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Centralnervoussystemtuberculosis

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Centralnervoussystemtuberculosis
Author
JohnMLeonard,MD

SectionEditors
CFordhamvonReyn,MD
MorvenSEdwards,MD

DeputyEditor
ElinorLBaron,MD,DTMH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2015.|Thistopiclastupdated:Mar16,2015.
INTRODUCTIONCentralnervoussystem(CNS)tuberculosis(TB)includesthreeclinicalcategories:
tuberculousmeningitis,intracranialtuberculoma,andspinaltuberculousarachnoiditis.Allthreecategoriesare
encounteredfrequentlyinregionsoftheworldwheretheincidenceofTBishighandtheprevalenceofpost
primarydisseminationiscommonamongchildrenandyoungadults[1,2].Inregionswheretheincidenceratesare
low,suchasNorthAmericaandWesternEurope,extrapulmonarymanifestationsofdiseasesareseenprimarilyin
adultswithreactivationinfection,andthedominantformofCNSdiseaseismeningitis.
Thepathogenesis,clinicalpresentation,diagnosis,andtreatmentofcentralnervoussystemtuberculosiswillbe
reviewedhere.ThegeneralprinciplesoftreatmentofTBarediscussedseparately.(See"Treatmentofpulmonary
tuberculosisinHIVuninfectedadults".)
PATHOGENESISDuringthebacillemiathatfollowsprimaryinfectionorlatereactivationtuberculosis(TB),
scatteredtuberculousfoci(tubercles)areestablishedinthebrain,meninges,oradjacentbone.(See"Natural
history,microbiology,andpathogenesisoftuberculosis".)
Thechanceoccurrenceofasubependymaltubercle,withprogressionandruptureintothesubarachnoidspace,is
thecriticaleventinthedevelopmentoftuberculousmeningitis[3].Thewidespreadanddensedistributionof
infectiousfociseeninassociationwithprogressivemiliarytuberculosisgreatlyincreasesthechancethatjuxta
ependymaltubercleswillbeestablished.(See"Epidemiologyandpathologyofmiliaryandextrapulmonary
tuberculosis".)
Consequently,meningitisdevelopsmostcommonlyasacomplicationofpostprimaryinfectionininfantsand
youngchildrenandfromchronicreactivationbacillemiainolderadultswithimmunedeficiencycausedbyaging,
alcoholism,malnutrition,malignancy,humanimmunodeficiencyvirus(HIV)infection,ordrugs(eg,tumornecrosis
factor[TNF]alphainhibitors).Advancingageorheadtraumamayalsoleadtodestabilizationofanestablished
quiescentfocusresultinginmeningitisintheabsenceofgeneralizedinfection.
Thespillageoftubercularproteinintothesubarachnoidspaceproducesanintensehypersensitivityreaction,giving
risetoinflammatorychangesthataremostmarkedatthebaseofthebrain.Threefeaturesdominatethepathology
andexplaintheclinicalmanifestations[3,4]:
Proliferativearachnoiditis,mostmarkedatthebaseofthebrain,eventuallyproducesafibrousmassthat
encasesadjacentcranialnervesandpenetratingvessels.
Vasculitiswithresultantaneurysm,thrombosis,andinfarctionaffectsvesselsthattraversethebasilaror
spinalexudateorarelocatedwithinthebrainitself[5].Multiplelesionsarecommonandavarietyofstroke
syndromesmayresult,involvingthebasalganglia,cerebralcortex,pons,andcerebellum[6].Intracranial
vasculitisisacommonfeatureofautopsystudiesandamajordeterminantofresidualneurologicdeficits.In
oneautopsystudyof27cases,forexample,phlebitisandvaryingdegreesofarteritisweredemonstratedin
22cases,includingeightpatientswithassociatedhemorrhagiccerebralinfarction[7].
Communicatinghydrocephalusresultsfromextensionoftheinflammatoryprocesstothebasilarcisternsand
impedanceofcerebrospinalfluidcirculationandresorption.Obstructionoftheaqueductdevelopsless
frequently,fromcontractionofexudatesurroundingthebrainstemorfromastrategicallyplacedbrainstem
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tuberculoma.
HostsusceptibilityTheTolllikereceptorpathwayappearstoinfluencethesusceptibilityofmantotuberculous
meningitisthiswasillustratedinacasepopulationstudydesigninvolving175HIVuninfectedpatientswith
tuberculousmeningitis,183HIVuninfectedpatientswithpulmonarytuberculosis,and392controlpatients[8].A
polymorphisminTollinterleukin1receptordomaincontaininganadaptorproteinthatmediatessignalingfrom
mycobacteriaactivatedTolllikereceptorswasassociatedwithsusceptibilitytomeningealtuberculosis(oddsratio
[OR]3.0)andtopulmonarytuberculosis(OR1.6).Thepolymorphismwasalsoassociatedwithdecreasedwhole
bloodinterleukin6production,suggestingimmunomodulationasamechanismforsusceptibility.
FORMSOFCNSTUBERCULOSIS
TuberculousmeningitisTuberculousmeningitisaccountsforabout1percentofallcasesoftuberculosis(TB)
and5percentofallextrapulmonarydiseaseinimmunocompetentindividuals[9].AlthoughpulmonaryTBinthe
UnitedStateshasdeclined,thenumberofmeningealTBcaseshaschangedlittleandthecasefatalityratio
remainsrelativelyhigh(15to40percent)despiteeffectivetreatmentregimens[9,10].
Earlyrecognitionoftuberculousmeningitisisofparamountimportancebecausetheclinicaloutcomedepends
greatlyuponthestageatwhichtherapyisinitiated.Empiricantituberculoustherapyshouldbestartedimmediately
inanypatientwithmeningitissyndromeandcerebrospinalfluid(CSF)findingsoflowglucoseconcentration,
elevatedprotein,andlymphocyticpleocytosisifthereisevidenceofTBelsewhereorifpromptevaluationfailsto
establishanalternativediagnosis.SerialexaminationoftheCSFbyacidfaststainandcultureisthebest
diagnosticapproach.Smearsandcultureswillyieldpositiveresultsevendaysaftertreatmenthasbeeninitiated.
Nucleicacidamplification(NAA)testingalsomaybehelpful(See'Diagnosis'below.)
ClinicalmanifestationsTypically,patientswithtuberculousmeningitispresentwithasubacutefebrile
illnessthatprogressesthroughthreediscerniblephases[1114]:
Theprodromalphase,lastingtwotothreeweeks,ischaracterizedbytheinsidiousonsetofmalaise,
lassitude,headache,lowgradefever,andpersonalitychange.
Themeningiticphasefollowswithmorepronouncedneurologicfeatures,suchasmeningismus,protracted
headache,vomiting,lethargy,confusion,andvaryingdegreesofcranialnerveandlongtractsigns.
Theparalyticphasesupervenesasthepaceofillnessacceleratesrapidlyconfusiongiveswaytostuporand
coma,seizures,andoftenhemiparesis.Forthemajorityofuntreatedpatients,deathensueswithinfiveto
eightweeksoftheonsetofillness.
Itisusefultocategorizepatientsonpresentationbythestageofillness,baseduponthementalstatusandfocal
neurologicsigns[15]:
StageIpatientsarelucidwithnofocalneurologicsignsorevidenceofhydrocephalus.
StageIIpatientsexhibitlethargy,confusiontheymayhavemildfocalsigns,suchascranialnervepalsyor
hemiparesis.
StageIIIrepresentsadvancedillnesswithdelirium,stupor,coma,seizures,multiplecranialnervepalsies,
and/ordensehemiplegia.
Aboutonethirdofpatientsonpresentationhaveunderlyinggeneralized(miliary)tuberculosis,inwhichcasecareful
funduscopicexaminationoftenshowschoroidaltubercles(image1).Thesearemultiple,illdefined,raisedyellow
whitenodules(granulomas)ofvaryingsizeneartheopticdisk.Ifpresentinapatientwithmeningitis,choroidal
tuberclesareavaluablecluetotheetiologicdiagnosis.(See"Tuberculosisandtheeye".)
SignsofactiveTBoutsidethecentralnervoussystem(CNS)areofdiagnosticimportifpresentbutareoften
absentornonspecific.Abnormalitiesonchestradiographmaybeseeninhalfofcases,rangingfromfocallesions
toasubtlemiliarypattern.Atuberculinskintestwillbepositiveinthemajority[11,12],althoughanegativeresult
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doesnotexcludethediagnosis.(See"Diagnosisoflatenttuberculosisinfection(tuberculosisscreening)inHIV
uninfectedadults".)
Caseswithatypicalfeaturesthatmimicotherneurologicconditionsareimportanttorecognize.Asanexample,
patientsmaypresentwithanacute,rapidlyprogressive,meningiticsyndromesuggestingpyogenicmeningitisor
withaslowlyprogressivedementiaovermonthsorevenyearscharacterizedbypersonalitychange,social
withdrawal,lossoflibido,andmemorydeficits.Lesscommonisanencephaliticcoursemanifestedbystupor,
coma,andconvulsionswithoutovertsignsofmeningitis[16].
DiagnosisThediagnosisofCNSTBcanbedifficultmaintainingahighdegreeofsuspicionisvitalinorder
toinitiatetherapypromptly.Diagnostictoolsconsistofcerebrospinalfluidexamination(includingcultureand
nucleicacidtesting)andradiography.
SpinalfluidexaminationTheexaminationofcerebrospinalfluidspecimensisofcriticalimportanceto
earlydiagnosisoftuberculousmeningitis.Typically,theCSFformulashowselevatedproteinandloweredglucose
concentrationswithamononuclearpleocytosis[17,18].CSFproteinrangesfrom100to500mg/dLinmost
patientshowever,patientswithsubarachnoidblockmayshowextremelyhighlevelsintherangeof2to6g/dL,
associatedwithxanthochromiaandapoorprognosis.TheCSFglucoseislessthan45mg/dLin80percentof
cases.TheusualCSFcellcountisbetween100and500cells/microL.
Earlyinthecourseofillness,thecellularreactionisoftenatypicalwithonlyafewcellsorwithpolymorphonuclear
leukocyte(PMN)predominance.Suchcasesusuallyrapidlychangetoalymphocyticcellularresponseon
subsequentCSFexaminations.Uponinitiationofantituberculouschemotherapy,theCSFofsomepatientsbriefly
revertstoaPMNcellularreaction,associatedwithtransientclinicaldeterioration("therapeuticparadox")[19].
CultureandsensitivityTheimportanceofrepeated,carefulexaminationandcultureofCSF
specimensforMycobacteriumtuberculosiscannotbeoveremphasized.Ingeneral,aminimumofthreeserial
lumbarpuncturesshouldbeperformedatdailyintervals,althoughempirictherapyneednotbedelayedduringthis
time.Inoneseries,37percentofcaseswerediagnosedonthebasisofaninitialpositiveacidfastbacilli(AFB)
smearthediagnosticyieldincreasedto87percentwhenuptofourserialspecimenswereexamined,eventhough
antituberculoustherapyhadbeenadministeredbeforeapositivesmearwasobtainedinsomecases[12].
Inastudyincluding132adultswithclinicaltuberculousmeningitis,abacteriologicdiagnosiswasachievedin82
percentofcasesAFBsmearandculturewerepositivein58and71percentofcases,respectively[20].The
sensitivityoftheAFBsmearofspinalfluidmaybeenhancedbyattentiontothefollowingprinciples[12,17,20]:
Itisbesttousethelastfluidremovedatlumbarpuncture,andrecoveryoftheorganismimprovesifalarge
volume(10to15mL)isremoved.
Organismscanbedemonstratedmostreadilyinasmearoftheclotorsediment.Ifnoclotforms,theaddition
of2mLof95percentalcoholgivesaheavyproteinprecipitatethatcarriesbacillitothebottomofthetube
uponcentrifugation.
0.02mLofthecentrifugeddepositshouldbeappliedtoaglassslideinanareanotexceedingonecentimeter
indiameterandstainedbythestandardKinyounorZiehlNeelsenmethod.
Between200and500highpoweredfieldsshouldbeexamined(approximately30minutes),preferablyby
morethanoneobserver.
NucleicacidtestsCSFspecimensshouldbesubmittedfornucleicacidtestingwheneverpossible,
particularlyinthesettingofhighclinicalsuspicionandnegativeAFBstaining.
WeareinagreementwiththeWorldHealthOrganization,whichhasrecommendeduseoftheXpertMTB/RIF
assayasaninitialtestfordiagnosisoftuberculousmeningitis[2128].Inasystemicreviewandmetaanalysis
including18studies,thesensitivityandspecificityfortheXpertMTB/RIFassayincerebrospinalfluid(compared
withculture)were81and98percent,respectively[27].
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TheassayMTBDRplusisamolecularprobecapableofdetectingrifampinandisoniazidresistancemutations
(rpoBgeneforrifampinresistancekatGandinhAgenesforisoniazidresistance)[29].Theassayhasbeenshown
tobeusefulfordetectionofdrugresistanceforCSFsamplesthathaveapolymerasechainreaction(PCR)
positiveresult[30].(See"Diagnosis,treatment,andpreventionofdrugresistanttuberculosis",sectionon'Nucleic
acidtests'.)
RadiographyComputedtomography(CT)andmagneticresonanceimaging(MRI)havegreatly
improvedcharacterizationandmanagementofCNSinfections[31].Inpatientswithtuberculousmeningitis,CT
andMRIcandefinethepresenceandextentofbasilararachnoiditis(image2),cerebraledema,infarction,and
hydrocephalus(image3).Intwolargecommunitybasedserieshydrocephaluswasseeninapproximately75
percentofpatients,basilarmeningealenhancementin38percent,cerebralinfarctsin15to30percent,and
tuberculomasin5to10percent[32,33].AcaseseriesfromHongKongdocumentedhydrocephaluson
presentationin9of31patientswithtuberculousmeningitishydrocephalusoccurredafterthestartof
antituberculoustherapyinonlyoneoftheremaining22patients[34].
Thefollowingobservationscanbederivedfromareviewofselectedclinicalseries[32,33,35]:
Inapatientwithcompatibleclinicalfeatures,CTorMRIevidenceofbasilarmeningealenhancement
combinedwithanydegreeofhydrocephalusisstronglysuggestiveoftuberculousmeningitis(image3).
TheCTscanisnormalinapproximately30percentofcaseswithstageImeningitis,andpatientswitha
normalscannearlyalwaysrecovercompletelyontherapy.
Hydrocephaluscombinedwithmarkedbasilarenhancementisindicativeofadvancedmeningiticdiseaseand
carriesapoorprognosis.Markedbasilarenhancementcorrelateswellwithvasculitisand,therefore,witha
riskforbasalgangliainfarction.
MRIissuperiortoCTindefininglesionsofthebasalganglia,midbrain,andbrainstemandforevaluatingallforms
ofsuspectedspinalTB(image2)[36,37].(See"Skeletaltuberculosis".)
DifferentialdiagnosisThedifferentialdiagnosisoftuberculousmeningitisisthatofasubacuteorchronic
meningitissyndromewithaCSFformulacharacterizedbyalymphocyticpleocytosis,loweredglucose
concentration,andahighproteincontent.Thisisseenmostcommonlywithcryptococcosisandoccasionallywith
otherdeepseatedgranulomatousfungalinfections,brucellosis,andneurosyphilis.Asimilarsyndromemaybe
encounteredinpatientswithaparameningealsuppurativeinfection(eg,sphenoidsinusitis,brainabscess,orspinal
epiduralspaceinfection).PatientswithherpesencephalitismayexhibitsimilarCSFfindings,includingmild
loweringofCSFglucoseconcentration.CarefulevaluationforCNStuberculosisiswarrantedinthepatient
suspectedofanyofthediagnoseslistedintheTable(table1).
TuberculomaTuberculomasareconglomerategranulomatousfociwithinthebrainparenchymatheymaybe
observedonhistopathologyorradiographicimaging(image4)[38].Theydevelopfromcoalescingtubercles
acquiredduringanearlierperiodofhematogenousbacillemia.Centrallylocatedlesionsmayreachconsiderable
sizewithoutproducingmeningealinflammation.Clinicallysilentsingleormultiplenodularenhancinglesionsare
commonlyseeninthesettingofmeningitisoccasionally,theyareseeninpatientswithmiliarytuberculosisand
nomeningitis[39,40].Theselesionsgenerallydisappearontherapybutmayhealwithcalcification.
Symptomaticintracranialmasslesions("clinicaltuberculomas")areobservedmostfrequentlyinindividualsfrom
areaswheretheprevalenceoftuberculosisishigh.Typically,achildoryoungadultpresentswithseizureor
headacheoccasionally,hemiplegiaorsignsofraisedintracranialpressureareobserved[41,42].OncontrastCT
imaging,earlystagelesionsarelowdensityorisodense,oftenwithedemaoutofproportiontothemasseffectand
littleencapsulation[4143].Laterstagetuberculomasarewellencapsulated,isodenseorhyperdense,andhave
peripheralringenhancement.
Symptomsofsystemicillnessandsignsofmeningealinflammationarerarelyobserved.Lumbarpunctureis
usuallyavoidedbecauseofconcernforraisedintracranialpressureandriskofbrainstemherniationinthe
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occasionalreportedcasewherecerebrospinalfluidhasbeenexamined,thefindingsarenormalornonspecific.The
diagnosisismadeinrelationtoclinical,epidemiologic,andradiographicfeaturesorbyneedlebiopsy.Unlessthe
locationofthelesionthreatensobstructivehydrocephalusorbrainstemherniation,surgicalinterventionshouldbe
avoidedasitmayprecipitateseveremeningitis.
DifferentialdiagnosisThediagnosticdistinctionbetweenclinicaltuberculomaandintraparenchymal
neurocysticercosis(NCC)canbechallenging,particularlyinchildren.BothCNSinfectionssharesimilarclinical,
epidemiologic,andradiographicfeatures.(See"Clinicalmanifestationsanddiagnosisofcysticercosis".)
Inadults,NCCisapleomorphicdiseasethattendstooccurmonthstoyearsafterprimaryinfection,andbrain
imagingusuallydemonstratesmultiplelesionsofvaryingageandmorphology.Therangeofradiographicfeatures
includescysticlesionsshowingthescolex,multiplecysts,giantcyst,ringordiscenhancinglesions,andmultiple
punctuateparenchymalcalcifications.CaseswithsolitaryCNSgranulomasmaybemisdiagnosedastumorand
identifiedonlyaftersurgicalresection.
Clinicaltuberculomaarisesasanearlypostprimaryinfectioneventandtypicallypresentsasasingle,large,dense
mass.ChildrenwithearlyNCCmaypresentwithfocalseizuresandasingleringenhancinglesion,oftenwith
surroundingedema.Insuchcases,thedistinctionbetweentuberculomaandNCCrequirescarefulattentionto
subtleradiographicfeaturescombinedwiththoroughevaluationforevidenceoftuberculosiselsewhereinthebody
[44].
SpinaltuberculousarachnoiditisSpinaltuberculousarachnoiditisisobservedmostcommonlyinendemic
areas[1,2].Thepathogenesisissimilartothatofmeningitis,withfocalinflammatorydiseaseatsingleormultiple
levelsleadingtogradualencasementofthespinalcordbyagelatinousorfibrousexudate.
Symptomsdevelopandprogressslowlyoverweekstomonthsandmayculminatewithameningitissyndrome.
Patientspresentwiththesubacuteonsetofnerverootandcordcompressionsigns:spinalorradicularpain,
hyperesthesiaorparesthesiaslowermotorneuronparalysisandbladderorrectalsphincterdysfunction[45].
Vasculitismayleadtothrombosisoftheanteriorspinalarteryandinfarctionofthespinalcord.Otherformsinclude
extraduralorintraduraltuberculomaandepiduralabscess.
Thediagnosisofspinaltuberculousarachnoiditisisbasedonfindingsofelevatedcerebrospinalfluidproteinlevels
andMRIfindingsofnodulararachnoiditiscombinedwithtissuebiopsy.
Thetreatmentforthisformofdiseaseisthesameasfortuberculousmeningitis.
TREATMENTSpecificantituberculouschemotherapyshouldbeinitiatedonthebasisofstrongclinical
suspicionandshouldnotbedelayeduntilbacteriologicproofhasbeenobtained.Theclinicaloutcomedepends
greatlyonthestageatwhichtherapyisinitiatedmuchmoreharmresultsfromdelay,evenforonlyafewdays,
thanfrominappropriatetherapyaslongaseffortsarecontinuedtoconfirmthediagnosis.
Antituberculoustherapy
GeneralapproachTreatmentbeginswithan"intensivephase"thatconsistsofafourdrugregimenthat
includesisoniazid,rifampin,pyrazinamide,andafourthdrug,eitherafluoroquinolone(moxifloxacinorlevofloxacin)
oraninjectableaminoglycoside,administereddailyfortwomonths.DrugdosesareshownintheTables(table2
andtable3).Thisisfollowedbya"continuationphase"thatconsistsofisoniazidandrifampinalone(iftheisolate
isfullysusceptible)administereddailyorthreetimesaweek(table2).Ethambutolpenetratespoorlyintoeven
inflamedmeningesandcanbereplacedinstandardtreatmentregimenswithafluoroquinolone(moxifloxacinor
levofloxacin)[46].Aminoglycosidepenetrationisoptimizedduringacuteinflammationanditsvaluebeyondinitial
treatmentisnotclear[46].
Therearenorandomized,controlledtrialstoestablishtheoptimaldrugcombination,dose,ordurationof
antituberculoustherapyforcentralnervoussystem(CNS)tuberculosis.Theprinciplesoftreatmentarethosethat
governthemanagementofpulmonaryTB.Ingeneral,treatmentconsistsofaninitial2monthperiodofintensive
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therapy(withfourdrugs)followedbyaprolongedcontinuationphase(withisoniazidandrifampin)lasting9to12
months,dependingontheclinicalresponseanddrugsensitivityoftheisolate[47,48].Theregimenfortuberculoma
generallywarrantstreatmentdurationof18months.Thenatureanddurationoftreatmentmayrequireadjustment
dependingonindividualpatientcircumstances.(See"TreatmentofpulmonarytuberculosisinHIVuninfected
adults".)
Isoniazid,rifampin,andpyrazinamidearebactericidal,canbeadministeredorally,penetrateinflamedmeninges,
andachievecerebrospinalfluid(CSF)levelsthatexceedtheinhibitoryconcentrationneededforsensitivestrains.
IsoniazidhasexcellentCNSpenetrationandismoreactiveagainstrapidlydividingthansemidormantorganisms.
Rifampinisactiveagainstbothrapidlydividingorganismsandsemidormantsubpopulationsoforganisms.
PyrazinamidereadilypenetratestheCSFandishighlyactiveagainstintracellularmycobacteria.Likewise,
moxifloxacinandlevofloxacinexhibitgoodCNSpenetration[46].
Inthepast,streptomycin(15mg/kgperdayintramuscularly[IM]inadultstoamaximumdoseof1g20to40
mg/kgperdayinchildren)wasaddedtoisoniazidinordertoenhancesterilizationandtoreducetheriskofclinical
relapsefromresistantorganisms.Withtheavailabilityofrifampinandpyrazinamide,relianceuponstreptomycinor
otherdrugsofitsclassisgenerallylimitedtoregionsoftheworldwithhighprevalenceofisoniazidresistance.
DrugresistanceTherearenodefinitiveguidelinesforthedurationoftherapyinpatientswithmultidrug
resistantinfection.Insuchcases,itmaybeadvisabletoextendthedurationoftherapyto18to24months,taking
intoaccounttheseverityofillness,rateofclinicalresponse,andthepatient'simmunestatus.(See"Diagnosis,
treatment,andpreventionofdrugresistanttuberculosis".)
TheprevalenceofCNSinfectioncausedbystrainsresistanttooneormorefirstlinedrugsisincreasing[49].
Thoseatgreatestriskfordrugresistantdiseaseincludeindividualsfromareasoftheworldwheretuberculosis
(TB)isendemic,thosewithahistoryofpreviousantituberculoustreatment,homelessindividuals,andthosewith
exposuretosourcepatientsharboringdrugresistantorganisms.
OnestudyinVietnamincluding180adultswithtuberculousmeningitisnotedresistancetoatleastone
antituberculosisdrugin40percentofisolatesresistancetoisoniazidandrifampinwasobservedin5percentof
cases[50].Combinedisoniazidandrifampinresistancewasstronglypredictiveofdeath(relativeriskofdeath11.6
[95%CI5.226.3])andindependentlyassociatedwithHIVinfection.Similarly,among350casesoftuberculous
meningitisinSouthAfrica,resistancetoisoniazidandrifampinwasobservedin8percentofcases57percentof
patientsdied[51].
GlucocorticoidsIngeneral,glucocorticoidtherapyiswarrantedforHIVuninfectedpatientswithconvincing
epidemiologicorclinicalevidencefortuberculousmeningitis[5255].Urgentwarningsignsthatwarrantprompt
initiationofglucocorticoidsinclude:
Patientswhoareprogressingfromonestagetothenextatorbeforetheintroductionofchemotherapy
Patientswithanacuteencephalitispresentation,especiallyiftheCSFopeningpressureis400mmH2Oor
ifthereisclinicalorcomputedtomographic(CT)evidenceofcerebraledema
Patientswhodemonstrate"therapeuticparadox,"anexacerbationofclinicalsigns(eg,fever,changein
mentation)afterbeginningantituberculouschemotherapy
Spinalblockorincipientblock(CSFprotein>500mg/dLandrising)
HeadCTevidenceofmarkedbasilarenhancement(portendsanincreasedriskforinfarctionofthebasal
ganglia)ormoderateoradvancinghydrocephalus
Patientswithintracerebraltuberculoma,whereedemaisoutofproportiontothemasseffectandthereare
anyclinicalneurologicsigns(alteredmentationorfocaldeficits)
Theregimenconsistsofdexamethasoneorprednisone,asfollows[52]:
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DexamethasoneChildren<25kg:8mg/dayfortwoweeks,thentapergraduallyoverfourtosixweeks.
Adolescentsandadults>25kg:0.3to0.4mg/kg/dayfortwoweeks,then0.2mg/kg/dayweekthree,then
0.1mg/kg/dayweekfour,then4mgperdayandtaper1mgoffthedailydoseeachweektotalduration
approximatelyeightweeks.
PrednisoneChildren:2to4mg/kgperday.Adolescentsandadults:60mg/day.Administerinitialdosefor
twoweeks,thentapergraduallyoverthenextsixweeks(ie,reducedailydoseby10mgeachweek)total
durationapproximatelyeightweeks.
Areviewincludingseventrialsinvolving1140participantsestablishedthatadjunctivecorticosteroidsreducedeath
anddisabilityfromtuberculousmeningitisbyabout30percent[55].
Arandomizedtrialincluding545adolescentsandadultswithCNStuberculosisinVietnamnotedreducedmortality
amongthosewhoreceiveddexamethasone(32versus41percent)[52].Themortalitybenefitwasmostevidentfor
patientswithstageIdisease(17versus30percent),approachedsignificanceforstageII(31versus40percent),
andwasnotsignificantinpatientswithstageIIIdisease(55versus60percent).Therewasnodemonstrable
reductioninresidualneurologicdeficitsanddisabilityamongsurvivingpatientsatninemonthsfollowup.The
survivalbenefitassociatedwithsteroidtherapymayhavebeeninpartduetoareductioninsevereadverseevents
(9.5versus16.6percent),particularlyhepatitis(whichnecessitatedchangesinantituberculosisdrugregimens).No
mortalitybenefitfromdexamethasonewasevidentin98HIVinfectedpatientsincludedinthestudy.
Anotherrandomizedtrialincluding141childrenwithtuberculousmeningitisnotedreducedmortalityamongchildren
withstageIIIdiseasewhoreceivedprednisoneforthefirstmonthoftreatment(4versus17percent)[53].In
addition,thosewhoreceivedprednisoneweremorelikelytohavesubsequentIQ>75(52versus33percent),and
enhancedresolutionofbasalexudateandtuberculomaswasobservedradiographically.
SurgeryPatientswithhydrocephalusmayrequiresurgicaldecompressionoftheventricularsysteminorderto
effectivelymanagethecomplicationsofraisedintracranialpressure.InsuchpatientswithclinicalstageIIdisease,
thecombinationofseriallumbarpunctureandsteroidtherapymaysufficewhilejudgingtheearlyresponseto
chemotherapy.However,surgicalinterventionshouldnotbedelayedinpatientswithstuporandcomaorwhenthe
clinicalcourseoftherapyismarkedbyprogressiveneurologicimpairment[56].
UnlikeotherCNSmasslesions,medicalmanagementispreferredforclinicaltuberculomasunlessthelesion
producesobstructivehydrocephalusorcompressionofthebrainstem.Inthepast,surgicalresectionwasoften
complicatedbysevere,fatalmeningitis.
HIVCOINFECTIONTherearefewreportstoindicatethatcentralnervoussystem(CNS)tuberculosis(TB)isa
widespreadprobleminAIDSpatients[57,58].Inonestudycomparingtheclinicalfeatures,laboratoryfindings,and
mortalityratesinpatientshavingtuberculousmeningitiswithorwithoutHIVinfection,cerebraltuberculomaswere
morecommonintheHIVinfectedgroup(60versus14percent)otherwise,coinfectionwithHIVdidnotalterthe
clinicalmanifestations,cerebrospinalfluid(CSF)findings,orresponsetotherapy[59].
InotherpartsoftheworldwhereTBisendemic,therehavebeenreportsofanincreaseintuberculousmeningitis
inHIVinfectedpatients[6062].Asanexample,inastudyof200patientswithconfirmedmeningitisfrom
Zimbabwe,12percenthadtuberculousmeningitiscomparedwith45percentwithcryptococcalmeningitis[61].
EightypercentofallpatientswithsuspectedmeningitiswereHIVinfectedinthisseriesHIVseropositivitywas88
and100percent,respectivelyforthosewithTBandcryptococcalmeningitis.
PatientswithHIVandCNStuberculosiswhoarenotalreadyonantiretroviraltherapyshoulddelayinitiationof
antiretroviraltherapyuntilaftercompletionofTBtherapy.Timingofinitiationofantiretroviraltherapyisdiscussed
separately.(See"TreatmentofpulmonarytuberculosisinHIVinfectedadults",sectionon'TimingofARTinthe
treatmentnaivepatient'.)
Amongpatientswithtuberculosisandimmunereconstitutioninflammatorysyndrome(IRIS),CNStuberculosis
occursinapproximately12percentofcases,andmortalityofupto30percenthasbeenreported[63].
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Manifestationsincludemeningitis,intracranialtuberculoma,brainabscess,radiculomyelitis,andspinalepidural
abscess[6366].TuberculousmeningitisinthesettingofIRISischaracterizedbyhighCSFneutrophilcountsand
CSFculturepositivityatpresentation[67].
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)
BeyondtheBasicstopics(see"Patientinformation:Tuberculosis(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONS
Clinicalmanifestations
Centralnervoussystem(CNS)tuberculosis(TB)includesthreeclinicalcategories:meningitis,intracranial
tuberculoma,andspinaltuberculousarachnoiditis.(See'Introduction'above.)
Clinicalmanifestationsinpatientswithtuberculousmeningitisprogressthroughthreephases(see'Clinical
manifestations'above):
Theprodromalphase,lastingtwotothreeweeks,characterizedbytheinsidiousonsetofmalaise,
lassitude,headache,lowgradefever,andpersonalitychange.
Themeningiticphasewithmorepronouncedneurologicfeatures(eg,meningismus,protracted
headache,vomiting,lethargy,confusion,andvaryingdegreesofcranialnerveandlongtractsigns).
Theparalyticphase,inwhichthepaceofillnessacceleratesrapidlyconfusiongiveswaytostuporand
coma,seizures,andoftenhemiparesis.
Patientswithtuberculousmeningitisarecategorizedbystageonpresentation,baseduponmentalstatusand
focalneurologicsignsasfollows:
StageIpatientsarelucidwithnofocalneurologicsignsorevidenceofhydrocephalus.
StageIIpatientsexhibitlethargy,confusiontheymayhavemildfocalsigns,suchascranialnerve
palsyorhemiparesis.
StageIIIrepresentsadvancedillnesswithdelirium,stupor,coma,seizures,multiplecranialnerve
palsies,and/ordensehemiplegia.
Tuberculomasareconglomeratecaseousfociwithinthesubstanceofthebrainthatdevelopfromdeep
seatedtuberclesacquiredduringarecentorremotehematogenousbacillemia.(See'Tuberculoma'above.)
Spinaltuberculousarachnoiditisisafocalinflammatorydiseaseatsingleormultiplelevelsproducinggradual
encasementofthespinalcordbyagelatinousorfibrousexudate.(See'Spinaltuberculousarachnoiditis'
above.)
Diagnosis
ThediagnosisofCNSTBcanbedifficult.However,earlyrecognitionisofparamountimportancebecause
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theclinicaloutcomedependsgreatlyuponthestageatwhichtherapyisinitiated.(See'Diagnosis'above.)
Theexaminationofcerebrospinalfluid(CSF)specimensisofcriticalimportancetoearlydiagnosisof
tuberculousmeningitis.Typically,theCSFformulashowselevatedproteinandloweredglucose
concentrationswithamononuclearpleocytosis.(See'Spinalfluidexamination'above.)
Thedemonstrationofacidfastbacilli(AFB)intheCSFremainsthemostrapidandeffectivemeansof
reachinganearlydiagnosis.Werecommendthataminimumofthreelumbarpuncturesbeperformedatdaily
intervals,bearinginmindthatempirictherapyneednotbedelayedduringthistime.(See'Cultureand
sensitivity'above.)
CSFspecimensshouldbesubmittedfornucleicacidtestingwheneverfeasible,particularlyinthesettingof
highclinicalsuspicionandnegativeAFBstaining.WeareinagreementwiththeWorldHealthOrganization,
whichhasrecommendeduseoftheXpertMTB/RIFassayasaninitialtestfordiagnosisoftuberculous
meningitis.(See'Nucleicacidtests'above.)
Magneticresonanceimaging(MRI)issuperiortocomputedtomography(CT)indefininglesionsofthebasal
ganglia,midbrain,andbrainstemandforevaluatingallformsofsuspectedspinalTB.(See'Radiography'
above.)
Treatment
WerecommendinitiationofantituberculoustherapyonthebasisofstrongclinicalsuspicionofCNS
tuberculosisandshouldnotbedelayeduntilproofofinfectionhasbeenobtained(Grade1B).(See
'Treatment'above.)
WeagreewithrecommendationsoftheAmericanandBritishThoracicSocieties,InfectiousDiseaseSociety
ofAmerica,andtheCentersforDiseaseControlandPrevention,whichrecommendaninitialtwomonth
periodofintensivetherapy,withfourdrugs(Grade1B).Theusualfourdrugregimenincludesdailyisoniazid,
rifampin,pyrazinamide,andeithermoxifloxacinorlevofloxacinorstreptomycinforfullysensitiveisolates.
(See'Antituberculoustherapy'above.)
Typically,intensivetherapyisfollowedbyaprolongedcontinuationphaselasting9to12months,depending
onclinicalresponseandestablisheddrugsensitivityoftheisolate.Theusualregimenindrugsensitive
diseaseisisoniazidandrifampin,givendailyorthreetimesaweek.(See'Antituberculoustherapy'above.)
TreatmentofdrugresistantCNSTBmustbeindividualizedandshouldbeguidedbythedrugsusceptibility
patternoftheparticularisolate.Wesuggestextendingthedurationoftherapyto18to24months.(See'Drug
resistance'above.)
Werecommendadjunctiveglucocorticoidtherapyforallchildrenandadultswithconvincingepidemiologicor
clinicalevidencefortuberculousmeningitis(Grade1A).Dosingissummarizedabove.(See'Glucocorticoids'
above.)
PatientswithHIVandCNStuberculosiswhoarenotalreadyonantiretroviraltherapyshoulddelayinitiation
ofantiretroviraltherapyuntilaftercompletionofTBtherapy.(See'HIVcoinfection'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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40. WeisbergLA.GranulomatousdiseasesoftheCNSasdemonstratedbycomputerizedtomography.Comput
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41. HarderE,AlKawiMZ,CarneyP.Intracranialtuberculoma:conservativemanagement.AmJMed1983
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42. TraubM,ColchesterAC,KingsleyDP,SwashM.Tuberculosisofthecentralnervoussystem.QJMed
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44. SinghiP,RayM,SinghiS,KhandelwalN.Clinicalspectrumof500childrenwithneurocysticercosisand
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45. WadiaNH,DasturDK.Spinalmeningitideswithradiculomyelopathy.1.Clinicalandradiologicalfeatures.J
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46. DonaldPR.Cerebrospinalfluidconcentrationsofantituberculosisagentsinadultsandchildren.Tuberculosis
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52. ThwaitesGE,NguyenDB,NguyenHD,etal.Dexamethasoneforthetreatmentoftuberculousmeningitisin
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53. SchoemanJF,VanZylLE,LaubscherJA,DonaldPR.Effectofcorticosteroidsonintracranialpressure,
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54. GirgisNI,FaridZ,KilpatrickME,etal.Dexamethasoneadjunctivetreatmentfortuberculousmeningitis.
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55. PrasadK,SinghMB.Corticosteroidsformanagingtuberculousmeningitis.CochraneDatabaseSystRev
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57. BraunMM,ByersRH,HeywardWL,etal.Acquiredimmunodeficiencysyndromeandextrapulmonary
tuberculosisintheUnitedStates.ArchInternMed1990150:1913.
58. BerenguerJ,MorenoS,LagunaF,etal.Tuberculousmeningitisinpatientsinfectedwiththehuman
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59. DubMP,HoltomPD,LarsenRA.Tuberculousmeningitisinpatientswithandwithouthuman
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60. SnchezPortocarreroJ,PrezCeciliaE,JimnezEscrigA,etal.Tuberculousmeningitis.Clinical
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64. AsselmanV,ThienemannF,PepperDJ,etal.Centralnervoussystemdisordersafterstartingantiretroviral
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67. MaraisS,MeintjesG,PepperDJ,etal.Frequency,severity,andpredictionoftuberculousmeningitis
immunereconstitutioninflammatorysyndrome.ClinInfectDis201356:450.
Topic8009Version24.0

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GRAPHICS
Choroidaltuberculosis

Miliarychoroids(tubercles)appearasilldefinednodulesvaryingin
sizefrompinpointtoseveraldiscdiametersonfunduscopic
examination.
Reprintedwithpermission.CopyrightAmericanSocietyofContemporary
Ophthalmology.AnnalsofOphthalmology1989.21(6)226.
Graphic61826Version5.0

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MeningealenhancementinTBmeningitisonMRI

ImageAisT1weightedsequencefollowingcontrastandshowsextensivebasilarmeningealenhancemen
ImageBisalsoacontrastenhancedstudyshowingmeningealenhancement(arrows).
MRI:magneticresonanceimagingTB:tuberculous.
CourtesyofAsimMian,MDandGlennBarest,MD.
Graphic98270Version2.0

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HydrocephalusinTBmeningitisonMRI

AT1weightedMRIofthebraininthesagittalprojectionshowshydrocephalusofthelateralventricle(as
andfourthventricle(arrow).ImageBisaFLAIRsequenceinaxialprojectionandshowsmoderate
hydrocephalusofthelateralventricles(asterisks)withtransependymaledema(arrows),anddiffusecer
edemaandeffacementofthesulci(arrowhead).ImageCisaFLAIRsequenceshowinghydrocephalusof
thirdventricle(asterisk),transependymaledema(arrows),andeffacementofthesulci(arrowhead)indic
cerebraledema.
MRI:magneticresonanceimagingTB:tuberculous.
CourtesyofAsimMian,MDandGlennBarest,MD.
Graphic98269Version1.0

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Differentialdiagnosisofcentralnervoussystemtuberculosis
Fungalmeningitis(cryptococcosis,histoplasmosis,blastomycosis,coccidioidomycosis)
Viralmeningoencephalitis(herpessimplex,mumps)
Parameningealinfection(sphenoidsinusitis,brainabscess,spinalepiduralabscess)
Partiallytreatedbacterialmeningitis
Neurosyphilis
Neoplasticmeningitis(lymphoma,carcinoma)
Neurosarcoidosis
Neurobrucellosis
Graphic69843Version2.0

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TuberculomaofthebrainonCTandMRI

AnoncontrastCTscan(A)ofasixyearoldmalepresentingwithleftsided
hemiplegiaandseizuresshowsalargesofttissuedensitymass(asterisk)
containingcentralcalcification(arrowhead)involvingalmosttheentire
visualizedfrontoparietalregion.ImageBisacontrastenhancedCTscan
reformattedinthecoronalplaneandshowsthelargemass(asterisk)with
centralcalcification(arrowhead)andanenhancingborder(arrows).ImageCisa
T1weightedsagittalsequenceshowinganisotohypointenselesion(asterisk).
ImageDisacontrastenhancedT1weightedMRIintheaxialplaneandshows
themass(asterisk)withanenhancingrim(arrows).ImageEisaT2weighted
MRIandshowsthecharacteristiclowintensitymass(asterisk),surrounding
edema(delta),midlineshift(arrowhead),andadilated,partiallyobstructedleft
lateralventricle(arrow).
CT:computedtomographyMRI:magneticresonanceimaging.
CourtesyofFourieBezuidenhout,MD.
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Dosesoffirstlineantituberculosisdrugsforadults*
Drug

Doses

Preparation

Daily

1x/week

2x/week

3x/week

Firstlinedrugs
Isoniazid

Tablets(50mg,100
mg,300mg)elixir(50
mg/5mL)aqueous
solution(100mg/mL)
forintravenousor

5mg/kg
(300mg)

15mg/kg
(900mg)

15mg/kg
(900mg)

15mg/kg
(900mg)

10mg/kg
(600mg)

10mg/kg
(600mg)

10mg/kg
(600mg)

5mg/kg

5mg/kg

5mg/kg

(300mg)

(300mg)

intramuscularinjection
Rifampin

Capsule(150mg,300
mg)powdermaybe
suspendedfororal
administration
aqueoussolutionfor
intravenousinjection

Rifabutin

Capsule(150mg)

(300mg)
Rifapentine

Tablet(150mg,film
coated)

10mg/kg
(continuation
phase)(600
mg)

Pyrazinamide

Tablet(500mg,scored)

Weight
baseddosing
summarized
inseparate
table

Ethambutol

Tablet(100mg,400

Weight

mg)

baseddosing
summarized
inseparate
table

*Dosesperweightisbasedonidealbodyweight.Forpurposesofthisdocument,adultdosingbeginsat
age15years.
Datafrom:BlumbergHM,BurmanWJ,ChaissonRE,etal.AmericanThoracicSociety/CentersforDisease
ControlandPrevention/InfectiousDiseasesSocietyofAmerica:Treatmentoftuberculosis.AmJRespir
CritCareMed2003167:603.
Graphic55978Version3.0

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Suggestedpyrazinamidedoses,usingwholetablets,foradults
weighing40to90kilograms

Weight(kg)*
40to55

56to75

76to90

Daily,mg(mg/kg)

1000(18.2to25)

1500(20to26.8)

2000 (22.2to26.3)

Thriceweekly,mg
(mg/kg)

1500(27.3to37.5)

2500(33.3to44.6)

3000 (33.3to39.5)

Twiceweekly,mg
(mg/kg)

2000(36.4to50)

3000(40to53.6)

4000 (44.4to52.6)

*Basedonestimatedleanbodyweight.
Maximumdoseregardlessofweight.
Reproducedwithpermissionfrom:BlumbergHM,BurmanWJ,ChaissonRE,etal.AmericanThoracic
Society/CentersforDiseaseControlandPrevention/InfectiousDiseasesSocietyofAmerica:Treatmentof
tuberculosis.AmJRespirCritCareMed2003167:603.OfficialJournaloftheAmericanThoracicSociety.
Copyright2003AmericanThoracicSociety.
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Disclosures
Disclosures:JohnMLeonard,MDNothingtodisclose.CFordhamvonReyn,MDNothingtodisclose.MorvenSEdwards,MD
Grant/Research/ClinicalTrialSupport:PfizerInc.[GroupBStreptococcus].Consultant/AdvisoryBoards:NovartisVaccines[GroupB
Streptococcus].ElinorLBaron,MD,DTMHNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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