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UncommonCausesofStroke

UncommonCausesofStroke

ThirdEdition

BethIsraelDeaconessMedicalCenter,Boston

JoséBiller

LoyolaUniversityStritchSchoolofMedicine,Chicago

UniversityPrintingHouse,CambridgeCB28BS,UnitedKingdom OneLibertyPlaza,20thFloor,NewYork,NY10006,USA 477WilliamstownRoad,PortMelbourne,VIC3207,Australia 314321,3rdFloor,Plot3,SplendorForum,JasolaDistrictCentre, NewDelhi110025,India

79AnsonRoad,#0604/06,Singapore079906

CambridgeUniversityPressispartoftheUniversityofCambridge. ItfurtherstheUniversity’smissionbydisseminatingknowledgeinthe pursuitofeducation,learning,andresearchatthehighestinternational levelsofexcellence.

www.cambridge.org

Informationonthistitle:www.cambridge.org/9781107147447

DOI:10.1017/9781316551684

©CambridgeUniversityPress2018

Thispublicationisincopyright.Subjecttostatutoryexception andtotheprovisionsofrelevantcollectivelicensingagreements, noreproductionofanypartmaytakeplacewithoutthewritten permissionofCambridgeUniversityPress.

FirstEditionCambridgeUniversityPress2001

SecondEditionCambridgeUniversityPress2008

ThirdEditionCambridgeUniversityPress2018

PrintedintheUnitedKingdombyTJInternationalLtd.Padstow Cornwall

AcatalogrecordforthispublicationisavailablefromtheBritishLibrary. LibraryofCongressCataloginginPublicationData Names:Caplan,LouisR.,editor.|Biller,José,editor.

Title:Uncommoncausesofstroke/editedbyLouisR.Caplan,JoseBiller. Description:Thirdedition.|Cambridge,UnitedKingdom;NewYork, NY:CambridgeUniversityPress,2018.|Includesbibliographical referencesandindex.

Identifiers:LCCN2017061460|ISBN9781107147447(hardback)

Subjects:|MESH:Stroke etiology|Infection complications|Genetic Diseases,Inborn complications|VascularDiseases complications| MetabolicDiseases complications|AutoimmuneDiseases complications

Classification:LCCRC388.5|NLMWL356|DDC616.8/1075dc23 LCrecordavailableathttps://lccn.loc.gov/2017061460 ISBN9781107147447Hardback

CambridgeUniversityPresshasnoresponsibilityforthepersistenceor accuracyofURLsforexternalorthirdpartyinternetwebsitesreferredto inthispublicationanddoesnotguaranteethatanycontentonsuch websitesis,orwillremain,accurateorappropriate.

Everyefforthasbeenmadeinpreparingthisbooktoprovideaccurateand uptodateinformationthatisinaccordwithacceptedstandardsand practiceatthetimeofpublication.Althoughcasehistoriesaredrawn fromactualcases,everyefforthasbeenmadetodisguisetheidentitiesof theindividualsinvolved.Nevertheless,theauthors,editors,and publisherscanmakenowarrantiesthattheinformationcontainedherein istotallyfreefromerror,notleastbecauseclinicalstandardsare constantlychangingthroughresearchandregulation.Theauthors, editors,andpublishersthereforedisclaimallliabilityfordirector consequentialdamagesresultingfromtheuseofmaterialcontainedin thisbook.Readersarestronglyadvisedtopaycarefulattentionto informationprovidedbythemanufacturerofanydrugsorequipment thattheyplantouse.

Contents

ListofContributors viii Preface xiii

Section1–InfectiousConditions

1 NeurosyphilisandStrokes 1 LarryE.DavisandGlennD.Graham

2 VasculitisandStrokesDuetoTuberculosis 7 SaroshM.Katrak

3 StrokesDuetoFungalInfections 13 MarcA.BouffardandLouisR.Caplan

4 StrokesandVasculitisinPatientswith Cysticercosis 20 OscarH.DelBrutto

5 StrokesinPatientswithBacterialMeningitiswith aFocusonPneumococcusandLymeDisease 26 JohnJ.Halperin

6 CerebrovascularandOtherNeurologic ComplicationsofKawasakiDisease 38 JonathanLiptonandMichaelJ.Rivkin

7 ChagasDisease 44 AyrtonR.Massaro

8 StrokesinPersonsInfectedwithHIV 52 KathleenBatemanandAlanBryer

9 InfectiveEndocarditis 63 KanjanaS.Perera,IanMoffatt,andRobertG.Hart

10 VaricellaZosterVirusVasculopathy 71 MariaA.NagelandDonGilden

Section2–InflammatoryConditions

11 PrimaryAngiitisoftheCentralNervousSystem 77 MathieuZuber

12 GiantCellArteritis 87 SachinKedarandJamesJ.Corbett

13 TakayasuDisease 96 YukitoShinohara

14 BehçetDisease 102 EmreKumral

15 StrokesandNeurosarcoidosis 111 JayShah,ChandniP.Kalaria,andBarneyJ.Stern

Section3–HereditaryandGeneticConditions andMalformations

16 PulmonaryArteriovenousMalformations 119 PamelaN.Correia,JulienMorier,andPatrikMichel

17 HereditaryHemorrhagicTelangiectasia 128 MichelLogakandMathieuZuber

18 CerebralAutosomal-DominantArteriopathywith SubcorticalInfarctsandLeukoencephalopathy (CADASIL) 134 HuguesChabriat

19 CerebralAutosomal-RecessiveArteriopathywith SubcorticalInfarctsandLeukoencephalopathy (CARASIL) 140 ToshioFukutake

20 SickleCellDiseaseandOther Hemoglobinopathies 147 HyacinthI.HyacinthandRobertJ.Adams

21 CerebrovascularComplicationsofFabry Disease 158 PanayiotisD.MitsiasandStevenR.Levine

22 MarfanSyndrome 170 LuísCunhaandJoãoSargento-Freitas

23 PseudoxanthomaElasticum 175 Chin-SangChung,MiJiLee,andLouisR.Caplan

24 Ehlers–DanlosSyndrome 181 E.SteveRoach

25 Progeria 187 E.SteveRoachandN.PaulRosman

26 MELASSyndromeandOtherMitochondrial Disorders 194 RussellP.SanetoandCatherineAmlie-Lefond

27 Sturge–WeberSyndrome 200 AnneComiandE.SteveRoach

28 VonHippel–LindauDisease 208 GiovannaS.Manzano,LucaRegli,andAmir R.Dehdashti

29 FamilialAneurysms 215 HarishBabuandWouterI.Schievink

30 CerebralCavernousMalformationsand DevelopmentalVenousAnomalies 227 KellyD.FlemmingandRobertD.Brown

31 CerebrovascularManifestationsof Neurofibromatosis 245 KrassenNedeltchevandHeinrichP.Mattle

32 MenkesDisease 250 LenoraM.LehwaldandJohnH.Menkes

33 Wyburn–MasonSyndrome 255 StephenD.ReckandJonathanD.Trobe

34 Divry–vanBogaertSyndrome 259 AnnaBersanoandGloriaBedini

35 BlueRubberBlebSyndrome 268 StephanieAhrensandMargieA.Ream

Section4–VascularConditionsoftheEyes, Ears,andBrain

36 EalesDisease 273 SamuelBidotandValérieBiousse

37 AcutePosteriorMultifocalPlacoidPigment Epitheliopathy 275 MarcD.Reichhart,MarcC.Patterson,and François-XavierBorruat

38 SusacSyndrome 290 IgnacioGarcía-Basterra,ThomasR.Hedges,and LouisR.Caplan

39 HereditaryEndotheliopathywithRetinopathy, Nephropathy,andStroke 298 JoannaC.JenandRobertW.Baloh

40 CoganSyndrome 302 SamuelBidotandValérieBiousse

Section5–DisordersInvolvingAbnormal Coagulation

41 AntiphospholipidAntibodySyndrome 305 ChristopherH.TopelandRobinL.Brey

42 DisseminatedIntravascularCoagulation 317 SanamBaghshomaliandMonishaA.Kumar

43 BleedingDisorders 328 RochelleSweisandJoséBiller

44 Thrombophilias 336 EalafAlRabiaandBruceM.Coull

45 ThromboticThrombocytopenicPurpura 347 JorgeMoncayo-GaeteandPatricioCorrea

46 CerebrovascularComplicationsofHenoch–Schönlein Purpura 356 LouisR.CaplanandSeanI.Savitz

Section6–SystemicDisordersThatAlsoInvolve theCerebrovascularSystem

47 MicroscopicPolyangiitisandPolyarteritis Nodosa 359 PamelaN.CorreiaandPatrikMichel

48 EosinophilicGranulomatosiswithPolyangiitis 378 ManuMehdirattaandLouisR.Caplan

49 SystemicLupusErythematosusandCerebrovascular Disease 381 ShamikBhattacharyyaandMartinA.Samuels

50 RheumatologicDiseasesandStrokes 389 SarahE.NelsonandJudithA.Hinchey

51 HyperviscosityandStrokes 408 JohnF.Dashe

52 Calcium,Hypercalcemia,Magnesium,andBrain Ischemia 418 FernandoD.TestaiandPhilipB.Gorelick

53 StrokesandSubstanceAbuse 429 JohnC.M.Brust

54 CancerandParaneoplasticStrokes 437 SusanaArias-Rivas,ManuelRodríguez-Yáñez, AntonioDávalosErrando,andJoséCastillo

55 MalignantAtrophicPapulosis 445 PradSelvanandDanielM.Rosenbaum

56 InflammatoryBowelDiseaseandStrokes 448 MichaelA.DeGeorgiaandDianaAbdul-Rahman

57 SweetSyndrome 461 LaurenJamesandPedroWeisleder

58 StrokesAssociatedwithNephroticSyndromeand OtherRenalDiseases 469 AmreNouh,RimaM.Dafer,andJoséBiller

59 EpidermalNevusSyndrome 478 MelissaG.Chung

60 SneddonSyndrome 482 JacquesL.DeReuck

61 BoneDisordersandCerebrovascularDiseases 489 NatanM.BornsteinandAlexanderY.Gur

62 Scleroderma 495

AdrianMarchidann,SusanW.Law,andSteven R.Levine

63 HypereosinophilicSyndrome 498 Chih-PingChung

64 Radiation-InducedVascularDisease 502 ErikJ.UhlmannandLouisR.Caplan

65 LymphomatoidGranulomatosis 506 LouisR.Caplan

Section7–Non-InflammatoryDisordersofthe ArterialWall

66 CervicocephalicArterialDissections 509 MarcelArnoldandMathiasSturzenegger

67 CerebralAmyloidAngiopathy 534 M.EdipGurolandStevenM.Greenberg

68 MoyamoyaDisease 545 JongS.Kim,OhYoungBang,andChangWanOh

69 Dolichoectasia 560 DavidRosenbaum-Halevi,SeanI.Savitz,andLouis R.Caplan

70 ParadoxicalEmbolismsandStrokes 565 DavidE.ThalerandSteven C.Cramer

71 FibromuscularDysplasia 575 LouisR.Caplan

72 AorticDissections 581 MarkMcAllisterandLouisR.Caplan

Section8–VenousOcclusiveConditions

73 CerebralVenousSinusThrombosis 589 JoséManuelFerro,PatríciaCanhão,andDiana AguiardeSousa

Section9–VasospasticConditionsandOther MiscellaneousVasculopathies

74 ReversibleCerebralVasoconstriction Syndrome 597 AneeshB.Singhal

75 EclampsiaandStrokesDuringPregnancyand Postpartum 606

JenniferJ.Majersik,MichaelW.Varner,and KathleenB.Digre

76 MigrainesandMigraine-LikeConditions 621 AliciaM.Zha,SeanI.Savitz,andLouisR.Caplan

77 IntravascularLymphomaoftheCentralNervous System 630 SomaSenguptaandRafaelRojas

Index 633

Colorplatesaretobefoundbetweenpp.274and275.

Contributors

DianaAbdul-Rahman,MD

JohnC.LincolnMedicalCenter,Phoenix,AZ,USA

RobertJ.Adams,MS,MD

SouthCarolinaStrokeCenterofEconomicExcellence, Charleston,SC,USA

DianaAguiardeSousa,MD HospitalSantaMaria,UniversityofLisbon,Lisbon,Portugal

StephanieAhrens,DO

TheOhioStateUniversity,Columbus,OH,USA

EalafAlRabia,MD

TheUniversityofArizona,Tucson,AZ,USA

CatherineAmlie-Lefond,MD SeattleChildren’sHospital,Seattle,WA,USA

SusanaArias-Rivas,MD,PhD HospitalClínicoUniversitario,SantiagodeCompostela,Spain

MarcelArnold UniversitätsspitalBern,InselspitalBern,Switzerland

HarishBabuMD,PhD

Cedars-SinaiMedicalCenter,LosAngeles,CA,USA

SanamBaghshomali,MD HospitaloftheUniversityofPennsylvania,Philadelphia,PA, USA

RobertW.Baloh,MD DavidGeffenSchoolofMedicineatUCLA,LosAngeles,CA, USA

OhYoungBang,MD,PhD SungkyunkwanUniversity,Seoul,SouthKorea

KathleenBateman,MBChB,MRCP(UK),FCNeurol(SA) GrooteSchuurHospital,CapeTown,SouthAfrica

GloriaBedini,MSc IRCCSFoundationNeurologicalInstitute,Milan,Italy

AnnaBersanoMD,PhD IRCCSFoundationNeurologicalInstitute,Milan,Italy

ShamikBhattacharyya,MD,MS BrighamandWomen’sHospital,Boston,MA,USA

SamuelBidot,MD FondationOphtalmologiqueAdolphedeRothschild,Paris, France

JoseBiller,MD LoyolaUniversity,StritchSchoolofMedicine,Chicago,IL, USA

ValérieBiousse,MD EmoryUniversitySchoolofMedicine,Atlanta,GA,USA

NatanM.Bornstein,MD TelAvivUniversity,TelAviv,Israel

RobinL.Brey,MD UniversityofTexasHealthScienceCenteratSanAntonio SchoolofMedicine,SanAntonio,TX,USA

MarcA.Bouffard,MD BethIsraelDeaconessMedicalCenter,Boston,MA,USA

RobertD.Brown,MD MayoClinic,Rochester,MN,USA

JohnC.M.Brust,MD NewYorkNeurologicalInstituteNewYork,NY,USA

AlanBryer,MBChB,FCP(SA),PhD GrooteSchuurHospital,CapeTown,SouthAfrica

LouisR.Caplan,MD BethIsrael-DeaconessMedicalCenter,Boston,MA,USA

PatríciaCanhão,MD,PhD HospitalSantaMaria,UniversityofLisbon,Lisbon,Portugal

JoséCastillo,MD,PhD HospitalClínicoUniversitario,SantiagodeCompostela,Spain

HuguesChabriat,MD,PhD UniversityDenisDiderot,Paris,France

Chih-PingChung,MD,PhD NationalYangMingUniversity,Taipei,Taiwan

Chin-SangChung,MD,PhD SungkyunkwanUniversitySchoolofMedicine, Seoul,Korea

MelissaG.Chung,MD OhioStateUniversity,Columbus,OH,USA

AnneComi,MD JohnsHopkinsSchoolofMedicine,BaltimoreMD,USA

JamesJ.Corbett,MD LoyolaUniversityChicago,StritchSchoolofMedicine, Maywood,ILUSA

PatricioCorrea,MD HospitalCarlosAndradeMarín,Quito,Ecuador

PamelaN.Correia,MD CentreHospitalierUniversitaireVaudois,Lausanne, Switzerland

BruceM.Coull,MD UniversityofArizona,Tucson,AZ,USA

StevenC.Cramer,MD,FAAN,FAHA UniversityofCalifornia,Irvine,CA,USA

LuísCunha,MD,PhD CentroHospitalareUniversitáriodeCoimbra,Coimbra, Portugal

RimaM.Dafer,MD,MPH NorthShoreUniversityHealthSystem,Evanston/Glenbrook, IL,USA

JohnF.Dashe,MD,PhD St.Elizabeth’sMedicalCenter,Boston,MA,USA

AntonioDávalosErrando,MD,PhD HospitalGermansTriasiPujol,Barcelona,Spain

LarryE.Davis,MD NewMexicoVAHealthCareSystem,Albuquerque,NM,USA

AmirR.Dehdashti,MD,FACS,FMH NorthShoreUniversityHospital,Manhasset,NY,USA

MichaelA.DeGeorgia,MD UniversityHospitalsClevelandMedicalCenter,Cleveland, OH,USA

JacquesL.DeReuck,MD UniversityHospital,Ghent,Belgium

OscarH.DelBrutto,MD Hospital – ClínicaKennedyGuayaquil,Ecuador

KathleenB.Digre,MD UniversityofUtah,SaltLakeCity,UT,USA

JoséManuelFerroMD,PhD HospitalSantaMaria,UniversityofLisbon,Lisbon,Portugal

KellyD.Flemming,MD MayoClinic,Rochester,MN,USA

ToshioFukutake,MD,PhD KamedaMedicalCenter,Chiba,Japan

IgnacioGarcía-Basterra,MD UniversityHospitalVirgendelaVictoria,Málaga,Spain

DonGilden,MD UniversityofColoradoSchoolofMedicine,Aurora,CO,USA

PhilipB.Gorelick,MDMPH MichiganStateUniversityCollegeofHumanMedicine,Grand Rapids,MI,USA

GlennD.Graham,MDPhD UniversityofCalifornia,SanFranciscoSchoolofMedicine, SanFrancisco,CA,USA

StevenM.Greenberg,MD,PhD MassachusettsGeneralHospital,BostonMA,USA

AlexanderY.Gur,MD,PhD Ben-GurionUniversityoftheNegev,Beer-Sheva,Israel

M.EdipGurol,MD,MSc MassachusettsGeneralHospital,BostonMA,USA

JohnJ.Halperin,MD,FAAN,FACP OverlookMedicalCenter,Summit,NJUSA

RobertG.Hart,MD McMasterUniversity,Hamilton,ON,Canada

ThomasR.Hedges,MD TuftsUniversitySchoolofMedicine,BostonMA,USA

JudithA.Hinchey,MD St.Elizabeth’sMedicalCenter,Boston,MA,USA

HyacinthI.Hyacinth,MBBS,PhD,MPH EmoryUniversity,AtlantaGA,USA

LaurenJames,MD TheOhioStateUniversity,Columbus,OH,USA

JoannaC.Jen,MD,PhD IcahnSchoolofMedicineatMountSinai, NewYork,NY,USA

ChandniP.Kalaria,MD UniversityofMaryland,Baltimore,MD,USA

SaroshM.Katrak,MD,DM,FRCPE JaslokHospital&ResearchCentre,Mumbai,India

SachinKedar,MD UniversityofNebraskaMedicalCenter,Omaha,NE,USA

JongS.Kim,MD,PhD UniversityofUlsan,Seoul,SouthKorea

MonishaA.Kumar,MD HospitaloftheUniversityofPennsylvania,Philadelphia,PA, USA

EmreKumral,MD SchoolofMedicine,EgeUniversity,Izmir,Turkey

SusanW.Law,DO,MPH NYCHealthandHospital/KingsCountyHospital,NewYork, NY,USA

MiJiLee,MD SungkyunkwanUniversitySchoolofMedicine, Seoul,Korea

LenoraM.Lehwald,MD TheOhioStateUniversityCollegeofMedicine,Columbus, OH,USA

StevenR.LevineMD,FAHA,FAAN,FANA SUNYDownstateMedicalCenter,NewYork,NY,USA

JonathanLipton,MD,PhD BostonChildren’sHospital,HarvardMedicalSchool,Boston, MA,USA

MichelLogak,MD Saint-JosephHospital,Paris,France

JenniferJ.Majersik,MD,MS UniversityofUtah,SaltLakeCity,UT,USA

GiovannaS.Manzano,MD MassachusettsGeneralHospital,BostonMA,USA

AdrianMarchidann,MD SUNYDownstateMedicalCenter,NewYork,NY,USA

AyrtonR.Massaro,MD HospitalSirioLibanes,SaoPaulo,Brazil

HeinrichP.Mattle,MD UniversityofBern,Bern,Switzerland

MarkMcAllister,MD MaineMedicalCenter,Portland,ME,USA

ManuMehdiratta,MD,FRCPC McMasterUniversity,Mississauga,ON,Canada

JohnH.Menkes

DavidGeffenSchoolofMedicineatUCLA,LosAngeles,CA, USA

PatrikMichel,MD CentreHospitalierUniversitaireVaudois,Lausanne, Switzerland

PanayiotisD.Mitsias,MD,PhD HenryFordHospital&WayneStateUniversity,Detroit,MI, USA

IanMoffatt,MD McMasterUniversity,Hamilton,ON,Canada JorgeMoncayo-Gaete,MD UniversidadInternacionaldelEcuador,Quito,Ecuador

JulienMorier,MD VidyMed,Epalinges,Lausanne,Switzerland

MariaA.Nagel,MD UniversityofColoradoSchoolofMedicine, Aurora,CO,USA

KrassenNedeltchev,MD KantonsspitalAarauAG,Aarau,Switzerland

SarahE.Nelson,MD JohnsHopkinsUniversity,BaltimoreMD,USA

AmreNouh,MD HartfordHospital,Hartford,CT,USA

MarcC.PattersonMD,FRACP,FANA,FAAN MayoClinicChildren’sCenter,Rochester,MN,USA

KanjanaS.Perera,MB,BS McMasterUniversity,Hamilton,ON,Canada

RafaelRojas,MD BIDMC,Boston,MA,USA

MargieA.Ream,MD,PhD TheOhioStateUniversity,Columbus,OH,USA

StephenD.Reck,MD ClarusEyeCentre,Lacey,WA,USA

LucaRegli,MD UniversityHospitalofZurich,Zurich,Switzerland

MarcD.Reichhart,MD NeurologueFMH,Bern,Switzerland

MichaelJ.Rivkin,MD BostonChildren’sHospital,HarvardMedicalSchool,Boston, MA,USA

E.SteveRoach,MD OhioStateUniversityCollegeofMedicine,Columbus,OH, USA

ManuelRodríguez-Yáñez,MD,PhD HospitalClínicoUniversitario,SantiagodeCompostela, Spain

DanielM.Rosenbaum,MD SUNYDownstateMedicalCenter,Brooklyn,NY,USA

DavidRosenbaum-Halevi UTHoustonMcGovernMedicalSchool, Houston,TX,USA

N.PaulRosman

BostonUniversitySchoolofMedicineandBostonMedical Center,Boston,MA,USA

MartinA.SamuelsMD,DSc(hon),FAAN,MACP,FRCP, FANA

HarvardMedicalSchool,Boston,MA,USA

RussellP.Saneto,DO,PhD SeattleChildren’sHospital,Seattle,WA,USA

JoãoSargento-Freitas,MD CentroHospitalareUniversitáriodeCoimbra,Coimbra, Portugal

SeanI.Savitz,MD InstituteforStrokeandCerebrovascularDisease,UTHealth, Houston,TX,USA

WouterI.Schievink,MD Cedars-SinaiMedicalCenter,LosAngeles,CA,USA

PradSelvan,MD SUNYDownstateMedicalCenter,Brooklyn, NY,USA

SomaSengupta,MBBChir,PhD WinshipCancerInstitute,EmoryUniversity,Atlanta.GA, USA

JayShah,MD UniversityofCalifornia,Irvine,CA,USA

YukitoShinohara,MD,PhD TacikawaHospital,Tokyo,Japan

AneeshB.Singhal,MD MassachusettsGeneralHospital,Boston,MA,USA

BarneyJ.Stern,MD UniversityofMaryland,Baltimore,MD,USA

MathiasSturzenegger UniversitätsspitalBern,InselspitalBern,Switzerland RochelleSweis,DO LoyolaUniversityChicago,Chicago,IL,USA

FernandoD.Testai,MD,PhD,FAHA UniversityofIllinoisatChicagoCollegeofMedicine, Chicago,IL,USA

DavidE.Thaler,DPhil,BM,BCh TuftsMedicalCentre,Boston,MA,USA

ChristopherH.Topel,DO UniversityofTexasHealthScienceCenter atSanAntonioSchoolofMedicine,SanAntonio, TX,USA

JonathanD.Trobe,MD KelloggEyeCenter,AnnArbor,MI,USA

ErikJ.Uhlmann,MD BethIsraelDeaconessMedicalCenterBoston, MA,USA

MichaelW.Varner,MD UniversityofUtah,SaltLakeCity,UT,USA

ChangWanOh,MD,PhD SeoulNationalUniversityBundangHosptial,Gyunggi-Do, SouthKorea

PedroWeisleder,MD,PhD TheOhioStateUniversity,Columbus,OH,USA

AliciaM.Zha,MD McGovernMedicalSchool,Houston,TX,USA

MathieuZuber,MD UniversityParis5 – RenéDescartes,Saint-JosephHospital Paris,France

Preface

This2018versionof UncommonCausesofStroke isthethird andlargestandmostcompleteeditionofthiswork.

Theideaforthistopicbeganduringtheearly1990s,duringa lunchtimediscussionbetweenJulienBogouslavskyandmyself. Theinitialideawastoeditandpublishabookthatwouldserve asasourcereferenceaboutvariousstrokesyndromesand variousunusualcausesofstroke.Contributorsweretobe internationallyrecognizedexpertsinthevarioustopicschosen. Thefirstvolume,publishedin1995,wasentitled Stroke Syndromes.The510-pagebookwascomposedofthreeparts: StrokeSyndromesandSigns – 24chapters;Arterialand TopographicSyndromes – 19chapters;andParticular VascularEtiologicSyndromes – 16chapters.

Duringtheensuingyearsnumerouscommentsfromcolleagues,rangingfromtraineestointernationalexperts,confirmed theinterestandimportanceofthesetopicsforcliniciansand researchersalike.Therewasclearlytoomuchmaterialto includeinonevolumeso,in2001,JulienBogouslavskyandI editedandpublishedtwoseparatevolumes – oneentitled StrokeSyndromes,2ndedition,andonecalled Uncommon CausesofStroke.Thelatterwasamajorenlargementofthe sectionthathadbeenentitledParticularVascularEtiologic Syndromesintheinitialpublication.

This391-pagefirsteditionof UncommonCausesofStroke contained48chapters,with71contributors.

Thisfirsteditionwasverysuccessfulbutinpostmortem analysesitbecameobviousthatthereweremanyomissions andsomechapterswerenotfullydetailedandwerenotwell written.Duringtheensuingyearstherehadbeenmajor improvementsindiagnostictechnologyandtherapeutics,and theliteratureaboutstrokeshadexpandeddramatically,especiallyfromregionsallaroundtheglobe.Idecidedtoedita secondedition,thistimealone.

Thesecondeditionof UncommonCausesofStroke was publishedin2008.This560-pagedouble-columnedvolume contained70chapters,writtenby110contributors.Thistime thechaptersweredividedintosections,suchasInfectious Causes,InflammatoryConditions,DisordersInvolving AbnormalCoagulation,HereditaryandMetabolic Conditions,etc.Whenthebookwasabouttogotopress,I noticedthatanumberofimportanttopicswerenotcovered,so

Iaddeda71stchapter,whichIwrote,andthiscontained relativelybriefdiscussionsofmiscellaneousconditionsthat hadnotbeencoveredinotherchapters.

Ithasnowbeenafulldecadesincethepublicationofthe secondeditionandI,togetherwithCambridgeUniversity Press,thepublisherofallofthepreviouseditions,feltitwas timeforanupdated,improved,andmorecompletethirdedition.Realizingthatthetaskwastoomuchforoneperson,I elicitedthehelpofDr.JoséBillertohelpmeeditthisnew edition.Thiseditioncontains77chapters,writtenby127 contributors.Newchaptershavebeenadded:CARASIL, SickleCellDisease,Divray–vanBogaertSyndrome,Blue RubberBlebSyndrome,AorticDissection,Hypereosinophilic Syndrome,Radiation-InducedVascularDisease,and LymphomatoidGranulomatosis.ThechapteronBleeding DisordersandThrombophiliahasbeendividedintotwoseparatechapters – BleedingDisordersandThrombophilias. Contributionscomefrommanycountries – Belgium,Brazil, Canada,Ecuador,France,India,Israel,Italy,Japan,Portugal, Spain,SouthAfrica,SouthKorea,Switzerland,Taiwan,and Turkey,aswellasfromtheUSA.

Dr.Billerhasperformedyeomanworkineditingthisedition.Hehasbeenasticklerforquality,detail,andreadability. Hehasreviewedallcontributionsandensuredthattheywere completeandup-to-date,containeddescriptive,diagnostic, andtherapeuticcomponents,andwerewritteninclearly understoodEnglishandwerewellreferencedandillustrated. JoséandIareproudofthisedition.Webelievethatitisamajor upgradeoverprioreditions.

ThanksareduetoCambridgeUniversityPress,thepublishersofalloftheeditions.NickDuntonshepherdedprior volumesflawlessly.NigelGravesandLindaTurnerwere mosthelpfulintheorganizationandinensuringthatthis editionisofthehighestquality.Wethankthemajorcontributors.Mostofallwethankthepatientswhosediseasesand conditionsaredescribedherein.Hopefully,theyandwehave madesomecontributiontooptimizingthecareofpatients whosestrokeetiologiesare uncommon.

Chapter

1 NeurosyphilisandStrokes

Treponemapallidum

Treponemapallidum subsp. pallidum spirochetesareslender, tightlycoiled,unicellular,helicalbacteria,6–15nminlength, and0.2μmindiameter(LaFondandLukehart,2006).The genomeisasingle,circularchromosomeofabout240,000base pairs,whichplacesitinthelowestrangeforallbacteria.In addition,unlikemostotherpathogenicbacteria,thegenome lacksapparenttransposableelements.Theseobservationsmay explainwhy T.pallidum hasremainedsensitivetopenicillinfor morethan60yearsandissodifficulttocultivate. T.pallidum hasnotbeensuccessfullyculturedinvitroalthoughthespirochetewillinfectexperimentalanimalssuchasmice,rabbits, andmonkeys,butmicedonotdevelopclinicaldisease.The widthof T.pallidum issonarrowthatthespirochetesarenot visualizedbylightmicroscopicexaminationoffixedcerebrospinalfluid(CSF)sedimentorbraintissuesusingGram orhematoxylinandeosinstains.However,spirochetesmaybe detectedbydarkfieldmicroscopyorbylightmicroscopywhen Warthin–Starrysilverstainorimmunohistochemistrystains areused.Theintactspirochetehasbeenfoundtohavefew surfaceproteinsthatelicitanimmuneresponse.Thetypical antibodydevelopswhenthespirocheteispartiallydamaged, exposingtheforeignantigens.Thisisonereasonwhythe developmentofsyphilisvaccineshasbeensodifficult.

Innature,theonlyhostsfor T.pallidum arehumans.The organismistransmittedfrompersontoperson,mainly throughvaginalorrectalsexualintercourse,whenthespirochetepenetratesintactmucosalmembranes.However,occasionaltransmissionhasfollowedkissing,oralsex,closecontact withaninfectedprimarylesion,infectedfreshbloodtransfusion,accidentalinoculation,orbyspreadacrosstheplacenta fromaninfectedmothertoherfetus(congenitalsyphilis).The numberofspirochetesrequiredtoinfectahumanisunknown butrabbitscanbeinfectedwithasmallnumberoforganisms.

HistoryandEpidemiologyofNeurosyphilis

Theoriginofsyphilisremainsunknown.However,bythe sixteenthcenturyithadrapidlyspreadthroughoutEurope, reportedlycausinghighmorbidityandmortality.Currentepidemiologyandhistoricalevidencearguesthatsyphiliswas endemicintheNewWorldandcametoEuropewhen Columbusreturned(FarhiandDupin,2010).Unfortunately, inpastcenturieslittleisknownaboutwhatsyphilisdidtothe centralnervoussystem(CNS)andthetypesofvasculardisease itmayhavecaused.Bythetwentiethcentury,butbeforethe

adventofpenicillin,itwasestimatedthatapproximately10 percentofadultslivinginNewYork,Paris,orBerlinhada positiveWassermanbloodtest(nontreponemalantibodytest similartotherapidplasmareagin[RPR]orVenerealDisease ResearchLaboratory[VDRL]assay).Inspiteofthehighprevalenceofsyphilis,relativelyfewpatientsdevelopedsevere disease.Inonestudyof473patientswithuntreatedearly syphilis,two-thirdsneverdevelopedclinicalsymptomsand only9.5percentdevelopedneurosyphilis(Moore,1941).A separatestudyestimatedthatonly6.5percentofinfected individualssubsequentlydevelopedsymptomaticneurosyphilis,with2.3percentdevelopingmeningovascularsyphilis (ClarkandDanbolt,1955).

Withthediscoveryofpenicillin,theprevalenceofsyphilis intheUnitedStatesrapidlyfellfromabout400cases/100,000 populationinthe1940s,tolessthan100cases/100,000inthe late1950s,andtolessthan30cases/100,000by1990(Peterman etal.,2005).However,theprevalenceofprimaryandsecondarysyphilisroseagaininearly2000,particularlyinyoungmen. InSanFrancisco,theincidenceofneurosyphilishasrisensixfoldsince2000andoccurredprimarilyinmenwhohadsex withmen(MSM)(SanFranciscoDepartmentofPublicHealth, 2005).ThecurrentincidenceofsyphilisintheUnited Statesis14.9casesper100,000withthehighestincidencein 20–24-year-olds(Shockman etal.,2014).Largemetropolitan citieshavehigherincidencesthansmallcities.Syphilisisa reportablediseaseineverystate.Worldwide,syphilisremains aseriousdiseasewithanestimated12millionnewcases occurringeachyear(HookandPeeling,2004).

PathogenesisofEarlyNeurosyphilis

NeurosyphilisbeginswithinvasionoftheCNSbyspirochetes duringtheperiodofspirochetedisseminationfromthe primarylesion(called “secondarysyphilis”).Theterm “early neurosyphilis” referstomeningitisassociatedwithsecondary syphilis,asymptomaticneurosyphilis,andmeningovascular syphilisandlastsuptotwodecades(Merritt etal.,1946; Simon,1985).Lateneurosyphilisinvolvesgeneralparesisand tabesdorsalis,developsfromspirocheteinvasionofthebrain orspinalcordparenchyma,andtypicallydevelopsdecades aftertheinitialinfection(Marra,2004;Simon,1985).

Secondarysyphilisbegins2–12weeks(mean6weeks)after theprimaryinfection(Marra,2004,2015).In40percentof thesepatients,thereisdisseminationtotheCNS.CSFfindings includeamononuclearcellpleocytosis,slightlyelevated protein,normalglucose,reactiveCSF-VDRLtest,andthe

identificationofspirochetesbyanimalinoculation,polymerase chainreaction(PCR),orhistologicstaining(DavisandSperry, 1978;Lukehart etal.,1988;MerrittandMoore,1935; Noordhoek etal.,1991).

Whilemostpatientswithsecondarysyphilisdonotdevelop signsofmeningitis,occasionallypatientsdevelopaseptic meningitiswithheadaches,nausea,stiffneck,andlow-grade fever(MerrittandMoore,1935).Afewpatientswillalso developunilateralorbilateralcranialnervepalsies,especially peripheralfacialpalsy,deafnessand/orvertigo,diplopia,or difficultyinswallowingorprotrudingthetongue(Alpers, 1954).Afewpatientswithsecondarysyphilisalsodevelop strokes(MerrittandMoore,1935).

InmostpatientswithCNSinvolvementduringsecondary syphilis,thespirochetesdisappearfromtheCSFandthe meningitisspontaneouslyterminateswithin3months.In somepatients,however,theCNSinfectionpersistsanda stageofasymptomaticneurosyphilisbegins.A2004neurosyphilisstudyfoundthataserumRPRtiterofgreaterthanor equalto1:32ishighlyassociatedwithneurosyphilisregardless ofthesyphilisstageorconcurrentHIVinfections(Marra etal., 2004b).Fivetotenyearslater,growthofspirochetesinthe meningesmayresultinmeningovascularsyphilis(i.e.tertiary syphilis)(Simon,1985).Theincidenceofdevelopingtertiary syphilisisunclearbuttheOslostudyinthepreantibioticera reportedthat6.5percentofcasesdevelopedtertiarysyphilis (Gjestland,1955).

MeningovascularSyphilis

Theincidenceofstrokesfrommeningovascularsyphilisinthe prepenicillinerahasbeenestimatedtorangefrom2.3to20 percentofallneurosyphiliscases(ClarkandDanbolt,1955; Kierland etal.,1942;Merritt etal.,1946;Moore,1941).Inthe post-antibioticera,thereportedincidenceofstrokesfrom meningovascularsyphilisrangesfrom7to23percentofall patientswithneurosyphilis(Aho etal.,1969;Burkeand Schaberg,1985;Danielsen etal.,2004;Hooshmand etal., 1972;Hotson,1981;NordenboandSorensen,1981;Perdrup etal.,1981;TimmermansandCarr,2004).Someofthese reportsgavedataonlyonmeningovascularsyphilisanddid notdistinguishbetweenthosepatientswithstrokesandthose withonlycranialnervepalsies.

Theincidenceofstrokesinmeningovascularsyphilisvaries bystudyandmethodofdiagnosis.Kelly etal.,instudyof218 consecutivepatientswithatransientischemicattack(TIA)or stroke,reportedonly0.4percentwerefrommeningovascular syphilis(Kelley etal.,1989).Lu etal.determinedthat4percent oftheir149patientswithmeningovascularsyphiliswithoutan HIVinfectionhadastroke(Liu etal.,2012).Cordato etal. examined893patientswithastrokeanddiagnosed37(4 percent)withmeningovascularsyphilis(Cordato etal.,2013). Thus,syphilisaccountsforonlyasmallproportionofstrokes. Thepathologyofmeningovascularsyphilishastwomajor components.Thecauseofmostcerebrovasculardiseaseis syphiliticendarteritis,usuallyinvolvingmedium-to-large meningealarteries,calledHeubner’sendarteritis(Grayand

Alonso,2002).Thesearterieshaveconcentriccollagenous thickeningoftheintima(endarteritisobliterans)andcorrespondingthinningofthemedia.Theelasticlaminaremains intact,buttheremaybesplitting.Lymphocytesandplasma cellsinfiltratethethickenedadventitiaandpenetratethe media.Thevasavasorumiscuffedbyinflammatorycells. Lumenconstrictionoccursfromendothelialproliferation andthickening,whichcanbesufficienttoproduceischemic lesionsofthebrainandspinalcord.Themiddlecerebralartery isthemostcommonlyinvolvedvesselleadingtoastroke,but occasionallytheanteriorcerebral,posteriorcerebral,orbasilar arterybranchesareinvolved(Merritt etal.,1946).Thepathologyofthecerebralinfarctiondoesnotdifferfromthatofother ischemicstrokes.

Themeningesprimarilyalongthebaseofthebrainhavea diffuseorlocalizedchronicinflammation,andsomearteries withinthemeningesareaffectedbyHeubner’sendarteritis (GrayandAlonso,2002).Lymphocytesandsomeplasma cellscombinewithfibroustissuetoformperivascular infiltratesaroundbloodvesselsalongthebrainsteminthe thickenedmeninges.Theperiarteritismayproducecranial nervepalsiesandoccasionallybrainstemischemicstrokes fromthrombosisofsmallpenetratingarteriesfromthevertebralorbasilarartery(Brightbill etal.,1995;Johns etal.,1987; Tyler etal.,1994;Umashankar etal.,2004).

Theclinicalfeaturesofbrainischemiafrommeningovascularsyphilisdifferfromthoseusuallyseeninothercausesof ischemicstrokes.Thepatient ’ sageatstrokeonsetisoften youngerthanthetypicalpat ientageseeninthemorecommoncausesofischemicstrokes.Ninetypercentofneurosyphilisstrokesareinpatientsbetween30and50yearsofage (Merritt etal .,1946).Thestrokeincidenceishigherinmen thanwomen.However,amorerecentstudyfromChina foundthemeanageoftheir28caseswas57years.Asurprisingnumber,whoinitiallywerenotdiagnosedashaving meningovascularsyphilis,hadevidenceofrecurrent strokes,andoftenhadthetypicalotherriskfactorsfor strokes(Liu etal .,2012).

Upto25percentofpatientsdevelopaprodromeofheadaches,dizziness,and/oremotionaldisturbancesdaysto weekspriortothestroke(Merritt etal .,1946).Signsand symptomsofcerebralvascularsyphilisvarybysiteofthe infarction.Overall,about80p ercentdevelopahemiparesis, 30percentaphasia,15percent hemihypesthesia,7percent hemianopia,and15percentseizures(Merritt etal .,1946; Alpers,1954;Perdrup etal .,1981).Becausethepatientmay havecoexistentchronicbasilarmeningitis,about10percent willalsohavecranialnervepalsies,and30percentwillhave abnormalpupils.Ofnote,25percentofpatientswithstrokes willhavetheirsymptomsevolveoverseveraldaysinstead ofthetypicalsuddenonset(Merritt etal .,1946).Because T.pallidum cansimultaneouslyinfectthemeningesand brainparenchyma,somepatientsalsomayhavecognitive declineordementiafromgeneralparesis.

BrainCTorMRIofpatientswithmeningovascular syphilisandstrokestypicallyshowabnormalitiesconsistent withischemiclesions,whichoccasionallymaybemultiple

(Holland etal.,1986;Brightbill etal.,1995).Conventional angiographyormagneticresonanceangiographymayshow evidenceofarteritiswithconcentricnarrowingoflargevessels andoftenfocalnarrowingandoccasionallydilatationsofsmallerarteries(Vatz etal.,1974;Peters etal.,1993;Gallego etal., 1994;Brightbill etal.,1995;Gaa etal.,2004;Flint etal.,2005; Peng etal.,2008).ThefindingsarenotspecificandarecompatiblewithothertypesofCNSvasculitisandwithvasoconstrictionunrelatedtovasculitis.Inafewpatientswithastroke andCSFevidenceofmeningovascularsyphilis,arterialimagingmayshowanothercauseforthestroke,suchasatherosclerosis.Atothertimes,atherosclerosismaybepresentalong witharteritis(Landi etal.,1990).MRIwithgadoliniumoften showsenhancementandthickeningofthemeningesaround thecisternsandbrainstemand,occasionally,overthecerebral cortex(Brightbill etal.,1995;GoodandJager,2000). Nontreponemalextracranialvasculardiseasemayalsobe present(Aldrich etal.,1983).

TheCSFshouldbeabnormal.Theopeningpressureina lumbarpuncturemaybenormaltoslightlyelevated.TheCSF typicallyhasamononuclearcellpleocytosisof10toseveral hundredcellspermicroliter,normalglucoselevels,andproteinlevelsrangingfromnormalto250mg/dL.Oligoclonal bandsandelevatedCSFimmunoglobulinG(IgG)levelsare oftenpresent(Vartdal etal .,1982).Inmeningovascular syphilis,theabilitytoisolatespirochetesbyanimalinoculationofCSFisverydifficultincontrasttosecondarysyphilis, inwhichspirochetescanbeisolatedinupto30percent ofcases(Lukehart etal .,1988).Likewise,thePCRassays for T.pallidum inCSFexistinresearchlaboratoriesbutare notsensitiveenoughforroutinedetectionof T.pallidum in serumorCSF(Wong etal .,2015).Unfortunately,thereisno singlespecificandsensitivetestforneurosyphilis,particularlyinthesettingofmarkedimmunosuppressionsuchas HIV(Marra,2015).

SyphiliticMyelitisandSpinalCordStroke

Syphilisofthespinalcordisaclinicalrarityandusuallyaccompaniesotherformsofcerebralsyphiliticinvolvement.Inthe classicpreantibioticseriesatBostonCityHospital,only31(1 percent)ofthe2,263patientswithsyphilishadnon-tabetic spinalcorddamage(Merritt etal.,1946).Onlyone-thirdof thosewithspinalcorddiseasehadspinalvascularsyphilis. Patientscouldpresentwithaninsidiousonsetorsuddenly developanacutetransversemyelitissyndrome.Theprincipal symptomsincludeparaparesisorparaplegia,urinaryandfecal incontinence,andsensoryabnormalitieswithparesthesias, pain,orsensorylossinthelowerbackandlegs.Available pathologyshowsthatthepatientshadachronicspinalmeningitiswithsomelargervesselsshowingtypicalHeubner’sendarteritis.Thethoracicspinalcordisthemostcommonlyaffected, andpatientsmaypresentlikeanacutetransversemyelitis. Spinalsyphilisisonlyrarelyseentoday(FisherandPoser, 1977;Harrigan etal.,1984;Lowenstein etal.,1987;Silber, 1989).TheMRItypicallyshowsshortsegment,highsignal intensityinthethoraciccordonT2-weightedimagesand abnormalenhancement,predominatelyinthesuperficial

partsofthespinalcord,ongadolinium-enhancedimages (Lowenstein etal.,1987;Nabatame etal.,1992). Involvementofthecervicalspinalcordwithquadriplegiais extraordinarilyrarebuthasdevelopedfollowingasyphilitic gummanecrosingthecervicalcordorfromdevelopmentofa firmfibroussheathsurrounding thecervicalcord(syphilitic hypertrophicpachymeningitis)(Merritt etal.,1946;Silber,1989).

HIVandNeurosyphilis

Considerableevidenceshowsthatimmunodeficiencyimpairs theclearanceof T.pallidum fromtheCNSandmayaccelerate thecourseofneurosyphilis(FunnyeandAkhtar,2003;Marra, 2004).Individualswith T.pallidum areathigherriskof concurrentHIVinfection.Thedualinfectionresultsina higherHIVload(Buchacz etal.,2004).Accordingly,HIV testsarerecommendedineverypatientwithneurosyphilis (Golden etal.,2003).Inaddition,HIVpatientswithuntreated syphilishaveanincreasedrisk(24percent)ofneurosyphilis (Bordon etal.,1995).Thus,aCSF-VDRLtestisneededinevery HIVpatientwhodevelopscerebrovasculardisease,especiallyif theserumfluorescenttreponemalantibodyabsorptionassay (FTA-ABS)orRPRtestisreactive.

Currently,intheHIVpatientboththeCSF-VDRLand CSF-FTA-ABStestsappearadequatefordiagnosisofmeningovascularsyphilis,butslightlymorefalse-positiveserumRPR testsareencountered.Treatingthepatientinfectedwithboth T.pallidum andHIVmaybedifficult.Thereisevidencethat penicillintreatmentforadurationlongerthan14daysis requiredformeningovascularsyphilisintheHIVpatient (Marra etal.,2004a).

DiagnosticEvaluationforSyphilisina PatientwithCerebrovascularDisease

Althoughcerebrovasculardiseasefromneurosyphilisis uncommonindevelopedcountries,thereareseveralrisk factorsthatincreasetheprobability(Table1.1).

Thelaboratorytestshelptoestablishthediagnosis.More than95percentofpatientswithearlyneurosyphilishavea positiveserumRPRtestwithtitersrangingfrom1:2to >1:128.TheRPR,VDRL,andtoluidineredunheatedserum test(TRUST)testsarenontreponemaltestsandmeasureIgG andimmunoglobulinM(IgM)antibodiestoacardiolipin–lecithin–cholesterolantigen.Thesetestsaregenerally expressedasatiter,withhighertitersreflectinggreaterdisease activity(Marra,2015).Thereactivityofthesetestsgenerally reflectstheactivityofthedisease,andtitersdeclineoftento zerofollowingeffectiveantibiotictreatment.Areactiveserum RPRtestmustbeconfirmedwithapositiveserumFTA-ABS, T.pallidum passiveparticleagglutination(TPPA)test(which measuresIgMandIgGreactivetothewholeorganism)or enzymeimmunoassays(EIAs)andchemiluminescentimmunoassays(CIAs)thatmeasureantibodiestorecombinant T.pallidum proteins.ThesetestsensurethattheRPRreactivity isspecificforsyphilisasotherpathogenictreponemes,suchas T.pallidum subspecies pertenue,theorganismthatcauses yaws,maycross-reactwiththeRPRtest(Marra,2015).Most

Table1.1 Diagnosticworkupforsyphilisinpatientswith cerebrovasculardisease

Riskfactorsthatincreasetheprobabilityofneurosyphilis

1. Patientis2560yearsold(youngerthan expectedageinmostcausesofstrokesor TIAs)

2. Patienthasahistoryofsyphilis(treatedor unknowntreatment)orothersexually transmitteddiseases

3. Presenceofophthalmicabnormalitiesor cranialnervepalsies

4. PatientisinfectedwithHIV

5. PatientimmigratedtotheUnitedStatesas anadultfromahigh-syphilis-riskcountry suchassub-SaharanAfrica,southor southeastAsia,LatinAmerica,orthe Caribbean

6. Patienthasstrokesymptomsprogressing over24hours

7. Patientisayoungadultwithastrokeplus ahistoryofprogressivecognitive impairmentorpriorcranialnervepalsies

8, Patienthasneuroimagingsuggestiveof arteritis

Recommendedlaboratorytests*

Serum:

CSF:

Neuroimaging*

RPR

FTA-ABSorothertreponemal-specific antibodytest

Cellcount

Glucose Protein

IgGlevelorIgGindex

Oligoclonalbands

CSF-VDRL

CSF-FTA-ABStestunderspecific conditions

Magneticresonanceangiographyor conventionalangiography

*Seetextfordetailsofinterpretationofresults

patientswhohavereactivespecifictreponemaltestswillhave reactivetestsfortheremainderoftheirlives,regardlessof treatmentordiseaseactivity(CDC,2015).Areactiveserum RPRorFTA-ABStestconfirmsthatthepatienthasactive syphilisbutdoesnotsignifythatthepatienthasneurosyphilis.

Thediagnosisofneurosyphilisrequiresalumbarpuncture andCSFexamination.TheCSFshouldalwayshaveapleocytosisof10toseveralhundredwhitebloodcells(predominately lymphocytesandplasmacells)permicroliter.TheCSFglucose isnormal.TheCSFproteinistypicallyelevatedintherangeof 60–250mg/dLandusuallycontainsanelevatedIgGindexand thepresenceofseveraloligoclonalbands(Vartdal etal.,1982). Theoligoclonalbandsaredirectedagainst T.pallidum antigens whentestedinaresearchlaboratory.

TheCSF-VDRLtestishighlyspecific,butisrelatively insensitive.Thetestisreactiveonlyinabout75percentof patientswithsyphilis(CDC,2002).AreactiveCSF-VDRL testisdiagnosticforneurosyphilisbecausefactorsthatcause false-positiveserumRPRtitersareonlyrarelypresentinCSF (CDC,2002).

ThedifficultycomeswhenthepatientlacksapositiveCSFVDRLtestbuthasclinical,arteriographic,andCSFfindings thataresuspiciousforneurosyphilis.Thisoccasionallydevelopsinpatientswhohavevasculardiseasefromsecondary syphiliticmeningitisorfrommeningovascularsyphilis(CDC, 2002;Marra,2004).Iftheclinicalpictureandtherestofthe CSFaresuspiciousformeningovascularsyphilis,areactive CSF-FTA-ABS(withoutbloodcontaminationintheCSF)is usuallyconsidereddiagnostic(CDC,2002).Conversely,a negativeCSF-FTA-ABStestexcludesneurosyphilis(CDC, 2015,2002;DavisandSchmitt,1989).

Treatment

Penicillinisthemaintreatmentforneurosyphilis,butpenicillinmustachievesustainedtreponemicidalCSFlevelsfora prolongedperiodtocure.Thelongtreatmentperiodisnecessarybecausepenicillinkillsonlyduringbacterialcelldivision and T.pallidum hasaslowreplicationrateofatleast30hours. AqueouscrystallinepenicillinG(18–24millionunitsperday) inadultsisadministeredas3–4millionunitsintravenously every4hoursorbycontinuousinfusionfor10–14days(Janier etal.,2014;CDC,2015).Followingtheendoftheintravenous treatment,thepatientoftenisgivenintramuscularbenzathine penicillin(2.4millionunits)at1-weekintervalsfor3weeks, especiallyifthereisalsoHIVinfection(Jay,2006).Undersome circumstances,procainepenicillin2.4millionunitsintramuscularlyoncedailyplusprobenecid500mgorallyfourtimesa day,bothfor10–14days,canbeadministered(Janier etal., 2014;CDC,2015).Themajoradverseeffectsofpenicillin includeanaphylaxis,rash,Stevens–Johnsonsyndrome,druginducedeosinophilia,hemolyticanemia,thrombocytopenia, neutropenia,seizures,interstitialnephritis,andpseudomembranousenterocolitis.Becauseeachmillionunitsofpenicillin contain1.7meQofpotassium,serumpotassiumlevelsshould becarefullyfollowedinpatientswithrenalinsufficiency(Jay, 2006;Stockman etal.,2014).

Ifthepatientisallergictopenicillin,desensitizationto penicillinshouldbeconsidered(seeCDC,2002,formethod). TheCDCsyphilistreatmentguidelinesarepublishedabout every4years,sooneshouldalwaysconsultthelatestversion. Ceftriaxone(inadults,2gintravenouslyorintramuscularly oncedailyfor14days)iscurrentlythealternativetreatmentof

choiceinthefewpatientswhocannotbedesensitizedtopenicillin(CDC,2015;Marra,2004).Ofnote,azithromycinasan alternativeantibioticshouldseldombeusedbecausemacrolide-resistantmutationsof T.pallidum arebeingdetected (Lukehart etal.,2004).

StrokeRehabilitation

Nostudieshavebeenspecificallyconductedregardingtherehabilitationofpatientsfollowingstrokesrelatedtosyphilis. However,individualcasereportsdescribeclinicalimprovement insyphiliticstrokepatientswithrehabilitation(Umashankar et al.,2004).Werecommendthatcurrentguidelinesforprovision ofrehabilitationservicesfollowingastrokebefollowed(Bates et al.,2005;Duncan etal.,2005;Winstein etal.,2016).Patients diagnosedwithmeningovascularorotherformsofsyphilis followingpresentationforanacutestrokewilltypicallyspend severalweeksashospitalinpatientstoreceiveintravenouspenicillintherapy.Thistreatmentperiodprovidesanaturaltime framewithinwhichtoinitiateinpatientrehabilitation,eitherin anacuteneurologic/medicalorrehabilitationwardsetting.

Follow-Up

Eventhoughthepeakinfectiousperiodforsyphilistransmissionoccursmanyyearsbeforeastroke,itisstillimportantto

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2 VasculitisandStrokesDuetoTuberculosis

Tuberculosis(TB)isconsideredoneoftheoldestdiseases knowntohumankind.Ahumanskeletonwithevidenceof spinalTBfromaneolithiccemeterywasfoundnear Heidelbergin1904.ThisisconsideredtobethefirstdocumentedrecordofhumanTB(Morse,1961).Itisunfortunatethat, despiteadvancesinprophylacticandtherapeuticmeasures, thisdiseasestillremainsascourgeinlargepartsoftheworld. AccordingtotheWHOGlobalTuberculosisreport2014,four regions(SouthEastAsia,WestPacific,Africa,andEast Mediterranean)accountfor91.6percentprevalenceand 93.7percentincidenceofTBworldwide.Thus,TBisstill amajorprobleminthedevelopingworld.Tomakematters worse,theHIVpandemichasbroughtaboutaresurgenceof thisdreadeddiseaseinmanydevelopedcountries(Berenguer etal.,1992;Dube etal.,1992)andanexplosionofallformsof TBinthedevelopingcountries,particularlyinSub-Saharan Africa,someofwhicharethepoorestcountriesintheworld. Fortunatelythereisarayofhope,asnewcaseshavedeclined since2011(WHOGlobalTBReport2014).

Tuberculousmeningitis(TBM)isthecommonestformof neurotuberculosis,accountingfor70–80percentofthecases (Udani etal.,1971).TBMisstillacripplingdiseasewithahigh degreeofmorbidityandmortality.Oneofthemostsevere complicationsofTBMisastrokeduetovascularinvolvement. Baumgarten(1881)isbelievedtobethefirsttodescribethese changesinautopsyspecimens.Thefirstclinicaldescriptionof diffusearteritisintheindexedliteraturewasina25-year-old malepatientwithTBMandparaplegiafromDakar,Senegal (Collomb etal.,1967).However,inthesameyearWadiaand Singhal(1967)describedthevascularchangesin33casesof TBMadmittedbetween1963and1965.Sincetheearly1970s, considerableworkhasbeenpublishedfromtheIndiansubcontinentontheclinical,pathologic,andangiographicstudies ofvasculitisandstrokesinTBM.Thenewertechniquesof neuroimaging – computedtomography(CT)scans,magnetic resonanceimaging(MRI),anddigitalsubtractionangiography (DSA) – haveaddedtoourunderstandingofthisdreaded complicationofTBM.

TBMisinvariablysecondarytoaprimaryinvolvementof someextracranialorgan,veryoftenpulmonaryTB(Vashishta andBanerjee,1999).Ourunderstandingofthepathogenesisof TBMbeginswithcomprehensiveandmeticulousstudiesby RichandMcCordock(1933).Theyshowedthattherewas asubcorticalormeningealfocus,latercalledthe “Rich focus,” fromwhichthebacillusgainedaccesstothesubarachnoidspace.Onceitgainsentry,therearemanyfactorsthat determinethetypeoflesionsseeninthecentralnervous

system(CNS).Thelatencybetweentheonsetofinfectionand theinstitutionoftherapy,theageofthepatient,theimmune statusofthepatient,andthevirulenceanddrugsensitivityof thebacillusareimportantdeterminantsmodifyingthepathologyandpathogenesisofneurotuberculosis.Grossexamination ofthebrainatautopsyshowedthatathickexudatewasmost frequentlypresentonthebasalaspect(DasturandLalitha, 1973;Thomas etal.,1997),wherethestructuresareobscured. Coronalslicesofthebrainrevealthick,organizedexudatesall aroundtheopticchiasm,extendingintotheSylvianfissures, entrappingthemiddlecerebralartery(MCA)anditsbranches.

Askanazy(1910)firstdescribedthetriadofvascular changesinTBM:panarteritisinvolvingallthethreecoatsin atuberculousprocess,caseationofthevesselwall,andfibrinoidswelling.Sincethen,changesinvolvingthevesselsinthe brainarethemostintensivelystudiedaspectandoneofthe landmarkhistopathologicfeaturesofTBM.Macroscopically, thebasalarteries,particularlytheMCAanditsbranches,are maximallyinvolved.Microscopically,thethreemostcommonlydescribedvascularpathologiesareinfiltrative/inflammation,proliferative,andnecrotizing.Thesemaybeinpure formsorincombination,withorwithoutthrombosis. Theinfiltrativeprocessspreadsfromtheadventitiatothe intimaandinvolvesthebasalvesselsmaximallyreflectingthe changesseeninthesubarachnoidspaces.Moststudiesshow thattheadventitiaandintimaaremostaffectedasthemediais relativelyresistanttothesechanges(Lammie etal.,2009). Smoothmusclecellproliferationleadstothickeningofthe mediaandocclusionofarteries.Thisprocessoccursintandem withinfiltrativeprocessesandisusuallyseeninchronicand/or partiallytreatedTBM.FibrinoidnecrosisisthemodernterminologyforwhatAzkanazy(1910)describedas “fibrinoid degeneration.” Thisprocessinvolvespredominantlytheintima ormediaorboth.Itisanon-specificinjuryandsimilarchanges havebeendescribedinmalignanthypertension,antineutrophilcytoplasmicantibody-associatedvasculitis,andradiation injury(Lammie etal.,2009).Shankar(1989)observedintracytoplasmicvacuolationsofthemediainbloodvesselsinTBM andfeltthatthesechangeswerealsonon-specificandcomparedthemtothoseseeninsubarachnoidhemorrhagesdueto vasospasm.

TheroleofthrombosisinproducinginfarctsinTBMis controversial.Whenspecificallylookedfor,somepathologists havedescribeditasrare(Lehrer,1966;Dalal,1979),uncommon(Poltera,1977;WinklemanandMoore,1940),orreasonablycommon(Deshpande etal.,1969,Poltera,1977). However,thrombosismayplayanimportantroleincerebral

venoussinusthrombosisorspinalarterythrombosis(Dastur andLalitha,1973).TheroleofthrombosismaybebestsummarisedbythestatementofDalal(1979) “ itisextremely uncommontofindanorganisingthrombusinanappropriate vascularterritorythatmatchestheageofthecerebral infarction” .

Inspiteofmeticuloushistopathologicstudies,thepathogenesisofcerebralinfarctionsisnotfullyunderstood. Theinitialinflammatoryreactionmaygivewaytoproliferative stenosisofarteriesasthebasalexudatesthicken.Manyauthors believethatthesechangesaremoreduetodiseaseduration ratherthantreatmentofTBM(WinklemanandMoore,1940; DasturandLalitha,1973).Thepathogenesismaybethatmost infarctsareduetohypoperfusionsecondarytoavariablecombinationofintimalproliferation,fibrinoidnecrosis,vasospasm, andthrombosis(Dalal,1979).

Insummary,thepathologicdataaredisparateandoften contradictory.Clinically,infarctsoccurinmoresevereorpartiallytreatedTBM,aphaseoftheillnessinwhichintimal proliferationislikelytooccur.Angiographicdataandthe presenceoffibrinoidnecrosismaypointtothepotentialrole ofvasospasmsinproducinginfarctsearlyinthecourseofthe disease.Similaritiestootherimmune-mediatedvasculopathies maysuggestanimmune-mediatedmechanism(Lammie etal., 2009).

InspiteoftheadvancesinthemolecularbiologyoftuberculosistheimmuneresponsewithinthebraininTBMremains poorlyunderstood.Severalcytokinesandchemokineshave beenstudied – tumornecrosisfactoralpha(TNF-α),interferon gamma(IFN-γ),interleukin-8(IL-8),interleukin-10(IL-10), interleukin-1beta(IL-1ß),andmatrixmetallopeptidase-9 (MMP-9) – andtheirserumandcerebrospinalfluid(CSF) levelscorrelatedwiththeseverityofthedisease,mortality, andalsowithCSFlactatelevelsasamarkerforischemicevents inthebrain.Theresultshavebeendisparateandsometimes contradictory.Akalin etal.(1994),Babu etal. (2008),andPatel etal. (2002)foundapositivecorrelationbetweentheCSFlevels ofTNF-α,IL-1ß,IFN-γ,andIL-10,andtheseverityofthe disease.Ontheotherhand,Donald etal. (1995)and Mastroianni etal.(1997)didnotdemonstrateanycorrelation althoughtherewasnodeclineinthelevelsofIFN-γ,TNF-α, andIL-10onafollowupof3–8months.HighlevelsofIL-8, IFN-γ,TNF-α,andMMP-9correlatedwithhighlevelsofCSF lactate,suggestingaroleinthepathogenesisofinfarcts(Babu etal.,2008andThwaites etal.,2004).However,others(Donald etal.,1995andLammie etal.,2009)havesuggestedthatthey aremerelymarkersindicatingvesselinvolvementratherthan thecauseofvasculitis.InarecentstudyfromIndia,Sinha etal. (2015)foundthatthelevelsofTNF-α inserumandCSFand IL-1ßinserumcorrelatedsignificantlywiththeseverityofthe diseaseandevenpredictedmortalityintheirpatients. Paradoxically,therewasnocorrelationofthesecytokines withstrokes,whichnotonlycontributestotheseverityofthe diseasebutalsotoitresultinginmortality.Itwouldbelogical topresumethatotherpathogeneticfactors – suchaschangesin microvascularreactivitytoneurochemicals,cytokines,andthe stateofcell-mediatedimmunity(CMI)ofthepatientatthat

particulartime – playanimportantroleinthegenesisofthese lesions.

InHIV-infectedindividualswithTBM,theimmune responsetothetuberculousbacilliisaltered;therefore,pathologicfeaturesareverydifferentfromthoseseeninpatients withrelativelynormalCMI.Thebrainsofsuchindividuals showedminimalinflammatoryresponsewithparenchymal infarctsandvasculitis,notonlyinthebasalgangliabutinthe corticalparenchymaaswell(Katrak etal.,2000).Thislackof inflammationisalsoreflectedintheCSF(Katrak etal.,2000). Theexactreasonforthisextensivevasculopathywasnotclear. ItisknownthatpolyclonalB-cellactivationoccursinHIVinfectedpatients,withresultanthypergammaglobulinemiaand circulatingimmunecomplexes(Cotran etal.,1999).However, itremainsspeculativethatsuchB-cellactivationoccurreddue tomycobacteriainthesepatients(Katrak etal.,2000). Simmons etal. (2005)correlatedlowCSFlevelsofIFN-γ withdeathinHIV-positivepatientsinVietnam.However, thisfindingwasnotcorrelatedwiththeincidenceofstrokes inthesepatients.

Thecontroversyregardingthepathogenesisofvasculitis, therefore,isfarfromresolved.Whethermorphologicchanges, vasospasm,oranimmunologicattackofthevesselwallby cytokinesplayamajorrole,isundetermined.Factorslike hostCMI,particularlyinHIV-Ppatients,andthelineageand virulenceof Mycobacteriumtuberculosis furthercompoundthe issueandstresstheneedforsystemicpathologicstudiesofthis entity.Thetruthmaylieinacombinationofthesefactors formingacascadeofevents.

Theclinicalfeaturesareusuallyprecededbyaprodromal phaseoffatigue,malaise,low-gradefever,andlossofappetite.Thefurthertemporalevolutiondependsontheseverity ofthediseaseandcomplicationsassociatedwiththeinvolvementofbasalstructures(namely,cranialnervepalsies,paraplegia,strokes,hydrocephalus,andalteredconsciousness). Traditionally,theseverityofthediseaseisgroupedinto threestages:mild(stage1),moderate(stage2),andsevere (stage3),withagoodcorrelationwiththefinaloutcome (Singhal etal .,1975;StreptomycininTuberculosisTrial Committee,1948).Strokesusuallyoccurinpatientsinstages 2or3.Hence,thisdreadedcomplicationisassociatedwith ahighmortalityandmorbidity(Katrak etal.,2000;Misra etal .,2011).

StrokesinTBMoccurin13 –57percentofpatients, dependingonthemethodofevaluation.Clinicallyevident focalneurologicdeficitsoccurin20percentofcases(Dalal, 1979);however,inaseriesfromTaiwan,theincidencewasas highas47percent(Lan etal.,2001).CTscansrevealinfarctionsin13– 35percentofpatientsandMRIhasagreater sensitivity,upto57percent(Shukla etal.,2008andKalita etal .,2009).

Inoneseries,8percentofstrokesintheyoungweredueto tuberculousvasculitis(DalalandDalal,1989).Focalneurologicdeficitsusuallyoccuracutelyandinvolvethebasalganglia andsubcorticalstructures.Thus,aphasia,apraxia,andagnosia areuncommon.However,whentheseoccurinsidiously,they shouldarousesuspicionofanevolvingtuberculomainthe

appropriatearea.Infarctsinthevertebrobasilarterritorywere reportedasuncommonintheearlierliterature(Dalaland Dalal,1989)butinarecentstudy,20percentofstrokes occurredinthisterritory,basedonclinicalandMRIevaluation (Kalita etal.,2009).Intracerebralorintraventricularhemorrhagesarerare(DalalandDalal,1989).Convulsionsmay presentatanystageofTBM,particularlyinchildren.They occurredin37.5percentofpatientswithvascularinvolvement ascomparedtoonly20percentofthosewithoutstrokesin acasestudy(Thomas etal.,1997).Convulsionsmayalsooccur duetoassociatedtuberculomas,hydrocephalus,ortuberculous meningoencephalitis.Clinically,strokesinindividualscoinfectedwithHIVarenodifferentthanthoseinpersonswithoutHIVinfection,asreportedbyseveralcaseseries(Yechoor etal.,1990;Berenguer etal.,1992;Dube etal.,1992;Porkert etal.,1997;Katrak etal.,2000).However,datafromIndiahave shownthatthemortalityismuchhigherinthesepatients (Katrak etal.,2000;Kawre etal.,2001).

ThediagnosisofTBMisusuallyestablishedbythedemonstrationofacid-fastbacilli,byadirectsmearorcultureinthe CSF,brainparenchyma,tuberculomas,ormeningesinbiopsy orautopsymaterial.ThesensitivityofZiehl–Neelsen(Z–N) smearcanvarybetween10and60percentandculturebetween 25and75percent(Brancusi etal.,2012).Themaindrawback ofculturesisthelongdelay(2–6weeks)beforeresultsare available.Newertechniqueshaveincreasedthediagnostic yieldwithaminimaldelay.Chen etal.(2012)reportedon amodifiedZ–Nstainwitha100percentsensitivityforboth intracellularandextracellularAFBdetection.Newertechniqueslikethepolymerasechainreaction(Takahashi etal.,2005) andGeneXpert(Denkinger etal.,2014)haveincreasedthe diagnosticyieldwithahighdegreeofsensitivity/specificity. Unfortunately,theequipmentisexpensiveandrequiresan elaborateinfrastructure,qualitycontrol,andhighmaintenancecosts,conditionsunavailableinmanycenters,particularlyindevelopingcountrieswhereTBMisrampant.

NeuroimagingproceduresarenotdiagnosticforTBMbut havebecomethestandardfordetectingitscomplications.CT orMRIoftheheadmayrevealintensebasalenhancementafter intravenouscontrastadministration,communicatingor obstructivehydrocephalus,cerebralinfarcts,tuberculomas,or acombinationoftwoormoreofthesefeatures(Figure2.1). Basalenhancementandtuberculomasaredirectfeaturesof TBMwhereasinfarctsandhydrocephalusaresignsofitscomplications.CTscanninglacksthesensitivityofMRI,especially forinfarcts.AlthoughtheincidenceofinfarctsonCTvaries from13to35percent(Kalita etal.,2009),thetechniqueis readilyavailableinmostcenters,particularlyindeveloping countries,itiscosteffective,andobviatestheneedforsedation inacutelyillpatientsandchildrenasthestudydurationis short.Infarctsaremorecommoninchildren(Kingsley etal. 1987;Andronikou etal.,2006).

MRI,particularlydiffusion-weightedimaging,isverysensitiveindetectinginfarctsatanearlystageandintheVB circulation(Shukla etal.,2008;Pienaar etal .,2009).Magnetic resonanceangiography(MRA)hassupersededDSAasitis nottraumaticandcanbeusedforfollow-upsofpatients.

Recently,Kalita etal .(2012)detectedinfarctsin40outof 67patients(59.7percent)andMRAabnormalitiesin50.7percentofcases.Moreimportantly,over40percentofpatients withabnormalMRAdevelopedinfarctsat3monthswhereas nonedidwithnormalMRAimages(Kalita etal.,2012). Ifconfirmedbyotherstudies,MRAmayhavethepotential forpredictingthechanceofaninfarction,therebyreducing themortalityandmorbidity.

IntheWesternliterature,neuroimagingfindingswereno differentinHIV-infectedindividualswhencomparedtononinfectedcases(Yechoor etal.,1990;Berenguer etal.,1992; Villora etal.,1995).Incontrasttotheabovefindings,we founddistinctdifferences.Thebasalexudatesweresparse andinfrequent,tendingtooccuronlyafterinitiationofantituberculoustherapy.Ventriculardilatationsoccurredsecondarytoatrophy.Granulomatouslesionsincludedtuberculomas aswellastoxoplasmagranulomas.Aninterestingobservation wasthatoftheoccurrenceofcorticalinfarctsinthesepatients withangiographicevidenceofarteritis(Katrak etal.,2000). Similarfindingshavebeendescribedfromothercentersin Indiaandabroad(Kawre etal.,2001;SzeandZimmerman, 1988;Andronikou etal.,2006).

TheinitialdataonvascularinvolvementinTBMwere basedoncerebralangiography.However,inthemodernera, theroleofcathetercerebralangiographyislimited.Itisusually necessaryinpatientswithclinicallyevidentfocalneurologic

Figure2.1 PostcontrastaxialCTscanshowingdensebasalexudatesaround thequadrigeminalcistern,hydrocephalus,rightparahippocampaltuberculous abscess,andaleftbasalgangliainfarct(arrow).

Figure2.2 LeftcarotidangiogramofthesamepatientasinFig.2.1showing organicstenosisorinducedvasospasmoftheM1segmentoftheMCA (betweenarrows).

Figure2.4 Rightcarotidangiogram,obliqueviewofapatientwithTBMand HIVinfection.TotalblockoftherightMCAandareasofsegmentalnarrowing arteritisalongtherightanteriorcerebralartery(arrows).

deficitsandinthosewithalteredmentation.Lehrerdescribed anangiographictriadofasweepingpericallosalartery,narrowingofthesupraclinoidportionoftheinternalcarotidartery, andnarrowedoroccludedsmallormedium-sizedintracranial arteries,withscantycollaterals(Lehrer,1966).Thiswassubsequentlyconfirmedinmanystudies(WadiaandSinghal,1967;

Figure2.3 Rightcarotidangiogramshowingmarkednarrowingofthe supraclinoidinternalcarotidarterywithsegmentalnarrowingofM1segments oftheMCA(bottomarrow).

Note:onlythelaterallenticulostriateperforatorsareseen(toparrow).

Dalal,1979;Rojas-Echeverri etal.,1996;MishraandGoyal, 1999).Theclinico–angiographiccorrelationisnotgood. Normalangiogramshavebeenfoundinpatientswithclinical orMRIevidenceofinfarctsin42–57percentofcases(Wadia andSinghal,1967;Dalal,1979;Rojas-Echeverri etal.,1996). Conversely,asignificantreductioninthevascularlumenhas beenfoundinpatientswithnoneurologicdeficit(Deshpande etal.,1969;Dalal,1979;Rojas-Echeverri etal.,1996)orneuropathologicchanges(Dalal,1979).Eventhemechanismfor theangiographicchangesisdebated.Itcouldbeduetoorganic stenosisofthevesselduetothickbasalexudates(Wadiaand Singhal,1967;Dastur etal.,1970;VashishtaandBanerjee, 1999)ortoarteritis-inducedvasospasms(Dalal,1979; Yamashima etal.,1985;Rojas-Echeverri etal.,1996);see Figures2.2and2.3.

InourcasesofTBMwithHIVinfectionandcerebral infarcts,wehadangiographicandpathologicevidenceofwidespreadarteritis(Figure2.4)(unpublisheddata).However,

thereiscompleteagreementthatthemajorityoftheinfarcts areintheterritoryofthelenticulostriateandthalamoperforatingbranchesoftheMCA,theso-called “TBzone,” comprising theheadofthecaudatenucleus,theanteromedialthalamus, andtheanteriorlimbandgenuoftheinternalcapsule,as describedbyHsieh etal.(1992).

DespitetheavailabilityofantimicrobialagentsthemorbidityandmortalityofTBMremainshigh,particularlyinpatients withstrokesandinwhomthereisadelayintheinitiationof therapy.Globaltreatmentguidelines,thoughnotuniform, recommendanintensivephaseof3monthswithfourdrugs (rifampicin[RFM],isoniazid[INH],pyrazinamide,andstreptomycin)followedbyatleast6monthsoftreatmentwithRFM andINH.Inmanydevelopingcountriesthedurationofthe therapymayextendto18–24months(Katrak,unpublished data).TheseguidelinesarebasicallyanextrapolationoftherapyforpulmonaryTB.Manyworkersfeelthatthereis anecessityto “tailor” thetherapyforCNStuberculosis,particularlyintermsofdosageandduration.Thereareongoing

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Therationaleforusingdexamethasoneisbasedonits propertiestorestoredamagedvascularpermeability,to decreasefreeradicalproduction/damage,andforantiinflammatoryactivity.InastudyinVietnam,theincidence ofinfarctsinthedexamethasonegroupwasreducedby50percent(Thwaites etal.,2007).Inasystematicreviewandmetaanalysis,Critchley etal.(2013)notedthatsteroidsreduced mortalityby17percentconsistentlyacrossallformsoftuberculosis.Theauthorsanalyzedatotalof761deathsofwhich536 (70percent)occurredinpatientswithTBMalone.Prasad etal. (2016),intherecentCochraneDatabaseReview,concluded thatsteroidshelptoreducetheswellingandcongestionnot onlyofthemeninges,butalsoofthebloodvessels.Thus,they helpinreducingtheintracranialpressureandtheriskofdeath buttheireffectondisablingresidualneurologicdeficit,includingstrokes,wasuncertain.Corticosteroidsaregiveninadose of1mg/kgperday,taperingthisdoseover4–6weeks (Thwaites etal.,2007).

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3 StrokesDuetoFungalInfections

Fungalinfectionsareanimportantcauseofstrokeinimmunocompromisedpatients,mediatedbyseveraldistinct mechanisms,andtheyarecriticaltorecognizepromptly, giventhehighratesofmorbidityandmortalitywhentreatmentisdelayed.Angioinvasionduetomold-formingspecies maydisrupttheintima,resultinginahemorrhage,small-vessel ischemia,oralarge-vesselinfarction.Infarctionsmaybebland orhemorrhagic.Similarprocessesmayoccurasaresultof externalvesselerosioninthesettingofmeningitis,dueto yeast-formingpathogens.Mycoticaneurysmsmaycause hemorrhagesorartery-to-arteryembolisms.Cardiacvegetationsmayprovideasourceofeitherasepticorclotembolus.

IntheirreviewoftheautopsyrecordsoftheJohns HopkinsHospitalfrom1953to1978,Walshe etal. (1985b) providedearlyinsightsintothepathologicsequelaeof variousfungiinthecentralnervoussystem(CNS).They identified60examplesofCNSinvolvementbyfungi(16 aspergillus,27ofcandida,14ofcryptococcus,2ofmucor, and1ofhistoplasmosis).Allcasesofaspergilluswerepathologicallyangioinvasive.Focalneurologicsigns,focalseizures, hemiplegia,andcranialnervedeficitsoccurredin50percent ofthepatientswithaspergillusinfection.Yeast-forming fungi,whicharenottypicallyangioinvasive(7percentin candidaandnoneofthecryptococcalcasesinWalshe’ s series),moreoftencausedameningitis.Meningealsigns wereclinicallypresentin86percentofcases,andpathologic evidenceofmeningealinvolvementwaspresentin100 percentofpatientswithcryptococcus.Instarkcontrastto aspergillus,only21percentofthosewithcryptococcusand 4percentofthosewithcandidapresentedwithfocalsigns, focalseizures,hemiplegia,orcranialnervedeficits.

Fungalinfectionsaremorecommoninimmunocompromisedpopulationsandasubstantialportionofpatients withinvasivefungalinfectionwillhaveCNSinvolvement. Kleinschmidt-Demasters(2002)identifiedCNSinvolvement of42of71patients(59percent)withinvasiveaspergillosis. OtherstudieshaveshownlessfrequentCNSinvolvementin thesettingofinvasivefungemia.Bodey etal. (1992)reviewed 4,096autopsiesofcancerpatientsandidentified455casesof fungalinfections(11.1percent).Candidaaccountedfor265 cases(58.2percentofallfungalinfections)with6percent ofcandidainfectionsaffectingtheCNS.Aspergilluswas identifiedin137patients(30percentoffungalinfections) andin20patients(15percent)itwasidentifiedintheCNS. Cryptococcuswasseeninnineautopsies(2percentoffungal infections)but22percentofthoseinvolvedtheCNS.Liu etal. (2003)examined149casesofnosocomialfungalinfections overa20-yearperiodatPekingUnionMedicalCollege Hospital.Themostcommonpathogenswere Candidaalbicans,C.tropicalis,C.parapsilosis,Cryptococcusneoformans, andvariousaspergillusspecies.Themostcommonriskfactors fornosocomialinfectionsincludedsteroids,cytotoxictherapy, prolongeduseofbroad-spectrumantibiotics,immunosuppression,andintravenouslines.

Aspergillus

Amongfungalpathogens,aspergillusismostlikelytopresent asastrokeorstroke-likesyndrome,includingasubarachnoid hemorrhage,anintraparenchymalhemorrhage,andan abscess(Walshe etal.,1985a).Themostcommonpathogenis Aspergillusfumigatus,butinfectionsmayalsooccurwith A.flavus,A.niger,A.terreus,andotherspecies(Lass-Florl etal.,2005).Invasivefungalinfectionwithaspergillusis amajorprobleminimmunocompromisedpatients,including thosewithmalignancyandthoseundergoingorgantransplantation.Aspergillussporesareubiquitous.Theyareoftenfound inhospitalventilationsystemsandthroughoutthecommunity environment.Themodeofinfectionisusuallybyinhalation withtheupperrespiratorytractthemostcommoninitialsiteof infection.Occasionally,airbornesporesmayinfectanopen woundorsurgicaldrain(Munksgaard,2004).Pulmonary infectionswithaspergilluscanleadtohematogenousspread oftheorganismtothebrain.CluestothepresenceofCNS aspergillosisincludethegradualextensionofinfarctionsduringafewdaysandthespreadofinvolvementacrossarterial

Strokesinimmunocompromisedpatientsareuncommon but,whentheydooccur,asubstantialproportionmaybe relatedtofungalinfections.Coplin etal. (2001)identified36 patientswithstrokesamong1,245bonemarrowtransplant patientsovera3-yearperiod.Infarctionsorhemorrhages werecausedbyfungiin30.6percentofthebonemarrow transplantpatientswhohadastrokeduringthatperiod.Nine ofthe12strokesfrominfectionwerecausedbyaspergillus, predominantlytheangioinvasiveformofinfection.Mortality intheseriesofCoplin etal. (2001)was89percent,underscoringtheimportanceofearlyconsiderationandtreatmentof fungalcausesofstrokes.Inanautopsystudyof4,326patients treatedattheMemorialSloan–KetteringCancerCenter, asepticembolismwasthoughttoresultin33ofthe500 identifiedstrokes.Themostcommonpathogenswereaspergillusandcandida,withaspergillusmorelikelytopresentwith focalsignsandseizuresandcandidamorelikelytopresentwith encephalopathy(Rogers,2003).

territories.Thespinalfluidusuallydoesnotshowamajor pleocytosisbecausecerebralinvolvementisdueto anecrotizingarteritisandnotameningitis.Otherfungi (exceptmucor)andthetuberclebacillusareorganismsthat almostinvariablycausemeningitis.

AspergillosisoftheCNScommonlyresultsinastroke. Torre-Cisneros etal. (1993)described22organtransplant patientswhosecoursewascomplicatedbyCNSaspergillosis. Tenpatientshadatleastoneblandinfarctionandninehadat leastonehemorrhagicinfarction.Seventy-fivepercenthad angioinvasiononpost-mortempathologicexamination. Gabelmann etal.(2007)reportedninepatientswhodeveloped cerebralaspergillosis,fourwithsingleormultipleabscesses, fourwithinfarctions,andonewithamycoticaneurysm.All infarctionswereirregularlycontrastenhancingandhemorrhagicconversionwasseeninonepatient.Infarctionsinvolved bothsmall-vesselterritories,suchasthecervicomedullary junction,aswellasthebasalgangliaandlargevesselterritories (onepatienthadamiddlecerebralartery[MCA]territory infarct).Boes etal. (1994)reportedon26patientswith autopsy-provenCNSaspergillosis.Mostpresentedwithfever andastroke-likesyndrome.Pathologically,thereweremultiplebraininfarctswiththrombosisduetoaspergillusinvasion ofarteries.Underlyingillnessesincludedbonemarrow transplants,livertransplants,AIDS,andotherimmunecompromisingconditions.

Aspergilluscancauseintracerebralandsubarachnoid hemorrhages.Themechanisminreportedcasesisusually directfungalinvasionofarteries,orembolismsofvegetations offungitointracranialarteries,causingmycoticbrainaneurysms.Angionecrosiscanalsocauseintraparenchymatous bleeding.Cleri etal. (2003)reportedafatalexampleofan intracerebralhemorrhageinapatientwithhemolyticanemia treatedwithcorticosteroids,complicatedbypulmonaryaspergillusinfectionandcandida.Asari etal. (1988)reportedan unusualcaseofdeathduetoamycoticaneurysmatthesiteof surgeryforananteriorcommunicatingarteryaneurysmtreatedbyclipping.Corvisier etal. (1987)reporteda54-year-old womanwithHodgkindisease,treatedwithcytotoxicdrugsand steroids,whohadinvasionofthecarotidarterybyaspergillus, leadingtoafatalruptureoftherightcarotidartery.Takahashi etal. (1998)reportedaspergillusinfectionoftheorbitand ethmoidsinusthatextendedposteriorlyintothebrainand involvedthecavernoussinusandinternalcarotidartery. Pathologicexaminationoftheinternalcarotidarteryshowed chronicinflammatorycellsandhyphae. A.fumigatus wasculturedfromthebrain.Terminally,therewasruptureofthe internalcarotidartery,withsubarachnoidandintracerebral hemorrhages.Davutgolu etal. (2005)reporteda36-year-old manwithaspergillusvegetationsintheleftventricle. Thepatientdiedofamassiveintracerebralhemorrhagedue toamycoticaneurysm.Embolicmaterialfromtheheartlikely lodgedintheMCAbranches,leadingtomycoticaneurysm formationandfatalintracerebralhemorrhage.

Endo etal. (2002)reporteda50-year-oldwomanwho underwentsuccessfulsurgeryforananteriorcommunicating arteryaneurysm.Shesustainedasecondsubarachnoid

hemorrhageonthe26thpostoperativeday,withevidenceof bilateralcerebellarhemisphereinfarcts.Post-mortemexaminationofthebrainshowedfusiformdilationofthebasilar arterywithaspergillusinvasionofthebasilarandvertebral arteries.Microscopically,therewerebranchinghyphaeof aspergilluswithvascularwallnecrosis.Thromboticocclusions ofthebasilararterywerecausedbyaspergillushyphae. Breadmore etal. (1994)reportedapatientwhodeveloped invasiveaspergillusofthecavernoussinuswithruptureof theinternalcarotidartery.HaranandChandy(1993)reported 13patientswithintracranialaspergillusinVelore,India.One ofthe13patientspresentedwithastroke-likesyndrome. Matsumura etal. (1988)reportedtwocasesofintracerebral hemorrhagesduetocerebralaspergillosis.Lau etal. (1991) reportedacaseofafatalsubarachnoidhemorrhagedueto amycoticaneurysmofthecarotidarteryduetoaspergillus. Ihara etal. (1990)reportedafatalsubarachnoidhemorrhage fromamycoticaneurysmofthebasilarartery.Suzuki etal. (1995)reportedacaseoffatalsubarachnoidhemorrhagedue toamycoticaneurysmoftheMCA.PiotrowskiandPilz(1994) reportedaspergillusarteritisafterananeurysmclippingthat mimickedavasospasm.

Althoughourfocusisonstrokes,thusmostlycentered upontheangioinvasivepropertiesofaspergillus,otherpathologicprocessesintheCNSmayalsoresult.Abscessformation isalsoanimportantmechanisminaspergillusinfection; magneticresonancespectroscopymayshowelevatedacetate, succinate,aminoacids,andlactate,helpingtodifferentiate abscessesfromneoplasms(Oner etal.,2006).Inthe22cases reviewedbyTorre-Cineros etal.(1993),sevenpatientshadat leastonebrainabscess.Murthy etal. (2000)reportedon21 patientswithCNSinvolvementwithaspergillus.In16ofthem, aspergillusspreadtothebrainfromsinusinfections.Skullbasedsyndromeswerefoundin16;sixpresentedasabrain abscessandtwohadstroke-likeonsets.Pagano etal. (1996) reported100patientswithleukemiaandaspergillosis. FourteenhadCNSinvolvement.Autopsiesshowedinvasive aspergillus;clinicalpresentationwasgenerallyasabrain abscesswithhemiparesisandseizures.Theprimaryfocuswas mostofteninthelungs.Beal etal. (1982)reported12patients withCNSaspergillosisinimmunosuppressedpatientsor patientsonhigh-dosecorticosteroids.Pulmonaryinfiltrates werepresentinallpatients.Suddenonsetofneurologicdeficits thatwerestroke-likeinonsetoccurredinninepatients. Pathologically,thereweremultiplebrainabscesses,withprominentarterialinvasionbythefungus.Baddley etal. (2002) reviewedtheirexperiencewith1,620transplantpatientsover a3-yearperiod,including230hematopoieticstemcelltransplantsand1,390organtransplants.Fungalbrainabscesses werediagnosedin17patients(1.05percent).Sixty-fivepercent oftheinfectionswereduetoaspergillusspecies.

Meningitisormeningoencephalitiscanalsoresult. Antinori etal.(2013)reviewedtheliteratureanddiscussed the93casesofaspergillusmeningitisreportedfrom January1973toDecember2011.Fifty-twoofthe93patients (55.9percent)hadnoimmunosuppression.Diagnosisduring lifewasnotedinonly52patients(55.9percent);cultureswere

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The work of carving and ornamenting the rood-lofts in the parish churches was constant up to the very eve of the Reformation, and bequests are very frequently met with in the wills of that period for this end, and to keep up the rood-lights. At St. Mary-at-Hill, for instance, in 1496-7 there are a set of accounts headed “costes paid for the pyntyng of the Roode, with karvyng and odir costes also”; and amongst the items is “to the karvare for makyng of 3 dyadems—and for mendyng the Roode, the cross, the Mary and John, the crowne of thorn, with all other fawtes, Summa 10 shillings”; and yet another item was for the painting and gilding. Towards these and other expenses of “setlyng up of the Roode” the parishioners contributed in a special collection. The legacy for beautifying and completing the rood at Leverton has already been noticed. To the “Rood” in one parish church a lady in her will leaves “my heart of gold with a diamond in the midst.” In 1510, at St. Margaret’s, Westminster, £10 was left “towards making a new rood-loft”; and the work was still apparently going on in 1516, when another donor left £38 for the same object. Lastly, in the churchwardens’ accounts of St. Edmund’s, Salisbury, there are entered expenses for the light kept burning before the rood; at which place, for example, in 1480 the candlemaker was specially employed in making “the rood-light.” A curious entry in the accounts of the parish church of St. Petrock’s, Exeter, shows how this light at the rood was kept up: “Ordinans made by the eight men for gathering to the wax silver for the light kept before the high cross, which says, that every man and his wife to the wax shall pay yerely one peny, and every hired servant that takes wages a half peny, and every other persons at Easter, taking no wages, a farthing.” In some places, as, for example, Cratfield, there was a “rowell,” or wheel or corona of candles, kept burning on feast-days before the rood.

The special destruction of the roods of the English churches in the early stages of the Reformation under Edward VI., and again under Elizabeth, causes many to think that the reverence shown to this representation of our Crucified Lord, probably the most prominent object visible in the churches, was not only excessive, but mistaken in its kind. If that were so, it must at least be allowed that the Church’s teaching on the matter was clear and definite. The author

of Dives and Pauper, for example, says that the representations of the Crucified Christ—

“ben ordeyned to steryn men’s mynds to thinke on Crist’s Incarnation and on hys passyon and on his levyng ... for oft man is more sterryed be syght than be heryng or redyng—also thei ben ordeyned to ben a tokne and a boke to the lewyd people that thei mon redyn in ymagery and peyntour that clerkes redyn in boke.”

Then, after describing what thoughts the sight of the crucifix should bring to the mind of the beholder, Pauper goes on—

“In this manner I pray thee read thy boke and fall down to the ground and thank thy God that would do so much for thee, and worship him above all things—not the stock, stone nor tree, but him that died on the tree for thy sin and thy sake: so that thou kneel if thou wilt afore the image, not to the image; do thy worship afore the image, afore the thing, not to the thing; make thy prayer afore the thing, not to the thing, for it seeth thee not, heareth thee not, understandeth thee not. Make thy offering if thou wilt afore the thing, but not to the thing; make thy pilgrimage not to the thing nor for the thing, for it may not help thee, but to him and for him that the thing representeth. For if thou do it for the thing or to the thing thou doest idolatry.”

We now pass from the chancel to the body of the church. The nave and aisles—if there were any—were in a special way under the care of the wardens chosen by the people. There seems to be little doubt that very generally, although perhaps not universally, the walls of the parish churches were painted with subjects illustrating Bible history, the lives of the saints, or the teaching of the sacramental doctrine of the Church. In the same way, although of course in a lesser degree, the windows were often filled with glass stained with pictures conveying the same lessons to the young and the unlettered. These were, as they were called, “the books of the poor and the illiterate,” who, by looking at these representations, could learn the story of God’s dealings with mankind, and could draw encouragement to

strive manfully in God’s service, from the example of the deeds of God’s chosen servants.

The work of beautifying the parish churches by wall decorations and painted windows was the delight of the parishioners themselves, for it all helped to make their churches objects both of beauty and interest. To take but one example: the church of St. Neots possesses many stained-glass windows, placed in their present positions between 1480 and 1530. The inscriptions inserted below the lights testify that most of them were paid for by individual members of the parish, but in the case of three it appears that groups of people joined together to beautify their church. Thus, a Latin label below one says that “the youths of the parish of St. Neots” erected the window in 1528; a second says that, the following year, the young maidens emulated the example of their brothers; and the “mothers” of the parish finished the third window in 1530.

Besides the high altar in the chancel, there were, from early times, few churches that did not have one or more, and sometimes many smaller or side altars. These were dedicated to various saints, and from the fifteenth century, and even earlier, they were used as chantries or guild chapels. The priests serving them were supported by the annuity left by some deceased benefactor to the parish church, or by a stipend paid by the guild to the priest who acted as its chaplain, or again by the private generosity of some benefactor. These chapels were frequently richly decorated, furnished with hangings, and supplied with their own vestments and altar furniture by their founders or by the guilds that supported them. To take an example: In 1471 an indenture or agreement was made between Mr. William Vowelle, master of the town of Wells, and the two wardens of our Lady’s altar in St. Cuthbert’s Church, and John Stowell, freemason, for making the front of the Jesse at the said altar. The work was to cost £40 (probably more than £500 of our money), and the mason was to be paid 40s. a week, with £5 to be kept in hand till the completion of the work. To take another example: at Heydon, in the East Riding of Yorkshire, the south aisle was dedicated to St. Catherine, and there is an item of expense in the churchwardens’

accounts showing the existence of a painted altar, an image of the saint, and a kneeling-desk in front of it.

In the accounts of St. Mary-at-Hill, where there were many such side chapels, there is an order of the wardens, made in 1518, “that every priest shall sing with his founder’s vestments, and that their chest is to be at the altar’s end, next where they sing.” In some of these small chapels there were statues, before which lights were kept burning by the devotion of various members, or groups of members, of a parish. Thus at Henley-on-Thames there were seven chapels and two altars in the nave, besides the high altar in the chancel. Lights were kept burning before the rood, the altar of Jesus, and the altar of the Holy Trinity. In 1482 the warden and the commonalty ordained that the chaplain in the chapel of the Blessed Virgin Mary say Mass every day at six o’clock, and the chantry priest of St. Katherine’s chapel at eight o’clock. In these accounts are entered the receipts and expenses of the Guild of the Holy Name, and amongst the rest is an entry “for painting the image of Jesus and gilding it.” The most curious entry, however, in this book of accounts is that of a gift to secure the perpetual maintenance of “our Lady’s light.” This was a set of jewels, given to the churchwardens in 1518 by Lady Jones. They were apparently very fine, and were to be let out by the wardens for the use of brides at weddings. The sum charged for the hire was to be 3s. 4d. for anyone outside the town, and 20d. for any burgess of Henley. Portions of what is called “the Bridegeer” were let at lower figures; but in one year the wardens received as much as 46s. 6d. from this source of income. At the Reformation the jewels were sold for £10 6s. 8d.

The floors of our churches, until late in the fifteenth century, were not generally so encumbered with pews or sittings, as they became later on, but were open spaces covered with rushes. The church accounts show regular expenses for straw, rushes, or, on certain festivals, box and other green stuff wherewith to cover the pavement. This carpet was renewed two or three times a year, and one almost shudders to think of the state of unpleasant dirt revealed on those periodical cleanings. Some accounts show regular payments made to “the Raker” on these occasions, whilst the purchase, in 1469, of “three

CORONA OF LIGHTS, ST. MARTIN DE TROYES— FIFTEENTH CENTURY

rat-traps” for the church of St. Michael’s, Cornhill, suggests that the rush covering must have been a happy huntingground for rats, mice, and suchlike vermin. In some places, however, mats were provided by the wardens, as at St. Margaret’s, Westminster, where, in 1538, 4s. 4d. was paid to provide “matts for the parishioners to kneel on when they reverenced their Maker.” So too, at St. Mary-at-Hill, London, there was a mat in the confession pew, and others were provided for the choristers, whilst we read of the expenditure of 4d. “for three mats of wikirs, boght for prestis and clerkis.”

The provision of fixed seats in parish churches, for the use of the people generally, was a late introduction. The practice of allowing seats to be appropriated to individuals was in early days distinctly discouraged. In 1287, for instance, Bishop Quevil, of Exeter, in his synodical Constitutions, condemns the practice altogether.

“We have heard,” he says, “that many quarrels have arisen amongst members of the same parish, two or three of whom have laid claim to one seat. For the future, no one is to claim any sitting in the church as his own, with the exception of noble people and the patrons of churches. Whoever first comes to church to pray, let him take what place he wishes in which to pray.”

This, of course, refers to a few seats or benches, and not to regular sittings or pews, which were begun to be set up in the English churches only in the middle of the fifteenth century, and in some not till late in the sixteenth. At Bramley church, for example, the wardens did not begin “to seat” the nave before 1538; at Folkestone some pews were in existence as early as in 1489; in 1477-8 the wardens of St. Edmund’s parish church, Salisbury, assigned certain seats to individuals at a yearly rent of 6d.; and even before that time, in 1455, seats were rented at St. Ewen’s church, Bristol. Apparently, once introduced, the churchwardens soon found out the advantages of being able to derive income from the pew or seat rents, especially as from some of the accounts it is evident that the seats were first made with money obtained at special collections for the purpose, as at St. Mary’s the Great, Cambridge, in 1518. In the first instance, apparently, the seats were assigned only to the women-folk, but the great convenience was, no doubt, quickly realised by all, and the use became general after a very short time.

BACKLESS BENCHES, CAWSTON, NORFOLK

One of the most conspicuous objects in every parish church was its Font. This stood at the west end of the church, and frequently in a place set apart as a baptistery. From the thirteenth century it was ordered, in the Constitutions of St. Edmund of Canterbury, that every font must be made of stone or some other durable material, and that it was to be covered and locked, so as to keep the baptismal water pure, and prevent any one except the priest from meddling with what had been consecrated on Easter Eve with Holy Oils and with solemn ceremony. Great care was enjoined on the clergy to keep the Blessed Sacrament, the Holy Oils, and the baptismal water safe under lock and key. For, says the gloss on this ordinance in Lyndwood, keys exist so that things may be kept securely; and he that is negligent about the keys would appear to be negligent about what the keys are supposed to guard. By the ordinary law of the Church a font could only be set up in a parish church; and in the case of chapels of ease, and other places in a parochial district, where it was lawful to satisfy other ecclesiastical obligations, for baptism the child had generally to be brought to the mother church. The instances in which permission was granted for the erection of any font in a chapel are very rare, and leave was never given without the consent of the rector of the parish church. Thus a grant was

FONT, ST. MICHAEL’S, SUTTON BONNINGTON, NOTTS

made in the fourteenth century to Lord Beaucha mp to erect a font for baptisms in his chapel at Beaucha mp, provided that the rector agreed that it would not harm his parochial rights.

Leading into the church

very generally there was a covered approach, greater or less in size, called the porch, from the Latin porta, “a door or gate.” This was usually at the south side of the church, and sometimes it was built in two stories, the upper one being used as a priest’s chamber, with a window looking into the church. In some cases this chamber was used as a safe repository for the parish property and muniments. In the lower porch, at the side of the church door, was the stoup, usually in a stone niche, with a basin to contain the Holy Water. With this people were taught to cross themselves before entering God’s house, the water being a symbol of the purity of soul with which they ought to approach the place where His Majesty dwelt. The mutilated

remains of those niches, destroyed when the practice was forbidden in the sixteenth century, may still frequently be seen in the porches of preReformati on churches. Sometime s it would seem that there was attached to the water stoup a sprinkler to be used for the

HOLY WATER STOUP, WOOTTON COURTNEY, SOMERSET

Blessed Water—as, for example, at Wigtoft, a village church near Boston, in Lincolnshire, where the churchwardens purchased “a chain of iron with a Holy Water stick at the south door.”

The land round about the church was also in the custody of the people’s wardens. It was called the Cemetery, from the word

cœmeterium, “a dormitory,” it being in the Christian sense the sleeping-place of the dead who had died in the Lord. It was likewise spoken of as the “church-yard,” or under the still more happy appellation of “God’s acre.” From an early period attempts were made from time to time to put a stop to the practice of holding fairs in the cemetery, or to prevent anything being sold in the porches of churches or in the precincts. Bishops prohibited the practice by Constitutions, and imposed all manner of spiritual penalties for disobedience. By the Synod of Exeter, in 1267, Bishop Quevil ordered that all the cemeteries in his diocese should be enclosed securely, and that no animal was to be allowed pasturage on the grass that grew in them, and even the clergy were warned of the impropriety of permitting their cattle to graze in “the holy places, which both civil and canon law ordered to be respected.” For this reason, the bishop continues, “all church cemeteries must be guarded from all defilement, both because they are holy (in themselves) and because they are made holy by the relics of the Saints.”

The reason for this belief in the holy character of cemeteries is set out clearly in a letter of Bishop Edyndon, in 1348, where he says that

“the Catholic Church spread over the world believes in the resurrection of the bodies of the dead. These have been sanctified by the reception of the Sacraments, and are consequently buried, not in profane places, but in specially enclosed and consecrated cemeteries, or in churches, where with due reverence they are kept, like the relics of the Saints, till the day of the resurrection.”

The trees that grew within the precincts of the cemetery were at times a fertile cause of dispute between the priest and his people. Were they the property of the parson or of the parish? And could they be cut down at the will of either? In the thirteenth century, when the charge of looking after the churchyards was regarded as weighing chiefly on the clergy, it was considered that to repair the church—either chancel or nave—the trees growing in them might be cut. Otherwise, as they had been planted for the purpose of protecting the churches from damage by gales, they were to be left

to grow and carry out the end for which they had been placed there. Archbishop Peckham had previously laid down the law that, although the duty of keeping the enclosure of the cemetery rested upon the parishioners, what grew upon holy ground being holy, the clergy had the right to regard the grass and trees and all that grew in the cemetery as rightly belonging to them. In cutting anything, however, the archbishop warned the clergy to remember that these things were intended to ornament and protect God’s house, and that nothing should be cut without reason. However the question of the ownership of the trees growing in churchyards may have been regarded by the parishioners, there are evidences to show that they did not hesitate to adorn their burial-places with trees and shrubs when needed. At St. Mary’s, Stutterton, for instance, in 1487, the churchwardens purchased seven score of plants from one John Folle, of Kyrton, and paid for “expenses of settyng of ye plants, 16d.”

The sacred character of consecrated cemeteries was recognized by the law. Bracton says that “they are free and absolute from all subjection, as a sacred thing, which is only amongst the goods of God—whatever is dedicated and consecrated to God with rites and by the pontiffs, never to return afterward to any private uses.” And amongst these he names “cemeteries dedicated, whether the dead are buried therein or not, because if those places have once been dedicated and consecrated to God, they ought not to be converted again to human uses.” Indeed, “even if the dead are buried there without the place having been dedicated or consecrated, it will still be a sacred place.”

The ceremony by which the mediæval churchyard was consecrated was performed by the bishop of the diocese, or some other bishop, by his authority and in his name. The fees were to be paid by the parish; and the parochial accounts give examples of this expense having been borne by the wardens. Thus at Yatton, in 1486, the churchyard was greatly enlarged, and, when the new wall had been constructed, the bishop came over and consecrated the ground. The parish entertained him and his ministers at dinner, and paid the episcopal fee, which was 33s. 4d. One of the expenses of this

ceremony, noted down by the churchwardens, was, “We paid the old friar that was come to sing for the parish, 8d.”

In the churchyards thus dedicated to God were set up stone crosses or crucifixes, as a testimony to the faith and the hope in the merits of Christ’s death, of those who lay there waiting for the resurrection. The utmost reverence for these sacred places was ever enjoined upon all. Children, according to Myrc, were to be well instructed on this point—

“Also wyth-ynn chyrche and seyntwary Do rygt thus as I the say. Songe and cry and such fare For to stynt thou schalt not spare; Castynge of axtre and eke of ston Sofere hem there to use non; Bal and bares and such play Out of chyrcheyorde put away.”

And the penitent soul was to inquire of itself whether it had done its duty in ever offering a prayer for the dead when passing through a cemetery—

“Hast thou I-come by chyrcheyorde And for ye dead I-prayed no worde?”

In concluding this brief survey of the material parts of preReformation churches, it is impossible not mentally to contrast the picture of these sacred places, as revealed in the warden’s accounts, the church inventories and other documents, with the bare and unfurnished buildings they became after what Dr. Jessopp has called “the great pillage.” Even the poorest and most secluded village sanctuary was in the early times overflowing with wealth and objects of beauty, which loving hands had gathered to adorn God’s house, and to make it, as far as their means would allow, the brightest spot in their little world, and beyond doubt the pride of all

their simple, true hearts. This is no picture of our imagination, but sober reality, for the details can be all pieced together from the records which survive. Just as a shattered stained-glass window may with care be put together again, and may help us to understand something of what it must have been in the glory of its completeness, so the fragments of the story of the past, which can be gathered together after the destruction and decay of the past centuries, are capable of giving some true, though perhaps poor, idea of the town and village parish churches in pre-Reformation days. “There is not a parish church in the Kingdom,” writes a Venetian traveller of England in 1500,—“there is not a parish church in the Kingdom so mean as not to possess crucifixes, candlesticks, censers, patens, and cups of silver.” What is most remarkable about the documents that have come down to us, and which are mere chance survivals amid the general wreck, is the consistent story they tell of the universal and intelligent interest taken by the people of every parish as a whole in beautifying and supporting their churches. In a real and true sense, which may be perhaps strange to us in these later times, the parish church was their church. Their life, as will be seen in subsequent chapters, really centred round it, and they one and all were intimately connected with its management. The building was their care and their pride; the articles of furniture and plate, the vestments and banners and hangings, all had their own well-remembered story, and were regarded, as in truth they were, as the property of every man, woman, and child of the particular village or district.

CHAPTER IV

THE PARISH CLERGY

The head of every parish in pre-Reformation days was the priest. He might be a rector or vicar, according to his position in regard to the benefice; but in either case he was the resident ecclesiastical head of the parochial district. The word “parson,” in the sense of a dignified personage—“the person of the place”—was, in certain foreign countries, applied in the eleventh century, in its Latin form of persona, to any one holding the parochial cure of souls. English legal writers, such as Coke and Blackstone, have stated the civil law signification of the word as that of any “person” by whom the property of God, the Patron Saint, the church or parish was held, and who could sue or be sued at law in respect to this property. In ecclesiastical language, at any rate in England, according to Lyndwood, the word “parson” was synonymous with “rector.”

Besides the rector or parson and the vicar, several other classes of clergy were frequently to be met with in mediæval parishes. Such were curates, chantry priests, chaplains, stipendiary priests, and sometimes even deacons and subdeacons. About each of these and their duties and obligations it will be necessary to speak in turn, but before doing so something may usefully be said about the clergy generally, and about their education, obligations, and method of life. From the earliest times the clerical profession was open to all ranks and classes of the people. Possibly, and even probably, the English landlords of the fourteenth or fifteenth centuries were only too glad to bestow livings, of which they had the right of presentation, upon younger sons or relations, who had been educated with this end in view. But in those same centuries there is ample evidence that the ranks of the clergy were recruited from the middle classes, and even from the sons of serfs, who had to obtain their overlord’s leave and pay a fine to him for putting their children to school, and thus taking

them from the land to which they were by birth adscripti, or bound. Mr. Thorold Rogers has given instances of the exaction of these fines for sending sons to school. In one example 13s. 4d. was paid for leave to put an eldest son ad scholas with a view of his taking orders; in another 5s. was paid, in 1335, for a similar permission for a younger son. In the diocesan registers, also, episcopal dispensations de defectu natalium are frequent, and show that a not inconsiderable number of the English clergy sprang from the class of “natives” of the soil, or serfs, upon whom the lord of the manor had a claim. Examples also could be given of a bishop allowing his “native” (nativus meus) permission to take sacred orders and to hold ecclesiastical benefices—acts of kindness on the bishops’ part shown to some promising son of one of the serfs of the episcopal domains.

The practice of introducing into the body of the clergy even those sprung from the lower ranks of life was not altogether popular, and the author of The Vision of Piers Plowman has left a record of the existing prejudice on the subject. He thinks that “bondmen and beggars’ children belong to labour, and should serve lords’ sons,” and that things are much amiss when every cobbler sends “his son to schole” and “each beggar’s brat” learns his book, “so that beggar’s brat a Bishop that worthen among the peers of the land prese to sytten ... and his sire a sowter (cobbler) y-soiled with grees, his teeth with toyling of leather battered as a saw.”

In 1406 the more liberal spirit of encouraging learning wherever it was found to exist asserted itself, and by a statute of the English Parliament of that date it was enacted that “every man or woman, of what state or condition he be, shall be free to set their son or daughter to take learning at any school that pleaseth them within the realm.” That such schools existed in the past in greater numbers than has been thought likely does not now appear open to doubt. Besides the teaching to be obtained at the cathedrals, religious houses, and well-known grammar schools, the foundations of education were furnished by numerous other smaller places, taught by priests up and down the country. This is proved by the numbers of students who came up to the Universities for their higher work at the

age of fourteen or so, after they had been prepared elsewhere, and the numbers of whom fell off almost to a vanishing point on the destruction of the religious houses, and the demolition of the smaller schools, under cover of the Act for dissolving Chantries, etc. In the Chantry certificates mention is made of numerous parochial schools taught by priests, who also served the parish in other ways, or by clerks supported by money left for the purpose of giving free education. These proofs appear on the face of the certificates, in order that a plea might be made for their exemption from the operation of the general dissolution of chantries and guilds; it is needless to add that the plea had no effect. In some places, too, as for example at Morpeth and Alnwick and Durham, a second school of music, called the “song school,” was kept. At the latter place a chantry was founded in the cathedral for two priests “to pray and to keep free schools, one of grammar and one of song, in the city of Durham, for all manner of children that should repair to the said schools, and also to distribute yearly alms to poor people.” At Lavenham, in Suffolk, a priest was paid by the parish to “teach the children of the town” and to act as “secondary” to the curate.

By the will of Archbishop Rotheram, in 1500, the foundation of a college in his native place was laid. In this will the archbishop, after saying that he had been born at Rotheram, gives an interesting biographical note about his early years—

“To this place a teacher of grammar coming, by what chance, but I believe it was God’s grace that brought him thither, taught me and other youths, by which others with me attained to higher (paths of life). Wherefore wishing to show my gratitude to our Saviour, and to celebrate the cause of my (success in life), and lest I should seem to be ungrateful and forgetful of God’s benefits and from whence I came, I have determined in the first place to establish there a teacher of grammar to instruct all without charge.”

Archbishop Rotheram’s case was not singular. Bishop Latimer, in one of his sermons before Edward VI., gives an account of his early life.

“My father,” he says, “was a yeoman, and had no lands of his own; only he had a farm of three or four pounds by the year at the uttermost, and hereupon he tilled so much as kept half a dozen men. He had a walk for a hundred sheep, and my mother milked thirty kine. He was able and did find the king a harness and his horse. I remember that I buckled on his harness when he went to Blackheath field. He kept me to school, or else I had not been able to have preached before the King’s majesty now.”

An ordinance of the diocese of Exeter in the synod of Bishop Quevil seems also to suggest that schools of some kind existed in most cities and towns. He had always understood, he says, that the benefice of the “Holy Water bearer” was in the beginning instituted in order to give poor clerks something to help them to school, “that they might become more fit and prepared for higher posts.” In this belief the bishop directs that in all churches, not more than ten miles distant from the schools of the cities and towns of his diocese, the “benefices” of the “Holy Water bearers” should always be held by scholars.

Seager’s Schoole of Virtue, although written in Queen Mary’s reign, refers, no doubt, to a previous state of things. The author seems to take for granted that attendance at school is a very common, if not the ordinary thing, and that it is in the power of most youths to make their future by study and perseverance.

“Experience doth teche, and shewe to the playne That many to honour, by learninge attayne That were of byrthe but simple and bace Such is the goodness of God’s speciale grace. For he that to honour by vertue doth ryse Is doubly happy, and counted more wyse.”

The writer then warns the boys he is addressing to behave themselves when leaving school. On their way home they would do well to walk two and two, and “not in heaps, like a swarm of bees.” Another educator, Old Symon, in his “Lesson of Wysedom for all

maner chyldryn,” urges diligence and plodding upon his pupils, with a jest as to possible positions to which the student may in time attain.

“And lerne as faste as thou can, For our byshop is an old man, And therfor thou must lerne faste If thou wilt be byshop when he is past.”

It is unnecessary to pursue the subject of the education of the parochial clergy further. After his elementary education had been received in the schools, the student’s preparation for the reception of Orders was continued and completed at the Universities. The ordinary course here was lengthy. Grammar, which included Latin and literature with rhetoric and logic, occupied four years. The student was then admitted a Bachelor In the case of clerical students this was followed by seven years’ training before the Bachelor’s degree in Theology was bestowed, and only after a further three years’ study of the Bible, and after the candidate had lectured at least on some one book of the Scriptures, was he considered to have earned his degree of Doctor in Theology.

ACOLYTHES

SACRAMENT OF BAPTISM

The age when the candidate for Orders could be promoted to the various steps leading to the priesthood was settled by law and custom. A boy of seven, if he showed signs of having a vocation to the sacred ministry, might be made a cleric by receiving the tonsure. In “rare instances” and under special circumstances he might then receive an ecclesiastical benefice, and so get the wherewith to live while he was studying to fulfil the duties attached to his office. In the course of the next seven years the youth could be given the minor Orders of “doorkeeper,” “lector,” “exorcist,” and “acolyte.” He would then be at least fourteen years of age, and thus at the time of life at which in those days students were supposed to begin their

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