Neuraxial anesthesia in patients with multiple sclerosis – a systematic review

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REVISTA

BRASILEIRA

DE

ANESTESIOLOGIA

PublicaçãoOﬁcialdaSociedadeBrasileiradeAnestesiologia

www.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,DepartmentofAnaesthesiologyandIntensiveCareMedicine,Graz,Austria

Received4March2016;accepted6September2016

KEYWORDS

Multiplesclerosis; Neuromyelitisoptica; Neuroaxialanesthesia

Abstract

Backgroundandobjectives: Currentguidelinesforneuraxialanalgesiainpatientswithmultiple sclerosisareambiguousandoffertheclinicianonlyalimitedbasisfordecisionmaking.This sys-tematicreviewexaminesthenumberofcasesinwhichmultiplesclerosishasbeenexacerbated aftercentralneuraxialanalgesiainordertorationallyevaluatethesafetyoftheseprocedures. Methods:A systematicliterature search with the keywords ‘‘anesthesia or analgesia’’ and ‘‘epidural, peridural, caudal, spinal, subarachnoid or intrathecal’’ in combination with ‘‘multiplesclerosis’’wasperformedinthedatabasesPubMedandEMBASE,lookingforclinical dataontheeffectofcentralneuraxialanalgesiaonthecourseofmultiplesclerosis.

Resultsandconclusions:Overaperiodof65years,oursearchresultedin37 reportswitha totalof231patients.In10patientsmultiplesclerosiswasworsenedandninemultiplesclerosis orneuromyelitisopticawasﬁrstdiagnosedinatimelycontextwithcentralneuraxialanalgesia. Noneofthecasesshowedaclearrelationbetweencauseandeffect.Currentclinicalevidence doesnotsupportthetheorythatcentralneuraxialanalgesianegativelyaffectsthecourseof multiplesclerosis.

PALAVRAS-CHAVE

Esclerosemúltipla; Neuromieliteóptica; Anestesianeuroaxial

Anestesianeuraxialempacientescomesclerosemúltipla---umarevisãosistemática

Resumo

Justiﬁcativaeobjetivos: Asdiretrizesatuaisparaanalgesianeuraxialempacientescom escle-rosemúltipla(EM)sãoambíguaseoferecemaoclínicoapenasumabaselimitadaparaatomada dedecisão.EstarevisãosistemáticaexaminaonúmerodecasosnosquaisaEMfoiexacerbada

∗_{Corresponding}_author.

E-mail:[email protected](H.Bornemann-Cimenti).

http://dx.doi.org/10.1016/j.bjane.2016.09.001

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gesia’’e‘‘epidural,peridural,caudal,espinhal,subaracnoideoouintratecal’’emcombinac¸ão com‘‘multiplesclerosis’’foirealizadanasbasesdedadosPubMedeEMBASEàprocuradedados clínicossobreaefeitodaanalgesianeuraxialcentralsobreocursodaesclerosemúltipla. Resultadoseconclusões: Duranteumperíodode65anos,nossabuscaresultouem37relatos comumtotalde231pacientes.Em10pacientes,aesclerosemúltiplafoiagravadae,emnove pacientes,aesclerosemúltiplaouneuromieliteópticafoidiagnosticadapelaprimeiravezem momentoconcomitantecomaanalgesianeuraxialcentral.Nenhumdoscasosapresentouuma clararelac¸ão entrecausaeefeito.Aevidência clínicaatualnão sustentaateoriadequea analgesianeuraxialcentralafetanegativamenteocursodaesclerosemúltipla.

Introduction

Multiplesclerosis (MS) is a chronic autoimmune condition ofthecentralnervoussystem(CNS),withdiffuseandfocal areasofinﬂammation,demyelination,gliosis,andneuronal injury.The exact mechanismsbehind thisdisease arenot 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 localanesthetics could precipi-tateorexacerbatethisdisease.3_As_a_consequence,_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 ischemia secondary to local anesthetics oradditives.OligopeptideswithNa-channelblocking activ-ities have recently been found in cerebrospinal ﬂuid of patients suffering from MS, leading to the assumption of increasedvulnerabilitytolocalanesthetics.6_Despite_many considerations, no commonly accepted theory exists on theparticularmechanismsofhowneuraxialanalgesiamay alterthe course of MS; italso remains unclear if neurax-ialtechniques areactually harmful. Nevertheless,several anesthesiologistsstillfearthepossibleexacerbationof pre-existingdeﬁcitsandarereluctanttoofferspinalorepidural analgesiatopatientswithMS.7

Current guidelines for central neuraxial analgesia in patientswithMSareambiguousandoffertheclinicianonly alimitedbasis for decision-making.The AmericanSociety ofRegional Anesthesiaand PainMedicine (ASRA) statesin its2008practiceadvisorythat‘‘theexistingliterature nei-therconﬁrmsnorrefutesthesafetyofneuraxialanesthesia in patients withCNS or peripheral nervous system neuro-logicdisorders,nordoesitdeﬁnitivelyaddresstherelative safetyofspinalvs.epiduralanesthesia(EA)oranalgesiain thesepatients’’.8_A_consensus_statement_from₂₀₁₄ recom-mendsthattheindicationofspinalanesthesiainpregnant patients with MS should be discussed on a case-by-case basis.9

In the absence of sufﬁcient high-level, large-scale, prospective studies, all theseguidelines refer tocases of deterioration of MS after neuraxial anesthesia. However, untilnowtheexactnumberof reportedcaseshasnot yet beeninvestigated.Thissystematicreviewaimstodetermine thenumberofcasesinwhichMShasbeenexacerbatedafter central neuraxialanalgesiain ordertorationallyevaluate thesafetyoftheseprocedures.

Methods

Asystematicliteraturesearchforarticlesreportingonthe clinicalcourseofMSafterepidural,spinal,combinedspinal and epidural or caudal analgesia in human subjects was carried out using the databasesPubMed and EMBASE. We included allkindsofarticlesprovidingclinicaldata, 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 Cochrane databaseand theclinicaltrials.gov study registry were searched to identify further ongoing or planned trials. As the distinctionbetween neuromyeli-tisopticaandMS wasunclear untilafew yearsago,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 reviews werescreened further for additional publications that were not detected by ourprimary literature search. ThemanuscriptwaspreparedaccordingtothePRISMA state-ment(PreferredReportingItemsforSystematicReviewsand Meta-Analyses).11

Results

The last literature search was conducted in May 2015. In total, 248 primary hits were identiﬁed. Thirty-seven

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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 ﬁrstdiagnosed afterspinal anesthesia, andin threecases neuromyelitis optica,a demyelinating disease that shares manysimilarities withMS, wasﬁrstdiagnosedafterspinal analgesia. In two cases, symptoms of MS improved after EA.

Discussion

In clinical practice,the patient with MS 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.12,13_On_the_other_hand,_neuraxial_analgesia inpatientswithMSremainscontroversial.Asguidelinesare ambiguousor recommendacase-by-casedecision,8,9_their clinical applicabilityis limited. The question, ifneuraxial techniquesaresafeinpatientssuffering fromMS,hasnot onlya medicalbutalsoa juridical dimension.Ina recent legalcaseinItaly,thedevelopmentofopticalneuritiswas

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Author (reference) Patients characteristics Typeof anesthesia

Typeofsurgery Complication Details

Fleiss2 ₃₆_years,_male _Spinal _Orthopedic _Yes _Multiple_sclerosis_ﬁrst

diagnosedafterspinal anesthesia

Warren24 ₂₁_years,_female _EA _Vaginal_delivery,

CS

Yes Hypesthesiaonthethigh, restitutionafter7days(1◦ delivery)and7weeks(2◦ delivery)

Levesque25 ₃₃_years,_female _Spinal _Plastic_surgery _Yes _Multiple_sclerosis_ﬁrst

Hosseini26 ₂₃_years,_female _Spinal _Hallux_valgus _Yes _{Neuromyelitis}_optica_ﬁrst

Lopez Ariztegui27

32years,female EA Vaginaldelivery Yes Acutetransversedisorderﬁrst diagnosedtwoweeksafterPDA Facco14 ₃₄_years,_female _Spinal _CS _Yes _{Neuromyelitis}_optica₆_months

afterspinal;conusmedullaris lesionwhilepuncturing;ﬁve yearsafterbilateralblindness, severetetraparesis,

neurogenicbladder Buraga28 ₄₂_years_old_female _Spinal _Urological _Yes _Multiple_sclerosis_ﬁrst

Berger29 ₅₃_years,_male _Spinal _{Urological/plastic}

surgery

No Leigh30 ₄₃_years,_male _Spinal _Laparotomy _No

Wang31 ₄₅_years,_female _EA _CS _No _Preexisting_diseases:_von

HippleLindaudisease Kohler32 ₂₉_years,_female _EA _Vaginal_delivery _No

Gunaydin21 ₂₉_years,_female _EA _CS _No _Improvement_of_neurological

symptomspostpartum Vadalouca33 ₅₆_years,_female _CSE _Hysterectomy _No

Marshak34 ₆₁_years,_female _EA _Thoracotomy _No

Barbosa35 ₃₂_years,_female _Spinal _CS _No

MayorgaBuiza36 ₃₇_years,_female _EA _CS _No

Martucci37 ₂₉_years,_female _Spinal _CS _No

Tympa38 ₄₅_years,_female _EA _Hysterectomy _No _Other_pre-existing_disease:

ischemicbraininfarct, antiphospholipidsyndrome, and_{␤-heterozygous} thalassemia

Shanmugam39 ₆₈_years,_female _EA _{Oesophagectomy} _No _{Postoperative}_improvement_of

lowerlimbmobilityand strength

Patel40 ₄₆_years,_female _EA _Cystectomy _No _Intrathecal_baclofen_pump

implanted Oouchi41 ₂₉_years,_female _Spinal _CS _No

Sethi42 ₃₂_years,_female _EA _CS _No

Bettencourt43 ₃₆_years,_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 withMS duringpregnancy and12 monthsafter delivery.15 Forty-two parturients had epidural analgesia for delivery.

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Table2 Caseseriesandstudiesofpatientswithmultiplesclerosisundergoingneuroaxialanalgesia. Author

(reference)

Studytype n Typeof anesthesia

Typeof surgery

Checkup Complication Artder Komplikation Bamford44 _Case_series ₈_patients

12interventions Spinal(9) Vaginal delivery, minor surgical interventions

--- Yes 1patientwith legweakness

Caudal(3) Stenuit45 _Case_series ₅ _Spinal _CS,

urological and orthopedica --- yes MSﬁrst diagnosedafter spinalanesthesia in2patients,1 patientwith exacerbationof symptomsfor1 year

Bouchard46 _Case_series ₉_patients

14interventions

Spinal Urological andplastic surgery

--- Yes 1patientwith temporary exacerbation,no further

descriptionof symptoms Bader47 _Case_series ₂₀_patients

32pregnancies

EA(14) CS,vaginal delivery

3month Yes 5patientswith relapse,no further descriptionof symptoms Dalmas48 _Case_series 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 _Case_series ₅ _EA₍₃₎ _Urological

andplastic surgery --- No Spinal(2) Vukosic16 _Prospective cohortstudy (PRIMSStudy follow-up) 42 EA Vaginal delivery,CS 2years No

Hebl6 _Case_series ₃₅ _EA₍₁₈₎ _Vaginal

delivery mixed surgery

46±38days No

Spinal(17)

May50 _Case_series ₅ _EA₍₄₎ _Vaginal

delivery,CS --- No Spinal(1) Pastó17 _Prospective cohortstudy 65 EA Vaginal delivery,CS 6month No

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severityofworseningofdisabilitieswasfound.Inthe follow-upanalysis2yearslater,theresultswereconﬁremd.16

In2012,Pastòetal.presentedtheirprospectivecohort studyfromtheItalianMSStudyGroup.17_They_collected_data fromthegestationalperioduntil12monthsafterdelivery from415paturientswithMS. Although65 patients under-wentepiduralanalgesia,thisdidnotaffecttherelapserate orthetime-dependentproﬁleofrelapse.

Thisistheﬁrstsystematicreviewwhichaimstoinclude allreportedcasesincurrentliterature.Althoughall avail-ableguidelinesandrecommendationsrefertocertaincases, theexactnumberwasnotyetinvestigated.Wespeciﬁcally decidedtoincludethesecasesinoursystematicreviewto provideanassessmentofthefrequencyofnoticeable post-operativecourses.TakingthehighprevalenceofMSbetween 20and200/100,00018 _into_{consideration,}_the_total_number ofreportedcasesinwhichsymptomsdeterioratedafter neu-raxialanalgesiaseemsextremelylow.However,thisnumber maybe highly biased,as the majority of cases are likely tobeunreported.Evenso,worseningofMSafterneuraxial analgesiacanbeconsideredarareevent.

Over a period of 65 years, our systematic literature searchresulted in10 patients,in whomMSwasworsened andnineinwhomMSorneuromyelitisopticawasﬁrst diag-nosedinatimelycontextwithcentralneuraxialanalgesia. However,timelycorrelationdoesnotimplycausality.

The majorityofcasesweredescribed inobstetric 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 aremorecommonlyappliedinpatientswithMScompared 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.20_Therefore,_strategies_to_decrease perioper-ativestresshelptopreventpostoperativedeteriorationof symptoms.OptimizingpainmanagementbyEAispotentially beneﬁcialinthepostoperativecourseofMS;intwocases, pre-existingneurologicaldeﬁcitsimprovedafterEA.21,22

Insomeclinicalrecommendations,epiduralispreferred tospinal analgesia in patients with MS.9,12 _Based _on _two independentprospective 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.7_One_may_argue thatthenumberofreportedcaseswithadeteriorated post-operativecourseonlyreﬂectsamarginalrisk,ifany,forthe individualpatient.

For CSE and caudal analgesia, we found only one and threecases,respectively.Thelownumberiseasilyexplained

withMSarescheduledforelective surgeryor deliveryand soearlyplacementofEA(ifany)isattempted.

Ourstudyislimitedasasystematicreview cannot ulti-matelyprovethesafetyofaprocedure,especiallywhenthe results mainly include case reports and series. Individual case cannot prove or refutea cause and effect relation-ship.Quantifyingthenumberofcases,however,permitsthe evaluationofthescientiﬁcbasisofsomeconcerns.

Anotherlimitationis thatwecannotprovide detailson the material and medication used in the reported cases, astheseinformationwerenotreportedinthemajority of publications.

Future approaches for elucidating this problem may involve prospectively collected, large, multinational databasesin whichpostoperativecoursesof patientswith MSarecollectedandriskfactorsmaybeidentiﬁed.

Conclusion

Inconclusion,itisimpossibletocompletelyruleout poten-tialrisksfromanyprocedure.Currentclinicalevidencedoes notsupportthetheorythatcentralneuraxialanalgesia neg-ativelyaffectsthecourseofMS.Therefore,weregardthis procedureasaviableoptionfordiscussionwiththepatient.

Conﬂicts

of

interest

Theauthorsdeclarenoconﬂictsofinterest.

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