Abstract
A variety of specialized studies are available for evaluating the nervous system of the newborn. In this chapter, we review several commonly used tests: cerebrospinal fluid examination, evoked responses (with emphasis on auditory evoked responses), electroencephalography (EEG), cranial ultrasound, and magnetic resonance imaging (MRI). We also touch on some tests that are not yet in common clinical use: near-infrared spectroscopy and magnetoencephalography. The discussion of EEG includes a description of the changes in EEG associated with early brain development and a brief review of amplitude-integrated EEG. The discussion of MRI covers conventional structural imaging (including diffusion imaging) as well as spectroscopy and functional imaging. Overall, we focus on the adaptations necessary to optimize these tests for infants. We also describe the characteristics and nuances relevant to their effective clinical use. The application of most of these tests for diagnostic purposes is mentioned in various other chapters of this book.
Keywords
auditory evoked responses, cerebrospinal fluid examination, electroencephalography, magnetic resonance imaging, magnetoencephalography, near-infrared spectroscopy, ultrasound
In addition to the neurological examination discussed in Chapter 9 , certain specialized studies are critical components of the neurological evaluation of the newborn. Most of these studies are presented in relation to relevant specific disorders throughout this book. However, certain of these specialized aspects, which are not discussed in detail elsewhere and are of definite or potential importance in the neurological evaluation, are reviewed here, including examination of the cerebrospinal fluid (CSF), certain neurophysiological studies (brain stem auditory evoked responses, visual cortical evoked responses, and electroencephalography [EEG]), the major techniques for imaging of brain structure (cranial ultrasound [CUS] and magnetic resonance imaging [MRI]), certain noninvasive continuous monitoring techniques, and methods for physiological brain imaging.
Cerebrospinal Fluid Examination
Examination of the CSF is an important part of the evaluation of a wide variety of neurological disorders, as noted in appropriate chapters throughout this book. In this section, we focus principally on normal CSF in the newborn, particularly the newborn considered at high risk for such neurological disorders.
The principal components of the CSF examination include measurement of intracranial pressure, assessment of the color (e.g., bloody, xanthochromic) and turbidity (e.g., purulent), red blood cell (RBC) and white blood cell (WBC) counts, WBC differential count, and concentrations of protein and glucose. Other, more specialized evaluations (e.g., for microorganisms, various metabolites, and enzymes) are determined by clinical circumstances. In this section, we focus on the WBC and RBC counts and concentrations of protein and glucose.
White Blood Cell, Protein, and Glucose Concentrations
Of the several studies that address normal CSF values in the newborn, the studies of Sarff and co-workers and Rodriguez and co-workers are the most informative (although all the data are generally consistent). Sarff and co-workers discussed the CSF findings in 117 high-risk infants (87 term, 30 preterm < 2500 g birth weight; 95 examined in the first week, most with clinical findings indicative of a high risk of infection but without positive cultures for bacteria or other organisms or grossly bloody CSF) ( Table 10.1 ). Mean values for term and preterm infants, respectively, were for WBC counts of 8 and 9/mm 3 (60% polymorphonuclear leukocytes), protein concentration 90 and 115 mg/dL, glucose concentrations 52 and 50 mg/dL, and ratio of CSF to blood glucose 81% and 74%. Although the ranges are wide, the values provide a useful framework for evaluating neonatal CSF.
| FINDINGS | TERM | PRETERM |
|---|---|---|
| White blood cell count per mm 3 | ||
| Mean ± standard deviation | 8 ± 7 | 9 ± 6 |
| Range | 0–32 | 0–29 |
| Protein concentration (mg/dL) | ||
| Mean | 90 | 115 |
| Range | 20–170 | 65–150 |
| Glucose concentration (mg/dL) | ||
| Mean | 52 | 50 |
| Range | 34–119 | 24–63 |
| Cerebrospinal fluid/blood glucose (%) | ||
| Mean | 81 | 74 |
| Range | 24–248 | 55–105 |
In a subsequent report, Rodriguez and co-workers obtained more detailed data for similarly high-risk infants but of very low birth weight (i.e., <1500 g). When the data were expressed as a function of postconceptional age when the CSF sample was obtained, the values for the more mature infants were similar to the values obtained by Sarff and co-workers ( Table 10.2 ). This similarity could be expected because the infants in the study by Sarff and co-workers were larger and presumably more mature. Notably, however, the least mature infants (26 to 28 weeks of postconceptional age) exhibited values of glucose and protein that were distinctly higher than values observed at later ages. This occurrence, as well as the finding of Sarff and co-workers that preterm infants had relatively high ratios of CSF to blood glucose (see Table 10.1 ), supports the notion of increased permeability of the blood-brain barrier in the small preterm infant. Moreover, increased permeability for other macromolecules (e.g., immunoglobulin G, alpha-fetoprotein) is suggested by other studies. Although the WBC counts in the premature infants studied by Rodriguez and co-workers did not differ as a function of postconceptional age and are similar to those reported by Sarff and co-workers, the percentage of polymorphonuclear leukocytes (7%) is much lower than in the latter study. This discrepancy may be related in part to the error inherent in the study of relatively small numbers of WBCs.
| POSTCONCEPTIONAL AGE (WEEKS) | WHITE BLOOD CELL COUNT (per MM 3 ± SD) | GLUCOSE (MG/DL ± SD) | PROTEIN (MG/DL ± SD) |
|---|---|---|---|
| 26–28 | 6 ± 10 | 85 ± 39 a | 177 ± 60 a |
| 29–31 | 5 ± 4 | 54 ± 81 | 144 ± 40 |
| 32–34 | 4 ± 3 | 55 ± 21 | 142 ± 49 |
| 35–37 | 6 ± 7 | 56 ± 21 | 109 ± 53 |
| 38–40 | 9 ± 9 | 44 ± 10 | 117 ± 33 |
a Values for glucose and protein were significantly greater at 26 to 28 weeks than at subsequent postconceptional ages.
These values for WBC count and protein and glucose concentrations are crucial for the evaluation of the infant with suspected bacterial meningitis or other central nervous system inflammatory processes. Although these issues are discussed in more detail later (see Chapters 34 and 35 ), combinations of abnormalities are important to recognize, and single values that are questionably abnormal are difficult to interpret conclusively. Under all circumstances, assessment of the CSF in the context of the clinical setting and the clinical features is most important.
Red Blood Cell Counts in High-Risk Newborns
Determination of normal values for RBCs in neonatal CSF is hindered by the relatively high incidence of germinal matrix–intraventricular hemorrhage, usually clinically silent in the preterm infant (see Chapter 24 ), and by the likelihood that the process of birth is associated with minor amounts of subarachnoid bleeding. In the study of Sarff and co-workers, the median value for RBC count was 180, with a very wide range (0 to 45,000) ( Table 10.3 ). A similar value was obtained for premature infants in that study. In both the term and preterm infants, the most common value (mode) for RBC count was 0. However, in the report of Rodriguez and co-workers, although a median value of 112 was observed, the mean was 785, and 20% of CSF samples had more than 1000 RBCs/mm 3 (see Table 10.3 ). These infants were smaller (<1500 g), but ultrasonographic examinations were said to show no evidence of intracranial hemorrhage. However, exclusion of minor subarachnoid hemorrhage by cranial ultrasonography is not reliable.
| Sarff and co-workers a | |
| Term infants | n = 87 |
| Median: 180 | |
| Range: 0–45,000 | |
| Preterm infants (<2500 g) | n = 30 |
| Median: 112 | |
| Range: 0–39,000 | |
| Rodriguez and co-workers b | |
| Preterm infants (<1500 g) | n = 43 |
| Mean: 785 | |
| RBCs >1000/mm 3 in 20% of samples | |
a Data from Sarff LD, Platt LH, McCracken Jr GH. Cerebrospinal fluid evaluation in neonates: comparison of high-risk infants with and without meningitis. J Pediatr . 1976;88:473–477.
b Data from Rodriguez AF, Kaplan SL, Mason Jr EO. Cerebrospinal fluid values in the very low birth weight infant. J Pediatr . 1990;116:971–974.
The aforementioned data indicate that the finding of more than 100 RBCs/mm 3 in the newborn is common and that, in very-low-birth-weight infants, values greater than 1000 occur in a substantial minority in the absence of apparently clinically significant intracranial hemorrhage. Again, the combination of findings is important in the evaluation of the CSF for intracranial hemorrhage. Thus the addition of xanthochromia and elevated protein concentration in CSF strongly raises the possibility of a more substantial and, clinically speaking, more important intracranial hemorrhage. This issue is discussed in more detail in Chapter 22 .
Neurophysiological Studies
Several specialized neurophysiological techniques have been particularly valuable in further defining the neurological maturation of the newborn. Moreover, some of these studies are commonly used in neurological diagnosis. In this section, we cover brain-stem auditory evoked responses, visual evoked responses, and EEG (including amplitude-integrated EEG). The most widely used of these neurophysiological techniques, EEG, is also discussed in relation to seizures in Chapter 12 .
Brain-Stem Auditory Evoked Responses
Electrophysiological investigations of the auditory system in the newborn have focused on brain-stem evoked responses. However, cortical auditory evoked responses have been studied, as have visual and somatosensory evoked responses (see later sections), through computer-averaged EEG recordings obtained over the scalp after graded stimuli. Such cortical responses have been described in premature and full-term infants, demonstrating that peripheral auditory stimuli are transmitted to the primary and secondary auditory cortex of the temporal lobe in the newborn period. Magnetoencephalography has been used to define the maturation of cortical evoked responses from 27 weeks of gestation to term in 18 fetuses. This work is noteworthy for the detection of a decrease in latency from 300 ms at 29 weeks of gestation to 150 ms at term. Further, auditory habituation has been demonstrated in fetuses, suggesting that fetal learning is taking place. This novel and noninvasive technique thus not only extends insights into the maturation of auditory cortical areas during the last trimester of human gestation but also demonstrates the applicability of magnetoencephalography to study of the fetus. Nevertheless, measurement of cortical auditory evoked potentials has been difficult to adapt to routine clinical circumstances, in part because the amplitude and latency of the observed responses vary with the infant’s level of arousal and in part because of the expense of the technology (magnetoencephalography). In contrast, major attention has been paid to the earlier potentials generated from subcortical structures after auditory stimulation (i.e., the brain-stem auditory evoked response ).
Major Waveforms and Anatomical Correlates
The brain-stem auditory evoked response reflects the electrical events generated within the auditory pathways from the eighth nerve to the diencephalon and is recorded by electrodes placed usually over the mastoid and vertex. The stimulation is usually a click or pure tone administered at a relatively rapid rate. The latency and amplitude of the components of the response are measured. To avoid movement and other artifacts, the infant is studied preferably during sleep. The complete response consists of seven components, designated consecutively by Roman numerals ( Fig. 10.1 ). Studies in animals and adult humans indicate that the waves derive from sequential activation of the major components of the auditory pathway. Thus, wave I represents activity of the eighth nerve, wave II the cochlear nucleus, wave III the superior olivary nucleus, wave IV the lateral lemniscus, and wave V the inferior colliculus. The precise origins of waves VI and VII remain to be established, but these waves are probably generated in the thalamus and thalamic radiations, respectively. Brain-stem auditory potentials have been well defined in the newborn infant, although all seven components are not observed (see later discussion).
Developmental Changes
Impressive ontogenetic changes in the brain-stem auditory response have been described. a
a References .
The most reproducible and easily definable components are waves I, III, and V; the last is sometimes fused with wave IV. Waves II, VI, and VII have generally been too variable to allow systematic study. The latencies of the most prominent components (I, III, IV to V) decrease as a function of gestational age, with a maximal shift occurring in the weeks before 34 weeks of gestation ( Fig. 10.2 ). Moreover, an increase in amplitude and a decrease in threshold of the response occur with increasing gestational age.
Detection of Disorders of the Auditory Pathways
Abundant findings indicate the value of brain-stem auditory evoked response studies in detecting disorders of the auditory pathways in the newborn infant. b
b References .
Definition of such disorders depends on the detection of responses that are abnormal in threshold sensitivity, conduction time (i.e., latency), amplitude, or conformation. In neonatal studies, deficits in threshold sensitivity and latency have been the most valuable. The general principle is that a lesion at the periphery (middle ear, cochlea, or eighth nerve) results in a heightened threshold and a prolongation of latency of all the potentials, including wave I, whereas a lesion in the brain stem causes longer latencies of only those waves originating from structures distal to the lesion, with wave I spared. The essential features of these two basic abnormal patterns of brain-stem auditory evoked responses observed in neonatal patients are depicted in Table 10.4 .| SITE OF DISORDER | ||
|---|---|---|
| RESPONSE CHARACTERISTIC | PERIPHERY | BRAIN STEM |
| Threshold (wave I) | Elevated | Normal |
| Wave I latency | Prolonged | Normal |
| Wave V latency | Prolonged | Prolonged |
| I–V interval | Normal | Prolonged |
Abnormalities of the evoked response in neonatal neurological disease are to be expected, in part because of the known neuropathological involvement of the following: the cochlear nuclei, the inferior colliculus, other brain-stem nuclei, and the cochlea itself by hypoxic-ischemic insult (see Chapter 18 ); the cochlear nuclei, inferior colliculus, and, perhaps, the cochlea or eighth nerve by hyperbilirubinemia (see Chapter 26 ); the eighth nerve by bacterial meningitis (see Chapter 35 ); the cochlea and eighth nerve by congenital viral infections (see Chapter 34 ); and the cochlea by intracranial hemorrhage (see Chapter 24 ) ( Table 10.5 ). Indeed, brain-stem evoked response audiometry has been used to describe peripheral and central disturbances in infants with congenital cytomegalovirus infection, hyperbilirubinemia, bacterial meningitis, asphyxia, persistent fetal circulation, aminoglycoside or furosemide administration, trauma to the cochlea or middle ear, and still undefined complications of low birth weight. a
a References .
The particular importance of combinations of these factors in the genesis of permanent deficits has been emphasized. Moreover, neonatal defects may be transient. For example, in one large study ( N = 92) of term asphyxiated infants, 35% exhibited brain-stem auditory evoked response deficit (increased threshold) in the first 3 days of life, but only 10% had abnormalities at 30 days. Among preterm infants with birth weight less than 1500 g who were studied at term, 14% had evidence of a peripheral impairment (increased threshold), 17% a central impairment (prolonged brain-stem latencies), and 4% a combined impairment, for a total of 27%.| NEUROLOGICAL DISORDERS | RELEVANT NEUROPATHOLOGY |
|---|---|
| Hypoxic-ischemic encephalopathy | Cochlear nuclei, inferior colliculus, cochlea |
| Hyperbilirubinemia | Cochlear nuclei, inferior colliculus, cochlea, eighth nerve |
| Bacterial meningitis | Eighth nerve |
| Congenital viral infection | Cochlea, eighth nerve |
| Intracranial hemorrhage | Cochlea |
Hearing Screening
Use of the brain-stem auditory evoked response as a screening device for hearing impairment in the neonate has become extremely common, and universal screening is the norm in many countries. a
a References .
The importance of early identification of infants with hearing impairment is based on the realization that acquisition of normal language and of social and learning skills depends on hearing. bb References .
The most commonly recommended screening procedure for preterm infants consists of testing the infant just before hospital discharge or at least as close to 40 weeks after conception as possible, when he or she is medically stable, and preferably in a room separate from the neonatal unit. Term infants are often tested at any point before discharge. c
c References .
The initial screening procedure has consisted of conventional brain-stem auditory evoked response, automated auditory evoked response, or transient evoked otoacoustic emission. The last detects signals generated by cochlear outer hair cells in response to acoustic stimulation. This technique is faster and less expensive than evoked response audiometry. However, the method does not detect retrocochlear abnormalities (e.g., auditory nerve disease). Infants who fail this test are retested by auditory evoked response study, often an automated study. The incidence of failure of either screening test at the time of hospital discharge is relatively high, with the actual value depending on the population studied. For low-birth-weight infants tested at term, failure rates as high as 20% to 25% are common. Retesting infants after test failure is usually carried out after several weeks or later, often after discharge. With this approach, many infants are lost to follow-up. Because most neonates who fail the first screening procedure exhibit normal responses at the time of the retest, dd References .
the initial failures are likely transient, reversible disturbances or false-positive results. For example, in one large series of more than 16,000 infants, retesting in the neonatal unit after early test failures resulted in an 80% reduction in failure rate by discharge. In certain high-risk groups, the importance of later testing is emphasized by the report of hearing deficits developing in the first months of life, after normal results in the neonatal period ( Table 10.6 ).| IMMEDIATELY AFTER DISCHARGE | BY 3 MONTHS OF AGE | AT 6–9 MONTHS OF AGE |
|---|---|---|
|
|
|
Visual Evoked Responses
Cortical Response
The term visual evoked response refers to the electrical response, recorded usually by surface electrodes on the occipital scalp, to a standardized stimulus, the most common of which is a light flash of graded intensity and frequency. Flash visual evoked responses are recorded in response to red light-emitting diodes in goggles placed over the infant’s eyes or in an array placed about 6 inches in front of the infant’s eyes. The fully developed response is complex, but the first two prominent waves consist of first a positive and then a negative deflection. The positive deflection is attributed to postsynaptic activation at the site of the predominant termination of visual afferents, and the negative deflection is attributed to secondary synaptic contacts in the superficial cortical layers. Two features of the response are studied: the quality of the waveform and the latency between stimulus and recorded response. With flash visual evoked responses, variability in latencies can lead to difficulties in interpretation.
An alternative and generally preferable stimulus for visual evoked responses, particularly for study of visual acuity, is a shift (reversal) of a checkerboard pattern (i.e., pattern-shift or pattern-reversal visual evoked response). This stimulus results in responses with less variable latencies than those obtained with a light-flash stimulus. Although the technique has been used in the newborn, a
a References .
including the preterm newborn, experience remains limited, in part because obtaining optimal data requires that the newborn fix on the visual display. However, reliable data have been obtained, and this technique should prove adaptable to the newborn for wider use.Developmental Changes
The ontogenetic changes of the visual evoked response in the human newborn have been well established. A prolonged negative slow wave can be identified as early as 24 weeks of gestation, and this wave ultimately is replaced by the more discrete negative wave noted earlier ( Fig. 10.3 ). The positive wave appears between approximately 32 and 35 weeks of gestation, and by 39 weeks the visual evoked response is quite well defined. As with the components of the brain-stem auditory evoked response, the latencies of both the positive and negative waves of the visual evoked response decrease in a linear fashion with increasing maturation ( Fig. 10.4 ). This evolution in the quality and latency of the response corresponds well with the behavioral studies of visual function noted in Chapter 9 . That this ontogenetic change is principally an inborn program is suggested by the finding that differences between infants born at term and healthy premature infants grown to term are small, and these differences dissipate completely shortly after the time of term. Although the anatomical substrate for the ontogenetic changes is undoubtedly complex, the major maturational changes correspond to the period of rapid dendritic development in the visual cortex and myelination of the optic radiations (see Chapters 7 and 8 ).
Detection of Disorders of the Visual Pathway
Although neonatal visual evoked responses are not used routinely in clinical practice, premature infants with serious hypoxemia secondary to respiratory distress syndrome were shown to lose visual evoked responses during the insult and to regain the responses with restoration of normal blood gas levels. Similarly, impairment of the visual evoked response has been demonstrated in the first day after asphyxia in term infants, and the severity of the abnormality correlated well with poor neurological outcome. In a study of 36 term infants who experienced birth asphyxia and were studied by serial assessment of visual evoked responses, 14 of 16 infants with normal responses in the first week of life were normal on follow-up, and all 20 with abnormal responses persisting beyond the first week died or were significantly handicapped at 18 months of age. A related observation in fetal and neonatal lambs indicates the sensitivity of the visual evoked response to asphyxial insult. Abnormalities of the visual evoked response have also been described in infants with posthemorrhagic hydrocephalus (see Chapter 24 ), a finding probably reflecting the disproportionate dilation of the occipital horns of the lateral ventricles and consequent affection of the geniculocalcarine radiations. Moreover, improvement in latencies was documented immediately after ventricular tap as well as over a prolonged period after placement of ventriculoperitoneal shunt. The data suggest that the determination of visual evoked responses in the neonatal period provides important information concerning cerebral function, effects of interventions, and outcome.
Electroencephalogram
Normal Development
Maturation of spontaneous EEG recorded activity has been studied in considerable detail in newborn infants, often in combination with studies of sleep states. With increasing gestational age, impressive elaborations of measurable function occur, characterized principally by more refined organization. Whether infants are born at term or grow to term after uncomplicated premature delivery has little or no effect on these developments. The normal development of EEG patterns in the neonatal period is evaluated best in relation to sleep states. In general, active sleep is the predominant sleep state in the newborn and consists of greater than 70% of definable sleep time in the smallest premature infants and approximately 50% in term infants. In the following discussion, we review the major changes in EEG over approximately the 12 to 13 weeks before term. Development of EEG is considered best in terms of the continuity of background activity, the synchrony of this activity, and the appearance and disappearance of specific waveforms and patterns (i.e., EEG developmental landmarks) ( Table 10.7 ).
| CONTINUITY OF BACKGROUND ACTIVITY a | SYNCHRONY OF BACKGROUND ACTIVITY b | ||||||
|---|---|---|---|---|---|---|---|
| POSTCONCEPTIONAL AGE (WEEKS) | AWAKE | QUIET SLEEP | ACTIVE SLEEP | AWAKE | QUIET SLEEP | ACTIVE SLEEP | EEG DEVELOPMENTAL LANDMARKS: SPECIFIC WAVEFORMS AND PATTERNS |
| 27–28 | − | D | D | − | ++++ | ++++ | — |
| 29–30 | D | D | D | 0 | 0 | 0 |
|
| — | — | — | — | — | — | — |
|
| — | — | — | — | — | — | — |
|
| 31–33 | D | D | C | + | + | ++ |
|
| — | — | — | — | — | — | — |
|
| — | — | — | — | — | — | — |
|
| 34–35 | C | D | C | +++ | + | +++ |
|
| — | — | — | — | — | — | — |
|
| — | — | — | — | — | — | — |
|
| 36–37 | C | D | C | ++++ | ++ | ++++ |
|
| — | — | — | — | — | — | — |
|
| 38–40 | C | C | C | ++++ | +++ | ++++ |
|
| — | — | — | — | — | — | — |
|
a C , Continuous activity; D , discontinuous activity.
27 to 28 Weeks.
Activity at this developmental stage is characteristically discontinuous, with long periods of quiescence (see Table 10.7 ). The activity that does interrupt the quiescence occurs in generalized rather synchronous bursts ( Fig. 10.5 ). No distinctions between wakefulness and sleep or change in EEG to external stimulus such as loud sound (i.e., reactivity) are apparent.
29 to 30 Weeks.
The discontinuity of the EEG continues at this stage, but now the activity is asynchronous (see Table 10.7 and Fig. 10.6 ). The principal developmental landmark is the appearance of delta brushes (i.e., delta waves of 0.3 to 1.5 Hz with superimposed fast activity in the beta range, usually 18 to 22 Hz), sometimes also called beta-delta complexes ( Fig. 10.7 ). These complexes appear in the central regions at this stage. In addition, temporal bursts of theta activity (4 to 6 Hz) are a second developmental landmark of this period (see Fig. 10.7 ). These bursts occur independently in left and right temporal areas; their sharp configuration has provoked the term sawtooth pattern .
31 to 33 Weeks.
At this stage, continuous activity appears during active (or rapid-eye-movement) sleep (see Table 10.7 ). Moreover, although EEG is generally asynchronous, a degree of synchrony appears in active sleep. The presence of more synchrony in active sleep than in quiet sleep persists throughout the developmental period of the third trimester. The delta brushes now become more prominent in occipital and temporal areas and are apparent particularly in quiet sleep. The temporal theta bursts of earlier stages give way to temporal alpha bursts, still, however, exhibiting the sharp sawtooth pattern ( Fig. 10.8 ).
34 to 35 Weeks.
The degree of continuity in the EEG now increases further and is apparent in the awake state as well as in active sleep (see Table 10.7 ). In concert, the degree of synchrony increases in the awake and active sleep states. Of the developmental EEG landmarks, the delta brushes now exhibit considerably higher-voltage, faster activity. The temporal theta bursts disappear during this phase. Frontal sharp-wave transients (i.e., sharp waves appearing as an abrupt change from background) become apparent ( Fig. 10.9 ) and are characteristic for their diphasic, synchronous, and generally symmetrical configuration. These normal waves should be distinguished from higher-voltage, unilateral, persistently focal, periodic, or semirhythmic sharp waves, which are abnormal and indicative of focal disease (see later discussion). At this stage, the EEG becomes reactive to external stimuli. Most commonly, this reactivity consists of a generalized attenuation of the amount and voltage of delta activity, especially apparent in response to sound.
36 to 37 Weeks.
The degree of continuity and of synchrony in the awake and active sleep states is still more apparent (see Table 10.7 ). At this stage, for the first time, the EEG in the awake state differs from that in sleep by the presence of low-voltage activity, with a mixture of activities in the alpha, beta, theta, and delta frequency bands ( Fig. 10.10 ). Of the developmental EEG landmarks, the delta brushes in the central region disappear. These are replaced by similar complexes in the occipital regions (i.e., bioccipital delta with superimposed 12- to 15-Hz activity, which appears during active sleep).
38 to 40 Weeks.
At this stage, continuous activity now appears in quiet sleep as well as in active sleep and the awake state (see Table 10.7 ). A considerable degree of synchrony is present in all states. The occipital delta brushes disappear, and the interesting tracé alternant pattern becomes apparent in quiet sleep ( Fig. 10.11 ). This quasiperiodic tracing is characterized by periods of 3 to 15 seconds of generalized voltage attenuation interrupted by higher-voltage, generally synchronous activity. Tracé alternant should not be confused with the more ominous burst-suppression pattern (see later discussion).
Clinical Application
The following sections focus on the application of conventional EEG in the clinical arena. The procedure requires skilled technicians and experienced interpreters of the tracing. Definitive assessment of EEG abnormalities in the premature and term newborn requires conventional multichannel EEG. In the following discussion, we review the principal EEG abnormalities of both the premature and term newborn ( Table 10.8 ) except for the EEG correlates of neonatal seizures (see Chapter 12 ).
| Disordered development |
| Depression: lack of differentiation |
| Excessively discontinuous activity, including burst-suppression pattern |
| Electrocerebral silence |
| Unilateral depression of background activity |
| Periodic discharges |
| Multifocal sharp waves |
| Central positive sharp waves |
| Rhythmic generalized or focal alpha activity |
| Hypsarrhythmia |
Disordered Development.
Delineation of abnormalities of EEG maturation clearly requires awareness of the normal developmental changes described in the previous section. Impairment of development level of more than 3 weeks, according to reported gestational age, is clearly abnormal. Such disturbances are often but not necessarily associated with other EEG abnormalities, and the degree of disturbance may differ according to the state of the infant. Abnormalities may be apparent only in quiet sleep; thus this sleep state should be included in the EEG evaluation of the newborn. Disturbed development of the EEG does not provide specific information regarding disease process and may reflect either an acute or a chronic disturbance.
Depression and Lack of Differentiation.
Depression of background activity, especially of the faster frequencies, often accompanied by lack of differentiation (i.e., disappearance of the normal multiple frequencies), is common after generalized insults, especially hypoxic-ischemic insults ( Fig. 10.12 ). Other EEG abnormalities are also often present. In addition to hypoxia and ischemia, other bilateral cerebral insults may produce this EEG pattern, particularly acutely (e.g., bacterial meningitis, encephalitis, and metabolic disorders). Persistence of this EEG pattern is an unfavorable prognostic sign.
Excessively Discontinuous Activity.
The development of continuous or intermittent discontinuity of EEG in the term infant is a very common feature of all neonatal encephalopathies. The most extreme of these discontinuous tracings is the burst-suppression pattern , which is associated with a very high likelihood of an unfavorable outcome. However, burst-suppression tracings account for the minority of excessively discontinuous neonatal EEGs. Recent data indicate that relatively simple analysis of the latter tracings is highly useful in predicting outcome (see later).
The burst-suppression pattern can be considered the most severe of the excessively discontinuous tracings just described. The EEG pattern is characterized by long periods (usually >10 seconds) of marked depression of background activity (voltage <5 µV), alternating with shorter periods of paroxysmal bursts, usually lasting 1 to 10 seconds and characterized by high-voltage (75 to 250 µV) theta and delta activity with intermixed spikes and waves ( Fig. 10.13 ). This EEG pattern should be distinguished from the normal discontinuous tracing of the very immature premature infant and from the tracé alternant of quiet sleep of the infant beyond 36 weeks of gestation. Two important distinguishing features of the burst-suppression pattern are persistence of the discontinuous pattern throughout the tracing and nonreactivity (i.e., no change in the EEG with arousal attempts and painful or other stimuli). A burst-suppression pattern that is reactive (i.e., is altered by external stimuli) is not as uniformly associated with a poor prognosis as the nonreactive variety described here. The poor prognosis of various EEG backgrounds, including burst-suppression, for infants with hypoxic-ischemic injury is shown in Table 10.9 . Bacterial meningitis is the one disturbance in which I have seen a favorable outcome despite the finding of a burst-suppression EEG during the acute disease.
| BACKGROUND PATTERN | SENSITIVITY (95% CI) | SPECIFICITY (95% CI) |
|---|---|---|
| Burst suppression | 0.87 (0.78–0.92) | 0.82 (0.72–0.88) |
| Low voltage | 0.92 (0.72–0.98) | 0.99 (0.87–1.0) |
| Flat trace | 0.78 (0.58–0.91) | 0.99 (0.88–1.0) |
Analysis of the duration of the predominant interburst interval (IBI) has proven to be a relatively simple means of quantitation of excessively discontinuous tracings in the term infant, and the analysis has major prognostic implications. Thus, of 43 term infants (70% with hypoxic-ischemic encephalopathy) with an excessively discontinuous EEG, 10 parameters regarding the burst and IBIs were quantitated and compared with outcome. One parameter, the IBI duration that accounted for more than 50% of all IBI durations (classified into 10-second blocks), also known as the predominant IBI duration , predicted an unfavorable neurological outcome with high specificity ( Table 10.10 ). Thus, IBI durations lasting longer than 30 seconds were invariably associated with an unfavorable outcome, and those with a duration of more than 20 seconds were associated with an unfavorable outcome in 92%. Of the 43 discontinuous tracings, only 7 (16%) exhibited a burst-suppression pattern , as defined earlier. Thus, the predominant IBI duration, readily quantitated at the bedside , was highly effective and, critically, applicable to the large group of excessively discontinuous tracings in term newborns with encephalopathy.
| PREDOMINANT INTERBURST INTERVAL DURATION b | UNFAVORABLE OUTCOME c |
|---|---|
| >30 s | 10/10 (100%) |
| >20 s | 12/13 (92%) |
| >10 s | 24/33 (72%) |
a Data from Menache CC, Bourgeois BFD, Volpe JJ. Prognostic value of neonatal discontinuous EEG. Pediatr Neurol . 2002;27:93–101.
b Interburst interval duration was obtained by manual measurement with classification into 10-second subintervals (1–10, 11–20, 21–30, >40 seconds); the predominant interval was defined as the interval that accounted for more than 50% of all interburst interval durations.
c Death or moderate or severe motor and cognitive deficits were noted on follow-up.
Electrocerebral Silence.
Electrocerebral silence, of course, is the worst end of the continuum from depressed EEG through excessive discontinuity and burst-suppression pattern. Persistence of electrocerebral silence for 72 hours or more is indicative of cerebral death. However, electrocerebral silence indicates cerebral cortical death and not necessarily brain-stem death; if clinical evidence of persistent brain-stem failure is not present, survival is possible, although in a persistent vegetative state (see Chapter 9 ).
Unilateral Depression of Background Activity.
A marked voltage asymmetry between hemispheres of background rhythms that persists in all states is clearly different from the normal shifting asymmetries, particularly during quiet sleep ( Fig. 10.14 ). Such persistent unilateral depressions of background activity are indicative usually of a unilateral cerebral lesion that is ischemic, hemorrhagic, or dysgenetic.
Periodic Discharges.
Numerous periodic discharges may be seen in neonatal disease states. These complexes may be either strikingly periodic ( Fig. 10.15 ) or only quasiperiodic. They can be separated from the normal transients noted earlier by their higher voltage, generally longer duration, often polyphasic appearance, and persistent focality. The discharges are located more commonly in the central regions in the premature and in temporal regions in term infants ( Table 10.11 ). Neuropathological substrates are multiple in premature infants, but in the term infant the most common is infarction in the distribution of the middle cerebral artery.
| PRETERM | TERM | |
|---|---|---|
| Characteristics of discharge | ||
| Location | Vertex-central | Temporal |
| Duration | <1 min | >1 min |
| Associated electrographic seizures | 35% | 88% |
| Origin | ||
| Infarction | 15% | 88% |
| Periventricular leukomalacia | 27% | 0 |
| Other structural abnormalities | 27% | 0 |
| Unknown | 31% | 12% |
| Outcome | ||
| Death | 46% | 38% |
| Deficits | 27% | 50% |
| Normal | 27% | 12% |
Watanabe and co-workers showed the predictive value of frontal or occipital sharp waves in identifying cystic periventricular leukomalacia ( Table 10.12 ). Thus the presence of one or both of these abnormal sharp waves was superior to the presence of positive rolandic sharp waves (see later) in sensitivity for identifying white matter injury.
| Frontal or occipital sharp waves, or both, present in 100% of cases of severe PVL and in 60%–70% of cases of mild or moderate PVL |
| PRSs present in 65%–90% of cases of severe white matter lesions (i.e., PVL, periventricular hemorrhagic infarction); sensitivity lowest for the most immature infants and for mild or moderate PVL (present in 25% of cases) |
| PRSs generally apparent when white matter lesions are echodense but not yet cystic by ultrasonography |
| Lateralization or symmetry of the abnormal waves generally corresponding to lateralization or symmetry of white matter necrosis |
| Onset of the abnormal waves as early as 2 days, generally peaking between 5 and 14 days; cystic PVL noted generally 5–10 days later |
Multifocal Sharp Waves.
Multifocal sharp waves are sharp waves of high voltage and relatively long duration occurring in multiple cerebral foci ( Fig. 10.16 ). These discharges tend to predominate in temporal regions and are usually accompanied by other EEG abnormalities. The types of underlying pathological features are multiple, and their specific nature determines outcome.
Central Positive Sharp Waves.
These distinctive sharp waves, often termed positive rolandic sharp waves , are surface positive and occur either unilaterally or bilaterally in central regions ( Fig. 10.17 ). Their particular relation to periventricular white matter injury in the premature infant has been established (see Table 10.12 and Chapter 16 ). The apparently superior value of frontal (positive) or occipital (negative) sharp waves regarding sensitivity for white matter injury is discussed earlier (see Table 10.12 ).
Rhythmic Generalized or Focal Alpha Frequency Activity.
This rare discharge may be generalized or focal and consists of periods of rhythmic 8- to 9-Hz activity that is generally synchronous ( Fig. 10.18 ). The activity tends to predominate in the central or temporal regions (an alpha pattern that occurs with seizure is not synchronous). This pattern has been noted with chromosomal abnormalities and inborn errors of metabolism.
Hypsarrhythmia.
Although the classical hypsarrhythmic EEG with infantile myoclonic spasms does not usually occur until the second month of life or later, one variety may appear in the newborn ( Fig. 10.19 ). Hypsarrhythmia is characterized by periods of marked voltage attenuation interrupted by bursts of asynchronous, high-voltage, slow activity mixed with multifocal spikes and sharp waves. This pattern is differentiated from the burst-suppression pattern described earlier, particularly by the high voltage of the activity during the bursts; in hypsarrhythmia, voltage may reach 1000 µV, whereas in a typical burst-suppression pattern, the voltage of the bursts is usually less than 250 µV.
Value of Serial EEG.
The particular value of serial EEG in estimating outcome is pronounced. A single EEG, particularly during the acute phase of the disease, may suggest a more ominous outcome than do subsequent EEG studies. The EEG evolves following injury, and the rate of improvement of EEG may be a stronger predictor of outcome than a single EEG in infants with hypoxic-ischemic injury (see Chapter 20 ). This point is illustrated well by the data recorded in Table 10.13 , based on a study of 62 infants.
| OUTCOME | ||||
|---|---|---|---|---|
| EEG | NORMAL | SUSPECT | ABNORMAL | DEATH |
| Normal, mildly abnormal, or only one EEG moderately abnormal | 76% | 13% | 4% | 7% |
| Moderately abnormal (≥2 EEGs) or any markedly abnormal | 6% | 6% | 63% | 25% |
Amplitude-Integrated Electroencephalogram
Methodology and Rationale
Amplitude-integrated EEG (aEEG) is an increasingly used method for the continuous monitoring of cerebral electrical activity in critically ill newborns. It involves either a single-channel recording obtained from one pair of biparietal electrodes or a dual-channel recording from two pairs of electrodes, one pair for each hemisphere. The EEG signal is band-pass filtered to attenuate activity lower than 2 Hz and higher than 15 Hz (to minimize artifacts). The signal is rectified and further processed before being displayed on a modified semilogarithmic scale at a relatively compressed time scale. With many devices, it is possible to select areas of recording and display the corresponding, expanded raw EEG trace, which is useful for confirming possible seizure activity.
Among the particular values of this method is ease of application, which means that aEEG leads may be placed by trained personnel in the neonatal intensive care unit (NICU) without necessarily involving a specially trained EEG technologist. Other advantages include the ability to monitor continuously and the capacity to detect seizures, particularly on devices with seizure-detection software. Further, the information provided on background activity can be useful for determining the degree of encephalopathy, effects of drugs, and prognosis. One disadvantage is that the device does not cover the entire brain, thereby potentially missing some focal abnormalities.
Recording
aEEG recordings are evaluated especially for background and seizure activity. The major background patterns identified are termed continuous normal voltage, discontinuous normal voltage, burst suppression, continuous low voltage , and flat trace ( Fig. 10.20 ). As described later, the last three of these are ominous tracings. Discontinuous normal voltage is considered an intermediate tracing.
Seizure activity on aEEG is characterized in general as a rapid rise in both the lower and upper margins of the trace ( Fig. 10.21 ). The experience of the reader is important for detection (see later).
Clinical Applications
As noted earlier, the principal clinical applications of aEEG are assessment of term infants shortly after perinatal asphyxia and detection of seizures . The value of aEEG in the former instance appears well established, whereas the role in seizure detection requires further clarification.
Assessment of Asphyxiated Term Infants.
aEEG has proven very useful in assessment of the asphyxiated term newborn. A particular goal has been to identify, in the first hours after birth, the likely outcome of the asphyxiated infant. The aEEG background tracings have been most useful, particularly the burst-suppression, continuous low-voltage, and flat trace patterns. In one large study, the positive predictive value for unfavorable outcome for aEEG detection of severe abnormalities at 3 hours of life was 78%; at 6 hours, it was 86%. The positive predictive value at 6 hours has been similar in other studies. Notably, approximately 10% to 40% of infants with marked background abnormalities may normalize within 24 hours, and more than 50% of this minority group will have a favorable outcome. Thus, monitoring the course of aEEG changes is useful, although for identification of candidates for neuroprotective therapies, such as therapeutic hypothermia, early detection is crucial (see Chapter 20 ). Finally, and of additional importance, although aEEG in the first 6 hours was superior to neonatal neurological examination in identifying infants with an unfavorable short-term outcome, the combination of aEEG and the neurological examination was optimal, with a specificity of 94%.
Detection of Seizures.
The value of aEEG in detection of seizures has been assessed primarily in asphyxiated term infants. aEEG was not designed as a seizure monitor, although some very experienced users of the method appear skilled at seizure detection. Nevertheless, in one comparative study of aEEG and standard EEG with experienced observers, of 10 infants with ictal activity on EEG, 8 were detected by aEEG, and notably of 16 infants with interictal “multifocal epileptiform activity,” only 4 were identified by aEEG. In addition, the experience of the observer is very important in aEEG detection of seizure activity. Thus, in one study involving four neonatologists with no prior experience with aEEG and trained for 3 to 5 hours in seizure detection on the aEEG tracing, only 38% of seizures were detected at the usual paper speed of 6 cm/h. Moreover, focal, low-amplitude, or brief seizures are also readily missed by aEEG. A more recent study comparing seizure detection by conventional EEG and two-channel aEEG with access to the raw EEG trace and using seizure-detection software showed better aEEG performance; the sensitivity, specificity, positive predictive value, and negative predictive value of aEEG were 75% to 80%. Thus the use of modern equipment is imperative for seizure detection with aEEG.
Other Applications.
In initial studies, aEEG has proven useful for a variety of other applications. Thus the method has been used for delineating the effects of anticonvulsant drugs (e.g., midazolam, phenobarbital), evaluating sleep-wake cycling in asphyxiated infants, predicting postneonatal epilepsy in asphyxiated infants, defining maturational changes in preterm infants, and predicting outcome in premature infants with large intraventricular hemorrhage. Related methods, involving spectral analysis of the EEG and focused more on frequency than on amplitude, are in the developmental stage in the study of the premature infant.
Structural Brain Imaging
The three major techniques for demonstrating normal and abnormal brain structure are ultrasonography, computed tomography (CT), and MRI. Ultrasound imaging is the most conveniently performed of these three procedures. CT was the first of the three methods to be used clinically but is now used sparingly, in considerable part because of the radiation exposure. MRI provides the greatest resolution and versatility, and advanced MRI techniques allow evaluation of microstructure and functional networks (see later). Cranial ultrasonography and CT are long-established techniques in the study of the newborn brain; they are noted only briefly here but are illustrated in most chapters of this book. I discuss MRI in more detail, including advanced MRI methods, because this modality has provided important insights into aspects of normal brain development.
Ultrasonography
Ultrasound scanning is one of several techniques that capitalize on the bone-free anterior fontanelle to provide a window into the neonatal brain. In addition, use of the posterior fontanelle and of the mastoid fontanelle has markedly improved the value of ultrasonography in the evaluation of posterior fossa structures. The enormous value of the technique in the study of the neonatal brain has been documented in a vast number of original papers and reviews and in several books. The specific uses of the technique are documented throughout this book, but it is important simply to emphasize here the value of ultrasound scanning in identification of such diverse intracranial processes as the following: developmental aberrations; hypoxic-ischemic injury; subdural, germinal matrix-intraventricular, and posterior fossa hemorrhage; ventriculitis; tumors; cysts; and vascular anomalies. The basic principles of the technique and the major normal anatomical features, reviewed in previous editions of this book, are summarized in standard writings. The correspondence between ultrasound imaging planes and brain anatomy is shown in Fig. 10.22 .
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