Rev. Bras. Reumatol. vol.56 número4

ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Case

report

Intracerebral

hemorrhage

with

a

favorable

outcome

in

a

patient

with

childhood

primary

angiitis

of

the

central

nervous

system

Marco

Felipe

Silva

_,

_Ana

_Raquel

_Feitosa

_,

_José

_A.

_Paz

_,

_Nádia

_Emi

_Aikawa

,

Clovis

A.

Silva

a_{PediatricRheumatologyUnit,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil}

b_{PediatricNeurologyUnit,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil}

c_{DivisionofRheumatology,FaculdadedeMedicina,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil}

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Articlehistory:

Received20December2013 Accepted21May2014

Availableonline30November2015

Keywords:

Childhoodprimaryangiitis Centralnervoussystem Vasculitis

Intracerebralhemorrhage Stroke

a

b

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Childhoodprimaryangiitisofthecentralnervoussystem(cPACNS)isarareinflammatory braindiseaseofunknownetiology.Ofnote,brainhemorrhagehasbeenrarelyreportedin cPACNSpatients,generallyassociatedwithadelayedclinicaldiagnosis,orwithadiagnosis onlyatnecropsy.WepresentthecaseofaboywithcPACNSthatpreviouslysufferedan ischemicstroke.Attheageof7yearsand10months,hepresentedasuddenandsevere headache,vomitingandreductioninconsciousnesslevel(Glasgowcomascale7),requiring prompttrachealintubation.Braincomputedtomographydemonstratedintraparenchymal hematomaintheright parieto-occipitallobeandasmallfocusofbleedingintheright frontallobe,vasogenicedema,herniationoftheuncusanda10mmdeviationtotheleft fromthemidline.C-reactiveprotein(9.2mg/dL)andvonWillebrandfactor(vWF)antigen (202%)wereelevated.Decompressivecraniotomywasperformedandmethylprednisolone andcyclophosphamidewereadministered.Oneweeklater,thepatienthadlefthemiparesis withoutothersequelae.Importantly,motordeficitshavebeenimprovingprogressively.Our casereinforcestheinclusionofthisvasculitisasadifferentialdiagnosisinchildrenand adolescentswithCNShemorrhage.

©2014ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Hemorragia

intracerebral

com

evoluc¸ão

favorável

em

paciente

com

angiíte

primária

do

sistema

nervoso

central

juvenil

Palavras-chave:

Angiíteprimárianainfância Sistemanervosocentral

r

e

s

u

m

o

Angiíteprimáriadosistemanervosocentraljuvenil(APSNCJ)éumadoenc¸ainflamatória cerebralraraedeetiologiadesconhecida.Hemorragiacerebraltemsidoraramente repor-tadaempacientescomAPSNCJ,geralmenteassociadacomatrasodiagnóstico,oucomum

∗ _{Correspondingauthor.}

E-mail:[email protected](C.A.Silva). http://dx.doi.org/10.1016/j.rbre.2014.05.007

Vasculite

Hemorragiaintracerebral Acidentevascularencefálico

diagnósticosomentepornecrópsia.Relata-seumcasodeumpacientedogêneromasculino comAPSNCJequepreviamentesofreuumacidentevascularcerebralisquêmico.Aos7anos e10mesesdeidade,omeninoapresentousubitamentecefaleiaintensa,vômitosereduc¸ão doníveldeconsciência(escalade comadeGlasgow7),requerendo imediataintubac¸ão traqueal.Umatomografiacomputadorizadacerebraldemonstrouhematoma intraparen-quimatosonoloboparieto-occipitaldireitoeumpequenofocodesangramentonolobo frontaldireito,edema vasogênico,herniac¸ãodoúncuse umdesviode10mm dalinha médiaparaaesquerda.AproteínaC_{-reativa(9.2mg/dL)eofatorantígenodevon} Wille-brand(202%)estavamelevados.Foirealizadaumacraniotomiadescompressiva,seguida pelaadministrac¸ãodemetilprednisolonaeciclofosfamida.Transcorridaumasemana,o pacienteapresentavahemiparesiaesquerda,semoutrassequelas.Édignodenotaqueo

déficitmotortemmelhoradoprogressivamente.Nossocasoreforc¸aainclusãodessa

vas-culitecomodiagnósticodiferencialemcrianc¸aseadolescentescomhemorragiadosistema nervosocentral.

©2014ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Vasculitidesarecharacterizedbyinflammationandnecrosis ofendothelium.1_{Theycanaffectbloodvesselsofanyorgan}

andsystem,includingthecentralnervoussystem(CNS).CNS vasculitismostoftenissecondarytoanunderlyingcondition, suchasinfectious,neoplastic,vascular,metabolicor inflam-matorydisorders,butitalsocanbeidiopathic.2,3

Ofnote,childhoodprimaryangiitisoftheCNS(cPACNS)is arareinflammatorybraindiseaseofunknownetiologythat occurs inpreviously healthy children. Ithas protean clini-calmanifestations,suchasseizures, cognitivedysfunction, behaviorchanges,headaches,neurologicdeficitsandstrokes.3

Ischemicstrokeseemstooccurmoreoftenthan hemor-rhagicevents,whichareseldomdescribedintheliterature. Asfarasweareconcerned,onlysevencaseswerereported regardinghemorrhagic strokeandcPACNS inthe literature, mostofwhichhaddelayedclinicalornecropsydiagnosis.1,4–8

We describe a patient with cPACNS and intracerebral hemorrhagesubmittedtopromptdrainageand immunosup-pressivetherapywithgoodprognosis.

Case

report

At the age of 7 years and 2 months, a boy presented

intenseheadacheduringabout5minuteswithspontaneous improvement.Inthe nexttwenty-four hours,hehadlabial commissure deviationto the rightside and left hemipare-sis,beinghospitalizedinanotherhospital.Laboratoryexams were:hemoglobin12.7g/L,hematocrit36%,whitebloodcell count10,300/mm3_{(neutrophils39%,lymphocytes52%,}

mono-cytes 5%and eosinophils 4%),platelets 300,000/mm3_{, urea}

30mg/dL(normalrange10-50),creatinine0.53mg/dL(normal range0.32-0.60),C-reactiveprotein(CRP)1.1mg/dL(normal< 5),erythrocytesedimentationrate(ESR)7mm/1st_hour

(nor-malrange 0-20) and activated partialthromboplastin time 27.2 s, International NormalizedRatio (INR)1.1. Homocys-teinelevels were 5.5micromol/L(normal range 5-15),total cholesterol176mg/dL(normal<200),low-densitylipoprotein

cholesterol 112mg/dL (normal<100), high-density lipopro-tein cholesterol 49mg/dL (normal > 40) and triglycerides 79mg/dL(normal<150). Brainmagneticresonance imaging (MRI) showed ischemic areas in the right middle cerebral arteryterritory,characterizedbysubcorticalfociofrestricted diffusion in the nucleocapsular region, whereas carotid andvertebralmagneticresonanceangiography,conventional angiographyandcarotidDopplerultrasoundwere unremark-able, aswell ascerebrospinalfluidanalysis.Immunological tests were positive for antinuclear antibodies (ANA) 1:80 (finedense speckledpattern)and negativeforother serum antibodies:anti-doublestrandedDNA(anti-dsDNA),anti-Sm, anti-RNP,anti-Ro,anti-La,anticardiolipinIgM,anticardiolipin IgG,lupusanticoagulant,anti-␤2-glycoprotein-1and antineu-trophil cytoplasmicantibodies.Urinalysiswas normal, and blood culture was negative. Protein C (115%), protein S (126%) and factor VIII(87%)activities were withinthe nor-malrange.FactorVLeidenmutationandprothrombingene polymorphismwerebothabsent.Aspirin(5.0mg/kg/day)was introduced,andafter4monthsofrehabilitation physiother-apy, complete recoveryof the motor deficits was achieved and aspirin was withdrawn. At the age of 7 years and 8 months, he returned asymptomatic in an outpatient visit, bringing a new brain MRI that revealed encephalomala-cia in the right nucleocapsular region and leptomeningeal enhancementintheleftprecentralsulcus,leftcentralsulcus, rightoccipitalsulcus,sphenoid portionofthe rightSylvian fissureandinferioraspectofthecerebellarhemispheres, com-patible with CNS angiitis(Fig. 1). Prophylactic aspirin was reintroduced, andhewasreferred toourUniversity Hospi-tal. Atthat moment,the patient did nothave complaints. He hadnormal weightand heightdevelopment.Peripheral artery pulses were palpable, there was no claudication of extremities,andblood pressurewas99×65mmHg,without

differencesinthelimbs.Noright-leftshuntwasobserved dur-ingechocardiographywithmicrobubbles,CRPwas0.9mg/dL, and ESRwas11mm/1st _{hour.Atthe age of7years and 10}

Figure1–MRIshowinggliosis(A),paramagneticcontrastenhancementintheleptomeningealcompartment(leftprecentral sulcus,leftcentralsulcus,rightoccipitalsulcus–BandC)andhyperintenselesionsinvolvinginferioraspectofthe

cerebellarhemispheres(D).

the right parieto-occipital lobe (Fig. 2) and a small focus ofbleedingintheright frontlobe,vasogenic edema,uncal herniationand a10mmdeviationfrom the midline tothe left. Decompressive craniotomy was promptly performed, and cerebral specimen was obtained for histopathological study.Methylprednisolonepulsetherapyforthreeconsecutive days (1.0g/day) was administered, followed by cyclophos-phamide500mg/m2_{ofbodysurface.Laboratorytestsshowed}

hemoglobin13.1g/L,hematocrit39.7%,whitebloodcellcount 23,300/mm3_{(neutrophils88%,lymphocytes5%,monocytes6%}

and 1%eosinophils),platelets 352,000/mm3_{, urea 23mg/dL,}

creatinine 0.37mg/dL,ESR 8mm/1st _{hour, activated partial}

thromboplastintime0.91s,andINRwas1.27.TheCRPwas ele-vated(9.2mg/dL),andvWFantigenwas202%(normalrange 50-160%).Newimmunologicaltestsfordetectionof anticardi-olipinIgM,anticardiolipinIgGandlupusanticoagulantwere persistentlynegativeinthreeoccasions.Biopsyrevealedlarge quantityofbloodclotscontainingseveralfragmentsof cere-braltissuewithgliosis,withnoevidenceofactivevasculitis. Afteraweekofhospitalization,hestillhadlefthemiparesis, but noother sequelae;hewas dischargedwithprednisone

2mg/kg/day.Onemonthaftertheneurosurgery,prednisone wastaperedto1.5mg/kg/day,andanewdoseof cyclophos-phamide500mg/m2_{wasadministered.ThevWFantigenwas}

108%,andESR,5mm/1st_{hour.Importantly,motordeficitsare}

progressivelyimproving,withverylightlefthemiparesisand lefthemianopsia,withoutapparentcognitivedysfunction.

Discussion

WedescribehereinacaseofcPACNSthatpresented hemor-rhagiceventwithafavorableoutcomeafterpromptdrainage andimmunosuppressivetherapy.TheassociationofcPACNS andhemorrhagicstrokehasbeenreportedonlyinsevencases intheliterature,mostlywithpooroutcomeassociatedwith deathorseveredisabilities.1,4–8

Figure2–Intraparenchymalhematomaintheright parieto-occipitallobe.

Ofnote,cPACNSisdiagnosedaccordingtoCalabrese crite-ria: acquired unexplained neuropsychiatric deficit, classic angiographicorhistopathologicfeaturesofCNSangiitisand no evidence of systemic vasculitis.3 _{Recently, it has been}

proposedtwoclinicalsubdivisionsforthisdisorder:small ves-sel vasculitis (SV-cPACNS) or angiography-negative cPACNS andlargeandmedium-sizedvesselvasculitis,alsoknownas angiography-positivecPACNS.2

Approximately30%ofbiopsiesperformedinchildrenwith suspectedSV-cPACNSwerenegative.2_{Thefirstchoicetobrain}

biopsyinthispopulationisinnon-dominantfrontallobe.The absenceofvasculitisobservedinthehistologicfindingsofour patientmightbeexplainedbyasampleofinadequate loca-tion atthe edgeofthe hematomawithconsequent gliosis predominance,probablyduetotheemergencyneurosurgical procedure.

MRIisanavailable tooltoidentifylesions ofactive SV-cPACNS.2 _{Although there is no pathognomonic radiologic}

finding,patientswithangiography-negativec-PACNSusually exhibitmultifocal lesionsaffectingmorethan onecerebral vesselterritory.9_{Indeed,Benseler etal.reportedfour cases}

ofbiopsy-confirmedSVc-PACNSandallofthepatientshad multifocalinjuriesinvolvingbothgrayandwhitematter,9

sim-ilarlyasobservedinthepresentcase.

Regarding clinical manifestations, SV-cPACNS has been reportedwithseizures,cognitivedysfunction,headachesand rarelywithintracranial hemorrhage.10 _Large-and

medium-sizedvesselssubtypeshowspredominantlymotordeficitsand speechchanges,andpositiveangiographyisthefundamental toolforitsclassification.10

Interestingly,theinflammatorymarkers,suchasCRPand ESR,mayhelptoassessdiseaseactivity,althoughtheseexams may oscillateduring the disease course.The vWF antigen hasbeendescribedasareliablebiomarkerforpatientswith active systemic vasculitis. It is a plasma protein synthe-sizedbymegakaryocyticandanendothelialcellthatreaches higher levelsin thepresenceofdamaged or inflamed vas-cular endothelium.2,11 _{Moreover, increased levels of vWF}

antigenwerereportedin65%ofc-PACNSpopulation. Remark-ably,theselevelsdecreasedsignificantlyaftertreatment,as observedherein.11

Additionaldetectionsofantiphospholipidantibodieswere prospectivelycollected,sincetheseantibodiesmayfluctuate duringthediseasecourse,reachingnon-detectablelevelsat theacutevascularevents.12

The early neurosurgical treatment in conjunction with immunosuppressant provided favorable outcome for our patient.Indeed,thetherapyforSV-cPACNSincludesinduction withglucocorticoidsandintravenouscyclophosphamide dur-ingthefirstsixmonthsandsubsequentmaintenancetherapy withmycophenolatemofetilfor18months.2,3

In conclusion, we reported a favorable prognosis in a SV-cPACNS patient with brainhemorrhage, reinforcing the inclusionofthesevasculitisasadifferentialdiagnosisin chil-drenandadolescentswithCNShemorrhage.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

ThisstudywassupportedbyFundac¸ãodeAmparoàPesquisa doEstadodeSãoPaulo–FAPESP(grant#08/58238-4toCAS), Conselho Nacional de Desenvolvimento Científico e Tec-nológico–CNPq(302724/2011-7toCAS),FedericoFoundation toCASandNúcleodeApoioàPesquisa“SaúdedaCrianc¸aedo Adolescente”daUSP(NAP-CriAd).Wethankthecolleaguesof IntensiveCareUnitofCentroMédicodeCampinas.

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Antiphospholipidantibodiesandantiphospholipidsyndrome in57childrenandadolescentswithsystemiclupus