Hypoxic-Ischemic Encephalopathy



Hypoxic-Ischemic Encephalopathy


Floris Groenendaal and Linda S. de Vries


Hypoxic-ischemic encephalopathy (HIE) following severe perinatal asphyxia (also described in the literature as perinatal hypoxia-ischemia or asphyxia neonatorum) has an incidence of 1 to 2 per 1000 live births in the western world, and is far more common in developing countries (see Chapter 10). Although metabolic disorders may mimic perinatal asphyxia, and genetic and placental factors may contribute to the clinical picture, brain imaging techniques have demonstrated acute changes in the term neonatal brain following perinatal asphyxia.


The chance of irreversible damage or death following perinatal asphyxia is high, up to 65% of patients enrolled in trials of neuroprotective strategies. Therapeutic hypothermia is neuroprotective as has been demonstrated in several trials, and is standard therapy for full-term or near-term neonates with severe perinatal asphyxia and encephalopathy.47 Ongoing studies will aim at additive strategies to augment the neuroprotection of hypothermia.87


Experiments in animals have demonstrated that the immature brain is more resistant to hypoxia-ischemia than the brain of the term neonate. The several reasons to explain this difference are a lower cerebral metabolic rate; lower sensitivity to neurotransmitters with potential neurotoxicity; and the greater plasticity of the immature central nervous system. Nevertheless, in the fetus and newborn, cerebral hypoxia-ischemia is a major cause of acute mortality and morbidity in survivors. However, the neuropathology will be different from that of the full-term neonate (see Chapters 59 and 60).



Definitions


Hypoxic-Ischemic Encephalopathy


This term describes abnormal neurologic behavior in the neonatal period following perinatal hypoxia-ischemia. Previously, the term post-asphyxial encephalopathy has been used, and some suggest that the term neonatal encephalopathy be better used, because the cause of encephalopathy is not always obvious.


The severity of HIE can be defined as mild, moderate, or severe depending on clinical findings as described by Sarnat and Sarnat93; this classification is widely used and is summarized in Table 61-1. More recently, other clinical scoring systems have been developed to assess the severity of HIE (Table 61-2).21,104








Pathophysiology


Systemic Adaptation to Hypoxic-Ischemic Insult


Severe fetal hypoxic-ischemic injury affects the entire organism, and these effects have been well studied in animal models. In particular studies, instrumented fetal sheep and monkeys in the 1960s and 1970s had been used to describe the physiologic and pathologic changes in the brain following hypoxia.22,74 Hypoxic-ischemic injury may occur at any time during pregnancy, the birth process, or the neonatal period. The pattern of brain damage is reflected by the gestational age of the fetus at the time that the injury occurs. Fetal hypoxic-ischemic injury may result from maternal, uteroplacental, or fetal problems (Box 61-1). The fetus may survive maternal hypoxia-ischemia such as transient hypoxia or hypotension. Correctable placental factors include hyperstimulation with oxytocic agents or intermittent cord compression, but these may cause irreversible brain damage before recovery occurs.



Box 61-1   Causes of Fetal Hypoxic-Ischemic Insult





Survival with brain damage as the result of early in utero hypoxic-ischemic insult does occur, but in the majority of cases severe maternal hypoxia in the second trimester of pregnancy will result in fetal death.100 Occasionally there is a history of a catastrophic maternal illness such as suffocation, anaphylaxis, or major physical trauma. In other situations, the antecedent pathogenic event is confined to the fetus, with or without an associated abnormality of the uteroplacental unit. Whatever the cause of the cerebral hypoxia-ischemia, the neuropathologic consequence is often devastating.


In the more mature fetus, a period of mild to moderate hypoxemia produces a consistent pattern of responses (Figure 61-1). Initially there is fetal bradycardia with an immediate rise in blood pressure and, in particular, an increase in perfusion to the brain and other vital organs at the expense of the rest of the body. With ongoing hypoxemia, fetal heart rate will decrease further, apnea will occur, and permanent brain injury occurs after 10 to 15 minutes. The fetus is very resistant to milder hypoxemia, and normal cardiovascular function will be maintained for up to an hour even with a Pao2 of 15 mm Hg (normal fetal Pao2 is 25 mm Hg). With prolonged moderate hypoxia, cerebral perfusion will remain normal, but (asymmetric) fetal growth restriction will occur. In fetuses with such prolonged moderate hypoxia, lactate levels may be elevated, indicating that anaerobic glycolysis has occurred in some tissues. The rapid changes in blood gas values have been documented in numerous experiments (Figure 61-2).


image
Figure 61-1 Physiologic responses of rhesus monkeys during asphyxia and on resuscitation. Brain damage was assessed histologically weeks or months after asphyxia. (From Dawes GS. Foetal and neonatal physiology: a comparative study of the changes at birth. Chicago: Yearbook Medical Publishers, Inc.; 1969.)

image
Figure 61-2 Changes in blood gas values in the term monkey fetus after acute, total asphyxia. (Adapted from Myers RE. Two patterns of perinatal brain damage and their conditions of occurrence. Am J Obstet Gynecol. 1972:112:246-276.)

As the hypoxic insult becomes more severe, changes in regional cerebral blood flow occur. The brainstem is able to extract sufficient oxygen to maintain metabolism despite very low Pao2 at the expense of the cerebrum. Failing myocardial function may cause a fall in cardiac output, and the watershed areas of the cerebral hemispheres are most exposed to damage (see Vascular Territories).


An acute hypoxic-ischemic insult, often referred to as a sentinel event, as may occur during cord prolapse or uterine rupture, is likely to damage the basal ganglia and brainstem, in contrast to the more chronic insult, which leads to damage in the cerebrum (see Neuropathology).74



Preconditioning


Preconditioning describes reduced sensitivity of the immature brain to injury depending on whether it has been exposed to previous nondamaging hypoxic events some hours before the main hypoxic-ischemic insult. Preconditioning of immature rat pups by exposure to moderate hypoxia or inflammation before hypoxia-ischemia appears to be neuroprotective.64 Preconditioning may work through stabilizing hypoxia-inducible factor-1α (HIF-1α) during hypoxia. When dimerized with HIF-1β to HIF-1, it acts on hypoxia response elements in the promoter of hypoxia-responsive genes, which will lead to induction of genes encoding erythropoiesis, angiopoiesis and antiapoptosis.31



Perinatal Hypoxic-Ischemic Brain Damage


During the last decades, the processes leading to neuronal death in the neonate have been described in more detail. This knowledge is important when considering neuroprotective strategies (see Specific Neuroprotective Strategies).


In contrast to adult ischemic stroke, neonatal hypoxia-ischemia is characterized in most cases by a combination of cerebral hypoxia (and ischemia during bradycardia), followed by reperfusion and potential excessive distribution of oxygen. The contribution of reperfusion to cerebral injury is recognized, and has led to the reduced use of supplemental oxygen during neonatal resuscitation.116


An acute hypoxic-ischemic insult leads to events that can be broadly categorized as early (primary) and delayed (secondary) neuronal death. Previously, two different patterns of cell death are reported in neonates.79 Necrosis is the lytic destruction of cells, whereas apoptosis is the programmed cell death, which is ATP-driven. More recently, these cell death patterns appear to be in continuum. The final pathway is dependent on tissue circumstances such as oxygen content.


Early or primary neuronal damage occurs as a result of cytotoxic changes caused by failure of the microcirculation, inhibition of energy-producing molecular processes, increasing extracellular acidosis, and failure of Na+/K+-adenosine triphosphatase (ATPase) membrane pumps, which result in excessive leakage of Na+ and Cl– into the cell with consequent accumulation of intracellular water (cytotoxic edema). Free radical production is also initiated, which further compromises neuronal integrity. If not reversed, these processes lead to neuronal death of the necrotic type within a short time of the acute insult.


Recovery and reperfusion as occur with resuscitation fuel the pathways to late (secondary) neuronal damage through a relatively large number of pathophysiologic mechanisms.


It has been demonstrated in experimental settings that secondary energy failure starts within 6 to 8 hours after the primary insult. The term energy failure reflects the fact that high energy phosphates are reduced as can be demonstrated in vivo using phosphorus magnetic resonance spectroscopy.59 This process is a result of changes in mitochondria, and may last up to 72 hours or even longer after the acute insult. Timing of hypothermia for neuroprotection is based on this “therapeutic window” of 6 hours before the onset of secondary energy failure.



Secondary Neuronal Death


A complicated cascade of intracellular events is triggered by the initial hypoxic-ischemic insult, which results in either cell necrosis or apoptosis (Figure 61-3).


image
Figure 61-3 Intracellular neurotoxic cascade and potential targets for neuroprotection after hypoxia-ischemia. After global hypoxia-ischemia, glutamate-induced excitotoxicity proceeds via N-methyl-d-aspartate receptor (NMDAR) activation, producing Ca2+ influx and therefore activation of Ca2+-dependent nitric oxide synthase (NOS), particularly neuronal NOS. At high concentrations, NO• reacts with superoxide (O•-) to produce peroxynitrite (ONOO–), which in turn induces lipid peroxidation and mitochondrial nitrosylation. During the acute energy depletion, some cells undergo primary cell death. After reperfusion, the initial hypoxia-induced cytotoxic edema and accumulation of excitatory amino acids typically resolve in 30 to 60 minutes, with apparent recovery of cerebral oxidative metabolism. Mitochondrial failure is a key step leading to delayed cell death. Potential neuroprotective targets are indicated. (Adapted from Robertson et al. Which neuroprotective agents are ready for bench to bedside translation in the newborn infant? J Pediatr. 2012;160:544-552.)


Glutamate Injury (Excitotoxicity)


Excessive neuroexcitatory activity occurs as a result of the asphyxial event, and this is mediated through glutamate toxicity.57 Glutamate activates N-methyl-d-aspartate (NMDA) receptors, which in turn cause calcium channels to open in an unregulated manner with excess entry of intracellular Ca2+. The high concentrations of this ion activate lipases, proteases, endonucleases, and phospholipase C, which in turn break down organelle membranes. This sets up a variety of abnormal processes with release of free radicals, including NO• and superoxide ions. This has further adverse effects on cell membranes and leads to mitochondrial failure with the release of caspase-3 and eventual DNA fragmentation, poly(ADP-ribose) polymerase, which causes further energy failure of intracellular membrane function. This process also triggers an apoptotic response in the cell. The process of cell death is different from that seen in adults,122 requiring specific neonatal animal models in the research of perinatal asphyxia.


Furthermore, cell death pathways differ between male and female rat pups (Figure 61-4).123 Some compounds like erythropoietin appear to be more protective in female than in male pups. The relevance for human neonates is not yet established.


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Figure 61-4 Pathways of apoptosis in neonatal male and female animals. AIF, Apoptosis-inducing factor; PARP, poly(ADP-ribose) polymerase. (Courtesy CHA Nijboer, PhD, Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center, Utrecht, The Netherlands.)


Free Radical Formation


Oxygen free radicals cause peroxidation of unsaturated fatty acids, and because the brain is especially rich in polyunsaturated phospholipids, it is especially susceptible to free radical attack. Mechanisms for quenching and inhibiting free radical production exist within the brain, but in the immature organ these mechanisms may be underdeveloped. Consequently the human neonatal brain is at particular risk for oxygen free radical–induced injury.12 Brain arteriole endothelium is the main source of free radical production by the action of xanthine oxidase, but free radicals are also produced by activated neutrophils, microglia, and intraneuronal structures. During reperfusion, free radical production from the arteriolar endothelium results in blood-brain barrier leakage and release of platelet-activating factor, platelet adhesion, and neutrophil accumulation, which may contribute to cellular damage. Resuscitation of human neonates with 100% oxygen has led to prolonged changes in oxidized glutathione as a result of excessive production of oxygen free radicals.116


A particularly important mechanism that exposes the newborn brain to oxygen free radical attack is the presence of free iron. Non–protein-bound (“free”) iron is found in higher concentration in the immature animal because of low transferrin levels. Free iron catalyzes mildly reactive oxygen species to more toxic free radicals through the Fenton reaction. There is evidence that after a hypoxic-ischemic insult, there is an increased presence of intraneuronal free iron within the first 24 hours that persists for several weeks.


The second important mechanism that leads to (nitrogen) free radicals is the production of neuronal-derived nitric oxide (NO). Nitric oxide is produced by three isoforms of the enzyme nitric oxide synthase (NOS): designated neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). Production of NO is accelerated by intracellular Ca2+ influx and in excessive concentrations is neurotoxic. It is thought that up to 80% of NMDA toxicity is mediated through NO. NO also combines rapidly with superoxide to produce peroxynitrous acid, which gives rise to the free radical peroxynitrite. Excessive NO can cause DNA strand breaks and induce neuronal apoptosis mediated through caspase-3 activation, and iNOS, produced during inflammatory processes, has also been reported to aggravate injury in the immature brain. However, NO from endothelial cells (eNOS), is essential in maintaining cerebral perfusion. For neuroprotection only nNOS- (and iNOS-) specific inhibitors can be used.



Apoptosis


Apoptosis (see Chapter 58), or programmed cell death, is perhaps the most important cause of neuronal death in the neonate following hypoxia-ischemia and resuscitation. It can be distinguished histologically from necrosis by shrinkage of affected cells with retention of the cell membrane. By contrast, necrosis is associated with cell rupture, which induces secondary inflammatory processes. DNA degradation develops in the apoptotic cell, giving a characteristic ladder appearance on gel electrophoresis.


Apoptosis is a gene-regulated process, and both proapoptotic and antiapoptotic genes influence the process, including BCL2, Bax, APAF1, and the caspase gene family. A major role in the apoptotic mechanism is played by the caspase family of proteins, with caspase-3 identified as the execution protein. Inhibitors of caspase can block apoptosis and attenuate injury.


Apoptotic pathways have been shown to differ between males and females. Apoptosis via an apoptosis inducing factor-dependent pathway was demonstrated in cultured XY neurons, whereas a cytochrome c-dependent pathway was seen in XX neurons.27,78,123




Human Studies


Studies in human neonates have confirmed the presence of secondary energy failure after perinatal asphyxia. 31P magnetic resonance spectroscopy (MRS) spectra in affected term infants were usually normal within the first 6 hours after birth, suggesting that mitochondrial phosphorylation had initially recovered with resuscitation. After 8 hours there was a significant decline in the high energy phosphates such as phosphocreatine and ATP, with a further decline in the most severely affected infants at 48 to 72 hours. In some infants, recovery occurred to normal values within 7 days. The delayed fall in phosphocreatine/inorganic phosphate (PCr/Pi) ratio represents secondary energy failure.45


In addition, proton MRS did not show lactate in the neonatal brain on very early scans, whereas high levels of lactate could be demonstrated after 48 hours.52 Studies using near-infrared spectrophotometry have shown reduced oxygen uptake, and higher brain oxygen saturations in neonates with perinatal asphyxia, suggesting secondary energy failure.53


Doppler studies of major intracranial arteries demonstrated loss of normal CO2 reactivity with high diastolic blood flow, first seen 12 to 24 hours after birth. In the most severe cases, overall cerebral blood flow will be reduced.84



Selective Vulnerability


In the human neonate, as well as in animal experiments, different patterns of brain injury following HIE have been demonstrated depending on the developmental stage of the fetus, and severity and duration of the hypoxic-ischemic insult. The factors influencing brain injury after perinatal hypoxia-ischemia can be summarized as follows:





Maturity


Gestational age plays an important role in the changing susceptibility of cerebral structures to hypoxic-ischemic insult for a number of reasons, including rapid changes in neuronal development, changing vascular watersheds, and biochemical variables within cells, such as relative proportions of excitotoxic and inhibitory expression. In addition, a low susceptibility of the immature myocardium compared to that of the term neonate may result in a more preserved cerebral perfusion during hypoxia.


Hypoxic-ischemic insults before 20 weeks’ gestational age, such as may occur as the result of severe maternal illness, may lead to neuronal heterotopia or polymicrogyria because the insult to the fetal brain occurs during the stage of neuronal migration, which is not complete until 21 weeks of gestation. Insults affecting the brain during midgestation (26 to 36 weeks) predominantly damage white matter, leading to cystic periventricular leukomalacia, and may have secondary negative effects on growth of the deep gray matter or may increase the risk of intracranial hemorrhage. Primary hypoxic-ischemic injury to the basal ganglia and thalamus in preterm infants has been reported and resulted in a poor outcome.27a,58a Insults near or at term (35 weeks and beyond) result predominantly in damage to deep gray matter or watershed areas of the brain.100



Vascular Territories


Watershed injury refers to tissue damage that occurs in regions that are most vulnerable to reduction in cerebral perfusion as the result of having the most tenuous blood supply. These tissues are at the furthest points of arterial anastomoses and are exposed to damage when perfusion pressure falls, usually as the result of impaired cardiac output and low blood pressure. Watershed areas change with advancing development.


In the term brain, a cortical watershed area (the parasagittal region) is present between the three main arteries supplying each hemisphere. Volpe and colleagues used positron emission tomography to measure regional cerebral blood flow in 17 full-term asphyxiated newborns, and found a consistent decrease in blood flow to the parasagittal region of both cerebral hemispheres in most of the infants.118 Modern techniques such as diffusion-weighted MRI have demonstrated these watershed-type lesions in the full-term neonate (see Neuroimaging).


The depths of the sulci are also sensitive to hypoxic-ischemic insult as the result of being watershed areas at term. Reduction in perfusion in small vessels at the base of sulci during hypoxia-ischemia leads to columnar necrosis and may lead to ulegyria in the older child’s brain.100


Ischemic infarction (stroke) has been recognized more commonly with the increased use of MRI in neonates with or even without encephalopathy. Although infarction of a major cerebral artery has been found in neonates with a hypoxic-ischemic insult, thrombosis and embolus, vasospasm, maternal smoking, or hypoglycemia are more common etiologic factors.40,92 The location of the lesions and neurodevelopmental outcome is dependent on the cerebral artery involved.




Types of Hypoxic-Ischemic Insult


Animal studies on primates have modeled two different patterns of hypoxic-ischemic insult and have shown different patterns of neuronal injury depending on the type of insult.74 Acute total asphyxia was produced in fetal monkeys by clamping the umbilical cord and preventing the animal from breathing. This produced injury to the thalamus, brainstem, and spinal cord structures. The longer the duration of the acute insult, the more extensive the damage was in these regions. Little damage was reported in higher structures.


The second model attempted to mimic a prolonged, partial asphyxial insult lasting 1 to 5 hours. This produced damage predominantly in the cerebral hemispheres and particularly in the watershed distribution (see Vascular Territories), often with sparing of brainstem, hippocampus, and temporal and occipital lobes. Damage was also seen not uncommonly in the basal ganglia and the cerebellum.



Others


Other types of hypoxic-ischemic insults include maternal fever during labor, which may accelerate fetal brain injury, fetal starvation with reduction in intracerebral glucose availability, sepsis, and twinning. The effects of these factors may act through one or a number of the variables discussed previously.


There has been much debate as to the role of pre-existing antenatal factors in exacerbating intrapartum HIE. Recently, placental changes were seen in asphyxiated full-term neonates with encephalopathy. Chronic villitis was associated with the basal ganglia/thalamus pattern of injury, whereas decreased placental maturation was linked to white matter and watershed injury.42 Polymorphisms of the MTHFR gene were demonstrated more often in neonates with HIE and cerebral lesions of the watershed type.39


An MRI study of term infants with hypoxic-ischemic encephalopathy has suggested that the majority of the brain damage present in these babies occurred in the immediate perinatal period and was not the result of long-standing damage,19 although this finding remains controversial.



Neuropathology


The neuropathologic features of hypoxic-ischemic injury vary depending on the type and duration of the insult and the gestational age of the child at the time of the insult. The pathologic features evident on examination also depend on the interval between the insult and death. The neuropathologic features become more apparent as they develop in a temporal sequence. The following represent some of the more consistent features of hypoxic-ischemic injury. Of course, findings on neuropathology are biased by the fact that these neonates have died. Thus, these findings will show different patterns when compared to imaging studies, for example MRI findings, in a cohort of neonates who survived after hypoxic-ischemic encephalopathy. In addition, MRI is less sensitive in detecting cerebral hypoxic-ischemic changes compared to histology.2



Cerebral Edema


Brain edema is thought to occur frequently in infants who have sustained a severe cerebral hypoxic-ischemic insult, and is widely reported in autopsy studies. Cellular edema develops rapidly and resolves by 7 days after its onset, although imaging cannot reliably detect edema until 24 hours after the event because of the higher water content of the neonatal brain. In primate studies of intrapartum asphyxia, partial intermittent hypoxia-ischemia with marked and prolonged hypoxemia was associated with severe edema in all cases, whereas brain swelling was not a feature of severe, acute, total hypoxic-ischemic insults. If the brain damage has been widespread and severe, on gross examination the brain appears swollen, with slitlike lateral ventricles, widening and flattening of the cerebral gyri with associated obliteration of the sulci, and herniation of hippocampal structures. In the most severe cases, herniation of the cerebellar tonsils and vermis through the foramen magnum has been described, but this is seen rarely in clinical practice.



Cellular Responses


Different cell lines in the brain react in varying ways to an acute hypoxic-ischemic insult. Neurons may undergo either necrosis or apoptosis (see Pathophysiology). The nature of these two mutually exclusive processes can be distinguished to some extent by histologic staining. In necrosis, sections stained with hematoxylin and eosin show changes from 5 to 6 hours after the injury. Nuclear membranes degenerate, with release of nuclear chromatin and a secondary inflammatory reaction.80


Activated microglia express a number of cytotoxic cytokines. Although microglial cells respond rapidly after a hypoxic-ischemic insult and undertake the function of ingesting and lysing dead tissue, CD68-positive cells, indicating activated microglia and macrophages, were seen not earlier than at least 24 hours after the hypoxic-ischemic insult in a cohort of 22 full-term neonates who died after severe perinatal asphyxia.35 In this paper, caspase activity could be seen in the brain examined within 24 hours of the hypoxic-ischemic insult. In addition, nitrotyrosine staining, considered the product of NO toxicity, was present in brain and spinal cord tissue.37


Hemoglobin released from damaged red blood cells is mobilized in this way, leaving residual hemosiderin present in the macrophage. Microglial cells present in the dentate gyrus are a reliable indication of previous hypoxic-ischemic insult in infants younger than 9 months of age.


Glial cells respond to hypoxic-ischemic insult by enlarging, proliferating, and later developing fibrillary processes with the expression of glial fibrillary acidic protein, which can be recognized by specific staining. A glial response occurs from 17 weeks of gestational age.100




Chronic Lesions


Cerebral atrophy is the end stage of cellular loss in the brain. Atrophy affects particularly vulnerable areas of the brain (described earlier under Selective Vulnerability). Various specific forms of end-stage pathologic lesions have been recognized in the brain for many years.


Status marmoratus describes a patchy, marble-like appearance of the basal ganglia and thalamus that may develop approximately 6 months after a severe perinatal hypoxic-ischemic insult. Histologic study shows abnormal myelination of glial bundles rather than neurons.


Ulegyria refers to a particular form of pathology seen in the depths of the cortical sulci and is probably caused by particular watershed vulnerability (see Vascular Territories). The chronic phase of this process produces the appearance of mushroom-like gyri because of loss of deep gray matter in the sulci.100



Assessment Tools


Many different tools have become available to aid in the more precise prediction of neurodevelopmental outcome in the full-term infant with HIE.



Clinical Examination


Previous studies have described the clinical changes in the encephalopathic term neonate in detail.93,104 The Sarnat classification is based on clinical and electroencephalography (EEG) findings 24 hours after the insult. It has been modified to be used shortly after the insult for selecting neonates to determine eligibility for therapeutic hypothermia.


The Thompson score is based on several clinical items and results in a quantitative score (see Table 61-2). The classification systems have been used not only for clinical purposes but also for inclusion of patients in clinical trials, as well as for stratification of patients within those trials.47 Although the predictive value for long-term neurodevelopment of mild and severe encephalopathy is good (no handicaps following mild encephalopathy, almost invariably poor outcome after severe encephalopathy), the predictive value of moderate encephalopathy is poor.111



Neurophysiology


EEG


Neonatal EEG is a well-recognized method to assess brain integrity after hypoxia-ischemia that results in hypoxic-ischemic encephalopathy. In newborn infants, the EEG commonly uses 16 channels and is in most centers only performed during the day; it requires skilled technicians and highly trained and experienced neurophysiologists to interpret the recordings. The 16-channel EEG provides detailed information and when performed with simultaneous video recording, helps to make a distinction between clinical and subclinical seizures. One study showed that less than 10% of neonatal seizures were correctly identified by the neonatal staff, compared with simultaneous video-EEG recordings (see Chapter 62).73 Normal and severely abnormal results on EEG are of important predictive value. Normal traces almost invariably predict a normal outcome, whereas persistent, severely abnormal traces predict an adverse outcome (Figure 61-5). Prediction in children with mild to moderate EEG abnormalities is less reliable and requires sequential recordings. EEG activity is fully differentiated in full-term infants. During quiet sleep, a discontinuous pattern (tracé alternant) alternates with a high-voltage continuous delta pattern. In wakefulness, the EEG is characterized by low-voltage mixed theta-delta activity. In active sleep, a mixed medium-voltage delta-theta activity is seen. Abnormalities on the EEG can be classified as background abnormalities, ictal abnormalities, and abnormalities in the organization of states and maturation. Background pattern abnormalities are highly predictive of outcome (Figure 61-6). It should be taken into account that antiepileptic drugs can (transiently) affect sleep states and the background pattern, especially in children with severe encephalopathy. The following background patterns can be recognized: isoelectric and extremely low voltage (less than 5 µV); burst suppression pattern, with long periods of inactivity (usually longer than 10 seconds) mixed with bursts of abnormal activity. Outcome is especially poor, with long periods of inactivity and brief periods of bursts (less than 6 seconds) with small-amplitude bursts and interhemispheric asymmetry and asynchrony.8,69


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Figure 61-5 Standard 16-channel electroencephalogram showing a normal continuous-voltage background pattern. (Courtesy AC van Huffelen, PhD, Department of Neurophysiology, University Medical Center, Utrecht, The Netherlands.)

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