Central nervous system infections in the absence of cerebrospinal fluid pleocytosis

Short

Communication

Central

nervous

system

infections

in

the

absence

of

cerebrospinal

fluid

pleocytosis

Hakan

Erdem

,

Derya

Ozturk-Engin

,

Yasemin

Cag

,

Seniha

Senbayrak

,

Asuman

Inan

,

Esra

Kazak

,

Umit

Savasci

,

Nazif

Elaldi

,

Haluk

Vahaboglu

,

Rodrigo

Hasbun

*,

ID-IRI

study

group

a

DepartmentofInfectiousDiseasesandClinicalMicrobiology,GulhaneMedicalAcademy,Ankara,Turkey

b

DepartmentofInfectiousDiseasesandClinicalMicrobiology,HaydarpasaNumuneTrainingandResearchHospital,Istanbul,Turkey

c

DepartmentofInfectiousDiseasesandClinicalMicrobiology,LutfiKirdarTrainingandResearchHospital,Istanbul,Turkey

d

DepartmentofInfectiousDiseasesandClinicalMicrobiology,UludagUniversitySchoolofMedicine,Bursa,Turkey

e

DepartmentofInfectiousDiseasesandClinicalMicrobiology,CumhuriyetUniversitySchoolofMedicine,Sivas,Turkey

f

DepartmentofInfectiousDiseasesandClinicalMicrobiology,MedeniyetUniversity,GoztepeTrainingandResearchHospital,Istanbul,Turkey

g_{DepartmentofInfectiousDiseases,UTHealthMcGovernMedicalSchool,Houston,TX,USA}

ARTICLE INFO Articlehistory: Received11April2017

Receivedinrevisedform11October2017 Accepted12October2017

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: CSF Pleocytosis Leukocyte Meningitis Encephalitis ABSTRACT

Previousmulticenter/multinationalstudieswereevaluatedtodeterminethefrequencyoftheabsenceof cerebrospinalfluidpleocytosisinpatientswithcentralnervoussysteminfections,aswellastheclinical impactofthiscondition.Itwasfoundthat18%ofneurosyphilis,7.9%ofherpeticmeningoencephalitis,3% oftuberculousmeningitis, 1.7%ofBrucellameningitis,and0.2%ofpneumococcalmeningitiscasesdidnot displaycerebrospinalfluidpleocytosis.Mostpatientswerenotimmunosuppressed.Patientswithout pleocytosis had a high rate of unfavorable outcomes and thus this condition should not be underestimated.

©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Thenormalwhitebloodcell(WBC)countinthecerebrospinal fluid(CSF)ofadultsisbetween0and5106_{cells/l(Tunkel,2015).}

CSFpleocytosisisimportantinestablishingthediagnosisofcentral nervoussystem(CNS)infectionssuchasmeningitis,encephalitis, and meningoencephalitis. However, the absence of pleocytosis representsadiagnosticchallengetoclinicianswhensuspectinga CNS infection. Under this particular circumstance, can the possibility of meningitis, encephalitis, or meningoencephalitis beexcluded?Accordingly,theexaminingphysicianshouldknow thefrequency, clinicalcharacteristics,andoutcomesofdifferent CNS infections that may present with an absence of CSF pleocytosis.Data onthis subject in the literature appear to be verylimited.

Methods

The Infectious DiseasesInternationalResearch Initiative (ID-IRI)studygrouphasbeenperforminglarge multicenter/multina-tionalstudiessince2008,withstudiesontuberculousmeningitis (Erdemet al.,2015a;Erdemetal.,2014a), herpetic meningoen-cephalitis(Erdemetal.,2015c),Brucellameningitis(Erdemetal., 2015b), pneumococcal meningitis (Erdem et al., 2014b), and neurosyphilis(Ozturk-Enginetal.,2016).Strengthsofallofthese studiesincludethelargenumbersofpatientsinvolved, microbio-logicalconfirmationforallpatientsenrolled,andtheinclusionof bothpatientswithandwithoutCSFpleocytosis.Additionally,the firstthreestudiesarethelargestseriespublishedtodateinthe literature:tuberculousmeningitis(n=507),herpetic meningoen-cephalitis (n=496),Brucella meningitis (n=294),pneumococcal meningitis(n=306),andneurosyphilis(n=141).

In this study,thedataof ID-IRIstudieswereinvestigatedto identifypatientswithoutCSFpleocytosis(WBCcountof5106

cells/l). Their clinical presentations, laboratory findings, and outcomeswereassessedtoprovideaninsightintothisparticular conditionforthetreatingclinician.

* Correspondingauthorat:UTHealthMcGovernMedicalSchool,6431FanninSt. 2.112MSB,Houston,TX77030,USA.

E-mailaddress:Rodrigo.Hasbun@uth.tmc.edu(R.Hasbun).

https://doi.org/10.1016/j.ijid.2017.10.011

1201-9712/©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

InternationalJournalofInfectiousDiseases65(2017)107–109

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

Results

The characteristics of the patients with CNS infections (pneumococcalmeningitis,tuberculousmeningitis,Brucella men-ingitis, neurosyphilis, herpes simplex virus (HSV) meningoen-cephalitis) without CSF pleocytosis are presented in Table 1. Accordingtothedata,32of141patients(18%)withneurosyphilis, 39of496patients(7.9%)withherpeticmeningoencephalitis,19of 507patients(3%)withtuberculousmeningitis,fiveof294patients (1.7%)withBrucellameningitis,andoneof306patients(0.2%)with pneumococcalmeningitisdidnot presentwith CSFpleocytosis. These96patientswereincludedinthisstudy.

ThemeanCSFproteininallfiveCNSinfectionswaselevated, withsomepatientsalsohavinghypoglycorrhachia(CSFtoserum glucoseratio0.5).ThemeanCSFproteinwashigherandthemean CSFtoserumglucoseratiowaslowerinthosewithtuberculous meningitis than in those with herpetic meningoencephalitis (p<0.05). The mean age was 49 years in all groups, and 55 (57%)patientsweremale.Forty(42%)ofthepatientshadafever andonlyseven(7.3%)hadtheclassicmeningitistriad.Astiffneck wasseenmorefrequentlyintuberculousmeningitis(63%)thanin theother infections. Immunosuppressive conditions that could predispose tothe absence of pleocytosis were not detected in

pneumococcalmeningitisorinBrucellameningitis.Furthermore, theywererelativelyinfrequentinneurosyphilis(37%),tuberculous meningitis(15.8%),and herpeticmeningoencephalitis(12.8%).A totalof51(53%)patientshadneurologicalsequelaeordied. Discussion

Thisappearstobethelargeststudyevaluatingthefrequency, clinical characteristics, and outcomes of patients without CSF pleocytosisinfivetypesofCNSinfection.Previousstudieshave described case series of patients without CSF pleocytosis in relationtobacterialmeningitis,herpessimplexencephalitis,and enteroviralmeningitis(Sarayaetal.,2016;HuiTanetal.,2016;Lin etal.,2016).ThelackofCSFpleocytosisinbacterialmeningitisis rare,butthiscanbeseenmorecommonlyinviralinfections.Inthis study,themeanvaluesofproteinandCSF/bloodglucosesuggested theprobablepresenceofaCNSinfectiondespitetheabsenceofCSF pleocytosis,stressingtheimportanceofconsideringthetotalCSF profilewhenrulingoutaCNSinfection.Eventhoughasignificant proportion ofpatients had fever, headache,and altered mental status, only seven of the 96 patients (7.3%) had the classic meningitistriad.Incontrast,althoughneckstiffnesswasdetected in two-thirds of tuberculous meningitis cases, it was seen

Table1

CharacteristicsofpatientswithaCNSinfectionwithnoCSFpleocytosis.a

Pneumococcalmeningitis Tuberculousmeningitis Brucellameningitis Neurosyphilis HSVmeningoencephalitis ID-IRIstudy Erdemetal.(2014b) Erdemetal.(2015a) Erdemetal.(2015b) Ozturk-Enginetal.(2016) Erdemetal.(2015c)

Number 306 507 294 141 496 CSFanalysis Pleocytosisabsent,n 1 19 5 32 39 Pleocytosisabsent,% 0.2% 3% 1.7% 22% 7.9% Protein(mg/dl),meanSD 1446 305.5457.63b 89.2363.43 74.9114.7 7748.89 CSF/bloodglucose,meanSD 0.1 0.450.16c

0.510.89 0.630.13 0.680.57 Demographicandclinicalparameters

Age(years),meanSD 68 49.1517.03 55.420.27 52.1514.09 5720.99 Sex,male,n(%) 1 9(47%) 2(40%) 26(81%) 17(44%) Fever>38_{C,n(%) 38.2}_{C 13(68%) 3(60%) 4(12%) 19(49%)} Neckstiffness,n(%) ( ) 12(63%) 1(20%) 6(18%) 6(15%) Headache,n(%) (+) 6(31%) 4(80%) 13(40%) 22(56%) Mentalchanges (+) 13(68%) 1(20%) 13(40%) 33(85%) Classictriadd _{( ) 1(5%) 1(20%) 1(3%) 4(10%)} GCS 5 10.133.99 152.38 14.261.45 113.92 Potentialimmunosuppressiveconditions

HIV-positive ( ) 2 ( ) 7e ( ) Diabetesmellitus ( ) ( ) ( ) 3 ( ) Immunosuppressivedrugs ( ) 1 ( ) ( ) 4f Solidtumor ( ) ( ) ( ) ( ) 1 Drugaddiction ( ) ( ) ( ) 3 ( ) Number(%) 0(0) 3(15.8%) 0(0) 12(37%) 5(12.8%) Outcome Sequelae,n(%)g _{( ) 6(31%) 1(20%) 12(37%) 15(39%)} Death,n(%) Died 5(26%) ( ) 3(9%) 8(21%)

CNS,centralnervoussystem;CSF,cerebrospinalfluid;HSV,herpessimplexvirus;ID-IRI,InfectiousDiseasesInternationalResearchInitiative;SD,standarddeviation;GCS, Glasgowcomascalescore.

a

Pleocytosis:numberofpatientswith5106

leukocytes/lintheCSF.

b

MeanCSFproteinhighercomparedtoHSVmeningoencephalitisbyanalysisofvarianceanalysis(p<0.05).NodifferencesseenwhencomparingBrucellameningitisand neurosyphilistoHSVmeningoencephalitis(p>0.05).

c_{MeanCSFglucose lowercomparedtoHSVmeningoencephalitis(p<0.05).NodifferencesseenwhencomparingBrucellameningitisandneurosyphilistoHSV}

meningoencephalitis(p>0.05).

d

Classictriad:symptomsoffever,headache,andalteredmentalstatus.

e

Onepatienthadco-existingdiabetesandHIVinfection.

f

Immunosuppressive medications (cyclosporine, methotrexate, cyclophosphamide, and systemic steroids) for kidney transplantation, chronic inflammatory demyelinatingpolyneuropathyandintestinaladenocarcinoma,pemphigoid,andTakayasuarteritis.

g

Focalneurologicaldeficits,seizures,andhydrocephalus.

infrequentlyinBrucella,herpetic,andsyphiliticCNSdiseases.The low frequency of meningismus in this studycould possibly be explained by the fact that meningeal irritation disappears in the absence of CSF inflammation. Furthermore, tuberculous meningitis had higher rates of hypoglycorrhachia and elevated CSFprotein.

Theabsenceof pleocytosiswasrelativelyinfrequent butnot rare in these CNS infections. Patients without CSF pleocytosis appearedtohaveahighrateofunfavorableoutcomes,including sequelaeanddeath.Arecentstudyof175childrenwithbacterial meningitis(Linetal.,2016)identifiedthelackofCSFpleocytosisas aprognosticfactorinthemultivariableanalysis.Theexamining clinicianshouldnotunderestimatethepresenceofaCNSinfection despitethelackofCSFpleocytosisforapatientwithasuspicionof meningitisorencephalitis.Inparticular,othercluesrelatedtothe clinicalpresentationorabnormalitiesin CSFanalysesshouldbe carefullyconsideredasawhole,andmicrobiologicalcluespointing toaCNSinfectionshouldbepursuedwhennecessary.

Funding

Grant-A-StarrFoundation. Conflictofinterest

RH is a consultant for bioMérieux and a speakerfor Pfizer, Merck,MedicinesCompany, andBioFire.Theremainingauthors havenocompetingintereststodeclare.

Acknowledgements

TheID-IRIstudygroupincludesallauthorsinreferencesErdem etal.(2015a),Erdemetal.(2015b),Erdemetal.(2015c),Erdem etal.(2014b),Ozturk-Enginetal.(2016).

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