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NEUROLOGÍA

www.elsevier.es/neurologia

REVIEW ARTICLE

Systematic review of the safety and effectiveness of peripheral neurostimulation of the sphenopalatine ganglion for the treatment of refractory chronic cluster headache

L.M. Sánchez-Gómez

a,b,c,∗

, M. Polo-deSantos

a

, A. Pinel-González

d

, C. Oreja-Guevara

e

, S. Luengo-Matos

a

aAgenciadeEvaluacióndeTecnologíasSanitarias(AETS),InstitutodeSaludCarlosIII(ISCIII),MinisteriodeEconomía,Industriay Competitividad,Madrid,Spain

bInstitutodeInvestigaciónSanitaria,HospitalUniversitariodeLaPrincesa(IP),Madrid,Spain

cReddeInvestigaciónenServiciosdeSaludenEnfermedadesCrónicas(REDISSEC),Spain

dServiciodeNeurología,HospitalUniversitariodeGetafe,Madrid,Spain

eServiciodeNeurología,HospitalUniversitarioClínicoSanCarlos,Madrid,Spain

Received6July2017;accepted7November2017

KEYWORDS Neurostimulation;

Sphenopalatine ganglion;

Clusterheadache;

Systematicreview

Abstract

Introduction: Thisstudyaimedtoassessthesafetyandeffectivenessofperipheralneurostim- ulation ofthesphenopalatineganglion (SPG)inthe treatmentofrefractorychroniccluster headache.

Development: Variousmedicaldatabaseswereusedtoperformasystematicreviewofthesci- entificliterature.Thesearchforarticlescontinueduntil31October2016,andincludedclinical trials, systematicreviews and/ormeta-analyses,health technologyassessmentreports,and clinicalpracticeguidelinesthatincludedmeasurementsofefficiency/effectivenessoradverse effectsassociatedwiththetreatment.Thereviewexcludedcohortstudies,case—controlstud- ies,caseseries,literaturereviews,letterstotheeditor,opinionpieces,editorials,andstudies thathadbeenduplicatedoroutdatedbylaterpublicationsfromthesameinstitution.Regarding effectiveness,we foundthatSPGstimulationhadpositiveresultsforpainrelief,attackfre- quency,medicationuse,andpatients’qualityoflife.Intheresultsregardingsafety,wefound asignificantnumberofadverseeventsinthefirst30daysfollowingtheintervention.Removal ofthedevicewasnecessaryinsomepatients.Littlefollow-updata,andnolong-termdata,is available.

Please citethisarticleas:Sánchez-Gómez LM,Polo-deSantos M,Pinel-González A, Oreja-Guevara C,Luengo-Matos S.Revisión sistemática sobre la eficacia y seguridad de los neuroestimu- ladoresperiféricosdelganglioesfenopalatinoparaeltratamiento de la cefalea crónica en racimos refractaria. Neurología.

2021;36:440—450.

Correspondingauthor.

E-mailaddress:luism.sanchez@isciii.es(L.M.Sánchez-Gómez).

2173-5808/© 2017SociedadEspa˜noladeNeurolog´ıa.Published byElsevierEspa˜na,S.L.U.Thisis anopenaccess articleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Conclusions: Theseresultsarepromising,despitethelimitedevidenceavailable.Weconsider itessentialforresearchtocontinueintothesafetyandefficacyofSPGstimulationforpatients withrefractorychronicclusterheadache.Incaseswherethisinterventionmaybeindicated, treatmentshouldbecloselymonitored.

©2017SociedadEspa˜noladeNeurolog´ıa.PublishedbyElsevierEspa˜na,S.L.U.Thisisanopen accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/

4.0/).

PALABRASCLAVE Neuroestimulación;

Ganglio esfenopalatino;

Cefaleaenracimos;

Revisiónsistemática

Revisiónsistemáticasobrelaeficaciayseguridaddelosneuroestimuladores periféricosdelganglioesfenopalatinoparaeltratamientodelacefaleacrónicaen racimosrefractaria

Resumen

Introducción:Elobjetivoes evaluarla eficaciay seguridaddelosneuroestimuladores per- iféricosdelganglioesfenopalatino(GEP)paraeltratamientodelacefaleaenracimoscrónica refractariaaltratamiento.

Desarrollo: Revisiónsistemáticadelaliteraturacientífica.Seidentificaronestudiosmediante unabúsquedaendiferentesbasesdedatos.Lasestrategias debúsquedaserealizaronhasta el31deoctubrede2016,incluyendoensayosclínicos,revisionessistemáticasometaanálisis, informesdeevaluación detecnologías sanitarias y guíasde prácticaclínica querecogieran medidasdeeficacia/efectividadoefectosadversosasociadosal tratamiento.Seexcluyeron estudiosdecohortes,casosycontroles,seriesdecasos,revisionesnarrativas,cartasaldirector, artículosdeopinión,editorialesyestudiosduplicadosodesfasadosporestudiosposterioresde lamismainstitución.Respectoalaeficacia, losresultadossonpositivostraslaestimulación delGEP enrelaciónconelaliviodedolor,elnúmerodeepisodios,elusodela medicación olacalidaddevidadelpaciente.Enrelaciónconlaseguridad,hayunnúmeroimportantede efectosadversosenlosprimeros30díasdelaintervenciónyenalgunospacientesfuenecesaria laretiradadeldispositivo.Losdatosdeseguimientosonacortoplazoyescasos.

Conclusiones: Losresultados resultan prometedoresapesardequela evidenciadisponible eslimitada. Consideramos fundamentalcontinuar con la investigación sobre la seguridady eficaciadelosneuroestimuladoresdelGEPenlacefaleaenracimoscrónica.Enaquelloscasos enquepuedaestarindicadalaintervención,eltratamientodeberíarealizarsesupervisadoen unestudiodemonitorización.

©2017 SociedadEspa˜nola de Neurolog´ıa.Publicado por Elsevier Espa˜na, S.L.U.Este es un art´ıculoOpenAccessbajolalicenciaCCBY-NC-ND(http://creativecommons.org/licenses/by- nc-nd/4.0/).

Introduction

Clusterheadache(CH)isaprimaryheadacheofthegroup oftrigeminalautonomiccephalalgias.Itischaracterisedby episodesofsevere,unilateralperiocularpaincombinedwith ipsilateral vegetative symptoms, including ptosis, myosis, sweating,tearing,rhinorrhoea,palpebraloedema,andrest- lessnessoragitation.CHcanbediagnosedintheabsenceof ipsilateralvegetative symptoms providedthat thepatient presents restlessness or agitation. Attacks may last 15- 180minutesandpresent 2-8times perday,predominantly during thenight.CH maybe episodic, withattacksalter- nating with pain-freeperiods lasting months toyears; or chronic,withattacksoccurringforoneyearorlongerwith- outremission,orwithremissionperiodslastinglessthana month.1

According totheliterature,theincidenceofCHranges from2.5to9.8casesper100000person-years;prevalence ranges from 53 to 381 cases per 100000 population. CH seems to be more frequent in men, with male-to-female ratiosrangingfrom7:1to3:1.2—7

Treatment focuses on eliminating the trigger factors of headache attacks, when applicable. Pharmacological treatmentincludessymptomaticmedications,aimedatcon- trollingacuteepisodes(sumatriptanisthedrugofchoice), and prophylactic medications. The prophylactic approach includes transitional treatment (with drugs intended to interrupttheactiveepisode,suchassteroids,orwithoccip- ital nerve block) and preventive maintenance treatment (with drugs consolidating remission and preventing early relapses;e.g.,verapamil).Preventivetreatmentshouldbe administeredduringtheattackandprogressivelywithdrawn afteramonthwithoutepisodes.2,8,9

Refractory patients may benefit from trigeminal nerve section surgery, which is associated with more adverse reactions and complications. Other alternatives, such as sphenopalatine ganglion neurostimulation, have recently been developed. The sphenopalatineganglion is an ovoid collectionofparasympatheticcellswithnosensoryfunction.

Ithasmultipleconnectionswithfacialandtrigeminalnerve branchesand isthought tobeinvolved in thepathogene- sisandmaintenance ofatypical facialpainand unilateral 441

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headache;thissupportsitsroleasa potentialtherapeutic target. Sphenopalatine ganglion stimulation may be per- formed withamicrostimulator, which isimplanted witha minimallyinvasiveprocedure.Themicrostimulatorispow- eredbyaremotecontroller,whichpatientsuseasrequired;

physicians canadjust parametersbasedon each patient’s needs.8,9

This study evaluates the safety and efficacy of sphenopalatine ganglion stimulation for the treatment of refractorychronicCH.

Development

We conducted a systematic literature review on several databases (Fig. 1). The search strategy used both free text searchingand controlled vocabulary,witheach term adapted tothe thesaurususedfor each database(Fig.1).

WealsosearchedtheInternetandthewebsitesofnational and international health technology assessment agencies for health technology reports. Furthermore, we manually reviewedthebibliographic referencesofthestudiesgath- eredtoidentifyanyarticlesnotreturnedbythedatabase search.Wegatheredallstudiespublishedbefore31October 2016,regardlessofarticlelengthorlanguage.

We included randomised clinical trials, systematic reviews and meta-analyses, health technology reports, and clinical practice guidelines for the use of peripheral sphenopalatineganglionstimulation forrefractorychronic CH,providingdata onthe efficacyor effectivenessof the intervention:percentageofpatientsreportingreducedpain after the intervention, percentage of patients remaining completely pain-free after the intervention, decrease in attackfrequency,qualityoflifeaccordingtotheHeadache ImpactTest-6(HIT-6)orthe36-ItemShortFormHealthSur- vey(SF-36),andadversereactionstotreatment.

Weexcludedothertypesofstudies,letterstotheeditor, opinionarticles,editorials,duplicatestudies,andoutdated studies.

Articlesweregathered,selected,andreviewedby2inde- pendentreviewers.The reviewersfirstreadthe titlesand abstractsofthearticlesgathered,thenreadthefulltextsof thoseinitiallymeetingtheinclusioncriteria.Disagreements were resolved by consensus with another memberof the researchgroup.Wecreatedatablewithinformationabout

thestudiesincludedandexcluded,specifyingthereasonfor exclusion.

WeusedtheAssessmentofMultipleSystematicReviews (AMSTAR) tool to evaluate the methodological quality of systematicreviews,andthe Cochranerisk-of-bias toolfor randomisedtrials.

Twoindependentreviewersgatheredthefollowingdata:

bibliographical data, study characteristics, patient char- acteristics, characteristics of the intervention, outcome measuresrelatedtotreatment efficacy/effectiveness,and safetyoftheprocedure.

Studyselection

We identified a total of 100 articles (3 were duplicate studies).Afterreadingthetitles andabstracts,62studies wereexcludedfornotmeetingtheinclusioncriteria;29of the35 remainingstudieswere excluded afterreadingthe fulltext(Fig.2)10—38:9narrativereviews,11,13,15,16,20—22,26,29

8 review articles not providing data on the variables studied,17—19,24,25,27,28,31 8 abstracts,14,32—38 3 studies not focusingonrefractorychronicclusterheadache,10,12,30and onestudynotevaluatingperipheralneurostimulation.23We finally reviewed 6 studies: a health technology report by theAustrianhealth technologyassessmentagency,follow- ingasystematicreviewmethodology39;areportissuedby theUnitedKingdom NationalInstituteforHealthandCare Excellence(NICE)40;aclinicaltrial(PathwayCH-1trial)reg- isteredonclinicaltrials.org(FAP01255813)41;2studies42,43 including24-month follow-up data fromthe Pathway CH- 1trial,includedonclinicaltrials.org(FAP01616511);anda post-marketingstudy44 registeredonclinicaltrials.org(FAP 01677026) and including patients from the Pathway CH-1 trial.AllthesestudieswerefundedbyAutonomicTechnolo- gies,Inc.,whichmanufacturestheneurostimulator.

Efficacy

BoththeNICEguidelines40andtheAustrianhealthtechnol- ogyreport39arebasedondatafromthePathwayCH-1trial,41 which included 32 participants randomly receiving either full,sub-perception,orshamstimulationofthesphenopala- tineganglion.Thesphenopalatineganglionwasstimulated

Database Search strategy No. references

PUBMED (Neurostimulation[All Fields]) AND ("cluster headache"[MeSH Terms] OR ("cluster"[All Field AND "headache"[All Fields]) OR "cluste headache"[All Fields])

81

NICE Neurostimulation AND Cluster Headache 4

CRD (Neurostimulation) AND (Cluster Headache) 3

COCHRANE PLUS #1 (Neurostimulation):TA

#2 Cluster headache: TA

#1 AND #2

209 170 5 CLINICALTRIALS.GOV Neurostimulation AND Cluster Headache 7

Figure1 Databasesandsearchstrategies.

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17 narrative reviews or reviews providing no data 97: title and abstract

35: full text

6 studies included

62 do not meet inclusion criteria

congress abstracts

3 do not focus on refractory chronic headache

1 provides no data on neurostimulators

Figure2 Flowchartshowingthearticleselectionprocess.

with the ATI NeurostimulationSystem, also knownas the PulsanteTMSPGMicrostimulator.45

ThePathwayCH-1trial41definedrefractorychronicclus- terheadacheasatleast4episodesofsevereheadacheper week,affectingqualityoflifeandnotrespondingtoatleast 3 consecutive preventive treatments administered at the maximum tolerable dose. The study comprised 5 stages:

pre-implantation baseline,post-implantation stabilisation, therapy titration period (in which electrodes and stim- ulation parameters were adjusted), experimental period (randomisationtothefull,sub-perception,andshamstimu- lationgroups),andanopen-labelperiodwhereallpatients receivedfullstimulation.

Atotalof28patientscontinuedtotheendoftheexperi- mentalperiod.Thestudyreportspainrelief15minutesafter stimulationin67%ofepisodestreatedwithfullstimulation vs 7%of episodestreatedwithsub-perception stimulation and 7%of thosetreated withsham stimulation(P<.0001) (Table 1). Complete resolution of pain at 15minutes was observed in 34% of episodestreated with full stimulation vs2%ofthosetreatedwithsub-perceptionstimulationand 2%ofthosetreatedwithshamstimulation(P<.0001).Pain decreased at 30, 60, and 90 minutes of neurostimulation in 56%, 61%, and 60%, respectively, of episodes treated withfullstimulation,vs8%,12%,and13%ofthosetreated withshamstimulation(P<.0001).Attackfrequencyin the 28patientscompletingtheexperimentalperioddecreased fromameanof17.4to12.5episodesper week(P=.005).

Sixty-eightpercentofpatientsrespondedtoneurostimula- tion:25% presented painreliefin ≥50% of episodes,36%

presenteda≥50%decreaseinattackfrequency,and7%pre- sentedboth.Medicationwasadministeredduringtheacute phasein31%ofepisodestreatedwithfullstimulationvs78%

ofthosetreatedwithsub-perceptionstimulationand77%of thosetreatedwithshamstimulation(P<.0001).HIT-6scores decreased by a mean (SD) of 6.8 (10.2) points between

baseline and the experimental period (P=.002). Quality of life (SF-36 scores) improved in 75% of patients: physi- calfunction in21%,intellectualfunction in29%,andboth dimensionsin25%.

Two studies, including 33 patients, published the 24- month follow-up results of the Pathway CH-1 trial.42,43 The first study monitored 10 patients presenting pain remissionforatleastonemonthaftersphenopalatinegan- glion stimulation, reporting the following results: 30% of patients presented at least one episode of pain remis- sion lastinga minimum of one month; the firstremission period started a mean of 134 (86) days after the proce- dure (range, 21-272); the longest remission period lasted a mean of 149 (97) days (range, 62-322); and 60% of patientspresenting painremissionhad reducedtheircon- sumption of preventive drugs at 24 months (Table 1).42 HIT-6scoreswerelowerafterpainremissionthanatbase- line: 67.7 (6.0) at baseline vs 55.2 (11.4) afterremission (P=.0118)and60.0(8.5)at24months(P=.1997).Improve- mentsremained24 monthspost-implantation;allpatients presenting pain remission were satisfied with the proce- dure.

ThestudybyJürgensetal.43gathered24-monthfollow- up data from 33 patients (Table 2) reporting complete resolution of pain in 50% of episodes. The benefits of treatment were still observable at 24 months in 64% of patients. Mean attack frequency in this sample did not changebetweenbaselineandfollow-up(17[3]vs17[15]).

At24 months,45%of patientswere acuterespondersand 35%werefrequencyresponders;atotalof61%ofpatients were responders. HIT-6 scores decreased by 4.8 points compared to baseline in the 29 patients completing the questionnaire(P=.0048).Treatment wasfound tobeuse- fulby69%ofpatients;duringthe24-monthperiod,33%of patientsreportedCHepisodescontralateraltomicrostimu- latorimplantation.

443

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Table1 EfficacyresultsfromthePathwayCH-1trialand24-monthfollow-updata.

PathwayCH-1trial PathwayCH-1trial24-monthfollow-updata(nocontrolgroup) Schoenenetal.41(2013) Barloeseetal.42(2016)

(providesdatafrompatients reportingpainresolution)

Jürgensetal.43(2017)

No.patients Baseline:32

Experimentalperiod:28

n=10(thestudyfollowsup patientswithpainremission lastingatleastonemonth;

n=10[30%])

n=33(follow-updatafrom31 patients)

Painreliefat15minutes 127/190(67%)FSvs14/184 (7%)SPS(P<.0001) 127/190(67%)FSvs15/192 (7%)SS(P<.0001)

14/184(7%)SPSvs7.4%SS (P=.96)

— —

Pain-freeat15minutes 65/190(34%)FSvs3/184(2%) SPS(P<.0001)

65/190(34%)FSvs3/192(2%) SS(P<.0001)

3/184(2%)SPSvs3/192(2%)SS (P<.97)

— Pain-freeduringfollow-up:50%

ofepisodestreated

Painreliefat30minutes (%episodes)

56%FSvs8%SS(P<.0001) — —

Painreliefat60minutes (%episodes)

61%FSvs12%SS(P<.0001) — —

Painreliefat90minutes (%episodes)

60%FSvs13%SS(P<.0001) — —

Medicationuse(%

episodes)

31%FSvs78%SPS(P<.0001) 31%FSvs77%SS(P<.0001) 44%SSvs78%SPS(P<.68)

Improvementsin4patients (40%)afterepisoderemission andin6(60%)at24months

21/33patients(64%)reduced orsuspendedmedicationuse at24monthsoffollow-up.

Frequency(meanno.

episodes/week)

Baseline:17.4(range,4—70);

experimentalperiod:12.5 (range,0—96)(P=.005)

Baseline:17.3(SD:13.3);

treatmentonset:16.4(SD:

16.8)(P=.7090)

Nochanges.Baseline:17(SD:

3);24months:17(SD:15)

Typeofpatients 19/28patients(68%) respondedtotreatment:

-Acuteresponders:7(25%) -Frequentresponders:10 (36%)

-Therapeuticresponders:2 (7%)

— -Acuteresponders:15/33

(45%).Treatmentwaseffective in78%ofthisgroup.

-Frequentresponders:11/31 (35%)

-Therapeuticresponders:

20/33(61%) HIT-6questionnaire Differencebetweenbaseline

andexperimentalperiod:−6.8 points(SD:10.2)(P=.002);

18/28patients(64%)showeda meandecreaseof2.3pointson theHIT-6questionnaire.

HIT-6scoreschangedfrom67.7 (SD:6.0;range,58-76)at baselineto55.2(SD:11.4;

range,40-73)afterpain remissionand60.0(SD:8.5)at 24months(P=.1997).

HIT-6scoresdecreasedby4.8 pointsat24monthscompared tobaselinein29patients (P=.0048)(4patientswere losttofollow-up).

SF-36scale Improvementsin21/28 patients(75%):

-6(21%)inphysicalfunction -8(29%)inintellectual function

-7(25%)inboth

— —

Patientsatisfaction — Allpatients(100%) Treatmentwasconsidered

usefulby69%(18/26)of responders.

Contralateralpain — — 11/33patients(33%)

FS:fullstimulation;HIT-6:HeadacheImpactTest-6;SF-36:36-ItemShortFormHealthSurvey;SPS:sub-perceptionstimulation;SS:sham stimulation.

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Table2 Adversereactionsfromthetimeofdeviceimplantationtotheendoftheexperimentalperiod(PathwayCH-1trial).

Author(year) Schoenenetal.41(2013)

Adversereactions Within30daysofimplantation Morethan30daysafterimplantation

Totalno.adversereactions 92in32patients 36in32patients

No.adversereactions (%),no.patients(%),no.

casesresolved(%) Leadadjustment/device

removal

— 5(14),5(16),5(100)

Leadmigration/deviceremoval 1(1),1(3),1(100) —

Sensoryalterations(including localisedsensoryloss, hypoaesthesia,paraesthesia, dysaesthesia,andallodynia)

32(35),26(81),15(58) 6(17),5(16),3(60)

Pain(face,cheeks,gums, temporomandibularjoint, periorbitalarea,nose,or incisionsite)

15(16),12(38),12(100) 6(17),6(19),3(50)

Headache 4(4),3(9),3(100) 3(8),3(9),1(33)

Toothache/sensitivity 5(5),5(16),4(80) 1(3),1(3),1(100)

Swelling 8(9),7(22),6(86) —

Swellingandpain(after surgery)

3(3),3(9),3(100) —

Trismus 5(5),5(16),4(80) —

Dryeyes 3(3),3(9),1(33) 1(3),1(3),—

Paraesthesia 2(2),2(6),1(50) —

Infection 2(2),2(6),2(100) 1(3),1(3),1(100)

Haematoma 3(3),3(9),3(100) —

Decreaseinautonomic symptoms(nasalcongestion, tearing)duringattacks

1(1),1(3),1(100) —

Facialasymmetry 1(1),1(3),1(100) 2(6),2(6),—

Tearing 1(1),1(3),1(100) —

Conjunctivitis — 2(6),1(3),1(50)

Itching — 1(3),1(3),1(100)

Other 6(7),6(19),4(67) 8(22),8(25),5(63)

Safety

The Pathway CH-1 trial reported 128 different adverse events in 32 patients (Table 2).41 In one patient, the microstimulatorhadtoberemovedwithin30daysofimplan- tation.In16%ofpatients,themicrostimulatorleadlocation had to be adjusted or the device removed between 30 daysand oneyear after implantation.Sensory alterations (including localised sensory loss, hypoaesthesia, paraes- thesia, dysaesthesia,andallodynia)wereobserved in 81%

of patients within 30 days of device implantation; symp- tomsresolvedin58%ofthesepatients.Sixteenpercentof patients reportedsensory alterations 30days toone year post-implantation,withsymptomsresolvingin60%ofthese.

Thirty-eightpercentofpatientsreportedpain(face,cheeks, gums,temporomandibularjoint,periorbitalarea,nose,or incisionsite)within30daysofimplantation.Thestudypro- vides nodata onpain intensity; symptomsresolved in all patients. Nineteen percent of patients reported pain 30 daystooneyear post-implantation;symptoms resolvedin 50%ofcases.Ninepercentofpatientspresentedheadache

otherthanCHwithin30daysoftheprocedure;symptoms resolvedinallcases.Furthermore,9%ofpatientsreported headache other than CH between 30 days and one year afterdevice implantation,withsymptomsresolvingin33%

ofcases.Swellingwasobservedin22%ofpatientswithin30 daysoftheprocedure,resolvingin86%ofcases.

Sixteenpercentofpatientsshowedtrismuswithin30days oftheprocedure;symptomsresolvedin80%ofcases.Nine percentofpatientsreporteddryeyeswithin30daysofthe procedure, withsymptomsresolving in 33%of cases. This symptomwasreportedby 3%ofpatientsbetween 30days and one year post-implantation and did not resolve dur- ing the follow-up period;6% presented mild paraesthesia ofthenasolabial muscleswithin30daysofdeviceimplan- tation,withsymptomsresolvinginhalf. Twopatients(6%) presentedinfectionswithin30daysoftheprocedure;this wassuccessfullymanagedwithantibioticsinbothcases.

Other adverse reactions recorded in the first 30 days after implantation included haematoma, improvement of autonomicsymptomsduringattacks,andfacialasymmetry;

thesesymptomsresolvedinmostpatients.Adversereactions

445

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reportedbetween30daysandoneyearpost-implantation includedconjunctivitisanditching,whichresolvedinmost patients(Table2).

The post-marketing study44 included 99 patients: the 32 patients of the Pathway CH-1 trial,41 11 continued- access Pathway CH-1 patients, and the56 participants in thePathwayR-1trial.Thestudygathereddataonadverse events recorded during the perioperative period(30 days post-implantation)(Table3).Furthermore,itprovidedinfor- mationonfollow-upprocedures:placementofanadditional neurostimulator on the opposite side of the face (n=2), adjustmentofthemicrostimulatorleadlocationwithinthe pterygopalatine fossa tobetter target thesphenopalatine ganglion (n=13), and device removal for other reasons (n=5).

Sensory alterations were the most frequent surgical sequelae(affecting67%ofpatients),with95differentsen- soryalterationsreported;44resolvedinameanof104days (range,12-313). Forty-seven percentof patients reported

pain/swelling,withatotalof79events;63oftheseresolved inameanof68days(range,0-312).Patientsrated92%of eventsasmildormoderatebypatientsthemselvesaccording to their impact on the activities of daily living. Twenty- nineofthe32patientsincluded inthePathwayCH-1trial completed a self-assessment questionnaire at 18 months post-implantation: 86%regarded the effectsof surgery as tolerableand90%indicatedthattheywouldmakethesame decision again to treat CH with sphenopalatine ganglion stimulation.

Biasandmethodologicalquality

AccordingtotheCochranerisk-of-biastoolforrandomised trials, the Pathway CH-1 trial41 had a low risk of bias in somedomains(Table4).However,thestudiesprovidingdata onlong-termfollow-upofthesepatientshadahighriskof biasforlong-termdataandselectivereportingofoutcomes,

Table3 Perioperativeadversereactions(30dayspost-implantation)listedinthepatientregistrypublishedbyAssafetal.44 (n=99).

Adversereactions No.patients(%)

Adjustmentofmicrostimulatorleadlocation 13/99(13)

Deviceremoval 6/99(6)

Deviceplacementontheoppositeside 2/96(2)

No.adversereactions(%) No.patients(%) No.adversereactionsresolved(%)

Totalno.adversereactions 258(100) 80(81) 167(65)

Sensoryalterations 95(37) 66(67) 44(46)

Painorswelling 79(31) 47(47) 63(80)

Trismus 8(3) 8(8) 6(75)

Limitedjawmovement 6(2) 6(6) 6(100)

Dryeyes 5(2) 5(5) 2(40)

Facialasymmetry 5(2) 5(5) 3(60)

Infectiona 5(2) 5(5) 4(80)

Haematoma 4(2) 4(4) 4(100)

Allodynia 3(1) 3(3) 3(100)

Bradycardiaduringsurgery 3(1) 2(2) 3(100)

Paraesthesiab 3(1) 3(3) 1(33)

Sensationofimplant 3(1) 3(3) 2(67)

Tastealterations 3(1) 2(2) 2(67)

Diminishedgagreflex 2(0.8) 2(2) 1(50)

Epistaxis 2(0.8) 2(2) 2(100)

Oculardamagec 2(0.8) 2(2) 2(100)

Nausea 2(0.8) 2(2) 2(100)

Paind 2(0.8) 2(2) 1(50)

Rhinorrhoea 2(0.8) 3(3)e 1(50)

Toothache 2(0.8) 2(2) 2(100)

Tonguebiting 1(0.4) 1(1) 1(100)

Bleeding 1(0.4) 1(1) 1(100)

Bloodinsaliva 1(0.4) 1(1) 0(0)

Difficultyswallowing 1(0.4) 1(1) 0(0)

Other 18(7) 18(18) 11(61)

a Infection:nose/sinusitis;incisionsite:resolvedwithantibiotics;mouth:resolvedwithantibiotics;incisionsite:resultedindevice removal,resolvedwithantibiotics;scaropening:resolvedwithantibiotics.

b Paraesthesia:perioral(mild,resolved);orbicularisoriswithasymmetryofmouth(mild);perioral(mild).

c Oculardamage:cornealscratchduringsurgery;ocularpainuponeyemovement.

d Pain:facial(resolved);jawmovement,post-surgical(resolved).

e Datacollectedfromoriginalstudy.

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Table 4 Cochrane risk-of-bias tool for randomised trials. Short-term (Schoenen et al.41) and 24-month follow-up results (Barloeseetal.,42Jürgensetal.43).

Item Assessment Supportforjudgement

Randomsequencegeneration(selection bias)

Lowrisk Thereisarandomcomponentintheprocessof allocationsequencegeneration.

Page819:‘‘Thestudyemployedarandom insertionofplacebothatused3stimulationdoses randomlyappliedwhentreatmentwasinitiated bythepatient.’’

Allocationconcealment(selectionbias) Lowrisk Participantsandresearcherswereunableto foreseeallocations.

Page819:‘‘Stimulationdosesweredelivered randomly(1:1:1)usingprespecified,

randomisationsequencesthatwereprogrammed intotheremotecontroller.’’

Blindingofparticipantsandpersonnel (performancebias)

Lowrisk Page819:‘‘Patients,investigatorsandthe sponsorblindedtothestimulationdosebeing appliedtoeachCHattack.’’

Blindingofoutcomeassessment(detection bias)

Lowrisk Outcomeassessmentwasnotblinded,but outcomemeasureswerenotlikelytobe influencedbylackofblinding.

Incompleteoutcomedata(attritionbias) (short-termresults)

Lowrisk 28/32patientscompletedtheshort-termperiod (<1year)(10%losttofollow-up)

Incompleteoutcomedata(attritionbias) (long-termresults)

Highrisk Studiesdonotprovide24-monthfollow-updata fromallpatientsincluded(Barloeseetal.,42 Jürgensetal.43)

Selectivereporting(reportingbias) Highrisk Datafromasinglepatientgrouponly(Barloese etal.42)

since they gathereddata from a subgroup of the patient sample.

The Austrian health technology report39 is of good methodological quality, scoring 8 out of 10 according to the AMSTAR tool: it has an ‘‘a priori’’ design, at least 2 individuals selected the studies andgathered data, the search strategy was comprehensive, publication type and status were not used as inclusion criteria, the charac- teristics of the studies included are stated, the scientific quality of the studies included was assessed and docu- mented, scientific quality was considered in formulating conclusions, andconflicts ofinterest arestated,although thestudydoesnotprovidealistofallstudiesincludedand excluded.

Discussion

Ourliteraturereview analysesthecurrently availableevi- denceontheefficacyandsafetyofsphenopalatineganglion stimulationasanewtreatmentalternativeforpatientswith refractorychronicCH.Despitethelowincidenceofrefrac- tory chronic CH, sphenopalatineganglion stimulationis a majorstepforwardinthetreatmentofdrug-resistantCHas itrepresentsanalternative tosurgery,whichisfrequently associatedwithseverecomplications.8

Although cohort and case—control studies may provide complementarydata,ourobjectivewastoevaluatetheeffi- cacyandsafetyofsphenopalatineganglionstimulation;to

thatend,weincludedclinicaltrials,systematicreviews,and meta-analyses,asthesemethodologiesprovidehigherqual- itydata.Regardingsafety,wedidincludeapatientregistry withdataonpotentialadversereactionstosphenopalatine ganglionstimulation.

Our literature search identified studies analysing the safety and effectiveness of peripheral stimulation of the sphenopalatineganglion for the treatment of chronic CH.

However,theinformationprovidedbythesestudiesmainly camefrompatients includedin asingleclinical trial. The triallastedoneyearandincluded32patientswithrefractory chronicCH.However,theexperimental,randomised,sham- controlledphaseofthestudylastedonly3-8weeksandwas completedby28patientsonly.41Twenty-four-monthfollow- updatafrom33patients42,43(vs32patientsinthePathway CH-1trial)onlyprovidedataonsomeindicatorsoftreatment efficacy.

The post-marketingstudyof99patients44 wasincluded inthereviewbecauseitincludedthe32patientsfromthe PathwayCH-1trial.Thestudyfocusesonadversereactions totreatment within 30 daysof device implantation. Lim- itedinformationisavailable ontheefficacy andsafetyof sphenopalatineganglionstimulationforchronicCH.

Sphenopalatine ganglion stimulation is a viable, easy- to-usetreatmentalternative.45 However,clinicaltrialdata showthatsomepatientsrequiredadjustmentofthemicros- timulatorleadlocationor deviceremovalwithinoneyear ofimplantation.41Thepost-marketingstudyreportsthat13 patients required adjustment of the microstimulatorlead locationand5requiredremovalofthedeviceduringthefirst

447

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dayspost-intervention.44Reasonsforremovalofthedevice included pain secondary to maxillary nerve involvement, device displacement, incorrect initial device placement, andinfectionattheimplantationsite.40Itisthereforenec- essarytoexercisecautionandtomonitortheprocedure.40

Regardingtheefficacyofsphenopalatineganglionstim- ulation, the clinical trial reported statistically significant improvements in patients receiving full stimulation (pain reliefor resolution;decreaseinattack frequencyor med- icationuse),comparedtothosereceivingsub-perceptionor shamstimulation.Thetrialalsoreportssignificantimprove- mentsin HIT-6 andSF-36scores. Although theresults are promising, theyshouldbeinterpretedwithcaution:these data are from a single clinical trial with a small number of patients (some of whomdropped out), a shortfollow- upperiod,anduncertainblinding(patientsmayhavebeen aware of the stimulation dose received).41 Furthermore, patients maypresent periods of spontaneousremission of chronic CH.42 Improvements were observed at 24 months comparedtobaseline.However,thenumberofpatientsis limited andfollow-up dataare scarce.42,43 Cases of unex- plainedcontralateralCHhavebeenreportedduringpatient follow-up; further research is therefore needed into the effectsofsphenopalatineganglionstimulation.43

Regarding safety, the studies reviewed report a wide rangeofadversereactionswithin30daysofdeviceimplan- tation.Infact,81%ofthepatientsincluded intheclinical trial presentedsensoryalterations,andahigh percentage of patients reported pain or swelling during that period.

Mostof thesereactions resolved,however.41 Although the numberofcomplicationsdecreasesafterthe30-daymark, a substantial percentage of patients continue to present adverse reactions to treatment. According to the post- marketingstudy,44 overhalfofpatientspresentsometype ofadverse reaction,althoughmostareconsideredmildor moderate.Someauthorsconsiderthatalthoughtheproce- dure is associated withmultiple adverse reactions, these arecomparabletothoseofsuchotheroral surgeryproce- duresastoothextractions,sinussurgery,anddentalimplant placement.44 Regardinglong-term safety, the studies pro- viding24-monthfollow-updatadonotincludeinformation about adverseevents.OnlyJürgensetal.43 reportmildor moderateadversereactions,resolvingin2—3months.

The efficacy andsafety resultsof thesestudies have a numberof limitations.AccordingtotheNICEguidelines,40 clinical trialsshouldthoroughly describepatientselection criteria, patientselectionshouldbe performedby ateam ofexpertsspecialisinginpainmanagement,andthestudy should provide detailed dataon stimulation intensity and duration,medicationuse,qualityoflife,andtheeffecton symptoms.Furthermore,thestudiesincludedinourreview are notindependent; we found nostudies evaluating the efficacyofneurostimulationascomparedtoothermedical or surgical treatments, which would have helped evalu- atethe efficacyof the procedure.Although some authors report the long-term results of sphenopalatine ganglion stimulation,42thelongestfollow-upperioddescribedinthe literatureis24months;thelong-termdataavailabletodate arethereforeinsufficient.

Health technology reports evaluating the efficacy and safety of sphenopalatine ganglion stimulators39,40 under- scorethefrequencyofadversereactionsandeventheneed

for removalof thedevice, concluding thatthe procedure should only be performed for research purposes.40 Based ontheavailable evidence,theAustrianhealth technology report recommends that the procedure not be included in the list of medical resources offered by the Austrian healthcaresystem.39 In our view, the 24-month follow-up dataavailablearenotsufficienttochallengetheseconclu- sions.

Most patients were satisfied with the intervention42 and found the treatment useful.43 According to the results of a self-assessment questionnaire completed at 18monthspost-implantation, 90%ofpatients wouldmake the same decision again to treat CH with sphenopalatine ganglionstimulation.44 Peripheralsphenopalatineganglion stimulation may be the only treatment alternative for refractorychronicCH,sincesomepatientsdonotrespond to standard treatments.46 Patient involvement and writ- ten informed consent are essential in choosing this treatment.40

Conclusions

The available evidence onthe efficacy of sphenopalatine ganglionstimulationforrefractorychronicCHismainlyfrom a single clinical trial, which followed up a small patient sampleover ashortperiod.Althoughthestudies included inthisreview haveanumber oflimitations,arenotinde- pendent,anddonotevaluatetheefficacyofthestimulator in comparisonwith other medical or surgical treatments, sphenopalatineganglionstimulationmayconstitutetheonly treatment alternativefor patients withrefractorychronic CH.

Regarding treatment efficacy, the studies reviewed report positive outcomes in terms of pain relief, attack frequency,medicationuse, patientsatisfaction,and qual- ity of life. Some patients showed positive results at 24 monthscomparedtobaseline,althoughfollow-updataare scarce.

Regardingsafety, patientspresented numerous adverse reactionswithin30daysoftheprocedure.Thedevicehad toberemovedinsomecases.Nolong-termsafetydataare available.

Efficacyandsafetyresultsarepromising,despitelimited evidence.Further research is needed into the safetyand efficacyofsphenopalatineganglionstimulationforpatients withrefractorychronic CH.Whentheinterventionis indi- cated,it shouldbeconductedunderclosesupervisionand followingaresearchprotocol,withcarefulattentionpaidto patientwritteninformedconsent.

Conflicts of interest

Theauthorshavenoconflictsofinteresttodeclare.

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