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BrainTumors

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BrainTumors:
MeningiomasandGliomas
GlenH.J.Stevens

Primarybraintumorsaretumorsthatarisefrombraintissueitselfascomparedwithmetastatictumors,
wherebytumorcellstraveltothebrainfromadistantsite.Thischapterdealsspecificallywithprimary
braintumorsofadults,usingthesubcategoriesofbenigntumorsmeningiomas,realizingthatasmall
subsetcanbemalignantandmalignantgliomas(oligodendrogliomasandastrocytomas).

Definition
BenignTumors
In1922,Cushingcoinedthetermmeningiomatodescribetumorsoriginatingfromthemeninges.1The
WorldHealthOrganization(WHO)hasnowsubdividedmeningiomasintothreeseparatecategories
definedasbenign(I),atypical(II),andanaplasticormalignant(III)(Table1).2
Table1:WorldHealthOrganization(WHO)ClassificationforMeningiomas

WHO
Description
Classification
I

Meningiomas,withlowriskofrecurrenceand/orlowriskofaggressivegrowth

II

Atypicalmeningiomas,withincreasedmitoticactivityorthreeormoreofthefollowing
features:increasedcellularity,smallcellswithhighnucleustocytoplasmratio,
prominentnucleoli,uninterruptedpatternlessorsheetlikegrowth,andfociof
spontaneousorgeographicnecrosis

III

Anaplastic(malignant)meningiomas:exhibitfrankhistologicfeaturesofmalignancy
farinexcessoftheabnormalitiespresentinatypicalmeningiomas

MalignantTumors
Oligodendrogliomasarecomposedofdiffuselyinfiltratingcellsresemblingoligodendrocyteswith
aggressivegrowthpotential.WHOhasstratifiedoligodendrogliomasaswelldifferentiatedtumors(II)and
anaplasticoligodendrogliomas(III).2
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Astrocyticneoplasmsarecharacterizedbyvaryingdegreesofbraininfiltrationandaggressivegrowth
potential.WHOhasstratifiedastrocytomasasdiffuseastrocytoma(II),anaplasticastrocytoma(III),and
glioblastomamultiforme(IV).2Forourpurposeshere,gradeItumorsactuallyrepresentaseparatetumor
genotypeandphenotypeandarenotdiscussed.
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Prevalence
TheCancerBrainTumorRegistryoftheUnitedStates(CBTRUS)wasformedin1992throughthe
AmericanBrainTumorAssociationasaresourceforepidemiologicdataonprimarybraintumors
(http://www.cbtrus.org).Therearecurrentlyelevenstateregistriesinvolvedindatacollection.Primary
braintumorsrepresentonly2%ofallcancers,with35,000newcasesdiagnosedeachyearintheUnited
States.Meningiomasoccuratarateof7.8per100,000peryear,butonly25%arebelievedtobe
symptomatic,withtheothersbeingfoundincidentally.3Themaletofemaleratiois1:1.8,andthe
incidenceincreaseswithage,peakingatage85years.
AccordingtoCBTRUS,theincidenceofoligodendrogliomas,includinganaplasticoligodendrogliomas,is
approximately0.3per100,000persons.Dependingonthestudy,thesetumorsaccountfor4%to15%of
intracranialgliomas.
Themostcommonlydiagnosedprimarybraintumorofadultsisglioblastomamultiforme(gradeIV).The
incidenceistwotothreecasesper100,000populationperyear.Anestimated13,000deathsin2000were
attributedtoprimarymalignantbraintumors(PMBTs).Approximately19,500caseswereexpectedtobe
diagnosedin2000.Diffuseastrocytomas(WHOII)represent10%to15%ofastrocyticbraintumorsand
haveanincidenceof1.4casesper1millionpopulationperyear.
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Pathophysiology
Onlyabout5%ofprimarybraintumorshaveknownhereditaryfactors.Specifically,theLiFraumeni
syndrome,p53defects,neurofibromatosis1(NF1)and2(NF2),tuberoussclerosis,vonHippelLindau
disease,Turcot'ssyndrome,andfamilialpolyposisincreasetheriskofbraintumors.Thepolymerasechain
reaction(PCR)assayanddirectsequencinganalysiscanbeusedtodiagnosevonHippelLindaudisease.
Formeningiomas,thestrongestgeneticlinkhasbeenassociatedwithNF2,withanalmost50%incidence.
Sporadicmeningiomashavebeenlinkedtochromosome22intheregionoftheNF2gene.4Meningiomas
areknowntoexpressestrogenandprogesteronereceptors,withtheformerbeingmorecommon.Ahigh
incidenceofsomatostatinreceptorshasalsobeenfound.Thesignificanceofthesefindingsisuncertainbut
hasledtodiagnostictests(e.g.,octreotidesinglephotonemissioncomputedtomography[SPECT],using
thesomatostatinreceptors)andtreatmentstrategies(antiprogesteronemifepristone[RU486]).Radiation
istheonlydefinitecause.Studieshaveshownthatchildrenreceivingaslittleas10Gyfortineacapitis
haveincreasedriskformeningiomas,withtumordevelopmenttakingatleast20yearsfromexposure.5,6
Headinjuryisoftencitedasacausativefactor,butaprospectivestudyof3000patientswithheadinjuries
foundnoincreasedincidence.7
Viralinfections,specificallytheJCvirus,hasbeenimplicatedinoligodendrogliomas,butthedataare
inconclusive.TheincidenceofPMBTs(specificallyastrocytomas)isincreasedinchildrenwithacute
lymphocyticleukemiawhohavehadpriorbrainradiotherapy.Therehavebeenreports8oflowgrade
astrocytomadevelopmentinpatientswithinheritedmultipleenchondromatosistypeI.Eventhoughmany
ofthemolecularalterationsinvolvedintheprogressionoflowgradeastrocytomastohighergradetumors
(glioblastomamultiforme)areknown,theunderlyingcausativefactorsarenotwellunderstood(Fig.1).
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Signsandsymptoms
Formeningiomas,theclinicalsymptomsareusuallydependentontheanatomicsiteinvolved,butmany
arefoundincidentally.Mostmeningiomasareslowgrowingandcausesignsandsymptomsby
compressionofnearbystructures.Thethreemostcommonsymptomsareheadaches,mentalstatus
changes,andparesis,andthemostcommonsignsareparesis,normalexaminations,andmemory
impairment.9ForPMBTs,themostcommonsignsandsymptomsareseizuresandheadache.Thelower
gradeglialtumorshaveamoreindolentcoursethatmaypersistoveryears,whereasthemostaggressive
tumors(e.g.,anaplasticoligodendrogliomas,anaplasticastrocytomas,glioblastomamultiforme)mayhave
arapidonsetofneurologicdecline.Patientsmay,however,presentwithsignsandsymptomsofincreased
intracranialpressure,includingnausea,vomiting,headache,andconfusion.
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Diagnosis
Aswithmostdiseaseprocesses,themedicalhistoryisthemostimportantinitialstepintheprocessof
braintumordiagnosis.Becausemanymeningiomasarefoundincidentally,imagingstudiesareimportant.
Aphysicalexaminationusuallyfollowsthemedicalhistory.Computedtomography(CT)isprobablyused
mostoftenastheinitialimagingstudy,butmagneticresonanceimaging(MRI)isconsideredtobethegold
standardwhendonewithandwithoutgadoliniumcontrast.OnMRI,meningiomasaretypicallyisodense,
durabasedmassesthatoftenshowhomogeneousenhancement(Fig.2).
Meningiomas
Meningiomastypicallyappearasextraaxiallesions,andthepresenceofaduraltailaidsinthediagnosis.
CTcanhelpevaluateboneinvolvementandthepresenceofcalcifications,whichcanbeseenin30%of
benignmeningiomasbutarerareinmalignantmeningiomas.Althoughbenigntumorscanhaveassociated
edema,itismuchmorecommoninmalignantmeningiomas.Othernoninvasiveimagingtestsinclude
octreotideSPECTscans,whichmeasuresomatostatinlevelsinmeningiomas.Magneticresonance
venogramscanhelpindeterminingvenoussinuspatency.Althoughnoninvasivetestsarehelpful,the
definitivediagnostictestisstillhistologictissueevaluationafterasurgicalbiopsyorlargerresection.Most
institutionsnowusetheWHOhistologicgradingcriteria.Gradingoftumorsisbasedoncelloriginand
biologicbehavior(seeTable1).Figure2demonstratesaverylargemeningiomathatcrossesbothsidesof
thetentoriumontheleft.Thistumorwassurgicallyresectedinastagedprocedure.Atypicalhistologic
appearanceofameningiomaisshowninFigure3.
PrimaryMalignantBrainTumors
Aswithmeningiomas,MRIwithandwithoutcontrastisthetestofchoiceforPMBTs.
OligodendrogliomasaremorelikelytodemonstratecalcificationsonCTthanastrocytomas.WithMRI
scans,PMBTsaretypicallyhypointenseonT1weightedimagesandhyperintenseonT2weightedand
fluidattenuatedinversionrecovery(FLAIR)images.Thehighergradelesions(WHOIIIandIV)aremore
likelytodemonstrateenhancement(anaplasticoligodendrogliomas,anaplasticastrocytomas,glioblastoma
multiforme),althoughringenhancementislesscommoninanaplasticoligodendrogliomasandusuallyis
associatedwithaworseprognosis.10Glioblastomamultiformeoftenhasringenhancementarounda
centralareaofnecrosis(Fig.4).Tumorassociatedcystsaremorecommonwiththeastrocytomas.The
highergradelesionsalsotendtoexhibitmoreperitumoraledema.Newertechnologiessuchasmagnetic
resonancespectroscopycanhelpinthedifferentialdiagnosisofintracraniallesions.Gliomastendto
demonstratedecreasedNacetylaspartate,increasedcholine,anddecreasedcreatinelevels.Alactatepeak
iscommoninhighergradetumors.11Thediagnosisisultimatelymadehistologicallyaftersurgicalbiopsy
orresection.Figure5showsahematoxylineosinslidefromanoligodendroglioma,andFigure6
representsaglioblastomamultiformeatlowpower.Asweincreaseourunderstandingofthemolecular
geneticsoftumors,thistechnologywillplayanincreasingroleintumordiagnosis(seelater,Advances).
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Treatment
PharmacologicTreatment
Initialtherapyissymptombasedandusuallyinvolvestheuseofsteroidsandanticonvulsantmedication.I
generallypreferdexamethasone(Decadron)asthesteroidofchoice.Foralltumorsotherthanlymphomas,
steroidsareusedsecondarytotheirantiedemafunction.Sideeffectscanbesignificant,andallpatients
shouldbetreatedwithahistamine2(H2)receptorblocker.Thedoseofsteroidsshouldbetailoredforeach
patientandassessedonaregularbasis.Itendtoavoidlatenightdosingifpossible,becauseitcanleadto
sleepdisturbancesandbehavioralproblems.Thetypicaldexamethasonedosageusedbymostphysicians
preoperativelyis4mg,POorIV,every6hours,andthedoseistaperedpostoperatively.Patientsneedto
befollowedcloselyduringthetaperingperiod.Antiepilepticdrugpracticehashistoricallydependedonthe
neurosurgeon'spreference,andmostpatientsarestartedonprophylacticanticonvulsants.TheAmerican
AcademyofNeurologyissuedapositionstatementinMay200012thatrecommendednotusing
prophylacticanticonvulsantsinpatientswhohavenewlydiagnosedbraintumorsandwhohaveneverhad
aseizure.Ifpatientsneedtobemaintainedonanantiepilepticdrug,Iattempttoconvertthemtoa
medicationthatwillnotaffecttheliver'scytochromeP450system(Table2),becausethiscouldaffect
chemotherapeuticdruglevelsifbothdrugsaremetabolizedintheliver.
Table2:Anticonvulsants

GenericName

TradeName

AntiepilepticDrugsthatCauseModestornoInductionofHepaticMetabolic
Enzymes
Gabapentin

Neurontin

Lamotrigine

Lamictal

Valproicacid

Depakene,
Depakote

Felbamate

Felbatol

Levetiracetam

Keppra

Tiagabine

Gabitril

Topiramate

Topamax

Zonisamide

Zonegran

AntiepilepticDrugsThatInduceHepaticMetabolicEnzymes
Phenytoin

Dilantin

Carbamazepine

Tegretol

Phenobarbital

Phenobarbital

Primidone

Mysoline

Oxcarbazepine

Trileptal

2003TheClevelandClinicFoundation.
Surgery,Radiation,andChemotherapy
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Mostpatientswillundergoasurgicalprocedurefordiagnosticandtreatmentpurposes.Forpatientswith
meningiomaorPMBT,locationusuallydefinesthesurgicalrisk.Formeningiomas,ifthetumorislocated
inproximitytoavenoussinus,amagneticresonancevenogramisgenerallyusedand,ifthesinusispatent,
itusuallyrepresentsahighersurgicalrisk.Surgeonsmayelecttocompletecerebralangiographyandhave
thepatientundergotumorembolizationbeforesurgicalresectiontodecreasebleedingcomplications.
Postsurgicaltreatmentsincludeobservation,usuallyforWHOIandIImeningiomasthatundergoagross
totalresectionfocusedexternalbeamradiationforsymptomatictumorsthatcannotberesected,recurrent
tumors,orhighlyaggressivetumorschemotherapy(theSouthwestOncologyGroupcurrentlyhasan
ongoinghydroxyureastudyforbenignmeningiomas)orhormonemodulation,becausemany
meningiomasexpressestrogenorprogesteronereceptors,orboth.However,antihormonaltherapy(anti
estrogentamoxifenortheantiprogestinagentmifepristone)hasnotbeenshowntobeeffectiveinclinical
trials.13Interferonalfa2bhasbeenusedwithsomesuccessforhighergrademeningiomas.14
Forallgradesofglialtumors,surgicalresectionisoftenrecommendedhowever,bytheverynatureof
theirinvasiveness,theycannotbecuredsurgically.Aglioblastomamultiformebeforeandaftersurgical
resection(seeFig.4)demonstrateswhatisreferredtoasagrosstotalresection.Dependingonthetumor
histology,grade,andpatient'sfunctionallevel(Karnofskyperformancestatus[KPS],Table315),patients
areusuallytreatedaftersurgery(biopsyorresection)withexternalbeamradiotherapyorchemotherapy.
Radiationtherapytypicallyisadministeredovera6weekperiodwithlimitedfieldexposure(i.e.,notthe
wholebrain).Patientsreceiveapproximately6000cGyin30fractions(200cGyperfraction).
Oligodendrogliomasareusuallymorechemosensitivethanastrocytomas,andhenceradiotherapyisoften
delayedforthesetumors.10Historically,oligodendrogliomasandanaplasticastrocytomashavebeen
treatedwithprocarbazinelomustinevincristine(PCV)chemotherapy,andglioblastomamultiformehas
beentreatedwithcarmustine(BCNU).TheU.S.FoodandDrugAdministration(FDA)hasapprovedthe
useoftemozolomide(Temodar)forrecurrentanaplasticastrocytomashowever,itisclinicallybeingused
fortumorsofallgrades,includingmeningiomas.ThelastseveralyearshaveseenanincreaseinphasesI
andIIclinicaltrials.ThroughourinvolvementinNewApproachestoBrainTumorTherapy(NABTT),a
NationalCancerInstitutesponsoredconsortiumof11institutions,newandinnovativetreatmentsare
beingdeveloped.
Table3:KarnofskyPerformanceStatus

Score

Description

100

Normalnocomplaints,noevidenceofdisease

90

Abletocarryonnormalactivityminorsymptoms

80

Normalactivitywitheffortsomesymptoms

70

Caresforselfunabletocarryonnormalactivities

60

Requiresoccasionalassistancecaresformostneeds

50

Requiresconsiderableassistanceandfrequentcare

40

Disabledrequiresspecialcareandassistance

30

Severelydisabledhospitalizedbutdeathnotimminent

20

Verysickactivesupportivecareneeded

10

Moribundfatalprocessesareprogressingrapidly

Dead

DatafromKarnofskyD,AbelmanW,CraverL,BurchenalJ:Theuseofnitrogenmustardsinthe
palliativetreatmentofcarcinoma.Cancer19481:634656.
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Outcomes
Meningiomas
Theoverallprognosisformeningiomasisgoodand,asexpected,somewhatdependsontumor
histopathology.Becausemanymeningiomasarefoundincidentally,observationmaybereasonablefor
manypatients.Radhakrishnanandcolleagues3followed57asymptomaticmeningiomasfor32months.
Noneofthepatientsbecamesymptomatic.Asubsetof10patientsshowedgrowthratesof0.24cm/year
however,35patientsshowednogrowthduringanaverage29monthfollowup.Inasingleseriesof1799
meningiomasfrom1582patientsfollowedforanaverageof13yearsafterresection,thenonrecurrence
ratewas93%ofWHOItumors,65%ofWHOII,and27.3%ofWHOIII.16Otherstudieshaveshown
higherrecurrenceratesaftersurgeryalone.17Forpatientsundergoingsubtotalresectionandradiation
therapy,the5yearprogressionfreesurvivalforWHOgradesIandIIwas98%and,forWHOIII,slightly
lessthan50%.18
Stereotacticradiosurgeryisnowbeingusedmorecommonly,butlongtermfollowupdataarelimited.
Lunsford19hasshown4yearcontrolratesof92%forbenignmeningiomastreatedwithstereotactic
radiosurgery.Therolesofhydroxyurea,temozolomide,tamoxifen,mifepristone,andinterferonalfa2b
remaintobedetermined.Severalofthesearebeingusedinclinicaltrialsbutasofnowplaynorealrolein
initialmanagementandareusedwhennoothertreatmentoptionsexist.
Gliomas
Outcomeforgliomasisbasedontumorpathologyorgrade.Foroligodendrogliomas,Iretrospectively
reviewedthelast96oligodendrogliomashistologicallyanalyzedatourinstitution.Prognosiswas
correlatedbestwithchromosome1pdeletion,notageortumorpathologygrade(alsoseelater,
Advances).20Cairncrossandassociates10haveshownamediansurvivaltimeofatleast10yearsin
anaplasticoligodendrogliomaswithacombined1p19qdeletion.TheRadiationTherapyOncologyGroup
(RTOG)hascompletedaphaseIIIstudyevaluatingthelongtermoutcomesoflowgradegliomas
(astrocytomas,oligodendrogliomas,andmixedoligoastrocytomas).Thestudy(RTOG9802)stratified
patientsintoanobservationarm(age<40yearsandgrosstotalresectionoftumor)andtreatmentarm(age
>40yearsplusbiopsyorsubtotaltumorresection,orboth)thatrandomizedpatientstoexternalbeam
radiationaloneorexternalbeamradiationfollowedbyPCVchemotherapy.ThestudyclosedJune2002,
withtheresultspendingatthistime.
Forhighergradeastrocytictumors,theRTOGhasreviewed1578anaplasticastrocytomaglioblastoma
multiformepatientsenteredinthreetrialsfrom1974to1989andperformedrecursivepartitionanalysis
(RPA).21Twentysixpretreatmentcharacteristicsandsixtreatmentrelatedvariableswereanalyzed.Based
onthisanalysis,sixclassesweredeveloped(Table4).Itwillbeimportantinfuturestudiesthatpatient
outcomesfornewtreatmentsarestratifiedbasedonRPA.
Table4:RecursivePartitionAnalysis

Age
(yr)

KPS

Description

Median
Survival(mo)

2yrSurvival
(%)

Anaplasticastrocytoma,normalmentalstatus

58.6

76

70

Anaplasticastrocytoma,symptomduration>3mo

37.4

68

Class
I
<50
Class
II
50

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100
Class
III
<50

Anaplasticastrocytoma,abnormalmentalstatus

<50

90
100

GBM

<50

<90

50

70
100

Anaplasticastrocytoma,symptoms%3mo

50

70
100

GBM,partialorcompleteremoval,andworking
neurologicfunction

50

70
100

GBM,partialorcompleteresection,nonworking
neurologicfunction

50

70
100

GBM,biopsy,radiationdose>5440cGy

50

<70

Normalmentalstatus

<70

Abnormalmentalstatus,radiationdose5440cGy

17.9

35

11.1

15

8.9

4.6

Class
IV

Class
V

Class
VI
50

GBM,glioblastomamultiformeKPS,Karnofskyperformancestatus(seeTable3).
DatafromReifenbergerJ,ReifenbergerG,LiuL,etal:Moleculargeneticanalysisofoligodendroglial
tumorsshowspreferentialallelicdeletionson19qand1p.AmJPathol1994145:11751190.
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Advances
Themajoradvancesinbraintumorunderstandingandtreatmentoverthepast5yearshavecomefromour
understandingofoligodendrogliomas,whichhavespecificmoleculargeneticalterationsthatdistinguish
themfromastrocytomas.Alleliclossofchromosomes1pand19qisamolecularsignatureof
oligodendrogliomasandoccursin50%to70%ofWHOIIandIIIoligodendrogliomas.22Molecular
testingofbraintumorshelpsdeterminetheirtreatment.Thelossofheterozygosity(LOH)ofchromosome
1pand19qarepredictiveofchemosensitivityforoligodendrogliomas,regardlessoftumorhistology,KPS
score,orage.20Figure7showshowchromosomalLOHisdeterminedinthemolecularlaboratory.The
integrityofchromosome1pand19qcanbeevaluatedbyfluorescenceinsituhybridization(FISH)andthe
polymerasechainreactionassay.
Cairncrossandcolleagues10werethefirsttoshowthisrelation.Theyinitiallylookedat39patientswith
anaplasticoligodendrogliomasandcorrelatedchromosome1pstatuswithtreatmenteffect.Theyfoundthat
alleliclossofchromosome1pisasignificantpredictorofchemosensitivityandthatcombinedlossof1p
and19qshowsasignificantassociationwithchemosensitivityandrecurrencefreesurvival.These
conditionswerestronglyassociatedwithlongeroverallsurvival,andtestsforthesedisordersarenowdone
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routinelyonallmygliomapatients.
Themolecularstoryformalignantgliomasismuchmorecomplicated(seeFig.1).Thepresenceofan
epidermalgrowthfactorreceptor(EGFR)likelyindicatesaprimary(denovo)glioblastomamultiforme,
whereasitsabsencesuggestsasecondaryglioblastomamultiforme.Mutationsofp53,ontheotherhand,
areseenmostcommonlyinsecondaryglioblastomamultiformeandEGFRandp53mutationsarenot
foundtogether.Treatmentsarecurrentlybeingdevelopedtotargetthesereceptors.Atmyinstitution,an
EGFRantagonisterlotinib(Tarceva,OSI774)trialhasbeeninitiated.
Thus,althoughmortalitystatisticsformostprimarybraintumorshavenotchangedsignificantlyoverthe
past10years,morbidityandourunderstandingofthemolecularbasisfortumordevelopmenthave
changed.Newstrategiesaimedattargetedsitesontumorsarenowbeingdeveloped.Welookforwardto
thechallenge.
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Summary
Primarybraintumorsrepresentonly2%ofallcancers,with35,000newcasesdiagnosedeachyear
intheUnitedStates.Meningiomasoccuratarateof7.8per100,000peryear,butonly25%are
believedtobesymptomatic,withtheothersbeingfoundincidentally.Themostcommonly
diagnosedprimarybraintumorinadultsistheglioblastomamultiforme.
Onlyabout5%ofprimarybraintumorshaveknownhereditaryfactors.
Formeningiomas,thethreemostcommonsymptomsareheadaches,mentalstatuschanges,and
paresis,andthemostcommonsignsareparesis,normalexaminations,andmemoryimpairment.For
primarymalignantbraintumors,themostcommonsignsandsymptomsareseizuresandheadache.
Computedtomographyisprobablyusedmostoftenastheinitialimagingstudy,butmagnetic
resonanceimagingisconsideredtobethegoldstandardwhendonewithandwithoutgadolinium
contrast.
Initialtherapyissymptombasedandusuallyinvolvestheuseofsteroidsandanticonvulsant
medication.
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