Clinical features, diagnosis, and treatment of neonatal encephalopathy

Author Yvonne Wu, MD, MPH Section Editors Douglas R Nordli, Jr, MD Leonard E Weisman, MD Deputy Editor John F Dashe, MD, PhD Disclosures Last literature review version 19.2: May 2011 | This topic last updated: April 20, 2011 INTRODUCTION AND DEFINITION Neonatal encephalopathy is a heterogeneous syndrome characterized by symptoms of central nervous system dysfunction in newborns born at term or late preterm (36 weeks gestation). An infant with neonatal encephalopathy may exhibit abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, and feeding difficulties [1,2]. Researchers have yet to adopt a consensus definition of neonatal encephalopathy. Some investigators require stringent criteria, such as two or more symptoms of encephalopathy lasting over 24 hours [2], while others require no more than a low 5 minute Apgar score [3]. Neonatal encephalopathy can result from a wide variety of conditions and often remains unexplained. Birth asphyxia and hypoxic-ischemic (anoxic) encephalopathy are responsible for some, but not all cases of neonatal encephalopathy. Given that the underlying nature of brain injury causing neurologic impairment in a newborn is often poorly understood, "neonatal encephalopathy" has emerged as the preferred terminology to describe central nervous system dysfunction in the newborn period, as it does not imply a specific underlying pathophysiology [4,5]. The incidence of neonatal encephalopathy depends on how the syndrome is defined, but varies between two to nine per 1000 term births [5-7]. As the term neonatal encephalopathy has become increasingly favored, it has been shown in one US population that the diagnosis of "birth asphyxia" has declined over the past decade [5]. This section will review the current state of knowledge regarding the diagnosis, prognosis and treatment of neonatal encephalopathy. The pathogenesis of neonatal encephalopathy is discussed elsewhere. (See "Etiology and pathogenesis of neonatal encephalopathy".) CLINICAL MANIFESTATIONS AND NEONATAL ASSESSMENT The neonate who is encephalopathic may have an abnormal state of consciousness (eg, hyperalert, irritable, lethargic, obtunded), respiratory or feeding difficulties, poor tone or seizure activity. In the delivery room, the infant will often exhibit low Apgar scores and a weak or absent cry. The diagnosis of neonatal encephalopathy necessitates a search for potential etiologies. A gross and histologic examination of the placenta and cord may provide evidence of a possible cause, such as a placental vascular lesion or infection, or a cord thrombosis [8]. A thorough maternal and family history is recommended, including a history of

thromboembolic disorders, prior pregnancy loss, maternal infection, and maternal drug use. Samples are drawn to determine arterial cord pH and base deficit. The presence of oliguria, cardiomyopathy, or abnormal liver function tests may suggest a global hypoxic-ischemic event. Metabolic derangements, unusual odors, dysmorphic features, and congenital anomalies may suggest the presence of an inborn error of metabolism or genetic disorder. Neuroimaging Neuroimaging has become increasingly important in the evaluation of neonatal encephalopathy, and may provide information regarding the type and timing of brain injury [9,10]. For instance, several patterns of brain injury seen in term and late preterm infants are considered to be typical of hypoxic-ischemic brain injury. These include parasagittal injury in the arterial watershed distribution and injury to the deep gray nuclei (lateral thalami, posterior putamina) [4,11-14] which correspond to brain damage seen in animal models of acute total asphyxia [15]. Alternatively, a head imaging study may reveal a developmental brain malformation, focal arterial infarction, or intraparenchymal hemorrhage, indicating a different underlying pathogenesis. In one study, 30 percent of infants with neonatal encephalopathy demonstrated a completely normal head MRI during the newborn period, indicating a good prognosis [13]. The findings on head CT and MRI may also provide insight into the time during which the injury occurred [16,17]. In a study of 351 term infants with neonatal encephalopathy, MRI scans performed in the first one to two weeks of birth suggested that the majority of infants sustained brain injury that occurred acutely in the perinatal period [16]. (See "Etiology and pathogenesis of neonatal encephalopathy".) Various modalities have been used to evaluate infant brains with neonatal encephalopathy, including cranial sonography (CS), computed tomography (CT) and magnetic resonance imaging (MRI) with MR spectroscopy. Head MR imaging techniques yield the most useful information, though the resources necessary for transporting, monitoring, and supporting sick babies during this procedure are not always readily available. (See "Approach to neuroimaging in children".) Cranial sonography Cranial sonography has the advantage of being noninvasive and available at the infant's bedside. Cranial sonography has a high sensitivity and specificity (91 and 81 percent, respectively) for locating hemorrhages and defining ventricular size [18]. It may also detect severe parasagittal white matter damage and obvious cystic lesions, but it does not adequately image the outer limits of the cerebral cortex [19], nor is cranial sonography a sensitive tool for identifying milder white matter abnormalities that can be appreciated on head MRI [20] Cranial sonography can be used to detect severe cerebral edema. Findings include increased echogenicity that causes sulci and fissures to be obscured, blurring of other anatomical landmarks, decreased arterial pulsations, and compression of the ventricles [21,22]. After a few days, areas of echodensity that correspond to regions of necrosis may be present [21,22]. However, determining if early echodensities are areas of infarction or hemorrhage in the term brain is not always possible [23]. Head CT Head CT is the most useful imaging modality for diagnosing intracranial hemorrhage and brain calcifications. Cerebral edema, denoted by decreased attenuation of white matter and difficulty distinguishing gray from white matter, may also be appreciated

on head CT, along with cerebral atrophy, ventricular size, and severe white matter lesions [24-27]. However, the white matter in a term newborn brain contains high water content, and therefore milder degrees of edema and white matter injury can be difficult to appreciate on head CT. Abnormalities of the posterior fossa are also often obscured by bony artifact. Head MRI A number of studies have described the increasing role that MR imaging plays in the diagnosis of neonatal encephalopathy [9,10,13,28-30]. A head MRI is the most sensitive imaging tool for detecting periventricular white matter injury, deep gray matter lesions, arterial infarction, hemorrhage, developmental brain malformations, and other underlying causes of neonatal encephalopathy. Deep gray matter lesions involving the bilateral basal ganglia and thalami are particularly common findings on brain MRI in encephalopathic term infants with a recognized preceding sentinel hypoxic-ischemic event such as placental abruption, uterine rupture, and cord prolapse [14]. The American Academy of Neurology (AAN) practice parameter suggests that a head CT be performed in cases of neonatal encephalopathy to rule out hemorrhagic lesions [9]. However, a head MRI is recommended in order to establish a pattern of injury and to predict neurologic outcome if the findings on head CT are inconclusive. (See 'Prognosis' below.) In addition to conventional MRI, MR spectroscopy and diffusion-weighted imaging (DWI) techniques can provide useful information regarding timing and outcome of brain injury resulting in neonatal encephalopathy [10,28,30,31]. Electroencephalography An electroencephalogram (EEG) can help to distinguish neonatal seizures from other phenomena, and can also identify subclinical seizures. Although the EEG is not helpful for determining the cause of neonatal encephalopathy, it can provide evidence for the presence and severity of encephalopathy, as well as provide prognostic information. (See 'Prognosis' below.) Amplitude integrated EEG, a continuous single channel recording of background cerebral electrical activity, is easy to use and interpret at the bedside, and has been used to distinguish mild from severe neonatal encephalopathy in large clinical trials [32]. Diagnosis of neonatal asphyxia Hypoxic-ischemic encephalopathy (HIE, also called birth asphyxia) is a subset of neonatal encephalopathy. It is unclear how often birth asphyxia is responsible for neonatal encephalopathy, as there is no gold standard for determining the presence of hypoxic-ischemic encephalopathy. It is well known that the various clinical signs of birth asphyxia, including Apgar scores, low cord pH, neonatal seizures and encephalopathy, are nonspecific and may occur in the absence of global hypoxic-ischemic brain injury or long-term neurologic sequelae. In a population-based study of neonatal encephalopathy, only 4 percent of cases had evidence of intrapartum hypoxia in the absence of antepartum risk factors, and 25 percent had both antepartum risk factors and intrapartum signs and symptoms of hypoxia [2]. (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Risk factors'.) ACOG criteria Although its true incidence is unclear, birth asphyxia is a well-known and important contributor to neonatal encephalopathy. In order to identify cases of perinatal brain injury due to birth asphyxia, the American College of Obstetricians and Gynecologists (ACOG) developed a consensus statement regarding the criteria needed to define an intrapartum hypoxic-ischemic insult that is severe enough to cause a neonatal

encephalopathy that subsequently leads to cerebral palsy [17]. The following four criteria are required: Profound metabolic acidosis (pH less than 7.00 and base deficit 12 mmol/L) on an umbilical cord arterial blood sample Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks of gestation Cerebral palsy of the spastic quadriplegic or dyskinetic type Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions, or genetic disorders

Additional criteria suggesting an intrapartum timing, but nonspecific to asphyxia, include a sentinel hypoxic event during labor, severe electronic fetal monitoring abnormalities, Apgar score of 0 to 3 beyond five minutes, onset of multisystem involvement within 72 hours of birth, and early imaging study showing evidence of acute nonfocal cerebral abnormality. Limitations of ACOG criteria It has been suggested that these guidelines are somewhat arbitrary (eg, the cut-off for cord pH), and that it may be too simplistic to think that a single set of nonspecific signs and symptoms can provide robust criteria for distinguishing underlying causal pathways. As an example, the presence of an infectious condition such as chorioamnionitis would preclude an intrapartum asphyxial event as being responsible for neonatal encephalopathy and subsequent cerebral palsy, according to the ACOG guidelines. Yet a maternal infection may play a role in causing hypoxic-ischemic brain injury in the fetus, and there is no reason to think that both cannot occur in the same infant [33]. Of note, the etiology of cerebral palsy is multifactorial. Most cases are thought to result from prenatal factors such as prematurity, intrauterine growth restriction, intrauterine infection, antepartum hemorrhage, severe placental pathology, and multiple pregnancies. Perinatal hypoxia and/or ischemia likely account for only a small minority of cases of cerebral palsy. This issue is discussed in detail separately. (See "Epidemiology and etiology of cerebral palsy".) Until a more specific diagnostic test for hypoxic-ischemic brain injury is widely available, the attribution of neonatal encephalopathy and cerebral palsy to birth asphyxia rests on clinical criteria as listed above. It remains to be established whether neuroimaging or other testing can one day be used as a gold standard for determining when birth asphyxia and hypoxicischemic brain injury is responsible for neonatal encephalopathy. PROGNOSIS The likelihood and extent of brain damage is related to the degree of neonatal encephalopathy. Most infants with mild to moderate degrees of encephalopathy develop normally, while infants with severe encephalopathy are more likely to develop longterm neurologic morbidity [7,34-38]. Severe MRI abnormalities are usually associated with marked EEG abnormalities and poor outcome. Permanent neurologic sequelae can be mild, such as learning difficulties or attention deficit disorder, or may be severe and disabling, including cerebral palsy, epilepsy, visual impairment and severe cognitive and developmental disorders. Clinical predictors Although definitions vary, the degree of neonatal encephalopathy has been categorized by some as follows [39]:

Mild: hyperalert, hyperexcitable, normal muscle tone, no seizures Moderate: hypotonia, decreased movements, and often seizures Severe: stuporous, flaccid, and absent primitive reflexes, usually with seizures

Term infants with mild neonatal encephalopathy in the neonatal period have a high probability of being normal at follow-up [7,34]. Infants with moderate encephalopathy have a 20 to 35 percent risk of later sequelae from the insult, although those whose neurologic examinations are completely normal within one week have a good likelihood of normal outcome [36]. Infants with severe encephalopathy have a 75 percent risk of dying in the neonatal period, and among survivors, an almost universal risk of sequelae exists [34,36,40,41]. Scoring systems have been devised to help predict an infant's subsequent risk for developing cerebral palsy or systemic morbidity [39,42,43]. One of the largest studies retrospectively evaluated 365 infants with HIE and found that three clinical parameters administration of chest compression for >1 minute, onset of regular respirations >30 minutes after birth, and base deficit value of >16 mmol/L on any blood gas analysis within the first four hours from birth were predictors of severe adverse outcome (death or severe disability) [43]. Severe outcome rates with none, one, two, or all three predictors were 46, 64, 76, and 93 percent, respectively. Seizures may be an independent predictor of poor outcome, as suggested by a study that evaluated 77 term newborns at risk for hypoxic ischemic encephalopathy who survived to age four [44]. After adjusting for severity of brain injury on MRI in the newborn period, infants with clinical seizures had worse motor and cognitive outcomes at age four than those without seizures. Neuroimaging predictors Neuroimaging findings can be helpful for predicting longterm outcome following neonatal encephalopathy [10,13,29]. Abnormal signal in the posterior limb of the internal capsule appreciated on a head MRI obtained in the first two weeks of life has been shown to predict adverse neurologic outcome [45]. In term infants with neonatal encephalopathy, lesions affecting bilateral basal ganglia and thalami that are detected by MRI in the first weeks of life have been associated with poor neurologic outcomes and death [13,14]. Diffusion-weighted MRI can detect the presence of acute brain injury in a neonate, and thus distinguish which infants with neonatal encephalopathy have suffered a significant brain injury that is associated with adverse outcome [12,46]. Magnetic resonance spectroscopy can detect increased lactate and decreased N-acetyl aspartate indicating derangements of the metabolic state of specific regions of the brain, which has also been shown to portend a worse prognosis [28,47-49]. In cases of perinatal arterial stroke, the presence of internal capsule and basal ganglia injury has been correlated with increased risk of hemiparesis and long-term neurologic sequelae, especially when seen in conjunction with cortical injury [50-52]. EEG predictors Findings on electroencephalogram (EEG) can also be used to help prognosticate. An EEG that shows severe background abnormalities including burst suppression, isoelectricity or extremely low voltage portends a high likelihood of death or significant long-term neurologic sequelae [53,54]. Since severe MRI abnormalities are

usually associated with marked EEG abnormalities and poor outcome, the EEG may be especially helpful as a prognostic tool in the setting of moderate MRI abnormalities [55]. Although severe abnormalities seen on EEG within the first 24 hours of life can be a useful predictor of outcome [56,57], a follow-up EEG showing recovery of normal electrical activity may be associated with a much improved outcome [57,58], indicating the importance of serial EEG examinations. In most [59-63], but not all [64] studies, amplitude-integrated EEG was useful for predicting outcome following neonatal encephalopathy. TREATMENT The management of moderate and severe neonatal encephalopathy should take place in a neonatal intensive care unit. Major goals include the maintenance of physiologic homeostasis and treatment of the outward manifestations of brain injury [65,66]. Central aspects of supportive care include the following (see 'Supportive management' below): Maintenance of adequate ventilation (avoidance of hypoxemia or hyperoxia) Maintenance of sufficient brain and organ perfusion (avoidance of systemic hypotension or hypertension; avoidance of hyperviscosity) Maintenance of normal metabolic status (eg, normoglycemia, nutritional status, pH) Control of seizures Control of brain edema (avoidance of fluid overload)

Therapeutic hypothermia Available evidence suggests that treatment with hypothermia improves outcome after neonatal asphyxia and/or neonatal encephalopathy. This conclusion is supported by a 2007 meta-analysis that evaluated randomized trials of therapeutic hypothermia to treat neonatal encephalopathy [67]. The following observations were noted: In four trials involving 479 infants that provided data on infancy or childhood outcomes, therapeutic hypothermia compared with usual care was associated with a significant reduction in the combined primary end-point of death or moderate to severe neurodevelopmental disability (relative risk [RR] 0.76, 95% CI 0.65-0.88; number needed to treat [NNT] 6, 95% CI 4-14). Therapeutic hypothermia was also associated with a significant reduction in the rates of severe neurodevelopmental disability and severe cerebral palsy [67]. In eight trials involving 650 infants that provided data on safety, therapeutic hypothermia was associated with a reduction in mortality (RR 0.74, 95% CI 0.580.94; NNT 11; 95% CI 7-50) and with an increased rate of clinically benign cardiac arrhythmias and thrombocytopenia [67].

A separate 2007 systematic review and meta-analysis of randomized trials assessing therapeutic hypothermia for term neonates with hypoxic ischemic encephalopathy also confirmed the effectiveness and safety of this therapy, with findings similar to those outlined above [68]. The two largest randomized controlled trials included in these metaanalyses were the CoolCap trial [32] and the NICHD Neonatal Research Network trial [69].

The CoolCap study of 234 infants with neonatal encephalopathy found that selective head cooling for 72 hours, started within the first six hours of life, did not result in a significant reduction in the rate of death or severe disability at 18 months of age compared with usual care [32]. However, a prespecified subgroup analysis found that head cooling was associated with improved outcome among infants with moderate, but not severe, EEG abnormalities. The NICHD trial enrolled 239 infants with moderate to severe encephalopathy who had either severe acidosis or perinatal complications and a need for resuscitation at birth [69]. Whole body cooling treatment initiated within six hours of birth and continued for 72 hours reduced the risk of death or disability at follow up (mean 20 months) compared with usual care (relative risk [RR] 0.72, 95% CI 0.54-0.95). Cooling was well tolerated and was not associated with any increase in death or serious adverse events. In addition, there was no increase in major disability among survivors; the rate of cerebral palsy was nonsignificantly reduced in the treatment group compared with the control group (19 versus 30 percent).

Of note, secondary analyses of control infants in the NICHD and CoolCap trials found a significant association between elevated temperature and adverse outcome [70,71]. These observational data do not establish causality, and additional studies are needed to determine whether reducing temperatures to normothermic levels will improve neurologic outcomes in infants who do not receive therapeutic hypothermia. Four later trials and a meta-analysis also provide support for the benefit of therapeutic hypothermia: The randomized controlled TOBY trial of 325 near-term infants with hypoxic-ischemic encephalopathy found that whole body cooling started within six hours of birth and continued for 72 hours did not significantly reduce the primary composite outcome of death or severe disability at 18 months (RR 0.86, 95% CI 0.68-1.07) [72]. However, a statistically significant benefit for whole body cooling was observed in five of 12 secondary outcome measures, including rate of survival without a neurologic abnormality (44 versus 28 percent, RR 1.57, 95% CI 1.16-2.12) and risk of cerebral palsy among survivors (28 versus 41 percent, RR 0.67, 95% CI 0.470.96). A 2010 meta-analysis that included data from the TOBY trial (as well as the CoolCap and NICHD trials) found that therapeutic hypothermia led to a significant reduction in the combined rate of death and severe disability at 18 months (risk ratio 0.81, 95% CI 0.71-0.93) [73]. The trials that follow were published after the 2010 meta-analysis: In the neo.nEURO.network trial that evaluated 111 infants with hypoxic ischemic encephalopathy, systemic hypothermia lead to a significant decrease in the combined outcome of death or severe disability at 18 to 21 months compared with normothermia (51 versus 83 percent, odds ratio [OR] 0.21, 95% CI 0.09-0.54, number needed to treat = 4) [74]. In subgroup analysis, hypothermia had a statistically significant benefit for the severe HIE group but not for the moderate HIE group, possibly because of the smaller sample size in the moderate HIE group.

A randomized trial from China, with data available for 194 neonates with hypoxic ischemic encephalopathy, showed that selective head cooling resulted in a significant decrease in the combined outcome of death and severe disability at 18 months compared with control (31 versus 49 percent, OR 0.47, 95% CI 0.26-0.84) [75]. In the ICE trial of 221 infants with moderate or severe hypoxic-ischemic encephalopathy, whole body hypothermia for 72 hours, started within six hours of birth, and continued for 72 hours, led to a significantly reduced risk of death or major disability at two years of age compared with standard treatment (51 versus 66 percent, RR 0.77, 95% CI 0.62-0.98) [76]. Unlike earlier trials evaluating hypothermia, the ICE trial used an early passive cooling protocol in non-tertiary care centers, followed by active cooling upon transfer to a tertiary center. Cooling was started at birth hospitals by simply turning off the radiant warmer and allowing the infant to be uncovered and exposed to ambient room temperature. When necessary, a refrigerated gel pack was applied to help in reaching target temperature, which was achieved in a median of two hours.

Conclusions Hypothermia is the only effective neuroprotective therapy currently available for treatment of neonatal encephalopathy, and is safe and easy to administer. There is an emerging consensus among experts that therapeutic hypothermia should be more widely available, based upon the mounting evidence of the benefit and safety of hypothermia, and the lack of other effective treatments [67,68,77,78]. Thus, an increasing number of neonatal intensive care units in the US, Europe, and Australia are providing therapeutic hypothermia as standard of care. Although direct comparisons are lacking, selective head cooling and whole body cooling appear to have similar safety and effectiveness. Whole body cooling is preferred in most centers in the United States due to ease of administration. Whole body cooling also provides easier access to the scalp for EEG monitoring. Despite the promising clinical trial results, therapeutic hypothermia has limited efficacy, as illustrated by the CoolCap, NICHD, TOBY, neo.nEURO.network, and ICE trials, in which as many as half of all infants who were treated with hypothermia either died or had moderate to severe disability at 18 months [32,69,72,74,76]. In addition, data regarding long-term safety and efficacy of therapeutic hypothermia beyond 18 to 24 months are not yet available, and the utility of this therapy has not been studied for premature infants or infants with severe intrauterine growth restriction [79-81]. Therefore, additional neuroprotective therapies are urgently needed for neonatal encephalopathy. Given the data from controlled trials and meta-analyses showing benefit for therapeutic hypothermia, our recommendations are as follows: For term or late preterm infants with neonatal encephalopathy, we suggest the use of therapeutic head cooling or whole body cooling as early therapy (in the first six hours of life) in experienced centers. Implementation of therapeutic hypothermia should follow published protocols employed in one of the published trials [32,69,72,74-76]. (See 'Therapeutic hypothermia' above.) When therapeutic hypothermia is not used, we suggest close monitoring of core body temperature. Although it is unknown whether lowering body temperature to

normothermic levels alters outcome in this setting, it is reasonable to avoid hyperthermia given currently available data. (See 'Therapeutic hypothermia' above.) Supportive management Aside from treatment with hypothermia, suggested management of HIE includes the following recommendations: Evaluate with an electroencephalogram (EEG) to gather information regarding diagnosis, treatment and prognosis of neonatal encephalopathy. Serial EEGs may be helpful in further defining the prognosis. The amplitude integrated EEG may be helpful for predicting outcome and identifying seizure activity in infants with neonatal encephalopathy. (See 'EEG predictors' above.) Obtain a head imaging study, preferably with MRI. Cranial sonography is not as sensitive as head MRI or CT. Specific findings on head MRI can be useful for establishing the pathogenesis and prognosis of neonatal encephalopathy. (See 'Neuroimaging' above.) Treat seizures with phenobarbital, lorazepam or fosphenytoin. The optimal therapeutic agent, as well as the duration of treatment, has not been adequately evaluated. This topic is discussed in detail separately. (See "Treatment of neonatal seizures".) Perform a lumbar puncture to assess for intracranial bleeding or infection, especially since meningitis can mimic the signs and symptoms of neonatal encephalopathy. Antibiotics are started until infection is ruled out, and acyclovir is initiated if herpes simplex virus is suspected. (See "Lumbar puncture: Indications, contraindications, technique, and complications in children".) Use high frequency ventilation, nitric oxide, or extracorporeal membrane oxygenation therapies, as available, for infants with persistent fetal circulation syndrome to maintain oxygenation. Replace volume and use inotropic agents as required to maintain blood pressure and adequate cerebral perfusion. However, systemic hypertension and volume overload, which can worsen cerebral edema, should be avoided. Arterial blood gases and serum calcium, magnesium, glucose, and electrolytes should be assessed early in the course and as needed. Liver enzymes and serum creatinine are measured to determine injury to other end organs. Early treatment may be crucial to outcome if a metabolic disorder is suspected. Feeds should be stopped, acidosis and hypoglycemia corrected, and specific treatment such as vitamin supplementation or hemodialysis considered after consultation with a geneticist. Specific testing for ammonia, lactate and pyruvate, serum amino acids and urine organic acids are also required to rule out a metabolic cause of neonatal encephalopathy.

Future prospects A variety of potential neuroprotective treatments are being studied both to prevent the cascade of injurious effects after hypoxia-ischemia. As an example, erythropoietin has neuroprotective properties in animal models of hypoxic-ischemic brain injury and neonatal stroke [82-85]. A preliminary randomized trial of 167 neonates with HIE found that treatment with recombinant human erythropoietin for two weeks, starting within 48 hours of birth, was associated with improved neurologic outcome at 18 months [86]. Confirmation of benefit in larger trials is needed.

Additional strategies that may be useful as adjuncts to hypothermia include the following [4,87-89]: Prevention of the build-up of superoxide radicals and other mediators of oxygen free radical-induced injury Reduction of glutamate receptor activation Prevention of intracellular calcium accumulation Administration of growth factors (monosialo-gangliosides, brain derived growth factor), nitric oxide synthase inhibitors, and blockers of apoptosis Reduction of secondary inflammatory reactions

SUMMARY AND RECOMMENDATIONS Neonatal encephalopathy is a heterogeneous syndrome characterized by symptoms of central nervous system dysfunction in newborns born at term or late preterm (36 weeks gestation). Neonatal encephalopathy can result from a wide variety of conditions and often remains unexplained. Birth asphyxia and hypoxic-ischemic (anoxic) encephalopathy are responsible for some, but not all cases of neonatal encephalopathy. (See 'Introduction and definition' above.) The neonate who is encephalopathic may have an abnormal state of consciousness (eg, hyperalert, irritable, lethargic, obtunded), respiratory or feeding difficulties, poor tone, or seizure activity. Neuroimaging is important in the evaluation of neonatal encephalopathy, and may provide information regarding the type and timing of brain injury. (See 'Clinical manifestations and neonatal assessment' above.) It is unclear how often birth asphyxia is responsible for neonatal encephalopathy, as there is no gold standard for determining the presence of hypoxic-ischemic encephalopathy. The various clinical signs of birth asphyxia, including Apgar scores, low cord pH, neonatal seizures and encephalopathy, are nonspecific. To define an intrapartum hypoxic-ischemic insult that is severe enough to cause a neonatal encephalopathy that subsequently leads to cerebral palsy, the following four consensus criteria have been proposed (see 'Diagnosis of neonatal asphyxia' above): Profound metabolic acidosis (pH less than 7.00 and base deficit 12 mmol/L) on an umbilical cord arterial blood sample Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks of gestation Cerebral palsy of the spastic quadriplegic or dyskinetic type Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious conditions, or genetic disorders Most infants with mild to moderate degrees of encephalopathy develop normally, while infants with severe encephalopathy are more likely to develop long-term neurologic morbidity. Severe MRI abnormalities are usually associated with marked EEG abnormalities and poor outcome. Permanent neurologic sequelae can be mild, such as learning difficulties or attention deficit disorder, or may be severe and disabling, including cerebral palsy, epilepsy, visual impairment, and severe cognitive and developmental disorders. (See 'Prognosis' above.)

The management of moderate and severe neonatal encephalopathy should take place in a neonatal intensive care unit. Central aspects of supportive care include the following (see 'Treatment' above and 'Supportive management' above): Maintenance of adequate ventilation (avoidance of hypoxemia or hyperoxia) Maintenance of sufficient brain and organ perfusion (avoidance of systemic hypotension or hypertension; avoidance of hyperviscosity) Maintenance of normal metabolic status (eg, normoglycemia, nutritional status, pH) Control of seizures Control of brain edema (avoidance of fluid overload) For term or late preterm infants with neonatal encephalopathy, we suggest the use of therapeutic head cooling or whole body cooling as early therapy (in the first six hours of life) in experienced centers (Grade 2A). When therapeutic hypothermia is not used, we suggest close monitoring of core body temperature and measures to avoid hyperthermia (Grade 2C). (See 'Therapeutic hypothermia' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

1. Nelson KB, Leviton A. How much of neonatal encephalopathy is due to birth asphyxia? Am J Dis Child 1991; 145:1325. 2. Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998; 317:1549. 3. Bartha AI, Foster-Barber A, Miller SP, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res 2004; 56:960. 4. Ferriero DM. Neonatal brain injury. N Engl J Med 2004; 351:1985. 5. Wu YW, Backstrand KH, Zhao S, et al. Declining diagnosis of birth asphyxia in California: 1991-2000. Pediatrics 2004; 114:1584. 6. Graham EM, Ruis KA, Hartman AL, et al. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol 2008; 199:587. 7. Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Paediatr 1995; 84:927. 8. Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 2005; 192:452. 9. Ment LR, Bada HS, Barnes P, et al. Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002; 58:1726. 10. Chau V, Poskitt KJ, Miller SP. Advanced neuroimaging techniques for the term newborn with encephalopathy. Pediatr Neurol 2009; 40:181. 11. Barkovich AJ. MR and CT evaluation of profound neonatal and infantile asphyxia. AJNR Am J Neuroradiol 1992; 13:959. 12. Roland EH, Poskitt K, Rodriguez E, et al. Perinatal hypoxic-ischemic thalamic injury: clinical features and neuroimaging. Ann Neurol 1998; 44:161. 13. Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005; 146:453. 14. Okereafor A, Allsop J, Counsell SJ, et al. Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics 2008; 121:906.

15. Myers RE. Two patterns of perinatal brain damage and their conditions of occurrence. Am J Obstet Gynecol 1972; 112:246. 16. Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet 2003; 361:736. 17. Hankins GD, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol 2003; 102:628. 18. Hope PL, Gould SJ, Howard S, et al. Precision of ultrasound diagnosis of pathologically verified lesions in the brains of very preterm infants. Dev Med Child Neurol 1988; 30:457. 19. Shankaran S, Kottamasu SR, Kuhns L. Brain sonography, computed tomography, and single-photon emission computed tomography in term neonates with perinatal asphyxia. Clin Perinatol 1993; 20:379. 20. Miller SP, Cozzio CC, Goldstein RB, et al. Comparing the diagnosis of white matter injury in premature newborns with serial MR imaging and transfontanel ultrasonography findings. AJNR Am J Neuroradiol 2003; 24:1661. 21. Martin DJ, Hill A, Fitz CR, et al. Hypoxic/ischaemic cerebral injury in the neonatal brain. A report of sonographic features with computed tomographic correlation. Pediatr Radiol 1983; 13:307. 22. Siegel MJ, Shackelford GD, Perlman JM, Fulling KH. Hypoxic-ischemic encephalopathy in term infants: diagnosis and prognosis evaluated by ultrasound. Radiology 1984; 152:395. 23. Hill A. Current concepts of hypoxic-ischemic cerebral injury in the term newborn. Pediatr Neurol 1991; 7:317. 24. Adsett DB, Fitz CR, Hill A. Hypoxic-ischaemic cerebral injury in the term newborn: correlation of CT findings with neurological outcome. Dev Med Child Neurol 1985; 27:155. 25. Fitzhardinge PM, Flodmark O, Fitz CR, Ashby S. The prognostic value of computed tomography as an adjunct to assessment of the term infant with postasphyxial encephalopathy. J Pediatr 1981; 99:777. 26. Graziani LJ, Pasto M, Stanley C, et al. Neonatal neurosonographic correlates of cerebral palsy in preterm infants. Pediatrics 1986; 78:88. 27. Lupton BA, Hill A, Roland EH, et al. Brain swelling in the asphyxiated term newborn: pathogenesis and outcome. Pediatrics 1988; 82:139. 28. Miller SP, Newton N, Ferriero DM, et al. Predictors of 30-month outcome after perinatal depression: role of proton MRS and socioeconomic factors. Pediatr Res 2002; 52:71. 29. Barnett A, Mercuri E, Rutherford M, et al. Neurological and perceptual-motor outcome at 5 6 years of age in children with neonatal encephalopathy: relationship with neonatal brain MRI. Neuropediatrics 2002; 33:242. 30. Heinz ER, Provenzale JM. Imaging findings in neonatal hypoxia: a practical review. AJR Am J Roentgenol 2009; 192:41. 31. Bydder GM, Rutherford MA. Diffusion-weighted imaging of the brain in neonates and infants. Magn Reson Imaging Clin N Am 2001; 9:83. 32. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365:663. 33. Wu YW, Escobar GJ, Grether JK, et al. Chorioamnionitis and cerebral palsy in term and nearterm infants. JAMA 2003; 290:2677. 34. Robertson C, Finer N. Term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years. Dev Med Child Neurol 1985; 27:473. 35. Robertson CM, Finer NN, Grace MG. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 1989; 114:753. 36. Finer NN, Robertson CM, Richards RT, et al. Hypoxic-ischemic encephalopathy in term neonates: perinatal factors and outcome. J Pediatr 1981; 98:112. 37. Levene ML, Kornberg J, Williams TH. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Hum Dev 1985; 11:21.

38. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr 2007; 166:645. 39. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33:696. 40. Shankaran S, Woldt E, Koepke T, et al. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991; 25:135. 41. Lacey JL, Henderson-Smart DJ. Assessment of preterm infants in the intensive-care unit to predict cerebral palsy and motor outcome at 6 years. Dev Med Child Neurol 1998; 40:310. 42. Thompson CM, Puterman AS, Linley LL, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr 1997; 86:757. 43. Shah PS, Beyene J, To T, et al. Postasphyxial hypoxic-ischemic encephalopathy in neonates: outcome prediction rule within 4 hours of birth. Arch Pediatr Adolesc Med 2006; 160:729. 44. Glass HC, Glidden D, Jeremy RJ, et al. Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury. J Pediatr 2009; 155:318. 45. Rutherford MA, Pennock JM, Counsell SJ, et al. Abnormal magnetic resonance signal in the internal capsule predicts poor neurodevelopmental outcome in infants with hypoxic-ischemic encephalopathy. Pediatrics 1998; 102:323. 46. Robertson RL, Ben-Sira L, Barnes PD, et al. MR line-scan diffusion-weighted imaging of term neonates with perinatal brain ischemia. AJNR Am J Neuroradiol 1999; 20:1658. 47. Amess PN, Penrice J, Wylezinska M, et al. Early brain proton magnetic resonance spectroscopy and neonatal neurology related to neurodevelopmental outcome at 1 year in term infants after presumed hypoxic-ischaemic brain injury. Dev Med Child Neurol 1999; 41:436. 48. Hanrahan JD, Cox IJ, Azzopardi D, et al. Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age. Dev Med Child Neurol 1999; 41:76. 49. Boichot C, Walker PM, Durand C, et al. Term neonate prognoses after perinatal asphyxia: contributions of MR imaging, MR spectroscopy, relaxation times, and apparent diffusion coefficients. Radiology 2006; 239:839. 50. Boardman JP, Ganesan V, Rutherford MA, et al. Magnetic resonance image correlates of hemiparesis after neonatal and childhood middle cerebral artery stroke. Pediatrics 2005; 115:321. 51. Mercuri E, Rutherford M, Cowan F, et al. Early prognostic indicators of outcome in infants with neonatal cerebral infarction: a clinical, electroencephalogram, and magnetic resonance imaging study. Pediatrics 1999; 103:39. 52. Lee J, Croen LA, Lindan C, et al. Predictors of outcome in perinatal arterial stroke: a population-based study. Ann Neurol 2005; 58:303. 53. Takeuchi T, Watanabe K. The EEG evolution and neurological prognosis of neonates with perinatal hypoxia [corrected]. Brain Dev 1989; 11:115. 54. Holmes GL, Lombroso CT. Prognostic value of background patterns in the neonatal EEG. J Clin Neurophysiol 1993; 10:323. 55. Biagioni E, Mercuri E, Rutherford M, et al. Combined use of electroencephalogram and magnetic resonance imaging in full-term neonates with acute encephalopathy. Pediatrics 2001; 107:461. 56. Pezzani C, Radvanyi-Bouvet MF, Relier JP, Monod N. Neonatal electroencephalography during the first twenty-four hours of life in full-term newborn infants. Neuropediatrics 1986; 17:11. 57. Pressler RM, Boylan GB, Morton M, et al. Early serial EEG in hypoxic ischaemic encephalopathy. Clin Neurophysiol 2001; 112:31.

58. van Rooij LG, Toet MC, Osredkar D, et al. Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed 2005; 90:F245. 59. al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D. Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics 1999; 103:1263. 60. Shalak LF, Laptook AR, Velaphi SC, Perlman JM. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics 2003; 111:351. 61. Shah DK, Lavery S, Doyle LW, et al. Use of 2-channel bedside electroencephalogram monitoring in term-born encephalopathic infants related to cerebral injury defined by magnetic resonance imaging. Pediatrics 2006; 118:47. 62. Shany E, Goldstein E, Khvatskin S, et al. Predictive value of amplitude-integrated electroencephalography pattern and voltage in asphyxiated term infants. Pediatr Neurol 2006; 35:335. 63. Spitzmiller RE, Phillips T, Meinzen-Derr J, Hoath SB. Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol 2007; 22:1069. 64. Sarkar S, Barks JD, Donn SM. Should amplitude-integrated electroencephalography be used to identify infants suitable for hypothermic neuroprotection? J Perinatol 2008; 28:117. 65. Volpe JJ. Hypoxic-ischemic encephalopathy: clinical aspects. In: Neurology of the Newborn, 5th, Volpe JJ (Ed), Saunders, Philadelphia 2008. p.400. 66. Yager JY, Armstrong EA, Black AM. Treatment of the term newborn with brain injury: simplicity as the mother of invention. Pediatr Neurol 2009; 40:237. 67. Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med 2007; 161:951. 68. Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet? BMC Pediatr 2007; 7:30. 69. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1574. 70. Wyatt JS, Gluckman PD, Liu PY, et al. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics 2007; 119:912. 71. Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics 2008; 122:491. 72. Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361:1349. 73. Edwards AD, Brocklehurst P, Gunn AJ, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340:c363. 74. Simbruner G, Mittal RA, Rohlmann F, et al. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics 2010; 126:e771. 75. Zhou WH, Cheng GQ, Shao XM, et al. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr 2010; 157:367. 76. Jacobs SE, Morley CJ, Inder TE, et al. Whole-Body Hypothermia for Term and Near-Term Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial. Arch Pediatr Adolesc Med 2011. 77. Perlman M, Shah P. Time to adopt cooling for neonatal hypoxic-ischemic encephalopathy: response to a previous commentary. Pediatrics 2008; 121:616. 78. Azzopardi D, Strohm B, Edwards AD, et al. Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial. Arch Dis Child Fetal Neonatal Ed 2009; 94:F260.

79. Papile LA. Systemic hypothermia--a "cool" therapy for neonatal hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353:1619. 80. Higgins RD, Raju TN, Perlman J, et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr 2006; 148:170. 81. Blackmon LR, Stark AR, American Academy of Pediatrics Committee on Fetus and Newborn. Hypothermia: a neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy. Pediatrics 2006; 117:942. 82. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000; 97:10526. 83. Chang YS, Mu D, Wendland M, et al. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res 2005; 58:106. 84. McPherson RJ, Demers EJ, Juul SE. Safety of high-dose recombinant erythropoietin in a neonatal rat model. Neonatology 2007; 91:36. 85. McPherson RJ, Juul SE. Erythropoietin for infants with hypoxic-ischemic encephalopathy. Curr Opin Pediatr 2010; 22:139. 86. Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics 2009; 124:e218. 87. Vannucci RC. Perinatal hypoxic-ischemic encephalopathy. Neurologist 1995; 1:35. 88. Tan WK, Williams CE, Gunn AJ, et al. Pretreatment with monosialoganglioside GM1 protects the brain of fetal sheep against hypoxic-ischemic injury without causing systemic compromise. Pediatr Res 1993; 34:18. 89. Han BH, D'Costa A, Back SA, et al. BDNF blocks caspase-3 activation in neonatal hypoxiaischemia. Neurobiol Dis 2000; 7:38.