2,4,46]. In the analysis of peripheral hearing loss following perinatal asphyxia, we also noted that the occurrence of peripheral hearing loss was not closely related to the degree of asphyxia [22]. There are several interpretations of this relatively poor relationship. The most likely one is that the occurrence of hypoxic-ischemic insults to the brain depends not only on the degree of asphyxia but also on its duration. This is supported by the finding that BAER results correlated better with 5-min Apgar scores than with 1-min scores, and that most subjects with abnormal BAER results suffered a prolonged period of asphyxia. Under asphyxia the brain is subjected not only to hypoxia, but also to ischemia and hypercarbia, which in turn can lead to cerebral

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edema and various circulatory disturbances. Brain damage may progress for variable periods of time after the event. Most neurological damage during the post-ischemic period is secondary to disorders of cerebral metabolism and blood flow occurring after hypoxic injury, resulting in further tissue injury and cerebral edema. The ultimate degree of neurological damage sustained, therefore, may depend largely on both the degree and length of the tissue injury during post-ischemic period. The second interpretation is that the susceptibility to asphyxia varies among individuals. The third one is that the relatively small sample, in which only a small proportion of the children showed BAER abnormalities, restricts statistical comparison. We have examined the BAER in a relatively large number of the neonates with perinatal asphyxia, and have observed that almost half of the cases showed some patterns of BAER abnormalities and the BAER results correlated significantly with Apgar scores at both I- and 5-min. In this study, BAER test was carried out more than 6 months following the episode of asphyxia when the brain damage produced by asphyxia may have largely recovered. It is therefore conceivable that only a small number of the subjects had residual brain damage and showed BAER abnormalities. 4.3. No significant d@erencebetweenperinatal and postnatal asphyxia in the long-term eflect on the developing auditory brainstem The present study indicates that perinatal and postnatal asphyxia exerts similar long-term effect on the brainstem auditory pathway or, in a wider sense, the central nervous system. Nevertheless, the long-term effects on the peripheral auditory system differed significantly [22]. In the children who exhibited residual neurodevelopmental deficits, permanent hearing loss was seen in 17.1% of those following perinatal asphyxia but in none of those following postnatal asphyxia. Why does perinatal and postnatal asphyxia produce a similar long-term change in the central auditory pathways but a different outcome for the peripheral auditory system? It has been well established that brain myelination and other maturational mechanisms proceed in a centripetal, or peripheral-central, direction [6,12,13,21,33,42,52]. The various auditory structures along the auditory pathway, such as the cochlea, cochlear nucleus, inferior colliculus, medial geniculate body and auditory cortex, demonstrate a centripetal pattern of maturation [42]. Similar to many BAER reports by others, our previous studies showed that peripheral BAER measures, including response threshold and wave I latency and amplitude, approach adult values earlier than central measures such as I-V interval, wave V latency and amplitude [25,27,29]. During the preterm and perinatal period both peripheral and central auditory systems undergo rapid maturational change. It is a time when both systems are particularly susceptible to specific, unfavourable factors. Accordingly, asphyxia occurring during the prenatal and perinatal period is likely to lead to both peripheral hearing loss and central auditory impairment. Shortly after term date, the peripheral auditory system is adult-like or nearly adult-like [43], and hence become relatively resistant to hypoxic-ischemic insults. By contrast the central auditory structures are far from mature and continue to

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develop well into childhood. In recent animal experiments, we have found that even though the gross anatomical topography of subcortical auditory projections to the superior colliculus in the young ferret is essentially the same as that in the adults the functional representation of auditory space in the superior colliculus is far from mature [23]. It is therefore not surprising that during the postnatal period of maturation, the central auditory structures remain susceptible to specific unfavourable factors such as asphyxia. 5. Conclusions Previous studies have shown that the abnormalities in the BAER shortly after asphyxia were gradually normalized following the recovery from hypoxic-ischemic encephalopathy [14,24,43]. The present work showed evidence that long after the episode of perinatal or postnatal asphyxia there remain residual abnormalities in the BAER in some of the asphyxiated children. Our findings indicate that asphyxia could result in residual neural dysfunction of the brainstem but does not appear to exert any major long-term effect on neuronal transmission. Perinatal and postnatal asphyxia exerts a similar long-term effect on the central nervous system. Although most of the children following asphyxia showed normal BAER results, some subtle degree of alterations in the central auditory pathways, which can not be revealed by conventionally used BAER test, cannot be ruled out. Increasing repetition rate of the stimuli in BAER testing has been suggested by some authors to be a ‘stress test’ for the dynamic properties of the brainstem auditory systems in some clinical situations, including asphyxia. Abnormal latency-rate effect has been shown to be associated with pathology in the central nervous system. The sensitivity of the BAER in diagnosis of brainstem pathology could be enhanced by changing stimulus repetition rate. It is possible that the technique of increasing stimulus rate could enhance the detectibility of residual deficits in the central auditory pathway in asphyxiated children who do not show any abnormalities in the BAER recorded at conventionally used stimulus rate, i.e. 10 or 20/s. The present study revealed that asphyxia exerts a major long-term effect on the rostra1 part of the brainstem, a crucial place for binaural processing and for generating binaural interaction components in BAER. It is therefore possible that the neural elements responsible for binaural interaction, referring to those expects of hearing for which two ears are necessary,may also be damaged by asphyxia. This potential damage cannot be shown by the conventionally used BAER test but could be demonstrated by examining binaural interaction components in the BAER. References [I] Barden, T.P. and Peltzman, P. (1980) Newborn brain stem auditory evoked responses and perinatal clinical events. Am. J. Obstetr. Gynecol. 136, 912-919. [2] Brown, J.K., Purvis, R.J., Forfar, J.O. and Cockburn F. (1974) Neurological aspects of the perinatal asphyxia. Dev. Med. Child. Neurol. 16, 5677580. [3] Coats, A.C. and Martin, J.L. (1977) Human auditory nerve action potentials and brain stem evoked responses. Arch. Otolaryngol. 103, 6055622.

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