Rev. Bras. Hematol. Hemoter. vol.38 número4

rev bras hematol hemoter. 2016;38(4):364–367

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Case

Report

Stroke-like

encephalopathy

following

high-dose

intravenous

methotrexate

in

an

adolescent

with

osteosarcoma:

a

case

report

Daniel

Almeida

do

Valle

_,

_Fabiana

_Maria

_Kakehasi,

Roberta

Maria

Pereira

Albuquerque

de

Melo,

Claudia

Machado

Siqueira,

Thaiane

Ferreira

Soares,

Karla

Emilia

de

Sá

Rodrigues

UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received14May2016 Accepted12September2016 Availableonline11October2016

Background

Methotrexate(MTX)isanimportantcytostaticdrugin can-cerchemotherapyandthemostwidelyusedantimetabolite inchildhoodcancers.Itiseffectiveinthetreatmentofacute lymphoblasticleukemia(ALL),non-Hodgkinlymphoma, histi-ocytosisandosteosarcoma.Althoughitsmechanismofaction isnotfullyunderstood,ithadbeenpostulatedasacellcycle specificfolatethatinhibitsdihydrofolatereductaseachieving elevated levelsofhomocysteine and excitatoryaminoacid neurotransmittermetabolites.

HighdoseMTX(HDMTX)iscommonlyusedinthe treat-ment of osteosarcoma.1 _{It can cause acute, subacute and}

chronic neurological complications. Stroke-like encephalo-pathyisasub-acuteMTXneurotoxicityandararesyndrome that manifests with an abrupt onset of focal neurological deficits.2_{Itcancausehemiparesis,slurredspeech,confusion,}

∗ _{Correspondingauthorat:UniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,AvenidaAlfredoBalena,n}◦_{110,30130-100}

BeloHorizonte,MG,Brazil.

E-mailaddress:[email protected](D.A.Valle).

emotionallability,headache,choreoathetosis,andseizure.1,3

Thesymptomspresentedbychildrenusuallyoccurdaysto weeksafter MTX administrationand resolveover hoursto days,withoutpermanentneurologicalsequelae.2,4

Wedescribetheneuroimagingfeaturesofamaleteenage patientwithosteosarcomawhopresentedwithanxiety, con-fusion and emotional liability characterizingan episodeof sub-acute transient cerebral dysfunction associated with alternatinghemiparesis12 daysafterreceivingintravenous HDMTX (12g/m2_{). Imaging within 24h of symptom onset}

showed bilateral symmetrical restricted diffusion involv-ing white matter of the cerebral hemispheres. Computed tomography (CT), magnetic resonance imaging (MRI) and angiographyshowednoevidenceofvasospasmorperfusion defects. MRI30daysafterfirstabnormalityevidenced com-plete resolution and no signal was seen on T2 or fluid attenuatedinversionrecovery(FLAIR).

http://dx.doi.org/10.1016/j.bjhh.2016.09.005

revbrashematolhemoter.2016;38(4):364–367

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Figure1–(A)Diffusionweightedimaging(DWI):symmetricalhyperintensesignalinparietallobewhitematter,neither corticalareanordeepgraymatterstructureswereaffected.(B)Decreasedapparentdiffusioncoefficient(ADC):symmetrical hyperintensesignal.(C)AxialT2/FLAIRimage:discreetsymmetricalhyperintensesignalinparietallobewhitematter.(D) AxialT2:discreetsymmetricalhyperintensesignalinparietallobe.NoabnormalitywasobservedinT1.

Case

presentation

A15-year-oldboydiagnosedwithosteosarcomaoftheright distaltibiaandpulmonarymetastasisinitiatedneoadjuvant chemotherapywithcisplatin(60mg/m2_{/dayfortwodays)and}

doxorrubicyn(37.5mg/m2_{/dayfortwodays)alternatingwith}

HDMTX(12g/m2_{)inasix-weekcycle.Leucovorinrescue(15mg}

eachsixhours)wasstarted24haftertheendofeverycycleof theHDMTXinfusionuntilsafeMTX plasmaconcentrations hadbeenreached.Toxiclevelswerenotobserved.

ThemonitoringofMTXplasmalevelsafterthefourthcycle showedconcentrationsof6.26␮mol/Lat24h,0.78␮mol/Lat 48handat0.13␮mol/Lat72h.Twelvedaysafterthiscycle,he presentedpsychomotoragitation,violentandbizarre behav-iorbutpreservedcomprehensionoftimeandspace.Hisvital signswerestable.Hewasadministeredanxietymedications (clonazepam)and oxygen by facemask and the symptoms graduallyresolved.

Subsequently,anabruptonsetofleft-sidedupperandlower limbparesthesiawithipsilateral hyporeflexiawas observed

without involvement ofthe face. Anurgent brainCT scan didnotshowanyevidenceofvascularabnormalitiesto sug-gest vasospasm or hemorrhage. Additional hematological, viralserology,cerebrospinalfluidandbloodchemistry(renal andliverfunctionsandserumelectrolytes)laboratoryexams wereperformedwithnoneidentifyinganyabnormalities.Five hours after the beginning ofneurological abnormalities, a physicalexaminationofthe patient wasnormaland there werenofurthercomplaints.

Thefollowingday,thepatientcomplainedofright-sided hemiparesiswithoutreflexesofupperandlower limbs,but withmentalstatusandvitalsignsbeingstable.

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Figure2–Magneticresonanceimaging(MRI)ofthebrain30daysafteronsetwithnoabnormalfindings.(A)Diffusion weightedimaging(DWI).(B)AxialT2/FLAIRimage.(C)AxialT2.

bloodfloworcerebralbloodvolume.Theabsenceofvascular orperfusionabnormalitiessuggeststhattransientcytotoxic edemaofthewhitemattermaybeexplainedbyMTX-induced stroke-likeencephalopathy.4,5

Thepatientrecovered movementswithin48h; however, ataxicgaitdisappearedonlyaftereightdaysoffollow-up.

FurtherMRIscansofthebrain30daysafteronsetshowed no abnormal findings on FLAIR, T2 and diffusion weight images(Figure2)andthepatientcontinuedtobe neurolog-icallyasymptomatic.

Discussion

Stroke-likeencephalopathyisarareMTXneurotoxicitythat manifests withsudden onset of focal neurologicaldeficits, such as hemiparesis, that occur days to weeks after MTX administration. Neurological symptoms recovercompletely over hours todays and no residual deficit nor intellectual impairmentare identified duringclinical follow-ups over a two-yearperiod.2,6

Inarecentstudy,3.8%ofallpatientswhoreceivedMTX developedarelatedsub-acuteneurotoxicevent.Neurotoxic events were identified by MRI in 20.6% of asymptomatic patientsandinallsymptomaticpatients.7

HighdosesofMTX(1.5–8g/m2_{)andageover10yearswere}

associatedwithstroke-likeencephalopathyinchildrenwith acutelymphoblasticleukemia.Headache,confusion, disori-entation,seizure,andfocalneurologicdeficitsweredescribed asthefirstmanifestations.4,8,9

Thepathophysiologicalmechanismofthissyndromeisnot wellunderstood,butitislikelytobemultifactorial.Authors havesuggestedthatpossiblemechanismsofMTX neurotoxic-itysuchaschronicfolatedepletioninbraintissue,increased excitatoryaminoacids,excesshomocysteineandalterations ofbiopterinandadenosinemetabolismsmayreduce neuro-transmittersynthesis.10

MTX promotesrelease ofadenosine from fibroblastand endothelial cells, elevating adenosine levels, which dilate cerebralbloodvessels,modifythereleaseofpresynapticand

postsynapticneurotransmittersandmayslowdischargerate ofneurons.4,10–12

Conventional CT scans, MRI and angiography have not showedapatternofconsistentabnormalitiestocharacterize MTXneurotoxicity.4

Stroke-like encephalopathy associated with MTX neu-rotoxicity can be diagnosed when MRI comprise transient symmetrical T2-weightedsignalhyperintensity inthe sub-cortical and periventricular white matter. Usually there is resolutionofrestricteddiffusiononfollow-upMRI.2,4,13

Thispatient’sMRIshowedtransientsymmetricalrestricted diffusion in the cerebral white matter and no evidenceof vasospasmorperfusiondeficit.Fourweekslater,therewereno residualabnormalities.Theradiographicfindingsoftransient restricteddiffusionwithoutvascularorperfusionchangesare consistentwithreversiblecytotoxicedemainvolvingthewhite matterofbothhemispheres.

Patientswithhigherriskforneurotoxiceventsare those olderthantenyearsandwithhigh-riskcancer.HigherMTX levelsat48handhigherhomocysteineconcentrationswere associatedwithincreasedriskofleukoencephalopathy.7

Despite multiple candidate-gene studies for toxicity, results are conflicting. It has been shown that single-nucleotide polymorphisms influence the risk of leukoen-cephalopathyandsymptomaticneurotoxicityalthoughthese findingswerenotreplicated.Inheritedgenomicvariationsare associatedwithHDMTXclearanceandtoxicityisassociated withapolymorphismoftheSoluteCarrierOrganicAnion Trans-porter Family Member 1B1 (SLCO1B1) gene, which encodes a hepaticsolutecarrierorganictransporterthatmediates med-icationssuchasMTX.7,14,15

revbrashematolhemoter.2016;38(4):364–367

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alterationsofbiopterinandadenosinemetabolismsthatlead todecreasedneurotransmittersynthesishavebeenproposed aspossiblemechanismsforsomeformsofacuteorchronic neurotoxicity.16

Asstroke-likeencephalopathy isgenerallybenign, tran-sient and does not recur, this event should not preclude furtheruseofthischemotherapeuticagent.Despitethe lim-itations of an analysis of isolated experience, these data highlightthenecessityofstudiesaddressingthe pathophysi-ologymechanismsofMTXneurotoxicity,itsincidenceandthe developmentofpreventivemeasures.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

Theauthors acknowledgethe contributionsofall the pedi-atric,pediatric oncologyand pediatricneurologyservice of HospitaldasClínicas,affiliatedtotheUniversidadeFederalde MinasGeraisforthecareandtreatmentofthispatient.

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