1© 2017 Journal of Pediatric Neurosciences | Published by Wolters Kluwer - Medknow

Introduction

Neonatal hypoxic‑ischemic encephalopathy (HIE)is one of the most common causes of cerebral

palsy (CP) and other severe neurological deficits inchildren.NeonatalHIEoccurs in 1.5/1000 live births. Itis caused by inadequate blood flow and oxygen supplyto the brain resulting in focal or diffuse brain injury.[1]Asphyxia is themost significant risk factor forHIE thatmay occur from a variety of conditions. The pattern ofbrain injury depends on the severity and duration ofhypoxia and degree of brain maturation. The imagingfindings in full‑term neonates (>36 weeks of gestation)may differ from those in preterm neonates (<36 weeksof gestation).[2] Neuroimaging modalities such asultrasound (US), computed tomography (CT), andmagnetic resonance imaging(MRI)help in identificationandcharacterizationof the accurate location, extent, andseverity of the brain injury. Newer imaging techniquessuchasdiffusion‑weighted imaging(DWI)andmagneticresonance spectroscopy (MRS) being more sensitive todiagnoseacutebrain injuryhaveapotential role inearlydiagnosis and timely intervention.[3,4] The treatment isprimarily supportive, aimed at correction of underlyingcause. The role of neuroprotective interventions to limitthe extentofbrain injury causedbyhypoxia‑ischemia is

under investigation. The prognosis of HIE depends ontheseverityofinjuryandgestationalageoftheinfant.[5,6]

In this article, we review the etiopathophysiologyand clinical manifestations of HIE, role of imaging inevaluation of the condition, patterns of brain injuryin term and preterm neonates, the treatment and theprognosis.

EtiopathogenesisPerinatal asphyxia is the most important cause ofHIE. Perinatal asphyxia may occur either in uteroor postnatally. Intrauterine asphyxia results due toinadequate placental perfusion and impaired gaseousexchange that may be caused by fetal factors (fetalbradycardia, fetal thrombosis, and fetal hemorrhage),maternal factors (preeclampsia, abruptio‑placentae,maternalhypotension,severeanemia,asthmaandchronicvasculardisease),ortightnuchalcordandcordprolapse.Postnatal asphyxia results from conditions causing

Review Article

Neonatal Hypoxic‑ischemic Encephalopathy: A Radiological ReviewShahina Bano, Vikas Chaudhary1, Umesh Chandra Garga

DepartmentofRadiodiagnosis,PGIMER,Dr.RMLHospital,1DepartmentofRadiodiagnosis,LadyHardingeMedicalCollegeandAssociatedHospitals,NewDelhi,India

Neonatal hypoxic‑ischemic encephalopathy (HIE) is a devastating condition thatmay result in death or severe neurologic deficits in children. Neuroimagingwithcranial ultrasound (US), computed tomography and magnetic resonance imagingarevaluable tools in theworkupofpatientswithHIE.Thepatternofbrain injurydepends on the severity and duration of hypoxia and degree of brainmaturation.Mild to moderate HI injury results in periventricular leukomalacia and germinalmatrix bleed in preterm neonates, and parasagittalwatershed infarcts in full‑termneonates. Severe HI injury involves deep gray matter in both term and preterminfants. Treatment of HIE is largely supportive. The current article reviews theetiopathophysiology and clinical manifestations of HIE, role of imaging in theevaluationof thecondition,patternsofbrain injury in termandpretermneonates,thetreatmentandtheprognosis.

Keywords: Computed tomography, cranial ultrasound, hypoxic ischemic encephalopathy, magnetic resonance imaging

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Address for correspondence: Dr. Shahina Bano, Room No. 603, PGIMER, Dr. RML Hospital,

New Delhi ‑ 110 001, India. E‑mail: dr_shahinaindia@yahoo.com

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Website: www.pediatricneurosciences.com

DOI: 10.4103/1817-1745.205646

How to cite this article: Bano S, Chaudhary V, Garga UC. Neonatal hypoxic-ischemic encephalopathy: A radiological review. J Pediatr Neurosci 2017;12:1-6.

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neonatal pulmonary failure such as severe hyalinemembrane disease, meconium aspiration syndrome,pneumonia,orcongenitalcardiacdisease.[2‑6]

The basic physiologic processes that result in HIE,both in preterm and term neonate, is asphyxia leadingto brain ischemia (reduced cerebral blood flow) andhypoxia (reduced cerebral oxygen). Hypoperfusion, inconjunction with hypoxia, leads to a cascade of eventsincluding acidosis, release of inflammatory mediatorsandfreeradicalformation.Thesebiochemicalsubstancesresult in loss of normal cerebral autoregulation anddiffuse brain injury (neuronal cell death). The exactnatureoftheinjurydependsontheseverityanddurationof hypoxia and degree of brain maturation. In terminfants,myelinated fibers aremoremetabolically activeandhencemorevulnerabletoHIE.[7]

Clinical ManifestationsAt delivery, HIE neonate may have low Apgarscore (bradycardia, poor respiratory effort, hypotonia,decreased alertness, weak or absent cry, and abnormalskin color) and metabolic acidosis in cord blood. Theinfant usually develops seizure within first 24 h oflife. Childrenwith periventricular leukomalacia (PVL)may develop spastic CP in the form of diplegia,quadriplegia,orhemiplegia.Involvementofsubcorticalwhite matter produces severe mental retardation andimpaired vision. Basal ganglia (BG) and thalamicinvolvement result in extrapyramidal symptoms.Multicystic encephalopathy is associated withquadriplegia, bulbar and choreoathetoid symptoms,microcephaly and mental retardation. Abnormalelectroencephalographic (EEG) findings may predictadverse clinical outcome such as long‑term neurologicsequelaeorimpendingdeath.[6]

Role of ImagingCranial ultrasound (US) is the initial investigationof choice in suspected cases of neonatal HIE as it isinexpensive, portable and imparts no radiation exposure.Cranial US is highly sensitive for detecting intracranialhemorrhage, hydrocephalus, and cystic PVL. Increasedresistive index (RI)of themiddlecerebralartery (MCA)on Doppler sonography helps to identify severe HIE.Normally, RI decreases with increasing gestational age.Despite the above advantages, cranial US has severallimitations such as low sensitivity for detecting corticallesions, marked interobserver variability and operatordependency. CT and MRI have greater sensitivity forthe detection of cortical injury and markedly lowerinterobservervariabilitythansonography.[2,8]

CT is less sensitive and specific than MRI to diagnoseneonatal HIE. However, multidetector CT may beused for screening intracranial hemorrhage in verysick neonates without need for sedation. The majordisadvantageofCTinneonatesisradiationexposure.[2]

MRIisthemostsensitiveandspecificimagingmodalityforevaluatingsuspectedneonatalHIE.Inneonatalbrainimaging as compared to the adult brain, a relativelyhigherrepetitiontimeforbothT1(800ms)andT2(6500ms) is used to optimize the signal‑to‑noise ratio andgray‑white matter differentiation. Conventional MRI isless sensitive than newer imaging techniques like DWIand MRS in diagnosing acute brain injury; however,theycanhelptoexcludeothercausesofencephalopathysuch as congenital malformation, neoplasm, cerebralinfarction and hemorrhage. On conventional MRI, HIinjury to gray matter (cortex and deep gray matter)demonstrates characteristic T1‑hyperintensity andvariableT2‑hyperintensitydependingondurationof theimagingandpathologicalconditionsuchashemorrhage,encephalomalacia, or gliosis. White matter injuryresults in T1‑hypointensity and T2‑hyperintensity dueto ischemia‑induced edema or cystic encephalomalacia.Whereas, white matter injury with abnormal T1hyperintensity and without marked T2 hypointensitydenotes astrogliosis. The fluid attenuation inversionrecovery (FLAIR) sequence is particularly useful fordemonstrating cystic leukomalacia and gliosis.Gradientrecalled echo‑T2*‑weighted sequence or susceptibilityweighted imaging is particularly sensitive for detectinghemorrhage and distinguishing it from astrogliosis.[2,9]DWImaydemonstratecytotoxicedema(due tohypoxicbrain injury) in acute phase before the signal intensitychangesareevidentonconventionalT1‑orT2‑weightedimages. Cytotoxic edema can be seen as diffusionrestriction on DWI evidenced by increased signalintensity on DWI and decrease signal intensity oncorresponding apparent diffusion coefficient mapping.ThelimitationofDWIis that itmaygivefalsenegativeresult if performedwithin first 24 h of HI injury. DWIchanges can be typically seen for only 10–12 daysafter tissue death and pseudonormalization occursthereafter. Early DWI is excellent for the detection ofwhite matter injury. However, DWI cannot detect theseverity of HI brain injury or predict adverse clinicaloutcome.[3,4,10] MRS performed within first 24 h afterbirth in a full‑term neonate is very sensitive to theseverity of HI brain injury and can predict adverseoutcome. Elevated lactate/creatine ratio on day 1 oflife is a predictor of adverse neurological outcome,whereas absence of lactate predicts a normal outcome.Decreased N‑acetylaspartate (NAA), increased choline

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andglutamine‑glutamatepeaksarealsoseeninneonatalHIE.MRS is not recommended in preterm neonates astheyusually showhigher lactateand lowerNAApeaks.TwomajordrawbacksofMRIislimitedaccessandneedforsedationinneonates.[3,4,10]

Patterns of Brain InjuryAlthough the pattern of brain injury may differin preterm (<36 weeks of gestation) and termneonates (>36 weeks of gestation) depending on theseverity and duration of hypoxia and degree of brainmaturation,someoverlappingfeaturesmayexist.[2]

Inpretermneonateswithimmaturebrain,periventricularwhite matter (supplied by ventriculopetal penetratingarteries) is most vulnerable to the HI injury. Mildto moderate HI injury results in PVL, that maybe focal (adjacent to frontal horns and trigones)or diffuse [Figure 1]. Progressive necrosis resultsin loss of periventricular white matter, passiveventriculomegaly (irregular margins of the bodies andtrigones of lateral ventricles) and thinning of corpuscallosum[Figures2and3].Cavitationandcystformationrepresents end‑stage PVL and is best demonstrated onFLAIR sequence [Figure 4]. Periventricular cysts areusually ≤2–3 mm, larger cysts carry poorer prognosis.DWI is a promising technique for early detection ofPVL, before any abnormality appears on conventionalMRI. Germinal matrix hemorrhage (GMH) is typicallyseen in preterm infants with HI injury. Subsequentreperfusion to ischemicbrain tissuemay result inGMHfrom rupture of weak capillaries and increased venouspressure. Depending on severity, GMH can be gradedintosubependymalhemorrhage(Grade1),intraventicularhemorrhage without (Grade 2) and with (Grade 3)ventricular dilatation or parenchymal extension of thebleed with coexisting venous infarction (Grade 4).Gradient recalled echo‑T2*‑weighted sequence ishighly sensitive to detect GMH [Figure 5]. Coexistingperiventricular white matter injury and germinalmatrix bleed may be present. Thalami, brainstem, andcerebellum in the immature brain have high metabolicactivity and hence are more susceptible to injury insevereHIinjury[Figure6].[11‑13]

In term neonates, mild to moderate HI injury producesparasagittal watershed zone infarcts between anterior/MCA and middle/posterior cerebral artery. Both thecortex and underlying subcortical white matter areinvolved[Figure7].SevereHI injuryresults in injury tometabolicallyactivetissuessuchasventrolateralthalami,posterior putamina, hippocampi, brainstem, corticospinaltracts,andsensorimotorcortex[Figures8‑11].BGinjury

Figure 1:Magneticresonanceimagingofbrain,fluidattenuationinversionrecovery(axial)imagesina5‑montholdpreterminfantshowingfeatureofmild‑moderate hypoxic‑ischemic injury in formof periventricularleukomalaciaseenasperiventricularwhitematterhyperintensity

Figure 2:Noncontrastcomputedtomographyhead(axial)ina4‑montholdpreterminfantshowingfeaturesofmild‑moderatehypoxic‑ischemicinjuryintheformofsignificantlossofperiventricularwhitematterandpassiveventriculomegalywithirregularmargins

Figure 3: Noncontrast computed tomography head (sagittal), in a6‑montholdpreterminfantwithneonatalhypoxiashowingfeaturesofperiventricularleukomalacia(arrow),passiveventriculomegaly(asterisk)andthinningofcorpuscallosum(arrowhead)

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Figure 4:Magneticresonanceimagingbrain,fluidattenuationinversionrecovery (axial) images, in two different preterm infants showingfeaturesofend‑stageperiventricularleukomalaciainformofmulticysticencephalomalacia (asterisk), best appreciated on fluid attenuationinversion recovery image. Passive ventriculomegaly (arrow) andprominentsubarachnoidspaceisalsopresent

is more common than parasagittal pattern and carriestheworst prognosis.DWI and protonMRS demonstrateBG injury earlier than any other imaging modality.Severe global hypoxiamay also lead to diffuse cerebraledema[Figure12].MRscanofterminfantswithchronic

HIEmay reveal cortical atrophy and thinning (ulegyria)andmulticysticencephalomalacia[Figure13].[2,12,14]

Treatment and PrognosisEarly diagnosis and timely intervention is the mainobjectiveinthemanagementofaneonatewithsuspectedHIE. The estimated therapeutic window is very short,of about 2–6 h during which intervention may beefficacious in reducing the severity of brain injury.Recent trials have shown that therapeutic hypothermia

Figure 5:Magneticresonanceimagingbrain,GradientrecalledechoandT1/T2weighted(axial)images,ina5‑montholdpreterminfantshowingsubependymalgerminalmatrixbleed(Grade1)ongradientrecalledechoimage(arrow).NotebleedisnotevidentonT1/T2weightedimages

Figure 6:Noncontrastcomputedtomographyhead(axial)in3‑montholdpreterminfantshowingfeaturesofbothsevereandmild‑moderatehypoxia‑ischemicinjuryinformofbilateralbasalgangliaandthalamicinjury (hyperdense basal ganglia and thalami) typical of severehypoxia(thinarrow);andmulticysticencephalomalacia(asterisk)andpassiveventriculomegaly(thickarrow)typicalofmild‑moderatehypoxia.Dystrophiccorticalcalcification(arrowhead)isalsopresent

Figure 7:Noncontrastcomputedtomographyhead(axial)ina4‑monthold term infant showing features ofmild‑moderate hypoxic‑ischemicinjuryinformofacutewatershedzoneinfarcts(wedgeshapedlowdensityareas)involvingbilateralfrontalandparieto‑occipitalregion(arrow)

Figure 8:Magnetic resonance imagingbrain in1‑year‑old termmaleshowingfeatureofseverehypoxic‑ischemicinjuryinvolvingventrolateralthalami(arrowhead),posteriorputamina(thinarrow),andprirolandiccortex(thickarrow),asfluidattenuationinversionrecoveryhyperintensity

Figure 9:Magnetic resonance imaging brain in 2.5‑year‑old termmaleshowingfeatureofseverehypoxic‑ischemicinjuryintheformofacutebasalgangliainfarctsappearinghyperintenseonfluidattenuationinversion recovery sequence and showing diffusion restriction ondiffusion‑weighted imaging and corresponding apparent diffusioncoefficientmapping(arrow)

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in the formof selectivebraincooling isneuroprotectiveand helps to improve neurological outcome amongHIEinfants with moderate EEG abnormalities. Research onthepotentialbenefitofotherneuroprotectiveagents(likecalciumchannel blockers) is goingon.The treatment isprimarily supportive with correction of the underlyingcause. The supportive care includes maintenance ofadequate ventilation, metabolic status and vitals, andcontrolofbrainedemaandseizure.[5,6,15]

The prognosis of HIE depends on the severity ofinjury and gestational age of the infant. Cortex andBGinvolvement on conventional MRI, diffusion restrictionon DWI, increased lactate on MRS within 24 h of lifeand severe EEG abnormalities predict poor outcome.Term infants with mild encephalopathy generally havegood prognosis and show complete recovery; however,20% of infants may die in the neonatal period and

another25%maydevelopsignificantneurologicaldeficit.Preterm infants, compared with term infants have poorprognosis.[5,6]

ConclusionHIE is an important cause of morbidity and mortalityin the neonatal period. Cranial US, CT and MRI showcharacteristicpatternofbrain injury andhelp to excludeother causes of encephalopathy. Imaging plays animportantroleinearlydiagnosisandtimelyintervention,therebyreducingtheseverityofneonatalbraininjury.

AcknowledgmentThe authors express their sincere gratitude to therespected Late Dr. Sachchida Nand Yadav (Sr.

Figure 10:Noncontrastcomputedtomographyhead(axial)in1‑montholdterminfantshowingfeatureofseverehypoxiainformofPrimarilythalamicinjury(hyperdensethalami)(arrow)

Figure 11:Noncontrastcomputedtomographyhead(axial)ina3‑year‑oldtermmale showing features of severe hypoxic‑ischemic injury in theformofhyperdensebasalganglia(thinwhitearrow)andthalami(arrowhead), loss of periventricularwhitematter, passive ventriculomegalywithirregularmargin(thickblackarrow)andatrophyofsensorymotorcortex(thickwhitearrow)

Figure 12:Noncontrastcomputedtomographyhead(axial)ina4‑montholdterminfantshowingfeaturesofsevereglobalhypoxiaintheformofdiffusecerebraledema(asterisk).Thalamiandbasalgangliaarespared

Figure 13: Noncontrast computed tomography head (axial) in6‑month old term infant showing features of chronicmild‑moderatehypoxic‑ischemic injury in form of chronicwatershed zone infarctinvolving bilateral parieto‑occipital region with areas of cysticencephalomalacia/gliosis (arrow), focal loss of whitematter andcolpocephaly(dilatedoccipitalhorns)(asterisk)

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Radiologist, PGIMER, Dr. RML Hospital) for alwaysbeing helpful unconditionally. He was a gentleman intruesense.Mayhisnoblesoulrestinpeace!

Financial support and sponsorshipNil.

Conflicts of interestTherearenoconflictsofinterest.

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