Hypoxic-Ischemic Brain Injury in the Term Newborn

NEUROLOGlC DISORDERS lN THE NEWBORN PART I

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Hypoxic-Ischemic Brain Injury in the Term Newborn Neuropathology, Clinical Aspects, and Neuroimaging Michael J. Rivkin, MD

One of the most compromising causes of neonatal neurologic morbidity in term infants is hypoxic-ischemic (HI) brain injury. The devastating effects on the nervous system caused by this type of injury emerges clearly from data derived from animal models of HI brain injury. 63• 64 The origin and timing of HI brain injury, however, often are less clear in the clinical setting than when observed in animal models. Recently, the importance of intrapartum events in the origin of cerebral palsy has been reassessed and the prevalence of unknown causes emphasized. 65 Nonetheless, several important insights have been gained in the last several years into the clinical features, mechanism of injury, and management of HI injury in the full-term infant. In this article, the basic pathogenesis of HI injury and the clinical settings in which this injury occurs are reviewed. Subsequently, the clinical presentation, neuropathologic correlates, and radiologic appearance are discussed. Finally, recent information regarding mechanism of injury, established treatment, potential interventions, and estimation of prognosis based on clinical presentation is presented. PATHOGENESIS

Tissue oxygen deficiency is presumed to underlie the neurologic injury caused by HI insults. An oxygen deficit may be incurred by either hypoxemia or ischemia. Hypoxemia is defined as a diminished oxygen content of blood. Ischemia is characterized by reduced blood perfusion in a particular tissue bed. Commonly, hypoxemia and ischemia occur simultaneously or in sequence. Asphyxia denotes an impairment in gas exchange that results not only in a deficit From the Department of Neurology, Harvard Medical School, and Children's Hospital, Boston, Massachusetts

CLINICS IN PERINATOLOGY VOLUME 24 • NUMBER 3 •SEPTEMBER 1997

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of oxygen in blood but also an excess of carbon dioxide, thereby causing acidosis. Further, sustained asphyxia almost always results in hypotension and ischemia. Asphyxia is the most common clinical insult resulting in brain injury during the perinatal period. 96 Vanucci and Duffy94 elucidated several important features of brain metabolism during asphyxia. First, survival declines as the duration of asphyxia increases. Mortality rates of 75% were observed after 20 minutes of asphyxia in neonatal animals. Second, acidosis and hypercarbia appear rapidly in asphyxia; a pH of substantially less than 7.0 may be found after only 10 minutes of asphyxia. Third, although initial cardiovascular responses preserve cerebral perfusion and thereby provide neuroprotection, eventually decreasing cardiac output, hypotension, and reduction of cerebral perfusion supervene. 40 Because autoregulation of cerebral blood flow is impaired in asphyxiated infants, cerebral circulation becomes pressure dependent. As a result, declining blood pressure results in inadequate cerebral perfusion, and thus, ischemia compounds hypoxic injury to brain. Cerebral metabolism changes substantially during asphyxia. Brain glucose levels decline quickly. This decline results from increased use of this substrate as comparatively inefficient glycolysis replaces oxidative metabolism in response to hypoxia. Adenosine triphosphate (ATP) production cannot keep pace with demand despite accelerated glycolysis. As a result, brain energy stores decline. 94 The biochemical consequences of this decline are discussed subsequently. Three different mechanisms may underlie ischemic injury of the brain: diminished systemic perfusion, embolism, or thrombosis. Should systemic pressure decline enough to compromise cerebral perfusion, then the CNS may suffer injury because of diminished systemic perfusion. Cardiac pump failure and systemic hypotension resulting from hypovolemia represent common causes of hypotensive cerebral ischemic injury. Often, in the circumstance of diminished cerebral perfusion, brain injury is much more diffuse than that found in the more focal injuries characteristic of thrombotic and embolic cerebral events. Embolic damage to the brain occurs when material formed at a site in the vascular system proximal to the brain lodges in a blood vessel, thus blocking cerebral perfusion. Emboli originate most commonly from the heart, arising from clot on cardiac chamber walls or from vegetations on valve leaflets. Arteryto-artery emboli are composed of clot or platelet aggregates that originate in vessels proximal to the brain but ultimately come to rest and occlude flow in vessels critical for cerebral perfusion. Thrombosis denotes vascular occlusion owing to a localized process within a blood vessel or vessels. Although atherosclerosis underlies most thrombotic processes affecting adults, it is not a common cause of thrombosis in children. Localized lumenal clot formation occurs in polycythemia or in a hypercoaguable state. Alternatively, anatomic abnormalities may lead to clot formation or mechanical obstruction, as in fibromuscular dysplasia, arteritis, or arterial dissection. Irrespective of mechanism, cerebral ischemia serves as the final common pathway leading to brain injury. Hemorrhage occurs when blood is released into the extravascular intracranial or intraspinal space. In this circumstance, focal injury of brain or spinal tissue occurs as a result of pressure exerted by the space-occupying mass of blood and hemorrhage-related ischemia. Such injury may be exacerbated by the damaging effects on neural tissue of substances released in the blood. Epidural and subdural hemorrhage represent intracranial collections of blood separated from brain parenchyma by dural or arachnoid membranes. Subarachnoid hemorrhage occurs when blood flows out of the intracranial vascular bed and onto the surface of the brain to admix with cerebrospinal fluid in the subarachnoid space. Intracerebral hemorrhage denotes bleeding into the parenchyma of the brain.

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WHICH NEONATAL HI INJURY IS

Evidence of HI injury to the term neonatal nervous system is reflected by a constellation of signs noticed early in the postpartum period. This constellation constitutes the clinical entity of HI encephalopathy (HIE). It remains clear that asphyxia serves as the most common pathogenetic mechanism underlying HIE. The asphyxiating event(s) may, however, occur at any point in the infant's antepartum, intrapartum, and postpartum life. In addition, indicators of fetal and newborn well-being now exist that prove helpful in the identification of those patients likely to have suffered an HI insult. In the process of describing the static encephalopathy that was first to bear his name and subsequently to be called cerebral palsy, John Little related its occurrence to problems of labor and delivery."" Little's observations focused attention on the intrapartum period as the time during which a brain insult was most likely to occur. Birth trauma mediated by forceps delivery was regarded as the most common cause of perinatal brain injury. As obstetric techniques improved and the incidence of mechanical birth trauma decreased, intrapartum asphyxia was invoked as a potent cause of neurologic damage of the newborn. 79 As perinatal care improved and fetal monitoring became more sophisticated, however, a decline in neonatal morbidity and mortality was not matched by a concomitant reduction in the incidence of cerebral palsy. 3"· 89 The observed persistence of cerebral palsy despite advanced intrapartum care suggested that insults at times other than the intrapartum period could result in neonatal encephalopathy. Additionally, lack of optimal methods of intrapartum fetal CNS monitoring could contribute to the unchanging incidence of cerebral palsy. The accumulated experience of several investigators has defined the relative contributions of antepartum, intrapartum, and postpartum insults to HIE in the newborn. 50 • 51 • 62 Nelson and Ellenberg"5 have posited that information regarding intrapartum and postpartum events do not identify appreciably larger numbers of patients afflicted with cerebral palsy than is found with antepartum information alone. In a separate population studied in Australia, intrapartum asphyxia could account for the origin of cerebral palsy in less than 10% of patients." An MR imaging study of 29 patients with cerebral palsy who were born at term revealed that perinatal insults were likely to have occurred in 17% to 24°/c"'n Finally, careful neuropathologic study of brain from perinatal deaths has permitted dating of neurologic injury due to asphyxia with respect to parturition. These results suggested that asphyxiating insults may occur in the antepartum period, immediately preceding onset of premature labor, in the intrapartum period or in the neonatal period. 53 These studies underscore the importance of considering the antepartum and postpartum periods as settings in which insults leading to neonatal HIE may occur. Nonetheless, it is crucial to recognize that even if perinatal insults account for cerebral palsy in only 17'/'o to 24'X, of cases, the number of affected infants is large because of the many term births and the relatively high prevalence of cerebral palsy. Based on admittedly imprecise historical data, it has been concluded that insults sustained by the fetus during the antepartum period account for approximately 20% of cases of HIE. Maternal cardiac arrest or hemorrhage leading to transplacental and fetal hypotension represent such prenatal insults. Intrapartum events, such as abruptio placentae, uterine rupture, or traumatic delivery, may account for 35% of cases of HIE. In an additional 35% of infants displaying signs of HIE, markers of intrapartum fetal distress and antepartum difficulty, such as maternal diabetes, intrauterine growth retardation or maternal infection, are

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found. In these cases, therefore, it is not entirely clear when the major underlying insult(s) occurred. It is possible that antepartum perturbations may render the fetus more susceptible to intrapartum insults that, alone, would not have caused HIE. Finally, postpartum difficulties, such as cardiovascular compromise, persistent fetal circulation, or recurrent apnea, account for approximately 10% of HIE cases (Table 1). Such postpartum difficulties are found more commonly in premature than in term infants. 101 Therefore, for at least 65% of cases of neonatal HIE, difficulties of the intrapartum period alone do not explain the encephalopathy. CLINICAL FEATURES OF HIE

Recognition of neonatal HIE requires careful observation and examination of the term newborn in the context of a detailed history of pregnancy, labor, and delivery. In general, newborns who have sustained intrapartum HI insults severe enough to cause permanent neurologic injury demonstrate abnormalities on neurologic examination. 29 ' 38 Similarly, should no overt neonatal neurologic syndrome be found in the history of a child with subsequent neurologic deficits, intrapartum events almost certainly are not the origin. Moreover, if the HI damage has occurred well in advance of parturition, it may appear asymptomatically in the neonate. 44 The signs of HIE extend across a spectrum that correlates with the severity of the insult (see Table l), Mild encephalopathy may be characterized by hyperalertness or by mild depression of the level of consciousness, which may be accompanied by uninhibited Moro and deep tendon reflexes, signs of sympathetic overdrive, and a normal or only slightly abnormal EEG. Typically, these symptoms last less than 24 hours before they subside. Moderate encephalopathy may be marked by obtundation, hypotonia, diminished numbers of spontaneous movements, and seizures. Infants with severe HIE are comatose, In addition, they are markedly hypotonic and display bulbar and autonomic dysfunction. 82 Neonates with moderate and severe HIE may show variation in level of consciousness during the first days after birth. Initially, depression of level of alertness may appear to improve after the first 12 to 24 hours of life; however, specific signs of improving alertness, such as visual fixation or following, will be lacking. In addition, other persistent or progressive neurologic deficits and functional deterioration of other extraneural systems will be inconsistent with a true improvement in neurologic state. Coma may persist, supervene, or even

Table 1. CLINICAL SIGNS OF HYPOXIC-ISCHEMIC CEREBRAL INJURY Mild Encephalopathy Mild depression or excitation of level of consciousness Hyperexcitation of sympathetic nervous system Brisk deep tendon reflexes and vigorous Moro reflexes Duration of less than 24 hours Moderate to Severe Encephalopathy Stupor or coma Depression of deep tendon reflexes and Moro response Hypotonia Seizures and interictal EEG abnormalities Duration of more than 24 hours

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progress to brain death 72 hours of life. If the infant survives through 72 hours of life without losing all cerebral function, a variable amount of improvement generally is observed.rn 2 Changes in level of alertness may accompany cerebrovascular events causing focal brain injury. Lethargy may be the initial sign of focal cerebral ischemia in neonates who have suffered a stroke. 17 Moreover, it has been reported that unexplained lethargy or stupor may mark cerebral venous thrombosis (CVT) when it occurs in neonates. 74 Although the cause of the observed lethargy is not clear, it may relate to increased venous pressure leading to local deficits in cerebral blood flow or brain edema. Abnormal respiratory patterns may be encountered in neonates with HIE. Periodic breathing, observed in the first 12 hours of life, has been considered the neonatal equivalent of Cheyne-Stokes respiration 23 and an indicator of bihemispheric brain injury. 15 In subsequent hours, a variety of other abnormal respiratory patterns may be observed, including recurrent apnea, ataxic respirations, or respiratory arrest. Signs of brain-stem involvement include eye deviation, loss of the oculocephalic reflex, and loss of ocular responsiveness to caloric stimulation. Pupillary abnormalities include mydriatic pupils that display diminished responsiveness to light or constricted pupils that retain responsiveness to light (diencephalic pupils). 72 Although brain-stem injury and resultant dysfunction usually accompany hemispheric injury, selective bulbar injury may occur. 45• 78 Diffuse hypotonia accompanied by a dearth of movement constitute the most frequently observed motor deficit found early in the course of neonatal HIE. 38 By the end of the first day of life, patterns of weakness may emerge that reflect the distribution of cerebral injury from a generalized HI insult. Term infants may demonstrate quadriparesis with predominant proximal limb weakness. This pattern of weakness is likely to derive from ischemia in the watershed or parasagittal regions of brain that correspond to the border zones of circulation between the anterior and middle-cerebral arteries and the middle and posterior cerebral arteries. 99 Premature infants may manifest weakness primarily in the lower extremities because of perinatal ischemic injury of motor fibers subserving the legs. These fibers lie dorsal and lateral to the external angles of the lateral ventricles. 5 · 6 This pattern of injury may, however, occur less frequently in term infants as well. Finally, focal injury or infarction consequent to focal ischemia may result in focal deficits reflective of the vascular territory in which the injury has occurred. As many as 70% of infants with moderate or severe HIE will experience seizures by the end of the first day of life. A review of neonatal seizures resulting from HI injury is beyond the scope of this article but is reviewed elsewhere. 61 • 85

NEUROPATHOLOGIC PATTERNS OF HI INJURY AND THEIR CLINICAL CONSEQUENCES HI injury may involve virtually every part of the CNS. Nonetheless, several topographic patterns of involvement have been observed. Although more than one pattern may be observed in a given neonate, usually one pattern emerges as the principal one. Most often, the patterns of injury found are influenced by the nature of the insult and the gestational age of the infant at the time of injury (Table 2).

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Table 2. NEUROPATHOLOGIC PATTERNS OF HYPOXIC-ISCHEMIC CEREBRAL INJURY Patterns Predominantly Found in Term Infants Selective neuronal necrosis Status marmoratus Parsagittal cerebral injury Focal and multifocal ischemic brain injury Pattern Predominantly Found in Premature Infants Periventricular leukomalacia

Selective Neuronal Necrosis

Selective neuronal necrosis, most often but not exclusively found in term infants, is characterized by neuronal injury in discrete parts of the CNS. Neurons demonstrate the greatest sensitivity to oxygen deprivation of all the cellular components of the brain. 86 Among term infants, neurons of the CA, region of hippocampus (Sommer's sector), deeper layers of cerebral cortex, and cerebellar Purkinje cells are injured most frequently by HI. Bulbar regions affected include inferior colliculus, oculomotor and trochlear nuclei, trigeminal and facial nuclei, and dorsal motor nucleus of the vagus nerve. When found in the premature population, this injury involves neurons of the hippocampal subiculum, basis pontis, and inferior olive. Often, neuronal necrosis is most pronounced in watershed regions of cerebral cortex and in depths of sulci, reflecting the greater effect of ischemia in these regions. Clinically, during the neonatal period, selective neuronal necrosis involving the cerebral hemispheres may be manifested by the seizures and electrographic discharge patterns typical of this injury. In addition, damage to modulatory and primary respiratory centers in hemispheres and brain stem presumably are responsible for apnea and other respiratory disturbances. Other abnormalities indicative of hemispheric or bulbar injury include hypotonia, oculomotor deficits, facial paresis, and oropharyngeal dysmotility. Chronic features of this injury constitute the static motor deficits commonly described as cerebral palsy. Cognitive deficits and seizures may accompany these long-term deficits. 97

Status Marmoratus

Status marmoratus may be found in basal ganglia and thalamus. It denotes the cellular responses of neuronal necrosis, gliosis, and hypermyelination after an HI injury. The lesion is found much more frequently in term infants than in premature infants. This discrepancy suggests that developmental and HI requirements must be met for the lesion to occur. It is the hypermyelination of the affected structures that creates the marbled appearance and suggests the lesion's name. Although controversy exists regarding exactly what is hypermyelinated within the lesion, the balance of evidence suggests that the plethora of astrocytic fibers is abnormally myelinated and far fewer residual axons may be myelinated. 10• 12 In addition to basal ganglionic changes, similar but less exuberant hypermyelination often accompanies ulegyria in cerebral cortex. 12 The clinical manifestations of the extrapyramidal injury include chorea, athetosis, and dystonia. 98

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The primary ischemic lesion of term infants is parasagittal cerebral injury. This injury comprises cortical necrosis with involvement of the immediately subjacent white matter in a characteristic distribution, encompassing the parasagittal, superomedial areas of the convexities bilaterally, with posterior (parietooccipital) regions more involved than anterior regions. 99 The injury's distribution demarcates the border zones among the anterior, middle, and posterior cerebral arteries. These distal fields of perfusion are most vulnerable to a fall in cerebral blood flow during hypotension that occurs in severe perinatal asphyxia. As noted previously, the cerebral effects of hypotension are exacerbated by the loss of vascular autoregulation that accompanies asphyxia. 73 During the neonatal period, weakness is indicated by less vigorous limb movement than usually is seen in newborns. Arms usually are affected more than legs, and proximal musculature is weaker than distal musculature. A proximal spastic quadriparesis involving arms more than legs represents the usual long-term sequela. 10.> Periventricular Leukomalacia

Periventricular leukomalacia (PVL) represents the primary ischemic lesion of the premature infant, though its occurrence in term infants has been observed. Necrosis of periventricular white matter dorsal and lateral to the external angles of the lateral ventricles occurs most commonly (1) at the level of the occipital radiation adjacent to the trigone of the lateral ventricles and (2) at the level of the foramen of Monro. 5 • 6 In the acute phase, venous congestion or even hemorrhage may accompany necrosis. Later, in the chronic stage, the affected areas become gliotic, delayed in myelin development, and variably calcified. PVL also results from ischemia to fetal brain. The affected regions of white matter reflect the border zones of arterial circulation as they are found in the premature newborn. 100 In addition, in both the term and premature newborn, white matter distant from the ventricle may be involved. 20 • 68 Involvement of these areas may reflect metabolic peculiarities of nascent, differentiating glia. 95 During the immediate postnatal period, premature infants with PVL will demonstrate hypotonia and weakness, especially of the lower extremities. Such leg dysfunction reflects the primary involvement of the periventricular leg fibers that run adjacent to the lateral ventricles. In the long term, spastic diplegia appears. In severe PVL, spastic quadriparesis and visual impairment may be found. 104 Focal and Multifocal lschemic Brain

Focal and multifocal ischemic brain injury may occur during the perinatal period in term infants. Such injury, most often infarction, occurs in a vascular distribution. Prenatal cerebral infarctions have been identified by intrauterine ultrasonography (US). 66• 84 In one autopsy study of neonates, 32 of 592 infants had cerebral infarcts, an incidence of 5%. Among neonates surviving only a few hours after birth, several had infarcts with subacute or chronic histologic characteristics indicating that the ischemic insult occurred well before parturition.8 Interestingly, focal seizures serve most frequently as the heralding sign of neonatal stroke. 17 Although clinical signs corresponding to the area of infarction

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are expected, they may be absent. 53 Neonatal strokes may follow uneventful deliveries and may occur in otherwise normal infants; however, stroke may accompany asphyxia, coagulopathy, polycythemia, and sepsis. A predilection for these ischemic lesions to occur in the territory of the left-middle cerebral artery has been noted by several investigators and remains unexplained. 53 The cause of the cerebral infarction frequently escapes detection among infants who have not been subjected to overt perinatal asphyxia. Indeed, in 37 of 51 reported cases of neonatal stroke, a cause could not be identified. Interestingly, a left hemispheric location has been noted to be most common; the reason for this neuroanatomic predilection has not been discovered. Embolic or thrombotic origins have been recognized. Emboli from placenta may lodge in cerebral vessels and cause stroke. Further, it is possible that features of the normal newborn's heart, such as a patent foramen ovale, permit the transmission of emboli into the systemic arterial circulation through right-to-left shunts. Once in the systemic arterial tree, the emboli may ultimately ramify in the cerebrovascular bed and cause focal infarction. In addition, congenital heart defects involving right-to-left shunts through septal defects or a patent ductus arteriosus serve as settings for embolic stroke in neonates. Other causes of neonatal stroke in term infants include thrombotic origins. Thrombotic infarction probably is most common in the newborn as a consequence of bacterial meningitis (see subsequent discussion). Polycythemia and its resultant hyperviscosity can cause abnormalities of blood flow and even thrombosis. Approximately 1.5% of neonates are found to be polycythemic. Newborns who are small for gestational age are affected most frequently. Most cases of polycythemia are idiopathic or secondary to acquired abnormalities of oxygen delivery (such as maternal smoking). Nonetheless, polycythemias bearing autosomal dominant or recessive inheritance patterns have been described. Cerebral venous disease occurs as dural sinus or deep CVT in neonates. CVT has been associated with coagulopathy,56 asphyxia,1° 9 sepsis, dehydration, or polycythemia. 14 As noted previously, neonates with idiopathic CVT have been reported. 74• 87 Lethargy, seizures, or both may constitute the only clinical signs of this disorder in neonates. Long-term outcome of children experiencing neonatal focal arterial infarction is variable. The most common sequelae are focal motor deficit (usually spastic hemiparesis) or cognitive deficits. Nonetheless, approximately 70% of children have been normal neurologically on follow-up. 28 • 47• 62• 88 • 92 Approximately 30% subsequently exhibit epilepsy. A favorable outcome has been observed thus far in most children who experienced neonatal CVT. 74 • 87 NEUROIMAGING IN THE EVALUATION OF NEONATAL HI INJURY Cranial Ultrasonography

Cranial or head US (HUS) is a particularly useful radiologic adjunct in the evaluation of the premature infant suspected of having sustained an HI insult. In the first day or two after a significant insult, HUS may reveal striking periventricular echoes. After 1 to 3 weeks, these echogenic regions may evolve into areas of numerous small cysts. Finally, as these cysts coalesce and gliosis is established, the lateral ventricles enlarge and lateral ventriculomegaly is found on subsequent HUS studies. 22• 26 These findings constitute the radiologic correlates of PVL. Despite the high value of detecting these neurosonographic features

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of PVL, it is necessary to recognize that one study employing 11europatholo?ic follow-up of patients diagnosed with PVL by HUS found tha t this modality detected only 30% of microscopically demonstrable lesions afld most often missed gliosis and areas of demyelination. 39 3 43 HUS aids in evaluation of the term infant after an HI ins ult. • HUS is especially accurate when used consecutively in the first week afld again i.n the second week of life.3 In severe HIE, US may detect increased echogemcity of 3 damaged subcortical structures, such as basal ganglia and thatamus." Fir:ally, focal areas of ischemic cerebral injury in the term neonate may be app.reciated with HUS. 37 The ability to use US at the bedside of a sick neonate continues to make this imaging modality very valuable. CT Scanning

CT scanning of the brain is useful particularly for evaluatio(l. of term infants after an HI insult. Diffuse injury appears as abnormal generali zed atte:iuat10n throughout the cerebral parenchyma. Some believe that this al:mormahty may represent cerebral edema.54 Parasagittal infarction, a pattern of injury found in 69 term infants, has been detected by others with cranial CT scan~ing. Focal and 37 multifocal brain injury is detected readily by cranial CT scanni(l.g. When used as a modality to follow brain development in infants and c hildren who as premature infants were found by HUS to have PVL, cranial CT scanning revealed white matter and ventricular changes that correlated well with both earlier US findings and current neurologic deficits.28 MR Imaging

. Important advances in the assessment of HI cerebral injur)" hav.e been.made m the general area of neuroima3ing and in nuclear MR imagj.11.g,. m particular. Although ease and rapidity of image acquisition characterize c J'.'amal US and CT scanning, neither of these imaging modalities provide detailed :iJ tained on followup showed the expected chronic changes, such as cerebral a rophy, paucity of white matter, delayed myelination, and ventriculomegaly.90 fZ.ecently, the val\1e of MR imaging obtained within the first 6 days of life wa ~ demonstrated m neonates who manifest clinical signs of HI cerebral injury.'" MR imagm? performed on 12 term neonates within the first 6 days of life reve ~led clear evidence of miury irrespective of whether injury occurred in a focal oi- diffuse pattern. . The evolution of diffusion-weighted (DW) MR imaging per~its. visualization of CNS infarction very early in its course. This technique capitalizes on the molecular motion of water rather than on Tl W, T2W, or contrast-enhanced images. An increase in intracellular water associated with a r~
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MR imaging visualizes differences in water flux between normal cerebral tissue and that damaged by ischemia before changes detected by conventional MR imaging are apparent. Thus, DW-MR imaging produced the most marked evidence of injury and correlated well with parenchymal involvement observed later using conventional MR imaging pulse sequences. 19 Discrete patterns of cerebral injury have been recognized from study of infants who have suffered perinatal HI injury of brain. Using MR imaging, Baenziger et al studied 88 neonates ranging in age from 28 to 42 weeks' gestation at birth. Each demonstrated clinical signs consistent with perinatal asphyxia. 4 Although this study population included both term and premature infants, patterns emerged on T2W imaging that were seen predominantly in term infants. Three patterns of injury, (1) diffuse hyperintensity of signal found throughout both hemispheres, (2) hyperintensity of parasagittal watershed regions, and (3) thalamic or basal ganglionic lesions, were found predominantly among the subpopulation of term infants studied. Barkovich et aF observed four patterns of cerebral injury with MR imaging study of asphyxiated neonates during the first 10 days of life (Table 3). Their study population was composed largely of term infants or infants very near term at the time of birth. The first group presented MR imaging abnormalities of subcortical gray matter, particularly the lateral half of thalamus, globus pallidus, and posterior putamen (Fig. 1) Periolandic cerebral changes on MR may accompany this pattern as well. The second group revealed abnormalities of cerebral cortex and subjacent white matter in a watershed or end-artery distribution (Fig. 2). Abnormal MR imaging signal in periventricular white matter, a pattern seen more commonly in premature infants than in term infants, characterized the third group (Fig. 3). It is hypothesized that this pattern of MR imaging signal abnormalities, when found in a term infant, represents prenatal cerebral injury from an insult that permitted gestation to reach term. Finally, a mixture of these patterns constituted the fourth group. Interestingly, less bradycardia, hypovolemia, or anemia was observed among the patients of the second group relative to the first group. As a result, the investigators speculate that the pattern of injury found among patients of the second group represented a similar but less severe HI cerebral insult than the insult that resulted in the injury pattern found in the first group. The prognostic significance of MR imaging data compiled during the first few days of life in term infants who have experienced perinatal asphyxia has been examined. Extensive brain edema with effacement of cerebral cortex portends a poor neurodevelopmental prognosis. 57 In addition, the two patterns of either diffuse brain injury or lesions of basal ganglia or thalamus correlated with poor neurodevelopment at a mean follow-up age of nearly 19 months.42 Importantly, neonates with either of these patterns on MR imaging in the first

Table 3. MR IMAGING PATTERNS OF CEREBRAL HYPOXIC-ISCHEMIC INJURY Deep subcortical gray matter injury Abnormalities found in thalamus, putamen, and globus pallidus Cortical and subjacent white matter injury Injury frequently found at watershed regions Gray-white matter junction often is blurred Injury localized in periventricular white matter Pattern of injury consists of a combination of above patterns Data from Barkovich AJ, Westmark K, Partridge C, et al: Perinatal asphyxia: MR findings in the first 10 days. AJNR American Journal of Neuroradiology 16:427-438, 1995; with permission.

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Figure 1. Infant of 37 weeks' gestation with profound hypoxic-ischemic encephalopathy due to abruptio placenta. A, Axial proton-density MR image shows bilateral thalamic high intensity (small arrows) and putaminal high-intensity abnormalities (large arrows). B, This axial brain image of the same patient reveals bilateral perirolandic cerebral high-intensity abnormalities (arrows). (Courtesy of P. Barnes, MD, Children's Hospital, Boston, MA.)

Figure 2. Cerebral MR images of an infant of 40 weeks' gestation who demonstrated signs of moderate to severe hypoxic-ischemic encephalopathy. A, Sagittal T1-weighted image shows frontal and parietal borderzone or watershed cortical abnormalities (arrows). B, Axial T2-weighted image of the same patient shows cortical and subcortical regions of abnormal high signal intensity in watershed regions separating middle cerebral artery and anterior cerebral artery territories (top arrows) and middle cerebral artery and posterior cerebral artery territories (bottom arrows). (Courtesy of P. Barnes, MD, Children's Hospital, Boston, MA.)

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Figure 3. Cranial MR images obtained from a 4-year-old boy whose gestation was marked by premature labor but term birth. A, T2-weighted image shows bilateral periventricular high-intensity abnormalities (arrows) and abnormal dilatation of the lateral ventricular bodies and atria. B, Another T2-weighted image obtained from the same patient demonstrates additional periventricular high-intensity abnormalities of white matter (open and closed arrows). The pattern is consistent with periventricular leukomalacia and preterm hypoxicischemic cerebral injury. (Courtesy of P. Barnes, MD, Children's Hospital, Boston, MA.)

few days of life later manifested acquired microcephaly, an accepted harbinger of poor neurodevelopmental outcome. Thus, although preliminary, these data indicate a correlation among MR imaging in the first few days of life, the occurrence of acquired microcephaly, and poor neurodevelopmental outcome. Clearly, more investigation is needed in this important clinical area.

THERAPY Currently, the most effective intervention against HI brain injury is prevention. Antenatal and intrapartum surveillance methods discussed previously will help detect the high-risk fetus and optimize obstetric responses to limit neurologic damage. Despite these preventive measures, HI neurologic injury continues to occur. Therapy may be considered in two categories: supportive care and pharmacologic care (Table 4). Supportive maneuvers serve as the mainstay of therapy. A growing body of evidence strongly suggests, however, that in the near future appropriate pharmacologic intervention may limit the extent of cerebral injury. Supportive Care

Careful regulation of systemic blood pressure prevents further ischemic damage owing to reduction of cerebral perfusion. Postnatal hypotension may

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Table 4. TREATMENT FOR NEONATAL HYPOXIC-ISCHEMIC CEREBRAL INJURY Supportive Monitor and control systemic blood pressure to ensure adequate cerebral perfusion Minimize apneas Minimize bradycardia Identify seizures and assess cerebral activity with electroencephalography Treat seizures aggressively Cerebral Neuroprotectant and Resuscitation (Experimental) Antiexcitotoxic aminoacid treatment (NMDA receptor antagonists) Antioxidative treatment Neurotrophic factor treatment CDP-choline Nitric oxide synthase inhibition

result from cardiac dysfunction, such as bradycardia or decreased contractility. Additional causes of hypotension include recurrent apnea,7 1 septic shock, or vascular abnormalities peculiar to the neonate, such as patent ductus arteriosus. 70 Prevention of hypotension may require judicious use of pressors, such as dopamine and dobutamine. Conversely, hypertension is to be avoided to prevent abrupt increases in cerebral blood flow. Sudden increases in cerebral blood flow may result in both intraventricular hemorrhage in the premature infant owing to rupture of vulnerable capillary beds in the friable germinal matrix and hemorrhagic infarction in the term infant owing to rupture of necrotic capillary beds in the margins of an ischemic infarction. Continuous attention must be devoted to oxygenation. In particular, recurrent apnea and bradycardia resulting in hypoxic and sometimes ischemic episodes may exacerbate previous hypoxic injury. Transcutaneous oxygenation monitoring permits titration of oxygen therapy so that hypoxia and hyperoxia may be kept to a minimum. Hyperoxia has potentially deleterious effects on retinal and cerebral circulation and may be involved in pontosubicular necrosis of the premature infant. Intracranial pressure may be elevated after HI cerebral injury; however, cerebral perfusion pressure (mean arterial blood pressure minus intracranial pressure) generally remains within the normal range throughout the postnatal course. This finding indicates that cerebral blood flow is not likely to be diminished by any increase in intracranial pressure unless it is a marked increase. 54 Continuous subarachnoid intracranial pressure monitoring has shown that clinical and electrographic abnormalities following HI injury in infants preceded the peak intracranial pressure measured. No additional change in clinical state was noted with peak elevation of intracranial pressure. 16 These observations indicate that cerebral edema is an epiphenomenon in HIE; the edema is a consequence rather than a cause of parenchymal injury. It is the primary HI parenchymal injury that determines neonatal neurologic state and outcome. Therefore, it is unlikely that aggressive treatment of the edema and elevated intracranial pressure will affect outcome.

Pharmacologic Care Pharmacologic therapy previously has focused on use of anticonvulsant drugs for treatment of seizures secondary to HI injury. HIE ranks as the most

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common cause of neonatal seizures. 9 Of neonates with HIE, approximately 50% experience seizures within the first 12 hours of life. Seizures commonly occur throughout the first 3 days of life and may be difficult to control. Because experimental evidence suggests that unremitting seizures may exacerbate HI injury, treatment of such seizures is important. 105- 107 Phenobarbital should be used first for seizure control. A loading dose of 20 mg/kg is given intravenously. If seizures do not cease, additional 5 mg/kg loading doses as needed may be administered until the patient has received a total of 40 mg/kg. 24• 30 In very few patients, Phenobarbital monotherapy does not control neonatal seizures. 49 • 63 In this event, phenytoin is used next in an intravenous loading dose of 20 mg/kg. The intravenous maintenance dose for each drug is 3 to 4 mg/kg/day. Elucidation of the role played by excitatory amino acids in HI brain injury (see previous discussion) has fostered interest in therapies designed to ameliorate their deleterious effects. Gamma-D-glutamylglycine, an excitatory aminoacid antagonist, first prevented neuronal death when added to cell culture before anoxia. 80 Use of an antagonist of the NMDA-type glutamate receptor channel (ketamine) has been observed to prevent in vitro injury to neurons caused by oxygen/ glucose deprivation. 108 Further, addition of antagonists to tissue culture after hypoxia has been found to attenuate injury. 33 Animal studies have yielded encouraging data about the neuroprotective effects of glutamate receptor-channel antagonists. Dextromethorphan and MK801, each an NMDA-type glutamate receptor-channel antagonist, have demonstrated neuroprotective properties against hypoxia in animals. 31 • 32 Additional excitatory amino-acid antagonists are under careful and intense study. 34 Some excitatory amino-acid antagonists have shown the ability to attenuate HI damage to brain when administered after the insult.2· 58 Results, such as these, encourage consideration of investigation related to use of glutamate receptorchannel antagonists in humans. Other agents currently under study offer promise as therapeutic agents for treatment of HI brain injury. CDP-choline administration provides both choline and cytidine, which in the brain can be used as substrates for phosphatidylcholine synthesis. Phosphatidylcholine, the principal lipid component of neuronal membrane, serves as an important building block in the repair and regeneration of axons and synapses following hypoxic injury. Several studies of CDP-choline treatment following HI cerebral injury have been conducted in animals and adults. These results indicate a beneficial effect of this agent on elemental neurologic and cognitive outcome when used following HI cerebral injury. 25 • 91 Finally, additional therapeutic promise may reside in manipulation of the glutamate-activated nitric-oxide synthase system. Experiments conducted in animal models suggest that down regulation of the glutamate-activated nitric oxide synthase pathway, which can lead to neurotoxicity and neuronal death, may provide a new avenue of treatment after cerebral hypoxia. 21 Indeed, down regulation of nitric-oxide synthase expression may constitute the neuroprotective action of such agents. 46 Currently, clinical trials in humans are under way. 23 More information about these drugs still is required before trials in human newborns can be designed. Nonetheless, this group of pharmacologic agents currently offers therapeutic promise. PROGNOSIS

When HIE has been identified in a newborn, parents and physicians seek information that is predictive concerning the child's development. Low et al

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found an association between motor and cognitive deficits at 1 year of age and the severity of acidosis observed at birth in asphyxiated neonates. 57 Neurologic impairment found at 1 year correlated with the severity of acidosis found at birth. The extent of these sequelae is dependent not only on the occurrence of asphyxia but also on its duration. The three stages of HIE described by Sarnat and Sarnat (see previous discussion) correlate with outcome at 1 year of age. 82 Followed through the first year of life, those neonates who had mild (stage 1) HIE or those who demonstrated moderate HIE (stage 2) for less than 5 days developed normally. Persistence of moderate encephalopathy or appearance of severe (stage 3) HIE was associated with seizures and motor and cognitive delay during the follow-up period. Using this essentially clinical classification scheme, Robertson and Finer followed children for 8 years who had experienced presumed intrapartum asphyxia and HIE. Those children who had mild HIE as neonates were free of handicap in motor, cognitive, and school performance. Significantly greater impairment of performance in each of these developmental spheres was found, however, among children who had exhibited moderate or severe neonatal HIE.75-77 The likelihood of long-term neurologic sequelae after HIE is increased by the presence of neonatal seizures. 59 EEG may provide valuable prognostic information after the occurrence of seizure. Interictal background abnormalities, such as burst-suppression, persistently low voltage, or electrocerebral inactivity, are correlated highly with poor outcome. Conversely, infants with normal EEGs or those revealing only maturational delay have much more favorable prognoses.81 Neuroimaging has proved useful in determination of prognosis. HUS findings have been shown to correspond to later abnormalities of the neurologic examination in premature infants. 13 Periventricular intraparenchymal echodensities correlated with motor and cognitive deficits in premature infants followed for as long as 58 months after births. 35 As mentioned previously, MR imaging obtained early in the neonatal course of HI brain injury may provide useful prognostic information.

References 1. Amato M, Huppi P, Herschkowitz N, et al: Prenatal stroke suggested by intrauterine

2.

3. 4. 5. 6. 7. 8.

ultrasound and confirmed by magnetic resonance imaging. Neuropediatrics 22:100111, 1991 Andine P, Lehman A, Ellren K, et al: The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection. 90:208-212, 1988 Babcock DS, Ball W Jr: Postasphyxial encephalopathy in fullterm infants: ultrtasound diagnosis. Radiology 148:417--423, 1983 Baenziger 0, Martin E, Good M, et al: Early pattern recognition in severe perinatal aphyxia: A prospective MRI study. Neurorad 35:437--442, 1993 Banker BQ: The neuropathological effects of anoxia and hupoglycemia ian the newborn. Dev Med Child Neurol 9:544-550, 1967 Banker BQ, Larroche JC: Periventricular leukomalacia of infancy: A form of neonatal anoxic encephalopathy. Arch Neurol 7:386--410, 1962 Barkovich AJ, Westmark K, Partridge C, et al: Perinatal asphyxia: MR findings in the first 10 days. AJNR 16:427--438, 1995 Barmada A, Moossy J, Shuman R: Cerebral infarcts with arterial occlusion in neonates. Ann Neurol 6:495-502, 1979

622

RIVKIN

9. Bergman I, Painter MJ, Hirsh RP, et al: Outcome in neonates with convulsions treated in an intensive care unit. Ann Neurol 14:642-647, 1983 10. Bignami A, Rakstib HJ: Myelination of fibrullary astroglial processes in long term Wallerian degeneration: The possible relationship to status marmoratus. Brain Res 11:710-713, 1968 11. Blair E, Stanley J: Intrapartum asphyxia: A rare cause of cerebral palsy. J Pediatr 112:515-519, 1988 12. Borit A, Herndon FM: The fine structure of plaques fibromyeliniques in ulegyria and in status marmoratus. Acta Neuropathol 14:304-311, 1970 13. Bozynski E, DiPietro A, Meisels SJ, et al: Cranial sonography and neurological examination of extremely preterm infants. Dev Med Child Neurol 32:575-581, 1990 14. Byers RK, Hass GM: Thrombosis of the dural venous sinuses in infancy and in childhood. Am J Dis Child 45:1161-73, 1933 15. Cherniack NS, von Euler C, Homma I, et al: Experimentally induced Cheyne-Stokes breathing. Respir Physiol 37:185-200, 1979 16. Clancy R, Legido A, Newall R, et al: Continuous intracranial pressure monitoring and serial elctroencephalographic recordings in severely asphyxiated term neonates. Am J Dis Child 142:740-747, 1988 17. Clancy R, Malin S, Laraque D, et al: Focal motor seizures heralding stroke in fullterm neonates. Am J Dis Child 139:601-606, 1985 18. Coker SB, Beltran TS, Nyers TF, et al: Neonatal stroke: Description of patients and investigation into pathogenesis. Pediatr Neurol 4:219-223, 1988 19. Cowan FM, Pennock JM, Hanrahan JD, et al: Early detection of cerebral infarction and hypoxic-ischemic encephalopathy in neonates using diffusion-weighted magnetic resonsnce imaging. Neuropeds 25:172-174, 1994 20. Dambska M, Laure-Kamionowska M, Schmidt-Sidor B: Early and late changes in perinatal white mattter damage. J Child Neurol 4:291-298, 1989 21. De Ryck M, Keersmaekers R, Duytschaever H, et al: Lubeluzole protects sensorimotor function and reduces infarct size in a photochemical stroke model in rats. J Pharm Exp Tuer 279:748-58, 1996 22. De Vries LS, Wigglesworrth JS, Regev R, et al: Evolution of periventricular leukomalacia during the neonatal period and infancy: Correlation of imaging and postmorten findings. Early Hum Dev 17:205-219, 1988 23. Diener HC, Hacke W, Hennerici M, et al: Lubeluzole in acute ischemic stroke: A double bond placebo phase II trial. Stroke 27:76-81, 1996 24. Donn SM, Grasela TH, Goldstein GW: Safety of a higher loading ddose of phenobarbital in the term newborn. Pediatrics 75:1061-1064, 1985 25. D'Orlando K, Sandage B: Citicoline (CDP-Choline): Mechanisms of action and effects in ischemic brain injury. Neurol Res 17:281-284, 1995 26. Dubowitz LMS, Bydder GM, Mushin J: Developmental sequence of periventricular leukomalacia. Arch Dis Child 6:349-355, 1985 27. Filipek PA, Krishnamoorthy KS, Davis KR, et al: Focal cerebral infarction in the newborn: A distinct entity. Pediatr Neurol 3:141-147, 1987 28. Flodmark 0, Roland EH, Hill A, et al: Periventricular leukomalcia: Radiologic diagnosis. Radiology 162:119-124, 1987 29. Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240249, 1988 30. Gal P, Toback H, Boer HR, et al: Efficacy of phenobarbital monotherapy in treatment of neonatal seizures: Relationship to blood levels. Neurology 32:1401-1404, 1982 31. George CP, Goldberg MP, Choi DW, et al: Dextromethorphan reduces neocortical ischemic neuronal damage in vivo. Brain Res 440:375-379, 1988 32. Gill R, Foster AC, Woodruff GN: Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 7:33433349, 1987 33. Goldberg MP, Monyer H, Choi DW: Cortical neuronal injury in vitro following combined glucose and oxygen deprivation: Ionic dependence and delayed protection by NMDA antagonists [abstr]. Soc Neurosci 14:745, 1988

HYPOXIC-!SCHEMIC BRAIN INJURY

623

34. Grotta J, Clark W, Coull B, et al: Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in Patients with acute ischemic stroke. Stroke 26:602-605, 1995 35. Guzzetta F, Shackelford GD, Volpe S, et al: Periventricular intraparenchymal echodensities in the premature newborn: Critical determinant of neurologic outcome. Pediatrics 78:995-1006, 1986 36. Hagberg B, Hagberg G, Olow I: The changing panorama of cerebral palsy in Sweden: IV. Epidemiological trends 1959-1977. Acta Paediatr Scand 73:433-440, 1984 37. Hill A, Martin DJ, Daneman A, et al: Focal hypoxic-ischemic cerebral injury in the newborn: Diagnosis by ultrasound and correlation with CT scan. Pediatrics 71:790-793, 1983 38. Hill A, Volpe JJ: Perinatal asphyxia: Clinical aspects. Clin Perinatol 16:435-457, 1989 39. Hope PL, Gould SJ, Howard S, et al: Precision of ultrasound diagnosis of pathologically verified lesoins in the brains of very preterm infants. Dev Med Child Neural 30:457-471, 1988 40. Johnson GN, Palahniuk RJ, Tweed WA, et al: Regional cerebral blood flow during severe fetal asphyxia produced by slow umbilical cord compression. Am J Obstet Gynecol 135:48-52, 1979 41. Keeney SE, Adcock EW, McArdle CB: Prospective observations of 100 High-risk neonates by high field (1.5 tesla) magnetic resonance imaging of the central nervous system, II: Lesions associated with hypoxic-ischemic encephalopathy. Pediatrics 87:431-438, 1991 42. Kuenzle C, Baenziger 0, Martin E, et al: Prognotstic value of early MR imaging in term infants with severe perinatal asphyxia. Neuropediatrics 25:191-200, 1994 43. Kreusser KL, Schmidt RE, Shackelford GD, et al: Value of ultrasound for identification of acute hemorrhagic necrosis of thalamus and basal ganglia in an asphyxiated term infant. Ann Neurol 16:361-363, 1984 44. Langendoerfer S, Haverdamp AD, Murphy J, et al: Pediatric follow-up of a randomized controlled trial of intrapartum monitoring techniques. J Pediatr 97:103-107, 1980 45. Leech RW, Brumback RA: Massive brain stem necrosis in the human neonate: Presentation of three cases with review of the literature. J Child Neural 3:258-263, 1988 46. Lesage AS, Peeters L, Leysen J: Lubeluzole: A novel long-term neuroprotectant inhibits the glutamate-activated nitric oxide synthase pathway. J Pharm Exp Ther 279:759-766, 1996 47. Levy SR, Abrams IF, Marshall PC, et al: Seizures and cerbral infarction in the fullterm newborn. Ann Neurol 17:366-337, 1985 48. Little WJ: On the influence of abnormal parturition, difficult labors, premature birth, and asphyxia neonatorum, on the mental and physical condition of the child, especially in relation to deformities. Trans Obstet Soc 3:293-344, 1862 49. Lockman LA, Kriel R, Zeske D, et al: Phenobarbital dosage for control of neonatal seizures. Neurology 29:1445-1449, 1979 50. Low JA, Galbraith RS, Muir DW, et al: The contribution of biological risk factors to the occurrence of motor and cognitive deficits. Dev Med Child Neural 27:578-587, 1985 51. Low JA, Galbraith RS, Muir D, et al: The relationship between perinatal hypoxia and newborn encephalopathy. Am J Obstet Gynecol 152:256-260, 1985 52. Low JA, Galbraith RS, Muir DW, et al: Motor and cognitive deficits after intrapartum asphyxia in the mature fetus. Am J Obstet Gynecol 158:356-361, 1988 53. Low JA, Robertson DM, Simpson LL: Temporal relationships of neuropathologic conditions caused by perinatal asphyxia. Am J Obstet Gynecol 160:608-614, 1989 54. Lupton BA, Hill A, Roland EH, et al: Brainswelling in the asphyxiated term newborn: Pathogenesis and outcome. Pediatrics 82:139-146, 1988 55. Mann I: Pregnancy events and brain damage. Am J Obstet Gynecol 155:6-9, 1986 56. Marciniak E, Wilson HD, Mariar RA: Neonatal prupura fulminans: A genetic disorder related to the absence of protein C in the blood. Blood 65:15-20, 1985 57. Martin E, Barkovich AJ: Magnetic resonance imaging in perinatal asphyxia. Arch Dis Child 72:62-70, 1995 58. McDonald JW, Silverstien FS, Johnston MV: MK-801 protects the neonatal brain from hpoxic-ischemic damage. Eur J Pharm 140:359-361, 1987

624

RIVKIN

59. Mellits ED, Holden KR, Freeman HM: Neonatal seizures: A multivariate analysis of factors associated with outcome. Pediatrics 70:177-185, 1982 60. Ment LR, Duncan CC, Ehrenkranz RA: Perinatal cerbral infarction. Ann Neural 16:559-568, 1984 61. Mizrahi EM, Kellaway P: Characterization and classification of neonatal seizures. Neurology 37:1837-1844, 1987 62. Mulligan JC, Painter MJ, O'Donoghue PA, et al: Neonatal mortality and long-term sequelae. J Pediatr 96:903-907, 1980 63. Myers RE: Four patterns of perinatal brain damage and the conditions of occurrence in primates. Adv Neural 10:223, 1975 64. Myers RE: Experimental models of perimatal brain damage: Relevance to human pathology. In Gluck L (ed): Intrauterine Asphyxia and the Developing Fetal Brain. Chicago, Yearbook Medical, 1977, pp 37-97 65. Nelson KB, Ellenberg JH: Antecedents of cerebral palsy: Multivariate analysis of risk. N Engl J Med 315:81-86, 1986 66. Ong BY, Ellison PH, Browning C: Intrauterine stoke in the neonate. Arch Neural 40:55-56, 1983 67. Painter MJ, Pipenger C, McDonald H, et al: Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr 92:315-319, 1978 68. Paneth M, Rudelli R, Monte W, et al: White mattter necrosis in very low birth weight infants: Neuropathologic and ultrasonographic findings in infants surviving six days or longer. J Pediatr 116:975-984, 1990 69. Pasternak JF: Parasagittal infarction in neonatal asphyxia. Ann Neural 21:202-203, 1987 70. Perlman JM, Volpe JJ: The effect of patent ductus arteriosis on flow velocity in the anterior cerebral arteries: Ductal steal in the premature newborn infant. J Pediatr 99:767-771, 1981 71. Perlman JM, Volpe JJ: Episodes of apnea and bradycardia in the preterm newborn: Impact on the cerebral circulation. Pediatrics 76:333-338, 1985 72. Plum F, Posner JB: The Diagnosis of Stupor and Coma, ed 3. Philadelphia, FA Davis, 1987, p 45 73. Pryds 0, Griesen G, Lou H: Vasoparalysis associated with brain damage in asphyxiated term infants. J Pediatr 117:119-125, 1990 74. Rivkin MJ, Anderson MA, Kaye EM: Neonatal idiopathic cerebral venous thrombosis: An unrecognized cause of transient seizures or lethargy. Ann Neural 32:51-57, 1992 75. Robertson C, Finer N: Term infants with hypoxic-ischemic encephalopathy: Outcome at 3.5 years. Dev Med Child Neural 27:473-484, 1985 76. Robertson C, Finer N: Educational readiness of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Dev Behav Pediatr 9:298-306, 1988 77. Robertson CM, Finer NN, Grace NG: School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 114:753-760, 1989 78. Roland EH, Hill A, Norman MG, et al: Selective brainstem injury in an asphyxiated newborn. Ann Neural 23:89-92, 1988 79. Rosen MG: Factors during labor and delivery that influence brain disorders. In Freeman JM (ed): Prenatal and Perinatal Factors Associated with Brain Disorders. NIH publication 85-1149, 1985, pp 237-261 80. Rothman SM: Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 4:1884-1891, 1984 81. Rowe RH, Holmes GL, Hafford H, et al: Prognostic value of electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol 60:183-186, 1985 82. Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress: A clinical and electroencephalographic study. Arch Neural 33:696-705, 1976 83. Schellinger DM, Grant EG, Manz HJ, et al: Ventricular shapes, distortions and deformities: Mirrors of past cerebral insults: A study based on early sonographic follow-up studies. Pediatr Neural 2:193-201, 1986 84. Scher MS: Cerebrovascular lesions of fetal onset: Antepartum causes of cerebral palsy. Ann Neural 28:451-460, 1990

HYPOXIC-ISCHEMIC BRAIN INJURY

625

85. Scher MS, Painter MS: Controversies concerning neonatal seizures. Pediatr Clin North Am 36:281-310, 1989 86. Scholz W: Topistic lesions. In Schade JP, McMeneney WH (eds): Selective Vulnerability of the Brain in Hypoxaemia. Philadelphia, FA Davis, 1963, p 257 87. Shevell MI, Silver K, O'Gorman AM, et al: Neonatal dural sinus thrombosis. Pediatr Neurol 5:161-165, 1988 88. Sran SK, Baumann RJ: Outcome of neonatal strokes. Am J Dis Child 142:1086-1088, 1988 89. Stanley FJ: The changing face of cerebral palsy. Arch Dis Child 29:263-265, 1987 90. Steinlin M, Dirr R, Martin E, et al: MRI following severe perinatal asphyxia: Preliminary experience. Pediatr Neural 7:164-170, 1991 91. Tazaki Y, Sakai F, Otomo E, et al: Treatment of acute cerebral infaction with a choline precursor in a multicentler double-blind placebo-controlled study. Stroke 19:211-216, 1988 92. Trauner DA, Mannino FL: Neurodevelopmental outcome after neonatal cerebrovascular accident J Pediatr 108:459-461, 1986 93. Truwit CL, 13arkovich AJ, Koch TK, et al: Cerebral palsy: MR findings in 40 patients. AJNR Am J Neuroradiol 13:67-78, 1992 94. Yannucci RC, Duffy TE: Cereral metabolism in newborn dogs during reversible asphyxia. Ann Neurol 1:528-534, 1977 95. Volpe JJ: Current concepts of brain injury in the premature infant. AJR Am J Radiol 153:243-251, 1989 96. Volpe JJ: Neurology of the newborn, ed 3. Philadelphia, WB Saunders, 1995, p 220 97. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 282285 98. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 285287 99. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 287291 100. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 291299 101. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 314315 102. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 315318 103. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 341342 104. Volpe JJ: Neurology of the newborn. ed 3. Philadelphia, WB Saunders 1995, pp 342343 105. Wasterlain CG: Breakdown of brain polysomes in status epilepticus. Brain Res 39:278282, 1972 106. Wasterlain CG: Inhibition of cerebral protein synthesis by epileptic seizures wtihout motor manifestations. Neurology 24:175-180, 1974 107. Wasterlain CG, Plum F: Vulnerability of developing rat brain to electroconvulsive seizures. Arch Neurol 29:38-44, 1973 108. Weiss JH, Goldberg MP, Choi DW: Ketamine protects cultured neocortical neurons from hypoxic injury. Brain Res 380:186-190, 1986 109. Wong VK, Le Mesurier J, Franceschini R, et al: Cerebral venous thrombosis as a cause of neonatal seizures. Pediatr Neural 3:325-327, 1987

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