Advances in Neonatal Neurology, An Issue of Clinics in Perinatology, 1e

316 Pages·2014·10.263 MB·English

by  Praveen Ballabh MD

Advances in Neonatal
Neurology
Editors
PRAVEEN BALLABH
STEPHEN A. BACK
CLINICS IN
PERINATOLOGY
www.perinatology.theclinics.com
Consulting Editor
LUCKY JAIN
March 2014 • Volume 41 • Number 1
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AdvancesinNeonatalNeurology
Contributors
CONSULTING EDITOR
LUCKYJAIN,MD,MBA
RichardW.BlumbergProfessorandExecutiveViceChairman,DepartmentofPediatrics,
EmoryUniversitySchoolofMedicine;ExecutiveMedicalDirector,Children’sPhysician
Group,EmoryChildren’sCenter,Children’sHealthcareofAtlanta,Atlanta,Georgia
EDITORS
PRAVEENBALLABH,MD
ProfessorofPediatricsandCellBiologyandAnatomy,RegionalNeonatalCenter,Maria
FareriChildren’sHospitalatWestchesterMedicalCenterandNewYorkMedicalCollege,
Valhalla,NewYork
STEPHENA.BACK,MD,PhD
ProfessorofPediatricsandNeurology,OregonHealth&ScienceUniversity,Clydeand
EldaMunsonProfessorofPediatricResearch,Director,NeuroscienceSection,Pape´
FamilyPediatricResearchInstitute,Portland,Oregon
AUTHORS
TOMOKIARICHI,MBChB,MRCPCH,PhD
CentrefortheDevelopingBrain,DepartmentofPerinatalImaging,StThomas’Hospital,
King’sCollegeLondon;DepartmentofBioengineering,ImperialCollegeLondon,London,
UnitedKingdom
STEPHENA.BACK,MD,PhD
ProfessorofPediatricsandNeurology,OregonHealth&ScienceUniversity,Clydeand
EldaMunsonProfessorofPediatricResearch,Director,NeuroscienceSection,Pape´
FamilyPediatricResearchInstitute,Portland,Oregon
PRAVEENBALLABH,MD
ProfessorofPediatricsandCellBiologyandAnatomy,RegionalNeonatalCenter,Maria
FareriChildren’sHospitalatWestchesterMedicalCenterandNewYorkMedicalCollege,
Valhalla,NewYork
OLIVIERBAUD,MD,PhD
Professor,UniversityofParisDiderot,Paris,France
MANONJ.N.L.BENDERS,MD,PhD
AssociateProfessorinNeonatology,DepartmentofNeonatology,WilhelminaChildren’s
Hospital,UniversityMedicalCenterUtrecht,TheNetherlands
LAURABENNET,PhD
ProfessorofPhysiology,DepartmentofPhysiology,UniversityofAuckland,Auckland,
NewZealand
iv Contributors
VANNCHAU,MD
DivisionofNeurology,DepartmentofPediatrics,TheHospitalforSickChildren;University
ofToronto,Toronto,Ontario;Child&FamilyResearchInstitute,Vancouver,British
Columbia,Canada
SERENAJ.COUNSELL,PhD
CentrefortheDevelopingBrain,DepartmentofPerinatalImaging,StThomas’Hospital,
King’sCollegeLondon,London,UnitedKingdom
LINDAS.DEVRIES,MD,PhD
ProfessorinNeonatalNeurology,DepartmentofNeonatology,WilhelminaChildren’s
Hospital,UniversityMedicalCenterUtrecht,TheNetherlands
PAULP.DRURY,BSc
DepartmentofPhysiology,UniversityofAuckland,Auckland,NewZealand
A.DAVIDEDWARDS,MBBS,FRCP,FRCPCH,FMedSci
CentrefortheDevelopingBrain,DepartmentofPerinatalImaging,StThomas’Hospital,
King’sCollegeLondon;DepartmentofBioengineering,ImperialCollegeLondon,London,
UnitedKingdom
DONNAM.FERRIERO,MD,MS
NeonatalBrainDisordersLaboratory,UniversityofCalifornia,SanFrancisco,
SanFrancisco,California
BOBBIFLEISS,PhD
SeniorLecturer,UniversityofParisDiderot;PremUP,Paris,France;Centrefor
theDevelopingBrain,StThomas’Campus,King’sCollege,London,UnitedKingdom
HANNAHC.GLASS,MDCM,MAS
AssociateProfessor,DepartmentsofNeurologyandPediatrics,Director,Neonatal
NeurocriticalCareServices,NeonatalNeurologyTrainingProgramDirector,Benioff
Children’sHospitalUniversityofCalifornia,SanFrancisco,California
PIERREGRESSENS,MD,PhD
UniversityofParisDiderot;PremUP,Paris,France;CentrefortheDevelopingBrain,
StThomas’Campus,King’sCollege,London,UnitedKingdom
RUTHE.GRUNAU,PhD
Professor,UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada;Queens
UniversityBelfast,Belfast,NorthernIreland,UnitedKingdom
PASCALEV.GUILLOT,PhD
InstituteofReproductiveandDevelopmentalBiology,ImperialCollegeLondon,London,
UnitedKingdom
ALISTAIRJ.GUNN,MBChB,PhD
ProfessorofPhysiologyandPaediatrics,DepartmentofPhysiology,FacultyofMedical
andHealthSciences,UniversityofAuckland;Paediatrician,StarshipChildren’sHospital,
Grafton,Auckland,NewZealand
ELEANORR.GUNN,MBChB
DepartmentofPhysiology,UniversityofAuckland,Auckland,NewZealand
Contributors v
HENRIKHAGBERG,MD,PhD
Professor,CentrefortheDevelopingBrain,StThomas’Campus,King’sCollege,London,
UnitedKingdom;DepartmentsofClinicalSciences&PhysiologyandNeuroscience,
PerinatalCenter,SahlgrenskaAcademy,GothenburgUniversity,Gothenburg,Sweden
PETRAS.HUPPI,MD,PhD
ChiefMedicalOfficer,DepartmentofChildandAdolescent,ServiceDevelopmentand
Growth,UniversityHospitalofGeneva,Geneva,Switzerland
SANDRAE.JUUL,MD,PhD
DepartmentofPediatrics,UniversityofWashington,Seattle,Washington
KARINAJ.KERSBERGEN,MD
PhDStudentinNeonatalNeurology,DepartmentofNeonatology,WilhelminaChildren’s
Hospital,UniversityMedicalCenterUtrecht,TheNetherlands
SOOHYUNKWON,MD
DepartmentofPediatrics,YaleUniversitySchoolofMedicine,NewHaven,Connecticut
SHADIN.MALAEB,MD
DepartmentofPediatrics,St.Christopher’sHospitalforChildren,DrexelUniversity
CollegeofMedicine,Philadelphia,Pennsylvania
DEBORAHE.MCFADDEN,MD
Child&FamilyResearchInstitute;DepartmentofPathology,BCChildren’s&Women’s
HealthCenter;UniversityofBritishColumbia,Vancouver,BritishColumbia,Canada
CHRISTOPHERMCPHERSON,PharmD
ClinicalPharmacist,NeonatalIntensiveCare,St.LouisChildren’sHospital,StLouis,
Missouri
LAURAR.MENT,MD
DepartmentsofPediatricsandNeurology,YaleUniversitySchoolofMedicine,
NewHaven,Connecticut
STEVENP.MILLER,MDCM,MAS
DivisionofNeurology,DepartmentofPediatrics,TheHospitalforSickChildren;
NeurosciencesandMentalHealthProgram,ResearchInstitute,UniversityofToronto,
Toronto,Ontario;Child&FamilyResearchInstitute,Vancouver,
BritishColumbia,Canada
KENNETHJ.POSKITT,MDCM
Child&FamilyResearchInstitute,UniversityofBritishColumbia;Departmentsof
PediatricsandRadiology,BCChildren’s&Women’sHealthCenter,Vancouver,
BritishColumbia,Canada
NATALINASALMASO,PhD
AssociateResearchScientist,ChildStudyCenter,YaleUniversity,NewHaven,
Connecticut
SEETHASHANKARAN,MD
ProfessorofPediatrics,WayneStateUniversitySchoolofMedicine;Director,Divisionof
Neonatal/PerinatalMedicine,Children’sHospitalofMichiganandHutzelWomen’s
Hospital,Detroit,Michigan
vi Contributors
BARBARAS.STONESTREET,MD
ProfessorofPediatrics,DepartmentofPediatrics,Women&InfantsHospitalofRhode
Island,TheAlpertMedicalSchoolofBrownUniversity,Providence,RhodeIsland
SIDHARTHATAN,MD
ClinicalProfessor,DepartmentofPediatrics,NorthShoreUniversityHealthSystem,
UniversityChicagoPritzkerSchoolofMedicine,Evanston,Illinois
LUIGITITOMANLIO,MD,PhD
Professor,UniversityofParisDiderot,Paris,France
SIMONETOMASI,MD,PhD
Post-DoctoralAssociate,ChildStudyCenter,YaleUniversity,NewHaven,Connecticut
NORATUSOR,MD
CentrefortheDevelopingBrain,DepartmentofPerinatalImaging,StThomas’Hospital,
King’sCollegeLondon,London,UnitedKingdom
FLORAM.VACCARINO,MD
Professor,ChildStudyCenter,YaleUniversity;DepartmentofNeurobiology,
KavliInstituteforNeuroscience,YaleUniversity,NewHaven,Connecticut
LANAVASUNG,MD,PhD
DepartmentofChildandAdolescent,ServiceDevelopmentandGrowth,University
HospitalofGeneva,Geneva,Switzerland
BETTYR.VOHR,MD
ProfessorofPediatrics,AlpertMedicalSchoolofBrownUniversity;DirectorofNeonatal
Follow-Up,WomenandInfantsHospital,Providence,RhodeIsland
AdvancesinNeonatalNeurology
Contents
Foreword:WhytheHumanFetusHasSuchaLargeVulnerableHeadAnd
WhyItIsOurJobtoProtectIt! xv
LuckyJain
Preface:AdvancesinNeonatalNeurology xvii
PraveenBallabhandStephenA.Back
CerebralWhiteandGrayMatterInjuryinNewborns:NewInsightsinto
PathophysiologyandManagement 1
StephenA.Back
Increasingnumbersofpretermneonatessurvivewithmotorandcogni-
tive disabilities related to less destructive forms of cerebral injury that
still result in reduced cerebral growth. White matter injury results in
myelination disturbances related to aberrant responses to death of
pre-myelinatingoligodendrocytes(preOLs).PreOLsarerapidlyregener-
atedbutfailtomaturetomyelinatingcells.Althoughimmatureprojection
neuronsaremoreresistanttohypoxia-ischemiathanpreOLs,theydis-
playwidespreaddisturbancesindendriticarbormaturation,whichpro-
videsanexplanationforimpairedcerebralgrowth.Thus,largenumbers
ofcellsfailtofullymatureduringacriticalwindowindevelopmentofneu-
ralcircuitry.Theserecentlyrecognizedformsofcerebralgrayandwhite
matter dysmaturation suggest new therapeutic directions centered on
reversaloftheprocessesthatpromotedysmaturation.
BrainDevelopmentinPretermInfantsAssessedUsingAdvancedMRITechniques 25
NoraTusor,TomokiArichi,SerenaJ.Counsell,andA.DavidEdwards
Infantswhoarebornpretermhaveahighincidenceofneurocognitiveand
neurobehavioral abnormalities, which may be associated with impaired
brain development. Advanced magnetic resonance imaging (MRI)
approaches,suchasdiffusionMRI(d-MRI)andfunctionalMRI(fMRI),pro-
videobjectiveandreproduciblemeasuresofbraindevelopment.Indices
derived from d-MRI can be used to provide quantitative measures of
preterm brain injury. Although fMRI of the neonatal brain is currently
aresearchtool,futurestudiescombiningd-MRIandfMRIhavethepoten-
tial to assess the structural and functional properties of the developing
brainanditsresponsetoinjury.
PathogenesisandPreventionofIntraventricularHemorrhage 47
PraveenBallabh
Intraventricularhemorrhage(IVH)isamajorneurologiccomplicationofpre-
maturity.PathogenesisofIVHisattributedtointrinsicfragilityofgerminal
matrixvasculatureandtothefluctuationinthecerebralbloodflow.Germi-
nalmatrixexhibitsrapidangiogenesisorchestratingformationofimmature
viii Contents
vessels. Prenatal glucocorticoid exposure remains the most effective
means of preventing IVH. Therapies targeted to enhance the stability of
the germinal matrix vasculature and minimize fluctuation in the cerebral
bloodflowmightleadtomoreeffectivestrategiesinpreventingIVH.
NeuroimagingofWhiteMatterInjury,IntraventricularandCerebellarHemorrhage 69
ManonJ.N.L.Benders,KarinaJ.Kersbergen,andLindaS.deVries
White matter injury and hemorrhage are common findings in extremely
preterminfants.Largehemorrhagesandextensivecysticlesionsareiden-
tified with cranial ultrasound. MRI, which is more sensitive, is especially
usefulintheidentificationofsmallintraventricularhemorrhage;cerebellar
hemorrhage; punctate lesion in the white matter and cerebellum; and
diffuse, noncystic white matter injury. Imaging sequences such as diffu-
sion-weighted,diffusiontensor,andsusceptibilityweightedimagingmay
improverecognitionandpredictionofoutcome.Thesetechniquesimprove
understanding of the underlying pathophysiology of white matter injury
anditseffectsonbraindevelopmentandneurodevelopmentaloutcome.
ChorioamnionitisinthePathogenesisofBrainInjuryinPretermInfants 83
VannChau,DeborahE.McFadden,KennethJ.Poskitt,andStevenP.Miller
Chorioamnionitis(orplacentalinfection)issuspectedtobeariskfactorfor
braininjuryinprematureinfants.Thesuggestedassociationbetweencho-
rioamnionitisandcysticperiventricularleukomalaciaandcerebralpalsyis
uncertain because of the variability of study designs and definitions of
chorioamnionitis. Improvements in neonatal intensive care may have
attenuatedtheimpactofchorioamnionitisonbrainhealthoutcomes.Large
multicenter studies usingrigorous definitions ofchorioamnionitis on pla-
centalpathologiesandquantitativemagneticresonancetechniquesmay
offer the optimal way to clarify the complex role of chorioamnionitis in
modifyingbrainhealthandlong-termoutcomes.
FaultandBlame,InsultstothePerinatalBrainmaybeRemotefromTimeofBirth 105
SidharthaTan
Thereisacertaintyinmalpracticecasesthatneurodevelopmentaldeficits
are caused by preventable events at birth when the onset, nature, and
timingoftheinsultintheantenatalandnatalperiodareunknown.Thebig-
gest problem is determining timing. Electronic fetal monitoring is given
excessiveimportanceinlegalcases.Beforeassigningfaultoneventsat
birth, abetterunderstanding ofdevelopmentalneurobiologyand limita-
tionsofthepresentclinicalbiomarkersiswarranted.Theissuesofsingle
versus repeated episodes, timing of antenatal insults, pros and cons of
legal arguments, interaction of various etiologic and anatomic factors
arediscussed.
PharmacologicNeuroprotectiveStrategiesinNeonatalBrainInjury 119
SandraE.JuulandDonnaM.Ferriero
Thisarticleexplainsthemechanismsunderlyingchoicesofpharmacother-
apyforhypoxic-ischemicinsultsofbothpretermandtermbabies.Some
preclinical data are strong enough that clinical trials are now underway.
Contents ix
Challengesremainindecidingthebestcombinationtherapiesforeachage
andinsult.
StemCellTherapyforNeonatalBrainInjury 133
BobbiFleiss,PascaleV.Guillot,LuigiTitomanlio,OlivierBaud,HenrikHagberg,
andPierreGressens
Thisarticleintroducesthebasicconceptsofmodelingneonatalbraininjury
and provides background information regarding each of the commonly
usedtypesofstemcells.Itsummarizesthefindingsofpreclinicalresearch
testingthetherapeuticpotentialofstemcellsinanimalmodelsofneonatal
braininjury,reportsbrieflyonthestatusofclinicaltrials,anddiscussesthe
importantongoingissuesthatneedtobeaddressedbeforestemcellther-
apyisusedtorepairtheinjuredbrain.
OutcomesofHypoxic-IschemicEncephalopathyinNeonatesTreatedwith
Hypothermia 149
SeethaShankaran
Thisarticleexaminestheevidenceregardingmortalityandneurodevelop-
mental outcomes following hypothermia for neonatal hypoxic-ischemic
encephalopathy.Datafromrandomizedcontrolledtrialsregardingneuro-
developmentaloutcomeattheendpointofthemajortrials,andfrom2of
thetrialsonchildhoodoutcomefollowinghypothermiaforneonatalhyp-
oxic-ischemicencephalopathyarepresented.Thepredictorsofoutcome
that can be evaluated in the neonatal period are also reviewed, as this
informationmayassistin thecounselingoffamilies. Mosttrialsofhypo-
thermiahavebeenperformedinhigh-resourcecountries;publishedstud-
iesfromthelow-andmiddle-incomecountriesarealsoreviewed.
MechanismsofHypothermicNeuroprotection 161
PaulP.Drury,EleanorR.Gunn,LauraBennet,andAlistairJ.Gunn
Prolonged, moderate cerebral hypothermia initiated within a few hours
afterseverehypoxia-ischemiaandcontinueduntilresolutionoftheacute
phase of delayed cell death can reduce acute brain injury and improve
long-term behavioral recovery in term infants and in adults after cardiac
arrest. The specific mechanisms of hypothermic neuroprotection remain
unclear,inpartbecausehypothermiasuppressesabroadrangeofpoten-
tialinjuriousfactors.Thisarticleexaminesproposedmechanismsinrela-
tion to the known window of opportunity for effective protection with
hypothermia. Knowledge of the mechanisms of hypothermia will help
guidetherationaldevelopmentoffuturecombinationtreatmentstoaug-
mentneuroprotection with hypothermia and identify those mostlikely to
benefit.
NeonatalSeizures:AdvancesinMechanismsandManagement 177
HannahC.Glass
Seizuresoccurinapproximately1to5per1000livebirthsandareamong
the most commonneurologic conditions managed by a neonatal neuro-
critical care service. There are several, age-specific factors that are
particulartothedevelopingbrain,whichinfluenceexcitabilityandseizure