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KEYWORDS
Brainstem auditory evoked response; Evoked potentials; Neonatal hearing; Auditory impairment; Neural development; Brainstem
Summary Over the last three decades, the brainstem auditory evoked response (BAER) has been used to assess functional integrity and development of the auditory system and the brain in conditions that affect the brainstem auditory pathway. As a non-invasive objective test, BAER is particularly suitable in very young or sick infants. It is the major tool to detect hearing impairment in high-risk infants, and a component in universal hearing screening. BAER is also a valuable adjunct to detect neurological impairment in many developmental disorders and functional abnormalities in a range of neurological diseases. The maximum length sequence (MLS) technique has recently been incorporated into neonatal BAER study. Recent results indicate that the MLS has the potential to improve the diagnostic value of BAER in some clinical situations, although the wider utility of this relative new technique remains to be further explored. 2006 Elsevier Ltd. All rights reserved.
Introduction
The brainstem auditory evoked response (BAER) or potential (BAEP) reects electrophysiological activity of a large number of neurons in the brainstem auditory pathway following acoustic stimulation. The BAER is the far-eld reection of sequentially activated neurons at successively higher levels of this pathway. The responses are very small compared with the electroencephalographic background activity, and it is necessary to average more than 1000 individual stimulations to improve the signal-to-noise amplitude ratio.
* Corresponding author. Tel.: 44 1865 221355; fax: 44 1865 221366. E-mail address: andrew.wilkinson@paediatrics.ox.ac.uk (A.R. Wilkinson).
After averaging several thousand times, the waveforms of BAER can be distinguished by signal averaging linked to the stimuli. The submicrovolt deections in BAER occur in the rst 10 ms after the stimuli and are identied as waves IeVII after Jewett and Williston in 1971. In the last three decades, non-invasive electrophysiological examination of the functional integrity of the brainstem and the auditory system in the neonate has focused on BAER. Technically BAER is easier to record than visual or somatosensory evoked potentials. The BAER can be used to assess peripheral auditory function e and also the functional integrity and development of the brain in general e in conditions that affect the brainstem auditory pathway. BAER is a non-invasive objective test that is unaffected by sedatives, general anaesthetics, or anticonvulsants, and so is particularly suitable in very young or sick patients. In neonatology, BAER has been widely used to
1744-165X/$ - see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2006.07.005
BAER in neonatal neurology study hearing and central neural function in various conditions such as perinatal asphyxia, fetal growth restriction, meningitis, hyperbilirubinaemia, and intraventricular haemorrhage (IVH). In this article, we review some recent advances in the use of BAER in neonatal neurology.
445 maturational changes up to term, and then more slowly in infancy. The most reproducible and easily denable components are waves I, III, and V. Waves II, VI, and VII are often too variable to allow systematic study and wave IV is sometimes fused with wave V. The latencies of the most prominent three BAER components (I, III, and V) decrease as a function of gestation, with a maximal shift occurring in the weeks prior to 34 weeks gestation. The maturational changes continue after term, although more slowly, up to approximately 2e4 years of age. The maturational phases of BAER parallel the critical period of brainstem myelination, axonal sprouting, increase in axonal diameter, development of central dendritic properties, formation of central synaptic connections, and improvement of synaptic efciency, summation, synchronization, and phase-locking capabilities of the auditory system. The decrease in the latency of wave I and BAER threshold with maturation indicates improvement in peripheral processing of the auditory stimulus, which is related to improvement of middle-ear conduction, the cochlear receptors, or the transduction of cochlear receptor potentials into VIIIth nerve activity (i.e. wave I). The maturational changes in BAER later waves e i.e. a decrease in wave latencies, interpeak intervals and threshold, and an increase in wave amplitudes with the increase in age e reect the change in myelination, axon diameter, and synaptic efcacy in the brainstem auditory pathways. Study of maturation of BAER can gain insight into the development of the auditory brainstem.
Figure 1 Neural origin of the brainstem auditory evoked response (BAER). VIII N, auditory nerve; E, extracranial; I, intracranial; DCN, dorsal cochlear nucleus; VCN, ventral cochlear nucleus; NTB, trapezoid body; SOC, superior olivary complex; LL, lateral lemniscus; IC, inferior colliculus; MGN, medial geniculate nucleus; and AC, auditory cortex.
446 retrocochlear abnormalities (e.g. auditory neural disease). Consequently, BAER screening is more suitable. Infants who fail otoacoustic emissions are re-tested by BAER. The incidence of failure of either screening test at the time of hospital discharge is relatively high. Re-testing after failure is best carried out at approximately 2e6 weeks of age when the large majority will have normal responses,5,6 suggesting that the initial failures were transient, reversible disturbances or false-positive results. The fact that hearing deficits develop in the rst months of life, after normal results in the neonatal period, emphasizes the importance of re-test after the neonatal period or after discharge from hospital. Increased evidence indicates that the universal hearing screening of neonates with and without audiological risk factors is feasible and effective.1,2,9
A.R. Wilkinson, Z.D. Jiang rate-dependent change decreased signicantly in IeIII interval, but increased signicantly in IIIeV interval and IIIeV/Ie III interval ratio. The IeIII interval decreased signicantly at higher click rates while the IIIeV interval and IIIeV/IeIII interval ratio increased signicantly at 21/s, 51/s, and particularly at 91/s. These results suggest that very-preterm infants have an advanced peripheral development of the brainstem auditory pathway, which is probably related to the earlier exposure to a sound environment ex utero, but a delayed central development, which may be related to the associated perinatal conditions.
Perinatal asphyxia
The BAER is very sensitive to arterial blood oxygen tension.16 After perinatal asphyxia infants are often found to have BAER abnormalities, including an elevated response threshold, increased wave latencies and interpeak intervals, reduced wave amplitudes, and decreased V/I amplitude ratio.15,17,18 Amplitude reduction in wave V is the main abnormality in children who survive perinatal asphyxia.17 The changes in BAER after asphyxia are basically similar in preterm and term infants. When preterm infants after asphyxia reached term age their BAER had only slight abnormalities, mainly increased IIIeV interval, suggesting minor impairment in central auditory function.
BAER in neonatal neurology To examine whether high presentation rates of clicks while recording BAER improves the detection of central auditory impairment, Jiang et al. analysed BAER at different repetition rates of clicks in infants after perinatal asphyxia.15,18 At the routinely used 21/s clicks, all BAER wave latencies increased signicantly. After excluding the neonates who had a signicantly elevated BAER threshold, only wave V latency increased slightly. The intervals of IeV and IIIeV also increased slightly. Similar results were found at 51/s clicks. When clicks were increased to 91/s, the IIIeV interval increased more significantly and, in particular, wave V amplitude reduced signicantly compared with normal controls (Fig. 2). The authors concluded that although a moderate increase in the click rate (e.g. 51/s) does not improve detection of hypoxiceischaemic brainstem impairment, an increase to 91/s does, mainly manifesting as an abnormal reduction of wave V amplitude. In experimental animals, BAER has also been used to study neural response of the brain to certain interventions such as hypothermia.16 Recent studies in newborn animals with experimental hypoxiaeischaemia have shown that BAER correlated with the severity of hypoxiaeischaemia, and that BAER is useful in assessing the neuroprotective effects of hypothermia.16,19,20
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Figure 2 Brainstem auditory evoked response (BAER) recordings at different repetition rates of clicks on days after birth in term infants. (A) Normal infant. (B) Infant after perinatal asphyxia. Although there were no apparent differences in BAER between the two infants at 21/s and 51/s clicks, all wave latencies and IeV and, in particular, IIIeV intervals increased at 91/s in the infant after asphyxia, compared with those in the normal infant. From Jiang et al. (2004, Clin Neurophysiol 115:1605e15) with permission.
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A.R. Wilkinson, Z.D. Jiang the potential to improve the sensitivity of BAER in the detection of neuropathology. The major advantage of this technique is that it can present acoustic stimuli up to 1000/s or even higher.42e46 This stimulus stress has the potential to improve detection of some neuropathology, particularly a subtle or early one, which may not be detected by presenting less stressful stimuli (i.e. low-rate stimulation) using conventional averaging techniques. In the last decade, Jiang et al. have used the MLS BAER to study functional integrity and maturation of the brainstem and central auditory system in neonates and to evaluate the value of MLS BAER in the detection of neurological abnormalities.42e46 By studying dynamic changes in the MLS BAER during the rst month after birth, Jiang et al. showed a time course of brainstem pathophysiology after perinatal asphyxia.43,44 On day 1, wave III and V latencies and all interpeak intervals increased signicantly at all rates of clicks used (91e910/s), especially the higher rates. On day 3, all these latencies and intervals increased further and differed more signicantly from the normal controls. Thereafter, the latencies and intervals decreased progressively. On day 7, wave V latency and all intervals still differed signicantly from the controls. These dynamic changes were more signicant at higher rates of clicks than at lower rates. On days 10 and 15, all intervals decreased signicantly. On day 30, all wave latencies decreased to the values in the normal controls on the same day. The intervals also approached normal values, although IIIeV and IeV intervals still increased slightly. These MLS BAER changes have been further conrmed in our recent larger samples (Fig. 3). These results indicate that hypoxiceischaemic brain damage persists during the rst week, with a peak on day 3, and recovers progressively thereafter. By 1 month, this has largely returned to normal. This correlates with other evidence that the rst week, particularly the rst 3 days, is a critical period of hypoxiceischaemic brain damage. This time course could be used as a reference to monitor cerebral function and might help to judge the value of neuroprotective and/or therapeutic interventions. In addition, these authors found that MLS BAER results correlated well with the stage of hypoxiceischaemic encephalopathy during the rst week. More recently, Jiang et al. studied functional integrity of the auditory brainstem in preterm infants using the MLS BAER.45,46 When preterm infants reached term age, those who had perinatal complications (high-risk infants) showed a tendency to an increase in wave V latency and IeV and IIIe V intervals at all 91e910/s clicks, with statistical signicance at higher rates. Wave V latency and IeV interval increased signicantly at 455/s and 910/s, but not at lower rates (Fig. 4A, B). IIIeV interval increased at all click rates, which was more signicant at higher rates (Fig. 4C). The IIIeV/IeIII interval ratio increased at most rates. Waves III and V amplitudes reduced signicantly mainly at 455/s and 910/s. In preterm infants who had no perinatal complications (low-risk infants), there were no major MLS BAER abnormalities except an increase in IIIeV interval at 91e910/s (Fig. 4AeC). Compared to these low-risk infants, the preterm infants with perinatal complications had a signicant increase in wave V latency, IeV and IIIeV intervals, and IIIeV/IeIII interval ratio at 455/s and 910/s clicks (Fig. 4AeC). On the other
Developmental disorders
BAER abnormalities found in infants with Downs syndrome include no response, decreased latencies of waves I and V and IeV interpeak interval, or increased latencies of waves I and V. These results indicate a high incidence of hearing loss at middle and inner ear levels, and some anomaly in the brainstem. In infantile spasms, BAER abnormalities include partial disappearance of latter waves, increase in IeV interpeak interval, and no responses. These abnormalities are compatible with the nding on MRI of brainstem atrophy in babies with infantile spasms. In Cornelia de Lange syndrome BAER manifests no response, mild wave V threshold elevation, and markedly increased wave V, suggesting a high prevalence of peripheral SNHL. BAER may predict the severity of clinical brainstem symptoms in myelomeningocoele as the brainstem is distorted and elongated due to the downward dislocation of the pons, medulla oblongata, and fourth ventricle. In nocturnal enuresis, BAER manifests increased IeIII and IeV intervals, suggesting functional delay in brainstem maturation.40 Patients with congenital hypothyroidism or transient hypothyroidism often have increased wave latencies and interpeak intervals in BAER.41 In addition, the BAER has been widely used to diagnose, localize, and monitor intracranial pathology in many myelin or degenerative diseases that involve the brainstem, such as Leigh disease, metachromatic leukodystrophies, maple syrup urine disease, and phenylketonuria. The abnormalities are mainly increased wave latencies and interpeak intervals.
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Figure 3 Means and standard errors of wave V latency (A) and IeV interval (B) in conventional brainstem auditory evoked response (BAER) (21/s) and maximum length sequence (MLS) BAER (91e910/s) at 40 dB above the BAER threshold during the rst month after birth in term infants after perinatal asphyxia. The symbols in sequence represent the data of normal controls on days 1e3, asphyxiated infants on days 1, 3, 5, 7, 10, 15, and 30, and the controls on day 30. During the period studied, the abnormality (i.e. signicant increase in wave V latency and IeV interval) increases with the increase in click rate. The dynamic change and abnormalities are more signicant at higher click rates than at lower rates during the rst week.
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hand, both low- and high-risk preterm infants had no major abnormalities in the IeIII interval that reect functional integrity of the more peripheral portion of the brainstem auditory pathway. Instead, the interval tended to decrease, which is probably due to the preterm birth that exposes the infants to a sound environment ex utero earlier than term infants, leading to accelerated maturation or myelination in the peripheral neural pathway of the auditory system. Fig. 5 shows sample MLS BAER recordings in a normal term infant (A), a preterm low-risk infant (B), and a preterm high-risk infant (C) recorded at term. These results suggest that, at term, although there are no major abnormalities in brainstem auditory function in preterm infants without perinatal complications, the auditory brainstem e mainly the more central part e in
Figure 4 Means and standard errors of wave V latency (A) and IeV (B) and IIIeV (C) intervals in conventional brainstem auditory evoked response (BAER) (21/s) and maximum length sequence (MLS) BAER (91e910/s) at 40 dB above the BAER threshold in preterm infants, recorded at term, and normal term controls. Compared to term controls, preterm high-risk infants show a signicant increase in wave V latency and IeV interval at 455/s and 910/s (P < 0.05e0.001). The IIIeV interval increases signicantly at all click rates (P < 0.05e0.001). These increases are more signicant at higher rates. Preterm low-risk infants do not have any major MLS BAER abnormalities except an increase in IIIeV interval at 91e910/s (P < 0.05e0.01). Compared to these low-risk infants, wave V latency and IeV and IIIeV intervals in preterm high-risk infants increase signicantly at 455/s and 910/s clicks (P < 0.05e0.001). From Jiang et al. (2005, Pediatr Res 58:1164e9) with permission.
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A.R. Wilkinson, Z.D. Jiang ndings indicate that the MLS technique has the potential to improve the diagnostic value of BAER. Compared to conventional BAER, MLS BAER is a better method to detect early brain damage and central auditory impairment in some clinical situations, e.g. perinatal asphyxia. However, further studies are needed to describe the wider utility of this relative new technique.
Practice points
BAER is an important objective tool to detect auditory impairment and neurological abnormalities in a range of neonatal diseases. Recent studies with BAER suggest that neural conduction in the central nervous system is delayed in neonatal CLD, reecting impairment of myelination. MLS BAER can detect early brain damage and central auditory abnormalities that affect the brainstem auditory pathway. The MLS technique has the potential to improve the diagnostic value of BAER in some clinical situations.
References
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Figure 5 Maximum length sequence brainstem auditory evoked response (MLS BAER) recordings in a normal term infant (A), a preterm low-risk infant (B), and a preterm high-risk infant (C) recorded at term. Compared to the infants in (A) and (B), the infant in (C) shows a signicant increase in wave V latency, IeV and particularly IIIeV intervals, and a signicant reduction in wave V amplitude at 455/s and 910/s clicks, but not at lower rates. From Jiang et al. (2005, Pediatr Res 58:1164e9) with permission.
preterm infants with perinatal complications is impaired, which becomes more apparent at very high stimulus rates. Thus, preterm infants with perinatal complications are at high risk of central auditory impairment. These studies show evidence that MLS BAER abnormalities are better detected with the increase in the rate of clicks, particularly at the very high rates 455/s and 910/s, which cannot be achieved in conventional BAER. These
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