Early symptomatic neurosyphilis and ocular syphilis: A comparative study between HIV-positive and HIV-negative patients

HAL Id: hal-03238856

https://hal-normandie-univ.archives-ouvertes.fr/hal-03238856

Submitted on 2 Jun 2021

HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Early symptomatic neurosyphilis and ocular syphilis: A comparative study between HIV-positive and

HIV-negative patients

Vero Rasoldier, J. Gueudry, C. Chapuzet, B. Bodaghi, M. Muraine, R.

Tubiana, L. Paris, M. Pestel-Caron, F. Caron, E. Caumes

To cite this version:

Vero Rasoldier, J. Gueudry, C. Chapuzet, B. Bodaghi, M. Muraine, et al.. Early symptomatic neu- rosyphilis and ocular syphilis: A comparative study between HIV-positive and HIV-negative patients.

Infectious Diseases Now, Elsevier, 2021, 51 (4), pp.351-356. �10.1016/j.medmal.2020.10.016�. �hal-

03238856�

Availableonlineat

ScienceDirect

www.sciencedirect.com

Original article

Early symptomatic neurosyphilis and ocular syphilis: A comparative study between HIV-positive and HIV-negative patients ^夽

V. Rasoldier

, J. Gueudry

, C. Chapuzet

, B. Bodaghi

, M. Muraine

, R. Tubiana

, L. Paris

, M. Pestel-Caron

, F. Caron

, E. Caumes

aCHUCharlesNicolle,ServicedesMaladiesinfectieusesetTropicales,1,ruedeGermont,76000Rouen,France

bCHUCharlesNicolle,Serviced’ophtalmologie,1,ruedeGermont,76000Rouen,France

cAP–HP,HôpitallaPitiéSalpêtrière,Serviceophtalmologie,47-83,boulevarddel’Hôpital,75013Paris,France

dSorbonneUniversité,AP–HP,HôpitauxUniversitairesPitié-SalpêtrièreCharlesFoix,ServicedeMaladiesinfectieusesetTropicales,75013Paris,France

eAP–HP,HôpitallaPitiéSalpêtrière,ServicedesMaladiesInfectieusesetTropicales,47-83,boulevarddel’Hôpital,75013Paris,France

fAP–HP,HôpitauxuniversitaireslaPitiéSalpêtrière/CharlesFoix,Pôlebiologieetpathologie,Servicedeparasitologie,47-83,boulevarddel’Hôpital,75013 Paris,France

gCHUCharlesNicolle,InstitutdeBiologieClinique,ServicedeBactériologie,1,ruedeGermont,76000Rouen,France

hSorbonneUniversité,INSERM,InstitutPierreLouisd’ÉpidémiologieetdeSantéPublique(IPLESP),Paris,France

a rt i c l e i nf o

Articlehistory:

Received2January2020

Receivedinrevisedform3May2020 Accepted14October2020 Availableonline22October2020

Keywords:

HIV Syphilis Neurosyphilis Ocularsyphilis

a b s t ra c t

Objectives:Sincethe2000s,therehasbeenanincreaseinprevalenceofneurosyphilis(NS)andocular syphilis(OS).AsdataaboutsymptomaticNS/OSislimited,thisstudyaimstoassessthecharacteristics ofsymptomaticNS/OS,accordingtoHIVstatus.

Methods: WecomparedtheclinicalandbiologicalpresentationofearlysymptomaticNS/OSandits outcomeinHIV-positiveandHIV-negativepatients.

Results:Ninety-sixpatients(93%men,49%HIV-positive)wereincludedfrom2000to2016intwocen- ters,with67(69%)havingOS,15(16%)NS,and14(14%)both.HIV-positivepatientswereyounger (P=0.006)andmorelikelytobemaleshavingsexwithmales(P=0.00048)ortohaveahistoryofsyphilis (P=0.01).Among81OS,therewere43posterioruveitis(57%),andbilateralinvolvementwasmorecom- moninHIV-positivepatients(62%versus38%,P=0.045).Among29NStherewere21casesofcranial nerveinvolvement(72%),sevenmeningitis(24%)and11paresthesia(38%).InvolvementoftheVIII^th cranialnervewasthemostcommon(16cases).Treponemaltestsweremorecommonlyfoundposi- tiveincerebrospinalfluidinHIV-positivepatients(88%versus76%,P=0.04).Visualacuity(VA)always improvedaftertreatment(initialVAlogMAR0.8±0.8versus0.1±0.1at3months),but32%and18%of thepatientsstillhadneurologicalorocularimpairmentrespectivelysixand12monthsaftertreatment.

Non-treponemalserologicalreversionwasobservedin43/50patients(88%)atsixmonths.

Conclusion: HIVinfectionhasnoconsequenceontheoutcomeofNSandOS.Sequelaearecommon, emphasizingtheimportanceofprevention,andscreening,andquestioningenhancedtreatment.

©2020ElsevierMassonSAS.Allrightsreserved.

1. Introduction

Sincethe2000s,therehasbeenanincreaseintheprevalenceof syphilisworldwide[1].Suchanincreaseparallelstheimprovement ofHIVinfectionprognosisandmanagement[2].Severalquestions have been raisedabout therelationship betweenHIV infection and syphilis [3,4]. While case reports have made it possibleto

夽 PresentedorallyattheJNI(Journéesnationalesdel’infectiologie2019).

∗Correspondingauthorat:CHUCharlesNicolle,ServicedesMaladiesinfectieuses etTropicales,1,ruedeGermont,76000Rouen,France.

E-mailaddress:vero.rasoldier@chu-rouen.fr(V.Rasoldier).

hypothesizeseveraldifferencesbetweenHIV-positivepatients,and HIV-negativepatients, largecomparativestudieshave foundno significantdifferencesbetweenthemdespitesomeexceptions[5].

Itisnoteworthythatduringacaseofsyphilisthecentralnervous system(CNS)isinvadedearlybyTreponemapallidum[6].However thereisnoformalsystemforreportingocularsyphilis(OS)orneu- rosyphilis(NS).HistoricallyintheOslostudy,of1404Scandinavian patientswithearlysyphilis,1.6%(23patients)developed symp- tomaticearlyNS(withnodataaboutOS)[7].Morerecentlyfrom 2009to2015intheUSA,of48,045ofthesyphiliscasesnotifiedto CDC,403(0,8%)wereNS[8].InanotherUSstudy,theprevalence ofsymptomaticNSwasestimatedat1,8%amongstoverallearly

https://doi.org/10.1016/j.medmal.2020.10.016

0399-077X/©2020ElsevierMassonSAS.Allrightsreserved.

V.Rasoldieretal. InfectiousDiseasesNow51(2021)351–356

syphiliscasesreportedtoCDCovertenUSstates[9]whiletheesti- matedprevalenceofOSwas0.65%amongst35,547syphiliscases in2015[9].OveralltheincidenceandprevalenceofNS/OSseems toaverage1%inpatientswithearlysyphilis.

TodatemoststudiesofNS/OS,whetherornotpatientswere infectedwithHIV,includedavaryingpercentageofasymptomatic patientswithbiological definitionofNS.Definition ofNSvaries according to the studies, and such studiesinclude 13% to 62%

asymptomaticformsforwhichthediagnosisofNSreliedonlyon the resultsofcerebrospinal fluid(CSF)[4,10–13]. However,the positivityofthenon-treponemaltestsinthecerebrospinalfluid (CSF-VDRL),whichisthegoldstandardfordiagnosisofNS,may havea lowsensitivityeveninsymptomaticpatients[14,15].On theotherhand,patientswithsyphilishavingneurologicalorocu- larsignshavetobetreatedasNSwhatevertheresultsofCSFtesting [16–18].Finally,thereisnoevidencetosupportvariationfromthe EuropeanrecommendationsorCDCguidelinesregardingthetreat- mentofsyphilisinpatientswithoutclinicalneurologicalfindings inwhomitisnotrecommendedtoperformCSFanalysis[16,17].

OverallstudiesfocusingononlysymptomaticpatientswithNSor OSarelacking.

WeassessedthecharacteristicsofearlysymptomaticNSandOS.

WealsoevaluatedwhetherHIVinfectioninfluencedtheclinical, andbiologicalcharacteristicsofNS/OSaswellasoutcomeinthese patients.

2. MaterialandMethods

We included allconsecutive cases of early symptomatic NS and OSdiagnosed between1stof January,2000,andDecember 31st,2016,intwoInfectiousDiseasesdepartmentsoftwoFrench Universityhospitals(CharlesNicolleHospital,Rouen,andLaPitié Salpêtrière,Paris).

NSwasdefinedbythepresence ofneurologicalsignswitha positiveserologyforsyphilis(TPHAorEIAandVDRL),CSFinflam- mation ANDa treponemal-test(T-test; i.e.TPHA ortreponemal enzymeimmunoassay)positiveinCSF.OSwasdefinedbyocular signs withpositiveserologyfor syphilisandnoothercausefor ocularinvolvement.Apositiveserologyforsyphiliswasdefinedas positivetreponemalandnon-treponemal(NT-test,i.e.VDRL)blood tests.ThediagnosisofearlyNS/OSreliedoncompatibleneurolog- icalorocularsigns,withorwithoutextra-neurologicalsigns,but withevidenceofseroconversionwithinthepastyearinthesub- groupofpatientsfollowedupregularly,andnohistoryofsyphilisin theremainingpatients,andlackofothercausefortheneurological orocularinvolvement.

Lumbarpunctureswereperformedsystematicallyinpatients withneurologicalsigns,andeventuallyinthosewithocularsigns.

WeassessedsignsofCSFinflammation(i.e.,havingpleiocytosis>5 cells/mm³ and/orelevatedCSF-protein>0,45g/l), reactiveT-test and/orreactiveCSF-VDRL.AnegativeVDRL-CSFdidnotruleout thediagnosisofNSaccordingtothemostrecentguidelines[16–18].

LatentandlateNS/OScaseswerenotincluded.

HIVinfectionwasalwaysconfirmedbyapositiveserumHIV enzymelinkedimmunosorbentassay(ELISA)andconfirmedwith awesternblot.

Treatmentsuccesswasdefinedbytheimprovementorcomplete remissionofclinicalsignsorsymptomsandasignificantdecrease (atleast4-fold)oftheVDRLatoneyear.

Treatmentfailurewasdefinedclinicallyasthepersistenceof NS/OSsignsorsymptoms.Anon-significantdecreaseoftheVDRL titer(i.e.lessthan4-fold)inbloodwithin6monthsoftreatment wasinterpretedasfailureof treatmentonlyiftheclinicalsigns persisted.Short-termoutcomewasevaluatedattheendofthefirst monthaftertreatmentended.Thenpatientswerefollowedupto

oneyearaftertreatment.Sequelaeweredefinedbythepersistence ofophthalmologicalorneurologicalsignsatoneyear.

Chartsfrompatientswerereviewedforthefollowingdata:age, gender,sexualorientation(distinguishingMSMfromtheothers), historyofsyphilis,durationofsymptoms,neurologicalsigns,oph- thalmologicalsigns,andgeneralfindings,aswellasCD4cellcount andHIVviralloadinHIVinfectedpatients,andresultsofbloodand cerebrospinalfluidanalysis,T-testandVDRLinbloodandCSF,fail- ure,recurrenceanddurationoffollowup.Visualacuity(VA)atfirst examinationandduringfollowupwascollectedintheophthalmo- logicaldepartmentofRouen’shospital.

We compared data between HIV-infected patientsand oth- ers.Resultsaregivenin meanswithstandarddeviation(SD)or in median withfirst and third interquartile range (IQ1-3), and minimal–maximal(min-max).Categoricaldatawascomparedin univariateanalysisusingFisher’sexacttestorChi-2testaccord- ingtosizepopulation.Associationbetweencontinuousvariables wasassessedbyStudenttest.Ordinalvariableswereanalyzedwith theWilcoxontest.Two-tailedP-values<0.05wereconsideredtobe significant.Onlinesoftwareforstatisticswasused[19].

3. Results

From2000to2016,earlysymptomaticNS/OSwasdiagnosedin 96patients,67(69%)havingOS,15(16%)havingNS,and14(15%) havingboth(Fig.1).

TheirdemographiccharacteristicsaccordingtoHIV-statusare describedinTable1.MeantimeHIVdiagnosiswas6.6±7.2years.

Among47HIVpatients,24(51%)had aCD4rate<350/mm³,16 (34%) wereunderantiretroviral therapy and 18 (38.3%) had an undetectableviralload(definitiondependingonyearsbetween20 and200cp/ml)atinitialdiagnosis.Ahistoryofsyphiliswasmore commoninHIV-positive patientsthanin HIV-negativepatients (17%versus2%,P=0.01).TheT-testin theCSFwassignificantly more often positive in HIV-positive patients (88% versus 76%, P=0.04),buttherewasnootherCSFdifferencebetweenthetwo groups.Therewasnodifferenceintheantibioticmanagementand outcomeuptoone-yearoffollow-upbetweenHIV-positiveand negativepatients.

4. Earlysymptomaticneurosyphilisandocularsyphilis characteristics

Neurological symptoms were found in 29 patients (30%) (Table2).ThemaincranialnervesinvolvedweretheVIIIth(76%), Vth(19%),VIIth(10%),IIIrdandXIIth(5%each).Involvementwas unilateral in 50% (data available for 18 of 21 patients). Eleven patients(38%) had paresthesia, unrelated toa sensitivecranial nerveinvolvementnoranidentifiedCNSormedullarlesion.Loca- tionoftheparesthesiawasperipheral,locatedonchestbeltfor2 patients,inthemediannerveterritory(3firstfingersofonehand) foronepatient,bilaterallowerlimbsfor2,unilaterallowerlimbfor 2withradicularL5painforone.Thislatterpatientalsohadpares- thesiaoftheextremitiesandthescalp.Onepatienthadwidespread paresthesia.Amongthese11patients,twohadsignsofsecondary syphilisplusVIIIthcranialnerveinvolvement,threehadonlysigns ofsecondarysyphilis,andfourhadonlyneurologicalsigns(VIIIth involvementin2patients,VIIthinonepatientandassociationof IIIrd,VthandXIIthinonepatient).OneotherHIV-positivepatient hadmeningitis(10cells,CSF-protein0.49g/l)withparesthesiaof thelowerlimbsthatdisappearedwithpenicillinG.ThelastHIV- negativepatienthadonlyfeetdysesthesiawithapositiveT-test inbloodandCSF,andpositiveVDRLinblood.Symptomsquickly disappearedwithpenicillinG.

352

Fig.1.Flowchart.

Table1

DemographiccharacteristicsaccordingtoHIVstatusin96patientswithearlyneurosyphilisorocularsyphilis.

Total(n=96) n(%)

HIV+(n=47) n(%)

HIV−(n=49) n(%)

P–value

Men 89(93) 49(98) 43(88) 0.11

Age(mean±SD) 45.3±11.4 41.8±8.8 48±12 0.006

Caucasian 74(77.1) 31(66) 43(88) 0.008

Sexualpractices

MSM 56(58.3) 36(76.6) 20(41) 0.0005

Heterosexuality 30(31.3) 8(17) 22(45) 0.0004

Unknown 10(10,4) 3(6.4) 7(14) 0.3

N:numberofcases;SD:standarddeviation;MSM:menwhohavesexwithmen.

Table2

ComparisonofsymptomsaccordingtoHIVstatusin96patientswithearlyneurosyphilisorocularsyphilis.

Total HIV+ HIV− P-value

n(%) n(%) n(%)

Neurologicalsymptoms 29 33 34 0.4

Meningitis 7(24) 4(29) 3(20)

Cranialnerveaffection 21(72) 10(71) 11(73)

Vascularitis 1(3) 0 1(7)

Isolatedparesthesias 11(38) 5(36) 6(40)

Ocularsymptoms 81 39 42 1

Anterioruveitis 10(13) 5(14) 5(13) 1

Intermediaruveitis 0 0 0

Posterioruveitis 43(57) 19(53) 24(62) 0,5

Panuveitis 18(22) 10(26) 8(19) 0,6

Keratitis 0 0 0

Opticneuritis 3(4) 1(3) 2(5) 1

Bilateralinvolvement 39(49%) 24(62) 15(38) 0,045

Visualimpairment 76(94) 35(88) 41(98) 0,1

V.Rasoldieretal. InfectiousDiseasesNow51(2021)351–356

Table3

CerebrospinalfluidcharacteristicsaccordingtoHIV-statusandclinicalformsin96patientswithearlyneurosyphilis(NS)orocularsyphilis(OS).

Allforms PureNSform PureOSform

Allpatients n=96

HIV+

n=47

HIV–

n=49

Allpatients n=15

HIV+

n=8

HIV–

n=7

Allpatients n=67

HIV+ n=33

HIV–

n=34 Lumbarpunture

performed,n

77 41 36 14 8 6 50 28 22

Pleiocytosis (/mm³±SD)

42±70 45±70 37±71 81±121 75±108 88±147 29±51 36±60 21±38

CSF-protein (g/l±SD)

0.66±0.45 0.70±0.54 0,62±0.32 0,92±0.8 0.94±0.97 0,9±,055 0,57±0.29 0,62±0.35 0,53±0.23 PositiveT-Test,

n(%)

63(83%) 37(88%)* 25(76%)* 14(100%) 8(100%) 6(100%) 39(78%) 24(86%)** 15(68%)**

PositiveVDRL, n(%)

17(22%) 10(24%) 7(21%) 4(29%) 2(25%) 2(40%) 10(20%) 7(25%) 3(14%)

n=numberofcases;CSF=cerebrospinalfluid;HIV:HumanImmunodeficiencyVirusStatus;T-Test:Treponemaltest;SD:standarddeviation.

*P=0,04

**P=0,025,significantdifferencebetweenHIV-infectedandHIV-uninfectedgroup.

Table4

Resultsofnon-treponemalbloodtest(VDRL)accordingtoHIVstatusonclinicalformin96patientswithearlyneurosyphilis(NS)orocularsyphilis(OS).

VDRLresults:median[range](numberofsampledpatients)

Allpatients HIV+ HIV– P-value

Allforms 32[2–512](94) 64[4–512](45) 32[2–512](47) 0.67

PureNSforms 32[4–256](16) 32[4–256](9) 32[4–128](7) 0.51

PureOSforms 32[2–512](65) 64[8–512](32) 32[2–256](33) 0.20

NSandOSforms 128[16–512](13) 87[16–128](6) 128[16–512](7) 0.21

One37-year-oldwomanhadstroke-likesymptomswithright hemiparesisandfacialparalysis,revealingmultipleintracerebral lesionsinimaging.Diagnosiswasconfirmedbyapositiveserology forsyphilis,apositiveVDRL-CSFandT-TestinCSF,andpositivePCR ofTreponemapallidumoncerebralbiopsy.Thiswasconsideredto bevasculitis[20].

Eighty-onepatients(84%)hadophthalmologicalinvolvement.

Posterior uveitis was themost commondiagnosis(n=43, 57%) before panuveitis (n=18, 22%). Bilateral involvement was seen more often inHIV-infected patientsthanin those non-infected (24(62%)versus15(38%)patients,P=0.045).

Forty-three(44%)patientswithNS/OShadnoothersymptoms ofsyphiliswhereas53hadsignsofearlysyphilis,49(51%)hadsigns ofsecondarysyphilis,andfourhadasyphiliticchancre.Amongthe 49 patientswithsignsof secondarysyphilis,a cutaneouserup- tionwasfoundin46patients(87%)and/oramucousmembrane involvementin12patients(22%).

5. Biologicalcharacteristics

Lumber punctures wereperformed in 77 patients(Table3).

Amongthe19patientswhodidnothaveCSFanalysis,18hadOS.

PleiocytosisandCSF-proteinlevelsweresignificantlyhigherinNS formsthaninOSforms(respectively81±121versus29±51;and 0.92±0.8versus0.57±0.29;P=0.04forboth).VDRLinbloodatini- tialdiagnosiswasnotsignificantlydifferentaccordingtoHIVstatus orNSpattern(Table4).ApositiveVDRL-CSFwasfoundin4of14 patientswithpureNSform(29%)when100%ofT-testinCSFwas positive.ForpureOSforms,theT-testinCSFwaspositivein39of 50patients(78%)whohadalumbarpuncturesandtheVDRL-CSF waspositivefor10(20%)ofthesepatients.

6. Treatmentandoutcome

Ninetypatients(95%)weretreatedwithintravenous(IV)peni- cillinG(18to24MUIperday),threepatientswithIVceftriaxone2g perday,andonewithoraldoxycycline200mgperday.Onepatient receivedanintramuscularinjectionofbenzathinebenzylpenicillin

beforeoraldoxycyclinewhereasanotherpatientwasnottreated, andwaslosttofollowup.

ThethreepatientstreatedwithceftriaxonehadOS:one(HIV- positive)hadacompleterecoveryatM3,one(HIV-positive)had apartialvisualrecoveryafteroneyearoffollow-upandone(HIV- negative)hadapartialvisualrecoveryafter3monthsandthenwas losttofollow-up.Theonlypatienttreatedwithdoxycyclinewas HIV-positive,hadOSandhadacompleterecoveryafter21daysof treatment.Afteronemonth,amongthe90patientstreatedwith IVpenicillinG,28patients(31%)stillhadneurologicalorocular symptoms.Amongthese28patients,penicillinwasprolongedfor onemonthinsixpatients,switchedforceftriaxoneinonepatient, andfordoxycyclineintwopatients.Treatmentdurationwasavail- ablein93patientsasthreewerelosttofollow-up.Ninetypatients (97%)receivedatleast15daysofantibiotics.Durationoftreatment was15daysfor41(44%)patientsand21daysfor40(43%)patients.

NinepatientsstillpresentedclinicalsignsofNS/OSandtheirtreat- mentwasextendedto28days.Thethreeremainingpatientswere treatedlessthan15daysbecauseofnoncomplianceintwopatients, andskinallergyatday13inonepatient.

Sixmonthsaftertreatment,18(34%)ofthe54patientswith follow-upstillhadclinicalsigns.Afteroneyear,7ofthe40evaluable patients(18%)hadsequelae(Table5).

VAevolutionwasanalyzedin26patients.Therewasaconstant improvement,atleastpartial,orstabilizationofVAforeverypatient atthreemonthsfollow-up(seeweb-onlySupplementaryFigure S3).Afterthreemonths,nopatientshadaVAbelow2/10compared to12patientsinitially(40%),and21patients(81%)hadaVAabove 5/10comparedto12patients(40%)beforetreatment,buttherewas stillfivepatients(19%)withanintermediaryVAbetween2/10and 5/10comparedto6(20%)beforetreatment(Fig.2).

VDRLbloodtestswerenegativeatsixmonthsin43ofthe50 patients(86%)inwhomthisdatawasavailable,andin37ofthe41 patientswhocouldbeevaluatedafteroneyear.

7. Discussion

ItwasfoundthatHIV-positivepatientswithearlysymptomatic NS/OSweremore likely tobeyounger, MSM,tohave a history 354

Table5

Evolutionat6monthsand12monthsaftertreatmentofnon-treponemabloodtest(VDRL)accordingtoHIVstatusandclinicalevolutionandinitialcohortof96patients withearlyneurosyphilisorocularsyphilis.

NegativationofVDRLat6months NegativationofVDRLat12months

Allpatients HIV+ HIV– Allpatients HIV+ HIV–

n/N (%) n/N (%) n/N (%) n/N (%) n/N (%) n/N (%)

Overallevolution 34/42 (76) 17/20 (85) 18/22 (82) 32/36 (89) 16/20 (80) 16/16 (100)

Completerecovery 21/24 (88) 12/13 (86) 9/11 (82) 21/22 (95) 12/13 (92) 9/9 (100)

Anysequelae 12/15 (80) 4/5 (80) 9/10 (90) 10/12 (83) 3/5 (60) 7/7 (100)

Reinfection 0/3 (0) 0/2 (0) 0/1 (0) 0/2 (0) 0/2 (0)

n:numberofpatientswithnegativeVDRLat6or12months;N:totalnumberofpatientswithclinicalandbiologicaldataavailableat6or12months.

Fig.2.EvolutionofvisualacuityaftertreatmentbylogMARscaleinasubcohort of26patientswithearlyocularsyphilis(thehigherlogMARscore,thelowerthe acuity).

of syphilis,bilateralocularinvolvement anda positiveT-testin theCSFcomparedtoHIV-negativepatients.Therewasnoother differencebetweenthetwogroups.

SimilarepidemiologicaldifferencesbetweenHIV-positiveand negativepatientswerealsofoundin severalstudies.A younger ageisfoundinthreeotherstudies:39versus55years(P=0.001) in41OS[21],44yearsversus53years(P=0.002)in66OS[21], and38yearsversus49years(P=0.003)in46NS[15].Incontrast noagedifferencewasfoundinthestudiesfocusingonallforms ofsyphilis[5,22].Otherwisecomparativestudiesusuallyfindthat HIV-positivepatientsweremoreoftenMSM[5,21,23]andhavea historyofsyphilis[5,11,22].

Themostrecentstudycomparedneurologicalandocularsigns inHIV-positiveandHIV-negativepatientsbutHIV-positivepatients with no neurological symptoms but considered at risk for NS (ie.RPR≥1:32andCD4≤350/␮l)werealsoincluded[24].Unfor- tunately the authors did not specify how many HIV-positive asymptomaticcaseswiththelattercriteriawereincluded.Of385 HIV-positivepatientsand81HIV-negativepatients,HIV-negative patientshadmorehearingloss(30.8%versus17.2%,P=0.006),sen- soryloss(8.8%versus3.7%,P=0.047)andgait(26.3%versus16.5%, P=0.041)thanHIV-positivepatients.Howeversuchresultscannot

becompared tooursourpopulationstudyonlyincludedsymp- tomaticpatientswithNSinbothgroups.

InthispostHAARTarea,ofour47HIV-positivepatients,39(83%) hadeyeinvolvement.Wereportedmorepatientswithposterior uveitis(58%)thanpanuveitis(24%).Thiscontrastwithotherstud- ieswherepanuveitiswastheleadingformofOS,foundin41%of 41patientsand42%of66patientsrespectively[21,23].However, thisissimilartotheresultsofanotherstudyon21OScasesseen from2012to2015whereposterioruveitis(69%)wasmorecommon thanpanuveitis(14%)[25].Wedonotexplainwhytheproportion ofpanuveitiswaslowerthaninpreviousreports,butwehypothe- sizethattheminimalsignsassociatedwithinvolvementofanterior segmentcouldhavebeenmissedbythephysicianspreviously.

Wefounda significantincreasein bilateraleyeinvolvement amongHIV-positivecomparedtoHIV-negativepatients.Similarly, somestudiesfoundahigherprevalenceofbilateralinvolvement inHIV-positivepatients,rangingfrom63%of83OS[13]to83%of 13uveitis[26].IncontrastintheBritishcohortof41OSsucha differencewasnotevidenced[21].

ThemainmanifestationofearlysymptomaticNSwascranial nerveinvolvementoftheVIIIthcranialnerve(76%ofthecasesof NS).Veryfewstudiesdetailedtheproportionofeachcranialnerve involvementinNS,andthosethatdoarerelativelyold.Thelargest reviewofcranialnerveinvolvementinNSwasperformedin1946, included195patientsandfoundapredominanceofVIIIth(23%)and VIIth(23%),followedbyIInd(15%),IIIrdandVIth(12%),butother cranialnerves(Vth,IXth-Xth,IVth,XIIth,Ist,XIth)wereinvolved [27].Thereforetheinvolvementofacranialnerve,mainlytheVIIth orVIIIth,inapersonwithat-risksexualbehaviorshouldraisethe diagnosisofNS.

We surprisingly identified 11 patients(38%of NS) who had paresthesianeitherassociatedwithasensitivenervedefectnor aCNSfocallesion.Amongthesepatients,twopatientshadonly paresthesiasasneurologicalsymptoms(associatedwithbiological meningitis)raisingthequestionofoverlappingofearlyandlateNS patternswithearlytabes.Thisisunlikelyasourcriteriaforearly syphiliswerestringent.Howeversuchsymptomwouldneedmore investigation.Meanwhilethediagnosisofsyphilisshouldberaised inanyepisodeofparesthesiasinapatientatrisk.

Only17patients(22%)of96whomhadalumbarpunctureshad positiveVDRL-CSF.Intheliterature,VDRL-CSFhasbeendescribed withvariablesensitivitiesdependingonstudiesfrom10.7to27%

[14,15,24,28]. Thus, it is admitted that CSF-VDRL alone is not enoughtoconfirmneurosyphilis[16],andshouldbeinterpreted alongwithotherclinicalandbiologicalparameters.

Furthermore, we chose to include positive T-test in CSF as mandatoryfordiagnosisofpureformNS.,Thelatest2014Euro- peanguidelinesonsyphilismanagementstatethat“apositiveCSF T-testdoesnotconfirmthediagnosisofNSbutanegativeCSFT-test resultishighlyunlikelyinneurosyphilis”[16].Intra-venouspeni- cillinGisstillthefirst-lineantibioticforNS/OS[16–18].Treatments otherthanpenicillingiveinconstantresultsandarenotconsidered asefficientaspenicillin[29,30].Wedidnottreatenoughpatients

V.Rasoldieretal. InfectiousDiseasesNow51(2021)351–356

withceftriaxoneordoxycyclinetofeedthisdebate.Howeverithas beenshowedthatdoxycyclincouldbeefficientinpatientswithOS [30].Ofnoteonly19%ofour63patientswithOSwhounderwent lumbarpunctureshadbiologicalsignsofNS.Thereforeoraldoxy- cyclincouldbeconsideredinatleast80%ofthepatientswithOS andcomparativestudiesareneededinordertoretainintravenous penicillinforthecasesofNS.

Wefoundahighrateofsequelae(18%at12months)incon- trast to previousstudieswhere the criteriaof judgement were biological(decreaseofVDRLinthebloodand/orintheCSF)and notclinical.Thesequelaeincludedvertigo,visualloss,orpersistent paresthesias.Incontrasttousualrecommendations[16–18],noCSF follow-upwasdoneinourstudyforthreedifferentreasons.Some ofourpatientshadOSwithnolumbarpunctureatonset.Other patientswerelosttofollow-up,orrefusedanotherlumbarpunc- tureastheywerecured.Howeverclinicaloutcomeseemsmore importantandweshowedahighrateofsequelae.

Ourstudyhassomelimitations.First,58%ofourpatientswere losttofollow-upatoneyear.Howeverthisrateissimilartothat foundinotherretrospectivestudieswhereitvariesfrom34%to 64%[3,5,11].Secondly,wechosetodistinguishOSandNSalthough treatmentofOSisassociatedwiththatofNSinusualguidelines [16–18].OurresultssupportthatNSandOScouldbeconsidered separatelyas22%ofourpatientsdiagnosedwithOShadanegative T-testintheCSF,and80%hadnobiologicalsignsofNS.Moreover sclera,cornea,vitreousanretinalvesselsdonotderivefromthe neuroepitheliumwhichformsthecentralnervoussystemduring theembryogenesis[31].Lastlydoxycyclinecouldbeconsideredin patientswithOS[30].Finally,lumbarpuncturewasnotsystematic inOS,reasonwhywedidnothaveCSFdataforeverypatient.It wasconsideredtobeaninvasiveprocedure,whichwasavoidable, asthetreatmentofOSandNSremainsthesame.

In conclusionearlysymptomatic NS/OSisincreasing,witha largemajorityofOS.Paresthesiasandcranialnerveinvolvement inapatientatriskofsyphilisshouldraisethediagnosisofNS.HIV- infectiondoesnotappeartoconferanychangeintheoutcomeof NSandOSinthispost-HAARTera.Thehighrateofsequelaeempha- sizestheimportanceofpreventionandscreening,andcallsforthe evaluationofanenhancedtreatmenteitherbyassociatingcorti- costeroidsorbyusinghigherdosesormoreprolongedcoursesof treatment.

EthicalApproval

Allproceduresperformedinstudiesinvolvinghumanpartici- pantswereinaccordancewiththe1964Helsinkideclarationand itslateramendments.

Authorcontributions

V.R.performedtheliteraturereview,thestatisticalanalysisand wrotethearticle.

J.G,B.B.andM.M.providedtheophthalmologicaldata.

J.G.helpedontheclassificationandanalysisofophthalmological data.

C.C.,R.T.providedclinicaldata.

L.P.,M.P.C.providedbiologicaldataandhelpedontheiranalyses.

F.C.supervisedV.R.inwritingtables.

E.C.supervisedV.R.inperformingtheliteraturereviewandwrit- ingthearticle.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]NdeikoundamN,ViriotD,FournetN,etal.Bacterialsexuallytransmittedinfec- tionsinFrance:recenttrendsandpatients’characteristicsin2016.EuroSurveill 2019;24:1–8.

[2]TrickeyA,MayMT,VehreschildJ-J,etal.SurvivalofHIV-positivepatientsstart- ingantiretroviraltherapybetween1996and2013:acollaborativeanalysisof cohortstudies.LancetHIV2017;4:e349–56.

[3]GhanemKG,ErbeldingEJ,WienerZS,RompaloAM.Serologicalresponseto syphilistreatmentinHIV-positiveandHIV-negativepatientsattendingsexu- allytransmitteddiseasesclinics.SexTransmInfect2007;83:97–101.

[4]MarraCM,MaxwellCL,TantaloL,etal.Normalizationofcerebrospinalfluid abnormalitiesafterneurosyphilistherapy:doesHIVstatusmatter?ClinInfect Dis2004;38:1001–6.

[5]FarhiD,BenhaddouN,GrangeP,ZiziN,etal.Clinicalandserologicbaselineand follow-upfeaturesofsyphilisaccordingtoHIVstatusinthepost-HAARTera.

Medicine(Baltimore)2009;88:331–40.

[6]LukehartSA,HookEW,Baker-ZanderSA,CollierAC,CritchlowCW,Handsfield HH.InvasionofthecentralnervoussystembyTreponemapallidum:implica- tionsfordiagnosisandtreatment.AnnInternMed1988;109:855–62.

[7]ClarkEG,DanboltN.TheOslostudyofthenaturalhistoryofuntreatedsyphilis;

anepidemiologicinvestigationbasedonarestudyoftheBoeck-Bruusgaard material;areviewandappraisal.JChronicDis1955;2:311–44.

[8]deVouxA,KiddS,TorroneEA.ReportedCasesofNeurosyphilisAmongEarly SyphilisCases-UnitedStates,2009to2015.SexTransmDis2017;45(1.).

[9]OliverSE,AubinM,AtwellL,etal.OcularSyphilis–EightJurisdictions,United States,2014–2015.MMWRMorbMortalWklyRep2016;65:1185–8.

[10]KatzDA,BergerJR,DuncanRC.Neurosyphilis.Acomparativestudyoftheeffects ofinfectionwithhumanimmunodeficiencyvirus.ArchNeurol1993;50:243–9.

[11]FloodJM,WeinstockHS,GuroyME,etal.NeurosyphilisduringtheAIDSepi- demic,SanFrancisco,1985–1992.JInfectDis1998;177:931–40.

[12]WangZ,LiuL,ShenY-Z,etal.Theclinicalandlaboratoryfeaturesofneu- rosyphilis inHIV-infected patients:Aretrospective study in92patients.

Medicine(Baltimore)2018;97:e0078.

[13]Conde-SendínMA,Amela-PerisR,etal. Currentclinicalspectrumofneu- rosyphilisinimmunocompetentpatients.EurNeurol2004;52:29–35.

[14]GoldenMR,MarraCM,HolmesKK.UpdateonSyphilis:ResurgenceofanOld Problem.JAMA2003;290:1510–4.

[15]DavisLE,SchmittJW.Clinicalsignificanceofcerebrospinalfluidtestsforneu- rosyphilis.AnnNeurol1989;25:50–5.

[16]JanierM,HegyiV,DupinN,etal.2014Europeanguidelineonthemanagement ofsyphilis.JEurAcadDermatolVenereolJEADV2014;28:1581–93.

[17]Centers for Disease Control Prevention. Sexually Transmitted Diseases:

Summary of 2015 CDC Treatment Guidelines. J Miss State Med Assoc 2015;56:372–5.

[18]WongT,FonsecaK,CherneskyMA,GarceauR,LevettPN,SerhirB.Canadian PublicHealthLaboratoryNetworklaboratoryguidelinesforthediagnosisof neurosyphilisinCanada.CanJInfectDisMedMicrobiol2015;26:18A–22A.

[19]BiostaTGV - Statistiques en ligne. http://marne.u707.jussieu.fr/biostatgv/?

module=tests.

[20]GirszynN,FaresJ,ProustF,etal.Lebergeretlablancheingénue.RevMed Interne2011;32(12):770–2.

[21]MathewRG,GohBT,WestcottMC.BritishOcularSyphilisStudy(BOSS):2-year nationalsurveillancestudyofintraocularinflammationsecondarytoocular syphilis.InvestOphthalmolVisSci2014;55:5394–400.

[22]RolfsRT,JoesoefMR,HendershotEF,RompaloAM,AugenbraunMH,ChiuM, etal.Arandomizedtrialofenhancedtherapyforearlysyphilisinpatientswith andwithouthumanimmunodeficiencyvirusinfection.TheSyphilisandHIV StudyGroup.NEnglJMed1997;337:307–14.

[23]HoogewoudF,FrumholtzL,LoubetP,etal.PrognosticFactorsinSyphilitic Uveitis.Ophthalmology2017;124:1808–16.

[24]DavisAP,SternJ,TantaloL,etal.HowWellDoNeurologicSymptomsIdentify IndividualsWithNeurosyphilis?ClinInfectDis2018;66:363–7.

[25]PratasAC,GoldschmidtP,LebeauxD,etal.IncreaseinOcularSyphilisCases atOphthalmologicReferenceCenter,France,2012–2015.EmergInfectDis 2018;24:193–200.

[26]Shalaby IA, Dunn JP, Semba RD, Jabs DA. Syphilitic uveitis in human immunodeficiencyvirus-infected patients.ArchOphthalmol ChicIll1960 1997;115:469–73.

[27]MerrittHH,AdamsRD,SolomonHC.Neurosyphilis.OxfordUniversityPress;

1946.p.443.

[28]SmibertOC,AbbingaS,SpelmanDW,JenneyAWJ.Neurosyphilis:Concordance betweencerebrospinalfluidanalysisandsubsequentantibioticstrategyfor patientsundergoingevaluationofadiagnosisofneurosyphilis.IntJInfectDis 2019;82:73–6.

[29]ShannS,WilsonJ.Treatmentofneurosyphiliswithceftriaxone.SexTransm Infect2003;79:415–6.

[30]AmodeR,MakhloufiS,Calin R,CaumesE.Oraldoxycyclineforsyphilitic uveitis:acasereporthighlightingpotentialefficacy.JAntimicrobChemother 2018;73:1999–2000.

[31]TuddenhamS,GhanemKG.Ocularsyphilis:opportunitiestoaddressimportant unansweredquestions.SexTransmInfect2016;92:563–5.

356