CNS infections 1 - JU Medicine · • Bloodborne bacteria can reach the intraventricular choroid plexus, directly infect choroid plexus epithelial cells, and gain access to the CSF.

CNSinfections1Bacterialmeningitis

Sources/tablesandfigures:HarrisonsInfectiousdiseases2nd ed Ch31

OxfordHandbookofInfectiousdiseasesandmicrobiology2nd ed Ch19

Acutemeningitis

• Definition:• Acutemeningitisisasyndromecharacterizedbytheonsetofmeningealsymptomsandcerebraldysfunction.• 1)meningealsymptomsare:headache,neckstiffness,vomiting,photophobia• 2)cerebraldysfunctionleadstoconfusion,lossofconsciousness.• Acutemeansithappensoverhourstodays.• ItisidentifiedbyanabnormalnumberofwhitebloodcellsintheCSF.

• Bacterialmeningitis:meningitiscausedbyanacutepurulentinfectionwithinthesubarachnoidspace.• BacterialmeningitisisassociatedwithEncephalitis,BrainAbscess,andEmpyemainflammatoryreaction(nextlecture)• Alltheseconditionsmayresultinacollectionofsimilarsymptomssuchas:• - decreasedconsciousness• - seizures• - raisedintracranialpressure(ICP)• - stroke.• Thisisduetothemeningesandthebrainparenchymathroughthesubarachnoidspace,beingallfrequentlyinvolvedintheinflammatoryreaction(called:meningoencephalitis).

https://www.researchgate.net/figure/288507711_FIGURE-13-Patient-with-meningitis-A-Axial-FLAIR-imaging-shows-prom-inent-subdural-collection

prominentsubduralcollectionespeciallyintherightfrontalregion

Epidemiology• Bacterialmeningitisisthemostcommonformofsuppurative (pusforming)CNSinfection,withanannualincidenceintheUnitedStatesof>2.5cases/100,000population.• Theorganismsmostoftenseenincommunity-acquiredbacterialmeningitisareStreptococcuspneumoniae(∼50%),Neisseriameningitidis(∼25%),groupBstreptococci(∼15%),andListeriamonocytogenes(∼10%).• Haemophilus influenzaetypebaccountsfor<10%ofcasesofbacterialmeningitisinmostseries.• N.meningitidisisthecausativeorganismofrecurringepidemicsofmeningitisevery8to12years

Bacterialmeningitis:Etiology

• Factorsthataffectthecausativeorganismofacutebacterialmeningitisare:• -Thepatient’sage(peopleareexposedtodifferentbacteriaatdifferentages)• -Immunestatus(extremesofagearemoresusceptible,orperhapscompromisedimmunitystate)

• -Recentheadtraumaorneurosurgery(directaccessfornasopharyngealfloratomeninges).

• Thetypicalstoryofhowmeningitisbegins,istheintroductionofanewpathogenintothenasopharynxfollowedbynasopharyngealcolonizationwhichwouldbethesteppingstoneforthispathogentogainentryintothebloodandcausesystemicinvasion.

• redisposingFactors:Adults• RecentOtitisMedia orBacterialSinusitis (25%ofcases)• Pneumonia (12%ofcases)• Immunocompromised state(16%)

http://www.ijciis.org/articles/2012/2/2/images/IntJCritIllnInjSci_2012_2_2_82_97273_b2.jpg

• Inorderforthisnewpathogentobesuccessfulinthisstoryitmusthavethemeans(tools/virulencefactors)tosucceed.• Thesefactorsare:• 1-fimbriae(adhesion)• 2- bacterialcapsuletoevadephagocytosisonceintheblood• 3-productionofIgAproteasestobreakdownIgAinmucosalsurfacestobeabletosuccessfullycolonizethesesurfaces.

• Ontheothersideoftheequation,therearehostfactorsthatpredisposetomeningitis:• -splenectomy(inabilitytoclearcapsulatedorganisms)• -complementdeficiencies(reducedopsonization).

• S.pneumoniae:isthemostcommoncauseofALLmeningitiscasesinadults>20yearsofage– thisaccountsforalmosthalfthereportedcases(1.1per100,000personsperyear).• ImportantProperties:• Pneumococciaregram-positivelancet-shapedcocci arrangedinpairs(diplococci)orshortchains(Thetermlancet-shapedmeansthatthediplococci areovalwithsomewhatpointedendsratherthanbeinground.)• Onbloodagar,theyproduceα-hemolysis,Incontrasttoviridansstreptococci,theyarelysedbybileordeoxycholate,andtheyaresensitivetooptochin

S.pneumoniae

Pathogenesis,virulencefactors:

• Themostimportantvirulencefactoristhecapsularpolysaccharide,andanticapsular antibodyisprotective.• Lipoteichoic acid:complementactivator,itinducesinflammatorycytokineproductioncontributestotheinflammatoryresponseandtothesepticshocksyndromethatoccursinsomeimmunocompromisedpatients(abitsimilartoproteinAinLPSinGramnegatives).• Pneumolysin,thehemolysin thatcausesα-hemolysis,mayalsocontributetopathogenesis.• PneumococciproduceIgAproteasethatenhancestheorganism’sabilitytocolonizethemucosaoftheupperrespiratorytract.

• Factorsthatlowerresistanceandpredisposepersonstopneumococcalinfectioninclude(factorsthatreducemucusclearingorfactorsthatdecreaseimmunereaction)

• (1)anythingthatcandepressthecoughreflux:alcoholordrugintoxicationorothercerebralimpairment,allcontributetoanincreaseaspiration ofsecretions(andthuspneumoniae)

• (2)abnormalityoftherespiratorytract(e.g.,viralinfections),poolingofmucus,bronchialobstruction,andrespiratorytractinjurycausedbyirritants(whichdisturbtheintegrityandmovementofthemucociliary blanket)allpreventclearingofmucusandpredisposetocommunityacquiredpneumoniacausedbypneumococcus.

• (3)abnormalcirculatorydynamics(e.g.,pulmonarycongestionandheartfailure)-willcongestthebloodinthelung,increasepulmonarysecretionsà pnumococcus

• (4)splenectomy(capsule,reducesimmunity) andcertainchronicdiseasessuchassicklecellanemiaandnephrosis,patientswithsicklecellanemiaautoinfarct theirspleen,becomefunctionallyasplenic,andarepredisposedtopneumococcalsepsis.

• Traumatotheheadthatcausesleakageofspinalfluidthroughthenosepredisposestopneumococcalmeningitis.

• Beingthedominantpathogen,therehavebeenanumberofpredisposingconditionsidentifiedthatincreasetheriskofpneumococcalmeningitis:

• - pneumococcalpneumonia(themostimportantriskfactor,howcome?BACTEREMIA).• -coexistingacuteorchronicpneumococcalsinusitisorotitismedia(closeproximity)• - alcoholism(reducedclearanceofbugsinrespiratorytract)• -diabetes(reducedimmunity)• - splenectomy (inabilitytoclearcapsulatedbacteria)• -hypogammaglobulinemia• -complementdeficiency• -headtraumawithbasilarskullfractureandCSFrhinorrhea.

Themortalityrateremains∼20%despiteantibiotictherapy(beforeantibioticsthisusedtobe100%fatal!!!).

N.meningitides:ImportantProperties

• Neisseriae areGram-negativecoccithatresemblepairedkidneybeansandareconsideredSTRICTAEROBES.• (1)N.meningitidis (meningococcus)hasaprominentpolysaccharidecapsulethatenhancesvirulencebyitsantiphagocytic actionandinduces(adaptive/TIMECONSUMING)protectiveantibodies=thatmeansiftheyhavemeningitis,thereisnotimetowaitforADAPTIVEimmuneresponseandmustTREAT.ButthatalsomeansIcanmakeaVACCINE!• Accordingtotheantigensoftheircapsulepolysaccharide,meningococciaredividedinto“sofar”13serologicgroups.• Fiveofthoseserotypescausethemostcasesofmeningitisandmeningococcemia(A,B,C,Y,andW-135).• SerotypeAistheleadingcauseofepidemicmeningitisworldwide.• SerotypeBaccountsformostdiseaseintheUnitedStates.

ThosethreearecolonizersoftheURT

• routineimmunizationof11- to18-agegroupwiththetetravalent(serogroupsA,C,W-135,andY)meningococcalglycoconjugatevaccinehasreduceditsincidence(thisvaccinedoesnotcontainserogroupB,whichcausesabout1/3ofcases).• petechialorpurpuricskinlesionscanprovideanimportantcluetothediagnosisofmeningococcalinfection.• Insomepatientsthediseaseisfulminant,progressingtodeathwithinhoursofsymptomonset.• nasopharyngealcolonizationcaninitiateinfection,butcolonizationcanresultineitheranasymptomaticcarrierstateorinvasivemeningococcaldisease.

• Hostandbacterialfactorsthatpromotemeningococcaldisease:• Thehostside:• -Theabilitytoproduceantimeningococcalantibodies• -competentclassicandalternativecomplementpathwaystolysethepathogeniccells.• Individualswithdeficienciesofanyofthecomplementcomponents,includingproperdin,arehighlysusceptibletomeningococcalinfection

http://old.infectionnet.org/wp-content/uploads/2010/09/Meningococcemia.jpg

• Thesepathogenscausemeningitisinsusceptiblehosts,particularlyinthosewithchronicillnesses:• A)diabetesB)cirrhosisc)alcoholismD)chronicurinarytractinfectionsE)postcraniotomyinneurosurgery.

-InfectionsintheskullsuchasOtitis,mastoiditis,andsinusitispredisposeforalltypesofmeningitisfromStreptococcus,gram-negativeanaerobes,S.aureus,Haemophilus ,andincludeEnterobacteriaceae(G-ve enterics).-Similarlymeningitiscanbeacomplicationofendocarditis(seedingfromtheheart)duetoviridans streptococci,S.aureus,S.bovis,theHACEKgroup(Haemophilus spp.,Aggregatibacteractinomycetemcomitans,Cardiobacterium hominis,Eikenellacorrodens,Kingella kingae),orenterococci.

Gramnegativeenterics

GroupBStreptococcus(S.agalactiae)

previouslyresponsibleformeningitispredominantlyinneonates• Thiswasusuallyduetocolonizationbythethisbugofthebirthcanal• Neonatalsepsisandmeningitisandusualconsequences• Ithasbeenreportedwithincreasingfrequencyinindividuals>50yearsofage,particularlythosewithunderlyingdiseases.

• Listeriamonocytogenesisanincreasinglyimportantcauseofmeningitisintwoagegroups:• neonatesand>60yearsoldandintheimmunocompromisedofallages.• InfectionisacquiredbyingestingfoodscontaminatedbyListeria(sonotcolonization).• Foodbornehumanlisterial infectionhasbeenreportedfromcontaminatedcoleslaw(cabbage),milk,softcheeses,andseveraltypesof“ready-to-eat”foods,includingdelicatessenmeatanduncookedhotdogs.

H.influenzae

• Thefrequencyoftypebmeningitisinchildrenhasdeclineddramaticallysincethethe Hibconjugatevaccine.• H.influenzaecausesmeningitisinunvaccinatedchildrenandolderadults,andnon-bH.influenzaeisanemergingpathogen.

ImportantProperties

• H.influenzae G-ve RODencapsulatedwithapolysaccharidecapsule• oneofthethreeimportantencapsulatedpyogens (pneumococcusandthemeningococcus).

• Usingserologicmethodsagainsttheantigenofthepolysaccharidecapsule,sixserotypesaredetected,withserotypeB(groupB)beingthemostsignificantone.

• SerotypeBistheonemostresponsibleforthemoreseriousillnesses(meningitis,epiglottitis,sepsis)

• ThetypeBcapsuleiscomposedofpolyribitol phosphate,promotesanti-phagocytosisandinvasiveness.

• Unencapsulated strainsarelessinvasivebutcancausediseaseusuallylimitedtotheupperrespiratorytract(sinusitisandotitismedia).

• Growthoftheorganismonlaboratorymediarequirestheadditionoftwocomponents,heme (factorX)andNAD(factorV),foradequateenergyproduction.

Pathogenesis&Epidemiology• H.influenzae infectsonlyhumanswithnoanimalreservoir.• Similartootherrespiratorypathogens,itistransmittedbytheinhalationofairbornedropletsintotherespiratorytract,thiscanresultinasymptomaticcolonizationorinfection(otitismedia,sinusitis,pneumonia).

• Alsolikeallrespiratorypathogens,tobeabletosurviveinthisenvironment,theorganismproducesanIgAproteasethatdegradessecretoryIgAwhichwouldotherwiseinhibititsattachmenttothemucosa.

• Afterbecomingestablishedintheupperrespiratorytract,theorganismcanenterthebloodstream(bacteremia)andspreadtothemeninges.

• Asmentioned,capsulatedstrainscausemeningitis(theyhavetohaveantiphagocytic capabilitytosurvivethetripthroughthebloodtoreachthemeninges,thisistrueforPneumococcusandMeningiococcus)

• meningitiscausedbycapsulartypebhasbeengreatlyreducedbyvaccinecontainsthetypebpolysaccharideastheimmunogen.

• Similartopneumococcusandmeningococcus,thepathogenesisofH.infleunzae ispyogenicwithnoexotoxinproduction(capsuleandendotoxinbased)

Staphylococcusaureus

• InfectionwithS.A.occursfollowingintroductionofforeignmaterialintotheCNSbyinvasiveneurosurgicalproceduressuchas• shuntintroductionforhydrocephalus• IntroductionofasubcutaneousOmmayareservoirsforadministrationofintrathecalchemotherapy.

• P.s.OmmayaisaPakistanineurosurgeon,heinventedareservoirthatprovidesentryintotheCSFtogivechemotherapywith

• SonowwehavearepresentativeofeachGramreactionandshapethatcauseMeningitis:• G+ve coccus:S.pneumoniae(lesssoS.aureus)• G+ve rod:Listeriamonocytogenes• G-ve coccus:Neisseria• G-ve rod:Haemophilus influenzae(Less E.coli)

Pathophysiology

• S.pneumoniaeandN.meningitidis,initiallycolonizethenasopharynxbyattachingtonasopharyngealepithelialcells.• Oncecolonized.Bacteriaboroughthroughthevascularlayersintothebloodstream.• Onceinthebloodstream,bacteriaareabletoavoidphagocytosisbyneutrophilsandclassiccomplement-mediatedbactericidalactivitybecauseofthepresenceofapolysaccharidecapsule.• Bloodbornebacteriacanreachtheintraventricularchoroidplexus,directlyinfectchoroidplexusepithelialcells,andgainaccesstotheCSF.• Somebacteria,suchasS.pneumoniae,canadheretocerebralcapillaryendothelialcellsandsubsequentlymigratethroughorbetweenthesecellstoreachtheCSF.

• BacteriaareabletomultiplyrapidlywithinCSFbecauseoftheabsenceofeffectivehostimmunedefenses(itisasterilearea!).• NormalCSFhasfewwhitebloodcells(WBCs)smallquantityofcomplementproteinsandimmunoglobulins.• SincethereislittleWBC,andlittleimmunoglobulinsandcomplementproteins,effectiveopsonization ishindered(whichisessentialforclearingthesecapsulatedorganisms).• PhagocytosisofbacteriaisfurtherimpairedbythefluidnatureofCSF,whichislessconducivetophagocytosisthanasolidtissuesubstrate• ReducedphagocytosisandopsonizationmakestheCSFavulnerableenvironment=bacteriagainentry,infectionismostlikelyimmanent

• Neurologicmanifestationsandcomplicationsofbacterialmeningitisresultfromtheimmuneresponsetotheinvadingpathogenandnotduetodirectinjurybythepathogen.• Thismeansevenafterclearingthepathogen(byAbx)neurologicinjurycancontinue(Abxdonotworkontheimmunesystem).• Afterlysisofbacteria,therewillbeareleaseofhighlyimmunogeniccell-wallcomponents(lipopolysaccharide(LPS)G-ve bacteriaandteichoicacidandpeptidoglycansofG+ve)intothesubarachnoidspacewhichisthefirststepintotheinflammatoryresponseandtheformationofapurulentexudat.

Harrison-s-Infectious-Diseases-2

Clinicalfeatures

• Classicalsymptomsandsignsare:fever,headache,meningism (neckstiffness,photophobia,positiveKernig’s signandBrudzinski’s sign),andcerebraldysfunction(confusionand/orreducedconsciouslevel).• Seizurescanoccurin1/3ofpatients.Cranialnervepalsiesandfocalsignsareseenin10–20%ofcases.Hemiparesismaybeduetoasubduraleffusion.• Skinrash(initiallymacular,thenpetechial)occursinpatientswithmeningococcalsepticaemia butcanoccurinpneumococcal,H. influenzae.• leakingoffluidfromnoseorear(Rhinorrhoea orotorrhoea)suggestsbasalskullfracture- portofentry-.

https://image.slidesharecdn.com/meningitis-130217195734-phpapp01/95/meningitis-meningococcal-meningitis-29-638.jpg?cb=1361131091

• •L. monocytogenesmeningitishasmoreriskofseizuresandfocalsigns;ataxia,cranialnervepalsies,andnystagmus• •Neonatesandeldery maypresentwithnon-specificsymptoms,• Neonatestemperatureinstability,listlessness(uninterested),poorfeeding,irritability,vomiting(mayindicatehighICP),diarrhoea,jaundice,respiratorydistress.• Seizuresoccurin40%,andabulgingfontanelleisalate sign.• •Inelderlyconfusion,lethargy,nofever,andvariablesignsofmeningealinflammation.

Dx

• Whenbacterialmeningitisissuspected,bloodculturesshouldbeimmediatelyobtainedandempiricalantimicrobialandadjunctivedexamethasonetherapyinitiatedwithoutdelay• ThediagnosisisconfirmedbyexaminationandcultureoftheCSF.• Inbacterialmeningitis,thefollowingaretypically seen:

Management

• ThefollowingalgorithmfromOxfordisextremelyimportant,learnitwell,keepitwithyou

Empiricalantimicrobialtherapyshouldbecommencedimmediately,pendinginvestigations

IftheCSFGramstainorcultureispositive,treatmentshouldbetailoredtotheinfectingorganism

• Asforsteroidadjunctivetherapy:• Therecommendedregimenwasdexamethasone10mgqds (4timesdaily)for4 days(4x4)givenbeforeorwiththefirstdoseofantibiotic.• Recentdatasuggesttheirvalueismoreindevelopedcountriesandlesssoindevelopingworld(AMR?)• •ReductionofhighICPmustbedoneifpresent• •Fracturesneedtobecorrected,neurosurgerymayberequired

Prevention

• •Vaccination—HibandmeningitisCaspartofscheduledvaccines.• Thequadrivalentmeningitisvaccine(ACYW135)isrecommendedforpatientswithcomplementorproperdindeficiency,asplenic patients,travellers toendemicareas,andmedicalorlaboratorypersonnelroutinelyexposedtoN. meningitidis.S. pneumoniae• vaccinationisrecommendedincertainhigh-riskpatients(chronicillnesses)• Chemoprophylaxisforexposedpeople:• RifampicinforH. influenzaetypeBmeningitis.• N. meningitidis,theagentsusedarerifampicin(600mgbd for2 days),ciprofloxacin(500mgstat),orceftriaxone(250mgIM).• Penicillins forpregnantwomencolonizedwithGBS

PROGNOSIS

• Mortalityratesarehigh:• 3–7%formeningitisby H.influenzae,N.meningitidis,groupBstreptococci• 15%forL.Monocytogenes• 20%forS.pneumoniae.

Signsthatpointtohigherriskofmortality

• (1)decreasedlevelofconsciousnessonadmission.(thishintsatlevelanddegreeofinvolvementofbrainparenchyma)

• (2)onsetofseizuresw/in24hofadmission(alsohintsatseriousfocalstructuraldamage,orseverealterationofthesupplyforthebrain)

• (3)increasedICP(highBP,headache,vomiting,lessresponsivepupillarylightreflex)• (4)extremesofage(infantor>50y/o)• (5)thepresenceshockand/ortheneedformechanicalventilation• (6)delayintheinitiationoftreatment.(thisoneisonyou)• DecreasedCSFglucoseconcentration[3g/L(>300mg/dL)]havebeenpredictiveofincreasedmortalityandpooreroutcomesinsomeseries.

• Moderateorseveresequelaeoccurin∼25%ofsurvivors,althoughtheexactincidencevarieswiththeinfectingorganism.Commonsequelaeincludedecreasedintellectualfunction,memoryimpairment,seizures,hearinglossanddizziness,andgaitdisturbances