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Specialized Neurological Studies
CEREBROSPINAL FLUID EXAMINATION
Examination of the cerebrospinal fluid (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 by Sarff and co-workers and Rodriguez and co-workers are the most informative (although all of 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 13.1 ). Mean values for term and preterm infants, respectively, were for WBC counts of 8 and 9 cells/mm 3 (60% polymorphonuclear leukocytes), protein concentrations 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 evaluation of neonatal CSF.
TABLE 13.1
Cerebrospinal Fluid Findings in High-Risk Newborns
Data from Sarff LD, Platt LH, McCracken GH Jr. Cerebrospinal fluid evaluation in neonates: comparison of high-risk infants with and without meningitis. J Pediatr 1976;88:473–477; based on 87 term infants and 30 low-birth-weight infants (<2500 g), 95 of whom were examined in the first week of life.
| FINDINGS | TERM | PRETERM |
|---|---|---|
| White Blood Cell Count (cells/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 13.2 ). 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 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 13.1 ), 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) was 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 were similar to those reported by Sarff and co-workers, the percentage of polymorphonuclear leukocytes (7%) was 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. In a more recent study of 148 preterm and 170 term infants, the upper reference limit of the CSF WBC count was 12 cells/mm 3 in preterm infants and 14 cells/mm 3 in term infants. CSF protein levels were significantly higher in preterm infants (upper reference limit, 209 mg/dL vs. 159 mg/dL in term infants; p < .001) and declined with advancing postnatal age in both groups (preterm, p = .008; term, p < .001). CSF glucose levels did not differ in term and preterm infants.
TABLE 13.2
Cerebrospinal Fluid Findings in High-Risk Infants of Low Birth Weight (<1500 g)
Data from Rodriguez AF, Kaplan SL, Mason EO Jr. Cerebrospinal fluid values in the very low birth weight infant. J Pediatr 1990;116:971–974; based on 43 infants, some studied more than once, approximately 80% studied after the first week of life.
| POSTCONCEPTIONAL AGE (WEEKS) | WHITE BLOOD CELL COUNT (CELLS/mm 3 ± SD) | GLUCOSE (mg/dL ± SD) | PROTEIN (mg/dL ± SD) |
|---|---|---|---|
| 26–28 | 6 ± 10 | 85 ± 39 * | 177 ± 60 * |
| 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 |
* Values for glucose and protein were significantly greater at 26–28 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 Chapter 38, Chapter 39 ), 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 RBC in neonatal CSF is hindered by the relatively high incidence of germinal matrix–intraventricular hemorrhage, usually clinically silent in the preterm infant (see Chapter 28 ), 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 (0–45,000) ( Table 13.3 ). 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 by 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 RBC/mm 3 (see Table 13.3 ). 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.
TABLE 13.3
Red Blood Cell Counts (Cells/mm 3 ) in Cerebrospinal Fluid of High-Risk Newborns
| SARFF AND CO-WORKERS ⁎ | |
|---|---|
| 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 † | |
| Preterm infants (<1500 g) | n = 43 |
| Mean: 785 | |
| >1000 cells/mm 3 in 20% of samples | |
* Data from Sarff LD, Platt LH, McCracken GH Jr. Cerebrospinal fluid evaluation in neonates: comparison of high-risk infants with and without meningitis. J Pediatr 1976;88:473–477.
† Data from Rodriguez AF, Kaplan SL, Mason EO Jr. 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 importance of combinations 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 26 . Contamination with red blood cells due to a traumatic lumbar puncture makes interpretation for WBC complicated, and correction factors are needed.
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 brainstem auditory evoked responses, visual evoked responses, somatosensory evoked responses and electroencephalography (EEG; including amplitude-integrated EEG). The most widely used of these neurophysiological techniques, EEG, also is discussed regarding seizures in Chapter 15 .
Brainstem Auditory Evoked Responses
Electrophysiological investigation of the auditory system in the newborn has focused on brainstem 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, and these responses demonstrate 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 detection of a decrease in latency from 300 milliseconds at 29 weeks of gestation to 150 milliseconds 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 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 brainstem auditory evoked response ).
Major Waveforms and Anatomical Correlates
The brainstem 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. 13.1 ). Studies in animals and in 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 probably are generated in the thalamus and thalamic radiations, respectively. Brainstem 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 brainstem auditory response have been described. 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. 13.2 ). 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 brainstem auditory evoked response studies in detecting disorders of the auditory pathways in the newborn infant. Definition of such disorders depends on 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 of the potentials, including wave I, whereas a lesion in the brainstem 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 brainstem auditory evoked responses observed in neonatal patients are depicted in Table 13.4 .
TABLE 13.4
Two Basic Abnormal Patterns of Brainstem Auditory Evoked Responses in Neonatal Disease
| SITE OF DISORDER | ||
|---|---|---|
| RESPONSE CHARACTERISTIC | PERIPHERY | BRAINSTEM |
| 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 brainstem nuclei, and the cochlea itself by hypoxic-ischemic insult (see Chapter 22 ); the cochlear nuclei, inferior colliculus, and, perhaps, the cochlea or eighth nerve by hyperbilirubinemia (see Chapter 30 ); the eighth nerve by bacterial meningitis (see Chapter 39 ); the cochlea and eighth nerve by congenital viral infections (see Chapter 38 ); and the cochlea by intracranial hemorrhage (see Chapter 26 ) ( Table 13.5 ). Indeed, brainstem 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. 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 brainstem 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 brainstem latencies), and 4% a combined impairment, for a total of 27%.
TABLE 13.5
Probable or Proven Examples of Neonatal Neurological Disease with Abnormal Brainstem Auditory Evoked Responses
| 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 brainstem 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. 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.
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. The initial screening procedure has consisted of conventional brainstem auditory evoked response, automated auditory evoked response, or transient evoked otoacoustic emission. The latter 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. It is recommended that low-birth-weight infants be tested before discharge, but even when tested at term, failure rates as high as 20% to 25% are common. Retesting infants after test failure usually is 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, 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 13.6 ).
TABLE 13.6
Follow-Up Audiologic Diagnostic Evaluation for Infants Who Pass Their Initial Hearing Screening
Adapted from the State of Massachusetts recommendations.
| IMMEDIATELY AFTER DISCHARGE | BY 3 MONTHS OF AGE | AT 6–9 MONTHS OF AGE |
|---|---|---|
|
|
|
CHARGE , coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities and ear abnormalities; CMV , cytomegalovirus; ECMO , extracorporeal membrane oxygenation; NICU , neonatal intensive care unit.
Visual Evoked Responses
Cortical Response
The 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, 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 in 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. 13.3 ). 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 brainstem 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. 13.4 ). This evolution in the quality and latency of the response corresponds well with the behavioral studies of visual function noted in Chapter 12 . 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 Chapter 7, Chapter 8 ).
Detection of Disorders of the Visual Pathway
Though 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 who 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. More recently, visual evoked potentials (VEPs) were studied in 35 infants who received therapeutic hypothermia and had a normal magnetic resonance imaging (MRI) scan. Flash visual evoked potentials showed a good positive predictive value (PPV) (0.91; 95% confidence interval [CI], 0.62–0.99) and specificity (0.93; 9% CI, 0.70–0.99) and performed better than somatosensory evoked potentials (SEPs) in predicting 2-year outcome. In another study of 54 neonates with hypoxic-ischemic encephalopathy (HIE) and receiving hypothermia, it was shown that the presence of P200 and N300 peaks was associated with decreased odds of brain injury in the visual processing pathway, whereas a delayed or absent N300 peak was associated with increased odds of brain injury in the posterior white matter. Abnormalities of the visual evoked response have also been described in infants with posthemorrhagic hydrocephalus (see Chapter 28 ), 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, within a week after ventricular reservoir placement, 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.
Somatosensory Evoked Responses
The somatosensory evoked response refers to the electrical response generated in the primary somatosensory cortex. The main neuro-axis of the tract from periphery to cortex contains the peripheral nerve, brachial plexus, dorsal root, posterior column, cuneate nucleus, and, after decussation, medial lemniscus, thalamus, and parietal cortex. The cortical response is elicited by an electrical stimulus, administered by bipolar transcutaneous electrical stimulation, applied on the skin to the upper limb (median nerve) or lower limb (posterior tibial nerve).
Major Waveforms and Anatomical Correlates
After median nerve stimulation, the first negative wave that can be recorded from an electrode placed over Erbs point (brachial plexus) is the N9. Negative waves N11 and N13 can be measured over the lower cervical vertebrae. At the scalp, contralateral to the site of stimulation and overlying the primary somatosensory cortex, wave N19 is recorded, which is considered to be cortically mediated. In the newborn, this component is usually referred to as N1. The N19 is followed by a positive component P22, not present in a preterm infant but often present in the term neonate.
Developmental Changes
It is possible to record SEPs in preterm neonates from 25 weeks of gestational age onward. In preterm infants the latency of the cortical peaks decreases as the infants mature, coinciding with increased waveform complexity ( Fig. 13.5 ). No effect was found of extrauterine life on maturation in infants born preterm.
Detection of Disorders of the Somatosensory Pathway
Several studies were reported in the 1990s showing a predictive value of especially motor outcome in full-term infants with perinatal asphyxia. In one study, 34 infants were studied within 6 hours after birth, comparing the predictive value of amplitude-integrated EEG (aEEG), SEPs and VEPs, cranial ultrasound, and Doppler ultrasound. The predictive value of the aEEG and SEPs were better than the other techniques that were studied, with a PPV of 81.8% and negative predictive value (NPV) of 91.7% for the SEPs. Because the aEEG provides similar results (PPV 84.2%; NPV 91.7%) and this technique is easier to use and provides continuous information, since its introduction, evoked potentials are often not performed. Furthermore, SEPs are also more difficult to perform than auditory or visual evoked potentials in the neonatal period. More recently, several studies have been reported using SEPs in infants who received therapeutic hypothermia, and the SEP tended to be performed following rewarming. In the study by Nevalainen and colleagues, 28 of the 50 infants included were treated with hypothermia. The flash VEPs and SEPs were performed between 15 hours and 10 days, simultaneously with the routine EEG. The prediction accuracy was highest with SEPs (98%), followed by EEG (90%), and lowest with VEPs (84%). In contrast to earlier prehypothermia studies, in which SEPs were considered abnormal when there was a delay or absence in latency, in this study only absent responses were considered an abnormal response. In the subgroup of newborns who received therapeutic hypothermia the prediction accuracy of SEPs was 100%, and that of EEG was 96%. Similar data were seen in a larger group of 58 infants, all treated with hypothermia and evaluated by neonatal MRI rather than neurodevelopmental outcome. Bilaterally absent responses were noted in 10/58 neonates (17%), and all showed moderate/severe MRI abnormalities; 36/48 neonates with present SEPs had normal MRI (75%). The PPV of SEPs for MRI outcome was 1.00, and the NPV was 0.72. The data obtained in the largest study so far, enrolling 84 cooled infants, confirmed previous data, with a significant relation between abnormal SEPs and injury, especially to the basal ganglia/thalami and internal capsule, and with 2-year outcome. In contrast to studies mentioned earlier, in a recent paper, SEPs were performed during the first postnatal days and were elicited during aEEG and EEG recording in 25 infants ( Fig. 13.6 ). Five infants had bilateral absent responses using either aEEG or EEG and had an unfavorable 12-month outcome. Of 18 infants with bilateral responses on aEEG, 17 had a normal outcome. In another study from the same group, 74 infants with HIE were studied and seen for follow-up to assess development of postneonatal epilepsy, which was noted in 6. Severe HIE, absence of SEPs, and poor EEG and MRI scores were all significantly associated with developing postneonatal epilepsy. Evaluating the predictive value of neurophysiological and neuroimaging markers, the overall accuracy was highest (97%) for inactive EEG (sensitivity 67%, PPV 100%) and bilaterally absent SEPs (sensitivity 100%, PPV 75%). All of these studies suggest that SEPs can provide additional valuable information in infants with HIE .
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 13.7 ).
TABLE 13.7
Developmental Aspects of Electroencephalographic Activity
Adapted from Hrachovy RA, Mizrahi EM, Kellaway P. Electroencephalography of the newborn. In: Daly DD, Pedley TA, eds. Current Practice of Clinical Electroencephalography . 2nd ed. New York: Raven Press; 1990.
| CONTINUITY OF BACKGROUND ACTIVITY | SYNCHRONY OF BACKGROUND ACTIVITY | ||||||
|---|---|---|---|---|---|---|---|
| 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 | ++++ | +++ | ++++ |
|
|
|||||||
0 , Total asynchrony; ++++ , total synchrony; C , continuous activity; D , discontinuous activity; EEG , electroencephalographic.
27 to 28 Weeks
Activity at this developmental stage is characteristically discontinuous, with long periods of quiescence (see Table 13.7 ). The activity that does interrupt the quiescence occurs in generalized, rather synchronous bursts ( Fig. 13.7 ). 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 13.7 ; Fig. 13.8 ). 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. 13.9 ). 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. 13.9 ). 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 13.7 ). 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. 13.10 ).
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 13.7 ). 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. 13.11 ) 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, 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 13.7 ). At this stage, for the first time, 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. 13.12 ). 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 13.7 ). 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. 13.13 ). 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).
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