Official reprint from UpToDate®

www.uptodate.com ©2011 UpToDate®

AuthorYvonne Wu, MD, MPH

Section EditorsDouglas R Nordli, Jr, MDLeonard E Weisman, MD

Deputy EditorJohn F Dashe, MD, PhD

Clinical features, diagnosis, and treatment of neonatalencephalopathy

Disclosures

Last literature review version 19.2: mayo 2011 | This topic last updated: abril 20,2011

INTRODUCTION AND DEFINITION — Neonatal encephalopathy is a heterogeneous syndromecharacterized by symptoms of central nervous system dysfunction in newborns born at term orlate preterm (≥36 weeks gestation). An infant with neonatal encephalopathy may exhibitabnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, and feedingdifficulties [1,2].

Researchers have yet to adopt a consensus definition of neonatal encephalopathy. Someinvestigators require stringent criteria, such as two or more symptoms of encephalopathy lastingover 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 remainsunexplained. Birth asphyxia and hypoxic-ischemic (anoxic) encephalopathy are responsible forsome, but not all cases of neonatal encephalopathy. Given that the underlying nature of braininjury causing neurologic impairment in a newborn is often poorly understood, "neonatalencephalopathy" has emerged as the preferred terminology to describe central nervous systemdysfunction 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 variesbetween two to nine per 1000 term births [5-7]. As the term neonatal encephalopathy hasbecome increasingly favored, it has been shown in one US population that the diagnosis of "birthasphyxia" has declined over the past decade [5].

This section will review the current state of knowledge regarding the diagnosis, prognosis andtreatment of neonatal encephalopathy. The pathogenesis of neonatal encephalopathy isdiscussed elsewhere. (See "Etiology and pathogenesis of neonatal encephalopathy".)

CLINICAL MANIFESTATIONS AND NEONATAL ASSESSMENT — The neonate who isencephalopathic may have an abnormal state of consciousness (eg, hyperalert, irritable,lethargic, obtunded), respiratory or feeding difficulties, poor tone or seizure activity. In thedelivery 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 grossand 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 maternaland family history is recommended, including a history of thromboembolic disorders, priorpregnancy loss, maternal infection, and maternal drug use. Samples are drawn to determinearterial cord pH and base deficit. The presence of oliguria, cardiomyopathy, or abnormal liverfunction tests may suggest a global hypoxic-ischemic event. Metabolic derangements, unusualodors, dysmorphic features, and congenital anomalies may suggest the presence of an inbornerror of metabolism or genetic disorder.

Neuroimaging — Neuroimaging has become increasingly important in the evaluation ofneonatal encephalopathy, and may provide information regarding the type and timing of braininjury [9,10]. For instance, several patterns of brain injury seen in term and late preterminfants are considered to be typical of hypoxic-ischemic brain injury. These include parasagittalinjury 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 ofacute total asphyxia [15].

Alternatively, a head imaging study may reveal a developmental brain malformation, focalarterial infarction, or intraparenchymal hemorrhage, indicating a different underlyingpathogenesis. In one study, 30 percent of infants with neonatal encephalopathy demonstrated acompletely 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 injuryoccurred [16,17]. In a study of 351 term infants with neonatal encephalopathy, MRI scansperformed in the first one to two weeks of birth suggested that the majority of infants sustainedbrain injury that occurred acutely in the perinatal period [16]. (See "Etiology and pathogenesisof 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 duringthis procedure are not always readily available. (See "Approach to neuroimaging in children".)

Cranial sonography — Cranial sonography has the advantage of being noninvasive andavailable at the infant's bedside. Cranial sonography has a high sensitivity and specificity (91and 81 percent, respectively) for locating hemorrhages and defining ventricular size [18]. Itmay also detect severe parasagittal white matter damage and obvious cystic lesions, but it doesnot adequately image the outer limits of the cerebral cortex [19], nor is cranial sonography asensitive tool for identifying milder white matter abnormalities that can be appreciated on headMRI [20]

Cranial sonography can be used to detect severe cerebral edema. Findings include increasedechogenicity that causes sulci and fissures to be obscured, blurring of other anatomicallandmarks, decreased arterial pulsations, and compression of the ventricles [21,22]. After a fewdays, 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 termbrain is not always possible [23].

Head CT — Head CT is the most useful imaging modality for diagnosing intracranialhemorrhage and brain calcifications. Cerebral edema, denoted by decreased attenuation of whitematter 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 milderdegrees 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 playsin the diagnosis of neonatal encephalopathy [9,10,13,28-30]. A head MRI is the most sensitiveimaging tool for detecting periventricular white matter injury, deep gray matter lesions, arterialinfarction, hemorrhage, developmental brain malformations, and other underlying causes ofneonatal encephalopathy. Deep gray matter lesions involving the bilateral basal ganglia andthalami are particularly common findings on brain MRI in encephalopathic term infants with arecognized preceding sentinel hypoxic-ischemic event such as placental abruption, uterinerupture, and cord prolapse [14].

The American Academy of Neurology (AAN) practice parameter suggests that a head CT beperformed in cases of neonatal encephalopathy to rule out hemorrhagic lesions [9]. However, ahead MRI is recommended in order to establish a pattern of injury and to predict neurologicoutcome 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 injuryresulting in neonatal encephalopathy [10,28,30,31].

Electroencephalography — An electroencephalogram (EEG) can help to distinguish neonatalseizures from other phenomena, and can also identify subclinical seizures. Although the EEG isnot helpful for determining the cause of neonatal encephalopathy, it can provide evidence forthe presence and severity of encephalopathy, as well as provide prognostic information. (See'Prognosis' below.)

Amplitude integrated EEG, a continuous single channel recording of background cerebralelectrical activity, is easy to use and interpret at the bedside, and has been used to distinguishmild from severe neonatal encephalopathy in large clinical trials [32].

Diagnosis of neonatal asphyxia — Hypoxic-ischemic encephalopathy (HIE, also called birthasphyxia) is a subset of neonatal encephalopathy. It is unclear how often birth asphyxia isresponsible for neonatal encephalopathy, as there is no gold standard for determining thepresence of hypoxic-ischemic encephalopathy. It is well known that the various clinical signs ofbirth asphyxia, including Apgar scores, low cord pH, neonatal seizures and encephalopathy, arenonspecific and may occur in the absence of global hypoxic-ischemic brain injury or long-termneurologic sequelae. In a population-based study of neonatal encephalopathy, only 4 percent ofcases had evidence of intrapartum hypoxia in the absence of antepartum risk factors, and 25percent 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 andimportant contributor to neonatal encephalopathy. In order to identify cases of perinatal braininjury due to birth asphyxia, the American College of Obstetricians and Gynecologists (ACOG)developed a consensus statement regarding the criteria needed to define an intrapartumhypoxic-ischemic insult that is severe enough to cause a neonatal encephalopathy thatsubsequently 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 anumbilical cord arterial blood sample

Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or moreweeks of gestationCerebral palsy of the spastic quadriplegic or dyskinetic typeExclusion of other identifiable etiologies such as trauma, coagulation disorders, infectiousconditions, or genetic disorders

Additional criteria suggesting an intrapartum timing, but nonspecific to asphyxia, include asentinel hypoxic event during labor, severe electronic fetal monitoring abnormalities, Apgarscore 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 somewhatarbitrary (eg, the cut-off for cord pH), and that it may be too simplistic to think that a single setof nonspecific signs and symptoms can provide robust criteria for distinguishing underlyingcausal pathways. As an example, the presence of an infectious condition such aschorioamnionitis would preclude an intrapartum asphyxial event as being responsible forneonatal encephalopathy and subsequent cerebral palsy, according to the ACOG guidelines. Yet amaternal infection may play a role in causing hypoxic-ischemic brain injury in the fetus, andthere is no reason to think that both cannot occur in the same infant [33]. Of note, the etiologyof cerebral palsy is multifactorial. Most cases are thought to result from prenatal factors such asprematurity, intrauterine growth restriction, intrauterine infection, antepartum hemorrhage,severe placental pathology, and multiple pregnancies. Perinatal hypoxia and/or ischemia likelyaccount for only a small minority of cases of cerebral palsy. This issue is discussed in detailseparately. (See "Epidemiology and etiology of cerebral palsy".)

Until a more specific diagnostic test for hypoxic-ischemic brain injury is widely available, theattribution of neonatal encephalopathy and cerebral palsy to birth asphyxia rests on clinicalcriteria as listed above. It remains to be established whether neuroimaging or other testing canone day be used as a gold standard for determining when birth asphyxia and hypoxic-ischemicbrain injury is responsible for neonatal encephalopathy.

PROGNOSIS — The likelihood and extent of brain damage is related to the degree of neonatalencephalopathy. Most infants with mild to moderate degrees of encephalopathy developnormally, while infants with severe encephalopathy are more likely to develop long-termneurologic morbidity [7,34-38]. Severe MRI abnormalities are usually associated with markedEEG abnormalities and poor outcome.

Permanent neurologic sequelae can be mild, such as learning difficulties or attention deficitdisorder, or may be severe and disabling, including cerebral palsy, epilepsy, visual impairmentand severe cognitive and developmental disorders.

Clinical predictors — Although definitions vary, the degree of neonatal encephalopathy hasbeen categorized by some as follows [39]:

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

Term infants with mild neonatal encephalopathy in the neonatal period have a high probability ofbeing normal at follow-up [7,34]. Infants with moderate encephalopathy have a 20 to 35percent risk of later sequelae from the insult, although those whose neurologic examinations arecompletely 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 amongsurvivors, 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 developingcerebral palsy or systemic morbidity [39,42,43]. One of the largest studies retrospectivelyevaluated 365 infants with HIE and found that three clinical parameters — administration ofchest compression for >1 minute, onset of regular respirations >30 minutes after birth, andbase 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 outcomerates 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 thatevaluated 77 term newborns at risk for hypoxic ischemic encephalopathy who survived to agefour [44]. After adjusting for severity of brain injury on MRI in the newborn period, infants withclinical seizures had worse motor and cognitive outcomes at age four than those withoutseizures.

Neuroimaging predictors — Neuroimaging findings can be helpful for predicting long-termoutcome following neonatal encephalopathy [10,13,29]. Abnormal signal in the posterior limb ofthe internal capsule appreciated on a head MRI obtained in the first two weeks of life has beenshown to predict adverse neurologic outcome [45]. In term infants with neonatalencephalopathy, lesions affecting bilateral basal ganglia and thalami that are detected by MRI inthe 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 thusdistinguish which infants with neonatal encephalopathy have suffered a significant brain injurythat is associated with adverse outcome [12,46].

Magnetic resonance spectroscopy can detect increased lactate and decreased N-acetyl aspartateindicating derangements of the metabolic state of specific regions of the brain, which has alsobeen shown to portend a worse prognosis [28,47-49]. In cases of perinatal arterial stroke, thepresence of internal capsule and basal ganglia injury has been correlated with increased risk ofhemiparesis and long-term neurologic sequelae, especially when seen in conjunction withcortical injury [50-52].

EEG predictors — Findings on electroencephalogram (EEG) can also be used to helpprognosticate. 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 withmarked EEG abnormalities and poor outcome, the EEG may be especially helpful as a prognostictool in the setting of moderate MRI abnormalities [55].

Although severe abnormalities seen on EEG within the first 24 hours of life can be a usefulpredictor of outcome [56,57], a follow-up EEG showing recovery of normal electrical activity maybe associated with a much improved outcome [57,58], indicating the importance of serial EEGexaminations.

In most [59-63], but not all [64] studies, amplitude-integrated EEG was useful for predictingoutcome following neonatal encephalopathy.

TREATMENT — The management of moderate and severe neonatal encephalopathy should takeplace in a neonatal intensive care unit. Major goals include the maintenance of physiologichomeostasis 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 orhypertension; avoidance of hyperviscosity)Maintenance of normal metabolic status (eg, normoglycemia, nutritional status, pH)Control of seizuresControl of brain edema (avoidance of fluid overload)

Therapeutic hypothermia — Available evidence suggests that treatment with hypothermiaimproves outcome after neonatal asphyxia and/or neonatal encephalopathy. This conclusion issupported by a 2007 meta-analysis that evaluated randomized trials of therapeutic hypothermiato 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 significantreduction in the combined primary end-point of death or moderate to severeneurodevelopmental disability (relative risk [RR] 0.76, 95% CI 0.65-0.88; number neededto treat [NNT] 6, 95% CI 4-14). Therapeutic hypothermia was also associated with asignificant reduction in the rates of severe neurodevelopmental disability and severecerebral palsy [67].

In eight trials involving 650 infants that provided data on safety, therapeutic hypothermiawas associated with a reduction in mortality (RR 0.74, 95% CI 0.58-0.94; NNT 11; 95%CI 7-50) and with an increased rate of clinically benign cardiac arrhythmias andthrombocytopenia [67].

A separate 2007 systematic review and meta-analysis of randomized trials assessing therapeutichypothermia for term neonates with hypoxic ischemic encephalopathy also confirmed theeffectiveness and safety of this therapy, with findings similar to those outlined above [68]. Thetwo largest randomized controlled trials included in these meta-analyses 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 headcooling for 72 hours, started within the first six hours of life, did not result in a significantreduction in the rate of death or severe disability at 18 months of age compared with usualcare [32]. However, a prespecified subgroup analysis found that head cooling wasassociated with improved outcome among infants with moderate, but not severe, EEGabnormalities.

The NICHD trial enrolled 239 infants with moderate to severe encephalopathy who hadeither 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 hoursreduced the risk of death or disability at follow up (mean 20 months) compared with usualcare (relative risk [RR] 0.72, 95% CI 0.54-0.95). Cooling was well tolerated and was notassociated with any increase in death or serious adverse events. In addition, there was noincrease in major disability among survivors; the rate of cerebral palsy wasnonsignificantly reduced in the treatment group compared with the control group (19versus 30 percent).

Of note, secondary analyses of control infants in the NICHD and CoolCap trials found asignificant association between elevated temperature and adverse outcome [70,71]. Theseobservational data do not establish causality, and additional studies are needed to determinewhether reducing temperatures to normothermic levels will improve neurologic outcomes ininfants who do not receive therapeutic hypothermia.

Four later trials and a meta-analysis also provide support for the benefit of therapeutichypothermia:

The randomized controlled TOBY trial of 325 near-term infants with hypoxic-ischemicencephalopathy found that whole body cooling started within six hours of birth andcontinued for 72 hours did not significantly reduce the primary composite outcome ofdeath or severe disability at 18 months (RR 0.86, 95% CI 0.68-1.07) [72]. However, astatistically significant benefit for whole body cooling was observed in five of 12 secondaryoutcome measures, including rate of survival without a neurologic abnormality (44 versus28 percent, RR 1.57, 95% CI 1.16-2.12) and risk of cerebral palsy among survivors (28versus 41 percent, RR 0.67, 95% CI 0.47-0.96).

A 2010 meta-analysis that included data from the TOBY trial (as well as the CoolCap andNICHD trials) found that therapeutic hypothermia led to a significant reduction in thecombined 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 ischemicencephalopathy, systemic hypothermia lead to a significant decrease in the combinedoutcome of death or severe disability at 18 to 21 months compared with normothermia (51versus 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 thesevere HIE group but not for the moderate HIE group, possibly because of the smallersample size in the moderate HIE group.

A randomized trial from China, with data available for 194 neonates with hypoxic ischemicencephalopathy, showed that selective head cooling resulted in a significant decrease inthe 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 for72 hours, led to a significantly reduced risk of death or major disability at two years of agecompared 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 passivecooling protocol in non-tertiary care centers, followed by active cooling upon transfer to atertiary center. Cooling was started at birth hospitals by simply turning off the radiantwarmer and allowing the infant to be uncovered and exposed to ambient roomtemperature. When necessary, a refrigerated gel pack was applied to help in reachingtarget 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 anemerging consensus among experts that therapeutic hypothermia should be more widelyavailable, based upon the mounting evidence of the benefit and safety of hypothermia, and thelack of other effective treatments [67,68,77,78]. Thus, an increasing number of neonatalintensive care units in the US, Europe, and Australia are providing therapeutic hypothermia asstandard of care.

Although direct comparisons are lacking, selective head cooling and whole body cooling appearto have similar safety and effectiveness. Whole body cooling is preferred in most centers in theUnited States due to ease of administration. Whole body cooling also provides easier access tothe scalp for EEG monitoring.

Despite the promising clinical trial results, therapeutic hypothermia has limited efficacy, asillustrated by the CoolCap, NICHD, TOBY, neo.nEURO.network, and ICE trials, in which as manyas half of all infants who were treated with hypothermia either died or had moderate to severedisability at 18 months [32,69,72,74,76]. In addition, data regarding long-term safety andefficacy of therapeutic hypothermia beyond 18 to 24 months are not yet available, and theutility of this therapy has not been studied for premature infants or infants with severeintrauterine growth restriction [79-81]. Therefore, additional neuroprotective therapies areurgently needed for neonatal encephalopathy.

Given the data from controlled trials and meta-analyses showing benefit for therapeutichypothermia, our recommendations are as follows:

For term or late preterm infants with neonatal encephalopathy, we suggest the use oftherapeutic head cooling or whole body cooling as early therapy (in the first six hours oflife) in experienced centers. Implementation of therapeutic hypothermia should followpublished 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 bodytemperature. Although it is unknown whether lowering body temperature to normothermiclevels alters outcome in this setting, it is reasonable to avoid hyperthermia given currentlyavailable data. (See 'Therapeutic hypothermia' above.)

Supportive management — Aside from treatment with hypothermia, suggested managementof 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 furtherdefining the prognosis. The amplitude integrated EEG may be helpful for predictingoutcome 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 sensitiveas head MRI or CT. Specific findings on head MRI can be useful for establishing thepathogenesis and prognosis of neonatal encephalopathy. (See 'Neuroimaging' above.)

Treat seizures with phenobarbital, lorazepam or fosphenytoin. The optimal therapeuticagent, as well as the duration of treatment, has not been adequately evaluated. This topicis discussed in detail separately. (See "Treatment of neonatal seizures".)

Perform a lumbar puncture to assess for intracranial bleeding or infection, especially sincemeningitis can mimic the signs and symptoms of neonatal encephalopathy. Antibiotics arestarted until infection is ruled out, and acyclovir is initiated if herpes simplex virus issuspected. (See "Lumbar puncture: Indications, contraindications, technique, andcomplications in children".)

Use high frequency ventilation, nitric oxide, or extracorporeal membrane oxygenationtherapies, as available, for infants with persistent fetal circulation syndrome to maintainoxygenation.

Replace volume and use inotropic agents as required to maintain blood pressure andadequate cerebral perfusion. However, systemic hypertension and volume overload, whichcan worsen cerebral edema, should be avoided.

Arterial blood gases and serum calcium, magnesium, glucose, and electrolytes should beassessed early in the course and as needed. Liver enzymes and serum creatinine aremeasured to determine injury to other end organs.

Early treatment may be crucial to outcome if a metabolic disorder is suspected. Feedsshould be stopped, acidosis and hypoglycemia corrected, and specific treatment such asvitamin supplementation or hemodialysis considered after consultation with a geneticist.Specific testing for ammonia, lactate and pyruvate, serum amino acids and urine organicacids are also required to rule out a metabolic cause of neonatal encephalopathy.

Future prospects — A variety of potential neuroprotective treatments are being studied both toprevent the cascade of injurious effects after hypoxia-ischemia. As an example, erythropoietinhas neuroprotective properties in animal models of hypoxic-ischemic brain injury and neonatalstroke [82-85]. A preliminary randomized trial of 167 neonates with HIE found that treatmentwith recombinant human erythropoietin for two weeks, starting within 48 hours of birth, wasassociated with improved neurologic outcome at 18 months [86]. Confirmation of benefit inlarger 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 freeradical-induced injuryReduction of glutamate receptor activationPrevention of intracellular calcium accumulationAdministration of growth factors (monosialo-gangliosides, brain derived growth factor),nitric oxide synthase inhibitors, and blockers of apoptosisReduction of secondary inflammatory reactions

SUMMARY AND RECOMMENDATIONS

Neonatal encephalopathy is a heterogeneous syndrome characterized by symptoms ofcentral nervous system dysfunction in newborns born at term or late preterm (≥36 weeksgestation). Neonatal encephalopathy can result from a wide variety of conditions and oftenremains unexplained. Birth asphyxia and hypoxic-ischemic (anoxic) encephalopathy areresponsible for some, but not all cases of neonatal encephalopathy. (See 'Introduction anddefinition' above.)

The neonate who is encephalopathic may have an abnormal state of consciousness (eg,hyperalert, irritable, lethargic, obtunded), respiratory or feeding difficulties, poor tone, orseizure activity. Neuroimaging is important in the evaluation of neonatal encephalopathy,and may provide information regarding the type and timing of brain injury. (See 'Clinicalmanifestations and neonatal assessment' above.)

It is unclear how often birth asphyxia is responsible for neonatal encephalopathy, as thereis no gold standard for determining the presence of hypoxic-ischemic encephalopathy. Thevarious clinical signs of birth asphyxia, including Apgar scores, low cord pH, neonatalseizures and encephalopathy, are nonspecific. To define an intrapartum hypoxic-ischemicinsult that is severe enough to cause a neonatal encephalopathy that subsequently leadsto cerebral palsy, the following four consensus criteria have been proposed (see 'Diagnosisof neonatal asphyxia' above):

Profound metabolic acidosis (pH less than 7.00 and base deficit ≥12 mmol/L) on anumbilical cord arterial blood sample

Early onset of severe or moderate neonatal encephalopathy in infants born at 34 ormore 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, whileinfants with severe encephalopathy are more likely to develop long-term neurologicmorbidity. Severe MRI abnormalities are usually associated with marked EEG abnormalitiesand poor outcome. Permanent neurologic sequelae can be mild, such as learningdifficulties or attention deficit disorder, or may be severe and disabling, including cerebralpalsy, epilepsy, visual impairment, and severe cognitive and developmental disorders. (See'Prognosis' above.)

The management of moderate and severe neonatal encephalopathy should take place in aneonatal 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 systemichypotension 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 oftherapeutic head cooling or whole body cooling as early therapy (in the first six hours oflife) in experienced centers (Grade 2A). When therapeutic hypothermia is not used, wesuggest close monitoring of core body temperature and measures to avoid hyperthermia(Grade 2C). (See 'Therapeutic hypothermia' above.)

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