Neonatal Brain Injury
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《新英格兰医药杂志》
PubMed Citation
The mortality from acute neurologic disorders of childhood, such as status epilepticus and stroke, is highest in infants under one year of age.1,2 Certain forms of newborn brain injury, such as stroke, have an incidence as high as 1 in 4000 live births.3 More than 95 percent of infants who have a stroke survive to adulthood, and many have residual motor or cognitive disabilities. Stroke and other forms of brain injury have a considerable effect on surviving babies, their families, and society. Since many adult diseases have their origins in prenatal or early postnatal life,4 delineating the mechanisms underlying the vulnerability of the developing central nervous system to diverse insults should lead to new therapeutic interventions that affect outcome.
The erroneous view that neonatal brain injury is uniform and due primarily to acquired insults such as birth asphyxia is slowly being modified by epidemiologic studies.5 The causes of neonatal brain injury are protean and are only now being revealed, owing to advances in neuroimaging and diagnostic laboratory techniques. Most neonatal brain injury is metabolic, whether from transient ischemia–reperfusion events or from defects in inherited metabolic pathways expressed soon after birth. A greater understanding of these mechanisms should provide opportunities to intervene therapeutically in both newborns and adults.
Neonatal brain injury is recognized on the basis of a unique encephalopathy that evolves from lethargy to hyperexcitability to stupor during the first three days of life.6 Neonatal brain injury often eludes diagnosis, especially in premature infants with very low birth weight, because obvious signs are lacking or because signs that are present are attributed to developmental immaturity.7 Clinically subtle signs and symptoms lead to a delay in the diagnosis of cerebral palsy, learning disabilities, and complex behavioral disorders until later in childhood.8 This review will focus on the clinical investigation of basic mechanisms of neonatal brain injury and on advances in neuroimaging and developmental biology that may affect potential therapeutic interventions.
Clinical Observations
Patterns of Injury
Advanced methods of neuroimaging, such as magnetic resonance imaging (MRI), magnetic resonance spectroscopy, and diffusion-weighted MRI, have identified patterns of damage after ischemic insult to the immature brain. Such patterns depend on the severity of the insult and the age at which it occurs9 (Figure 1A and Figure 1B). In addition to defining patterns of injury, neuroimaging has shown, through serial studies, that brain injury evolves over days, if not weeks.10 This has been substantiated in animal models.11 If time permits, various treatment interventions may be attempted as the injury evolves12 (Figure 2). The recognition that different regions of the brain have different susceptibility to injury at different maturational stages has led investigators to identify particular types of cells within the central nervous system that are selectively vulnerable to brain insults. Neural cells in the immature nervous system are selectively vulnerable in a way that is similar to the selectivity seen in the mature brain in patients with Parkinson's disease and those with Huntington's disease.13
Figure 1. Selective Regional Vulnerability Determined According to Age at Insult.
Panel A shows an image of a neonate who was born at 24 weeks of gestation. The T1-weighted, spin-echo MRI was performed at 28 weeks and reveals subacute white-matter injury with cystic changes and volume loss. A T2-weighted, spin-echo image of the brain of a two-year-old child who had a documented ischemic insult at term shows chronic injury to the basal ganglia and thalamus (Panel B). A T1-weighted image on day 2 of life revealed hyperintensity in the scarred regions shown in Panel B. In Panel C, a T2-weighted, spin-echo image of a term newborn who presented with seizures reveals multiple acute arterial infarcts. In Panel D, a T2-weighted, spin-echo image shows a thrombosed left transverse sinus and hemorrhagic venous infarction in a six-day-old term newborn who presented with focal seizures.
Figure 2. Mechanisms of Brain Injury in the Term Neonate.
Oxidative stress and excitotoxicity, through downstream intracellular signaling, produce both inflammation and repair. Cell death begins immediately and continues during a period of days to weeks. The cell-death phenotype changes from an early necrotic morphology to a pathology resembling apoptosis. This evolution is called the necrosis–apoptosis continuum.
If an ischemic insult occurs early in gestation and the baby is born prematurely, some developing oligodendrocytes and subplate neurons are lost.14,15 Preoligodendrocytes and oligodendrocyte progenitor cells seem to be more vulnerable to ischemic injury than are mature oligodendrocytes.16 Subplate neurons appear transiently during brain development and play a critical role in the formation of connections between the thalamus and the visual cortex.17 In the term neonate with ischemic brain injury, however, certain neurons in the deep gray nuclei and perirolandic cortex are most likely to be injured, whereas other cells, such as neurons expressing nitric oxide synthase, seem to be resistant to ischemic injury.18 Within the basal ganglia, neurons expressing nitric oxide synthase participate in processes of oxidative stress and excitotoxicity14,19 that lead to the death of neighboring cells.20
Oxidative Stress
The neonatal brain, with its high concentrations of unsaturated fatty acids, high rate of oxygen consumption, low concentrations of antioxidants, and availability of redox-active iron, is particularly vulnerable to oxidative damage.19 In the very immature brain, oligodendrocyte progenitor cells and preoligodendrocytes are selectively vulnerable to the depletion of antioxidants or exposure to exogenous free radicals.21 Mature oligodendrocytes, in contrast, are highly resistant to oxidative stress, owing in part to differences in the levels of expression of antioxidant enzymes and proteins involved in programmed cell death. These characteristics of oligodendrocytes may explain why white matter often is injured selectively in the brain of the premature newborn.
Excitotoxicity
Excitotoxicity refers to excessive activation of glutamatergic neurotransmission and leads to cell death.22 Cell death due to excitotoxicity occurs in many types of cells in the newborn brain, and the initial trigger may be impairment of the uptake of glutamate by glia, resulting in overactivation of the receptors.23 Developmental differences in the function and expression of glutamate receptors dictate the response of the newborn brain to injury. For example, oligodendrocyte progenitor cells express glutamate receptors, including -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (usually referred to as AMPA) and kainate receptors. Experimental data indicate that blockade of these receptors protects against hypoxic–ischemic injury to the white matter in the immature rodent.24
The production of nitric oxide by neurons that are resistant to ischemic injury depends on the coupling and activation of the N-methyl-D-aspartate (NMDA) receptor and, subsequently, calcium entry into the cells of the thalamus and basal ganglia.25 When nitric oxide is produced in excessive amounts during periods of oxidative stress in these regions, it contributes to the production of free radicals.26 However, neurons that produce nitric oxide are themselves resistant to both hypoxic–ischemic and NMDA-mediated excitotoxicity18,27 in the immature brain; these cells become vulnerable as the brain matures. In regions where the immature NMDA receptor is expressed, such as the basal ganglia,28 neurons that produce nitric oxide synthase are abundant. Elimination of these neurons and disruption of the postsynaptic density complex that links NMDA to these neurons result in a reduction of ischemic injury.29 Therefore, both excitotoxicity and oxidative stress seem to mediate neonatal ischemic damage but must be understood in relation to normal development.
Inflammation
Maternal infection and its association with white-matter disease in the premature brain suggest other converging pathways that contribute to neonatal brain injury.30 A population-based study that used cerebral palsy as one outcome measure for neonatal brain injury suggested that chorioamnionitis is an independent risk factor for cerebral palsy among term infants,31 and previous studies have documented an association between chorioamnionitis and poor neurologic outcome for the preterm infant.32
The use of maternal infection as a marker for neonatal brain injury is problematic because of the inherent difficulty in defining chorioamnionitis. It is rare today to document chorioamnionitis by histologic examination of the placenta, and chorioamnionitis is a term that is used liberally in conditions as vague as maternal fever.33 Nevertheless, the roles of inflammatory responses by the fetal systemic and central nervous systems seem to be critically important to understanding the genesis of brain injury in the newborn.30 It is not known whether the inflammatory response is causal or modulatory in the cascade of events that occurs during an intrauterine or a perinatal insult to the brain.
Apoptosis during Hypoxic–Ischemic Injury to the Neonatal Brain
Programmed cell death, or apoptosis, is the mechanism for refining cell connections and pathways during brain development.34 Recent data suggest that apoptosis plays a prominent role in the evolution of hypoxic–ischemic injury in the neonatal brain and may be more important than necrosis after injury.35 During neonatal brain injury, excitotoxicity, oxidative stress, and inflammation all contribute to accelerated cell death by means of either apoptosis or necrosis, depending on the region of the brain affected and the severity of the insult.36 Signals from cytokine death receptors, for example, result in nitric oxide–mediated necrosis when endogenous inhibitors of apoptosis are abundant37 and in apoptosis when the inhibitors are deficient.38 These death-receptor proteins have been documented in the brain and the cerebrospinal fluid of newborns after brain injury,39,40 suggesting that this pathway may be a potential therapeutic target.
Genetic Effects
Similar insults to the neonatal brain will manifest themselves differently in different babies in terms of the injury, as observed on imaging studies such as MRI, and in terms of neurodevelopmental outcome. Such variability has also been observed in animal models and appears to be genetically based.41 Certain polymorphisms may increase the risk for many complex diseases.42,43 However, susceptibility factors for neonatal brain injury have yet to be identified clearly. Large population-based studies have indicated that biomarkers may prove useful in predicting outcome after neonatal brain injury44,45; similarly, population-based studies examining genetic factors may prove instructive. A recent exploratory study of very preterm infants showed an association of single-nucleotide polymorphisms such as endothelial nitric oxide synthase A(–922)G, factor VII (Arg353Gln) and del(–323)10bp-ins, and lymphotoxin (Thr26Asn) with spastic cerebral palsy.46
Clinical Syndromes
Neonatal Encephalopathy
Neonatal encephalopathy is a major predictor of neurodevelopmental disability in term infants and occurs in 1 to 6 of every 1000 live term births.47 The terms hypoxic–ischemic encephalopathy and birth asphyxia have been used to describe this clinical state, but many cases that are labeled neonatal encephalopathy have occurred in neonates who had neither documented hypoxia–ischemia nor asphyxia.48 Neonatal encephalopathy is a serious condition: 15 to 20 percent of affected infants die during the newborn period, and an additional 25 percent have permanent neurologic deficits.49
Studies of risk factors for neonatal encephalopathy reveal that many cases are associated with antepartum risks such as maternal hypotension, infertility treatment, or thyroid disease, whereas some have both antepartum and intrapartum risk factors. Only a few cases have been associated with intrapartum risk factors such as forceps delivery, breech extraction, prolapse of the cord, abruptio placentae, or maternal fever.5 Postnatal complications such as severe respiratory distress, sepsis, and shock occur in fewer than 10 percent of term infants with neonatal encephalopathy. Although prenatal risk factors may be present, prospective studies with the use of MRI suggest that the majority of infants with neonatal encephalopathy sustained brain injury at or near the time of birth.9
The severity of neonatal encephalopathy depends on both the timing and the duration of the insult. Symptoms usually evolve during a period of days, making it important to perform serial detailed neurologic examinations.6 In the first hours after a severe ischemic insult, neonates exhibit a depressed level of consciousness. Typically, periodic breathing with apnea or bradycardia is present, yet cranial-nerve function may be spared and intact pupillary responses and spontaneous eye movements may be present if the injury is not severe. Hypotonia with decreased movement is associated with injury to cortical regions, and seizures may occur in the most severely affected infants very soon after the insult.
A transient improvement in the level of alertness may occur during the first week of life, but this change in mental status is not accompanied by other signs of improvement in neurologic function. Refractory seizures accompanied by apneic episodes, shrill cry, and jitteriness may be seen during this period. Hypotonia and weakness in the proximal limbs, face, and bulbar musculature and exaggeration of Moro's and muscle-stretch reflexes are often observed and persist for many months. Gestational age is important in interpreting these symptoms, since premature babies have lower muscle tone than term infants and may appear abnormal if their age is not considered.
Eventually, in neonates with severe injury, respiratory arrest and other signs of brain-stem dysfunction may precede a deterioration in the level of consciousness. Scoring the clinical signs of encephalopathy (Table 1) can standardize the approach to the newborn with brain injury and help select neonates who require therapeutic intervention.50
Table 1. Encephalopathy Score.
Neonatal Seizures
Neonatal seizures occur in patients with neonatal encephalopathy and may be a sign of reversible metabolic disorders, structural injury, or malformations. Seizures can be manifested subtly as ocular movements such as horizontal tonic deviation of the eyes or sustained eye opening or blinking, orolingual movements such as tongue or lip smacking or sucking, rowing or bicycling movements of the extremities, or recurrent apnea. Focal clonic seizures are seen often in patients with arterial or venous infarction. The development of bedside monitoring devices such as the amplitude-integrated electroencephalograph (cortical-function monitor)51 permits nurses and neonatology personnel to assess brain-wave activity. Although cortical-function monitoring can help evaluate newborns for seizures, brain-wave activity should be validated with standard electroencephalography.51,52
Neonatal seizures may result from metabolic disorders such as a congenital deficiency of sulfite oxidase, and the use of MRI can help distinguish these seizures from those due to hypoxic–ischemic events and other forms of metabolic or genetic disease.53,54 In conjunction with laboratory testing, MRI also provides information regarding traumatic and infectious causes. Skull fractures, occurring during delivery or as a result of blunt trauma to the maternal abdomen, can be associated with underlying cortical damage. Reversible causes of seizures such as hypoglycemia, hypocalcemia, hyponatremia, hypoxemia, acidosis, and hyperbilirubinemia are often part of an underlying disorder (Table 2). Lumbar puncture has reemerged as a major tool for diagnosing certain genetic disorders, such as pediatric neurotransmitter diseases (diseases involving inborn errors of metabolism that affect the central nervous system in children) and glucose-transporter defects.55
Table 2. Differential Diagnosis of Neonatal Seizures by Day of Presentation.
Neonatal seizures do not always imply poor neurodevelopmental outcome, although they are difficult to treat effectively.56 It is unclear how aggressively neonatal seizures should be treated, or for how long and with what medications. The development of anticonvulsant drugs has not been directed toward the treatment of neonatal seizures, even though most seizures begin in the first year of life.1 Therefore, drug therapy for the newborn is empirical and based on limited data. Most pediatric neurologists are reluctant to prescribe continuous anticonvulsant therapy for newborns after symptoms of brain injury have resolved or the underlying disease process has been identified and treated. Clinical trials are needed in this area.
Neonatal Stroke
Many affected newborns appear healthy in the immediate newborn period and, because they may not have clinical signs of stroke, the diagnosis is made only retrospectively.57 Neonatal strokes are often arterial in origin and ischemic in nature, although at least 30 percent are due to sinovenous thrombosis.58 Recent attempts to identify risk factors with the use of population-based studies have implicated prepartum factors such as preeclampsia and intrauterine growth restriction.48 Coagulation abnormalities (decreased levels of protein C, protein S, and antithrombin III and elevated plasma levels of Lp(a) lipoprotein and homocysteine) as well as certain genetic mutations and polymorphisms (including factor V Leiden G1691A, factor II G20210A, and methylenetetrahydrofolate reductase C677T) have been identified as risk factors,59,60 especially in neonates with stroke due to cerebral venous thrombosis. Newborns with stroke usually have more than one risk factor,61,62 and perinatal complications such as hypoxic–ischemic events are frequently present.
In newborns presenting with neonatal encephalopathy and stroke, MRI will help document the type of stroke, and testing for prothrombotic disorders may improve diagnostic yield63 (Figure 1C and Figure 1D). The risk of recurrence of neonatal stroke is low (less than 5 percent) and seems to be associated with intercurrent illnesses or complications of systemic disorders such as congenital heart disease. However, children in whom recurrent thromboembolism develops may have coagulation factor defects.64
Intraventricular hemorrhage, which occurs commonly in very premature newborns, should not be confused with fetal hemorrhagic stroke, which occurs between 14 weeks of gestation and the onset of labor.65 Intraventricular hemorrhage, unlike stroke, is not associated with poor neurodevelopmental outcome unless there is evidence of parenchymal brain injury.66
Patterns of brain injury seen on MRI and subsequently on clinical examination are strongly influenced by the gestational age of the newborn at the time of the stroke.67 Although most strokes occur at or near the time of birth, resulting in hemiplegic cerebral palsy, some that are diagnosed later in a child's life have more subtle findings on examination (e.g., mild dystonia and cognitive disabilities), and MRI is unable to document precisely the time of the insult.
Subtle Neonatal Syndromes
Although subtle brain-injury syndromes, such as subclinical neonatal stroke, may take months to identify, screening procedures have improved the diagnostic yield. These screening procedures include ultrasonographic examination of the head and cortical-function monitoring. MRI has been the definitive test for identifying both abnormalities in the periventricular white matter and loss of brain volume, but many hospitals do not yet have MRI facilities for evaluating sick newborns. MRI-compatible incubators have been developed for transporting sick newborns, but they are expensive and their availability is limited.68,69
Insights from Neuroimaging
Patterns of brain injury are emerging with the use of MRI, and regional changes seen on MRI are predictive of particular neurodevelopmental syndromes later in childhood.70,71 High-quality MRI has expanded the differential diagnoses of neonatal encephalopathy, which was previously limited to histopathological conditions such as periventricular leukomalacia, kernicterus, and very large cortical malformations. Since myelination is still occurring in the neonatal brain, and since the water content of the neonatal brain is greater than that of the mature brain, injury has a different appearance and time course in the neonatal brain than in the adult brain.9,70,71,72 Since the posterior limb of the internal capsule is the first area to myelinate in the immature brain, loss of signal on T1-weighted spin-echo MRI in this region is a reliable indicator of severe hypoxic–ischemic injury.71
In a study of 104 children with evidence of bilateral hypoxic–ischemic brain damage, at least three different patterns were observed with the use of MRI.73 Periventricular leukomalacia was observed in premature infants with a history of subacute or chronic hypoxia and ischemia. Lesions in the basal ganglia and thalamus occurred in full-term babies who had profound asphyxia. Multicystic changes were seen in a minority of infants who had severe encephalopathy but only a mild hypoxic–ischemic event; this group may include babies who had underlying fetal infections or metabolic disorders that had eluded diagnosis. These data suggest that injury is related to the gestational age at the time of the insult, although the severity or chronicity of the insult may be a better indicator of eventual outcome.
In a study of 351 term infants presenting with neonatal encephalopathy or seizures documented by either MRI of the brain or postmortem histopathological procedures, most showed evidence of injury acquired at or near the time of birth. The timing of the lesion, however, does not exclude the possibility of genetic or antenatally acquired risk factors.9
Diffusion-weighted MRI of the neonate can identify early injury after an insult74 owing to its ability to detect subtle alterations in brain water. Simple diffusion-weighted MRI can detect, but may often overestimate, areas of cytotoxic edema, in which cystic changes may gradually develop.75 Diffusion tensor imaging is a technique that permits observation of molecular diffusion of water and microstructural organization, particularly the myelination of fibers in the white matter, and early detection of small injuries or abnormalities.76 Serial diffusion tensor imaging can detect differences in the maturation of white matter in infants with or without injury and can provide detailed and quantifiable data regarding brain development in injured newborns.77
Magnetic resonance spectroscopy, especially three-dimensional magnetic resonance spectroscopy of the neonatal brain, can detect metabolites such as lactate, N-acetyl aspartate, choline, and creatine that provide functional data regarding metabolic integrity in specific regions of the brain78 (Figure 3). These techniques can be used to define the injury at its inception and can potentially be linked to future neurodevelopmental outcome measures to determine which neonates are at high risk for adverse neurologic sequelae79 and should receive therapy. The combination of clinical signs of neonatal encephalopathy (Table 1) and patterns of injury seen with various MRI techniques may improve selection.80,81
Figure 3. Evolution of Brain Injury as Seen with MRI.
A normal structural image (Panel A), a diffusion-weighted MRI (Panel B), and lactate accumulation in the basal ganglia on magnetic resonance spectroscopy (Panel C, arrow) are shown in the same newborn at 1 day of life. At day 8, T1-weighted MRI (Panel D) and T2-weighted MRI (Panel E) reveal extensive damage to the deep gray nuclei, and magnetic resonance spectroscopy shows diminution of the lactate peak (Panel F, arrow).
Interventions
It is very difficult to predict during the neonatal period which neonates will suffer the most profound damage after an insult to the central nervous system, since more than 30 percent of neonates presenting with moderate encephalopathy have normal outcomes.49 Preliminary results of two randomized clinical trials of either systemic cooling or selective head cooling in encephalopathic neonates82,83 suggest that moderate hypothermia is safe in the high-risk newborn.84 In at least one study, newborns with moderate encephalopathy had better neurodevelopmental outcomes at 18 months than did newborns in the normothermic group.82 Neonates with congenital heart disease seem to be vulnerable to white-matter injury during surgical correction of their cardiac defects,85 and the clinical use of hypothermia for these infants suggests that hypothermia is safe and can be beneficial.86 However, the therapeutic window for the use of hypothermia has yet to be defined.
Studies in laboratory animals have shown that the immature brain responds differently to treatment than does the mature brain. Therapy designed to ameliorate brain injury in adults may worsen outcomes in neonates, possibly by accentuating apoptosis. Drugs that block NMDA receptors or potentiate -aminobutyric acid type A receptors can trigger widespread apoptosis in the developing brain of rodents.87 Indeed, drugs that act at these sites, such as midazolam, nitrous oxide, and isoflurane, and that are commonly used for analgesia in the human neonate also produce persistent learning impairments when administered to seven-day-old rats.88 However, drugs such as allopurinol, deferoxamine, and 3-iminobiotin, when given soon after the insult, interrupt injuries caused by free radicals and have shown benefit in large-animal models.89,90,91 The neuroprotective effect of exogenously administered erythropoietin has received much attention for ischemic disease, and promising data are emerging for the newborn.92 Judiciously choosing various methods of treatment aimed at particular phases of the injury cascade (Figure 2) may enhance protection or repair. The administration of growth factors, such as erythropoietin or brain-derived neurotrophic factor, throughout or even late in the injury process, might enhance repair. Recent data show that combination therapy with hypothermia and topiramate to block excitotoxicity improves outcome in a rodent model.93 The search for whom to treat and the best therapy is ongoing. Meanwhile, the standards of care in the neonatal intensive care unit continue to affect the evolution of brain injury.94 No longer is hypocapnia or hypoxemia induced in sick newborns to treat respiratory distress, and reduction in the use of mechanical ventilation has been associated with a decreasing incidence of cystic periventricular leukomalacia during the past decade.95 Attention to drug use and careful identification and management of neonatal seizures might improve outcome even if there are severe underlying metabolic disorders. However, careful management strategies that take into account the age of the newborn brain and its inherent susceptibility to oxidative stress and programmed cell death in combination with pharmacologic therapies may optimally protect the brain.
Prevalence data suggest that 8000 babies are born each year in the United States with cerebral palsy, which is only one outcome of neonatal brain injury.96 Since improved management in the first decade of life has led to survival into adulthood, current medical practice should incorporate plans for care that include the management of seizures and spasticity as well as cognitive and behavioral assessments that will improve the quality of life.
Summary
A reasoned approach to the newborn with brain injury is emerging from both clinical and laboratory data that have been accumulating during the past decade. Early recognition of at-risk newborns by means of advanced methods of neuroimaging, combined with a plan for rational intervention, may result in the prevention or the reduction in the incidence of lifelong disabilities such as cerebral palsy, epilepsy, and behavioral and learning disorders.
Dr. Ferriero reports having received a consulting fee and grant support from Johnson & Johnson.
I am indebted to Drs. Steven P. Miller, Yvonne W. Wu, and Thomas A. Rando for helpful suggestions with the manuscript; to Dr. Faye Silverstein for manuscript development; to Dr. A. James Barkovich for magnetic resonance images; and to Kei Kaneshiro for assistance in the preparation of the manuscript.
Source Information
From the Departments of Neurology and Pediatrics, University of California at San Francisco, San Francisco.
Address reprint requests to Dr. Ferriero at the Departments of Neurology and Pediatrics, University of California at San Francisco, 521 Parnassus Ave., C215, San Francisco, CA 94143-0663, or at dmf@itsa.ucsf.edu.
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Toet MC, van der Meij W, de Vries LS, Uiterwaal CS, van Huffelen KC. Comparison between simultaneously recorded amplitude integrated electroencephalogram (cerebral function monitor) and standard electroencephalogram in neonates. Pediatrics 2002;109:772-779.
Rennie JM, Chorley G, Boylan GB, Pressler R, Nguyen Y, Hooper R. Non-expert use of the cerebral function monitor for neonatal seizure detection. Arch Dis Child Fetal Neonatal Ed 2004;89:F37-F40.
Barkovich AJ. The encephalopathic neonate: choosing the proper imaging technique. AJNR Am J Neuroradiol 1997;18:1816-1820.
Barkovich AJ. Magnetic resonance imaging: role in the understanding of cerebral malformations. Brain Dev 2002;24:2-12.
Hyland K. The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 2003;54:Suppl 6:S13-S17.
Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-489.
Golomb MR, MacGregor DL, Domi T, et al. Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. Ann Neurol 2001;50:163-168.
deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med 2001;345:417-423.
Gunther G, Junker R, Strater R, et al. Symptomatic ischemic stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors. Stroke 2000;31:2437-2441.
Mercuri E, Cowan F, Gupte G, et al. Prothrombotic disorders and abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction. Pediatrics 2001;107:1400-1404.
Heller C, Heinecke A, Junker R, et al. Cerebral venous thrombosis in children: a multifactorial origin. Circulation 2003;108:1362-1367.
Wu YW, Hamrick SE, Miller SP, et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol 2003;54:123-126.
deVeber G. Arterial ischemic strokes in infants and children: an overview of current approaches. Semin Thromb Hemost 2003;29:567-573.
Kurnik K, Kosch A, Strater R, Schobess R, Heller C, Nowak-Gottl U. Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study. Stroke 2003;34:2887-2892.
Ozduman K, Pober BR, Barnes P, et al. Fetal stroke. Pediatr Neurol 2004;30:151-162.
Vohr BR, Allan WC, Westerveld M, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2003;111:e340-6.
Takanashi J, Barkovich AJ, Ferriero DM, Suzuki H, Kohno Y. Widening spectrum of congenital hemiplegia: periventricular venous infarction in term neonates. Neurology 2003;61:531-533.
Dumoulin CL, Rohling KW, Piel JE, et al. Magnetic resonance imaging compatible neonate incubator. Magn Reson Engineering 2002;15:117-28.
Erberich SG, Friedlich P, Seri I, Nelson MD Jr, Bluml S. Functional MRI in neonates using neonatal head coil and MR compatible incubator. Neuroimage 2003;20:683-692.
Barnett A, Mercuri E, Rutherford M, et al. Neurological and perceptual-motor outcome at 5-6 years of age in children with neonatal encephalopathy: relationship with neonatal brain MRI. Neuropediatrics 2002;33:242-248.
Rutherford MA, Pennock JM, Counsell SJ, et al. Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998;102:323-328.
Roland EH, Poskitt K, Rodriguez E, Lupton BA, Hill A. Perinatal hypoxic-ischemic thalamic injury: clinical features and neuroimaging. Ann Neurol 1998;44:161-166.
Sie LT, van der Knaap MS, Oosting J, de Vries LS, Lafeber HN, Valk J. MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. Neuropediatrics 2000;31:128-136.
Westmark KD, Barkovich AJ, Sola A, Ferriero D, Partridge JC. Patterns and implications of MR contrast enhancement in perinatal asphyxia: a preliminary report. AJNR Am J Neuroradiol 1995;16:685-692.
Roelants-van Rijn AM, Nikkels PG, Groenendaal F, et al. Neonatal diffusion-weighted MR imaging: relation with histopathology or follow-up MR examination. Neuropediatrics 2001;32:286-294.
Partridge SC, Mukherjee P, Henry R, et al. Diffusion tensor imaging: serial quantitation of white matter tract maturity in premature newborns. Neuroimage 2004;22:1302-1314.
Miller SP, Vigneron DB, Henry RG, et al. Serial quantitative diffusion tensor MRI of the premature brain: development in newborns with and without injury. J Magn Reson Imaging 2002;16:621-632.
Vigneron DB, Barkovich AJ, Noworolski SM, et al. Three-dimensional proton MR spectroscopy imaging of premature and term neonates. AJNR Am J Neuroradiol 2001;22:1424-1433.
Miller SP, Newton N, Ferriero DM, et al. MRS predictors of 30-month outcome following perinatal depression: role of proton MRS and socioeconomic factors. Pediatr Res 2002;52:71-77.
Kadri M, Shu S, Holshouser B, et al. Proton magnetic resonance spectroscopy improves outcome prediction in perinatal CNS insults. J Perinatol 2003;23:181-185.
Kaufman SA, Miller SP, Ferriero DM, Glidden DH, Barkovich AJ, Partridge JC. Encephalopathy as a predictor of magnetic resonance imaging abnormalities in asphyxiated newborns. Pediatr Neurol 2003;28:342-346.
Gluckman PD, Wyatt JS, Azzopardi RB, et al. Selective head cooling with mild systemic hypothermia to improve neurodevelopmental outcome following neonatal encephalopathy: the CoolCap Study. Pediatr Res 2004;55:Suppl:582A-582A. abstract.
Shankaran S, Laptook AR, Ehrenkranz RA, et al. Safety of whole body hypothermia for hypoxic-ischemic encephalopathy (HIE). Pediatr Res 2004;55:Suppl:582A-582A. abstract.
Feigin V, Anderson N, Gunn A, Rodgers A, Anderson C. The emerging role of therapeutic hypothermia in acute stroke. Lancet Neurol 2003;2:529-529.
Miller SP, McQuillen PS, Vigneron DB, et al. Preoperative brain injury in newborns with transposition of the great arteries. Ann Thorac Surg 2004;77:1698-1706.
Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;332:549-555.
Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-74.
Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-882.
Sarco D, Becker J, Palmer C, Sheldon RA, Ferriero DM. The neuroprotective effect of deferoxamine in the hypoxic-ischemic immature mouse brain. Neurosci Lett 2000;282:113-116.
Peeters-Scholte C, Braun K, Koster J, et al. Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. Pediatr Res 2003;54:516-522.
Peeters-Scholte C, Koster J, Veldhuis W, et al. Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia. Stroke 2002;33:2304-2310.
Juul SE. Nonerythropoietic roles of erythropoietin in the fetus and neonate. Clin Perinatol 2000;27:527-541.
Liu Y, Barks JD, Xu G, Silverstein FS. Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 2004;35:1460-1465.
Gressens P, Rogido M, Paindaveine B, Sola A. The impact of neonatal intensive care practices on the developing brain. J Pediatr 2002;140:646-653.
Hamrick SE, Miller SP, Leonard C, et al. Trends in severe brain injury and neurodevelopmental outcome in premature newborns: the role of cystic periventricular leukomalacia. J Pediatr (in press).
Winter S, Autry A, Boyle C, Yeargin-Allsopp M. Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 2002;110:1220-1225.(Donna M. Ferriero, M.D.)
The mortality from acute neurologic disorders of childhood, such as status epilepticus and stroke, is highest in infants under one year of age.1,2 Certain forms of newborn brain injury, such as stroke, have an incidence as high as 1 in 4000 live births.3 More than 95 percent of infants who have a stroke survive to adulthood, and many have residual motor or cognitive disabilities. Stroke and other forms of brain injury have a considerable effect on surviving babies, their families, and society. Since many adult diseases have their origins in prenatal or early postnatal life,4 delineating the mechanisms underlying the vulnerability of the developing central nervous system to diverse insults should lead to new therapeutic interventions that affect outcome.
The erroneous view that neonatal brain injury is uniform and due primarily to acquired insults such as birth asphyxia is slowly being modified by epidemiologic studies.5 The causes of neonatal brain injury are protean and are only now being revealed, owing to advances in neuroimaging and diagnostic laboratory techniques. Most neonatal brain injury is metabolic, whether from transient ischemia–reperfusion events or from defects in inherited metabolic pathways expressed soon after birth. A greater understanding of these mechanisms should provide opportunities to intervene therapeutically in both newborns and adults.
Neonatal brain injury is recognized on the basis of a unique encephalopathy that evolves from lethargy to hyperexcitability to stupor during the first three days of life.6 Neonatal brain injury often eludes diagnosis, especially in premature infants with very low birth weight, because obvious signs are lacking or because signs that are present are attributed to developmental immaturity.7 Clinically subtle signs and symptoms lead to a delay in the diagnosis of cerebral palsy, learning disabilities, and complex behavioral disorders until later in childhood.8 This review will focus on the clinical investigation of basic mechanisms of neonatal brain injury and on advances in neuroimaging and developmental biology that may affect potential therapeutic interventions.
Clinical Observations
Patterns of Injury
Advanced methods of neuroimaging, such as magnetic resonance imaging (MRI), magnetic resonance spectroscopy, and diffusion-weighted MRI, have identified patterns of damage after ischemic insult to the immature brain. Such patterns depend on the severity of the insult and the age at which it occurs9 (Figure 1A and Figure 1B). In addition to defining patterns of injury, neuroimaging has shown, through serial studies, that brain injury evolves over days, if not weeks.10 This has been substantiated in animal models.11 If time permits, various treatment interventions may be attempted as the injury evolves12 (Figure 2). The recognition that different regions of the brain have different susceptibility to injury at different maturational stages has led investigators to identify particular types of cells within the central nervous system that are selectively vulnerable to brain insults. Neural cells in the immature nervous system are selectively vulnerable in a way that is similar to the selectivity seen in the mature brain in patients with Parkinson's disease and those with Huntington's disease.13
Figure 1. Selective Regional Vulnerability Determined According to Age at Insult.
Panel A shows an image of a neonate who was born at 24 weeks of gestation. The T1-weighted, spin-echo MRI was performed at 28 weeks and reveals subacute white-matter injury with cystic changes and volume loss. A T2-weighted, spin-echo image of the brain of a two-year-old child who had a documented ischemic insult at term shows chronic injury to the basal ganglia and thalamus (Panel B). A T1-weighted image on day 2 of life revealed hyperintensity in the scarred regions shown in Panel B. In Panel C, a T2-weighted, spin-echo image of a term newborn who presented with seizures reveals multiple acute arterial infarcts. In Panel D, a T2-weighted, spin-echo image shows a thrombosed left transverse sinus and hemorrhagic venous infarction in a six-day-old term newborn who presented with focal seizures.
Figure 2. Mechanisms of Brain Injury in the Term Neonate.
Oxidative stress and excitotoxicity, through downstream intracellular signaling, produce both inflammation and repair. Cell death begins immediately and continues during a period of days to weeks. The cell-death phenotype changes from an early necrotic morphology to a pathology resembling apoptosis. This evolution is called the necrosis–apoptosis continuum.
If an ischemic insult occurs early in gestation and the baby is born prematurely, some developing oligodendrocytes and subplate neurons are lost.14,15 Preoligodendrocytes and oligodendrocyte progenitor cells seem to be more vulnerable to ischemic injury than are mature oligodendrocytes.16 Subplate neurons appear transiently during brain development and play a critical role in the formation of connections between the thalamus and the visual cortex.17 In the term neonate with ischemic brain injury, however, certain neurons in the deep gray nuclei and perirolandic cortex are most likely to be injured, whereas other cells, such as neurons expressing nitric oxide synthase, seem to be resistant to ischemic injury.18 Within the basal ganglia, neurons expressing nitric oxide synthase participate in processes of oxidative stress and excitotoxicity14,19 that lead to the death of neighboring cells.20
Oxidative Stress
The neonatal brain, with its high concentrations of unsaturated fatty acids, high rate of oxygen consumption, low concentrations of antioxidants, and availability of redox-active iron, is particularly vulnerable to oxidative damage.19 In the very immature brain, oligodendrocyte progenitor cells and preoligodendrocytes are selectively vulnerable to the depletion of antioxidants or exposure to exogenous free radicals.21 Mature oligodendrocytes, in contrast, are highly resistant to oxidative stress, owing in part to differences in the levels of expression of antioxidant enzymes and proteins involved in programmed cell death. These characteristics of oligodendrocytes may explain why white matter often is injured selectively in the brain of the premature newborn.
Excitotoxicity
Excitotoxicity refers to excessive activation of glutamatergic neurotransmission and leads to cell death.22 Cell death due to excitotoxicity occurs in many types of cells in the newborn brain, and the initial trigger may be impairment of the uptake of glutamate by glia, resulting in overactivation of the receptors.23 Developmental differences in the function and expression of glutamate receptors dictate the response of the newborn brain to injury. For example, oligodendrocyte progenitor cells express glutamate receptors, including -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (usually referred to as AMPA) and kainate receptors. Experimental data indicate that blockade of these receptors protects against hypoxic–ischemic injury to the white matter in the immature rodent.24
The production of nitric oxide by neurons that are resistant to ischemic injury depends on the coupling and activation of the N-methyl-D-aspartate (NMDA) receptor and, subsequently, calcium entry into the cells of the thalamus and basal ganglia.25 When nitric oxide is produced in excessive amounts during periods of oxidative stress in these regions, it contributes to the production of free radicals.26 However, neurons that produce nitric oxide are themselves resistant to both hypoxic–ischemic and NMDA-mediated excitotoxicity18,27 in the immature brain; these cells become vulnerable as the brain matures. In regions where the immature NMDA receptor is expressed, such as the basal ganglia,28 neurons that produce nitric oxide synthase are abundant. Elimination of these neurons and disruption of the postsynaptic density complex that links NMDA to these neurons result in a reduction of ischemic injury.29 Therefore, both excitotoxicity and oxidative stress seem to mediate neonatal ischemic damage but must be understood in relation to normal development.
Inflammation
Maternal infection and its association with white-matter disease in the premature brain suggest other converging pathways that contribute to neonatal brain injury.30 A population-based study that used cerebral palsy as one outcome measure for neonatal brain injury suggested that chorioamnionitis is an independent risk factor for cerebral palsy among term infants,31 and previous studies have documented an association between chorioamnionitis and poor neurologic outcome for the preterm infant.32
The use of maternal infection as a marker for neonatal brain injury is problematic because of the inherent difficulty in defining chorioamnionitis. It is rare today to document chorioamnionitis by histologic examination of the placenta, and chorioamnionitis is a term that is used liberally in conditions as vague as maternal fever.33 Nevertheless, the roles of inflammatory responses by the fetal systemic and central nervous systems seem to be critically important to understanding the genesis of brain injury in the newborn.30 It is not known whether the inflammatory response is causal or modulatory in the cascade of events that occurs during an intrauterine or a perinatal insult to the brain.
Apoptosis during Hypoxic–Ischemic Injury to the Neonatal Brain
Programmed cell death, or apoptosis, is the mechanism for refining cell connections and pathways during brain development.34 Recent data suggest that apoptosis plays a prominent role in the evolution of hypoxic–ischemic injury in the neonatal brain and may be more important than necrosis after injury.35 During neonatal brain injury, excitotoxicity, oxidative stress, and inflammation all contribute to accelerated cell death by means of either apoptosis or necrosis, depending on the region of the brain affected and the severity of the insult.36 Signals from cytokine death receptors, for example, result in nitric oxide–mediated necrosis when endogenous inhibitors of apoptosis are abundant37 and in apoptosis when the inhibitors are deficient.38 These death-receptor proteins have been documented in the brain and the cerebrospinal fluid of newborns after brain injury,39,40 suggesting that this pathway may be a potential therapeutic target.
Genetic Effects
Similar insults to the neonatal brain will manifest themselves differently in different babies in terms of the injury, as observed on imaging studies such as MRI, and in terms of neurodevelopmental outcome. Such variability has also been observed in animal models and appears to be genetically based.41 Certain polymorphisms may increase the risk for many complex diseases.42,43 However, susceptibility factors for neonatal brain injury have yet to be identified clearly. Large population-based studies have indicated that biomarkers may prove useful in predicting outcome after neonatal brain injury44,45; similarly, population-based studies examining genetic factors may prove instructive. A recent exploratory study of very preterm infants showed an association of single-nucleotide polymorphisms such as endothelial nitric oxide synthase A(–922)G, factor VII (Arg353Gln) and del(–323)10bp-ins, and lymphotoxin (Thr26Asn) with spastic cerebral palsy.46
Clinical Syndromes
Neonatal Encephalopathy
Neonatal encephalopathy is a major predictor of neurodevelopmental disability in term infants and occurs in 1 to 6 of every 1000 live term births.47 The terms hypoxic–ischemic encephalopathy and birth asphyxia have been used to describe this clinical state, but many cases that are labeled neonatal encephalopathy have occurred in neonates who had neither documented hypoxia–ischemia nor asphyxia.48 Neonatal encephalopathy is a serious condition: 15 to 20 percent of affected infants die during the newborn period, and an additional 25 percent have permanent neurologic deficits.49
Studies of risk factors for neonatal encephalopathy reveal that many cases are associated with antepartum risks such as maternal hypotension, infertility treatment, or thyroid disease, whereas some have both antepartum and intrapartum risk factors. Only a few cases have been associated with intrapartum risk factors such as forceps delivery, breech extraction, prolapse of the cord, abruptio placentae, or maternal fever.5 Postnatal complications such as severe respiratory distress, sepsis, and shock occur in fewer than 10 percent of term infants with neonatal encephalopathy. Although prenatal risk factors may be present, prospective studies with the use of MRI suggest that the majority of infants with neonatal encephalopathy sustained brain injury at or near the time of birth.9
The severity of neonatal encephalopathy depends on both the timing and the duration of the insult. Symptoms usually evolve during a period of days, making it important to perform serial detailed neurologic examinations.6 In the first hours after a severe ischemic insult, neonates exhibit a depressed level of consciousness. Typically, periodic breathing with apnea or bradycardia is present, yet cranial-nerve function may be spared and intact pupillary responses and spontaneous eye movements may be present if the injury is not severe. Hypotonia with decreased movement is associated with injury to cortical regions, and seizures may occur in the most severely affected infants very soon after the insult.
A transient improvement in the level of alertness may occur during the first week of life, but this change in mental status is not accompanied by other signs of improvement in neurologic function. Refractory seizures accompanied by apneic episodes, shrill cry, and jitteriness may be seen during this period. Hypotonia and weakness in the proximal limbs, face, and bulbar musculature and exaggeration of Moro's and muscle-stretch reflexes are often observed and persist for many months. Gestational age is important in interpreting these symptoms, since premature babies have lower muscle tone than term infants and may appear abnormal if their age is not considered.
Eventually, in neonates with severe injury, respiratory arrest and other signs of brain-stem dysfunction may precede a deterioration in the level of consciousness. Scoring the clinical signs of encephalopathy (Table 1) can standardize the approach to the newborn with brain injury and help select neonates who require therapeutic intervention.50
Table 1. Encephalopathy Score.
Neonatal Seizures
Neonatal seizures occur in patients with neonatal encephalopathy and may be a sign of reversible metabolic disorders, structural injury, or malformations. Seizures can be manifested subtly as ocular movements such as horizontal tonic deviation of the eyes or sustained eye opening or blinking, orolingual movements such as tongue or lip smacking or sucking, rowing or bicycling movements of the extremities, or recurrent apnea. Focal clonic seizures are seen often in patients with arterial or venous infarction. The development of bedside monitoring devices such as the amplitude-integrated electroencephalograph (cortical-function monitor)51 permits nurses and neonatology personnel to assess brain-wave activity. Although cortical-function monitoring can help evaluate newborns for seizures, brain-wave activity should be validated with standard electroencephalography.51,52
Neonatal seizures may result from metabolic disorders such as a congenital deficiency of sulfite oxidase, and the use of MRI can help distinguish these seizures from those due to hypoxic–ischemic events and other forms of metabolic or genetic disease.53,54 In conjunction with laboratory testing, MRI also provides information regarding traumatic and infectious causes. Skull fractures, occurring during delivery or as a result of blunt trauma to the maternal abdomen, can be associated with underlying cortical damage. Reversible causes of seizures such as hypoglycemia, hypocalcemia, hyponatremia, hypoxemia, acidosis, and hyperbilirubinemia are often part of an underlying disorder (Table 2). Lumbar puncture has reemerged as a major tool for diagnosing certain genetic disorders, such as pediatric neurotransmitter diseases (diseases involving inborn errors of metabolism that affect the central nervous system in children) and glucose-transporter defects.55
Table 2. Differential Diagnosis of Neonatal Seizures by Day of Presentation.
Neonatal seizures do not always imply poor neurodevelopmental outcome, although they are difficult to treat effectively.56 It is unclear how aggressively neonatal seizures should be treated, or for how long and with what medications. The development of anticonvulsant drugs has not been directed toward the treatment of neonatal seizures, even though most seizures begin in the first year of life.1 Therefore, drug therapy for the newborn is empirical and based on limited data. Most pediatric neurologists are reluctant to prescribe continuous anticonvulsant therapy for newborns after symptoms of brain injury have resolved or the underlying disease process has been identified and treated. Clinical trials are needed in this area.
Neonatal Stroke
Many affected newborns appear healthy in the immediate newborn period and, because they may not have clinical signs of stroke, the diagnosis is made only retrospectively.57 Neonatal strokes are often arterial in origin and ischemic in nature, although at least 30 percent are due to sinovenous thrombosis.58 Recent attempts to identify risk factors with the use of population-based studies have implicated prepartum factors such as preeclampsia and intrauterine growth restriction.48 Coagulation abnormalities (decreased levels of protein C, protein S, and antithrombin III and elevated plasma levels of Lp(a) lipoprotein and homocysteine) as well as certain genetic mutations and polymorphisms (including factor V Leiden G1691A, factor II G20210A, and methylenetetrahydrofolate reductase C677T) have been identified as risk factors,59,60 especially in neonates with stroke due to cerebral venous thrombosis. Newborns with stroke usually have more than one risk factor,61,62 and perinatal complications such as hypoxic–ischemic events are frequently present.
In newborns presenting with neonatal encephalopathy and stroke, MRI will help document the type of stroke, and testing for prothrombotic disorders may improve diagnostic yield63 (Figure 1C and Figure 1D). The risk of recurrence of neonatal stroke is low (less than 5 percent) and seems to be associated with intercurrent illnesses or complications of systemic disorders such as congenital heart disease. However, children in whom recurrent thromboembolism develops may have coagulation factor defects.64
Intraventricular hemorrhage, which occurs commonly in very premature newborns, should not be confused with fetal hemorrhagic stroke, which occurs between 14 weeks of gestation and the onset of labor.65 Intraventricular hemorrhage, unlike stroke, is not associated with poor neurodevelopmental outcome unless there is evidence of parenchymal brain injury.66
Patterns of brain injury seen on MRI and subsequently on clinical examination are strongly influenced by the gestational age of the newborn at the time of the stroke.67 Although most strokes occur at or near the time of birth, resulting in hemiplegic cerebral palsy, some that are diagnosed later in a child's life have more subtle findings on examination (e.g., mild dystonia and cognitive disabilities), and MRI is unable to document precisely the time of the insult.
Subtle Neonatal Syndromes
Although subtle brain-injury syndromes, such as subclinical neonatal stroke, may take months to identify, screening procedures have improved the diagnostic yield. These screening procedures include ultrasonographic examination of the head and cortical-function monitoring. MRI has been the definitive test for identifying both abnormalities in the periventricular white matter and loss of brain volume, but many hospitals do not yet have MRI facilities for evaluating sick newborns. MRI-compatible incubators have been developed for transporting sick newborns, but they are expensive and their availability is limited.68,69
Insights from Neuroimaging
Patterns of brain injury are emerging with the use of MRI, and regional changes seen on MRI are predictive of particular neurodevelopmental syndromes later in childhood.70,71 High-quality MRI has expanded the differential diagnoses of neonatal encephalopathy, which was previously limited to histopathological conditions such as periventricular leukomalacia, kernicterus, and very large cortical malformations. Since myelination is still occurring in the neonatal brain, and since the water content of the neonatal brain is greater than that of the mature brain, injury has a different appearance and time course in the neonatal brain than in the adult brain.9,70,71,72 Since the posterior limb of the internal capsule is the first area to myelinate in the immature brain, loss of signal on T1-weighted spin-echo MRI in this region is a reliable indicator of severe hypoxic–ischemic injury.71
In a study of 104 children with evidence of bilateral hypoxic–ischemic brain damage, at least three different patterns were observed with the use of MRI.73 Periventricular leukomalacia was observed in premature infants with a history of subacute or chronic hypoxia and ischemia. Lesions in the basal ganglia and thalamus occurred in full-term babies who had profound asphyxia. Multicystic changes were seen in a minority of infants who had severe encephalopathy but only a mild hypoxic–ischemic event; this group may include babies who had underlying fetal infections or metabolic disorders that had eluded diagnosis. These data suggest that injury is related to the gestational age at the time of the insult, although the severity or chronicity of the insult may be a better indicator of eventual outcome.
In a study of 351 term infants presenting with neonatal encephalopathy or seizures documented by either MRI of the brain or postmortem histopathological procedures, most showed evidence of injury acquired at or near the time of birth. The timing of the lesion, however, does not exclude the possibility of genetic or antenatally acquired risk factors.9
Diffusion-weighted MRI of the neonate can identify early injury after an insult74 owing to its ability to detect subtle alterations in brain water. Simple diffusion-weighted MRI can detect, but may often overestimate, areas of cytotoxic edema, in which cystic changes may gradually develop.75 Diffusion tensor imaging is a technique that permits observation of molecular diffusion of water and microstructural organization, particularly the myelination of fibers in the white matter, and early detection of small injuries or abnormalities.76 Serial diffusion tensor imaging can detect differences in the maturation of white matter in infants with or without injury and can provide detailed and quantifiable data regarding brain development in injured newborns.77
Magnetic resonance spectroscopy, especially three-dimensional magnetic resonance spectroscopy of the neonatal brain, can detect metabolites such as lactate, N-acetyl aspartate, choline, and creatine that provide functional data regarding metabolic integrity in specific regions of the brain78 (Figure 3). These techniques can be used to define the injury at its inception and can potentially be linked to future neurodevelopmental outcome measures to determine which neonates are at high risk for adverse neurologic sequelae79 and should receive therapy. The combination of clinical signs of neonatal encephalopathy (Table 1) and patterns of injury seen with various MRI techniques may improve selection.80,81
Figure 3. Evolution of Brain Injury as Seen with MRI.
A normal structural image (Panel A), a diffusion-weighted MRI (Panel B), and lactate accumulation in the basal ganglia on magnetic resonance spectroscopy (Panel C, arrow) are shown in the same newborn at 1 day of life. At day 8, T1-weighted MRI (Panel D) and T2-weighted MRI (Panel E) reveal extensive damage to the deep gray nuclei, and magnetic resonance spectroscopy shows diminution of the lactate peak (Panel F, arrow).
Interventions
It is very difficult to predict during the neonatal period which neonates will suffer the most profound damage after an insult to the central nervous system, since more than 30 percent of neonates presenting with moderate encephalopathy have normal outcomes.49 Preliminary results of two randomized clinical trials of either systemic cooling or selective head cooling in encephalopathic neonates82,83 suggest that moderate hypothermia is safe in the high-risk newborn.84 In at least one study, newborns with moderate encephalopathy had better neurodevelopmental outcomes at 18 months than did newborns in the normothermic group.82 Neonates with congenital heart disease seem to be vulnerable to white-matter injury during surgical correction of their cardiac defects,85 and the clinical use of hypothermia for these infants suggests that hypothermia is safe and can be beneficial.86 However, the therapeutic window for the use of hypothermia has yet to be defined.
Studies in laboratory animals have shown that the immature brain responds differently to treatment than does the mature brain. Therapy designed to ameliorate brain injury in adults may worsen outcomes in neonates, possibly by accentuating apoptosis. Drugs that block NMDA receptors or potentiate -aminobutyric acid type A receptors can trigger widespread apoptosis in the developing brain of rodents.87 Indeed, drugs that act at these sites, such as midazolam, nitrous oxide, and isoflurane, and that are commonly used for analgesia in the human neonate also produce persistent learning impairments when administered to seven-day-old rats.88 However, drugs such as allopurinol, deferoxamine, and 3-iminobiotin, when given soon after the insult, interrupt injuries caused by free radicals and have shown benefit in large-animal models.89,90,91 The neuroprotective effect of exogenously administered erythropoietin has received much attention for ischemic disease, and promising data are emerging for the newborn.92 Judiciously choosing various methods of treatment aimed at particular phases of the injury cascade (Figure 2) may enhance protection or repair. The administration of growth factors, such as erythropoietin or brain-derived neurotrophic factor, throughout or even late in the injury process, might enhance repair. Recent data show that combination therapy with hypothermia and topiramate to block excitotoxicity improves outcome in a rodent model.93 The search for whom to treat and the best therapy is ongoing. Meanwhile, the standards of care in the neonatal intensive care unit continue to affect the evolution of brain injury.94 No longer is hypocapnia or hypoxemia induced in sick newborns to treat respiratory distress, and reduction in the use of mechanical ventilation has been associated with a decreasing incidence of cystic periventricular leukomalacia during the past decade.95 Attention to drug use and careful identification and management of neonatal seizures might improve outcome even if there are severe underlying metabolic disorders. However, careful management strategies that take into account the age of the newborn brain and its inherent susceptibility to oxidative stress and programmed cell death in combination with pharmacologic therapies may optimally protect the brain.
Prevalence data suggest that 8000 babies are born each year in the United States with cerebral palsy, which is only one outcome of neonatal brain injury.96 Since improved management in the first decade of life has led to survival into adulthood, current medical practice should incorporate plans for care that include the management of seizures and spasticity as well as cognitive and behavioral assessments that will improve the quality of life.
Summary
A reasoned approach to the newborn with brain injury is emerging from both clinical and laboratory data that have been accumulating during the past decade. Early recognition of at-risk newborns by means of advanced methods of neuroimaging, combined with a plan for rational intervention, may result in the prevention or the reduction in the incidence of lifelong disabilities such as cerebral palsy, epilepsy, and behavioral and learning disorders.
Dr. Ferriero reports having received a consulting fee and grant support from Johnson & Johnson.
I am indebted to Drs. Steven P. Miller, Yvonne W. Wu, and Thomas A. Rando for helpful suggestions with the manuscript; to Dr. Faye Silverstein for manuscript development; to Dr. A. James Barkovich for magnetic resonance images; and to Kei Kaneshiro for assistance in the preparation of the manuscript.
Source Information
From the Departments of Neurology and Pediatrics, University of California at San Francisco, San Francisco.
Address reprint requests to Dr. Ferriero at the Departments of Neurology and Pediatrics, University of California at San Francisco, 521 Parnassus Ave., C215, San Francisco, CA 94143-0663, or at dmf@itsa.ucsf.edu.
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