Chapter 17 Hypoxic-Ischemic Brain Injury in the Term Newborn
Scope of the Problem
The syndrome of neonatal encephalopathy in the term newborn occurs in up to 6 per 1000 live term births and is a major cause of neurodevelopmental disability, with one-quarter of survivors sustaining permanent neurological deficits [Volpe, 2008]. While the syndrome of neonatal encephalopathy may result from a number of causes, this chapter will focus on the etiology, pathophysiology, and management of hypoxic-ischemic brain injury in the term newborn. Hypoxic-ischemic brain injury is recognized clinically by a characteristic encephalopathy with either a lack of alertness or hyperalertness, abnormal tone, abnormal reflex function, poor feeding, compromised respiratory status, and seizures [Miller et al., 2004]. Brain imaging has revealed patterns of brain injury following a hypoxic-ischemic insult that are unique to the immature brain; they depend on the age at which it occurs and on the severity and duration of the insult (Figure 17-1) [Miller et al., 2005; Cowan et al., 2003]. The capacity to repeat brain imaging safely in the newborn following hypoxia-ischemia has enabled studies confirming the clinical and experimental observations that neonatal brain injury evolves over days, if not weeks [Ferriero, 2004]. These clinical investigations are consistent with the prolonged temporal evolution of brain injury in neonatal animal models [Ferriero, 2004]. This time-course “opens the door” for therapeutic interventions instituted not only hours, but also days, after the hypoxic-ischemic insult, with different interventions needed as the injury evolves [Ferriero, 2004].
Etiology of Brain Injury in the Term Newborn
There is increasing recognition that neonatal brain injury is related to antenatal, perinatal, and postnatal factors, and is not always the result of “birth asphyxia” [Badawi et al., 1998]. While hypoxia-ischemia accounts for a substantial fraction of neonatal brain injury, a documented hypoxic-ischemic insult is lacking in many term newborns with encephalopathy [Volpe, 2008; Ferriero, 2004]. Many risk factors for neonatal encephalopathy are clearly prenatal [Badawi et al., 1998], such as maternal hypotension, infertility treatment, and thyroid disease. A minority of cases have only intrapartum risk factors, such as breech extraction, cord prolapse, or abruptio placentae [Badawi et al., 1998]. However, recent cohorts evaluated with magnetic resonance imaging (MRI) studies demonstrate that brain injury actually happens at or near the time of birth [Cowan et al., 2003; Miller et al., 2005]. It is also important to recognize that postnatal causes may account for up to 10 percent of neonatal encephalopathy in the term infant. Therefore, metabolic abnormalities such as acute bilirubin encephalopathy and inborn errors of metabolism, infection, severe respiratory distress, and trauma should be considered in the clinical evaluation.
Clinical Syndromes and Natural History
Clinical Syndromes
Neonatal encephalopathy and seizures are the most overt manifestation of the severity of brain injury. Clinical signs and symptoms depend on the severity, timing, and duration of the insult, as well as the newborn’s maturity, even within ages considered “full term.” It is equally important to note that not all newborns with significant acquired brain injuries present with an easily recognizable encephalopathy or seizures. Some conditions, such as stroke and perinatal white matter injury, discussed in Chapters 18 and 19, may only have subtle manifestations that may not be recognized on clinical examination. This chapter will focus on the clinical syndrome of neonatal encephalopathy secondary to hypoxia-ischemia. The diagnosis and management of neonatal seizures is discussed in Chapter 16.
Neonatal Encephalopathy
The major components of the syndrome of “neonatal encephalopathy” include: alertness, tone, respiratory status, reflexes, feeding, and seizures (Table 17-1). The severity of brain injury, reflecting the duration and magnitude of the hypoxic-ischemic insult, determines the severity of evolution of this clinical encephalopathy. In newborns with moderate to severe encephalopathy, symptoms usually evolve over days, making serial detailed examinations important. As with any neurologically ill newborn, the baby’s gestational age must be considered in the interpretation of physical findings. As described by Volpe, there is a characteristic progression of signs in newborns with a severe hypoxic-ischemic insult [Volpe, 2008]. The affected neonate exhibits a depressed level of consciousness from the very first hours of life. Periodic breathing with apnea and bradycardia often heralds this initial presentation. Hypotonia with decreased movement is almost universally found. In the first day of life, the pupillary response is often preserved and abnormalities of eye movements are not detected. In severely injured newborns, seizures may be seen within 6–12 hours after birth. Seizures at this stage are often subtle, manifesting as ocular movements, lip smacking, apnea, or bicycling movements of the extremities. The nursing staff should be alerted to identify and document paroxysmal behaviors. Multifocal or focal clonic seizures may also occur, and often indicate focal cerebral infarction. In the latter hours of the first day of life, there may be a transient increase in the level of alertness that is not accompanied by other signs of neurological improvement. This should not be falsely reassuring, as this apparent increase in alertness is frequently accompanied by more seizures and apnea, a shrill cry, and jitteriness. With careful bedside examination, weakness in the proximal limbs and increased muscle stretch reflexes may be observed, but in the very severely injured newborn, diffuse weakness with absent movements and reflexes is common.
Documenting this clinical evolution is a critical component of the evaluation, and use of a simple encephalopathy score as a bedside tool can help the clinician standardize assessment of encephalopathic newborns, monitor the evolution of the clinical syndromes, and help in systematically identifying neonates who require therapeutic intervention (see Table 17-1) [Miller et al., 2004].
| Sign | Score = 0 | Score = 1 |
|---|---|---|
| Feeding | Normal | Gavage feeds, gastrostomy tube, or not tolerating oral feeds |
| Alertness | Alert | Irritable, poorly responsive, or comatose |
| Tone | Normal | Hypotonia or hypertonia |
| Respiratory status | Normal | Respiratory distress (need for continuous positive airway pressure or mechanical ventilation) |
| Reflexes | Normal | Hyperreflexia, hyporeflexia, or absent reflexes |
| Seizure | None | Suspected or confirmed clinical seizure |
(From Miller et al. Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy. Am J Obstet Gynecol 2004;190(1):93–99.)
Subtle Neonatal Syndromes
Stroke and white matter injury in the term newborn may present with clinical signs that are so subtle that they remain undetected for months or years. Advances in brain monitoring (amplitude integrated EEG, prolonged video-EEG monitoring) and brain imaging (MRI) in the neonatal intensive care unit have increased recognition of these injuries. However, both stroke and white matter injury may present in the neonatal period with an overt encephalopathy [Li et al., 2009; Ramaswamy et al., 2004]. These conditions share many of the risk factors of “global” hypoxic-ischemic brain injury considered in this chapter.
Management of Neonatal Encephalopathy
Clinical Management
As many etiologies of neonatal encephalopathy have specific therapies, the clinician’s initial task is to determine the underlying etiology through careful history taking, neurological examination, and laboratory and brain imaging studies. The history should elicit indicators of intrauterine distress that may have contributed to decreased placental or fetal blood flow: fetal heart tracing abnormalities, passage of meconium, or a history of a difficulty in labor or delivery. The Apgar score will indicate who is at risk for mortality. The details of the delivery-room resuscitation, medications, and ventilatory support should be noted. Because the clinical signs of encephalopathy and seizures are often not specific for an etiology, laboratory tests are critical to exclude reversible causes of neonatal encephalopathy. The management of moderate or severe encephalopathy should occur in a neonatal intensive care unit in close collaboration with a neonatologist. Immediate management requires securing an appropriate airway and maintaining adequate circulation. Ventilatory support with mechanical ventilation or continuous positive airway pressure (CPAP) is often required. Metabolic complications, such as hypoglycemia, hypocalcemia, hyponatremia, and acidosis, frequently accompany hypoxic-ischemic encephalopathy (HIE), and should be identified and treated. Liver enzymes and serum creatinine levels should be performed to detect injury to other organs, while serum ammonia and lactate levels can screen for possible inborn errors of metabolism. Lumbar puncture to evaluate for intracranial infections should be performed if the history is not typical for HIE, or if a clinical suspicion of infection exists. If infection is suspected, ampicillin and gentamicin are started in addition to acyclovir if herpes simplex virus infection is a consideration. If the history, examination, or initial laboratory investigation points to an inborn error of metabolism, early treatment is crucial and a biochemical geneticist should be consulted. Additional diagnostic tests, such as serum amino acids and urine organic acids, as well as specific management strategies, are required (detailed in Chapter 20). The diagnosis of a severe intracranial hemorrhage should prompt consultation with a neurosurgeon to manage raised intracranial pressure from mass effect or hydrocephalus; platelet levels and coagulation function should be measured. Since the clinical syndrome evolves considerably over the first 72 hours of life, management of specific complications, such as respiratory compromise or seizures, can often be anticipated.
Investigation of term newborns with encephalopathy addresses three primary questions:
Addressing these questions is critical for the application of “neuroprotection” strategies, such as hypothermia [Eicher et al., 2005; Gluckman et al., 2005; Shankaran et al., 2005; Azzopardi et al., 2009]. To assess the encephalopathic term newborn, diagnostic tools available to the clinician include clinical features and biochemical and electrophysiological tests. However, the severity of brain injury in term asphyxiated newborns is not reliably predicted by clinical indicators commonly used during the first days of life, such as umbilical cord pH and Apgar scores [Shevell et al., 1999]. On the other hand, the severity of clinical encephalopathy is a strong predictor of neurodevelopmental outcome [Miller, 2004]. However, while the risk of motor and cognitive deficits appears to be minimal in mild encephalopathy, and pronounced at the severe end of the spectrum, it is inconsistent in neonates with moderate encephalopathy [Sarnat and Sarnat, 1976; Robertson et al., 1989; Dixon et al., 2002; Marlow et al., 2005]. Newborns with moderate encephalopathy are thus the most likely to benefit from the improved prognostic capabilities of brain imaging.
Brain Imaging of Newborns with Encephalopathy
Current guidelines for neuroimaging term newborns with encephalopathy suggest a noncontrast computed tomography (CT) scan to detect hemorrhage in infants with a history of significant birth trauma, and evidence of low hematocrit or coagulopathy [Ment et al., 2002]. If CT findings cannot explain the newborn’s clinical status, then MRI is recommended. For other encephalopathic term newborns, MRI is recommended between days 2 and 8 to assess the location and extent of injury [Ment et al., 2002]. In a recent study, the neuroimaging findings from a group of 48 term newborns with encephalopathy uniformly scanned with CT and MRI (T1 and T2-weighted images) with diffusion-weighted imaging (DWI) on the third day of life were compared [Chau et al., 2009]. On the third day of life, both CT and MRI with DWI reliably identify injury to the basal nuclei. However, DWI more readily detects cortical injury and focal and multifocal lesions, such as strokes and white matter injury, than either CT or conventional MRI. The choice of the best neuroimaging technique must balance the risk of transport and sedation involved in MRI against the risk of ionizing radiation with CT [Brenner et al., 2003; Berrington de Gonzalez and Darby, 2004; Hall et al., 2004]. With the development of MR-compatible incubators and monitoring equipment [Dumoulin et al., 2002; Bluml et al., 2004], as well as improved capacity to scan newborns without pharmacological sedation, MRI should now be the modality of choice when possible. MRI with DWI appears to be the most sensitive imaging study to detect abnormalities associated with other causes of neonatal encephalopathy, such as cerebral dysgenesis, infections, stroke, and metabolic disorders [Volpe, 2008; Cowan et al., 2003]. In order to confirm the diagnosis of hypoxic-ischemic brain injury and determine the extent of injury, MRI and DWI are optimally obtained between 3 and 5 days of life in term newborns with encephalopathy [Chau et al., 2009; Barkovich, 1997; Rutherford et al., 2004; Barkovich et al., 2006]. In newborns treated with hypothermia, further studies are needed to determine the optimal timing of MRI. The importance of rigorous imaging protocols with appropriate quality controls, and high quality neuroradiological review, must be emphasised.
Advanced MR Techniques
Advanced MR techniques, such as diffusion and spectroscopic imaging, allow us to observe the progression of neonatal brain injury. Diffusion MRI and MR spectroscopy (MRS) can be used to measure brain maturation and also provide important measures of brain microstructure and metabolism following injury. Given the widespread availability of these techniques on current MR scanners, their application will be discussed below. In addition to diffusion MRI and MRS, other advanced MR techniques are emerging. Computer-assisted morphometric techniques, including voxel-based and deformation-based morphometry, are used to correlate regional brain volumes in newborns, children, and adolescents with a history of neonatal encephalopathy with their neurodevelopmental outcomes [Maneru et al., 2003; Nishida et al., 2006; Srinivasan et al., 2007]. Moreover, diffusion tensor tractography, an extension of diffusion MRI, is providing new insights into recovery and resilience by measuring microstructural development of specific functional pathways [Glenn et al., 2007]. Together, these quantitative techniques are helping to identify injuries and abnormalities of subsequent brain development that may not be apparent on conventional MRI.
Magnetic resonance spectroscopy imaging
MRS can be used to measure changes in certain brain metabolites from a given brain region. Of the compounds measured by MRS at long echo times, N-acetylaspartate (NAA) and lactate are the most useful in assessing brain injury. NAA is an acetylated amino acid found in high concentrations in neurons of the central nervous system (CNS). NAA levels increase with advancing cerebral maturity [Barkovich, 2000; Novotny et al., 1998], and decrease with cerebral injury or impaired cerebral metabolism [Barkovich, 2000; Novotny et al., 1998]. Lactate is normally produced in the brain by astrocytes and used as fuel by neurons to replenish energy stores via oxidative phosphorylation [Pellerin and Magistretti, 2004]. Lactate levels are elevated with disturbed brain energy substrate delivery and oxidative metabolism, as seen with hypoxia-ischemia. Elevated lactate and reduced NAA levels are highly predictive of neurodevelopmental outcome following neonatal brain injury [Barkovich, 2000; Novotny et al., 1998]. Given this, lactate/NAA ratios are especially discriminatory of newborns with adverse outcomes [Shanmugalingam et al., 2006; Thayyil et al., 2010]. Myo-inositol, one of the major brain osmolytes, is best measured with MRS at short echo times, and is elevated with neonatal hypoxic-ischemic brain injury [Robertson et al., 2001].
Diffusion imaging
Diffusion-weighted MR imaging (DWI) detects alterations in free water diffusion. Diffusion tensor imaging (DTI) measures the amount (apparent diffusion coefficient [ADC] or average diffusivity) and directionality of water motion (fractional anisotropy [FA]). With brain maturation, ADC decreases in gray and white matter, presumably due to a reduction in water content and the development of cell membranes that restrict water diffusion [Mukherjee et al., 2002; Beaulieu, 2002, Coats et al., 2009]. Over this period, FA increases in white matter, even before myelin is evident on T1 and T2-weighted images [Miller et al., 2002b; Drobyshevsky et al., 2005; Prayer et al., 2001]. DWI and DTI also provide sensitive measures of brain injury [Barkovich et al., 2001; McKinstry et al., 2002]. With acute injury, intracellular water increases and water movement are “restricted” by the cell membrane when a diffusion gradient is applied. The DWI image will show an area of restricted diffusion as increased signal intensity that is a complicated product of T2* properties and restricted diffusion. The ADC or average diffusivity map (Dav) is a quantitative water diffusion map that shows restricted diffusion as areas of diminished signal intensity. Reduced ADC values in the posterior limb of the internal capsule are associated with a greater risk of adverse neurodevelopmental outcome in term newborns with encephalopathy [Hunt et al., 2004]. FA values in the white matter and basal nuclei are decreased with significant injury during the first week of life in term newborns with encephalopathy [Ward et al., 2006]. In newborns with brain injury, DTI also detects abnormalities of microstructural brain development remote from the primary injuries, in areas of the brain that are normal on T1 and T2-weighted images [Miller et al., 2002b].
Patterns of Brain Injury
In a primate model of brain injury in the “term newborn,” the distribution of injury was associated with the duration and severity of ischemia. While acute-profound asphyxia produced injury in the basal ganglia and thalamus, partial asphyxia caused white matter injury [Myers, 1972, 1975]. Similar patterns of injury are found in term newborns following hypoxia-ischemia (see Figure 17-1). The basal ganglia-predominant pattern involves both the basal ganglia and thalamus, and perirolandic cortex [Miller et al., 2005; Sie et al., 2000; Chau et al., 2009]. The watershed pattern predominantly involves the vascular watershed, from the white matter and extending to the cerebral cortex [Miller et al., 2005; Sie et al., 2000]. Maximal injury in both the watershed region and basal nuclei results in the total pattern of brain injury [Miller et al., 2005; Sie et al., 2000]. Identifying the predominant pattern of brain injury is helpful to the clinician caring for a term newborn with encephalopathy, as the predominant pattern is more strongly associated with neurodevelopmental outcome than the severity of injury in any given region [Miller et al., 2005].
The final pattern of injury, increasingly recognized by MRI, is the “focal- or multifocal” pattern of injury: stroke or white matter injury (WMI). Recent data suggest that strokes (arterial or venous) are also associated with neonatal encephalopathy in the term newborn [Cowan et al., 2003]. Many newborns with stroke have multiple risk factors for brain injury, including intrapartum complications.
While WMI is the characteristic pattern of brain injury in premature newborns, it is increasingly recognized in term newborns with encephalopathy, identified in 23 percent in one series (see Figure 17-1) [Li et al., 2009]. In this series, WMI demonstrated restricted diffusion on ADC maps in almost all newborns, suggesting that these lesions were acquired near birth. As newborns with WMI had milder encephalopathy relative to other newborns in the cohort, these lesions may have been underdetected in the past. Lower gestational age at birth, within the range of term birth, was associated with an increasing severity of WMI, suggesting a role for brain maturation in the etiology of this injury pattern [Li et al., 2009]. In sequential studies of term newborns with encephalopathy, delayed white matter degeneration, extending past the first week of life, is also seen [Barkovich et al., 2006; Neil and Inder, 2006]. This delayed WMI might follow injury to the basal nuclei, just as Wallerian degeneration of the corticospinal tract is found following some middle cerebral artery strokes in the term newborn [De Vries et al., 2005; Kirton et al., 2007]. It should be noted that full-term infants with congenital heart disease also have a strikingly high incidence of WMI on MRI and at autopsy [McQuillen et al., 2007; Mahle et al., 2002; Galli et al., 2004; Gilles et al., 1973; Kinney et al., 2005]. Similar to premature newborns and term newborns with encephalopathy, those with congenital heart disease are at risk of impaired delivery of energy substrates due to ischemia, inflammation, and oxidative stress, particularly with cardiopulmonary bypass. Recent data from autopsy and brain imaging studies suggests that in utero brain development is delayed in newborns with some forms of serious congenital heart disease [Miller et al., 2007; Rosenthal, 1996; Licht et al., 2009]. These abnormalities in early brain development might explain the predominance of WMI in term newborns with congenital heart disease, as opposed to the more expected “term” predominance of injury to the basal nuclei or watershed regions predominantly.
Progression of Neonatal Brain Injury
Timing the onset and determining the progression of brain injury have been greatly facilitated with the use of diffusion MR techniques and MRS. Recent studies have shown that the reduction in ADC on diffusion imaging due to brain injury in term newborns evolves over the initial days of life, reaching their nadir by 2–4 days after injury [Barkovich et al., 2006; McKinstry et al., 2002]. Thus, MR diffusion images obtained prior to the nadir, as in the first day following an injury, may not show the full extent of injury. Importantly, diffusion abnormalities persist for 7–8 days in the newborn before returning towards normal values (pseudonormalization) and ultimately reflect increased diffusion [Barkovich et al., 2001; McKinstry et al., 2002; Coats et al., 2009]. In a proportion of patients, brain injury will progressively worsen over the first 2 weeks of life to involve new brain areas, particularly the white matter tracts [Barkovich et al., 2006]. It is critical to interpret diffusion imaging in the context of the time between injury and the acquisition of the scan [Barkovich et al., 2001; McKinstry et al., 2002]. MRS data in newborns mirror this time course of injury progression. In the first 24 hours following brain injury in the term newborn, lactate increases, followed by a decrease in NAA in the 3 days after injury [Barkovich, 2000; Barkovich et al., 2001; Novotny et al., 1998]. The prolonged progression of neonatal brain injury is consistent with the mechanisms of cell injury, discussed below, that persist for days following hypoxic-ischemic brain injury in the newborn. These observations also suggest that the opportunity to intervene to prevent or ameliorate brain injury may extend over days in the term newborn, if not weeks. These quantitative MR techniques now offer a dynamic measure of brain injury in the newborn that can be safely used to determine the short-term effects of novel intervention strategies.
Outcomes
Neurodevelopmental outcomes following neonatal encephalopathy depend on the pattern and severity of the brain injury. Neurodevelopmental deficits may involve motor, visual, and cognitive functions. Both genetic and postnatal variables such as socioeconomic factors (e.g., environmental exposures and parental education) likely modify an individual’s neurodevelopmental outcome following neonatal brain injury [Miller et al., 2002a; Robertson and Finer, 1993]. Given the broad spectrum of neurodevelopmental impairments following neonatal encephalopathy, follow-up of these newborns should include assessment of motor function, vision and hearing, cognition, behavior, and quality of life, through infancy and childhood. Epilepsy is identified in up to one-half of survivors from moderate to severe neonatal encephalopathy [Brunquell et al., 2002; Clancy and Legido, 1991], and is particularly common in those infants with cerebral palsy and developmental delay [Toet et al., 2005].
The American College of Obstetricians and Gynecologists (ACOG) Task Force on Neonatal Encephalopathy concluded that an acute intrapartum event could result in cerebral palsy of the spastic quadriplegic or dyskinetic type, but could not account for isolated cognitive deficits [ACOG, 2004]. Recently reviewed data [Gonzalez and Miller, 2006] indicate that cognitive deficits may feature prominently following term neonatal encephalopathy of presumed hypoxic-ischemic brain injury, even in the absence of cerebral palsy. This pattern of neurodevelopmental deficits follows an overt neonatal encephalopathy, often in the context of a critical illness, and is most commonly associated with the watershed pattern of injury and white matter damage, rather than the basal nuclei-predominant pattern of injury. A complete assessment of neurodevelopmental outcome must include aspects of cognition most readily assessed at school age: learning, executive function, behavior, and social competence. In addition, developmental coordination disorder, autism spectrum disorder, or specific language impairments should be considered as possibilities in follow-up of newborns with a history of encephalopathy [van Handel et al., 2007]. Finally, “quality of life,” an individual’s subjective perception of physical and psychological health, should be evaluated by the clinician assessing outcomes to tailor rehabilitation and monitoring services best.
Motor Function
In term survivors of hypoxic-ischemic brain injury, the risk of cerebral palsy or severe disability may involve more than one-third of affected newborns, and is most common in those with a severe encephalopathy [Volpe, 2008; Dixon et al., 2002; Barnett et al., 2002]. Spastic quadriparesis is the most common type of cerebral palsy, although athetoid or spastic hemiparesis also occurs. The diagnosis and management of cerebral palsy are addressed in Chapter 69. A complete assessment of neurosensory and cognitive functions is critical in children with cerebral palsy [Marlow et al., 2005]. Minor motor impairments that do not meet diagnostic criteria for cerebral palsy [Shevell et al., 1999] are diagnosed in more than one-third of children with moderate encephalopathy, and in more than one-quarter of children with mild encephalopathy [Van Kooij et al., 2008].
Vision and Hearing
Severe visual impairment occurs in up to one-quarter of children after moderate or severe encephalopathy [Robertson and Finer, 1985; Shankaran et al., 1991]. This may be due to injury to the posterior visual pathway, including the primary visual cortex, resulting in “cortical visual impairment” [Van Hof-van Duin and Mohn, 1984]. Injuries to the basal nuclei may also affect acuity, visual fields, or stereopsis (depth perception) [Mercuri et al., 1997]. Sensorineural hearing loss, likely secondary to brainstem injury, is also seen following neonatal encephalopathy [Robertson and Finer, 1985; Robertson et al., 1989], affecting 18 percent of survivors of moderate encephalopathy without cerebral palsy [Lindstrom et al., 2006].
Cognition
Overall, cognitive deficits are seen in 30–50 percent of childhood survivors of moderate neonatal encephalopathy [Dilenge et al., 2001]. Intellectual performance in children with severe encephalopathy without cerebral palsy is also affected [Marlow et al., 2005]. School-age survivors of moderate neonatal encephalopathy are more likely to have difficulties with reading, spelling, and arithmetic, or require additional school resources [Moster et al., 2002; Robertson et al., 1989]. Cognitive deficits, such as those in language and memory, may be seen, even when IQ scores are “normal.” [Marlow et al., 2005]. Behavioral difficulties, such as hyperactivity and emotional problems, should also be considered, even in individuals without motor disability [Marlow et al., 2005].
Brain Imaging and Outcome
The pattern of brain injury on neuroimaging conveys important prognostic information regarding the “pattern” of neurodevelopmental abnormalities. The basal nuclei pattern of injury and abnormal signal intensity in the posterior limb of the internal capsule are both predictive of severely impaired motor and cognitive outcomes [Rutherford et al., 1998; Miller et al., 2005]. The cognitive deficits associated with this pattern are not surprising, given the common involvement of the cerebral cortex [Miller et al., 2005] and cerebellum [Le Strange et al., 2004; Sargent et al., 2004]. In contrast, the watershed pattern is associated with cognitive impairments that are not necessarily accompanied by major motor deficits [Miller et al., 2005]. Importantly, the cognitive deficits following the watershed pattern may only be evident after 2 years of age [Miller et al., 2005]. In survivors of neonatal encephalopathy without functional motor deficits assessed at 4 years of age, the severity of watershed-distribution injury was most strongly associated with impaired language skills [Steinman et al., 2009]. While neurodevelopmental outcomes may be significantly better than anticipated, neurological deficits may also be found in some newborns whose brain imaging studies are normal [Bax et al., 2006]. More subtle brain injuries associated with later neurodevelopmental deficits, such as white matter injuries or hippocampal volume loss, may only be detectable with quantitative brain imaging techniques [Miller et al., 2002a; Nagy et al., 2005; Gadian et al., 2000].
Pathophysiology of Neonatal Hypoxic-Ischemic Brain Injury
In term infants with neonatal encephalopathy, perinatal hypoxia-ischemia predominates as the major cause of future neurologic disability. The adverse consequences of cerebral ischemia include deprivation of energy substrates and oxygen, and an inability to clear accumulated, potentially toxic metabolites. Although linear flow charts cannot accurately convey the complex cascade of interrelated molecular pathways that lead to hypoxic-ischemic neurodegeneration, Figure 17-2 highlights some of the critical mechanisms.
Over the past 20 years, considerable information has emerged about the cellular and molecular consequences of cerebral hypoxia-ischemia and the molecular events that lead to neuronal cell death. The underlying rationale for this scientific focus is the hope that a better understanding of the basic molecular mechanisms of neurodegeneration may provide ways to modulate these events pharmacologically to limit their adverse consequences and to protect the brain from irreversible damage. A complementary focus that has emerged – and will likely become particularly important in the setting of neonatal brain injury – is the delineation of the intrinsic neuronal mechanisms of adaptation and repair after hypoxic-ischemic brain injury. Despite the traditional view of greater resistance to CNS injury in the neonate because of lower metabolic demands and the greater plasticity of the developing CNS, at specific stages of brain maturation, susceptibility to hypoxia-ischemia may be amplified. Clinical and experimental data have demonstrated that specific brain structures and neural cells in the developing brain may be selectively vulnerable to hypoxic-ischemic injury [McQuillen and Ferriero, 2004]. One of the best-characterized examples is the increased vulnerability of immature oligodendroglia to hypoxic-ischemic injury, which is evident clinically in premature infants and which has been successfully demonstrated in fetal and neonatal animal models [Back et al., 2002; Segovia et al., 2008].
Risk of injury to the immature brain may be heightened by certain therapeutic interventions; this risk stems from the complex roles that pivotal molecular mediators of hypoxic-ischemic injury (e.g., glutamate, calcium) play in brain development. For example, some studies have provided compelling experimental evidence of maturational stage-dependent deleterious effects of several commonly used antiepileptic drugs [Ikonomidou and Turski, 2009].
This section reviews information about the pathophysiology of hypoxic-ischemic brain injury, integrates data obtained from experimental and clinical studies, and highlights mechanisms that are particularly relevant to understanding perinatal brain injury and repair. Several reviews can provide complementary perspectives [Gonzalez and Ferriero, 2008; Vexler and Yenari, 2009; Northington et al., 2005; Pediatric Neurology, 2009]. Please also see Part III of this book on emerging neuroscience concepts (Chapters 13, 14, and 15).
Cerebral Blood Flow and Energy Metabolism
Disruption of cerebrovascular autoregulation has been implicated as an important factor in the pathophysiology of neonatal hypoxic-ischemic brain injury. It is widely accepted that preterm infants have a “pressure-passive” cerebral circulation; however, term infants may remain at risk for impairment of cerebrovascular autoregulation [Boylan et al., 2000] and susceptibility to cerebral ischemia with fluctuations in systemic blood pressure. Several basic physiologic mechanisms may contribute to impaired autoregulation in the neonate. Increased expression of inducible and neuronal isoforms of nitric oxide synthase (iNOS and nNOS), as well as endothelial NOS, may narrow the autoregulatory window, and downregulation of prostaglandin receptors in response to high circulating prostaglandin levels may blunt the prostaglandin-mediated vasoconstrictive response to hypertension and thereby contribute to inappropriately increased cerebral blood flow [Chemtob et al., 1996]. After an ischemic insult, the neonate remains at high risk for further damage in the acute recovery phase because neonatal encephalopathy is often associated with blood pressure fluctuations.
An inadequate supply of glucose or alternate substrates plays a pivotal role in hypoxic-ischemic neuronal cell death. Although overall metabolic demands are lower in the neonatal than in the adult brain, during periods of rapid brain growth, particularly the perinatal period, metabolic needs rise. The pattern of injury after hypoxia-ischemia can be explained in part on the basis of this metabolic demand; brain regions most susceptible to hypoxic-ischemic injury in the term infant (e.g., subcortical gray matter structures such as the basal ganglia and thalamus) are the same regions that are most vulnerable to mitochondrial toxins. Brain development is associated with a transition from the ability to use glucose and ketones as energy substrates in the neonate to an absolute requirement for glucose in the adult. The immature brain can use lactate as an alternate fuel source to some degree, and the deleterious effects of lactate accumulation after hypoxia-ischemia therefore may be attenuated in the neonate compared with the adult. However, normal maturation is characterized by limitations in glucose transport capacity and increased use of these alternative fuels such as lactate. The inability to transport glucose across the blood–brain barrier threatens cerebral glucose utilization. These factors illustrate the importance of understanding the use of glucose, lactate, and ketones in the newborn brain under normal and pathologic conditions [Vannucci and Vannucci, 2000; Vannucci and Hagberg, 2004].
Excitotoxicity
Glutamate can activate a variety of excitatory amino acid receptors that are broadly classified based on their selective responses to specific agonists (e.g., NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], kainate) or their signaling mechanisms (i.e., ionotropic [ligand-gated ion channel] or metabotropic [G-protein-coupled]). Excitatory amino acid neurotransmission plays a pivotal role in brain development and in learning and memory. A substantial body of data has emerged over the past 30 years documenting the fact that overactivation of excitatory amino acid receptors (i.e., excitotoxicity) contributes to neurodegeneration in a broad range of acute and chronic neurologic disorders [Johnston, 2005].
