Chapter 52. Brain Abnormalities and Injuries

Neonatal encephalopathy is a clinically defined syndrome of disturbed neurological function in the early postnatal days of life in the term infant, manifested by a combination of signs including altered consciousness, abnormal muscle tone or reflexes, altered respiration or seizures. Etiologies of neonatal encephalopathy include the combination of intrapartum or antepartum hypoxia and ischemia (hypoxic-ischemic encephalopathy), which may be accompanied by some prenatal signs of fetal distress; vascular pathologies, including intracranial bleeding and stroke; injuries secondary to birth trauma; infections; genetic and metabolic disorders; and congenital brain abnormalities. This chapter is focused on brain injuries and abnormalities in term newborn infants, with particular emphasis on infants who present with biochemical and clinical evidence of hypoxic-ischemic encephalopathy, and the current diagnostic and treatment approaches to such injury. Other birth injuries associated with central nervous system damage including vascular malformations and birth trauma are briefly discussed as well.

Neonatal encephalopathy occurs in 1 to 6 per 1000 live full-term births, with a recent population-based estimate of 1.9 to 3.8 per 1000.1 Fifteen to 20% of affected newborns will die in the postnatal period, and an additional 25% will sustain childhood disabilities.2 Neonates with mild encephalopathy do not have an increased risk of motor or cognitive deficits. Neonates with severe encephalopathy have an increased risk (> 60%) of death or of cerebral palsy and mental retardation. Neonates with moderate encephalopathy have a higher likelihood of death or deficits, such as memory impairment, visual motor or visual perceptive dysfunction, increased hyperactivity, and delayed school readiness, that is approximately half that of those with severe encephalopathy.

The cause and timing of such injuries is usually unknown. Since neonatal encephalopathy has myriad causes, diagnostic criteria that suggests a hypoxic-ischemic insult is attributable to an acute intrapartum event has been suggested. These include metabolic acidosis with a cord pH below 7 or a base deficit of 12 mmol/L or greater, early onset of encephalopathy, and exclusion of another etiology such as trauma, coagulation disorder, and genetic and metabolic causes. Infants with severe injury and hypoxic-ischemic encephalopathy related to an intrapartum event develop either spastic quadriplegia or dyskinetic type cerebral palsy. Signs consistent with an event in the 48 hours prior to delivery, but not necessarily an acute event, include a sentinel event occurring immediately before or during labor; a sudden sustained fetal bradycardia or absence of fetal heart rate variability in the presence of persistent, late, or variable decelerations, usually after a sentinel event before which the fetal heart rate pattern was normal; Apgar scores less than 3 at 5 minutes; multisystem organ involvement apparent within 72 hours of birth; and early imaging studies demonstrating evidence of acute nonfocal cerebral abnormalities.3

The vast majority of infants with encephalopathy do not have an identifiable intrapartum event such as cord prolapse or uterine rupture.4 Although there is no specific diagnostic test for hypoxic-ischemic encephalopathy, neuroimaging studies identifying injury to the basal ganglia and parasagittal white matter suggest an injury that occurred to tissues susceptible to hypoxic-ischemic injury in the perinatal period rather than long-standing antenatal compromise or an acute vascular event. Although the neuroimaging results may identify perinatal injury, precise timing of perinatal injury by neuroimaging alone is not possible.

The pathophysiology of brain injury secondary to hypoxia-ischemia is simplified into 2 phases of pathologic events that culminate in sustained brain injury. These phases are primary and secondary energy failure based on characteristics of the cerebral energy state used to describe the temporal sequence in newborn animals.5,6 Primary energy failure is characterized by reductions in cerebral blood flow and delivery of oxygen and substrates to brain tissue. High-energy phosphorylated compounds such as adenosine triphosphate and phosphocreatine are reduced, and tissue acidosis is prominent. This phase is an essential prerequisite for all deleterious events that follow. Primary energy failure is associated with acute intracellular derangements, such as loss of membrane ionic homeostasis, excessive release or blocked reuptake of excitatory neurotransmitters, defective osmoregulation, and inhibition of protein synthesis. Excessive stimulation of neurotransmitter receptors and loss of ionic homeostasis mediate an increase in intracellular calcium and osmotic dysregulation. Elevation in intracellular calcium triggers a number of destructive pathways by activating lipases, proteases, and endonucleases.

Resolution of hypoxia-ischemia within a specific time interval reverses the fall in high-energy phosphorylated metabolites and intracellular pH and promotes recycling of neurotransmitters. The therapeutic window for hypoxia-ischemia to be successfully reversed and to promote recovery is influenced by maturation, preconditioning events, substrate availability, body temperature, and coexisting disease processes. Although recovery of the cerebral energy state may occur following primary energy failure, a second interval of energy failure may occur at a time remote from the initiating event. Secondary energy failure differs from primary energy failure in that declines in phosphocreatine and adenosine triphosphate are not accompanied by brain acidosis. The presence and severity of secondary energy failure depends on the extent of primary energy failure. The pathogenesis of secondary energy failure is not as well understood as that of primary energy failure but likely involves multiple pathophysiologic processes, including accumulation of excitatory neurotransmitters, oxidative injury, apoptosis, inflammation, and altered growth factors and protein synthesis. Much of the later injury occurs secondary to the process of apoptosis, or programmed cell death. Apoptosis occurs in normal brain development and is useful for refining cell connections and pathways. The cellular signals after hypoxic-ischemic injury accelerate this process in normal brain tissue, contributing significantly to the later evolving injury noted in infants with hypoxic-ischemic encephalopathy.

The interval between primary and secondary energy failure represents a latent phase that corresponds to a potential therapeutic window, as clinicians usually do not know the precise time of primary energy failure. Initiation of therapies during this latent phase in perinatal animals has been successful in reducing brain damage, substantiating the concept a therapeutic window. The duration of the therapeutic window is approximately 6 hours in near-term fetal sheep based on the neuroprotection associated with brain cooling initiated at varying intervals following brain ischemia.

Neonatal encephalopathy is characterized by the presence of an abnormal neurologic examination in the first postnatal days, ranging from lethargy, hypotonia, or hypertonia to a normal appearance with the sudden occurrence of apnea or seizures, which can be subtle and subclinical, focal, or generalized and clinically obvious.7 The clinician also must be aware that many infants present with myoclonus, which may appear to be seizures. In extreme cases, an otherwise apparently wellgrown, healthy term neonate may present with coma after extremely low Apgar scores and severe metabolic acidosis on cord blood gases.

The first step in diagnosis of neonatal encephalopathy is to obtain a detailed history of the pregnancy and intrapartum period. Any event likely to compromise blood or oxygen supply to the fetus, such as placental abruption, uterine rupture, amniotic fluid embolism, tight nuchal cord, cord prolapse or avulsion, maternal hemorrhage, trauma or cardiorespiratory arrest, severe and sustained fetal bradycardia, or prolonged labor, may be causative. Most infants with encephalopathy do not have an obvious cause for the encephalopathy. A history of maternal elevation of temperature has prognostic significance that increases the risk of neonatal encephalopathy and cerebral palsy. A history of fetal tachycardia and maternal tachycardia may also raise suspicions of chorioamnionitis. The placenta should be examined to determine if there was placental infection or noninfectious etiologies for hypoxic-ischemic encephalopathy.

All neonates with encephalopathy should have detailed neurologic examinations repeatedly during the first postnatal days to evaluate the presence of mild, moderate, or severe encephalopathy based on the Sarnat classification7 (Table 52-1). The physical examination, acid-base data, intrapartum history and Apgar scores provide useful indicators of status. Ongoing encephalopathy through the first postnatal week, along with serial neuroimaging and continuing burst suppression on electroencephalograph, can be considered poor prognostic signs. Neuroimaging with magnetic resonance imaging, particularly with added diffusion weighted imaging, which measures diffusion of water in tissues (less apparent diffusion noted using this methodology is proportional to more injury), in the first week of life and then repeated during the postnatal months is also helpful in gaining understanding about the extent and etiology of injury. In adults, biomarkers such as various inflammatory cytokines are beginning to be used to identify individuals with stroke and to guide therapy. The use of these biomarkers to grade injury, guide therapy, and predict outcome in neonatal encephalopathy is currently being investigated.

The best current bedside tool for cerebral function monitoring in term and near-term infants is the amplitude integrated EEG (aEEG), which correlates well with conventional EEG. The aEEG records a single-channel EEG from biparietal electrodes; the signal is then filtered, rectified, and smoothed, and amplitude is integrated. The aEEG interpretation is based primarily on pattern recognition. It appears to be predictive of neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy, and coupled with an early neurologic examination, the aEEG correlates well with persistent encephalopathy. It has been suggested that aEEG should become part of the initial evaluation of near-term and term infants with hypoxic-ischemic encephalopathy. Additionally, early work combining analysis of regional cerebral oxygen saturation and fractional cerebral tissue oxygen extraction(FTOE) measured by near-infrared spectroscopy in infants with hypoxic-ischemic encephalopathy suggests the aEEG plus the FTOE are somewhat predictive of outcome, and the regional saturation and the FTOE can identify the period of secondary injury and energy failure that may be our best target for therapeutic intervention. The aEEG should not be used for the detection and treatment of neonatal seizures because it has not been proven to reliably detect subclinical seizures. Cerebral oximetry is also early in its development for use in therapeutic decision making in the intensive care nursery.

The management of neonates with hypoxic-ischemic encephalopathy has been limited to generally supportive intensive care that includes correction of hemodynamic and pulmonary disturbances (hypotension and hypoventilation), correction of metabolic disturbances (related to glucose, calcium, magnesium, and electrolytes), treatment of seizures, and monitoring for other organ system dysfunction, especially hepatic, renal, and coagulation status. Avoidance of hyperthermia may also be beneficial, and monitoring of urine output can guide fluid maintenance and drug dosing. This management approach is directed at avoiding injury from secondary events associated with hypoxia-ischemia. Over the past 15 years specific therapies to block or dampen the cascade of events triggered by hypoxia and ischemia, and to prevent or treat neonatal seizure have been evaluated. These include the use of anticonvulsants, and brain hypothermia.

Treatment of Seizures

Because neonatal seizure may have adverse effects, their prevention and treatment with prophylactic administration of anticonvulsants has been considered. However, the consequences of subclinical or electroencephalogram detected neonatal seizures on neurodevelopmental outcome has not been adequately evaluated. There is no current data that demonstrates treatment with anticonvulsants or barbiturates can effectively control seizures or that treatment with these agents reduces cerebral palsy or mental retardation in infants with encephalopathy. The existing studies are small and there is concern that treatment may have adverse effects on the central nervous system. Therefore, larger scale clinical trials of anticonvulsant and barbiturate therapy are needed before these agents becomes widespread.

Brain Hypothermia

In experimental models of brain ischemia in neonatal animals, it has been demonstrated that a small reduction in brain temperature (1–6°C) during or immediately after ischemia decreases the release of excitatory neurotransmitters, caspase 3 activation, decreases apoptosis, and blunts the usually observed decrease in protein synthesis, increase in free radicals and changes in microglia activation and cytokine production.

These findings justified clinical trials. To date, there have been 2 large, randomized, controlled trials and 1 large pilot study to evaluate the efficacy of hypothermia as neuroprotection for term and near-term infants with hypoxic-ischemic encephalopathy.

The multicenter CoolCap study involved 243 infants, with moderate or severe encephalopathy and an abnormal aEEG, who were either cooled to a core body temperature of 34 to 35°C for 72 hours or treated with temperature maintenance in normothermia range with conventional care. The primary outcome of the study was death or disability at 18 months. Cooling was provided by selective head cooling with mild systemic cooling. Death or severe disability occurred in 66% of infants randomized to conventional care and 55% randomized to the cooled group: odds ratio (95% CI) 0.61 (0.34 – 1.09), P = 0.10.8 The effect of head cooling for infants with the most severe aEEG changes was not protective; on the other hand, the effect of head cooling for infants with less severe aEEG changes (n = 172) was protective: odds ratio 0.42 (0.22 – 0.80; P = 0.009).

One smaller randomized, controlled pilot study performed at 7 centers with 65 infants involved moderate systemic whole-body hypothermia to 33°C for 48 hours compared to normothermia maintained at 37°C.9 The safety report of this pilot study documented that infants in the hypothermia group had more significant bradycardia, longer dependence on pressor medications, higher prothrombin times, more seizures, and need for more plasma and platelets transfusions. At 12 months of age, death or severe motor disability occurred in 52% of hypothermia group compared to 84% of normothermia group (P = 0.02), but the normothermia group lacked follow up information on 8 of 33 enrolled infants versus only 5 of 32 for the treated group. In a subgroup analysis, outborn infants were more likely than inborn infants to die: odds ratio 10.7 (1.3 – 90.0).

The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial evaluated 102 infants randomized to hypothermia with whole-body cooling to 33.5°C for 72 hours compared to 106 control infants randomized to conventional care.10 The primary outcome, death or moderate to severe disability at 18 months of age, was noted in 44% of infants in the hypothermia group compared to 62% of infants in the control group with a risk ratio of 0.72 (0.54 – 0.95). The infants in the hypothermia group had significantly lower heart rates than the infants in the control group throughout the 72-hour intervention period. There was no significant difference in systolic or diastolic blood pressure between groups. The frequency of adverse events was low: 1 infant in each group had arrhythmia, 2 infants in the hypothermia group had acidosis, 3 infants in the hypothermia group and 2 infants in the control group had bleeding, and 4 infants in the hypothermia group had altered skin integrity. There was a trend for cooling to benefit infants in both moderate and severe encephalopathy groups.

Other secondary analyses have been published from the NICHD randomized clinical trial. In one study, examining the relationship of elevated temperature after hypoxic-ischemic encephalopathy, 22% of esophageal core temperatures measured among the control group infants were higher than 37.5°C.11 The odds of death or disability were increased 3.6-fold to 4-fold for each centigrade increase in the highest quartile of temperature in the control group. These results may reflect underlying brain injury and/or adverse effects of high core temperature on outcome. Another study evaluating predictors of outcome revealed that the classification and regression tree model, but not the scoring system developed from identified variables and odds ratios, was superior to the early neurologic examination in predicting death and disability in this study.12 Lastly, a secondary analysis involving spot urine samples collected in 58 study participants revealed that high urinary lactate–to-creatinine ratio was associated with death and disability.13

There are important differences between the CoolCap8 and the whole-body hypothermia trials.10 The 2 trials use different entry criteria distinguished primarily by the use of the aEEG in the CoolCap trial. The mode of cooling used in each trial was different, and it is unknown if one cooling regimen is superior to the other. The primary outcomes were defined differently in the 2 trials. Although not powered to evaluate moderate or severe encephalopathy separately, decrease in death and moderate to severe disability was seen in the whole-body cooling trial in both moderate and severe encephalopathy. Because the primary outcome of each trial was the combined end point of death or disability, it is important to ascertain that the therapies did not salvage infants with severe disabilities who would have otherwise died in the absence of the intervention. The results are plotted in Figure 52-1 and eFigure 52.1. The Mental Development Index less than 70 was reduced in both trials, (Fig. 52-1), as was the rate of disabling cerebral palsy (reduced from 31% in the control group to 18% in the CoolCap study and from 30% in the control group to 19% in the whole-body cooling trial of the NICHD Network) and visual impairment (eFig. 52.1).

The European Network study of whole-body cooling to 33.5°C was closed to recruitment after 129 infants were enrolled because investigators felt that current evidence of benefits of hypothermia do not justify randomization of participants; follow-up is ongoing. The UK Total Body Hypothermia (TOBY) trial of total whole-body cooling to 33.5°C for 72 hours has completed enrollment of a planned 325 infants, and follow-up of infants is ongoing. Lastly, the Australasian Infant Cooling Evaluation (ICE) whole-body cooling study (33.5°C for 72 hours) closed recruitment after 218 of a planned 300 infants due to lack of equipoise. Follow-up is ongoing.

Three independent recently published systemic reviews of this data conclude that therapeutic hypothermia (1) significantly reduces both death and disability after perinatal encephalopathy (see Table 52-2), (2) is safe, and (3) results in homogeneous outcomes both within and between trials.14-16

The age of follow-up for infants enrolled in trials of neuroprotection therapy for hypoxic-ischemic encephalopathy is a critical issue in evaluating efficacy of therapy. All the current published trials have evaluated hypothermia as a neuroprotective strategy with the primary outcome of death or disability at 18 months of age. This is the earliest age at which major disability can be ruled out with a high level of confidence. To assess effects beyond 18 to 22 months, it is necessary to evaluate the relationship of intervention to early childhood outcome because hypothermia may influence not only major motor and cognitive deficits detected at 18 months but also more subtle effects of brain injury in childhood. These include behavior, learning, fine motor development, executive function, attention, and psychosocial outcome. Both the current trials are in the process of evaluating follow-up of the studied infants at early childhood.

MRI findings in near-term and term infants with hypoxic-ischemic encephalopathy differ depending upon the severity of hypotension or ischemia in the perinatal/neonatal period. In mild to moderate hypotension, the typical MRI features are characterized by parasagittal lesions involving the vascular boundary zones, whereas profound hypotension involves primarily the lateral thalami, posterior putamina, the hippocampi, and the corticospinal tract including the perirolandic area but mainly sparing the remaining cortex. Positron emission tomography has demonstrated that lesions in the basal ganglia, perirolandic area, and hippocampi are related to impairment of energy substrates in areas with higher metabolic requirements. The major patterns of brain injury detectable by conventional MRI in near-term and term newborns with encephalopathy include the watershed-predominant pattern involving the white matter, particularly in the vascular watershed extending to the cortical gray matter when severe, and a basal nuclei–predominant pattern involving the deep gray nuclei and perirolandic cortex extending to the whole cortex when severe ischemia occurs. Involvement of specific structures at the posterior limb of the internal capsule is also noted with acute perinatal asphyxia.17 Clinicians should note that the neuroimaging picture, even on specialized MRI scans, is quite dynamic even in the first 2 postnatal weeks following hypoxic-ischemic injury. Areas that appear abnormal on initial examination may appear normal later, and tissue that initially appeared normal may worsen.18

There appears to be an association of the neonatal MRI patterns and outcome in childhood. Abnormal signal intensity with the posterior limb of the internal capsule in the neonatal MRI predicts abnormal outcome in term infants with hypoxic-ischemic encephalopathy. The basal ganglia and thalamic (BGT) lesions give rise to motor impairment in cerebral palsy. Approximately 50% of neonates with these lesions have extensive concurrent white matter abnormalities. White matter involvement is often associated with cognitive deficits. Severe BGT injury may be associated with spastic quadriplegia, cognitive impairment, feeding difficulties, and poor head growth. Moderate BGT injury may be associated with athetoid or dyskinetic cerebral palsy with normal cognition and normal head growth. Purely dyskinetic cerebral palsy has been noted with a mild pattern of brain injury in the BGT region, purely spastic cerebral is seen with severe BGT pattern, and dyskinetic or spastic cerebral palsy is seen with either moderate or severe BGT or white matter injury pattern.

No relationship between antenatal and perinatal conditions and the pattern of predominate brain injury has been shown; antenatal conditions such as maternal substance use, gestational diabetes, premature rupture of membrane, preeclampsia, and intrauterine growth restriction did not differ across patterns. The BGT pattern was associated with the most severe neonatal events, including more intensive resuscitation at birth, severe encephalopathy, and seizures. Among infants born following a sentinel event such as placenta abruption, BGT lesions are likely to be isolated. A BGT and white matter lesion may be found in a large proportion of neonates presenting without an apparent precipitating event.

Encephalopathy secondary to birth trauma and vascular events often presents with seizures in the first postnatal days without other preceding neurologic signs. Since these early seizures may be due to other causes including metabolic disorders, infection, hypoglycemia, hypocalcemia, hyponatremia, acidosis, and hyperbilirubinemia, it is important to consider these diagnoses in assessing for possible vascular injury with neuroimaging.

Perinatal stroke is estimated to occur in approximately 1 out of 4000 births,19 while the overall incidence of birth trauma–related brain injury that may influence neurologic outcome is much smaller in developed countries. There is an increased risk for major trauma, including depressed skull fracture, intracranial hemorrhage, or brachial plexus palsy in vaginal deliveries assisted with instrumentation, either forceps or vacuum. There does not appear to be a difference in mortality risk for infants born via vacuum versus forceps assist, but vacuum may be associated with a higher risk of cephalohematomas than forceps delivery. When both modalities are used sequentially, risk of any injury is greatly increased. Infants with these injuries often present with seizures in the first postpartum hours to days. Appropriate diagnostic testing includes the evaluation of coagulation factors, platelet counts, and hemoglobin and hematocrit to assess the degree of blood loss and need for replacement.

Perinatal arterial stroke (see also Chapter 552) as a cause of cerebral palsy in term and near-term infants occurs in approximately 17 per 100,000 live births.20 Cases of perinatal stroke may present after the immediate neonatal period. Peripartum risk factors for perinatal stroke include preeclamptic toxemia and intrauterine growth restriction. Approximately two thirds of all neonatal strokes are arterial in origin, while the remainder are secondary to sinovenous thrombosis.

Arterial stroke usually causes wedge-shaped infarcts, often in the distribution of the middle cerebral artery. Antenatal infarcts can occur in cases of monozygotic twins with demise of 1 twin, with passage of thromboplastin-rich blood to the survivor. Significant fetomaternal hemorrhage can also result in hypoperfusion and infarction in watershed areas of the brain. Birth trauma may be contributory to ischemic stroke, with increased pressure from subdural bleeding putting pressure on internal vascular structures. Postnatal arterial strokes may be related to congenital heart lesions and repair when the pulmonary vasculature is bypassed. Clearly delineated diagnostic and risk factor analyses, as well as mechanism-based rapid intervention treatment approaches, similar to the “brain attack” approach in adults, are still in development.22

Venous infarction is less common than arterial. It has been related to problems with blood flow such as hypovolemia, polycythemia, and poor flow related to preeclampsia. Thrombosis has also been associated with infection. Venous infarcts, especially those that are hemorrhagic, are noted in the deep nuclear gray matter and the thalamus. Neuroimaging with MRI, and with added magnetic resonance venography, may reveal the occluded venous structure, but development of collateral circulation or recanalization of the vessel often has occurred between injury and imaging. The diagnostic workup for venous thrombosis should include, in addition to consideration of systemic illness, activity assays for antithrombin, protein C, protein S, and the lupus anticoagulant; immunologic assays for anticardiolipin antibody; and molecular assays for the presenceof factor V Leiden and the G20210A mutation in the prothrombin gene, and the methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C (see Chapter 439). Recent work, however, casts doubt on the importance of these and other polymorphisms for the pathogenesis of neonatal stroke.22 To date, there are no large randomized trials of anticoagulant therapies for venous stroke in neonates. The American College of Chest Physicians recently published evidence-based clinical practice guidelines for antithrombotic therapy in neonates and children. The guidelines include dose and duration recommendations for antithrombotic therapies and thrombolytic therapies, as well as diagnostic and therapeutic guidance.23 Further information for clinicians, in the absence of informative definitive clinical trials, is currently available from the 1-800-NOCLOTS toll-free pediatric stroke telephone consultation service initiated in 1994. This program has 3 goals: first, to provide free telephone consultation to physicians requesting advice on the management of children with stroke on the basis of best available evidence; second, to document the patient characteristics and most urgent questions facing these physicians; and third, to make these data available for planning future clinical trials in pediatric stroke. In animal models, higher than physiologic doses of erythropoietin after hypoxic-ischemic injury as well as neonatal strokes demonstrated benefits.24 Human clinical trials of erythropoietin in neonates with hypoxic-ischemic encephalopathy are in early phases.