pathologic correlations

Review Article

Neonatal Encephalopathies as Classified by EEG-Sleep Criteria: Severity and Timing Based on Clinical/Pathologic Correlations Mark S. Scher, MD Neonatal encephalopathies can be characterized in functional terms using electroencephalography. Severity of an encephalopathic state can also be estimated by electrographic interpretation independent of the time of disease process onset. Moderately or markedly abnormal electroencephalographic patterns on serial studies are highly correlated with neurologic sequelae in survivors. Electroencephalography is rarely pathognomonic or specific in determining when a condition initially occurred. However, electroencephalographic abnormalities are associated with different clinical situations, and brain lesions documented on neuroimaging or with postmortem neuropathologic examination are observed in infants with certain abnormal electrographic patterns. When interpreted in the context of history, clinical findings, and other laboratory information, the neurophysiologic studies augment the understanding of both the severity and timing of an encephalopathic state. Scher MS. Neonatal encephalopathies as classified by EEG-sleep criteria: Severity and timing based on clinical/ pathologic correlations. Pediatr Neurol 1994; 11:189-200.

Introduction The neurologic evaluation of the neonate is an enormously difficult task because of the newborn's underdeveloped clinical repertoire, which is based primarily on levels of arousal, muscle tone, and developmental reflexes [1]. Brain immaturity limits the ability to diagnose initially and then evaluate serially an encephalopathic process. This is particularly true for the preterm infant. Obstacles imposed by the intensive care setting also impede successful examination of the neonate; a confined isolette

From the DevelopmentalNeurophysiologyLaboratory; Magee-WomensHospital; Departmentof Neurology;Children's Hospital of Pittsburgh; Pittsburgh, Pennsylvania. This study was supportedin part by grants NS01110, NS26793, and NS26946 to Dr. Mark S. Scher, the ScaifeFamilyFoundation,the Twenty-FiveClub of Magee-WomensHospital, the Cradle Roll Auxiliary, and Magee-WomensHospital.

© 1994by ElsevierScienceInc. • 0887-8994/94/$7.00

space, prolonged intubation, multiple catheters, and the use of sedative and paralytic agents detract from the clinician's accuracy on physical examination. The development and improvement of brain imaging techniques have expanded our abilities to diagnose major structural disorders of the neonatal brain. Cranial ultrasonography and computed tomography [2], magnetic resonance imaging [3], and positron emission tomography [4] expand the major features of brain structure and metabolic function. However, encephalopathic states may be expressed only in functional terms, without demonstrable structural lesions evident on imaging studies. Neurophysiologic assessment, therefore, complements neuroanatomic assessment by providing continuous documentation of brain dysfunction. Technological advances in neurophysiologic assessment permit new opportunities for the evaluation of the encephalopathic newborn, using portable multichannel paper recordings or synchronized video EEG monitoring, sensory evoked responses, and multimedia neurophysiologic monitoring [5]. Both structural and functional brain assessments, of course, must be anchored by solid clinical judgment that derives from accurate historical evidence and examination findings. Correlations of EEG-sleep abnormalities with different neuropathologic lesions and clinical situations highlight the importance of neurophysiologic assessment for diagnostic and prognostic purposes. The following discussion of specific EEG-sleep patterns and abnormalities may assist the evaluation of the presence, severity, and timing of the neonatal encephalopathic process.

Estimation of Gestational Maturity Before considering if a neonate is encephalopathic, the electroencephalographer must initially determine if an

Communicationsshouldbe addressedto: Dr. Scher; DevelopmentalNeurophysiologyLaboratory; Magee-WomensHospital; 300 HalketStreet;Pittsburgh, PA 15213. ReceivedApril 15, 1994;acceptedJune 10, 1994.

Scher: NeonatalBrain DisordersExpressedby EEG Sleep 189

EEG-sleep pattern is age-appropriate and reflects a healthy medical status for the given postconceptional age and state of arousal of the neonate [1]. Investigations by many researchers offer a wealth of information regarding the evolution of neurophysiologic patterns expressed by the immature brain [6-13]. Regional or hemispheral EEG patterns are related to gestational maturity of the neonate within 2 weeks accuracy for preterm infants, and 1 week for term infants, compared with other clinical criteria [ 1]. After EEG-sleep patterns are compared with those expected for a given postconceptional age, one can more confidently establish if an electrographic feature is abnormal and reflects an encephalopathic state. Current methods for indirectly assessing central nervous system maturation include calculations of fetal or neonatal gestational age. These estimates can be based on the mother's last menstrual period, sonographic interpretation of fetal dimensions of head and body parts in utero, and a variety of clinical examination findings after birth. Clinical scoring techniques for assessing gestational maturity utilize both nonneurologic examination features such as lanugo (i.e., body hair) and areolar development, and neurologic parameters such as muscle tone and posture [14,15]. These methods, however, may be inaccurate for the premature infant or the neonate who is medically compromised. In either situation, an electroencephalographer's estimation of central nervous system maturation is an alternative method which may either suggest a level of gestational maturity or diagnose an encephalopathic state. In a recent study, electrographic estimates of gestational maturity were assessed by pattern recognition for 24 EEG records of healthy preterm neonates between 28-43 weeks postconceptional age [16]. These estimates were originally assessed by EEG pattern recognition, without knowledge of fetal sonographic or clinical examination criteria. All infants were neurodevelopmentally normal at 2 years of age. Thirteen of these recordings were the initial studies obtained for neonates who were <32 weeks gestation, at which time a clinical examination was considered less accurate because of the newborn's immaturity. Independent obstetric/sonographic estimations of maturity were also obtained in these 13 infants without knowledge of these EEG estimates. After analyzing the data by multivariate regression, no differences were noted among electrographic, anatomic, and obstetric estimations of maturity. The encephalographer's assessment of gestational age was as accurate as fetal sonographic estimates for asymptomatic preterm neonates whose gestational age was <32 weeks at birth. These results support the use of EEG to estimate brain maturity in healthy preterm neonates (i.e., <32 weeks) whose clinical examination findings are limited based on immaturity. EEG estimates of maturity are also useful when clinical examinations are inaccurate because of systemic illness. Under such circumstances, 25 infants were assessed by serial EEG studies [17]. Each infant was symptomatic because of postnatal medical conditions, principally hya-

190 PEDIATRICNEUROLOGY Vol. II No. 3

line membrane disease. All infants died between 1 and 12 weeks after birth because of complications from chronic lung disease or sepsis. Comparisons of sulcal-gyral development at postmortem examination in this medically ill group were compared with EEG information on the initial study pertaining to gestational maturity. Ninety-two percent of infants demonstrated an agreement (i.e., within 2 weeks) between the initial EEG study after birth and convolutional measurements of the brain that were performed on neuropathologic examination. This compared more favorably than a 74% agreement between EEG and clinical examination findings that were performed when the infant was medically ill. Unlike the previous report in which obstetric and sonographic data were available for a selected group of healthy infants [16], many high-risk pregnancies include situations where accurate information is unavailable. EEG can, therefore, estimate brain maturity for both the asymptomatic and the medically ill infant. More rigorous correlations between quantitative EEG and neuroimaging procedures, however, need to be performed for the surviving neonate. In vivo anatomic measurements for regional or hemispheral data sets have been described [18], which can now be compared with spectral neurophysiologic signals from the same brain locations. Such comparisons will result in a more detailed structuralfunctional template of brain maturation under both normal and abnormal situations.

Classification of Severe EEG-Sleep Background Abnormalities in Newborns

Recent discussions of EEG background disturbances describe the neurophysiologic expression of encephalopathic states in neonates [5,8,11,19-24]. Electrographic disturbances are visually analyzed and graded as mild, moderate, or severe to reflect increasing degrees of abnormality concerning neonatal encephalopathies. The interpretation of such findings, unfortunately, may vary from laboratory to laboratory, particularly with respect to mild abnormalities. However, moderately or markedly abnormal EEG-sleep patterns on serial studies more closely correlate with specific pathophysiologic and neuropathologic situations. Specific abnormal EEG-sleep patterns are described not only in relation to brain lesions, but also neurodevelopmental outcome in preterm and term survivors [22-25]. EEG and neuropathologic comparisons document the association of types and degrees of severity of brain lesions, particularly with moderately to markedly severe EEG pattern abnormalities [25]. These associations have been described for both specific brain locations (e.g., cerebral cortex) and neuropathologic changes (e.g., cerebral infarction) (Tables 1 and 2; Figures 1 and 2). However, the interval between the last EEG recording and death in this study [25] ranged from 0 to 23 days (mean 5 days), and therefore, pathologic lesions that occurred after the last EEG recording must also be considered. Prompt neu-

Table 2. EEG background and periventricular-intraventricular hemorrhage grading compared with the incidence of parenchymal lesions*

Table 1. Correlation between EEG background and neuropathology Spearman Rank Correlation Coefficient

Each Structure and EEG Background* Cerebral cortex White matter Corpus cailosum Corpus striatum Cerebellum Thalamus Hypothalamus Midbrain Pons Medulla

0.615 0.621 0.228 0.673 0.524 0.648 0.538 0.610 0.589 0.700

Structures

<.001 <.001 NS <.001 < .01 <.001 < .01 <.001 <.01 <.001

Specific Neuropathologic Change and EEG Background~" Herniation Cerebral edema Ischemic neuronal necrosis Cerebral infarction Periventricular leukomalacia Pontosubicular necrosis PVH-IVH grade IV PVH-IVH grades I-III

0.301 0.322 0.559 0.407 - 0.209 0.250 0.263 - 0.143

NS <.05 <.01 <.05 NS NS NS NS

* The correlations were measured using the following codes: EEG: markedly abnormal 4; moderately abnormal 3; mildly abnormal 2; normal 1. Neuropathologic change: severe 4; moderate 3; mild 2; normal 1. t The correlations were measured using the following codes: EEG: markedly abnormal 4; moderately abnormal 3; mildly abnormal 2; normal 1. Neuropathologic change: present 2; absent 1. Reprinted with permission from Aso K, Barmada M, Scber MS. Electroencephalographyand the neuropathology in premature infants with intraventricular hemorrhage. J Clin Neurophysiol 1993;10:304-13. Abbreviations: IVH = Intraventricular hemorrhage NS = Not significant PVH = Periventricular hemorrhage

roimaging concurrent with EEG recordings is desirable when possible.

Electrocerebral Inactivity (Isoelectric Recording) Cerebral activity below 5 p N , despite high sensitivity settings and long intraelectrode distances, occurs on neonatal EEG recordings for both preterm and term infants. Lack of reactivity to stimuli usually accompanies this severe expression of encephalopathy. Some authors include EEGs with minimal activity [11,22,26,27], while others define " i s o e l e c t r i c " as a total absence o f cerebral activity [25,28]. After diagnostic possibilities to explain an isoelectric E E G are eliminated including a postictal state, hypothermia, or metabolic-toxic condition, this abnormal pattern carries grave prognostic implications. Most infants die or have severe neurologic sequelae. In 1 study, 90% or 17/20 [24] infants died with only 1 survivor who was developmentally normal at 6 years o f age, while 2 other

Cerebral cortex White matter Corpus striatum Cerebellum Thalamus Midbrain Pons Medulla

EEG Coefficient

2.5327 . 1.7107 . 2.0321 1.0925 1.1382 1.6559

. .

P <.001 . <. 001 . <.001 .007 .002 <.001

Gradin8 Coefficient

P

--

--

1.2426

.009

---1.2098

---.010

. .

* Multivariate stepwise regression analysis. Coding for EEG background and periventricular-intraventricularhemorrhage grade is as follows: EEG background: normal = 1; mildly abnormal = 2; moderately abnormal = 3; and markedly abnormal = 4. PVH-IVH grade: grade I = 1; grade II = 2; grade III =3; grade IV = 4. Reprinted with permission from Aso K, Barmada M, Scher MS. Electroencephalographyand the neuropathology in premature infants with intraventricularhemorrhage. J Clin Neurophysiol 1993;10:304-13.

children had seizures and developmental delay. Another study involving preterm and term infants with isoelectric records gave a survival rate of 25%, but only 1 survivor was normal at 7 years o f age [28]. In a comparative study of EEG and neuropathologic findings by Aso et al. [25], infants with isoelectric records who subsequently died were observed to have widespread encephalomalacia and ischemic neuronal necrosis. They examined l0 different anatomic sites in 43 neonates; 6 neonates had isoelectric EEGs. Cerebral cortex, corpus callosum, thalamus, midbrain, and pons were moderately to markedly damaged in all these children. Other locations such as the central white matter, cerebellum, hypothalamus, and medulla were also damaged. These sites, however, were spared in at least 1 infant who initially had an isoelectric record with qualitative improvement on a subsequent recording. A variety o f clinical situations can result in an isoelectric recording, ranging from massive intracranial hemorrhage to meningitis [29]. Even congenital malformations (e.g., hydranencephaly) and inborn errors o f metabolism (e.g., nonketotic hyperglycemia) can be functionally expressed as this type of abnormality. Experimentally induced acute hypoxic-ischemic insults in laboratory animals also result in isoelectric recordings [30], Such inactive tracings are then replaced on subsequent recordings by electrographic seizures, as well as other interictal E E G background disturbances. Isoelectric records m a y be associated with chronic pathologic processes during fetal life, as well as acute neonatal comatose states. Barabas et al. [28] reported that 15/20 infants with at least 1 isoelectric record had clinical signs o f at least partially preserved brain function. Although these examinations reflected severe encephalopathies, only 3/20 satisfied clinical criteria o f neonatal brain

Scher: Neonatal Brain Disorders Expressed by EEG Sleep 191

I

90% I N c 80% I D E 7O% N c E 60% O F 50% L E 40°/* $ I O 30% N S 20% 10% 0

CORTEX

~-I1~ Mad Ibet

CORPUS CORPUS CALLOSUM b"IRIATU M

~ BELLUM

"IV/KAMIR

HYPOtHALAMUS

I~DIBRNN

FONS

MBXILtA

Figure 1. Incidence of neuropathologic lesions compared with increasing severity of EEG background abnormalities. (Solid bar = markedly abnormal; heavily stippled bar = moderately abnormal; lightly stippled bar = mildly abnormal; open bar = normal.)

death; at least 7 were associated with an antepartum disease process. An additional 10 newborns had historical evidence that antepartum events contributed to an encephalopathic process which continued into the intrapartum period. As will be discussed in the final section of this paper concerning the timing of neurologic insults, pathologic processes associated with severe EEG disturbances (e.g., an isoelectric EEG pattern) may represent chronic conditions which predate labor and delivery with or with-

out the occurrence of an acute process during partuition. Assessment of the medical history and examination findings would support either scenario. Preterm infants with isoelectric EEG patterns have the same prognosis as term infants with this EEG abnormality. Tharp et al. [23] described 2 infants, both of whom expressed this pattern, who died. Barabas et al. [28] described 7 preterm infants with isoelectric records, some of whom survived with major neurologic sequelae. How-

100% 90% I N C 80% I D E 70% N C E 60% 0 F L E S I 0 N S

5O% 40% 30%

10%

ILl

NEURONAL

IWFARCIK~

LEUKI)MALatCIA

NECROSIS

GRADE IV

GRADES HU

Figure 2. Incidence of specific neuropathologic changes compared with increasing severity of EEG background abnormalities. (Solid bar = markedly abnormal; heavily stippled bar = moderately abnormal; lightly stippled bar = mildly abnormal; open bar = normal.)

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ever, of those who died, severe brain lesions such as neuronal necrosis, periventricular leukomalacia, and microcalcifications [25] were documented.

Paroxysmal or Suppression Burst Patterns The gestational age of the infant must be considered before identifying this EEG abnormality. Preterm infants commonly display a discontinuous EEG tracing (i.e., trac6 discontinu) which superficially resembles a paroxysmal pattern abnormality [21]. It is, therefore, difficult to interpret this abnormal feature for most EEGs of preterm neonates. Conventional descriptions of a suppression burst or paroxysmal pattern consist of a nonreactive discontinuous tracing with long periods of quiescence >20 s in duration [22,29], interrupted by asynchronous bursts of poorly organized high-amplitude slow-background activity. Modified burst suppression patterns have also been described which contain better organized periods of activity and shorter quiescent intervals [31]. These modified forms may emerge after aggressive resuscitation of an acutely asphyxiated neonate. It also may be present with a reversible metabolic/toxic encephalopathy with drug intoxication, as commonly noted after phenobarbital infusion for seizure control [31]. Partial preservation of ageappropriate EEG background and electrographic reactivity to stimulation have been described. Holmes et al., for example, reported 5 infants with these types of suppression burst patterns that later became continuous with tactile stimulation; none of the infants were normal on follow-up, but only 1 child suffered severe neurologic deficits [31]. In the preterm child, suppression burst EEG patterns may be described in exceptional circumstances. Tharp et al. [23] described 6 infants who either died or suffered severe neurologic sequelae. Low amplitude and slow background patterns were also seen for these preterm neonatal survivors. A wide variety of etiologies are associated with paroxysmal records, in addition to hypoxic ischemic insults or drug intoxication. Inborn errors of metabolism and cerebral malformations can also result in a paroxysmal or burst suppression EEG pattern for either preterm or term infants [32,33].

Low Amplitude~Lack of Background Activity This electrographic pattern is characterized by EEG background frequencies that are 5-15 ~V in amplitude during the awake state, and 10-25 IxV during sleep [ 11,22]. While changes in EEG amplitude occur between sleep states in healthy infants, these abnormal records have persistently low background amplitude without clear state differentiation. In a healthy term neonate, the presence of a low amplitude admixture of faster frequencies follows the quiet sleep trac6 alternant segment and comprises approximately 10-15% of the total sleep cycle (i.e., low voltage irregular) [1,29]. Preservation of an organized

ultradian sleep cycle over a 30-60 min interval includes this low amplitude active sleep segment. A persistently low-voltage background abnormality has prognostic significance [22,26], particularly if it persists beyond the first week of life. At times, low amplitude recordings are intermixed with monotonous nonreactive 0 activity. As with isoelectric records, one should be alert to situations that result in low amplitude recordings, such as postictal recordings or barbituate administration. In these situations, recording times of more than 1-hour duration are required to distinguish persistent from iatrogenic and transient forms of electrographic suppression of EEG background activities.

Excessive Discontinuity While excessive discontinuity occurs with some paroxysmal patterns in term infants, such an abnormality may be the predominant EEG disturbance in preterm infants. Discontinuous activity may be alternately described as either excessively brief EEG bursts or prolonged interbursts. Pezzani et al. [24] described abnormal bursts <3 s in duration. By contrast, Aso et al. [25] defined interburst intervals in excess of 60 s as representative of this abnormality. No children with this background pattern survived without sequelae, and 5 of 8 children died. These authors also noted that the longer the interburst interval, the more compromised the neurologic outcome. No child escaped major sequelae when interburst intervals were longer than 40 s. Fourteen of 15 children with permanently discontinuous background and absence of normal physiologic EEG patterns either died or had severe sequelae. Tharp et al. [23] reported 5 preterm infants with unreactive low amplitude recordings consisting of primarily slow wave activity. Only 1 child survived with minor sequelae.

Diffusely Slow Background A diffusely slow background pattern consists of monotonous ~ activity during either wakefulness or sleep with little activity at higher frequencies [26,27,34]. Invariant and diffusely distributed ~ slow rhythms are usually noted during the first week of life, but may persist into the convalescent period for several weeks after birth. While this pattern was described in earlier studies that predated the establishment of the modern NICU [22], more recent studies suggest that this pattern has become less common [11,261. Slow-frequency background activities may also be seen in the preterm infant, but less frequently [23]. Two infants with this abnormality survived with major neurologic sequelae. No representative neuropathologic lesions, however, have been reported with this type of EEG pattern.

Hemispheral Amplitude Asymmetry Hemispheral amplitude asymmetry is defined as >50% difference in amplitude or frequently suppression within

Scher: NeonatalBrain DisordersExpressedby EEG Sleep 193

each hemisphere. Neuropathologic correlates have been described [25]. Four infants had hemorrhagic or ischemic cerebral lesions with attenuated amplitude over the more pathologically involved hemisphere. Congenital lesions such as porencephaly also may contribute to hemispheral attenuation of background and amplitude. Before assigning pathologic significance, however, cephalohematomas, scalp edema, or technical considerations such as head positioning, electrode paste smearing, sweat, or asymmetric electrode placement must be verified [5,21]. Serial records are strongly recommended to verify if an asymmetry persists. Asymmetries may also follow seizures with transient suppression of activity over the area of seizure generation, with resolution after seizures have been controlled. Unlike older patients who exhibit slowing of EEG background in the diseased region or hemisphere, the attenuated hemisphere or region indicates the more involved brain region on neonatal EEG. Approximately 20% of attenuated regions, however, convert to ~ and/or 0 slowing within 2-3 weeks after the initial documentation of EEG asymmetry [35]. Transient asymmetries have also been described in asymptomatic healthy neonates. Brief EEG background attenuations [36,37] are seen, particularly during the first several minutes of a quiet sleep segment. Such EEG asymmelries do not persist during the entire recording. No imaging procedures, however, were performed in these asymptomatic populations to verify the presence or absence of structural lesions. Asymmetric patterns have also been associated with regional pathology in preterm infants. Tharp et al. [23] documented 9 preterm infants with at least 1 EEG with persistent asymmetry who either died or had sequelae. Aso et al. [25] found that hemispheral asymmetry was associated with significant brain lesions in all 4 preterm infants in the same hemisphere as EEG background attenuation.

Focal Attenuation Records that contain focal attenuation involve only 1 or 2 scalp regions without involvement of the entire hemisphere. Focal attenuation also can be seen with lateralized neuropathologic lesions. Aso et al. [25] reported 5 infants with at least 1 EEG record with focal attenuation who had lesions in that hemisphere on postmortem examination. Three of these patients had extensive lesions which were unilateral to the attenuation, and 1 infant showed more severe white matter infarction in the opposite hemisphere. An additional infant showed no pathologic changes that could be correlated with attenuation of EEG. These authors conversely describe unilateral lesions on postmortem examination which involve necrosis or hemorrhage in the cortex or the white matter with no demonstrable EEG attenuation. Accurate detection of morphologic lesions was estimated to be 74% with a specificity of 85% [25].

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Interhemispheral Asynchrony The definition of asynchrony is traditionally assigned based on interpretation of the quiet sleep or discontinuous portion of a neonatal EEG recording. Asynchronous EEG waveforms are morphologically similar bursts in either contiguous brain regions in the same hemisphere or homologous regions in each hemisphere which occur more than 1.5 s out of time [ 1,11,21,29]. While Lombroso suggests that physiologic asynchrony occurs in the preterm infant (<37 weeks postconceptional age) in the absence of disease states [11], Anderson et al. [37] emphasized that a high percentage of interhemispheral synchrony is expected in healthy infants who are <30 weeks gestation. Greater elaboration of the cortical mantle with gyral-sulcal maturation after 30 weeks EGA may account for the transient asynchrony seen on EEG. By a postconceptional term age (i.e., >138 weeks), however, asynchrony of any degree is considered an abnormality. Neuropathologic findings associated with patients with marked asynchrony (i.e., >50% of the record) are uncommon, but some examples have been described [35]. Nine patients with excessive asynchrony include 2 patients with lesions within the corpus callosum. In general, white matter lesions in the periventricular area, which include periventricular hemorrhage or intraventricular hemorrhage, have been observed in infants with asynchrony when compared to infants without this EEG abnormality. Normative values for physiologic asynchrony must be more firmly established for each postconceptional age and for all segments of the sleep cycle, before assigning clinical significance to this EEG feature in the preterm infant [21].

Absent or Disrupted EEG State Cycling Electroencephalographers must consider the approximate sleep state percentages for healthy term infants: 50% for active sleep, 30-35% for quiet sleep, and 10-20% for indeterminate sleep segments [1,11,29]. Wakefulness is usually limited to 1-5% of the sleep cycle on a brief recording. Also, sleep architecture percentages will change because of postnatal adaptation [38]. Sleep cycling in the preterm infant is difficult to ascertain; however, state differentiation may be seen as early as 30 weeks postconceptional age [39]. By a postconceptional term age, a complete sleep cycle includes active and quiet sleep segments. In situations in which the child is disturbed by either excessive light, sound, or tactile stimulation, this complete sleep cycle may be disrupted. The child may have difficulty initiating sleep or experience shortened sleep segments with excessive arousals. The absence or disruption of this sleep cyclicity may also be diagnostic of an encephalopathic state. Pezzani et al. [24] found that EEGs obtained during the first 24 hours of life in 80 term infants included 12 infants with the absence of sleep cycle organization. These infants either

died or survived with major sequelae. Three additional infants without sleep state organization during the first 24 hours developed normally. Serial studies are recommended to ascertain if disrupted sleep cycling persists. Metabolic-toxic states, hyperthermia, and other environmental factors may transiently disturb sleep cycling on only initial recordings. Excessively labile EEG sleep states also occur, characterized by rapid transitions between states over seconds to minutes without clearly defined active or quiet sleep segments. Lombroso observed that excessive indeterminate or transitional sleep can be seen with encephalopathic states [11]. While such an EEG disturbance may reflect transient forms of an encephalopathy, infants with more chronic problems, such as hypoplastic left heart syndrome [40], maternal substance use [41], and maternal preeclampsia [42], also can exhibit excessive percentages of indeterminate or transitional sleep.

Abnormalities of EEG/Sleep Maturation Disorders of electrographic maturation suggest cerebral insults during either intrauterine or neonatal life. Dysmaturity of more than 2 weeks earlier than the stated postconceptional age of an infant suggests such an abnormality [1,5,11,21,29]. Dysmature patterns may be transient in infants who suffer severe, but reversible hyaline membrane disease [43], and have little prognostic significance. Persistently dysmature EEG-sleep patterns at postconceptional term ages, however, are associated with higher risks for neurodevelopmental sequelae. For instance, dysmature patterns on the EEG (e.g., excessive spindle brushes and asynchrony) have been described in neonates with bronchopulmonary dysplasia, who later demonstrated delayed neurodevelopmental milestones at 3 years of age [44,45]. Dysmature sleep architecture and continuity measures have also been documented in infants with chronic lung disease [46]. Dysmyelination, neuronal necrosis, and microcalcifications are among the neuropathologic findings documented at postmortem examination in expired neonates who suffered with chronic lung illnesses [47-49] and may be associated with EEG dysmaturity in infants with chronic lung disease.

Positive Sharp Waves Sharp waves of positive polarity have been described on neonatal EEG records in preterm infants. This surface positive waveform is between 50-250 I~V and persists for 200 ms. Such a discharge can be unilateral or bilateral in the central or midline regions. Waveform morphology may also be complex with small surface negative deflections prior to the major positive component. Cukier et al. [50] initially suggested an association of positive central or rolandic sharp waves with intraventricular hemorrhage

(IVH). However, this finding has been associated with other white matter lesions with or without IVH from diverse etiologies such as meningitis, hydrocephalus, amino acidopathies, and asphyxia [21]. Clancy and Tharp [51] found positive central sharp waves in 13/22 infants with IVH on 30 EEG studies. Only one other infant had positive rolandic sharp waves without IVH. These same authors reported 30 preterm infants with multifocal white matter necrosis with and without IVH on cranial ultrasound or autopsy who demonstrated central positive sharp waves on EEG [52]. Infants with grade III or IV IVH had a high prevalence of central positive sharp waves (63%). The greatest prevalence of sharp waves occurred between the fifth and eighth postnatal days of life. Novotny et al. [53] later reported an association of rolandic sharp waves with white matter necrosis. Scher [54] reported the association of midline positive sharp waves with different pathologic lesions including white matter necrosis. Twenty-five records from 16 preterm infants (mean gestational age: 27 weeks) indicated that 14 patients (88%) with midline positive sharp waves had cerebral lesions; IVH in 8 infants; periventricular leukomalacia in 5 infants; and cerebral infarction in 1 infant. The amplitude of the discharges ranged from 20-180 ~V with an anterior to posterior electrical field maximal at CZ extending from FZ to PZ. Myoclonic movements may occur with these discharges. Waveforms were predominantly biphasic, but triphasic and polyphasic waveforms also can appear. For infants with IVH, positive rolandic sharp waves were present with a mean repetitive rate of 1.3/min, while vertex positive sharp waves had a slightly faster repetitive rate of 1.9/min. However, patients with periventricular leukomalacia displayed even higher mean repetitive rates of vertex positive discharges (i.e., 2.5/ min). Seventy-six percent of records that documented positive vertex sharp waves were recorded when infants were older than 1 week of age. Besides identifying positive sharp waves, electrographic interpretation of EEG background activity in neonates with IVH also can assess the severity of an encephalopathy. Eighty-eight EEGs from 32 preterm infants with autopsy-proven IVH were compared with 10 neuropathologic lesions [55]. IVH was rarely an isolated lesion at autopsy. Twenty-seven infants (84%) had additional parenchymal brain lesions which included periventricular leukomalacia (47%), ischemic neuronal necrosis (22%), pontosubicular necrosis (22%), cerebral infarction (13%), and cerebellar hemorrhage (13%). A significant correlation was found between the patient's most abnormal EEG and the presence and severity of these brain lesions. Not surprisingly, the grading of IVH did not correlate with the degree of EEG abnormality, except with IVH with interparenchymal extension (Table 2). Positive rolandic vertex sharp waves were observed in only 8 patients (25%), all of whom had white matter lesions. The sensitivity of positive central sharp waves to reflect white matter necrosis was only 38% for this autopsied population. EEG has limited

Scher: Neonatal Brain Disorders Expressed by EEG Sleep

195

seizure and neuropathologic site could be documented in only 3 infants. Seizure activity originated from the same hemisphere in which the cerebral infarction occurred in only 3 infants. While the location of seizures and brain lesions are reported higher in surviving neonates, more widespread injury may prevent such a correlation in those who die. Infants with seizures had more cerebellar lesions than those without seizures (7/9 vs 16/36, P < .05, ×2 analysis with Yates correction factor). Cerebellar lesions consisted of neuronal necrosis in 3 patients, white matter abnormalities in 2 patients, and diffuse necrosis in 2 patients. The incidence of midline lesions was also significantly higher in infants with seizures than in those without seizures (89% vs 28%, P < .001, ×2 analysis with Yates correction factor). Midline lesions consisted of neuronal necrosis, isolated or widespread lesions in 6 infants, dissecting hemorrhage from periventricular-intraventricular hemorrhage in 1 infant, and spongy myelinopathy in 1. The substantia nigra was also involved in 6 of these patients. Experimental evidence suggests that subcortical locations may be involved in seizure propagation in animal populations [61]. While direct evidence cannot be demonstrated for human neonates without EEG depth recordings, electroclinical dissociation (ECD) has recently been described which may at least be indirect neurophysiologic evidence that subcortical onset of a seizure event may occur with inconsistent propagation to the cortical surface as reflected on scalp EEG [62]; ECD was described in 16 of 51 neonates with seizures; the identical clinical seizure event occurred both prior to the EEG seizure and concurrently with an electrographic seizure. The authors suggest

value in the diagnosis of grades I through III IVH, compared with cranial sonography. Yet the study provides valuable information regarding an electrographic encephalopathy that correlates with multiple severe brain lesions.

Neonatal Seizures Clinicopathologic correlations of neonates with seizures have been stressed by many authors [56-59]. Structural lesions, particularly cerebral infarction and IVH, have been documented either by neuroimaging or postmortem brain examination in neonates with seizures. In 1 study, nearly 90% of term and preterm infants with electrographically confirmed seizures had associated brain lesions [59]. Intraventricular hemorrhage (i.e., grade III or IV IVH) was noted in preterm infants with seizures (45%), while 87% of term infants had cerebral infarction. Nine of 43 infants who died and had postmortem brain examination had EEG-confirmed seizures during 1 or more EEG recordings [25,60]. Five infants were paralyzed with pharmacologic agents during EEG seizures, while 3 others had no clinical concomitants. As listed in Table 3, the neuropathologic findings at postmortem examination varied considerably among patients with seizures. Extensive encephalomalacia involved 9 of the 10 structures in 4 infants, whereas mild to moderate neuronal necrosis and/or astrocytosis in 4 or fewer structures was observed in 3 infants. The number of damaged sites ranged from 3 to 9 (mean: 6). No structure was consistently affected in all infants. Nevertheless, at least 1 brain structure was involved in all infants. Abnormal electrographic discharges originated from a limited brain region in 8 infants, but correlation between the origin of the Table 3.

Neuropathologic lesions in patients with seizures

Seizure Case No.

GA (wk)

Origin

Type

Cortex*

Hippocampus

010

30

T3

EP

--

Hypoplasia

013 014 $4 $5 $8

37 37 26 26 38

01 T3 Fpl, Fp2, T3 Cz-C3 T3-01

EP Sub EO EO EP

Necrosis Edema Necrosis Necrosis Necrosis

Hemorrhage, edema Hemorrhage Necrosis Necrosis Necrosis, hemorrhage

S 11

40

Fpl-Fp2

EO

Necrosis

Necrosis

S12 S 13

40 41

Cz-C3 01

EP EP

---

---

Neuropatholos.v Cerebellum Decrease in white matter, granular layer -Necrosis of Purkinje cell Diffuse necrosis Diffuse necrosis Astrocytosis in white matter Loss of Purkinje cell and dentate nucleus Spongy myelinopathy --

Focality -Left occipital infarction --Left occipital infarction Left parietooccipital infarct --Right hypothalamus hemorrhage

* Hippocampus is excluded. Reprinted with permission from Aso K, Barmada M, Scher MS. Electroencephalography and the neuropathology in premature infants with intraventricular hemorrhage. J Clin Neurophysiol 1993; 10:304-13. Abbreviations: EO = Seizure discharge without clinical movement EP = Electrical seizure discharge in paralyzed baby Sub = Subtle seizure (chewing and nystagmus)

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that subcortical onset of some neonatal seizures results in only intermittent electrographic spread to the cortical surface, as documented by surface EEG recordings. Our findings of subcortical damage (i.e., midbrain, cerebellum, and substantia nigra) in neonates with electrographically conf'Lrmed seizures [25] may help support the speculation of initiation of seizures in "deep" grey matter structures.

Periodic Discharges Periodic discharges are stereotypic paroxysmal complexes, separated by nearly identical intervals between individual recurrent complexes. Periodic lateralized epileptiform discharges (PLEDs) of at least 10 rain in duration or 20% of the recording time have been traditionally defined [63]. A recent report [64] reviewed 1,114 records on 592 neonates; periodic discharges were documented in 57 (5%) of the recordings from 34 neonates (26 preterm and 8 term). PLEDs were noted only in 4 infants. Sixteen patients (47%) with focal periodic discharges also had electrographic seizures on the same or subsequent record. Cerebral infarction was the most common brain lesion (53%) in this neonatal population. Preterm neonates had discharges that were <60 s in duration and located near the parasagittal regions. Discharges in term neonates were longer than a minute and were usually located in the temporal region. Of 34 neonates, 15 (44%) died, and l 1 of 19 (58%) were abnormal with respect to neurodevelopmental outcome. PLEDs in the neonatal population had an incidence of only 0.3%, which is below the rate of 0.6-8.5% documented in older patients [63]. Focal periodic discharges of shorter duration than PLEDs occur in the neonate, but have the same clinical significance as PLEDs that are seen in older children and adults. The neurologic examination of the preterm neonate with periodic discharges may be misleading. Term infants with periodic discharges were abnormal in their levels of arousal and exhibited hypotonia. However, more than 50% of preterm neonates lacked any neurologic abnormality on examination at the time periodic discharges were noted on EEG recordings. While acute hypoxic ischemic encephalopathies may be associated with periodic discharges in term infants [64], either acute or chronic etiologies may be present in the preterm infant. Periodic discharges have been documented with neonatal herpes encephalitis, but bilateral periodic high amplitude sharp and slow complexes have also been described with severe metabolic encephalopathies due to inborn errors of metabolism [32].

Abnormal EEG-Sleep Patterns and Timing of the Neurologic Insult To what extent do clinical signs of neonatal encephalopathy actually reflect chronic, as well as acute brain

damage [65]? The clinical profile of a postasphyxial encephalopathy may include neonatal depression, seizures, and focal neurologic deficits, and has traditionally been associated with recent hypoxic-ischemic stress [66]. However, it may be difficult to distinguish on a clinical basis whether a brain disorder had its onset in the antepartum period in addition to, or instead of, the intrapartum period. Encephalopathic infants have been described with obstetric and postmortem evidence of antepartum and/or intrapartum adverse events [67-69]. Intrapartum fetal surveillance methods (e.g., fetal heart rate monitoring) may document acute fetal distress, but are not predictive of later neurologic deficits [69]. Such monitoring only documents cardiac dysfunction that occurs during a stressful delivery; preexisting injury to the central nervous system during the antepartum period may have ultimately led to end organ failure during parturition. Better diagnostic efforts are required to assess the neurologic integrity of the fetus prior to problematic intrapartum events. Three clinical situations have been selected from our neonatal neurology consultation service to illustrate this issue of timing concerning neonatal encephalopathies. Both symptomatic and asymptomatic newborns with brain injuries are described with antepartum and intrapartum events which may contribute to the neonatal brain disorder. Interpretation of EEG abnormalities certainly cannot estimate when an encephalopathy began; the same EEG disturbance can be observed with acute or chronic processes, or clinical situations that combine both situations.

Isoelectric EEG As pointed out in the previous section concerning this type of EEG abnormality, neonates with significant neonatal neurologic depression can exhibit EEG inactivity (i.e., isoelectric EEG). Twenty neonates (7 preterm, 9 term, and 4 postterm), who had at least 1 isoelectric EEG record, were evaluated over a 6-year period at our obstetrical center [28]. Seventy-four EEG records were obtained in this cohort, including 36 isoelectric recordings. At least 7 infants in this group had antepartum conditions which primarily contributed to a pathologic process leading to brain injury. This conclusion was based on obstetric history and placental or neuropathologic postmortem examinations. Lack of fetal movements prior to labor, significant placental or cerebral calcifications, and infarctions on placental or postmortem examinations were cited. Of 16 placentas examined, chronic lesions were noted in 13/16 specimens including villitis, infarction, dysmaturity, and thrombosis. Seven of 9 patients with postmortem neuropathologic examinations had evidence of chronic lesions, principally neuronal necrosis, infarction, and microcalcifications. An additional 10 infants had evidence of a pathologic process that began in the antepartum, but continued into the intrapartum or neonatal periods, as suggested by review of the maternal and neonatal medical records. Examples included intrauterine growth retarda-

Scher: NeonatalBrainDisordersExpressedby EEG Sleep 197

tion, antepartum maternal hemorrhage, abnormal antepartum fetal heart rate tone patterns, and lack of fetal response on fetal heart monitoring to stress. Only 3 patients had exclusively intrapartum or neonatal onset of a process leading to brain injury. Irrespective of the timing of the pathologic process, clinical signs of a severe neonatal depression (i.e., postasphyxial encephalopathy) were present during the immediate postnatal period in 18/20 patients or 90% (i.e., metabolic acidosis, depressed Apgar scores, decreased arousal, multiorgan system involvement). Evidently, the clinical presentation of a newborn with postasphyxial encephalopathy syndrome does not only reflect an acute process leading to brain injury.

Hydrops F etalis Obstetric and neonatal records were reviewed of infants and fetuses with the diagnosis of nonimmune hydrops fetalis (NIHF) over a 6-year period [70]. Forty-five infants were initially identified with NIHF of whom 37 were liveborn. Maternal sonography diagnosed this condition in 33/37 (89%) of liveborn fetuses. Twenty-nine of the 37 died either in utero or within 7 days of birth. Seventeen of these 29 (60%) had cranial ultrasound examinations. Fifteen of 29 infants had EEG studies, and 25/29 had postmortem examinations. Thirteen of 15 (85%) infants had moderately to markedly abnormal EEG patterns, reflecting significant encephalopathic states. Three infants had EEG seizures. Cranial ultrasound examination failed to document pathologic lesions that were later observed on postmortem examination; pathologic lesions principally were cerebral dysgenesis, encephaiomalacia, and microcalcifications. Ten infants survived, but only 4 neonates were normal at the time of discharge. EEG patterns associated with patients with NIHF included inactivity on the EEG, low amplitude recordings, isoelectric patterns, and severe lack of EEG background rhythms for the neonate's stated postconceptional age. While such EEG findings are not pathognomonic for the timing of the neurologic insult and can also be seen after acute brain injury, infants with NIHF clearly suffered antepartum damage to the brain, as well as other major organs. Diffuse or multifocal chronic brain lesions, as seen on postmortem examination, highlight the antepartum time-course during which the pathophysiologic process that is associated with nonimmune hydrops fetalis adversely affected fetal brain.

Neonatal Seizures Seizures reflect an acute and transient encephalopathic process, which may resolve spontaneously or with antiepileptic medications [21]. Seizures may be associated, however, with chronic as well as acute pathologic processes which are responsible for brain injury. Two clinical situations may arise in which seizures occur, either with or without signs of postasphyxial encephalopathy [28,71 ]. In the absence of signs of a neonatal encephalopathy, 4 of 6

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neonates developed isolated seizures within 30 hours of life while in a well-child nursery [72]. Computed tomography scans of the brain within 30 hours of life documented chronic encephalomalacia or porencephaly that clearly predated labor and delivery in all infants, including those with seizures. The 2 remaining newborns were totally asymptomatic during the immediate neonatal period, but had been previously followed during the antepartum period by the neurology service because of sonographic evidence of porencephaly. All infants later developed neurologic signs consistent with a static encephalopathy (i.e., cerebral palsy) during the first year of life. Placental examinations were unremarkable for all 6 pregnancies, and all infants had normal Apgar scores and fetal heart rate tracings, as well as no evidence of postasphyxial encephalopathy syndrome. While neonatal seizures clearly require emergent treatment, their presence may reflect longstanding in utero injury. Stresses of parturition may transiently lower seizure threshold for some infants during the immediate postnatal period, even without accompanying signs of neurologic depression. In addition to asymptomatic neonates with isolated seizures, encephalopathic neonates with seizures also may have experienced chronic pathologic processes, as supported by placental or postmortem examination findings [28]. Nine of 20 patients with 20 isoelectric EEGs, also had electrographic seizures. Six of these 9 patients had pathologic evidence on autopsy of antepartum pathologic processes leading to brain injury. An additional 3 patients had antepartum processes that were based on clinical information without pathologic confirmation. Placental examinations in another group of neonates with electrographically confirmed seizures also suggest a rate of chronic placental lesions higher than that in infants who did not exhibit seizures [72]. Chronic lesions include infarction, reduced placental weight (i.e., < 10th percentile), and dysmaturity. Placental examinations of a healthy control group without seizures were obtained and matched for postconceptional age and gender and for who were subsequently normal at 2 years of age. Neonates >33 weeks EGA with EEG seizures had a higher percentage of chronic lesions (30%) as compared with 12% in the control population (P < .01, ×2 analysis with Yates correction factor) (Table 4). Adverse intrapartum events may lower the threshold for seizures in a neonate who has been already stressed because of antepartum medical complications. Chronic placental lesions suggest that long-standing placental insufficiency situations may contribute to the pathogenetic mechanism of seizures in the immediate newborn period. Conclusion

One can document the progression of a neonatal encephalopathic state with serial EEG recordings. At least 1 EEG during the initial days after birth followed by a second or third study during subsequent days to weeks may

Table 4. Chronic Versus Acute Placental Lesions in Neonates With and Without EEG Seizures Neonates With Electrographic

Seizures (n = 43) GA (wk) 24-32 33-36 >36

Healthy Neonates Without Seizures (n = 33)

AJC

A/C

N

A

or C

N

A

or C

4.7% (2) 4.7% (2) 0% (0)

51.2% (22) 2.3% (1) 4.7 (2)

2.3% (1) 9.3% (4) 20.9% (9)

3.0% (1) 0.0% (0) 15.2% (5)

30.3% (10) 9.1% (3) 15.2% (5)

15.2% (5) 6.1% (2) 6.1% (2)

Abbreviations: GA = Gestational age A = Acute C = Chronic N = Normal

reflect the persistence or resolution of an encephalopathic process. E E G studies after the first week during the convalescent period m a y be extremely helpful for prognostic purposes. Neurophysiologic studies offer important information which s u p p l e m e n t clinical e x a m i n a t i o n and neuroimaging data. The pathophysiologic processes which define an encephalopathic state m a y not o n l y be widespread or focal throughout different brain regions, but also reflect acute and/or chronic disease processes. E E G abnormalities express antepartum, as well as intrapartum and neonatal insults to the central nervous system and are rarely p a t h o g n o m o n i c for a specific clinical pathologic situation. The clinician should, therefore, make every attempt to consider the E E G findings in the context o f all clinical and laboratory facts before reaching the most accurate i n t e r p r e t a t i o n o f the p a t h o p h y s i o l o g i c process. While the clinical neurophysiologist m a y not reach a specific diagnosis that is based solely o n electrographic interpretation, E E G studies c o m p l e m e n t structural studies and the clinical history and e x a m i n a t i o n to better define the severity and timing of neonatal brain disorders. Proper interpretation o f E E G - s l e e p patterns will broaden the child neurologist's diagnostic and prognostic assessments of the high-risk infant with central nervous system dysfunction.

The author thanks Margie Phillips for manuscript preparation.

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