REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
PublicaçãoOficialdaSociedadeBrasileiradeAnestesiologiawww.sba.com.br
REVIEW
ARTICLE
Neuraxial
anesthesia
in
patients
with
multiple
sclerosis
---
a
systematic
review
Helmar
Bornemann-Cimenti
∗,
Nikki
Sivro,
Frederike
Toft,
Larissa
Halb,
Andreas
Sandner-Kiesling
MedicalUniversityofGraz,DepartmentofAnesthesiologyandIntensiveCareMedicine,Graz,Austria
Received4March2016;accepted6September2016 Availableonline1October2016
KEYWORDS
Multiplesclerosis; Neuromyelitisoptica; Neuroaxialanesthesia
Abstract
Backgroundandobjectives: Currentguidelinesforneuraxialanalgesiainpatientswithmultiple
sclerosisareambiguousandoffertheclinicianonlyalimitedbasisfordecisionmaking.This sys-tematicreviewexaminesthenumberofcasesinwhichmultiplesclerosishasbeenexacerbated aftercentralneuraxialanalgesiainordertorationallyevaluatethesafetyoftheseprocedures.
Methods:A systematic literature search with thekeywords ‘‘anesthesia oranalgesia’’ and
‘‘epidural, peridural, caudal, spinal, subarachnoid or intrathecal’’ in combination with ‘‘multiplesclerosis’’wasperformedinthedatabasesPubMedandEmbase,lookingforclinical dataontheeffectofcentralneuraxialanalgesiaonthecourseofmultiplesclerosis.
Resultsandconclusions: Overaperiod of65years,oursearchresultedin37reportswitha
totalof231patients.In10patientsmultiplesclerosiswasworsenedandninemultiplesclerosis orneuromyelitisopticawasfirstdiagnosedinatimelycontextwithcentralneuraxialanalgesia. Noneofthecasesshowedaclearrelationbetweencauseandeffect.Currentclinicalevidence doesnotsupportthetheorythatcentralneuraxialanalgesianegativelyaffectsthecourseof multiplesclerosis.
©2016SociedadeBrasileiradeAnestesiologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).
PALAVRAS-CHAVE
Esclerosemúltipla; Neuromieliteóptica; Anestesianeuroaxial
Anestesianeuraxialempacientescomesclerosemúltipla---umarevisãosistemática
Resumo
Justificativaeobjetivos: Asdiretrizesatuaisparaanalgesianeuraxialempacientescom
escle-rosemúltipla(EM)sãoambíguaseoferecemaoclínicoapenasumabaselimitadaparaatomada dedecisão.EstarevisãosistemáticaexaminaonúmerodecasosnosquaisaEMfoiexacerbada
∗Correspondingauthor.
E-mail:helmar.bornemann@medunigraz.at(H.Bornemann-Cimenti).
http://dx.doi.org/10.1016/j.bjane.2016.09.001
apósanalgesianeuraxialcentralparaavaliarracionalmenteaseguranc¸adessesprocedimentos.
Métodos: Umabuscasistemáticadaliteraturausandoaspalavras-chave‘‘anestesiaou
anal-gesia’’e‘‘epidural,peridural,caudal,espinhal,subaracnoideoouintratecal’’emcombinac¸ão
commultiplesclerosisfoifeitanasbasesdedadosPubMedeEmbaseàprocuradedadosclínicos
sobreaefeitodaanalgesianeuraxialcentralsobreocursodaesclerosemúltipla.
Resultadoseconclusões: Duranteumperíodode65anos,nossabuscaresultouem37relatos
comumtotalde231pacientes.Em10pacientes,aesclerosemúltiplafoiagravadae,emnove,a esclerosemúltiplaouneuromieliteópticafoidiagnosticadapelaprimeiravezemmomento con-comitantecomaanalgesianeuraxialcentral.Nenhumdoscasosapresentouumaclararelac¸ão entrecausaeefeito.Aevidênciaclínicaatualnãosustentaateoriadequeaanalgesianeuraxial centralafetanegativamenteocursodaesclerosemúltipla.
©2016SociedadeBrasileiradeAnestesiologia.PublicadoporElsevierEditoraLtda.Este ´eum artigo OpenAccess sobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Multiple sclerosis(MS) is a chronic autoimmune condition ofthecentralnervoussystem(CNS),withdiffuseandfocal areasofinflammation,demyelination,gliosis,andneuronal injury.The exact mechanisms behindthis diseaseare not completelyunderstood,butcurrentconceptssuggesta com-plex multifactorial genesis with genetic, environmental, immunological,andmicrobiologicalfactors.1
In 1949, Fleiss reported the appearance of MS after spinal anesthesia,2 and this led to the speculation that
intrathecal application of local anesthetics could precipi-tateorexacerbatethisdisease.3Asaconsequence,central
neuraxial analgesia was regarded to be relatively con-traindicated in MS.4,5 Direct toxicity of local anesthetics
was discussed as potentially harmful as was mechanical trauma or neural ischemiasecondary tolocal anesthetics oradditives.OligopeptideswithNa-channelblocking activ-ities have recently been found in cerebrospinal fluid of patients suffering from MS, leading to the assumption of increasedvulnerabilitytolocalanesthetics.6Despitemany
considerations, no commonly accepted theory exists on theparticularmechanismsofhowneuraxialanalgesiamay alter thecourse of MS; it alsoremains unclear if neurax-ialtechniques are actuallyharmful. Nevertheless, several anesthesiologistsstillfearthepossibleexacerbationof pre-existingdeficitsandarereluctanttoofferspinalorepidural analgesiatopatientswithMS.7
Current guidelines for central neuraxial analgesia in patientswithMSareambiguousandoffertheclinicianonly alimited basisfor decision-making.The AmericanSociety of RegionalAnesthesia andPain Medicine (ASRA)statesin its2008practiceadvisorythat‘‘theexistingliterature nei-therconfirmsnorrefutesthesafetyofneuraxialanesthesia in patients withCNS or peripheral nervoussystem neuro-logicdisorders,nordoesitdefinitivelyaddresstherelative safetyofspinalvs.epiduralanesthesia(EA)oranalgesiain thesepatients’’.8Aconsensusstatementfrom2014
recom-mendsthattheindicationofspinalanesthesiainpregnant patients with MS should be discussed on a case-by-case basis.9
In the absence of sufficient high-level, large-scale, prospectivestudies, all these guidelinesrefer tocases of deterioration of MS after neuraxial anesthesia. However, untilnowtheexact numberofreportedcaseshasnotyet beeninvestigated.Thissystematicreviewaimstodetermine thenumberofcasesinwhichMShasbeenexacerbatedafter centralneuraxialanalgesia inordertorationallyevaluate thesafetyoftheseprocedures.
Methods
Asystematicliteraturesearchforarticlesreportingonthe clinicalcourseofMSafterepidural,spinal,combinedspinal and epidural or caudal analgesia in human subjects was carriedout using the databases PubMedand Embase. We includedallkindsofarticlesprovidingclinical data, espe-ciallycase-seriesorcase-reports.Thesearchtermincluded the keywords ‘‘anesthesia or analgesia’’ and ‘‘epidural, peridural, caudal, spinal, subarachnoid or intrathecal’’ in combination with ‘‘multiple sclerosis.’’ Language was restricted to English, German, French, Spanish and Por-tuguese.The Cochranedatabase andtheclinicaltrials.gov study registry were searched to identify further ongoing or planned trials.As thedistinction between neuromyeli-tisopticaand MSwasunclearuntila fewyearsago,10 we
decidedtoincludecasesaboutbothdiseases.
Title,abstract,andfull-textscreeningswereconducted consecutively by two independent reviewers (HBC and FT). If diverging appraisal of literature occurred, a third reviewerdecidedhowtoproceed.Referencesofarticlesand reviewswere screened furtherfor additionalpublications thatwere not detected by our primaryliterature search. ThemanuscriptwaspreparedaccordingtothePRISMA state-ment(PreferredReportingItemsforSystematicReviewsand Meta-Analyses).11
Results
Embase and pubmed search
(anesthesia OR analgesia) AND (epidural OR peridural OR caudal OR spinal OR subarachnoid OR intrathecal) AND “multiple sclerosis”.
248 primary hits
Title screening
79 publications remaining
Abstract screening
53 publications remaining
Full-text screening
35 relevant publications 6 publications
from further sources included
11 studies and
case series 26 case reports
22 publications excluded 26 publications
excluded 169 publications
excluded
Figure1 Flowchart.
publicationswereselectedbytitle,abstract,and full-text-screening,including11studiesand26casereports(Fig.1,
Tables1and2).
A total of 243 interventions in 231 patients were included. EA was used in 180 cases, spinal analgesia in 59, caudal analgesia in three, and Combined Spinal and Epidural (CSE) once. In 10 patients, a deterioration of MS was observed in context with central neuraxial anal-gesia (three spinals, seven EAs). In six cases, MS was firstdiagnosedafter spinalanesthesia, and inthreecases neuromyelitisoptica, a demyelinating disease thatshares manysimilaritieswithMS,wasfirstdiagnosedafterspinal analgesia. In two cases, symptoms of MS improved after EA.
Discussion
In clinical practice, the patient withMS is a rare event. Most anesthesiologists encounter less than one of these patients per year,7 and therefore, experience in
periop-erative management is often limited. General anesthesia is most frequently used in this population and generally regardedassafe.12,13Ontheotherhand,neuraxialanalgesia
inpatientswithMSremainscontroversial.Asguidelinesare ambiguousor recommendacase-by-casedecision,8,9 their
Table1 Casereportsofpatientswithmultiplesclerosisundergoingneuroaxialanalgesia. Author
(reference)
Patients characteristics
Typeof anesthesia
Typeofsurgery Complication Details
Fleiss2 36years,male Spinal Orthopedic Yes Multiplesclerosisfirst
diagnosedafterspinal anesthesia
Warren24 21years,female EA Vaginaldelivery,
CS
Yes Hypesthesiaonthethigh, restitutionafter7days(1◦
delivery)and7weeks(2◦
delivery)
Levesque25 33years,female Spinal Plasticsurgery Yes Multiplesclerosisfirst
diagnosedafterspinal anesthesia
Hosseini26 23years,female Spinal Halluxvalgus Yes Neuromyelitisopticafirst
diagnosedafterspinal anesthesia
Lopez Ariztegui27
32years,female EA Vaginaldelivery Yes Acutetransversedisorderfirst diagnosedtwoweeksafterPDA Facco14 34years,female Spinal CS Yes Neuromyelitisoptica6months
afterspinal;conusmedullaris lesionwhilepuncturing;five yearsafterbilateralblindness, severetetraparesis,
neurogenicbladder Buraga28 42yearsoldfemale Spinal Urological Yes Multiplesclerosisfirst
diagnosedafterspinal anesthesia
Berger29 53years,male Spinal Urological/plastic
surgery
No
Leigh30 43years,male Spinal Laparotomy No
Wang31 45years,female EA CS No Preexistingdiseases:von
HippleLindaudisease Kohler32 29years,female EA Vaginaldelivery No
Gunaydin21 29years,female EA CS No Improvementofneurological
symptomspostpartum Vadalouca33 56years,female CSE Hysterectomy No
Marshak34 61years,female EA Thoracotomy No
Barbosa35 32years,female Spinal CS No
MayorgaBuiza36 37years,female EA CS No
Martucci37 29years,female Spinal CS No
Tympa38 45years,female EA Hysterectomy No Otherpre-existingdisease:
ischemicbraininfarct, antiphospholipidsyndrome, and-heterozygous thalassemia
Shanmugam39 68years,female EA Oesophagectomy No Postoperativeimprovementof
lowerlimbmobilityand strength
Patel40 46years,female EA Cystectomy No Intrathecalbaclofenpump
implanted Oouchi41 29years,female Spinal CS No
Sethi42 32years,female EA CS No
Bettencourt43 36years,female EA CS No
EA,epiduralanesthesia;CSE,combinedspinalandepidural;CS,cesareansection.
regarded to be related to spinal anesthesia, resulting in financialcompensationforthepatient.14
In our systematic literature search, we found two prospective studies, both on epidural analgesia in an
obstetricsetting.ThefirstwasthePRIMS(PregnancyandMS) study.ThisEuropeanmulticenterstudyfollowed254women withMSduring pregnancyand 12months afterdelivery.15
Table2 Caseseriesandstudiesofpatientswithmultiplesclerosisundergoingneuroaxialanalgesia. Author
(reference)
Studytype n Typeof anesthesia
Typeof surgery
Checkup Complication Artder Komplikation Bamford44 Caseseries 8patients
12interventions
Spinal(9) Vaginal delivery, minor surgical interventions
--- Yes 1patientwith legweakness
Caudal(3) Stenuit45 Caseseries 5 Spinal CS,
urological and orthopedica
--- yes MSfirst
diagnosedafter spinalanesthesia in2patients,1 patientwith exacerbationof symptomsfor1 year
Bouchard46 Caseseries 9patients
14interventions
Spinal Urological andplastic surgery
--- Yes 1patientwith temporary exacerbation,no further
descriptionof symptoms Bader47 Caseseries 20patients
32pregnancies
EA(14) CS,vaginal delivery
3month Yes 5patientswith relapse,no further descriptionof symptoms Dalmas48 Caseseries 19 EA CS,vaginal
delivery
4years Yes 1patient developed5 monthpostnatal retrobulbar neuritisand dysesthesiaof theextremities Confavreux15 Prospective
cohortstudy (PRIMSstudy)
42 EA Vaginal
delivery,CS
12month No
Kyttä49 Caseseries 5 EA(3) Urological
andplastic surgery
--- No
Spinal(2) Vukosic16 Prospective
cohortstudy (PRIMSStudy follow-up)
42 EA Vaginal
delivery,CS
2years No
Hebl6 Caseseries 35 EA(18) Vaginal
delivery mixed surgery
46±38days No
Spinal(17)
May50 Caseseries 5 EA(4) Vaginal
delivery,CS
--- No
Spinal(1) Pastó17 Prospective
cohortstudy
65 EA Vaginal
delivery,CS
6month No
When compared to 180 parturients with MS who had no epiduralanalgesia,nosignificanteffectonrelapserateor severityofworseningofdisabilitieswasfound.Inthe follow-upanalysis2yearslater,theresultswereconfiremd.16
In2012,Pastòetal.presentedtheirprospectivecohort studyfromtheItalianMSStudyGroup.17Theycollecteddata
fromthegestationalperioduntil12monthsafterdelivery from415 paturientswithMS.Although 65patients under-wentepiduralanalgesia,thisdidnotaffecttherelapserate orthetime-dependentprofileofrelapse.
Thisisthefirstsystematicreviewwhichaimstoinclude allreportedcasesincurrentliterature.Althoughall avail-ableguidelinesandrecommendationsrefertocertaincases, theexactnumberwasnotyetinvestigated.Wespecifically decidedtoincludethesecasesinoursystematicreviewto provideanassessmentofthefrequencyofnoticeable post-operativecourses.TakingthehighprevalenceofMSbetween 20and200/100,00018intoconsideration,thetotalnumber
ofreportedcasesinwhichsymptomsdeterioratedafter neu-raxialanalgesiaseemsextremelylow.However,thisnumber may behighly biased, asthe majority of cases arelikely tobeunreported.Evenso,worseningofMSafterneuraxial analgesiacanbeconsideredarareevent.
Over a period of 65 years, our systematic literature searchresulted in 10patients,in whomMSwasworsened andnineinwhomMSorneuromyelitisopticawasfirst diag-nosedinatimelycontextwithcentralneuraxialanalgesia. However,timelycorrelationdoesnotimplycausality.
The majorityof casesweredescribedinobstetric sett-ings. This can be explained by two facts: first, due to the combined effect of sex and age, the incidence for MS is increased in the obstetric population. Second, in obstetric anesthesia and analgesia, neuraxial techniques aremorecommonly appliedinpatients withMScompared to healthy controls.19 During pregnancy, symptoms of MS
oftenimprove,whereaspostpartumrelapserateshavebeen shown toincrease.15 Worsening of symptoms could
there-forealsobeattributedtothenormalcourseofdiseaseafter childbirth.
Stress is a well-known risk factor for the onset and relapseofMS.20Therefore,strategiestodecrease
perioper-ativestresshelptopreventpostoperativedeteriorationof symptoms.OptimizingpainmanagementbyEAispotentially beneficialinthepostoperativecourseofMS;intwocases, pre-existingneurologicaldeficitsimprovedafterEA.21,22
Insomeclinicalrecommendations,epiduralispreferred to spinal analgesia in patients withMS.9,12 Based on two
independent prospective studies, EA in obstetric patients showed no negative outcome.15---17 For spinal anesthesia,
onlycasereportsexist,andthesedonotshowaclear rela-tionbetweencauseandeffect.Theintrathecalapplication ofhigherconcentrationsoflocalanestheticscomparedwith EAisdiscussedaspossiblyincreasingtheriskofrelapse.6,13
However,thereisneitheraclearhypothesisofthepotential mechanismbehindthisassumptionnorclinicaldatato sup-portthisassumption.Ontheotherhand,spinalanesthesiais performedfrequentlyinpatientswithMS.7Onemayargue
thatthenumberofreportedcaseswithadeteriorated post-operativecourseonlyreflectsamarginalrisk,ifany,forthe individualpatient.
For CSE and caudal analgesia, we found only one and threecases,respectively.Thelownumberiseasilyexplained
ascaudalanalgesia isa rarely usedtechniqueinadults.23
CSE,ontheother hand,isoftenomittedasmostpatients withMSarescheduledfor electivesurgeryordeliveryand soearlyplacementofEA(ifany)isattempted.
Ourstudyis limitedasasystematicreviewcannot ulti-matelyprovethesafetyofaprocedure,especiallywhenthe results mainly include case reports and series.Individual case cannot prove or refute a cause and effect relation-ship.Quantifyingthenumberofcases,however,permitsthe evaluationofthescientificbasisofsomeconcerns.
Anotherlimitationisthatwe cannotprovidedetails on the material and medication used in the reported cases, astheseinformationwerenotreportedinthemajority of publications.
Future approaches for elucidating this problem may involve prospectively collected, large, multinational databasesinwhichpostoperative coursesofpatients with MSarecollectedandriskfactorsmaybeidentified.
Conclusion
Inconclusion,itisimpossibletocompletelyruleout poten-tialrisksfromanyprocedure.Currentclinicalevidencedoes notsupportthetheorythatcentralneuraxialanalgesia neg-ativelyaffectsthecourseofMS.Therefore,weregardthis procedureasaviableoptionfordiscussionwiththepatient.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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