Neonatal Brain Disorders

Brain Development in the Fetus and the Newborn

Maturation of the brain is defined through descriptions of sequential and overlapping developmental processes, beginning with conception and involving continual interactions of the gene environment. Beginning during gestation and following trimester-specific stages of development of the embryo and fetus, anatomic, biochemical, and physiologic processes occur: neural induction followed by neuronogenesis, programmed cell death and neuroblast migration, formation of axons and dendrites, continuous energy generation to provide membrane excitability, synaptogenesis, neurotransmitter biosynthesis, and myelination of axons. These prenatal time periods are fundamental for brain development. However, postnatal processes of programmed cell death, continued synaptogenesis, and neurotransmitter maturation highlight important brain maturational events needed for continued preservation of appropriate structure and function. Regional differences in the rate of maturation of the nervous system also must be recognized. Different brain structures do not express equivalent function at specific times during the development of the fetus, premature infant, and full-term neonate. Table 17.1 summarizes the major prenatal developmental sequences in brain maturation that occur in the cerebrum and cerebellum, and lists representative disorders at each stage. Both volume and gyral-sulcal complexity increase during prenatal development, with prominent changes in the last 3 months of gestation ( Fig. 17.1 ), reflecting major molecular and histologic maturational changes during the formation of maturing cortical-subcortical cellular connections.

Neurological Examination of the Preterm and Term Born Infant

A systematic approach to the neurological examination of the newborn is an important first step in the diagnostic evaluation. Observation is critical in each domain of the neurological examination of the newborn. It is important to remember that the neurologic system is derived from ectoderm, and thus one should pay particular attention to the examination of the skin. Outgrowths such as encephaloceles, cutaneous lesions such as port-wine stains, and the presence of sacral dimples or sinuses should be sought as clues to underlying neurologic dysfunction. Additionally, head circumference should be measured with a tape measure. The normal term infant’s head circumference is approximately 35 cm and is reflective of the underlying intracranial volume. Macrocephaly and microcephaly can be indications of underlying metabolic, genetic, or infectious processes.

Brain Injury in the Preterm Infant

Intraventricular Hemorrhage

Neonatal germinal matrix hemorrhage/intraventricular hemorrhage (GMH/IVH) is the most common form of intracranial hemorrhage in preterm infants and an important cause of long-term morbidities among survivors of neonatal intensive care. In its least severe form, the hemorrhage may be restricted to the germinal matrix area or subependyma. However, frequently, the hemorrhage extends beyond the germinal matrix into the cerebral ventricles, following rupture of the GMH into the ventricular space.

Incidence

GMH/IVH is a neurological disorder that occurs most frequently among preterm infants. Its incidence decreases as gestational age and birth weight increase. Because of improvements in perinatal and neonatal care, the incidence of GMH/IVH has decreased over the past several decades but to a lesser extent than the decline in neonatal mortality. In the 1970 to 1980s, GMH/IVH was noted in 45% of very low-birth-weight (VLBW) infants and in greater than 60% of those with birth weight of 750 g or less. By the mid-1990s, it had decreased further to 24% of VLBW infants. Since that time, however, the incidence has become static, remaining about 25% among all VLBW infants based on data from the Vermont Oxford database ( Fig. 17.2 ). The more severe hemorrhages, grades III and IV, occur in 12% to 17% of extremely low-birth-weight (ELBW) infants and in as high as 20% of those with birth weight of 750 g or less. These severe hemorrhages occur in 17% to 28% of those with gestational age 22 to 26 weeks and in 9% to 14% of those 27 to 32 weeks’ gestation.

Pathogenesis

The pathogenesis of GMH/IVH is complex and involves multiple risk factors and disorders that may cause biochemical, inflammatory, and hemodynamic alterations, predisposing to the development of hemorrhage. The origin of hemorrhage is the germinal matrix, a prominent structure in the preterm brain in the second and early third trimesters that undergoes involution beginning at 24 to 26 weeks. The germinal matrix structure contains neuronal precursor cells before 20 weeks of gestation. As development progresses, the differentiating glioblasts give rise to oligodendroglial cells, which are important to myelination. The germinal matrix is supplied by a complex vascular network but is a low blood flow structure. The origin of the hemorrhage appears to be from the endothelial lined vessels of the matrix, in particular, vessels in communication with the venous circulation, including capillary-venule junctions and small venules. The susceptibility of the thin-walled germinal matrix capillaries to rupture may be because of their large diameter, which offers lesser resistance to changes in intravascular pressure, to immature endothelial cell tight junctions, and to lower levels of structurally stabilizing proteins such as fibronectin and collagen in the extracellular matrix.

Among the clinical risk factors associated with IVH are lower gestational age, lack of antenatal corticosteroids, clinical chorioamnionitis, male sex, significant delivery room resuscitation, mechanical ventilation, and hypotension requiring multiple inotropes. Table 17.2 lists cerebrovascular factors and alterations in cerebral hemodynamics that may result from a variety of antenatal and postnatal conditions that are thought to be associated with the pathogenesis of GMH/IVH.

TABLE 17.2

Factors That Influence Pathogenesis of Germinal Matrix Hemorrhage/Intraventricular Hemorrhage

	Factors in the Pathogenesis of GMH/IVH	Antenatal and Postnatal Conditions Leading to Vascular and Hemodynamic Alterations, Increasing Risks for GMH/IVH
Intravascular	Increased Cerebral Blood Flow	Systemic hypertension in presence of a pressure-passive circulation
		Rapid volume expansion
		Hypercarbia
		Reduced hematocrit
		Hypoglycemia
	Fluctuating Cerebral Blood Flow	Fluctuating systemic blood pressure in presence of a pressure-passive circulation
		Hypercarbia
		Hypovolemia
		Hypotension
		Patent ductus arteriosus
		High FiO 2
	Decreased Cerebral Blood Flow (Resulting in Reperfusion Injury)	Systemic hypotension in presence of a pressure-passive circulation
		Asphyxia
	Increased Cerebral Venous Pressure	Asphyxia
		Venous anatomic arrangement
		Prolonged labor and vaginal delivery (some conflicting reports)
		Respiratory management (high peak inspiratory pressure, tracheal suctioning, pneumothorax)
Vascular	Immature Vasculature	Preterm birth and low birth weight
	Undergoing remodeling and involution
	Simple endothelial-lined vessels without collagen or muscle
	Immature tight junctions
	Large diameter of germinal matrix vessels relative to cortical vessels	Conditions associated with ↓PaO 2 , ↑PaCO 2 , ↓pH
	Vulnerability to hypoxemia-ischemia as located in vascular border zone	Hypoxia-ischemia reperfusion
	Vessel endothelial damage	Inflammation/infection
		Hypotension/shock
		Oxygen therapy, hyperoxia, generation of oxygen-reactive species and other free radicals
Extravascular	Deficient vascular and extracellular matrix support	Preterm birth and low birth weight
	Excessive fibrinolytic activity	Low factor XIII levels (conflicting reports of significance)

GMH/IVH, Germinal matrix hemorrhage/intraventricular hemorrhage.

Clinical Manifestations and Diagnosis

GMH/IVH is usually detected in the first 4 to 5 days of life, with approximately 40% to 50% occurring in the first day of life and up to 90% within the first 72 hours. Approximately 20% of early-onset hemorrhage may evolve to become more severe, with the maximum extent typically seen within the first week of life. The majority of hemorrhages, in particular smaller ones, are asymptomatic and are only detected by routine cranial ultrasound (CUS). However, larger GMH/IVH may present with sudden clinical deterioration, especially when there is significant blood loss. Other clinical manifestations include anemia; seizures; tense, full, and/or bulging fontanels; split and wide sutures; apnea and bradycardia with desaturation episodes; poor perfusion; hypotension; severe metabolic acidosis; increase in oxygen requirement; and increase in ventilator support.

Imaging studies will establish the diagnosis of GMH/IVH. The current standard approach to diagnosis is the use of cranial ultrasonography. The procedure can be performed at the bedside, thus avoiding the risks of transporting the infant for either a computed tomography (CT) scan or magnetic resonance imaging (MRI) procedure. Table 17.3 shows the grading of GMH/IVH, based on Papile criteria from CT scanning still employed by clinicians and researchers for CUS findings. Volpe proposed a modification to the grading system for CUS findings. This newer, modified grading system takes into consideration the location of hemorrhage and the amount of blood detected in the ventricles. Examples of CUS findings are shown in Fig. 17.3 .

TABLE 17.3

Cranial Ultrasound Findings and Grades of Hemorrhages

Papile Criteria	Description	Volpe Criteria	Description
Grade I	Hemorrhage limited to the germinal matrix; may be unilateral or bilateral	Grade I	Blood in the germinal matrix area with or without minimal intraventricular hemorrhage (less than 10% of the ventricular space with blood)
Grade II	Blood noted within the ventricular system but not distending it	Grade II	Intraventricular hemorrhage with blood occupying 10%–50% of the ventricular space (sagittal view)
Grade III	Blood in ventricles with distension or dilation of the ventricles	Grade III	Intraventricular hemorrhage with blood occupying greater than 50% of the ventricles with or without periventricular echodensities
Grade IV	Intraventricular hemorrhage with parenchymal extension	Separate notation of other findings	Periventricular hemorrhagic infarction Cystic periventricular leukomalacia

Complications and Neuropathological Associations of Germinal Matrix Hemorrhage/Intraventricular Hemorrhage

GMH/IVH may be associated with destruction of the germinal matrix, periventricular hemorrhagic infarction, ventriculomegaly or hydrocephalus, white matter injury, and loss of cerebellar volume, each of which may have implications on the prognosis for the infant. During the second trimester, the ganglionic eminence and subventricular zone, which are part of and immediately associated with the germinal matrix, respectively, are rich locations for neuronal and glial proliferation. Therefore destruction of the germinal matrix during this vulnerable period leads to a reduction in proliferation and migration of neuronal and glial precursor cells, which in turn is thought to impact brain growth and potentially the developmental outcome of these infants.

Periventricular hemorrhagic infarction (PVHI) can be seen as large echodensities on CUS within the parenchyma adjacent to the GMH/IVH. Papile initially described this as extension of the IVH into the parenchyma. However, subsequent study has indicated that although PVHI is strongly associated with IVH, it is not an extension of the IVH; rather, it occurs because of obstruction of venous drainage leading to a venous hemorrhagic infarct. The area of infarction evolves into tissue loss such that a porencephalic cyst may be noted on later follow-up CUS.

About 2 to 3 weeks after detection of GMH/IVH, some infants may present with increasing head circumference, separation of sutures, full and tense fontanelles, and sunsetting appearance. A repeat CUS in the presence of these manifestations of increased intracranial pressure will reveal prominence and enlargement of the cerebral ventricles (ventriculomegaly) and thus a diagnosis of posthemorrhagic hydrocephalus (PHH). PHH results from disturbance in cerebrospinal fluid (CSF) dynamics because of (1) the obstruction of the CSF pathway by blood clots, in the posterior fossa cisterns, aqueduct of Sylvius, or foramen of Monroe; and (2) postinflammatory changes in the arachnoid villi, which may impair CSF absorption. Obstruction and delayed absorption of CSF leads to progressive increase in ventricular size. Among those with GMH/IVH who survive for more than 14 days, 50% will develop ventricular dilation, which will progress in half of these infants. In 62% of those with progressive ventricular dilation, spontaneous arrest occurs, whereas the remaining 38% will require nonsurgical or surgical treatment. Surgical intervention to relieve the increase in intracranial pressure and ameliorate-associated clinical manifestations will be necessary for rapidly increasing head size, frequent apnea and bradycardia, and the need for increasing ventilatory support.

Studies have demonstrated that GMH/IVH is associated with reductions in cerebellar volume. This is thought to occur secondary to (1) a direct toxic effect of hemosiderin on the surface of the cerebellum, impairing the proliferation of the external granular layer; and (2) the loss of cortical neuronal inputs, leading to underdevelopment of the contralateral cerebellum from the site of the cortical injury (a maturation-distinctive form of diaschisis).

Management of Germinal Matrix Hemorrhage/Intraventricular Hemorrhage

The treatment of GMH/IVH is primarily supportive. Management strategies include initiation of mechanical ventilation or increase in ventilatory support and/or administration of oxygen to maintain optimal levels of PaCO ₂ and PaO ₂ , treatment of hypotension with slow volume expansion and cautious use of pressors if unresponsive to volume expansion, blood transfusion to correct anemia from blood loss, correction of metabolic acidosis, anticonvulsant therapy for seizures, and administration of fresh frozen plasma, platelets, and other products if there is associated coagulopathy. Progression or evolution of GMH/IVH is monitored by serial CUSs, especially when needed for decision making and parental counseling in the face of rapid clinical deterioration.

During early posthemorrhagic hydrocephalus, interventions such as diuretics and intraventricular fibrinolytic therapy have been trialed; however, both were shown to have no benefit in small, randomized trials. The infants must be monitored with frequent CUSs, which will provide data on the alterations in the ventricular size. If there is increasing ventriculomegaly and raised intracranial pressure, the management is then directed at drainage of the CSF fluid to reduce the ventricular size, either by serial lumbar puncture or surgical intervention with the creation of a ventricular reservoir, or drainage of CSF by ventriculostomy. The optimum timing of intervention is unclear; however, retrospective data suggests that earlier intervention with serial therapeutic lumbar punctures may avoid the need for surgical intervention and improve neurodevelopmental outcome. Ventriculoperitoneal shunt is the definitive surgical treatment when there is continued progression of ventriculomegaly accompanied by increase in intracranial pressure. Shunt obstruction, malfunction, and infection can complicate shunt placement and long-term function. Endoscopic third ventriculostomy with choroid plexus cauterization may avoid the necessity for a shunt among those requiring surgical intervention; however, although the data has been encouraging for its use to treat hydrocephalus because of alternate etiologies, to date, it has been less successful for the management of PHH in preterm infants, and ventriculoperitoneal shunt remains the gold standard.

Prognosis and Long-Term Outcomes

In severe GMH/IVH, sudden deterioration may be observed with no response to any attempt at escalation of support. Mortality in severe GMH/IVH, especially with associated periventricular hemorrhagic infarction, is 40%. Among those who survive for weeks after detection of hemorrhage and with complicating progressive and persistent ventricular dilation, death occurs in 18%. In ELBW infants, after excluding deaths because of extreme immaturity, 7% to 9% of the deaths are attributed to hemorrhage.

Some 40% of ELBW infants who survive following a grade III or IV GMH/IVH have moderate–severe neurosensory impairments. This includes cerebral palsy, which occurs in 30% of survivors, severe neurodevelopmental impairment (developmental quotients two standard deviations below the mean) in 15% to 20%, bilateral deafness in 8%, and blindness in 2%. Among infants with lower grades of IVH (grade I and II), there is reported to be a twofold increase in the risk for neurodevelopmental impairment and a 2.6-fold increase in the risk of cerebral palsy compared with those children of similar birth weight but normal CUS. An alternate large cohort study of infants less than 29 weeks’ gestation reported that 20% of those with grade I or II IVH had moderate to severe neurosensory impairment, with 10% having cerebral palsy and 8% having a severe neurodevelopmental impairment (developmental quotients two standard deviations below the mean).

Prevention

Several studies have addressed prevention from the antenatal through the postnatal period. Antenatal prevention is directed toward prevention of preterm birth through use of tocolytics, the treatment of maternal complications (bleeding, chorioamnionitis, conditions that may predispose to preterm delivery), intrapartum fetal surveillance, and preference for epidural anesthesia, controlled vaginal delivery, and administration of antenatal steroids. Antenatal steroids in particular have been repeatedly shown to significantly reduce the incidence of severe IVH, with data from the Neonatal Research Network finding the odds ratio for a severe IVH following a complete course of antenatal steroids was 0.39 (95% confidence interval [CI]: 0.27–0.57).

Postnatal preventive strategies include supportive measures such as resuscitative measures as indicated at delivery with a goal of preventing hyperoxia, maintenance of optimal oxygenation and acid-base balance, gentle ventilation to prevent pneumothoraces and other air-leak syndromes, minimizing abrupt hemodynamic alterations, including slow volume expansion for low blood pressure and judicious use of inotropic agents (noting the risks associated with sudden changes in systemic pressures in the presence of a pressure passive cerebral circulation), and careful surfactant administration to improve respiratory status and oxygenation. Studies of pharmacologic agents such as pancuronium, ethamsylate, vitamin E, and phenobarbital do not demonstrate clear benefit. Indomethacin, a prostaglandin H synthase inhibitor, inhibits generation of oxygen-free radicals, promotes maturation of the germinal matrix, stabilizes cerebral blood flow, and attenuates the hyperemic response to hypoxia and hypercapnia. Indomethacin has been shown to reduce the incidence of severe IVH, but despite this, its use has not been associated with an improvement in neurodevelopmental outcome. Additionally, administration of indomethacin has been associated with increased risk of renal insufficiency, ileal perforation, and chronic lung disease.

Editorial Comment:

As quality improvement projects have been implemented in neonatal intensive care units (NICUs) across the globe, some have created care bundles aimed at reducing intraventricular hemorrhage (IVH). At Swedish Medical Center in Seattle, a meticulous care bundle was created including education of NICU staff, improving antenatal corticosteroid and magnesium for neuroprotection, delayed cord clamping and preventing delivery room hypothermia, and a protocol to maintain midline head positioning in the neonate from birth to 72 hours. Additionally, there was minimal handling and stimulation, no daily weights, and slow infusion of boluses in the first 72 hours. Despite improved compliance in most bundle components, IVH rates did not decrease and, in fact, increased, showing the difficulty in decreasing a condition with such a complex and multifactorial etiology.

(Nervik T, Moore L, Ryan A, et al. Reducing Intraventricular Hemorrhage Using a Care Bundle website. https://media.vtoxford.org/meetings/AMQC/Handouts2015/LearningFair/swedish_reducingintraventricularhemorrhage.pdf . Accessed August 28, 2018.)

Periventricular Leukomalacia

Periventricular leukomalacia (PVL) is a form of white matter injury that is commonly associated with GMH/IVH. It occurs in the periventricular arterial border zones. Although the exact mechanism of injury is not fully defined, it is thought to occur secondary to ischemia and/or inflammation, with associated glial activation and damage of the preoligodendrocytes.

PVL may be either focal or diffuse. The classic description of focal PVL consists of macroscopic areas of necrosis. These initially appear as echodense lesions in the periventricular area with or without blood in the ventricles. After several weeks, these echodense areas can become cystic, and are referred to as cystic PVL (see Fig. 17.4 ). Cystic PVL occurs in less than 5% of VLBW infants and represents the minority of PVL. More commonly, focal PVL consists of microscopic areas of necrosis and is termed noncystic PVL . Diffuse PVL is characterized by a loss of preoligodendrocytes rather than areas of necrosis. It leads to hypomyelination, and is associated with ventriculomegaly because of decreased cerebral tissue volume. CUS has limited use in identifying noncystic and diffuse PVL, with MRI being a superior neuroimaging modality to screen for these types of injury. MRI findings among these infants include abnormalities on diffusion-weighted imaging (DWI) and diffuse signal abnormalities.

Neonatal Encephalopathy and Brain Injury in the Term Infant

Neonatal encephalopathy occurs in 2 to 5 per 1000 live births and is principally related to hypoxic-ischemic injury to the newborn brain in the peripartum period. In the last decade, there have been significant advances in neuroprotection that have been successful in reducing the risk of death and disability in infants who have suffered from a potential hypoxic-ischemic cerebral injury. The advent of therapeutic hypothermia has led to a major focus on the early clinical recognition of infants who may benefit from such therapies.

It is important to recognize that not all neonatal encephalopathies are related to hypoxic-ischemic disease. Antepartum and postpartum disorders (e.g., infectious, metabolic, dysgenetic) may lead to neonatal encephalopathies, as discussed later in this chapter. In one large population-based observational study, the prevalence of moderate to severe encephalopathy was 1.64 per 1000 live term births, and the prevalence of “birth asphyxia” was 0.86 per 1000 live term births. Fully 56% of all cases of newborn encephalopathy were related to hypoxic-ischemic injury that occurred during the intrapartum period. These findings are consistent with a more recent large cohort study of 4,165 singleton term infants with any one of the following: seizures, stupor, coma, Apgar score at 5 minutes less than 3, and/or receiving hypothermia therapy. In this study, 15% of the infants experienced a clinically recognized sentinel event, such as antenatal hemorrhage (presumably, often placental abruption), uterine rupture, or cord prolapse, all of which are capable of compromising oxygen supply. Almost one-half of the infants displayed umbilical cord blood gas acidemia and/or fetal bradycardia. Of note, signs of inflammation were also not uncommon, with 27% of mothers displaying elevated maternal temperature in labor and 11% clinical chorioamnionitis. However, the contributing role of chorioamnionitis varies in different studies. Although intrapartum sentinel events provide clear evidence of a hypoxic-ischemic insult, in three studies of neonatal encephalopathy sentinel, intrapartum events were only identified in 8% to 25% of infants.

In a referral sample of 500 term infants with neonatal encephalopathy evaluated for therapeutic hypothermia, 48 (9%) had a sentinel birth event. Thus it can be challenging to confirm a hypoxic-ischemic etiology for the infant with neonatal encephalopathy and/or the need for resuscitation because only 10% to 20% of such infants may have a clinical history of a major risk factor, whereas approximately 50% or more may have a constellation of risk factors, including maternal history, cord acidemia, and need for resuscitation that supports this as an etiology for their neurological syndrome.

Additionally, although obvious, hypoxic-ischemic injury may affect the infant’s brain during the antepartum and postnatal periods, albeit less commonly than the intrapartum period. On the basis of earlier work, approximately 20% of hypoxic-ischemic injury recognized in the newborn period was said to be related primarily to antepartum insults. These data should be interpreted with the awareness that assessment of timing of insults to the fetus in these reports generally were based on imprecise methods, and the variability of findings is considerable.

Antepartum factors also appear to be of some importance in the risk for neonatal encephalopathy related to peripartum events. Such factors may predispose to intrapartum hypoxia-ischemia during the stresses of labor and delivery, especially through threats to placental flow. Maternal and fetal factors ( Table 17.4 ) may include maternal diabetes, preeclampsia, placental vasculopathy, intrauterine growth restriction, and twin gestation that may compromise fetal cerebral perfusion. In one series, such factors were present in approximately one-third of cases of intrapartum asphyxia. Indeed, “perinatal asphyxia” was identified in 27% of infants of diabetic mothers, and its occurrence correlated closely with diabetic vasculopathy (nephropathy) and presumed placental vascular insufficiency. In a more recent cohort of infants that received therapeutic hypothermia ( n = 98), the frequency of pregestational diabetes and preeclampsia were significantly higher (three- to fivefold) in women with infants requiring cooling.

Although the importance of intrauterine hypoxic-ischemic injury, especially intrapartum asphyxia with or without antepartum predisposing factors, in the genesis of the clinical syndrome of neonatal hypoxic-ischemic encephalopathy (HIE) is apparent, most infants who experience intrapartum hypoxic-ischemic insults do not exhibit overt neonatal neurological features or subsequent neurological evidence of brain injury. The severity and duration of the hypoxic-ischemic insult is obviously critical. Studies have demonstrated a relationship between the severity and duration of intrapartum hypoxia, assessed by the use of fetal acid-base studies, the subsequent occurrence of a neonatal neurological syndrome, and later neurological deficits. Current data suggest that approximately 10% of all term deliveries require some resuscitation, with 1% requiring extensive resuscitation. Of the latter, only 1 to 3 per 1000 will develop signs of evolving encephalopathy consistent with HIE.

Earlier in this chapter, we reviewed the neurological examination of the newborn. However, the evaluation of an infant who required resuscitation following delivery and may meet criteria for the administration of therapeutic hypothermia poses a special challenge to the neonatologist and neonatal neurologist. To improve interobserver reliability, standardized scores have been developed and have proven useful in large-scale clinical research studies (see later) ( Table 17.5 ).

The initial neurological examination classification systems developed evaluated infants over the first week of life to define the severity of their encephalopathy for prognostication. The first of these scorings systems was that developed by Sarnat and based on serial examinations of 21 term born infants over the first few weeks of life. This scoring system was then simplified and referred to as the Modified Sarnat Scoring System.

The next scoring system developed for prognostication in neonatal encephalopathy was the Thompson Encephalopathy Score, developed in 1997 ( Table 17.5 ). This scoring system was simpler to apply and did not require electroencephalograph (EEG) to increase its widespread applicability. The initial evaluation showed a good correlation between the maximal score in the first 7 days of life and neurodevelopmental outcome at 18 months in 44 infants with neonatal HIE. Note that both the Sarnat and Thompson scoring systems aimed to define neonatal neurological signs during the first week of life to improve the prediction of subsequent neurological deficits. However, as the era of neuroprotection emerged, it became apparent that a standardized neonatal neurological examination tool to be applied in the first few hours of life would be necessary to define eligibility for randomized controlled trials, such as therapeutic hypothermia. For some of the latter trials, the modified Sarnat and Thompson scales were utilized. For the largest North American study, a new scoring system was developed, that is, the National Institute of Child Health and Human Development (NICHD) Neonatal Encephalopathy Scoring System ( Table 17.5 ). The aim of this scoring system was to identify infants with moderate–severe encephalopathy who were eligible for entry into the trial within the first 6 hours of life. There was recognition that the examination could evolve and usually worsen consistent with secondary energy failure over the 24 hours of life.

To further refine the NICHD scoring system by the addition of a mild encephalopathy grouping, the HIE Score of the Iberoamerican Society of Neonatology was developed in 2016 and involved the assessment of 10 clinical aspects that could be undertaken from immediately after delivery room resuscitation ( Table 17.5 ). The recognition of mild encephalopathy is of great relevance, as it is recognized that at least 40% of hypoxic-ischemic cerebral injury presents as mild disease. It remains the only current published scoring system to include the evaluation of all three grades of neonatal encephalopathy in the first 6 hours of life. It is important to note that there has been no systematic investigation for the utility in application of any of the scoring systems in relationship to their inter- and intraobserver reliability and/or their validity to the evaluation of all infants requiring resuscitation who may benefit from therapeutic hypothermia.

Neurological Investigations in Term Neonatal Encephalopathy

The EEG changes in HIE may provide valuable information concerning the severity of the injury. Most commonly, the initial alteration is voltage suppression and a decrease in the frequency (i.e., slowing) into the delta and low theta ranges. Within approximately 1 day and often less, an excessively discontinuous pattern appears, characterized by periods of greater voltage suppression interspersed with bursts, usually asynchronous, of sharp and slow waves. Some infants exhibit multifocal or focal sharp waves or spikes at this time, often with a degree of periodicity. Over the next day or so, the excessively discontinuous pattern may become very prominent, with more severe voltage suppression and fewer bursts, now characterized by spikes and slow waves. This burst-suppression pattern can be of ominous significance, particularly if it persists after 24 hours of life. Continuous monitoring of conventional EEG with portable equipment has been found to be particularly useful in the identification of seizure activity.

Amplitude-integrated EEG (aEEG), an increasingly common method for continuous monitoring of electrical activity in the newborn, has been of considerable value in the assessment of the encephalopathic term newborn. The most useful tracings for detection of severe encephalopathy have been continuous low-voltage, flat, and burst-suppression tracings. Positive predictive values for an unfavorable outcome with such tracings in the first hours of life are 80% to 90%. Of infants with these marked background abnormalities, 10% to 50% may normalize within 24 hours. Rapid recovery is associated with a favorable outcome in 60% of cases. However, with the evolution of hypothermia therapy, the predictive value of early aEEG has changed, and infants have been shown to have a normal neurological outcome if the aEEG background voltage activity recovers by 48 hours. In a recent meta-analysis of 520 infants treated with therapeutic hypothermia for moderate or severe HIE, the authors found that (1) a persistent severely abnormal aEEG background at 48 hours of age or beyond predicted an adverse outcome (positive predictive value of 85% and diagnostic odds ratio of 67 at 48 hours); and (2) at 6 hours of age, the aEEG background in hypothermia-treated infants had a good sensitivity of 96% (95% CI: 89%–97%) but low specificity at 39% (95% CI: 32%–45%).