EVALUACIÓN CUANTITATIVA DE LA LESIÓN DE LA SUSTANCIA ... prematuros.pdf · lóbulos frontal,...

EVALUACIOacuteN CUANTITATIVA DE LA LESIOacuteN DE LA SUSTANCIA BLANCA

EN NEONATOS PREMATUROS ASOCIACIOacuteN CON RESULTADOS

Neurology 2017 Vol 88 (7) 614 622

OBJETIVO Evaluar cuantitativamente el volumen y localizacioacuten de la lesioacuten de la

sustancia blanca (LSB) en los recieacuten nacidos muy prematuros y examinar la

asociacioacuten del volumen y localizacioacuten de la lesioacuten con los resultados del desarrollo

neuroloacutegico a los 18 meses

MEacuteTODOS El volumen y la localizacioacuten de LSB se cuantificaron en RNM en 216

neonatos (mediana de edad gestacional 279 semanas) que tuvieron

evaluaciones motoras cognitivas y del lenguaje a los 18 meses de edad corregida

Los neonatos fueron escaneados a las 321 semanas postmenstruales (mediana)

y 68 (315) tuvieron LSB De 66 supervivientes 58 (879) teniacutean RNM y

resultados a los 18 meses Las LSB se segmentaron manualmente y se

transformaron en un espacio de imagen comuacuten teniendo en cuenta la variabilidad

anatoacutemica entre sujetos Se desarrollaron mapas de probabilidad que describen la

probabilidad de una lesioacuten prediciendo resultados adversos a los 18 meses

RESULTADOS La LSB se presenta en una topologiacutea caracteriacutestica con la

mayoriacutea de las lesiones en la regioacuten periventricular central seguidas por las

regiones posterior y frontal Independientemente de la localizacioacuten de la lesioacuten

mayores voluacutemenes de LSB pronosticaron resultados motores deficientes (p =

0001) El anaacutelisis regional lobar reveloacute que los voluacutemenes mayores LSB en

loacutebulos frontal parietal y temporal tienen resultados motores adversos (todos p

lt005) pero soacutelo los voluacutemenes frontales de LSB predijeron resultados cognitivos

adversos (p = 0002) Para explicar la ubicacioacuten y el volumen de la lesioacuten los

mapas de odds ratio (OR) de voxel-wise demuestran que las lesiones del loacutebulo

frontal predicen un desarrollo cognitivo y del lenguaje adverso con odds ratio (OR)

de 789 y 175 respectivamente mientras que los pronoacutesticos motores adversos

son predichos por una lesioacuten generalizada con una OR maacutexima de 638

CONCLUSIONES El valor predictivo del volumen de la LSB del loacutebulo frontal

pone de relieve la importancia de la localizacioacuten de la lesioacuten al considerar la

importancia del desarrollo neuroloacutegico de la LSB Las lesiones del loacutebulo frontal

son especialmente preocupantes

ARTICLES

Ting Guo PhDEmma G Duerden PhDElysia Adams MDVann Chau MDHelen M Branson

MBBSM Mallar Chakravarty

PhDKenneth J Poskitt

MDCMAnne Synnes MDCMRuth E Grunau PhDSteven P Miller MDCM

Correspondence toSP Millerstevenmillersickkidsca

Editorial page 610

Supplemental dataat Neurologyorg

Quantitative assessment of white matterinjury in preterm neonatesAssociation with outcomes

ABSTRACT

Objective To quantitatively assess white matter injury (WMI) volume and location in very pretermneonates and to examine the association of lesion volume and location with 18-month neurode-velopmental outcomes

Methods Volume and location of WMI was quantified onMRI in 216 neonates (median gestationalage 279 weeks) who had motor cognitive and language assessments at 18 months correctedage (CA) Neonates were scanned at 321 postmenstrual weeks (median) and 68 (315) hadWMI of 66 survivors 58 (879) had MRI and 18-month outcomes WMI was manuallysegmented and transformed into a common image space accounting for intersubject anatomicalvariability Probability maps describing the likelihood of a lesion predicting adverse 18-monthoutcomes were developed

ResultsWMI occurs in a characteristic topology with most lesions occurring in the periventricularcentral region followed by posterior and frontal regions Irrespective of lesion location greaterWMI volumes predicted poor motor outcomes (p 5 0001) Lobar regional analysis revealed thatgreater WMI volumes in frontal parietal and temporal lobes have adverse motor outcomes (allp 005) but only frontal WMI volumes predicted adverse cognitive outcomes (p 5 0002) Toaccount for lesion location and volume voxel-wise odds ratio (OR) maps demonstrate that frontallobe lesions predict adverse cognitive and language development with maximum odds ratios(ORs) of 789 and 175 respectively while adverse motor outcomes are predicted by widespreadinjury with maximum OR of 638

Conclusions The predictive value of frontal lobe WMI volume highlights the importance of lesionlocation when considering the neurodevelopmental significance of WMI Frontal lobe lesions areof particular concern Neurologyreg 201788614ndash622

GLOSSARYCA 5 corrected age GA 5 gestational age IQR 5 interquartile range IVH 5 intraventricular hemorrhage IZ 5 intermediatezone OR 5 odds ratio PMA 5 postmenstrual age PVL 5 periventricular leukomalacia SVZ 5 subventricular zone TEA 5term-equivalent age WMI 5 white matter injury

Very preterm neonates are at high risk of motor cognitive and language deficits across theirlifespan1 Sensitive early neonatal markers of risk are needed to identify those infants who wouldbenefit most from developmental interventions as well as to provide families reassurance whenoutcomes are expected to be favorable

With advances in neonatal intensive care white matter injury (WMI) the characteristic pat-tern of brain injury in preterm neonates has shifted from periventricular leukomalacia (PVL) tosmall punctate lesions Punctate WMI is most readily diagnosed on T1-weighted imagesacquired early in life as areas of hyperintensity2ndash4 Neuroimaging studies of preterm infantsdemonstrate that multifocal WMI is accompanied by altered white matter microstructuredisrupted white matter maturation and reduced functional connectivity in motor cognitiveand attention networks in the brain5ndash8 However current clinical scores of WMI account for the

From Neurosciences and Mental Health (TG EGD VC SPM) The Hospital for Sick Children Research Institute Departments ofPaediatrics (TG EGD EA VC SPM) and Diagnostic Imaging (HMB) The Hospital for Sick Children and the University of TorontoCerebral Imaging Centre (MMC) Douglas Mental Health Research Institute Verdun Department of Psychiatry (MMC) and Biological andBiomedical Engineering (MMC) McGill University Montreal and Department of Pediatrics (KJP AS REG) University of BritishColumbia and BC Childrenrsquos Hospital Research Institute Vancouver Canada

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

614 copy 2017 American Academy of Neurology

ordf 2017 American Academy of Neurology Unauthorized reproduction of this article is prohibited

number of lesions and their relative size byvisual inspection and are imperfect predictorsof neurodevelopmental disability39ndash15 Thusfurther research is required to delineate thespecific role of WMI on neurodevelopmentaloutcomes particularly when accounting forlesion location and volume quantitatively16ndash20

We hypothesize that the total lesion volumeand the spatial location of punctate WMI affectneurodevelopmental outcomes of childrenborn preterm Thus we sought to quantitativelyassess the association between the volume andlocation of WMI identified on early MRI withmotor cognitive and language function at 18months corrected age (CA) To assess this rela-tionship we calculated the volume of WMIand generated probabilistic WMI maps andodds ratio (OR) maps for outcomes in a pro-spective cohort of very preterm neonates Prob-abilistic mapping of WMI in a neonatal braintemplate using nonlinear registration2122 ena-bles the assessment of WMI on a voxel-wisebasis across participants to determine the char-acteristic topology of WMI OR maps23 arecomplementary to these maps and describethe risk of adverse outcomes associated witha lesion in each voxel in the template

METHODS Study population and clinical evaluation Atotal of 216 very preterm neonates (113 boys 52) who were admit-

ted to the neonatal intensive care unit at British ColumbiarsquosWomenrsquos

Hospital Canada and delivered at 24ndash32 weeks of gestation were

enrolled in this study over a 7-year period (2006ndash2012)24 Newborns

with antenatal infections congenital malformationssyndromes or

a parenchymal hemorrhagic infarction 2 cm were excluded The

clinical characteristics of the cohort are described in table e-1 at

Neurologyorg

Standard protocol approvals registration and patientconsents A written informed consent from the legal guardian of

each participating neonate was obtained This study was reviewed

and approved by the Clinical Research Ethics Board at the

University of British Columbia and BC Childrenrsquos and Womenrsquos

Hospitals

Neurodevelopmental outcomes A total of 184 infants

(852) had follow-up at 18 months CA (median age 186

months interquartile range [IQR] 183ndash192) Examiners

assessed the infantsrsquo neurodevelopmental abilities using the

Bayley Scales of Infant and Toddler Development third edition

(Bayley III) The Bayley-III includes standardized composite scores

for motor cognitive and language skills with means of 100 and SD

of 15 Scores more than 1 SD below the mean (85) were

considered to reflect adverse outcome otherwise ($85) typical

neurodevelopmental outcome Fifty-nine of 66 surviving infants

with WMI returned for neurodevelopment assessment One of

these infants had a shunt inserted causing MRI distortion that

precluded accurate quantification of WMI Thus 58 neonates

with WMI and 18-month outcomes were included in the

analysis (table e-2) No clinical differences were evident between

infants who did or did not return for follow-up (p 005)

MRI and brain injury scoring BrainMRIs were acquired with-

out sedation on a 15T Siemens Avanto scanner (Erlangen Germany)

early in life when the neonates were clinically stable (median age

321 wk IQR 304ndash34) or at term-equivalent age (TEA) (median

age 401 wk IQR 387ndash420) as previously reported25

Blinded to the medical history of each neonate an experi-

enced neuroradiologist (KJP) assessed brain injury on the first

scan WMI intraventricular hemorrhage (IVH) ventriculome-

galy and cerebellar hemorrhage Severity of WMI was scored

based on a 3-point scale (minimal 5 1 3 lesions of 2 mm

moderate 5 2 3 lesions or lesions 2 mm and 5 hemi-

spheric involvement severe 5 3 5 of the hemisphere)1025

Manual segmentation of WMI Without knowledge of neuro-

developmental outcomes 2 trained raters delineated theWMI on the

T1-weighted early in life images as areas of abnormal T1 shortening

6 cystic degeneration As described in Results we focused on

punctate WMI and labeled macrocystic lesions separately WMI

segmentation was performed with simultaneous coronal sagittal and

axial views of the brain (figure e-1) using Display software (bicmni

mcgillcaServicesSoftwareVisualization) Tricubic interpolation was

used for visualization as it permitted accurate and consistent

segregation of the WMI from the surrounding structures26 The

high signal intensity periventricular band in frontal white matter was

not considered pathologic Images were inspected to ensure that voxels

with ambiguous signal intensity were not erroneously considered

within the WMI segmentation Experienced neonatal neurologists

(VC and SPM) reviewed the segmented WMI for quality

control Intrarater and interrater reliability was high (intrarater

reliability 085 and 084 interrater reliability 081) using Dice

Kappa (supplemental material) Total WMI volume was calculated

based on the manual segmentation (figure e-1)

Development of early preterm brain template and WMImaps Early preterm brain template To compare the occur-

rence of WMI across participants within the cohort of very preterm

neonates we created an early preterm brain template using MICe

build model (wikimouseimagingcadisplayMICePubMICe-

build-model) with 137 T1-weighted early in life images (mean

postmenstrual age [PMA] 312 weeks range 27ndash339 weeks)

Probabilistic WMI maps The manually labeled WMI on

each infant brain image was mapped to the common space of

the early preterm template using a nonlinear transformation

which accommodates the anatomical variability between the

patient and the template images2122 The probabilistic WMI

map was then generated based on the cumulative number of

WMI lesions that occurred in homologous brain regions across

participants in the standard template The map permits the iden-

tification of WMI vulnerable regions and whether the lesions

occur in a characteristic spatial distribution

We employed similar techniques to develop 3 WMI maps

based on the motor cognitive and language outcomes assessed

at 18 months CA The WMI data that are unique to the neonates

from typical and adverse outcome groups and those common to

them are labeled in 3 distinguishable colors As we hypothesized

that neurodevelopmental outcomes are affected byWMI volumes

and spatial location these outcome-based WMI maps enable us

to visually assess the differences in terms of WMI location

between typical and adverse outcome groups intuitively

To quantify the relationships between WMI location and

outcome evident from the probabilistic maps we calculated brain

volumes in each of the 4 brain lobes (frontal parietal temporal

Neurology 88 February 14 2017 615


occipital) delineated manually using Display software for regional

WMI volumetric measurements (figure e-2)

Statistical analyses examining the association of WMIand neurodevelopmental outcomes Statistical analysis wasperformed using the Statistical Package for the Social Sciences

(SPSS v22 IBM Armonk NY) Clinical characteristics and

demographic variables were compared using x2 or Fisher exact

tests for categorical data and Kruskal-Wallis tests for continuous

data variables

To assess whether greater WMI volume is associated with

adverse neurodevelopmental outcomes we used a multivariate

linear regression to compare the total WMI volumes of neonates

in the typical (Bayley III scores$85) and adverse outcome groups

(scores 85) for motor cognitive and language outcomes con-

trolling for gestational age (GA) sex age at scan and brain vol-

ume In subsequent analyses we applied the same multivariate

model to compare WMI lesion volume in each of the 4 brain

regions (frontal parietal temporal and occipital lobes) in neo-

nates with typical and adverse outcomes With our central

hypothesis that WMI volume is associated with outcome we

consider p values 005 significant

OR maps of motor cognitive and language outcomes Todetermine whether lesion location is a better predictor of

morbidity than is total lesion volume we created voxelwise

OR maps according to previously reported methods23 As an

approach to synthesize lesion volume and location as a predictor

of adverse neurodevelopmental outcomes the OR maps quan-

tify the levels of risk that WMI occurring at different anatomical

regions pose for adverse outcomes (supplemental data)

RESULTS Clinical evaluation of study participants

Fifty-eight neonates with WMI and 124 without WMIidentified on their early in life MRI had follow-up at18-month CA (table e-1) Clinical factors as well as thelevel of maternal education did not differ in neonateswith and without WMI (p 005) (table e-1) SevereIVH and ventriculomegaly were uncommon in the studycohort the incidence of IVH and ventriculomegaly didnot differ based on the presence and absence of WMI(both p 005 table e-1)

The median 18-month outcome scores aremotor 97 (IQR 85ndash103) cognitive 108 (IQR100ndash110) and language 103 (IQR 91ndash112) Only2 of the 58 infants with WMI were diagnosed withmoderate to severe cerebral palsy at 18 months

Figure 1 Noncystic white matter injury (WMI) volume in adverse and typical developmental outcome groups

The total WMI volumes and the percentage of WMI volume within the brain in the adverse and typical developmental out-come groups The data on the left represent the WMI volumes of neonates who had adverse outcomes (Bayley III 85)those on the right are from neonates who had typical outcomes at 18 months corrected age Some neonates with similarWMI volumes had different outcomes indicating the WMI volume is not directly predictive of the outcome The macrocysticlesion volumes were not included The mean postmenstrual age (PMA) at MRI for the 58 neonates with WMI is 322 weeksand the median PMA is 32 weeks Larger total WMI volumes are found in neonates with adverse motor outcomes (b 5

28856 p 5 0001) but not for cognitive (b 5 21018 p 5 08) or language (b 5 698 p 5 08) outcomes

616 Neurology 88 February 14 2017


(1 of these 2 infants had macrocystic lesions) In-fants with severe WMI (grade 3) had lower motorscores (p 5 0001) The 18-month cognitive andlanguage outcome scores did not differ among

infants without WMI and with varying severitiesof WMI (table e-2)

Of the 58 neonates withWMI 54 had scans at TEAConsistent with previous reports1027 WMI is most

Figure 2 Probabilistic white matter injury (WMI) map of 58 very preterm neonates on T1-and T2-weightedimages

Probabilistic WMI map of 58 very preterm neonates overlaid on (A) the T1-weighted early preterm brain template and (B)a T2-weighted image Noncystic WMI that occurred at a homologous region in 2 or more very preterm neonates are dis-played WMI seen only in a single neonate are omitted (A) The cumulative (summed) WMI map of 58 neonates is overlaidon the neonatal brain template in coronal (top) and axial (bottom) planes The axial planes along the superior to inferior direc-tion are displayed from left to right in the figure The color bar on the left indicates the color coding of the WMI summationThe maximum value on the map is 14 The cross on the coronal and axial planes of the T1-weighted brain template in eachcolumn with (top) and without (bottom) the WMImap is placed at the exactly identical location (B) The probabilistic WMI mapnonlinearly transformed and overlaid on the high-resolution T2-weighted image of a very preterm neonate (postmenstrualage [PMA] 297 weeks) First row the probabilistic WMI map of 58 very preterm neonates nonlinearly transformed and over-laid on the T2-weighted image Second row the T2-weighted image The lesions are seen in the subventricular zone andintermediate zone The cross on the axial plane of the T2-weighted image in each column with (top) and without (bottom)the WMI map is placed at the same location



apparent on the first scan 24 neonates had less severeWMI at TEA and only one had more severe WMI

Quantitative measurements of WMI volumes and

location Macrocystic lesions (volume $10 mm3)were found in 2 neonates and were not consideredin the primary analyses Total volumes of punctate(ie noncystic) WMI varied dramatically from4 mm3 to 4801 mm3 (median 44 mm3) (figure 1)

The WMI probabilistic map indicates that WMIoccurs at homologous brain regions across participantsand central regions are more prone to have WMI(figure 2A) The probabilistic WMI map overlaid ona high-resolution T2-weighted image revealed thatWMI occurs most commonly in the intermediate zone(IZ) or outer subventricular zone (SVZ) (figure 2B)

Association of total WMI volumes with outcome Com-parable absolute WMI volumes and WMI percentageof total brain volume are found in neonates in bothoutcome groups (figure 1) In multivariate modelsneonates with adverse motor outcomes have largertotal WMI volumes (b 5 28856 p 5 0001) rela-tive to infants with typical motor outcomes account-ing for GA sex age at scan and total brain volumeIn comparable models total WMI volumes do not

differ across cognitive (b 5 21018 p 5 08) orlanguage (b 5 698 p 5 08) outcome groups

Relationship between WMI location and outcome Qual-

itative assessment Outcome-based WMI mapsWhenWMIis labeled relative to outcome it is apparent that lesionscommon to both typical and adverse outcome groupsare in the central and posterior regions (figure 3) Le-sions only identified in neonates with adverse outcomesextend anteriorly to the frontal lobes lesions solely seenin neonates with typical outcomes are distributed moreposteriorly Consistent with our hypothesis the spatiallocation of WMI is predictive of outcome

Of note for the 2 neonates with anteriorly locatedmacrocystic lesions one had adverse motor cognitiveand language outcomes and one had only adversemotor outcomes

Quantitative assessment WMI volumes by lobe

Accounting for GA sex age at scan and total brainvolume infants with adverse motor outcomes hadgreater WMI volumes in frontal (b 5 5412 p

0001) parietal (b 5 1669 p 5 0006) and tem-poral (b5 1472 p5 003) lobes Adverse cognitiveoutcomes are associated with greater WMI in frontallobes (b 5 4132 p 5 0002) Language outcomesare not associated with WMI volumes in any of the

Figure 3 Motor cognitive and language outcome-based probabilistic white matter injury (WMI) maps

Probabilistic noncystic WMI map of 58 very preterm neonates based on the motor cognitive and language composite scores of Bayley III at 18 months ofcorrected age Voxels in blue WMI that are unique to the neonates who had typical outcomes (scores $85) voxels in magenta WMI that are unique to theneonates who had adverse outcomes (scores 85) voxels in white WMI common to neonates in both typical and adverse outcome groups Left panethe cross is at the territory of the left primary motor area in the neonatal template Right pane The cross is at territory of the right inferior parietal lobule inthe brain template The cross indicates the intersecting point for the coronal (top) axial (middle) and sagittal (bottom) planes on the left and the right panes



lobes (p5 03) These models are consistent with theprobabilistic maps indicating that frontal lobe WMIis most predictive of adverse motor and cognitiveoutcomes (figure 4)

OR maps of motor cognitive and language outcomes Asan approach to account for lesion volume and locationas predictors of outcome OR maps (figure 5) demon-strate the odds of an adverse outcome if WMI occurs ina specific voxel The brain region with the highest WMIoccurrence rate (right posterior central region) is notassociated with the highest risk of developing adverseoutcomes The OR maps illustrate that WMI at differ-ent locations poses different risks for adverse outcomesthe highest OR values for the motor cognitive andlanguage maps are 638 789 and 175 respectively

DISCUSSION In this prospective cohort of very pre-term neonates we demonstrate that WMI occurs in

a characteristic pattern in circumscribed brain regionsconsistent with previous reports6910 Yet total WMIvolume alone does not accurately predict neurodevelop-mental outcomes at 18 months CA Outcome-basedmaps and OR maps indicate that lesion location inthe frontal lobes is key to predicting adverse cognitiveand motor outcomes These findings should assist incounseling of families including providing reassuranceafter the diagnosis of posteriorly located WMI and willimprove our ability to identify neonates for earlydevelopmental interventions or emerging strategies topromote brain repair

When overlaid on a T2-weighted image to visualizethe ldquowhite matter layersrdquo in the third trimester of ges-tation WMI appears to be primarily distributed in theSVZ and the IZ28 While distinguishing the IZ fromthe outer SVZ is difficult in the absence of specifichistologic markers2930 these findings are consistentwith prior neuroradiologic assessment24 In the currentwork WMI associated with the poorest outcomes wasprimarily located in the IZ of the frontal lobes WMImay have affected the underlying connectivity of thestriatum and frontal lobes perhaps underlying the de-lays in cognitive and motor functions that are primarilysubserved by these regions31

The incidence of WMI peaks during a critical win-dow of WM maturation and the establishment of crit-ical neuronal connections and occurs in brain regionscentral to these processes Neonatal WMI was previ-ously linked to reduced cortical thalamic and basalganglia volumes at TEA and later in childhood andadolescence1132 Punctate WMI that appears hyperin-tense on T1-weighted MRI is accompanied by diffuseWMI characterized by preoligodendrocyte maturationarrest16192033 WMI is also related to dysmature whitematter microstructural abnormality and abnormalfunctional connectivity5ndash82534 Consequences ofWMI may have been previously underestimated asearly multifocal lesions may affect microstructural andmetabolic brain development over time in more wide-spread areas2 For example increases in measures ofneuronal metabolism in the neonatal brain were morestrongly associated with neurodevelopmental outcomesin comparison to qualitative scoring of WMI severity25

In addition the evolution of white matter fractionalanisotropy from early in life to TEA has more prognos-tic significance than isolated values measured early inlife52535 We demonstrate that frontalWMI evident onearly scans predicts adverse neurodevelopmental out-comes Furthermore the stronger association betweenlesion location rather than volumes with adverse neuro-developmental outcomes supports the hypothesis thatWMI results in disrupted frontal-striatal connectivityaffecting later cognitive and motor abilities

Although WMI is still visible on images at TEAthe burden of WMI in very preterm neonates is best

Figure 4 Lobar regional white matter injury (WMI) volume difference andneurodevelopmental outcomes

Regional differences between noncystic WMI volumes in the 4 brain lobes (frontal parietaltemporal and occipital) in relation to neurodevelopmental outcomes at 18months ([A] motor[B] cognitive [C] language Bayley III85 adverse outcome Bayley III$85 typical outcome)The symbols reflect estimated marginal means of the volumes Error bars are the 95confidence intervals p 0001 p 001 p 005



visualized on earlier T1-weighted MRI (median PMAof 32 weeks)4102736 As the abnormal signal intensityof WMI resolves over time measurement of WMI atTEA does not provide the most accurate lesion vol-ume and location Given this we focused our assess-ment of the WMI lesions on the earlier scan whenWMI volume and location is most readily measured

Prior research revealed that moderate to severeWMI identified on MRI at TEA in very preterm in-fants was predictive of adverse neurodevelopmentaloutcomes at 2 years of age11 However WMI wasassessed at a time punctate lesions may be harder todetect and quantitative lesion volumes and locationwere not established Our quantitative analysis at a timemost sensitive to WMI detection demonstrated thatalthough the total WMI volume was significantlylarger in infants with adverse motor outcomes differ-ences in lesion volumes were not evident between thecognitive and language outcome groups

Illustrated on outcome-based probabilistic WMImaps the lesions associated with adverse outcomes weremore anteriorly distributed while the lesions related totypical outcomes tended to be more posterior By assess-ing the association of WMI volumes within differentbrain lobes with outcomes we found that adverse motorand cognitive outcomes were associated with greaterWMI volumes in frontal lobes These findings indicatethat lesion location contributes to the prediction of

neurodevelopmental outcomes Of note macrocystic le-sions were uncommon and contributed little to anincreased risk of adverse outcome on the OR mapsThus at a population level frontal macrocystic lesionsare not the main contributors of neurodevelopment out-comes in contemporary practice With evidence froma number of centers confirming a decline in macrocysticWMI (ie PVL)3738 our findings highlight the urgentneed for strategies to prevent punctate WMI

Detecting early or very small lesions beyondthe spatial resolution parameters afforded by MRI isa limitation of our technique31 We also recognize thatthere are pathways to adverse outcomes in pretermneonates that are independent of WMI such assevere IVH as well as clinical factors for which specificimaging biomarkers are not yet available Examiningquantitative WMI maps in larger cohorts of neonatesparticularly from multiple centers will enable otheraspects of clinical illness to be considered in predictionmodels We also recognize that motor cognitive andlanguage abilities assessed at 18 months of age are notextensive descriptors of childrenrsquos long-term cognitiveand physical abilities nor their overall well-beingFuture studies should consider developmental outcomesassessed in later childhood to specifically determine thelonger-term impact of WMI

In this article we present evidence that punctatewhite matter lesions in the territory of frontal lobes

Figure 5 Odds ratio (OR) maps of white matter injury (WMI) for adverse motor cognitive and languageoutcomes

ORmaps of noncysticWMI for motor (second column) cognitive (third column) and language (fourth column) outcomes over-laid on the T1-weighted neonatal brain template The first column shows the spatial cumulative WMI map including all non-cystic WMI seen in any of the 58 very preterm neonates Note the different scaling of the images in each column asindicated by each color bar The purple cross is at exactly the same location in each of the 4 maps The area with highWMI occurrence rate does not necessarily indicate high risk in developing adverse outcomes The maximum OR valueson the motor cognitive and language OR maps are 638 789 and 175 respectively



were associated with clinically significant adversemotor and cognitive outcomes at 18 months in verypreterm neonates Probabilistic WMI maps illustratethat WMI occurs in a characteristic spatial patternacross participants in the neonatal brain Further-more both outcome-based and OR maps as well asthe quantitative assessment of WMI volumes withindifferent lobes demonstrate that lesion location addsimportant information to lesion volume when con-sidering the neurodevelopmental trajectories of pre-term neonates The creation of the neonatal WMIprobabilistic and OR maps will facilitate the analysisof other neurologic conditions associated with WMIfor better understanding of how these insults affectbrain function and relate to outcome

AUTHOR CONTRIBUTIONSTG EGD EA VC MMC KJP AS REG and SPM

contributed to the conception and design TG EGD EA VC

HB MMC KJP AS REG and SPM contributed to the data

acquisition and analysis TG EGD VC and SPM contributed to

drafting the manuscript and figures All authors contributed to editing

the manuscript for content

ACKNOWLEDGMENTThe authors thank the families that participated in this research Janet

Rigney Sandy Belanger RN and Mark Chalmers RRT for data collec-

tion Ivan Cepeda and Cecil Chau for database development Marco

Germani and Samantha Podrebarac for contributions to the total cerebral

volume calculation Alessandra De Petrillo for manual segmentation work

and Dr Jason Lerch and Matthijs van Eede for assistance with the neonatal

brain template creation Computation of brain volumes was performed on

the SciNet supercomputer at the SciNet HPC Consortium

STUDY FUNDINGThis work was supported by the Hospital for Sick Children (TG) the

Canadian Institutes of Health Research (CIHR) (MOP79262 to SPM

and MOP86489 to REG) the Ontario Brain Institute and the Neuro-

DevNet National Centres of Excellence SPM is currently Bloorview

Childrenrsquos Hospital Chair in Paediatric Neuroscience and was supported

by a Tier 2 Canadian Research Chair in Neonatal Neuroscience and the

Michael Smith Foundation for Health Research Scholar Award REG is

supported by a Senior Scientist award from the Child and Family Research

Institute SciNet is funded by the Canada Foundation for Innovation under

the auspices of Compute Canada the Government of Ontario Ontario

Research FundndashResearch Excellence and the University of Toronto

DISCLOSURET Guo has funding from the Research Training Centre The Hospital

for Sick Children E Duerden E Adams V Chau and H Branson

report no disclosures relevant to the manuscript M Chakravarty has

funding from CIHR K Poskitt reports no disclosures relevant to the

manuscript A Synnes has funding from CIHR R Grunau has funding

from CIHR NIH Child and Family Research Institute S Miller has

funding from CIHR SickKids Foundation NeuroDevNet and the

Ontario Brain Institute and prior support from a Canada Research

Chair the Michael Smith Foundation and the March of Dimes Founda-

tion Go to Neurologyorg for full disclosures

Received February 23 2016 Accepted in final form September 29 2016

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of preterm birth from infancy to adulthood Lancet 2008

371261ndash269

2 Back SA Miller SP Brain injury in premature neonates

a primary cerebral dysmaturation disorder Ann Neurol

201475469ndash486

3 Glass HC Bonifacio SL Chau V et al Recurrent postnatal

infections are associated with progressive white matter injury

in premature infants Pediatrics 2008122299ndash305

4 Raybaud C Ahmad T Rastegar N Shroff M Al Nassar M

The premature brain developmental and lesional anatomy

Neuroradiology 201355(suppl 2)23ndash40

5 Adams E Chau V Poskitt KJ Grunau RE Synnes A

Miller SP Tractography-based quantitation of corticospi-

nal tract development in premature newborns J Pediatr

2010156882ndash888

6 Bassi L Chew A Merchant N et al Diffusion tensor

imaging in preterm infants with punctate white matter

lesions Pediatr Res 201169561ndash566

7 He L Parikh NA Aberrant executive and frontoparietal func-

tional connectivity in very preterm infants with diffuse white

matter abnormalities Pediatr Neurol 201553330ndash337

8 Smyser CD Snyder AZ Shimony JS Blazey TM Inder TE

Neil JJ Effects of white matter injury on resting state

fMRI measures in prematurely born infants PLoS One

20138e68098

9 Cornette LG Tanner SF Ramenghi LA et al Magnetic

resonance imaging of the infant brain anatomical charac-

teristics and clinical significance of punctate lesions Arch

Dis Child Fetal Neonatal Ed 200286F171ndashF177

10 Miller SP Ferriero DM Leonard C et al Early brain

injury in premature newborns detected with magnetic res-

onance imaging is associated with adverse early neurode-

velopmental outcome J Pediatr 2005147609ndash616

11 Woodward LJ Anderson PJ Austin NC Howard K

Inder TE Neonatal MRI to predict neurodevelopmental out-

comes in preterm infants N Engl J Med 2006355685ndash694

12 Krishnan ML Dyet LE Boardman JP et al Relationship

between white matter apparent diffusion coefficients in

preterm infants at term-equivalent age and developmental

outcome at 2 years Pediatrics 2007120e604ndashe609

13 Boardman JP Craven C Valappil S et al A common

neonatal image phenotype predicts adverse neurodevelop-

mental outcome in children born preterm Neuroimage

201052409ndash414

14 Iwata S Nakamura T Hizume E et al Qualitative brain

MRI at term and cognitive outcomes at 9 years after very

preterm birth Pediatrics 2012129e1138ndashe1147

15 Parikh NA He L Bonfante-Mejia E et al Automatically

quantified diffuse excessive high signal intensity on MRI

predicts cognitive development in preterm infants Pediatr

Neurol 201349424ndash430

16 Buser JR Maire J Riddle A et al Arrested preoligoden-

drocyte maturation contributes to myelination failure in

premature infants Ann Neurol 20127193ndash109

17 Bassi L Ricci D Volzone A et al Probabilistic diffusion trac-

tography of the optic radiations and visual function in preterm

infants at term equivalent age Brain 2008131573ndash582

18 Segovia KN McClure M Moravec M et al Arrested

oligodendrocyte lineage maturation in chronic perinatal

white matter injury Ann Neurol 200863520ndash530

19 Back SA Luo NL Mallinson RA et al Selective vulnera-

bility of preterm white matter to oxidative damage defined

by F2-isoprostanes Ann Neurol 200558108ndash120

20 Volpe JJ Brain injury in premature infants a complex

amalgam of destructive and developmental disturbances

Lancet Neurol 20098110ndash124



21 Avants BB Epstein CL Grossman M Gee JC Symmetric

diffeomorphic image registration with cross-correlation

evaluating automated labeling of elderly and neurodegen-

erative brain Med Image Anal 20081226ndash41

22 Avants BB Tustison NJ Song G Cook PA Klein A Gee JC

A reproducible evaluation of ANTs similarity metric perfor-

mance in brain image registration Neuroimage 201154

2033ndash2044

23 Sprenger T Seifert CL Valet M et al Assessing the risk of

central post-stroke pain of thalamic origin by lesion map-

ping Brain 20121352536ndash2545

24 Duerden EG Guo T Dodbiba L et al Midazolam dose

correlates with abnormal hippocampal growth and neuro-

developmental outcome in preterm infants Ann Neurol

201679548ndash559

25 Chau V Synnes A Grunau RE Poskitt KJ Brant R

Miller SP Abnormal brain maturation in preterm neo-

nates associated with adverse developmental outcomes

Neurology 2013812082ndash2089

26 Guo T Winterburn JL Pipitone J et al Automatic segmen-

tation of the hippocampus for preterm neonates from early-in-

life to term-equivalent age Neuroimage Clin 20159176ndash193

27 Kersbergen KJ Benders MJ Groenendaal F et al Differ-

ent patterns of punctate white matter lesions in serially

scanned preterm infants PLoS One 20149e108904

28 Kostovic I Judas M Rados M Hrabac P Laminar orga-

nization of the human fetal cerebrum revealed by histo-

chemical markers and magnetic resonance imaging Cereb

Cortex 200212536ndash544

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human and ferret neocortex are epithelial-like and

expand by integrin signaling Nat Neurosci 201013

690ndash699

30 Martinez-Cerdeno V Cunningham CL Camacho J et al

Comparative analysis of the subventricular zone in rat

ferret and macaque evidence for an outer subventricular

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32 Thompson DK Warfield SK Carlin JB et al Perinatal

risk factors altering regional brain structure in the preterm

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33 Haynes RL Folkerth RD Keefe RJ et al Nitrosative and

oxidative injury to premyelinating oligodendrocytes in

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Decreasing incidence and severity of cerebral palsy in pre-

maturely born children J Pediatr 201115986ndash91

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DOI 101212WNL0000000000003606201788614-622 Published Online before print January 18 2017Neurology

Ting Guo Emma G Duerden Elysia Adams et al outcomes

Quantitative assessment of white matter injury in preterm neonates Association with

This information is current as of January 18 2017

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2017 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

httpwwwneurologyorgcontent887614fullhtmlincluding high resolution figures can be found at

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003606DC2httpwwwneurologyorgcontentsuppl20170118WNL0000000000

003606DC1httpwwwneurologyorgcontentsuppl20170118WNL0000000000Supplementary material can be found at

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Citations httpwwwneurologyorgcontent887614fullhtmlotherarticles

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httpwwwneurologyorgcgicollectionvolumetric_mriVolumetric MRI

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ARTICLES

Ting Guo PhDEmma G Duerden PhDElysia Adams MDVann Chau MDHelen M Branson

MBBSM Mallar Chakravarty

PhDKenneth J Poskitt

MDCMAnne Synnes MDCMRuth E Grunau PhDSteven P Miller MDCM

Correspondence toSP Millerstevenmillersickkidsca

Editorial page 610

Supplemental dataat Neurologyorg

Quantitative assessment of white matterinjury in preterm neonatesAssociation with outcomes

ABSTRACT

Objective To quantitatively assess white matter injury (WMI) volume and location in very pretermneonates and to examine the association of lesion volume and location with 18-month neurode-velopmental outcomes

Methods Volume and location of WMI was quantified onMRI in 216 neonates (median gestationalage 279 weeks) who had motor cognitive and language assessments at 18 months correctedage (CA) Neonates were scanned at 321 postmenstrual weeks (median) and 68 (315) hadWMI of 66 survivors 58 (879) had MRI and 18-month outcomes WMI was manuallysegmented and transformed into a common image space accounting for intersubject anatomicalvariability Probability maps describing the likelihood of a lesion predicting adverse 18-monthoutcomes were developed

ResultsWMI occurs in a characteristic topology with most lesions occurring in the periventricularcentral region followed by posterior and frontal regions Irrespective of lesion location greaterWMI volumes predicted poor motor outcomes (p 5 0001) Lobar regional analysis revealed thatgreater WMI volumes in frontal parietal and temporal lobes have adverse motor outcomes (allp 005) but only frontal WMI volumes predicted adverse cognitive outcomes (p 5 0002) Toaccount for lesion location and volume voxel-wise odds ratio (OR) maps demonstrate that frontallobe lesions predict adverse cognitive and language development with maximum odds ratios(ORs) of 789 and 175 respectively while adverse motor outcomes are predicted by widespreadinjury with maximum OR of 638

Conclusions The predictive value of frontal lobe WMI volume highlights the importance of lesionlocation when considering the neurodevelopmental significance of WMI Frontal lobe lesions areof particular concern Neurologyreg 201788614ndash622

GLOSSARYCA 5 corrected age GA 5 gestational age IQR 5 interquartile range IVH 5 intraventricular hemorrhage IZ 5 intermediatezone OR 5 odds ratio PMA 5 postmenstrual age PVL 5 periventricular leukomalacia SVZ 5 subventricular zone TEA 5term-equivalent age WMI 5 white matter injury

Very preterm neonates are at high risk of motor cognitive and language deficits across theirlifespan1 Sensitive early neonatal markers of risk are needed to identify those infants who wouldbenefit most from developmental interventions as well as to provide families reassurance whenoutcomes are expected to be favorable

With advances in neonatal intensive care white matter injury (WMI) the characteristic pat-tern of brain injury in preterm neonates has shifted from periventricular leukomalacia (PVL) tosmall punctate lesions Punctate WMI is most readily diagnosed on T1-weighted imagesacquired early in life as areas of hyperintensity2ndash4 Neuroimaging studies of preterm infantsdemonstrate that multifocal WMI is accompanied by altered white matter microstructuredisrupted white matter maturation and reduced functional connectivity in motor cognitiveand attention networks in the brain5ndash8 However current clinical scores of WMI account for the

From Neurosciences and Mental Health (TG EGD VC SPM) The Hospital for Sick Children Research Institute Departments ofPaediatrics (TG EGD EA VC SPM) and Diagnostic Imaging (HMB) The Hospital for Sick Children and the University of TorontoCerebral Imaging Centre (MMC) Douglas Mental Health Research Institute Verdun Department of Psychiatry (MMC) and Biological andBiomedical Engineering (MMC) McGill University Montreal and Department of Pediatrics (KJP AS REG) University of BritishColumbia and BC Childrenrsquos Hospital Research Institute Vancouver Canada

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

614 copy 2017 American Academy of Neurology











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Now offering




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Reprints










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2010156882ndash888










20138e68098



















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201679548ndash559


















690ndash699














200362441ndash450








2015361565ndash1571













Now offering




bull RSS Feeds































Reprints
























































































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201679548ndash559


















690ndash699














200362441ndash450








2015361565ndash1571













Now offering




bull RSS Feeds































Reprints











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