03Etiology and Pathogenesis of Neonatal Encephalopathy

4/17/14, 0:10Etiology and pathogenesis of neonatal encephalopathy

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Official reprint from UpToDate www.uptodate.com 2014 UpToDate

AuthorsSidhartha Tan, MDYvonne Wu, MD, MPH

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

Deputy EditorJohn F Dashe, MD, PhD

Etiology and pathogenesis of neonatal encephalopathy

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2014. | This topic last updated: Jan 15, 2014.

INTRODUCTION Neonatal encephalopathy is a heterogeneous syndrome characterized by signs of central nervoussystem dysfunction in newborn infants. Clinical suspicion of neonatal encephalopathy should be considered in any infantexhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, aspiration, feedingdifficulties [1,2], and an abnormal hearing screen.

This topic will review the etiology and pathogenesis of neonatal encephalopathy. Other clinical aspects of this syndromeare discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

TERMINOLOGY "Neonatal encephalopathy" has emerged as the preferred term to describe central nervous systemdysfunction in the newborn period [2,3]. The terminology does not imply a specific underlying pathophysiology, which isappropriate since the nature of brain injury causing neurologic impairment in a newborn is poorly understood. Whileneonatal encephalopathy was once automatically ascribed to hypoxia-ischemia [4], it is now known that hypoxia-ischemia is only one of many possible contributors to neonatal encephalopathy. Whether a particular newborn'sencephalopathy can be attributed to hypoxic-ischemic brain injury is often unclear.

Some investigators require stringent criteria for using the term neonatal encephalopathy, such as two or more symptomsof encephalopathy lasting over 24 hours [5], while others require no more than a low five minute Apgar score [6].However, the use of Apgar scores alone is problematic, as Apgar scores may be low due to maternal analgesia orprematurity, or can be normal in the presence of acute hypoxia-ischemic injury.

Neonatal encephalopathy usually refers to central nervous system dysfunction in term and near term infants, but for thepurposes of this review, encephalopathy of the preterm infant has also been included.

When neonatal encephalopathy is indisputably due to hypoxic-ischemic (anoxic) brain injury, it is appropriate to use theterm hypoxic-ischemic encephalopathy (HIE) [7]. Since the precise cause and temporal onset of neonatalencephalopathy is unknown in most cases, some experts advocate calling the condition presumed HIE or apparentHIE when the clinical features and neonatal brain injury patterns on MRI suggest that HIE is the most likely mechanism[8]. Others favor using the non-specific term neonatal encephalopathy whenever there is doubt as to the underlyingmechanism of injury [3]. It remains to be established whether neuroimaging or other testing can one day be used as agold standard for determining when prenatal hypoxia, birth asphyxia, or hypoxic-ischemic brain injury is responsible forneonatal encephalopathy. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

There is an increased risk of cerebral palsy associated with neonatal encephalopathy but it is not an inevitableconsequence. In most cases of cerebral palsy or later developmental deficits, the cause is unknown or is related toconditions other than prior neonatal encephalopathy. (See "Epidemiology and etiology of cerebral palsy".)



Timing of insult A common but crucial problem is the inability to time the onset, duration, magnitude, and the singleor repetitive nature of the exact insult that causes brain injury resulting in neonatal encephalopathy. This is an importantpoint to consider in view of neuroprotective therapies such as hypothermia. The uncertain timing and etiology of braininjury in most cases of neonatal encephalopathy also fuels birth injury malpractice litigation. Malpractice cases, and toooften clinicians, typically focus on events around the time of delivery, which happens to be the time (hours) when themajority of data from pregnant women are obtained, whereas the rest of pregnancy is relatively unmonitored [4].However, it is usually unknown whether the ultimate brain injury is caused by the events only around delivery or bycumulative insults throughout pregnancy.

The definition of asphyxia is "a condition of impaired blood gas exchange leading, if it persists, to progressivehypoxemia and hypercapnia. Diagnosis requires a blood gas [9]. However, even with state-of-art monitoring, there ispresently no reliable measure of brain function, brain oxygenation, or cerebral blood flow during the prenatal period oreven in the intrapartum period. Therefore, the terms "birth asphyxia" and "fetal distress" are not always usedappropriately [10].

Data from studies of neonatal encephalopathy using brain MRI, near-infrared spectroscopy and electroencephalogrammonitoring suggest that the immediate perinatal period is important for evolution of brain injury in many cases [11]. Onereport evaluated 351 term infants with either neonatal encephalopathy (defined as the presence of abnormal tone,feeding difficulties, altered alertness, and at least three of several criteria suggesting possible perinatal hypoxic-ischemia) or seizures alone during the first three days of life [12]. Brain MRI was performed in the first one to two weeksafter birth.

Clinical signs that point to an early antenatal onset of neonatal encephalopathy include intrauterine growth restriction,small head size (if both head and body size are small then the insult could be in the first two trimesters of pregnancy),contractures, and features suggestive of arthrogryposis. (See 'Risk factors' below.)

Criteria The American College of Obstetricians and Gynecologists (ACOG), in collaboration with the AmericanAcademy of Pediatrics, convened a task force on neonatal encephalopathy and cerebral palsy. According to ACOG taskforce, four essential criteria (table 1) are required to define an intrapartum asphyxial event sufficient to cause cerebralpalsy [13]. However, only one criterion metabolic acidosis on umbilical cord arterial blood at birth is helpful to theclinician in the immediate postnatal period. (See "Epidemiology and etiology of cerebral palsy", section on 'Perinatalasphyxia'.)

More importantly, for timing of the peripartum events that may be related to development of cerebral palsy, ACOGsuggests the following criteria (table 2) [10]:

There is a presumption that the absence of metabolic acidosis rules out hypoxia-ischemia [14] but this may notnecessarily be true for early antepartum episodes of hypoxia-ischemia.

In the group with encephalopathy, lesions suggestive of acute brain injury were found in 80 percent; most of thelesions were bilateral abnormalities in basal ganglia, thalami, cortex, or white matter, although focal infarction wasdetected in eight infants.

In the group with only neonatal seizures, acute ischemic or hemorrhagic strokes were found in 69 percent.

Presence of a signal event immediately before or during laborSudden onset of fetal bradycardia patternsApgar score of 0 to 3 after five minutesOnset of a multisystem disorder in the first 72 hoursEarly brain imaging showing acute nonfocal cerebral abnormality



RISK FACTORS Few studies have adequately evaluated risk factors for neonatal encephalopathy other thanhypoxia-ischemia. The studies evaluating prenatal and obstetric factors often include symptoms but not pathogenicevents that could provide information regarding the timing of the hypoxic-ischemic event. Epidemiologic populationstudies of neonatal encephalopathy typically lack brain MRI data to determine the presence and degree of brain injury,and also lack information regarding long-term outcomes. In contrast, studies of neonatal encephalopathy that do includeneuroimaging data are rarely population-based, and are underpowered to determine the effect of a broad range ofmaternal antenatal risk factors.

The disparate results of these reports are likely due to several reasons, including different inclusion/exclusion criteriaamong the studies and the assessment of variables that do not necessarily lead to critical brain injury (eg, shoulderdystocia, meconium aspiration, and abnormal fetal heart rate rhythms are ominous only if associated with fetal hypoxia,which is rare).

Antepartum Most cases of neonatal encephalopathy have their antecedents in the prenatal period. It is unknownwhether neonatal encephalopathy occurs as a result of a single insult (such as hypoxia-ischemia), multiple insults (eg,infection plus hypoxia-ischemia), or combinations of acute or chronic conditions. In cases with multiple insults, it ispossible that the one closest to birth might be only a minor event that tips the balance to irreversible injury.

The highest quality population-based study that evaluated risk factors for neonatal encephalopathy compared 164infants with neonatal encephalopathy and 400 randomly selected controls from term infants born in Western Australia

In a large population-based cohort of cases of neonatal encephalopathy from Western Australia, 69 percent hadonly antepartum risk factors, 25 percent had both antepartum and intrapartum risk factors, 4 percent had evidenceof only intrapartum hypoxia, and 2 percent had no identified risk factors [15]. Thus, approximately 70 percent ofneonatal encephalopathy cases were associated with events arising before the onset of labor [13].

Similarly, in a registry of over 4100 infants with neonatal encephalopathy, 46 percent had fetal risk factors and 27percent had maternal risk factors predating the onset of labor, while only 15 percent had a clinically recognizedsentinel event capable of causing asphyxia (35 percent if fetal bradycardia was included as an indicator) [16].

In a case-control study from the UK, 405 term infants with encephalopathy were compared with 239 neurologicallynormal infants [17]. Overall, 7 percent of cases had only antepartum factors, 20 percent had only intrapartumfactors, 70 percent had both antepartum and intrapartum factors, and 4 percent had no identifiable risk factors forthe development of neonatal encephalopathy. Limitations of this study include potential bias related to differencesin the populations (eg, compared with controls, cases were from different years of collection, had a greaterincidence of intrauterine growth restriction and twinning, and were more likely to have mothers who were younger,primipara, and of non-Caucasian origin), the exclusion of infection, the absence of placental data, the absence of adiagnosis of chorioamnionitis, and inclusion of some questionable intrapartum factors such as induced labor andvariable decelerations.

A case-control study from Italy compared 27 term infants with neonatal encephalopathy and 100 control infants,suggesting a combination of antepartum and intrapartum events explain moderate to severe neonatalencephalopathy [18]. Compared with controls, neonates with encephalopathy had more frequent antepartum (74percent versus 18 percent) and intrapartum (67 percent versus 19 percent) risk factors, including acute intrapartumevents (33 percent versus 2 percent). On the whole, 26 percent of cases of NE had only antepartum risk factors,22 percent had only intrapartum risk factors, and , and 44 percent had a combination of the two.

In a case-control study in Ireland that compared 237 term infants with neonatal encephalopathy with 489 controlinfants, variables independently associated with neonatal encephalopathy included meconium, oligohydramnios,and obstetric complications, suggesting involvement of a combination of antepartum and intrapartum risk factors[19].



[5]. The study identified a number of antepartum risk factors can be grouped under categories based on the maternal-placental-fetal unit (figure 1):

Among these antepartum risk factors, intrauterine growth restriction (IUGR) was the strongest (relative risk [RR] 38.2,95% CI 9.4-154.8) [5]. Although most babies with neonatal encephalopathy do not meet the criteria of IUGR, a smallhospital-based case-control study found that a greater proportion of infants with neonatal encephalopathy were belowthe 10th percentile of growth potential compared with controls, and the difference was statistically significant [20]. Thesestudies suggest that there are antenatal factors contributing to the brain injury. Unfortunately, IUGR provides no clue tothe etiology (figure 2) because both external maternal and placental factors can affect fetal growth in addition to intrinsicfactors.

Placental thrombosis, infection, and disturbed uteroplacental flow have also been associated with neonatalencephalopathy.

Most of the placental lesions result in some form of hypoxic-ischemic damage. It is suspected that both the placentalvasculopathies and inflammation can cause synergistic injury when combined with hypoxia-ischemia. Placental lesionsmay underlie the finding of some studies that >41 weeks gestation is an antepartum risk factor [17].

Intrapartum Intrapartum risk factors for neonatal encephalopathy can be grouped as follows [15-17]:

Maternal

Preconceptual factors including maternal unemployment, family history of seizures or neurologic disorder,and infertility treatment

Maternal thyroid disease

Placental

Severe preeclampsiaPost-datesAbnormal appearance of the placenta

Fetal

Intrauterine growth restriction

In a hospital-based case-control study comparing 93 cases of neonatal encephalopathy to 387 controls, placentalfindings of fetal thrombotic vasculopathy, funisitis, and accelerated villous maturation were independentlyassociated with neonatal encephalopathy [21].

Another study found that the frequency of severe placental lesions was fivefold higher among 83 cases of neonatalencephalopathy from a medicolegal registry than among 250 controls (52 to 10 percent). These lesions includedfetal thrombotic vasculopathy, chronic villitis with obliterative fetal vasculopathy, chorioamnionitis with severe fetalvasculitis, and meconium-associated fetal vascular necrosis [22].

In a retrospective study of 100 term newborns who received hypothermia therapy for neonatal encephalopathy,placental abnormalities were more common among newborns (n = 49) who did not have a sentinel event (ie, aclinical history of disruption of blood flow to the fetus during delivery) such as placental abruption, uterine rupture,tight nuchal cord or cord prolapse [23]. As an example, an inflammatory pathology was significantly more frequentin infants without sentinel events (43 percent, versus 14 percent for infants with sentinel events).

Persistent occipitoposterior positionShoulder dystocia



An acute intrapartum event, such as a placental abruption or uterine rupture, conferred a four-fold increased risk ofneonatal encephalopathy, but was present in only 8 percent of infants with neonatal encephalopathy [15]. Uterine rupturealone is associated with only a 2 to 3 percent incidence of neonatal death but a 6 to 23 percent neonatal encephalopathy[24,25]. In the series of 158 medicolegal cerebral palsy cases, sentinel intrapartum events were present in 11 percent[26].

Outcomes in another study of birth sentinel events with a minimum of 12 months follow-up included death in 20 percent,cerebral palsy in 41 percent, developmental delay in 15 percent, and normal development in 24 percent [27]. The lattertwo numbers suggest that plasticity and repair responses often determine outcome to well-defined single insults.

Some of the so-called intrapartum risk factors include obstetric treatments to prevent further fetal hypoxia, such asemergency cesarean delivery and operative vaginal delivery. These may or may not be true risk factors depending uponthe duration of the underlying insult. In addition, increased duration of second stage of labor related to shoulder dystociaor failed vacuum may not necessarily result in critical brain injury unless accompanied by fetal hypoxia.

Some inflammatory factors, such as prolonged rupture of membranes, may exert a pathogenic influence even beforeterminal labor. The importance of inflammation as a risk factor for neonatal encephalopathy is illustrated by the followingreports [28]:

Other studies have found that maternal fever, often accompanied by a diagnosis of chorioamnionitis, is associated withlow Apgar scores, neonatal seizures, and a diagnosis of "birth asphyxia" among infants who develop cerebral palsy[32,33].

An interaction between brain injury due to inflammation and hypoxia-ischemia has been suggested by the finding in acase-control study of an association between maternal chorioamnionitis and cerebral palsy in children with evidence ofhypoxic-ischemic brain injury [34], and by the observation of increased cytokines in the cerebrospinal fluid of patientswith neonatal encephalopathy [35].

The need for resuscitation in the delivery room is itself a poor prognostic sign as it is associated with an increased risk ateight years of age of having a lower (



more so in the legal perspective. Fetal heart rate variables are not considered as good as umbilical cord acidemia forestimation of timing of birth insults [18,37] although both have deficiencies. The correlation of fetal heart rateabnormalities with umbilical acidemia may have a stronger association with the presence of intrauterine vascular disease(ie, preeclampsia, placental abruption, birth weight



was significantly higher in monochorionic than in dichorionic infants (30 vs 3.3 percent) [40].

In preterm infants meeting criteria for HIE, placental abruption is more likely to be identified as the antecedent event [41]than uterine rupture and cord prolapse, which are more common sentinel events among term infants diagnosed with HIE[27]. In preterm infants, HIE is associated with injury on 36 week MRI scan involving the basal ganglia (mostly severe),white matter (mostly mild), brainstem, and cortex in 75, 89, 44 and 58 percent, respectively [41].

These studies emphasize the importance of early brain imaging in documenting, and possibly timing, brain lesions, aswell as the importance of postmortem examinations in cases of stillbirth and neonatal deaths. (See "Clinical features,diagnosis, and treatment of neonatal encephalopathy".)

Level and duration of hypoxia-ischemia The level of hypoxia-ischemia that causes neonatal encephalopathy isunknown, but animal studies provide some information. There are two experimental paradigms that present with differentpathophysiological pathways: umbilical cord occlusion and acute placental insufficiency.

The clinical corollary of umbilical cord prolapse has a more varied response, probably because of the presence of someblood flow in the prolapsed cord. In humans, umbilical cord prolapse is an obstetric emergency except for the extremepremature gestation mother. In a chart review of 87 cases of cord prolapse among 36,500 deliveries, the median timefrom discovery to delivery was 15 minutes, with the longest being 14 hours [46]. There was no relation between time ofdiscovery to delivery and postnatal mortality or morbidity [46]. The longest tolerated time of umbilical cord prolapsewithout major consequences three days was observed in an extremely premature infant [47], suggesting that theduration becomes critical only near term.

Unfortunately, the onset of acute placental insufficiency states such as placental abruption in humans is almost alwaysunknown.

The spectrum of hypoxic-ischemic injury and outcome can be summarized as in the Figure (figure 3). The intensity of theinsult can be modified by prior events that may serve as a preconditioning stimulus. Also, there is a complex interactionof infection with hypoxia-ischemia. As an example, preeclampsia may be a protective factor for infants born to motherswith chorioamnionitis and at risk for cerebral palsy [52].

Occlusion of the umbilical cord results in cardiovascular compromise because of the removal of a low resistivevascular bed

In sheep, fetuses can survive up to 30 minutes of occlusion with increasing brain damage observed in term sheepcompared to premature sheep fetuses [42], while 20 minute occlusion may not cause any brain injury [43]

In non-human primates, it was long believed that permanent neurologic injury occurred with occlusion of 12 to 17minutes [44,45]

Acute placental insufficiency results in fetal compromise due to impaired ability to exchange gas and nutrients.

A study of acute placental insufficiency (via uterine ischemia) in rabbits at 70 percent gestation found that animalssubjected to 30 minutes of global hypoxia-ischemia were no different than controls [48]. However, 40 minutes ofglobal hypoxia-ischemia increased fetal mortality from 0 to 25 percent, and increased marked motor deficits at birthin the survivors from 0 to 75 percent [48]. In a population of normal fetuses, the susceptibility to injury is notdependent solely on the duration of hypoxia-ischemia. Rabbit fetuses at 79 percent gestation undergoing additionalreperfusion-reoxygenation injury just after the cessation of hypoxia-ischemia have a greater chance of motordeficits that in those without reperfusion-reoxygenation injury [49].

When experimental global hypoxia-ischemia is mild and chronic, it results in intrauterine growth restriction but mayor may not result in brain injury [50,51].



Vulnerable regions of developing brain Hypoxia-ischemia may have deleterious effects on vulnerable cellpopulations peculiar to the developmental stage (figure 4), causing discrete injuries that could also affect seizurethreshold or cognition.

Both gray and white matter injury occur in preterm and term neonates with HIE. Early detection of recent hypoxic-ischemic insults depends upon apparent diffusion coefficient (ADC) measurements on MRI. Beyond a week after theonset of the insult, evidence of gray matter injury by neuroimaging is scant unless there is a significant decrease involume of gray matter regions or an increase in ventricular size or obvious infarcts and hemorrhage. White matter injuryis somewhat easier to detect by diffusion tensor imaging (DTI), as the fractional anisotropy of white matter bundlesnormally increase with age, leading to an ability to detect minor decreases in fractional anisotropy in WM regions.However, while DTI is performed at some tertiary centers, it is not yet widely available in clinical practice.

Mechanisms of neuronal injury Hypoxia-ischemia initially causes energy failure and loss of mitochondrial function.This is accompanied by membrane depolarization, brain edema, an increase of neurotransmitter release and inhibition ofuptake, and an increase of intracellular calcium that sets off additional pathologic cascades [54]. These include oxidativestress, with the production of reactive oxygen species and interaction with nitric oxide pathway to produce reactivenitrogen species [55].

It was once believed that reactive species caused damage only if antioxidant defenses were overwhelmed, thusupsetting the balance between oxidants and antioxidants. However, it is now realized that the interaction itself betweenreactive species and antioxidant defenses ultimately causes cellular injury and death (ie, the yin-yang theory of bothbeing necessary) [56]. Reperfusion exacerbates the oxidative stress with a burst of reactive oxygen species.

The response of the fetus to the hypoxic-ischemic insult determines the subsequent injurious cascades and the clinicalmanifestations that result. One study monitored the response of rabbit fetus brains in utero to global hypoxia using MRIdiffusion-weighted sequences and apparent diffusion coefficient (ADC) mapping as a marker of ischemic injury [57].Fetuses that showed a precipitous drop in brain ADC at the end of 40 minutes of global hypoxia manifested hypertoniaand postural changes after birth, while those without a drop in ADC were relatively normal at birth. Thus, after thehypoxic-ischemic insult, the initial energy failure and oxidative stress probably play a critical role in subsequent cascades(figure 5) [49].

Excitotoxic injury Excitotoxic cellular injury occurs via excess activation of glutamate receptors, which leads toseveral forms of cell death. There are four receptor types for glutamate [58], which are the N-methyl-d-aspartate(NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and metabotropic glutamatereceptors. The metabotropic receptors are not directly coupled to ion channels.

Late oligodendroglial progenitors are vulnerable to injury in early prematurity with resulting predominant whitematter injury in premature infants [53].

In the term neonate with ischemic brain injury, however, certain neurons in the deep gray nuclei and perirolandiccortex are most likely to be affected. Acute cell injury can trigger continuing loss of cells. There are neural-glial cellinteractions that can increase the brain injury. Selective damage to neurons in the subcortical gray matter candirectly contribute to long-term apoptosis in distal neuronal structures.

The NMDA receptors are the most avid and physiologically active. The channels activated by NMDA receptors arevoltage-dependent and calcium-permeable. Their activation causes neuron depolarization [59]. Repeateddepolarization of a neuron by unregulated glutamate release results in accumulation of intracellular calcium. Duringhypoxia-ischemia, there is failure to rapidly pump synaptically released glutamate back across the cell membrane,resulting in exposure of NMDA receptors to accumulated glutamate, which leads to lethal elevation of intracellularcalcium levels. The cascade of events initiated by this process also can induce apoptosis [60].



Oligodendroglia are particularly vulnerable to glutamate [61]. Preoligodendrocyte subtypes O4 and O1+ expresssubunits for both the AMPA (GluR1, GluR2, GluR3, and GluR4) and kainate (KA1, GluR5/6, and GLuR7) receptors butnot NMDA receptors, whereas mature MBP+ oligodendrocytes have little to no expression of either NMDA receptors ornon-NMDA receptors.

Mature oligodendrocytes in mixed cocultures die after exposure to kainate, but AMPA receptors are the most importantmediators of cellular demise, with kainate receptors playing a smaller role [62]. In this paradigm, cell death occurspredominantly by necrosis, not apoptosis [62]. However, there is evidence that mature oligodendrocytes expressingmyelin basic protein are resistant to excitotoxic injury produced by kainate, whereas earlier stages in the oligodendrocytelineage are vulnerable to this insult [63].

Nitric oxide and oxygen-free radicals Nitric oxide (NO) and oxygen-free radicals appear to play important rolesin brain injury induced by hypoxia-ischemia.

Nitric oxide can behave as an oxidant as well as an antioxidant. Under pathological conditions there is excess NOproduction that results in cell toxicity through direct biochemical effects or through reactive nitrogen species that isformed from the reaction of NO and reactive oxygen species [64].

Nitric oxide is synthesized by nitric oxide synthase (NOS) from L-arginine in the presence of essential cofactor,tetrahydrobiopterin. Nitric oxide synthase exists in three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), andinducible NOS (iNOS).

Available evidence suggests that eNOS has a predominant protective role in hypoxia-ischemia, whereas nNOS andiNOS have a facilitative role.

The use of specific NOS inhibitors as neuroprotectants is currently being studied.

PERINATAL STROKE Perinatal stroke is an increasingly recognized entity in term newborns with encephalopathyand cerebral palsy. Perinatal stroke occurs about once in 4000 births. (See "Stroke in the newborn", section on'Epidemiology'.)

The majority of infants with ischemic perinatal stroke develop neonatal seizures. Additional signs of neonatalencephalopathy may also be present, such as lethargy, hypotonia, feeding difficulties, or apnea [68].

A specific cause for perinatal stroke is not identified in most affected newborns. Factors contributing to the risk includematernal conditions such as prothrombotic disorder and cocaine abuse; placental complications such as preeclampsia,chorioamnionitis and placental vasculopathy; and newborn conditions such as prothrombotic disorders, congenital heartdisease, meningitis, and systemic infection [69]. During the delivery process, an infant may develop a cervical arterialdissection that leads to stroke.

Potential long-term sequelae of perinatal arterial stroke include cerebral palsy, cognitive deficits, hemiparesis, andepilepsy. However, development is normal in approximately 19 to 33 percent of infants with neonatal ischemic infarction.

AMPA and kainate receptors are both coupled to sodium and potassium ion channels. Whereas NMDA receptorsare always permeable to Ca(2+), cation permeability of AMPA receptors depends on subunit composition. Ca(2+)influx is differentially regulated by AMPA receptors compared to kainate receptors.

Histopathologic studies have shown that nNOS knockout neonatal animals are protected from focal hypoxic-ischemic-induced histopathologic brain damage [65].

Similarly, iNOS knockout animals show a reduction of focal ischemic brain damage and locomotor deficits [66].

Animals lacking the eNOS gene have enlarged cerebral infarcts after ischemic injury [67].


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(See "Stroke in the newborn", section on 'Prognosis'.)

PROGRESSIVE ENCEPHALOPATHY One must always consider the possibility of progressive disorders in cases ofneonatal encephalopathy. These include metabolic, neurodegenerative, infectious or toxic etiologies that are rare, with acombined incidence of approximately 6 per 10,000 live births [70], but a much higher mortality rate than the generalpopulation [71]. A history of parental consanguinity is associated with a marked increase in the risk of progressiveencephalopathy, and thus is an important clue suggesting metabolic and neurodegenerative disease [72].

Metabolic abnormalities A large number of metabolic and genetic abnormalities may cause neonatalencephalopathy. Inborn errors of metabolism that present in the newborn period typically share strikingly similar clinicalfeatures, including decreased level of consciousness, seizures, poor feeding, hypotonia, and vomiting. Examplesinclude:

Specific disorders such as multiple sulfite oxidase deficiency may produce neuroimaging and clinical findings that veryclosely mimic hypoxic-ischemic brain injury. Genetic disorders such as Prader-Willi and chromosomal abnormalities mayalso present with newborn encephalopathy. However, metabolic and genetic disorders account only for a very smallproportion of cases of neonatal encephalopathy.

OTHER CAUSES Given that neonatal encephalopathy is an umbrella term that includes any type of brain injury orinsult resulting in central nervous system dysfunction, the list of brain disorders that can cause neonatal encephalopathyis quite long [73]. As examples, brain anomalies, intracranial hemorrhage and infection can all lead to seizures andencephalopathy in the newborn period.

Intraventricular hemorrhage in term infants may cause symptoms of neonatal encephalopathy, and is often related tosinovenous thrombosis as opposed to the more typical intraventricular hemorrhage associated with germinal matrixhemorrhage seen in preterm infants [74]. Intracerebral hemorrhage in a term infant is often idiopathic, but may be relatedto birth trauma, congenital vascular malformation, or a clotting disorder.

Finally, a variety of maternal toxins can cause encephalopathy in the newborn period. For instance, passive addiction tonarcotics, barbiturates, alcohol, tricyclic antidepressants, and serotonin reuptake inhibitors can produce seizures andencephalopathy in the neonate [75].

SUMMARY

Disorders of amino acid metabolism (eg, maple syrup urine disease, phenylketonuria, nonketotic hyperglycinemia)(see "Overview of maple syrup urine disease" and "Overview of phenylketonuria")

Hyperammonemia (eg, urea cycle defects) (see "Urea cycle disorders: Clinical features and diagnosis")

Neonatal hypoglycemia (see "Neonatal hypoglycemia")

Organic acidemias (see "Organic acidemias")

Mitochondrial disorders (see "Mitochondrial myopathies: Clinical features and diagnosis")

Severe peroxisomal disorders (eg, Zellweger syndrome) (see "Peroxisomal disorders")

Neonatal encephalopathy is the preferred terminology to describe central nervous system dysfunction in thenewborn period. It can result from a wide variety of conditions but often remains unexplained. The nature of braininjury causing neurologic impairment in a newborn is poorly understood. Hypoxia-ischemia is only one of manypossible contributors to neonatal encephalopathy. Whether a particular newborn's encephalopathy can beattributed to hypoxic-ischemic brain injury is often controversial. (See 'Terminology' above.)

Approximately 70 percent of neonatal encephalopathy cases are associated with events arising before the onset of



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labor (figure 1 and figure 2). These include:

Maternal factors, including unemployment, family history of seizures or neurologic disorder, infertilitytreatment, and thyroid disease

Placental conditions, including severe preeclampsia, post-dates, and abnormal appearance of the placentaFetal problems, such as intrauterine growth restriction

Of these, intrauterine growth restriction is the strongest risk factor. (See 'Risk factors' above and 'Antepartum'above.)

Intrapartum risk factors for neonatal encephalopathy include the following:

Persistent occipitoposterior positionShoulder dystociaEmergency cesarean delivery, which may include failed vacuumOperative vaginal deliveryAcute intrapartum events or sentinel events (eg, uterine rupture, placental abruption, cord prolapse, tightnuchal cord, maternal shock/death)

Inflammatory events (eg, maternal fever, chorioamnionitis, prolonged rupture of membranes)

An acute (ie, sentinel) intrapartum event, such as a placental abruption or uterine rupture, confers an increased riskof neonatal encephalopathy, but is present in only a small minority of infants with neonatal encephalopathy. (See'Intrapartum' above.)

Perinatal stroke is a separate recognized entity in term newborns with encephalopathy. (See 'Perinatal stroke'above.)

Metabolic and neurodegenerative disorders can underlie neonatal encephalopathy. (See 'Progressiveencephalopathy' above.)



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Topic 6205 Version 9.0



GRAPHICS

Criteria for acute intrapartum events sufficient to cause cerebral palsy

All four criteria must be met:

Evidence of metabolic acidosis: umbilical artery pH



Criteria that suggest an intrapartum timing of an event that may berelated to the development of cerebral palsy but is not specificallyasphyxial

A sentinel hypoxic event occurring immediately before or during labor

A sudden and sustained fetal bradycardia or absence of fetal heart rate variability in the presence ofpersistent late or variable decelerations. This usually occurs after a hypoxic sentinel event with anormal fetal heart rate pattern prior to the event.

Apgar score of 0 to 3 after five minutes

Onset of multisystem involvement within 72 hours of birth

Early imaging studies showing evidence of an acute nonfocal cerebral abnormality

Adapted from: Task force on neonatal encephalopathy and cerebral palsy, American College of Obstetriciansand Gynecologists (ACOG). Neonatal Encephalopathy and Cerebral Palsy: Executive Summary. ObstetGynecol 2004; 103:780.

Graphic 67282 Version 4.0



Timing and anatomy of risk factors for brain injuryresulting in neonatal encephalopathy

Sidhartha Tan, MD.




Anatomy and etiology of risk factors for brain injury resultingin neonatal encephalopathy

Sidhartha Tan, MD.




Mechanisms of neonatal hypoxic-ischemic encephalopathy

Anatomical unit Examples

Maternal

Impaired oxygenation Asthma

Pulmonary embolism

Pneumonia

Inadequate perfusion of maternal placenta Cardiorespiratory arrest

Maternal hypotension

Preeclampsia

Chronic vascular disease

Placental

Abruptio placenta

Tight nuchal cord

Cord prolapsed

True knot

Uterine rupture

Fetal

Impaired fetal oxygenation/perfusion Fetomaternal hemorrhage

Fetal thrombosis

Sidhartha Tan, MD.




Outcome following neonatal hypoxic-ischemic encephalopathy

Sidhartha Tan, MD.




Timeline of neonatal hypoxic-ischemic injury

Hypoxia-ischemia may have deleterious effects on vulnerable cell populationspeculiar to the developmental stage.

WM: white matter.

Sidhartha Tan, MD.




Pathophysiology of hypoxic-ischemic encephalopathy

The downward pointing blue line represents the cascade of events that occurs with oxidativestress, and the downward pointing black line depicts events associated with energy failure.

Sidhartha Tan, MD.


Documents

03Etiology and Pathogenesis of Neonatal Encephalopathy