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Meningitis

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CHAPTER5
INFECTIONSOFTHENERVOUSSYSTEM
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SuppurativeInfections

SubduralEmpyema

TreponemalInfections

FungalandProtozoanInfections

HerpesSimplexEncepalitis
PrionDiseases

Test

BacterialMeningitis

CMVEncephalitis

PathogenesisofPrionDiseases

LearningObjectives
BrainAbscess

Cryptococcosis

MycobacterialInfections

Toxoplasmosis

EnterovirusMeningoencephalitis
PathologyofPrionDiseases

ViralDiseases

HIVInfections

AutoimmuneEncephalitis

CreutzfeldtJakobDisease

BacterialInfections
Thebrainisprotectedfrombacterialinvasionfromtheenvironmentbytheskull,thedura,thearachnoid
membrane,thepia,andtheglialimitans,whichisadensemeshofastrocyticprocessesonthesurfaceof
thebrain.Consequently,mostbacterialinfectionsspreadtothebrainbythebloodstream.Bacteriacan
penetrateintothebrainfromtheenvironmentifthereisabreakinthecontinuityoftheseprotective
layers.Suchadiscontinuitymaybeduetocongenitaldefects(encephalocele,meningomyelocele)ormay
becausedbytraumaorashunt.Bacteriacanalsospreadtothebrainfrominfectedadjacentairsinuses,
themiddleearandthemastoids.Theycanreachthebraineitherdirectlythroughthebone,especiallyin
areaswheretheboneplateisthin,orthroughveins(diploicveins,duralvenoussinuses,intracerebral
veins).Thevariousprotectivelayersmayalsohelpcontaininfectionswithincertainspacesorplanes.

EpiduralAbscess
Anepiduralspacefilledwithadiposetissueexistsnormallyaroundthespinalcord.Aspinalepiduralabscessariseswhenorganisms
fromosteomyelitisortuberculosisofthevertebralcolumnspreadtothisspace.Thereisnoepiduralspacenormallyinthecranium.
However,acranialepiduralabscessmaydevelopwhenbacteriacolonizeatraumaticepiduralhematoma,orwheninfectionfromair
sinusesextendsintheplanebetweentheduraandbone.

SubduralAbscess(SubduralEmpyema)
Infectionmayspreadtothesubduralspacefromairsinusesorfromthemiddleear.The
subduralspaceistraversedbybridgingarteriesandveinsbuthasnovascularnetworkof
itsown.Therefore,antibioticshavenoaccesstothisspace.Treatmentofthesubdural
abscessconsistsofevacuationplusintravenousantibiotics.Epiduralandsubdural
abscessesarecollectionsofpus.Iftheyarelargeenough,theycompressthebrainand
spinalcord,resultinginlossoffunctionandincreasedintracranialpressure.Locally,
Thecoveringsofthebrain

Subdural
empyemaand
brainabscess

neutrophilsdestroytissueswiththeirenzymes.Thisdamageisfollowedbyformation,in
thesubduralspace,ofavascularizedinflamedconnectivetissueandthenafibrousscar.
Histologically,acutesubduralempyemashowsalayerofneutrophilsoverlyingthe
arachnoidmembrane.Theinflammatorycellsmayinfiltratethearachnoidmembraneand

extendintothesubarachnoidspace.

BacterialMeningitis
Bacterialmeningitisistheinfectionofthearachnoidmembrane,subarachnoidspace,andcerebrospinalfluidbybacteria.
Thesubarachnoidspaceisboundedexternallybythearachnoidmembraneandinternallybythepia,anddipsintothebrainalong
bloodvesselsintheperivascular(VirchowRobin)spaces.Itextendsfromtheopticchiasmtothecaudaequinaandsurroundsthebrain
andspinalcordcompletely.
Theinfectionmayspreadtothemeningesfromanadjacentinfectedareasuchassinusitis,otitismedia,andmastoiditisorfromthe
environmentthroughapenetratinginjuryorcongenitaldefect,suchasamenigomyelocele.Mostcommonly,however,meningitis
resultsfromhematogenousdisseminationofbacteria.Themostcommonorganismsofbacterialmeningitisinchildrenandadultsare
StreptococcuspneumoniaeandNeisseriameningitidis.Streptococcuspneumoniaeisdecliningaftertheintroductionof
conjugatedvaccines.Hemophilusinfluenzae,onceverycommoninchildren,isnowrarethankstovaccination.Innewborns,themost

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commonorganismsarebetahemolyticStreptococcusgroupB(Streptococcusagalactiae)andEschericiacoli.Inbabies,group
Bsreptococcalinfectionisfrequentlyacquiredduringpassagethroughthebirthcanalbutmeningitismayalsodevelopafewdaysor
weeksafterbirth.Nosocomialsourcesofmeningitisincludecraniotomy,internalandexternalventricularshunts,penetratingcranial
fractures,closedheadinjurieswithCSFleakingbasilarskullfractures,externallumbarcatheters,andrarelylumbarpuncture.The
complementsystemisimportantforbacterialkilling.Deficiencyofcomplement,e.g.,inpatientswithsicklecelldiseaseorwhohave
undergonesplenectomy,increasestheriskforpneumococcalmeningitis.

Pathogenesis
Theorganismsthatcausebacterialmeningitiscolonizethenasopharynxand,fromthere,theygetintothebloodstream.Theyenter
thesubarachnoidspacebypassingthroughendothelialcells(transcytosis),gettingacrosstheporouschoroidplexuscapillaries,or
beingcarriedbygranulocytes.TheCSFisanidealmediumforthespreadofbacteriabecauseitprovidesenoughnutrientsfortheir
multiplicationandhasfewphagocyticcells,andlowlevelsofantibodiesandcomplement.Initially,bacteriamultiplyuninhibitedand
canbeidentifiedinsmears,cultures,orbyELISAdetectionoftheirantigensbeforethereisanyinflammation.
Bacterialproductscandamagethebrainandbloodvesselsdirectly.Bacterialtoxinscauseneuronalapoptosis,andcellwall
lipopolysaccharide(endotoxin),releasedfrombacteria,activatesclottingcausingdisseminatedintravascularcoagulation(DIC).
Moresevereinjuryresultsfromtheinflammatoryresponsetobacteria.Cellsoftheinnateimmunesystemofthebrain,locatedin
theBBB,choroidplexus,andependyma,detectbacteriaandsecretecytokines,chemokines,andcomplement,whichattract
circulatinggranulocytesintotheCSF.Granulocytesandmacrophageshavepowerfullysosomalenzymesandfreeradicals,which
theyusetokillbacteria,buthaveashortlifespan.Astheylyse,thesecompoundsarespilledandcandestroyeverythingintheir
way.Ifneutrophilsaccumulate,theycandamagebraintissue,nerves,andbloodvessels.Vasculitisandclottingcausecerebral
infarcts.So,braindamageinbacterialmeningitisiscausedinpartbythedirectactionofbacteriaandinpartbytheantibacterial
inflammatoryresponse.Thebrainhaselaboratemechanismsforcontrollinginflammationbut,insomecases,unbalanceddefense
reactionscancausesevereinjury.Themostdangerouscomplicationofbacterialmeningitisisincreasedintracranialpressurefrom
cerebraledema.Cerebraledemamaybevasogenic,fromincreasedvascularpermeability,cytotoxicfromcerebralhypoxia,
interstitial,fromincreasedCSFvolume,oracombinationofall.Increasedintracranialpressure,inturn,causesdecreasedcerebral
perfusion,hypoxia/ischemia,andneuronalnecrosis.

ClinicalFindings
Theinitialsymptomsofmeningitisarefever,severeheadache,andstiffneck.Theinflamedspinalstructuresaresensitiveto
stretch,andpaincanbeelicitedbymaneuversthatstretchthespine,suchasbendingthelegwithanoutstretchedknee(Kernigsign)
orbendingtheneck(Brudzinskisign).Asthediseaseprogresses,confusion,coma,andseizuresdevelop.Thesecomplicationsare
duetoHIE,increasedintracranialpressure,andatoxicmetabolicencephalopathy.HIEisduetoshock.Thetoxicmetabolic
encephalopathyisprobablycausedbyunknowndiffusiblesubstances(perhapscytokines)thathaveaneurotoxicaction.Ininfants,
meningitismaypresentwithnonspecificsignssuchasadepressedstate,apneicspells,changesinheartrate,andatypicalseizures.

DiagnosisAndPathology
ThecornerstoneinthediagnosisofbacterialmeningitisisCSFexamination.TheCSFinmeningitisshowshundreds,eventhousandsof
neutrophilsandisteemingwithorganisms.CSFproteiniselevatedandglucoseislow(becauseitisconsumedbyinflammatory
cells).TheCSF:bloodglucoseratioislowerthan50%.
Acreamypurulentexudatecoversthecerebralhemispheresandsettles
alongthebaseofthebrain,aroundcranialnervesandtheopeningsofthe
fourthventricle.TheMRIshowsenhancementandhighFLAIRsignal
intensityinthemeninges,correspondingtothepathology.
Achildpresentingwithfever,headache,andCSFpleocytosisisadiagnostic
BacteriaintheCSF

Inflammatorycellsinthe
subarachnoidspace

dilemma.Lessthan5%ofsuchcasesareduetobacterialmeningitisand
therestareduetoviral(aseptic)meningitis(seeviralinfections).Yet,to
playitsafe,physiciansadmitsuchpatientstohospitalandtreatthemwith
antibiotics.Unnecessaryhospitalizationscanbeavoidedifastandardsetof
criteriaaretakenintoaccount.Theseare:CSFpositiveGramstain,CSF
absoluteneutrophilcount(ANC)>100cells/L,CSFprotein>80mg/dL,
peripheralbloodANC>10,000,andahistoryofprecedingseizure.The
presenceofthesefindingsstronglyfavorsbacterialmeningitis.

Meningitispurulentexudate

Meningitispurulentexudate

Alternatively,viralPCRofCSF,whichhasaturnaroundtimeofafewhours,
canconfirmasepticmeningitis.
Neutrophilsinthesubarachnoidspaceinfiltrateand
damagecranialnervesresultingincranialnerve

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deficits,andinvadeleptomeningealvesselscausing
phlebitisandarteritiswiththrombosisandischemic
infarction.Sinovenousthrombosismayalsooccur.The
thickfibrinopurulentexudateinthesubarachnoid
spaceorganizesintofibroustissuethatblockstheexits

Phlebitis

Vascularnarrowingafter
meningitis

Postmeningitic
hydrocephalus

ofthefourthventricleandimpairsCSFcirculation
aroundthecerebralconvexities.Thiscauses
hydrocephalus.Thesecomplicationstaketimeto
developandmayappearaftertheinflammationhas

subsided.Theymaybepreventedbyprompttreatment.TheeffectsofHIEandcerebralinfarctionare
especiallydevastatinginnewbornbabiesinwhomthebraincanliterallymeltaway.
Theglialimitans,athicktightmeshofastrocyticprocesses,joinedbydensejunctionsandcoveredby
basementmembrane,resistspenetrationbybacteriaandneutrophils.Undamaged,itprovidesaneffective
barrierthatpreventstheinfectionfromspreadingintobraintissue.Thus,brainabscessasacomplicationof

Severebrainatrophy
postneonatal
meningitis

meningitisisrare.
Braindamageinmeningitisiscausednotonlybybacteriabutprobablymorebyhostresponses.These

responseshaveaprotectivepurpose(toeliminatebacteria)butareexcessiveandindiscriminateandsetinmotiondestructive
cascadesthatdamageeverythingintheirway,mostlyhosttissues.Modulatingthesereactions,inadditiontokillingbacteria,can
reducethemorbidityandmortalityofmeningitis.

BrainAbscess
Brainabscessisanewlyformedcavityinbraintissue,filledwithpus.Thebacteriathatcausebrainabscessspreadfromadjacentair
sinusesorthemiddleear,orviathebloodstreamfromthelungs(bronchiectasis,lungabscess),orfromtheheart(bacterial
endocarditis).Brainabscessmayalsodevelopafterneurosurgicalproceduresandopenheadinjuries.Thelocationoftheabscess
correspondstoitssource.Frontalsinusitiscausesfrontallobeabscess,andmastoiditistemporallobeabscess.Hematogenousabscesses
areoftenmultiple.
Thebacterialfloraofbrainabscessdepends
onthesourceoftheinfection.Inthecase
ofsinusitisandotitis,itisoften
polymicrobial,includinganaerobes.
Hematogenousabscessesaremostoften
causedbystaphylococcusandstreptococcus
Abscess,earlyphase

Temporallobeabscess

Multipleabscesespostmeningitis

species.Bacteremiaalonedoesnotcause
brainabscess.Sometissuedamage,
probablyasmallischemiclesion,isrequired

tostarttheprocess.Bacteriainthebloodseedthisnecroticnidusandspreadarounditcausingbrainnecrosisandacuteinflammation
(cerebritis).Thesameearlypathologydevelopsfromcontiguousspreadofinfection.Thenecroticcentercavitateswhile,atthe
periphery,avascularzoneofbraintissuewithmacrophages,mononuclearcells,andreactiveastrocytescontainstheinfection.In45
weeks,collagen(derivedfromvascularcells)islaiddowninthisreactivezoneformingathickcapsulethatwallsofftheinfection.
Increasedvascularpermeabilityintheinflamedtissuecausescerebraledema.Hypervascularityandvascular
leakageaccountforthe"ringenhancing"patternaftercontrastinjection,whichgivesabscessitscharacteristic
radiologicalimage(necrotictumorsmayhaveasimilarappearance).Patientswithbrainabscesspresentmost
frequentlywithheadacheandmayalsohavesymptomsofinfection,focalneurologicaldeficitsduetodestruction
ofbraintissue,andseizures.Moreimportant,abscesscausesincreasedintracranialpressure.Itsmasseffectis
duetothecollectionofpusandtocerebraledemaaroundtheabscess.Sincetheinfectioniscontainedwithin
Brainabscess

braintissue,theCSFusuallyshowsonlyafewmononuclearcellswithnormalproteinandglucose.CSFcultures
arepositiveinaminorityofcases,howeverlumbarpunctureshouldbeavoidedbecauseoftheriskofherniations.
Systemicantibioticsareeffectiveinthephaseofcerebritis.Onceacapsuledevelops,itisabarriertoantibiotics.

Thus,thetreatmentofchronicabscessrequiresdrainageorsurgicalexcisioninadditiontosystemicantibiotics.

FURTHERREADING
NauR,BrckW.Neuronalinjuryinbacterialmeningitis:mechanismsandimplicationsfortherapy.TrendsNeurosci
200225:3845.PubMed
NigrovicLEetal.ClinicalPredictionRuleforIdentifyingChildrenWithCerebrosipnalFluidPleocytosisatVeryLowRiskof

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BacterialMeningitis.JAMA2007297:5260.PubMed
VandeBeekD,DrakeJM,TunkelAR.NosocomialBacterialMeningitis.NewEnglJMed2010362:14654.PubMed
RoosKL,vandeBeekD.Bacterialmeningitis.HandbClinNeurol201096C:5163.PubMed
BrouwerMC,TunkelAR,McKhannIIGM,vandeBeekD.BrainAbscess.NEnglJMed2014371:44756.PubMed

Updated:June,2016
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