Chapter 4. Specialized Studies in the Neurological Evaluation

Chapter 4

TABLE 4-1



Cerebrospinal Fluid Findings in HighRisk Newborns



Findings



Term



9±6

0–29



Protein Concentration

(mg/dL)

Mean

Range



90

20–170



115

65–150



Glucose Concentration

(mg/dL)

Mean

Range



52

34–119



50

24–63



74

55–105



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 88:473-477, 1976; based on

87 term infants and 30 low-birth-weight infants (<2500 g), 95 of

whom were examined in the first week of life.



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 11)

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,11 the median

value for RBC count was 180, with a very wide range

(0 to 45,000) (Table 4-3). 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,12 although a median value

of 112 was observed, the mean was 785, and 20% of

CSF samples had more than 1000 RBC/mm3 (see Table

4-3). These infants were smaller (<1500 g), but



SARFF AND CO-WORKERS*

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/mm3

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 88:473-477, 1976.

{Data from Rodriguez AF, Kaplan SL, Mason EO Jr: Cerebrospinal fluid

values in the very low birth weight infant, J Pediatr 116:971-974,

1990.



ultrasonographic examinations were said to show no

evidence of intracranial hemorrhage. However, exclusion of minor subarachnoid hemorrhage by cranial

ultrasonography is not reliable.

The aforementioned data indicate that the finding of

more than 100 RBCs/mm3 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 10.

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, I particularly discuss brain stem

auditory evoked responses, visual evoked responses,

somatosensory evoked responses, and EEG (including



Cerebrospinal Fluid Findings in High-Risk Infants of Low Birth Weight (<1500 g)



Postconceptional

Age (Weeks)

26–28

29–31

32–34

35–37

38–40



Red Blood Cell Counts (Cells/mm3) in

Cerebrospinal Fluid of High-Risk Newborns



Term infants



Cerebrospinal Fluid/Blood

Glucose (%)

Mean

81

Range

24–248



TABLE 4-2



TABLE 4-3



Preterm



White Blood Cell Count

(cells/mm3)

Mean ± standard deviation 8 ± 7

Range

0–32



155



Specialized Studies in the Neurological Evaluation



White Blood Cell Count

(cells/mm3 ± SD)

6

5

4

6

9



±

±

±

±

±



10

4

3

7

9



Glucose (mg/dL ± SD)

85

54

55

56

44



±

±

±

±

±



39*

81

21

21

10



Protein (mg/dL ± SD)

177

144

142

109

117



±

±

±

±

±



60*

40

49

53

33



*Values for glucose and protein were significantly greater at 26 to 28 weeks than at subsequent postconceptional ages.

SD, standard deviation.

Data from Rodriguez AF, Kaplan SL, Mason EO Jr: Cerebrospinal fluid values in the very low birth weight infant, J Pediatr 116:971-974, 1990; based

on 43 infants, some studied more than once, approximately 80% studied after the first week of life.



156



Unit II



NEUROLOGICAL EVALUATION



V



I

III

IV



VI

II



Figure 4-1 Brainstem auditory-evoked response, major wave

forms. The responses obtained with several sequential trials

were superimposed. The complete response, with the seven

definable waves, is not observed in the newborn (see text for

details). (From Starr A, Amlie RN, Martin WH, Sanders S:

Development of auditory function in newborn infants revealed

by auditory brainstem potentials, Pediatrics 60:831-839, 1977.)



+

100 nV

–



2 msec



amplitude-integrated EEG). The most widely used of

these neurophysiological techniques, EEG, also is discussed regarding seizures in Chapter 5.

Brain Stem Auditory Evoked Responses

Electrophysiological investigation of the auditory

system in the newborn has 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,17-33 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.34,35 This work is noteworthy for detection

of a decrease in latency from 300 milliseconds at 29

weeks of gestation to 150 milliseconds at term. 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 Wave Forms 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 signal is amplified, then summed in a computer,

and finally displayed by an X-Y plotter for measurements of the latency and amplitude of the various

components.23,24,36-42 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. 4-1).24,36,39 Studies in animals and in

adult humans indicate that the waves derive from

sequential activation of the major components of the

auditory pathway.37,38,43-45 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. Brain stem auditory potentials have been well

defined in the newborn infant,23,24,36,39-41,46-61

although all seven components are not observed (see

later discussion).

Developmental Changes

Impressive ontogenetic changes in the brain stem auditory response have been described.23,24,36,39,47,49,

50,54,55,61-75 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.36

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. 4-2). Moreover, an increase in amplitude and a decrease in threshold of the response occur

with increasing gestational age.

The decrease in latency of wave I with maturation

indicates improvement in peripheral processing of the

auditory stimulus. Whether this effect is at the level of

middle ear conduction, the cochlear receptors, or the



Chapter 4

Brain stem evoked responses

60 dB 10 cs (N = 74)

Maturation of Wave I & V



157



Specialized Studies in the Neurological Evaluation



8

(IV-V)-I



9.5

Latency (msec)



7

9.0



8.5

Wave V



Latency (msec)



8.0



6



5

1.10 msec



7.5



4

24

0.85 msec



7.0



2.5



Wave I



0.95 msec

0.30 msec



2.0

30-31



32-33



34-35 36-37 38-39

Gestational age (wk)



28



40



30

34

32

36 38

Conceptional age (wk)



42



44



Figure 4-3 Decrease in latency of brain stem portion (i.e., time difference between waves I and IV to V) of brain stem auditory evoked

response as a function of gestational age. (From Starr A, Amlie RN,

Martin WH, Sanders S: Development of auditory function in newborn

infants revealed by auditory brainstem potentials, Pediatrics 60:831839, 1977.)



3.5



3.0



26



40-41



42-43



Figure 4-2 Decrease in latencies of major waves of neonatal brain

stem auditory evoked response as a function of gestational age.

(From Despland PA, Galambos R: The auditory brainstem response

[ABR] is a useful diagnostic tool in the intensive care nursery,

Pediatr Res 14:154-158, 1980.)



transduction of cochlear receptor potentials into eighth

nerve activity (i.e., wave I) is unknown.

The time difference between wave I and the wave IVV complex depends on transmission through the brain

stem auditory pathway (i.e., the brain stem transmission

time), and this maturational change is shown in Figure

4-3. Whether this decrease in latency relates to changes

in nerve conduction velocity or synaptic efficiency is

unknown. Active myelination within this brain stem

system is occurring during the time period shown in

Figure 4-3 (see Chapter 2); however, distinct postnatal

changes in brain stem auditory evoked responses69,70,76

appear to occur after rapid myelination has ceased.

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.23,24,36,39-41,53,56-61,77-104 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 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 4-4.

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 8); the cochlear

nuclei, inferior colliculus and, perhaps, the cochlea or

eighth nerve by hyperbilirubinemia (see Chapter 13);

the eighth nerve by bacterial meningitis (see Chapter

21); the cochlea and eighth nerve by congenital viral

infections (see Chapter 20); and the cochlea by intracranial hemorrhage (see Chapter 11) (Table 4-5).

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

TABLE 4-4



Two Basic Abnormal Patterns of

Brain Stem Auditory Evoked

Responses in Neonatal Disease

SITE OF DISORDER



Response

Characteristic



Periphery



Brain Stem



Threshold (wave I)

Wave I latency

Wave V latency

I–V interval



Elevated

Prolonged

Prolonged

Normal



Normal

Normal

Prolonged

Prolonged



158

TABLE 4-5



Unit II



NEUROLOGICAL EVALUATION



Probable or Proven Examples of Neonatal

Neurological Disease with Abnormal Brain

Stem Auditory Evoked Responses



Neurological Disorders



Relevant Neuropathology



Hypoxic-ischemic

encephalopathy

Hyperbilirubinemia



Cochlear nuclei, inferior colliculus, cochlea

Cochlear nuclei, inferior colliculus, cochlea, eighth

nerve

Eighth nerve

Cochlea, eighth nerve

Cochlea



Bacterial meningitis

Congenital viral infection

Intracranial hemorrhage



or furosemide administration, trauma to the cochlea or

middle ear, and still undefined complications of low

birth weight.23,24,36,39-41,56-61,75,77,79-93,96,97,100,102,104,

105,105a 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.59 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%.57

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 is the norm in

many countries.24,39,94,98,99,102,106,107 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.24,39,89,98-102,106,108-114

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.24,98,99,106,110,112 The initial

screening procedure has consisted of conventional

brain stem auditory evoked response, automated auditory evoked response, or transient evoked otoacoustic

emission technique. 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.106,107,112 Notably, retesting in the

neonatal unit has been shown to result in reduction of

failure rate by at least 80%.114 The incidence of failure

of either screening test at the time of hospital discharge

is relatively high, 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.24,94 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,24,39,49,52,53,94,98,99,106,110,114 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.114 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.81,82,112



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.115-117 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.118

Two features of the response are studied: the quality of

the wave form 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).37,38,115,119-121 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,37,38,115,119,120,122

including the preterm newborn,119,120,123 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.115117,119-121,124-136 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



Chapter 4



Specialized Studies in the Neurological Evaluation



159



VEP latency vs gestational age

350



24 wk



320



N300

27 wk

+

5 μV



Latency (msec)



22 wk



290



260



230



29 wk

+

12 μV



200

24



27



30

33

Gestational age (wk)



36



VEP amplitude vs gestational age

300

P200



37 wk



40 wk

+

2.5 μV



0



200



400

600

msec



800



1000



Figure 4-4 Visual evoked potentials to light-emitting diode stimulation from newborn infants, showing no recordable response at

22 weeks of postconceptional age (PCA), the emergence of N300

at 24 weeks of PCA, the late positivity following the N300 (usually

c 450 milliseconds), which is evident from about 27 weeks onward,

and then little change until closer to term. The P200 then emerges

and becomes the most prominent wave in the normal term newborn’s

visual evoked potential. (From Taylor MJ: Visual evoked potentials. In

Eyre JA, editor: The Neurophysiological Examination of the Newborn

Infant, New York: 1992, MacKeith Press.)



noted earlier (Fig. 4-4). 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. 4-5). This evolution in the quality

and latency of the response corresponds well with the

behavioral studies of visual function noted in Chapter 3.

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,137 and these differences

dissipate completely shortly after the time of term.138

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 2).



240

Amplitude (μV)



+

5 μV



180

120

60



0

24



27



30



33



36



Gestational age (wk)

Figure 4-5 Visual evoked potential (VEP) latency and amplitude

versus gestational age (ga) in weeks in 86 preterm infants. The

regression line and the 95% confidence interval are indicated.

(Latency = 370.7 À 3.4 Â ga; amplitude = 440.4 À 11.2 Â ga.)

(From Pryds O, Trojaborg W, Carlsen J, Jensen J: Determinants of

visual evoked potentials in preterm infants, Early Hum Dev 19:117125, 1989.)



Detection of Disorders of the Visual Pathway

Attempts to use the neonatal visual evoked response as a

measure of cerebral disturbance have been promising.22,23,41,115,117,121,132,135,136,139-147 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 (Fig. 4-6).133,139

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.41,135,142,147

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.147 A related

observation in fetal and neonatal lambs indicates



160



Unit II



NEUROLOGICAL EVALUATION



is demonstrated as a function of increasing gestational

age, with the most marked decrease in the last several

weeks before term (Fig. 4-7). The decrease in latencies

in the somatosensory evoked response relates principally to myelination evolving in the brain stem and

thalamocortical components of the somatosensory

system (see Chapter 2). As with visual responses, maturation of somatosensory evoked responses does not

differ significantly between term infants and healthy

premature infants studied at term.

The potential clinical value of the somatosensory

evoked response in the study of disorders of the sensory



85



9.45



10.15



11.00



12.10



–100 μV

12.40



msec

200



400



600



N 13/AL (msec/min)



11.30

70

60

50

40



800



Somatosensory Evoked Responses

Somatosensory evoked responses have been studied

most extensively in the newborn by electrical stimulation of the median nerve at the wrist or, less commonly,

the posterior tibial nerve above the ankle or in the popliteal fossa and recording of the computer-averaged

responses on the EEG over the contralateral parietal

scalp.41,125,151-169a Constant primary components

appear at approximately 27 weeks of age (i.e., a few

weeks earlier than the comparable visual response),

and the response pattern of the mature newborn

appears at 37 to 38 weeks of age. As with the visual

evoked response, a linear decrease in response latency



N 19 lat (msec)



14



12



10



30



20



10



50

N 19 peak lat (msec)



the sensitivity of the visual evoked response to asphyxial

insult.148 Abnormalities of the visual evoked response

have also been described in infants with posthemorrhagic

hydrocephalus (see Chapter 11),115,149,150 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,150 as well as over a prolonged

period after placement of ventriculoperitoneal shunt.149

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.



N 13 peak lat (msec)



FLASH

Figure 4-6 Visual evoked potentials after single flashes from a premature infant recorded at 9.45 hours after birth, at 10.15 hours after

intubation and start of mechanical ventilation, at 11.00 hours during

a 5-minute episode of hypoxia (partial pressure of arterial oxygen

[PaO2] = 2.9 kPa), and at 11.30, 12.10, and 12.40 hours during

recovery. (From Pryds O, Greisen G, Trojaborg W: Visual evoked potentials in preterm infants during the first hours of life, Electroencephalogr

Clin Electrophysiol 71:257-265, 1988.)



40

30

20

10

34



38



42



46



50



Postconceptional age (wk)

Figure 4-7 Percentile curves (P97, P50, P3) for the postconceptional age of 36 to 48 weeks estimated from the somatosensory

evoked potentials of 103 normal infants. (From Bongers-Schokking

JJ, Colon EJ, Hoogland RA, Van den Brande JL, et al: Somatosensory

evoked potentials in term and preterm infants in relation to postconceptional age and birth weight, Neuropediatrics 21:32-36, 1990.)



Chapter 4



pathway in the newborn relates to the finding that by

appropriate placement of surface electrodes closest to

the presumed generator sources, the several components of this pathway can be monitored, as demonstrated in older patients.37,38,168,169a Thus, conduction

through peripheral nerve, plexus, dorsal root, posterior

column, gracile or cuneate nucleus, (contralateral)

medial lemniscus, thalamus, and parietal cortex is

involved. Considerable experience in adult patients

indicates that evaluation of the somatosensory evoked

response can provide insight into disease at various

levels along this pathway. Clear application to the newborn has been demonstrated for spinal cord trauma and

myelodysplasia,170-172 as well as for a variety of cerebral

abnormalities, including hypoxic-ischemic insult in the

term or preterm infant, intraventricular hemorrhage and

posthemorrhagic ventricular dilation in the preterm

infant, hypoglycemia, and congenital hypothyroidism.41,162-164,167-169,173-179 Because the thalamus, the

thalamocortical projections, and the parietal cortex of

the somatosensory system (areas interrogated by

measurement of the somatosensory evoked potentials)

are all involved in and are contiguous to other

areas related to cognitive and motor development,

persistent abnormalities in these potentials in the neonatal period may be predicted to be associated with

subsequent deficits. Indeed, in a study of 63 term

and preterm infants, two thirds of whom were

‘‘asphyxiated,’’ abnormal somatosensory evoked

responses in the neonatal period in 14 were associated

with abnormal neurological outcome at 1 year in

11 infants; normal responses in the neonatal period

occurred in 26, with normal neurological outcome in

23.180 Prognostic value in the preterm infant is clearly

less than in the term infant.41,166



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.138,169,181-214 The theme apparent from the

studies of specific sensory evoked responses recurs:

with increasing gestational age, impressive elaborations

of measurable function occur, characterized principally

by more refined organization, and 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, I 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



Specialized Studies in the Neurological Evaluation



161



waveforms and patterns (i.e., EEG developmental

landmarks) (Table 4-6).200

27 to 28 Weeks. Activity at this developmental stage is

characteristically discontinuous, with long periods of

quiescence (see Table 4-6).200 The activity that does

interrupt the quiescence occurs in generalized, rather

synchronous bursts (Fig. 4-8). 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 4-6; Fig. 4-9).200 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. 4-10).200

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. 4-10). These bursts occur independently in left and right temporal areas; their sharp configuration has provoked the term saw-tooth pattern.

31 to 33 Weeks. At this stage, continuous activity

appears during active (or rapid eye movement) sleep

(see Table 4-6).200 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. 4-11).

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 4-6).200 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. 4-12)

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



162



Unit II



TABLE 4-6



NEUROLOGICAL EVALUATION



Developmental Aspects of Electroencephalographic Activity

SYNCHRONY OF

BACKGROUND

ACTIVITY{



CONTINUITY OF

BACKGROUND

ACTIVITY*

Postconceptional

Age (Weeks)



Awake



Quiet

Sleep



Active

Sleep



Awake



Quiet

Sleep



Active

Sleep



27–28

29–30



À

D



D

D



D

D



À

0



++++

0



++++

0



31–33



D



D



C



+



+



++



34–35



C



D



C



+++



+



+++



36–37



C



D



C



++++



++



++++



38–40



C



C



C



++++



+++



++++



EEG Developmental

Landmarks: Specific

Waveforms and Patterns

1. ‘‘Delta brushes’’ in central

regions

2. Temporal theta bursts (4–6 Hz)

3. Occipital slow activity

1. ‘‘Delta brushes’’ in occipitaltemporal regions

2. Temporal alpha bursts replace

theta bursts (33 weeks)

3. Rhythmic 1.5-Hz activity in

frontal leads in transitional

sleep

1. Extremely high-voltage

beta activity during ‘‘delta

brushes’’

2. Temporal alpha bursts

disappear

3. Frontal sharp-wave

transients

1. Central ‘‘delta brushes’’

disappear

2. Continuous bioccipital

delta activity with

superimposed 12–15-Hz

activity during active

sleep

1. Occipital ‘‘delta brushes’’

decrease and disappear

by 39 weeks

´

2. Trace alternant pattern

during quiet sleep



*C, continuous activity; D, discontinuous activity.

{

0, total asynchrony; ++++, total synchrony.

EEG, electroencephalographic.

Adapted from Hrachovy RA, Mizrahi EM, Kellaway P: Electroencephalography of the newborn. In Daly DD, Pedley TA, editors: Current Practice of

Clinical Electroencephalography, 2nd ed, New York: 1990, Raven Press.



F1C3

F2C4

C3O1

C4O2

C3T3

C4T4



1 sec 100 μv



T3F1

T4F2

Figure 4-8 Electroencephalogram of a male infant of 27 to 28 weeks of postconceptional age. The bursts of generalized, bilaterally synchronous activity separated by prolonged periods of electrical quiescence are characteristic of this age. Selected sample from a 16-channel recording.

(From Hrachovy RA, Mizrahi EM, Kellaway P: Electroencephalography of the newborn. In Daly DD, Pedley TA, editors: Current Practice of Clinical

Electroencephalography, 2nd ed, New York: 1990, Raven Press.)



F1C3

F2C4

C3O1

C4O2

C3T3

C4T4

T3F1



1 sec 100 μv



T4F2



´

Figure 4-9 Trace discontinu pattern in a male infant with a postconceptional age of 29 to 30 weeks. Selected sample from a 16-channel

recording. (From Hrachovy RA, Mizrahi EM, Kellaway P: Electroencephalography of the newborn. In Daly DD, Pedley TA, editors: Current Practice of

Clinical Electroencephalography, 2nd ed, New York: 1990, Raven Press.)



F1C3

F2C4

C3O1

C4O2

C3T3

C4T4

T3F1

T4F2

T3C3

C3Cz

CzC4

C4T 4



1 sec 100 μv



EOG

Resp

(Nasal)



Resp

(Chest)



ECG



Figure 4-10 Electroencephalogram of a female infant with a postconceptional age of 30 to 32 weeks. Left, Brief bursts of 4- to 6-Hz waves of

sharp configuration occurring asynchronously in the temporal regions. Right, Beta-delta complexes in the central and temporal regions. Selected

sample from a 16-channel recording. ECG, electrocardiogram; EOG, electro-oculogram. (From Hrachovy RA, Mizrahi EM, Kellaway P:

Electroencephalography of the newborn. In Daly DD, Pedley TA, editors: Current Practice of Clinical Electroencephalography, 2nd ed, New York:

1990, Raven Press.)



F1C3

F2C4

C3O1

C4O2

C3T3

C4T4

T3F1



1 sec 100 μv



T4F2



Figure 4-11 Brief bursts of 8- to 9-Hz waves occurring bilaterally in the temporal regions in a female infant with a postconceptional age of 32

to 33 weeks. Selected sample from a 16-channel recording. (From Hrachovy RA, Mizrahi EM, Kellaway P: Electroencephalography of the newborn. In

Daly DD, Pedley TA, editors: Current Practice of Clinical Electroencephalography, 2nd ed, New York: 1990, Raven Press.)



164



Unit II



NEUROLOGICAL EVALUATION



F1C3

F2C4

C3O1



1 sec 100 μv



C4O2

Figure 4-12 Diphasic, bilaterally synchronous and virtually

symmetrical, frontal sharp waves in transitional sleep in a male

infant with a postconceptional age of 36 weeks. Selected sample

from a 16-channel recording. (From Hrachovy RA, Mizrahi EM,

Kellaway P: Electroencephalography of the newborn. In Daly DD, Pedley

TA, editors: Current Practice of Clinical Electroencephalography, 2nd ed,

New York: 1990, Raven Press.)



apparent (see Table 4-6).200 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. 4-13). 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 4-6).200 A considerable degree of

synchrony is present in all states. The occipital delta

brushes disappear, and the interesting trace alternant pat´

tern becomes apparent in quiet sleep (Fig. 4-14).

This quasiperiodic tracing is characterized by periods

of 3 to 15 seconds of generalized voltage attenuation,

interrupted by higher-voltage, generally synchronous

´

activity. Trace 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, I review the principal EEG abnormalities of both the premature and term newborn

(Table 4-7), except for the EEG correlates of neonatal

seizures (see Chapter 5).

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.200,215 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.215-217

Abnormalities may be apparent only in quiet sleep,

and thus this sleep state should be included in the

EEG evaluation of the newborn.200 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 hypoxicischemic insults (Fig. 4-15).200,213,215,218,219 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



F1C3

F2C4

C3O1

C4O2

T3C3

C3Cz



1 sec 100 μv



CzC4

C4T4

Figure 4-13 Typical awake pattern in a male term infant, characterized by a mixture of activities in the alpha, beta, theta, and delta frequency

bands. Selected sample from a 16-channel recording. (From Hrachovy RA, Mizrahi EM, Kellaway P: Electroencephalography of the newborn. In

Daly DD, Pedley TA, editors: Current Practice of Clinical Electroencephalography, 2nd ed, New York: 1990, Raven Press.)



Chapter 4



Specialized Studies in the Neurological Evaluation



165



F1C3

F2C4

C3O1

C4O2

C3T3

C4T4

1 sec



T3F1



100 μv



T4F2

´

Figure 4-14 Trace alternant pattern in a male term infant. (From Hrachovy RA, Mizrahi EM, Kellaway P: Electroencephalography of the newborn.

In Daly DD, Pedley TA, editors: Current Practice of Clinical Electroencephalography, 2nd ed, New York: 1990, Raven Press.)



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 mV),

alternating with shorter periods of paroxysmal bursts,

usually lasting 1 to 10 seconds and characterized by

high-voltage (75 to 250 mV) theta and delta activity

with intermixed spikes and waves (Fig. 4-16). This

EEG pattern should be distinguished from the

normal discontinuous tracing of the very immature

´

premature infant and from the trace 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 so

uniformly associated with a poor prognosis as the

nonreactive variety described here.220-225 The poor

prognosis of burst-suppression EEG is illustrated

by the data depicted in Table 4-8.226 Bacterial meningitis is the one disturbance in which I have seen a

TABLE 4-7



Major Electroencephalographic

Abnormalities of the Premature and

Term Newborn



Disordered development

Depression: lack of differentiation

Excessively discontinuous activity, including burstsuppression pattern

Electrocerebral silence

Unilateral depression of background activity

Periodic discharges

Multifocal sharp waves

Central positive sharp waves

Rhythmic generalized or focal alpha activity

Hypsarrhythmia

Data primarily from Hrachovy RA, Mizrahi EM, Kellaway P:

Electroencephalography of the newborn. In Daly DD, Pedley TA,

editors: Current Practice of Clinical Electroencephalography, 2nd

ed, New York: 1990, Raven Press.



favorable outcome, despite the finding of a burstsuppression EEG during the acute disease. In

the group described in Table 4-8, the one infant with

a favorable outcome also had acute bacterial

meningitis.

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.227 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 4-9). 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.

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.228,229 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. 4-17). Such persistent

unilateral depressions of background activity are