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AbstractandIntroduction
Abstract
Clusterheadache(CH)painisthemostsevereoftheprimaryheadachesyndromes.Itischaracterizedbyperiodicattacksofstrictlyunilateralpainassociatedwith
ipsilateralcranialautonomicsymptoms.ThemajorityofpatientshaveepisodicCH,withclusterperiodsthattypicallyoccurinacircannualrhythm,while10%suffer
fromthechronicform,withnosignificantremissionsbetweenclusterperiods.SumatriptaninjectionoroxygeninhalationisthefirstlinetherapyforacuteCHattacks,
withthemajorityofpatientsrespondingtoeithertreatment.ThecalciumchannelblockerverapamilisthedrugofchoiceforCHprevention.Otherdrugsthatmaybe
usedforthispurposeincludelithiumcarbonate,topiramate,valproicacid,gabapentin,andbaclofen.Transitionalprophylaxis,mostcommonlyusingcorticosteroids,
helpstocontroltheattacksatthebeginningofaclusterperiod.Peripheralneuralblockadeiseffectiveforshorttermpaincontrol.Recently,thetherapeuticoptionsfor
refractoryCHpatientshaveexpandedwiththeemergenceofbothperipheral(mostlyoccipitalnerve)andcentral(hypothalamic)neurostimulation.Withtheemergence
ofthesenoveltreatments,theroleofablativesurgeryinCHhasdeclined.
Introduction
Clusterheadache(CH)painisconsideredthemostsevereoftheprimaryheadachesyndromesandisarguablyoneofthemostseverepainsyndromesthatafflict
humans.
[1]
Thedisorderischaracterizedbyattacksofsevere,strictlyunilateralpain,typicallyintheretroorbitalandfrontotemporalareas,associatedwithsymptoms
andsignsofcranialautonomicdysfunction(tearing,conjunctivalinjection,rhinorrhea/nasalcongestion,andHorner'ssyndrome)ipsilateraltothepain.Patientstypically
pacerestlesslyduringanacuteattack.ThehallmarkofCHisthecircadianperiodicityoftheattacks.Also,inepisodicCH(ECH),theclusterperiodsoftenoccurat
predictabletimesoftheyear(circannualperiodicity).RecentimagingstudiesconfirmactivationofthehypothalamusduringCHattacks.
[2]
Thesefindingsmayexplain
thecharacteristicperiodicityofCH.Activationofthetrigeminovascularsystemhasalsobeenshownduringacuteattacks.
ThemanagementofCHincludes:(1)patienteducationaboutthenatureofthedisorder(2)adviceonlifestylechanges(eg,avoidingalcoholduringanactivecluster
period)(3)prompttreatmentoftheacuteattackand(4)prophylactictreatment.Mostpatientscanbemanagedwithmedicaltherapy.Rarely,surgicaltreatmentis
indicated.Recently,neurostimulationhasemergedasatherapeuticoptionforselectpatients.
WeperformedaPubMedsearchoftheEnglishliteraturetofindstudiesontheacuteandprophylactictreatmentofCH.SearchtermswereCHandeachofthe
following:acutetreatment,prophylactic(orpreventive)treatment,triptans,oxygen,ergotamine,dihydroergotamine,lidocaine,somatostatin,octreotide,verapamil,
lithium,topiramate,valproicacid,methysergide,gabapentin,baclofen,melatonin,botulinumtoxin,corticosteroids,neurostimulation,occipitalnerveblock/stimulation,
sphenopalatineganglionblock/stimulation,hypothalamicstimulation,radiofrequency,trigeminalrhizotomy,gammaknifesurgery,microvasculardecompression.Wedid
notlimitoursearchtoaspecifictimeperiod.Wefocusedonclinicalefficacyandtolerabilityofthevariousdrugsandproceduresbasedondatafromhumanstudies.
Weincludedthebestavailablestudiesforeachdiscusseddrugorprocedure.Theserangedfromrandomizedcontrolledtrialsforsometreatments,tosmallcaseseries
ClusterHeadacheAcuteandProphylacticTherapy
AviAshkenazi,MD,ToddSchwedt,MD
Headache.201151(2):272286.
forothers.
TreatmentoftheAcuteAttack(Table1)
Table1.DrugsfortheAcuteTreatmentofClusterHeadache
Therapy
LevelofEvidence
(EFNS
Guidelines)
42,87
*
Dose MoreCommonAEs Comments
Oxygen A
710L/min(higher
flowratesmaybe
needed)
None Inhaledviaanonrebreathablemaskfor1520minutes
SumatriptanSC A 6mg
Nausea,fatigue,paresthesias,
chest/throattightness
Maybetakenuptotwicedailyduringaclusterperiod
contraindicatedinpatientswithCVdiseases
SumatriptanIN A 20mg
Nausea,fatigue,paresthesias,
chest/throattightness,unpleasant
taste
SloweronsetofactionthensumatriptanSC
contraindicatedinpatientswithCVdiseases
ZolmitriptanIN A 510mg
Nausea,fatigue,paresthesias,
chest/throattightness,unpleasant
taste
ComparableinefficacytosumatriptanIN
contraindicatedinpatientswithCVdiseases
OctreotideSC B 100g
Injectionsitepain,abdominalpain,
nausea,hyperglycemia
CanbeusedinpatientswithCVdiseases
LidocaineIN B 1mL(410%) none Onlymoderateeffectonheadpain
Dihydroergotamine
IV,IM,SC,orIN
Notrated 1mg
Nausea,diarrhea,musclecramps,
chesttightness,unpleasanttaste
(IN)
IVprobablythemosteffectiveroutecontraindicatedin
patientswithCVdiseasescannotbeusedwithtriptans
*SeeAppendixfordetailedguidelines.
AEs=adverseeffectsCV=cardiovascularEFNS=EuropeanFederationofNeurologicalSocietiesIM=intramuscularIN=intranasalIV=intravenousL/min=
litersperminuteSC=subcutaneous.
BecausethepainofacuteCHattacksevolvesrapidly,oralmedicationsareusuallynotaseffectiveforthispurposeastheyareformigraineattacks.Forrapidand
effectivepaincontrol,thetherapeuticagentneedstobegivenparenterally.
[1]
Triptans
The5HT
1B/1D
agonists(knownastriptans),inaninjectableorintranasalpreparation,areamainstayofacuteCHtreatment.
[13]
Sumatriptan
Sumatriptan,injectedsubcutaneously,isthedrugofchoiceforacuteCHattacks.
[1]
Theefficacyofthedrugforthisindicationwasexaminedinanumberofwell
designedstudies.
[47]
In1randomized,placebocontrolledstudytheefficacyofsubcutaneoussumatriptan(6mg)foracuteCHtreatmentwasexamined.
[4]
Datafrom
39patientswereevaluated.Headacheseveritydecreasedwithin15minutesinasignificantlyhigherproportionofsumatriptantreated,ascomparedwithplacebo
treated,attacks(74%vs26%).Also,asignificantlyhigherproportionofsumatriptantreatedpatientswerepainfree15minutesafterinjection,ascomparedwiththose
whoreceivedplacebo(46%vs10%).Sumatriptanwaswelltolerated.Inanothercontrolledstudy,subcutaneoussumatriptanatadoseofeither6mgor12mg,or
placebo,wasgivento134CHpatients.
[5]
Fifteenminutesafterinjection,theproportionofpatientswhoexperiencedheadachereliefwas80%,75%and35%for
sumatriptan12mg,sumatriptan6mg,andplacebo,respectively.Thehigherdoseofsumatriptanwasnotsignificantlysuperiortothelowerdose,andwasassociated
withmoreadverseeffects(AEs).Inanopenlabelstudyfromthesamegroup,thelongtermsafetyandefficacyofsubcutaneoussumatriptanwasexaminedin138CH
patients.
[6]
Eachpatienttreatedamaximumof2attacksperdaywithasingleinjectionperattack.Atotalof6353attacks,thatoccurredover3months,were
evaluated.Headachereliefwasobtainedin96%ofattacks.Therewasnoevidencefordecreasedefficacyofthedrugwithcontinueduse.Sumatriptanwaswell
tolerated,andtherewasnoincreaseinAEswithhigherfrequencyofusingthedrug.Inanotheropenlabelstudy,theefficacyandtolerabilityofsumatriptaninCH
treatmentwereevaluatedoveraperiodofupto1year.
[7]
Themaximumdailydoseofsumatriptanwas12mg.Atotalof2031attacks,experiencedby52patients,
wereevaluated.In88%oftheattacks,treatmentwaseffectivewithin15minutesafterinjection,and57%ofpatientswerepainfreeatthattimepoint.Therewasno
significantchangeintheefficacyofthedrugwithrepeateduse.TheresponsetotreatmentofpatientswhohadchronicCH(CCH)wassomewhatlessrobust,and
slowertooccur,ascomparedwiththatofECHpatients.Adverseeffectswerereportedby62%ofpatients.Withdrawalratewas33%,with4(8%)patientswithdrawing
becauseofAEs.
Table1.DrugsfortheAcuteTreatmentofClusterHeadache
Therapy
LevelofEvidence
(EFNS
Guidelines)
42,87
*
Dose MoreCommonAEs Comments
Oxygen A
710L/min(higher
flowratesmaybe
needed)
None Inhaledviaanonrebreathablemaskfor1520minutes
SumatriptanSC A 6mg
Nausea,fatigue,paresthesias,
chest/throattightness
Maybetakenuptotwicedailyduringaclusterperiod
contraindicatedinpatientswithCVdiseases
SumatriptanIN A 20mg
Nausea,fatigue,paresthesias,
chest/throattightness,unpleasant
taste
SloweronsetofactionthensumatriptanSC
contraindicatedinpatientswithCVdiseases
ZolmitriptanIN A 510mg
Nausea,fatigue,paresthesias,
chest/throattightness,unpleasant
taste
ComparableinefficacytosumatriptanIN
contraindicatedinpatientswithCVdiseases
OctreotideSC B 100g
Injectionsitepain,abdominalpain,
nausea,hyperglycemia
CanbeusedinpatientswithCVdiseases
LidocaineIN B 1mL(410%) none Onlymoderateeffectonheadpain
Dihydroergotamine
IV,IM,SC,orIN
Notrated 1mg
Nausea,diarrhea,musclecramps,
chesttightness,unpleasanttaste
(IN)
IVprobablythemosteffectiveroutecontraindicatedin
patientswithCVdiseasescannotbeusedwithtriptans
*SeeAppendixfordetailedguidelines.
AEs=adverseeffectsCV=cardiovascularEFNS=EuropeanFederationofNeurologicalSocietiesIM=intramuscularIN=intranasalIV=intravenousL/min=
litersperminuteSC=subcutaneous.
TheefficacyofintranasalsumatriptaninthetreatmentofacuteCHattackswasexaminedin1placebocontrolledstudy.
[8]
PatientswithECHorCCH,whoseattacks
lastedatleast45minutes,weregivenintranasalsumatriptan20mg,orplacebo.Datafrom154attacks,experiencedby118patients,wereanalyzed.At30minutes
aftertreatment,headacheresponseratesweresignificantlyhigherforsumatriptancomparedwithplacebotreatedattacks(57%vs26%).Thecorrespondingpainfree
ratesatthattimewere47%and18%.Thedrugwaswelltolerated.Anotherstudy,thatwasopenlabel,reportedonlowerefficacyofintranasal,ascomparedwith
subcutaneoussumatriptan,inacuteCHtreatment.
[9]
Alimitationofthatstudy,inadditiontoitsopenlabeldesign,wasthefactthattreatmentoutcomeswere
evaluatedatarelativelyearlytimepoint(15minutesposttreatment).
Insummary,injectablesumatriptaniseffectiveandwelltoleratedforthemajorityofCHpatients.Thedrughasarapidonsetofaction.Itremainswelltoleratedand
effectiveevenwhentakenfrequently(uptotwicedaily)duringaclusterperiod.Therecommendeddoseis6mg,althoughlowerdoses(23mg)maybeeffectivein
somepatients.
[10]
Intranasalsumatriptanappearstobelesseffective,andtohaveasloweronsetofactionthantheinjectablepreparation.Sumatriptanis
contraindicatedinpatientswithcoronaryarterydiseaseorcerebrovasculardisease.BecauseCHtypicallyafflictsmiddleagedmen,manyofwhomsmoke,aclinical
evaluation,orientedtowardtheriskofvasculardiseases,needstobedonebeforeprescribingthedrug.
Zolmitriptan
TheefficacyofintranasalzolmitriptanforacuteCHattackshasbeenstudiedin2controlledtrials.
[11,12]
In1study,92patientsreceivedeitherintranasalzolmitriptan(5
mgor10mg)orplacebo,foracuteattacks.
[11]
Thirtyminutesaftertreatment,headachereliefratesweresignificantlyhigherforzolmitriptancomparedwithplacebo
(62%,40%,and21%forzolmitriptan10mg,zolmitriptan5mg,andplacebo,respectively).PatientswithECHhadhigherresponseratestozolmitriptan(andto
placebo)comparedwiththosewhohadCCH.Zolmitriptanwaswelltolerated.Inasimilarlydesignedstudy,52CHpatientstreated151attackswithintranasal
zolmitriptan(10mgor5mg)orplacebo.
[12]
Zolmitriptan,atbothdoses,wassuperiortoplacebowithregardstoheadachereliefat30minutes(63%,50%and30%for
zolmitriptan10mg,zolmitriptan5mg,andplacebo,respectively).Thecorrespondingpainfreeratesatthattimepointwere47%,39%,and20%.Zolmitriptan,atboth
doses,waswelltolerated.
OralzolmitriptanwasevaluatedasanacutetreatmentforCHattacksinarandomizedcontrolledstudy.
[13]
ThedrugwasfoundtobesuperiortoplaceboinECH,but
notCCH,patients.Thirtyminutesaftertreatment,headacheresponseratesinECHpatientswere47%and29%,forzolmitriptan10mgandplacebo,respectively.
Insummary,intranasalzolmitriptanmaybeusedfortheacutetreatmentofCH,withcomparableefficacytothatofintranasalsumatriptan.Oralzolmitriptanhasonly
limitedefficacyforthispurpose.Aswithsumatriptan,zolmitriptaniscontraindicatedinpatientswithahistoryofcardiovascularorcerebrovasculardisease.
Oxygen
OxygeninhalationhasbeenusedforthetreatmentofacuteCHattacksfordecades.
[1]
ThemajoradvantageofoxygenisthevirtuallackofAEs.Asopposedto
triptans,oxygencanbegiventopatientswithahistoryofcardiovascularorcerebrovasculardisease.ThemechanismofactionofoxygenonCHhaslongbeenrelated
toitsvasoconstrictiveeffect.
[14]
Morerecently,however,ithasbeenshownthatoxygeninhibitsneuronalactivationinthetrigeminalnucleuscaudaliswhenthis
activationisinitiatedbystimulationoftheparasympatheticoutflowthroughthefacialnerve.
[15]
OxygenhasbeenevaluatedasanacutetreatmentofCHinanumber
ofstudies.
[16]
Inanopenstudy,KudrowexaminedtheefficacyofoxygenforacuteCHattacksin52patients.
[17]
Oxygen100%wasinhaledviaafacialmaskatarate
of7liters/minute(L/min)for15minutes.Thirtynine(75%)patientsexperiencedsignificantpainreliefwithin15minutes.Thebestresponsewasobservedinyounger
(<50yearsold)patientswhohadECH.FoganexaminedtheefficacyofoxygenforacuteCHinadoubleblindcrossoverstudy.
[18]
Nineteenmenweretreatedwith
eitheroxygen,orairinhalation,atarateof6L/min.Aftertreatment,averagepainreliefscorewassignificantlyhigherforoxygen,ascomparedwithair.Rozen
examinedtheeffectofhighflowoxygenonCHpainin3patientswhohadbeenrefractorytooxygengivenatthestandardflowrateof710L/min.
[19]
All3patients(2
withCCHand1withECH)hadcompleteornearcompleteheadacheresponseafterinhaling100%oxygenatarateof1415L/min.Twoofthepatientswereheavy
smokers.Theauthorsuggestedthatpatientswhofailtorespondtooxygenatthestandardflowrateshouldbetriedonhigherflow.Inarecentlargecontrolledtrial,
CohenetalexaminedtheefficacyofhighflowoxygeninthetreatmentofacuteCHattacks.
[20]
Atotalof109patientstreated4CHattackswitheitheroxygen(12
L/min)orinhaledair,givenviaafacialmaskfor15minutes.Oxygenwassignificantlysuperiortoplacebowithregardstotheprimaryendpoint(eliminationofpainor
"adequatepainrelief"at15minutes78%vs20%,withoxygenandair,respectively).
Hyperbaricoxygen(HBO)hasalsobeenstudiedasatreatmentforacuteCHattacks.
[21,22]
WeissetaltreatedaCHpatientwithhyperbaric(2atmospheres)100%
oxygen,aftershehadbeenrefractorytoconventionaloxygentherapy.
[21]
TwoattacksweretreatedwithHBO,withpromptandcompletepainrelief.DiSabatoetal
treated7ECHpatientswithHBOinaplacebocontrolledstudy.
[22]
Sixpatientsrespondedwelltotreatment,withinterruptionoftheirattack.Moreover,in3ofthe
responderstheCHperiodendedafterHBOtreatment.Placebotreatmenthadnoeffectonpain.
Insummary,normobaricoxygenisaneffectivetreatmentofacuteCHattacksinthemajorityofpatients.ItiswelltoleratedandhasvirtuallynoAEs.Asopposedto
triptans,thereisnolimitationtothenumberoftimesperdayitcanbeused.Apropertechniqueofuseiscrucialforgoodresultswithoxygentherapy.Thepatient
shouldbeinstructedtousetheoxygenviaanonrebreathablemask,atarateof710L/min,inasittingposition,foratleast1520minutes.Patientsmayincrease
theflowrateupto15L/minifneeded.Theoptimalflowrateshouldbedeterminedindividuallyforeachpatient.Themajordisadvantageofoxygentherapyisits
inconvenienceofuse,particularlywhenthepatientisoutofhome.Portableoxygentanksareavailableforpatientswhowishtouseitinthesecircumstances.Oxygen
therapyforCHshouldbeusedwithcaution,orevenavoided,inpatientswithchronicobstructivepulmonarydisease,becauseoftheriskofrespiratorydepression.HBO
maybeconsideredforrefractoryCHpatients.However,becausethisisnotareadilyavailabletherapy,andthereisnoevidenceforasustainedeffectofitonCH,
[23]
themajorityofpatientsarenotlikelytobenefitfromit.
ErgotamineandDihydroergotamine
ErgotderivativeswereamongthefirstagentstobeusedinCHtreatment.Reportsontheefficacyofergotamineforthisindicationdatebacktothe1940sand1950s.
[1]
Thesedata,however,werebasedonsmall,openlabelstudiesandoncasereports.Thedrughasnotbeenevaluatedincontrolledstudiesforthisindication.
Kudrowcomparedtheefficacyofsublingualergotaminewiththatofoxygenin50patientswithCH.
[17]
Theresponseratetoergotaminewas70%,ascomparedwith
82%foroxygen(withnosignificantbetweengroupdifference).Oxygenwasbettertoleratedthanergotaminehowever,thelatterwasmoreconvenienttouse.Because
oflimitedavailabilityandpotentiallyseriousAEs,mostnotablythoserelatedtothedrug'svasoconstrictiveeffect,ergotamineiscurrentlyrarelyusedforacuteCH.
Dihydroergotamine(DHE)isavailableininjectable(intravenous,intramuscular,orsubcutaneous)andintranasalformulations.Althoughnodatafromcontrolledtrials
areavailable,clinicalexperiencesuggestsefficacyofintravenousDHEforacuteCH.Thistreatment,however,isnotpracticalforthemajorityofpatientsbecauseof
thedifficultyinreceivingitpromptlywithattackonset.Basedonourclinicalexperience,intramuscularandsubcutaneousDHEinjectionsarenotaseffectiveasthe
intravenousroute,although,toourknowledgetherearenostudiesthatcomparedthevariousroutesofadministrationofthedrugforCH.Theefficacyandtolerability
ofintranasalDHE(1mg)inthetreatmentofacuteCHwasexaminedinacontrolledstudyof25patients.
[24]
IntranasalDHEdecreasedtheintensity,butnotthe
duration,oftheattacks,andwaswelltolerated.Theauthorssuggestedthatthemoderateefficacyofthedrugintheirstudymayhavebeenrelatedtothedosethey
used.Theyrecommendedthatthedrugbeexaminedatahigherdoseinfuturetrials(themaximalrecommendeddoseofintranasalDHEforacuteheadache
treatmentinadultsis2mg).
Insummary,becauseofthemoderateefficacyofmostergotpreparationsandthedifficultyofreceivingintravenousDHE(probablythemosteffectivepreparationfor
thispurpose)inatimelymanner,theroleofergotsintheacutetreatmentofCHislimited.
Lidocaine
DataontheefficacyoflocallyappliedlidocaineonacuteCHattacksarederivedfromseveralnoncontrolledstudiesand1randomizedcontrolledtrial.
[2528]
Kittrelleet
alexaminedtheeffectoflidocaine,appliedtopicallytothesphenopalatinefossa,onacuteCHattacks.
[25]
Fourofthe5treatedpatientsexperiencedrapidrelieffrom
painandassociatedsymptomsofnitrateinducedCHattacks.Thetreatmentwasalsoeffectiveforspontaneousattacks.Inanotherstudy,HardeboandElner
examinedtheeffectoflidocaine4%,selfappliedusinganasaldropperthroughthenostrilipsilateraltothepain,onCHpainandassociatedsymptoms.
[26]
Twentyfour
patientswerestudied,withmoderatelypositiveresults.Robbinsexaminedtheeffectofintranasallidocaine,administeredthroughaspraybottle,onpainin30men
withECH.
[27]
Patientstreated2consecutiveCHattacks.Resultsweremodest,with27%reportingon"moderaterelief,"27%on"mildrelief,"and46%onnorelief.In
aplacebocontrolledstudy,Costaetalexaminedtheefficacyoflidocaine10%,appliedbilaterallytothesphenopalatinefossaviaacottonswabusinganterior
rhinoscopy,onnitroglycerininducedCHattacks.
[28]
Lidocaineapplicationresultedineliminationofpaininall(15)patients.However,therewasaconsiderabledelay(of
37minutesonaverage)betweenthetimeoflidocaineapplicationandpainrelief(thecorrespondingtimeintervalforplacebowas59minutes).
Insummary,intranasallidocaineisatbestmoderatelyeffectiveinthetreatmentofacuteCHattacks.Itshouldnotbeusedasafirstlinetherapyforthisindication.
Thistreatmentmaybeusedasadjunctivetherapyinsomepatientswhoseattacksdonotcompletelyrespondtoother,moreeffective,therapies.
SomatostatinandOctreotide
SicuterietalconductedacontrolledstudytoexaminetheefficacyofintravenoussomatostatinforacuteCHattacks.
[29]
Seventytwoattacks,experiencedby8men,
werestudied.Somatostatininfusionwassuperiortoplacebo,andcomparabletointramuscularergotamine,inrelievingCHpain.Matharuetalevaluatedtheefficacyof
octreotide,asomatostatinanalogthatcanbegivensubcutaneously,foracuteCH.
[30]
Octreotide100gwassignificantlysuperiortoplacebowithregardtoheadache
responserates(52%vs36%).
Animportantadvantageofthesedrugsistheirlackofvasoconstrictiveeffect,makingthemaviabletreatmentoptionforpatientswhocannotusetriptansbecauseof
vasculardiseases.
SummaryTreatmentoftheAcuteAttack
Insummary,injectablesumatriptanandinhaledoxygenarebothafirstlinetherapyforacuteCH.Thedecisiononwhichoftheseoptionstouseshouldbemadeafter
consideringthepatient'smedicalcomorbiditiesandpersonalpreference.Inpatientswhodonotrespondwelltothesetreatments(orinthosewhocannotusetriptans),
somatostatinoritsanalogsappeartobeapromisingtherapeuticoption.Intranasallidocainemaybetriedasadjunctivetherapyinrefractorypatients.
TherearelittledatawithregardtoclinicalparametersthatmaypredictresponsetothevariousacuteCHtreatments.Inaprospectivestudyof246CHpatients,older
agewasapredictorfordecreasedresponsetotriptans,whereasnausea,vomiting,andrestlessnesspredicteddecreasedresponsetooxygen.
[31]
Asopposedto
migraine,therearefewknowntriggerstotheacuteCHattack,mostnotableofwhichisalcohol.Patientsshouldbeadvisedtoavoidalcoholicbeveragesduringa
clusterperiod(or,inthecaseofCCH,toavoiditaltogether).
ProphylacticTherapy
ProphylactictherapyforCHisdividedintomaintenanceprophylaxisandtransitionalprophylaxis.Maintenanceprophylactictherapiesareusedthroughouttheentire
courseoftheclusterperiodwiththeintentofreducingthefrequencyandseverityofclusterattacks.WhentreatingECH,maintenanceprophylacticsaregenerally
discontinuedafterresolutionoftheclusterperiodandthenrestartedattheonsetofthenextclusterperiod.Althoughmaintenanceprophylaxismonotherapyisoptimal,
somepatientswillrequireacombinationofmaintenancemedicationsforadequatecontrolofCH.However,caremustbetakentoavoidpotentiallynegativedrug
interactions.Transitionalprophylacticsareadministeredforshortdurationsasadjunctivetherapiestomaintenanceprophylacticsinanattempttoabortthecluster
periodortofurtherreducethefrequencyandseverityofclusterattacks.Theyareoftenbegunsimultaneouslywithinitiationofmaintenanceprophylaxisbecausethey
tendtoworkmorequicklyandthusprovidecontrolofCHuntilthemaintenancetherapyhastimetotakeeffect.
MaintenanceProphylaxis(Table2)
FirstlineTherapy
Table2.MaintenanceProphylacticTherapyforClusterHeadache
Therapy
LevelofEvidence(EFNS
Guidelines)
42,87
*
TargetDose
perDay
Monitoring MoreCommonAEs
Verapamil A 200900mg EKG Hypotension,constipation,peripheraledema
Lithium
carbonate
B 600900mg
Lithiumlevels,renalfunction,
thyroidfunction
Diarrhea,tremor,polyuria
Topiramate B 50200mg Serumbicarbonate
Paresthesias,weightloss,cognitivedysfunction,fatigue,
dizziness,tastealteration
Valproicacid C 5002000mg CBC,liverfunction Weightgain,fatigue,tremor,hairloss,nausea
Melatonin C 10mg None Fatigue,sedation
Baclofen C 1530mg None Drowsiness,dizziness,ataxia,muscleweakness
Botulinum
toxin
Notrated 50units None Muscleweakness,injectionsitepain
Gabapentin Notrated 8003600mg CBC
Somnolence,fatigue,dizziness,weightgain,peripheral
edema,ataxia
Clonidine Notrated 0.20.3mg None Fatigue,hypotension
*SeeAppendixfordetailedguidelines.
AEs=adverseeffectsCBC=completebloodcountEFNS=EuropeanFederationofNeurologicalSocietiesEKG=electrocardiogram.
Verapamil,acalciumchannelblocker,isthefirstlinemaintenanceprophylacticmedicationforCH.Verapamilisconsideredfirstlinetherapybecauseofitsefficacy,
relativesafety,andtheabilitytocoadministersymptomaticandtransitionaltherapieswithlessconcernaboutdruginteractionscomparedwithsomeoftheother
maintenanceprophylacticmedications(eg,lithiumcarbonate).Inopenlabelstudies,approximately70%ofECHandCCHpatientshavesubstantialimprovementwith
verapamiltherapy.
[32]
InadoubleblindplacebocontrolledtrialofverapamilformaintenanceprophylaxisofECH,15patientswererandomizedto120mgofverapamil
3timesdailywhile15subjectswererandomizedtoplacebo.
[33]
During2weeksoftreatment,80%ofpatientsreceivingverapamilhadagreaterthan50%reductionin
headachefrequency,including4patientswhobecameattackfree.Verapamiltookeffectquickly,withonehalfofrespondershavingsubstantialimprovementwithinthe
firstweekandtheotheronehalfrespondingduringthesecondweek.Meanwhile,zeropatientsreceivingplacebohadagreaterthan50%reductioninheadache
frequency.Adverseeffectsduetoverapamilweremild,withconstipationbeingthemostcommonandmostbothersome.Adoubleblind,crossoverstudyofverapamil
vslithiumcarbonateforCCHsuggeststhatverapamilisasuperiortreatment.
[34]
Inthisrandomizedtrial,eachofthe24subjectsreceivedverapamil360mgperdayor
lithiumcarbonate300mg3timesdailyfor8weeks,andthenfollowinga2weekwashoutperiodwasswitchedtotheothertherapyforanadditional8weeks.
Verapamilandlithiumbothprovidedsimilarreductionsinbothheadacheindexandanalgesicconsumption.However,verapamilworkedmorequickly,withover50%of
patientshavingsignificantimprovementinheadacheindexwithinthefirstweekcomparedwith37%ofthosetakinglithium.Furthermore,only12%ofthosetaking
verapamilreportedAEscomparedwith29%ofthosetakinglithium.
Targetdosagesofverapamilrangingfrom200mgto960mgperdayindivideddosesaretypicallyusedforclusterprophylaxis.
[35]
Mostpatientswillrespondtodoses
of200mgto480mgperday.
[36]
Immediateorextendedreleaseformulationsmaybeused.SlowtitrationsuptothetargetdosemayreduceAEsincluding
hypotension,constipation,andperipheraledema.Amethodoftitratingandtaperingverapamildosagein40mgintervalsisdescribedinapaperbyBlauandEngel.
[36]
EKGmonitoringisnecessaryduringverapamiltherapybecauseoftheriskofheartblockandbradycardia,AEsthatcandevelopwithinitiationoftherapy,increasesin
dose,andevenduringcontinuedstabledosetherapy.
[37]
Inourpractice,weobtainabaselineEKGbeforeinitiatingverapamiltherapy,repeatEKGwitheachincrease
indoseofatleast80mg,andanEKGeach3monthsifthedosehasbeenunchanged.Patientsshouldbeinformedofthepossibilityofdevelopinggingival
hyperplasiabecauseoflongtermuseofverapamil.
Table2.MaintenanceProphylacticTherapyforClusterHeadache
Therapy
LevelofEvidence(EFNS
Guidelines)
42,87
*
TargetDose
perDay
Monitoring MoreCommonAEs
Verapamil A 200900mg EKG Hypotension,constipation,peripheraledema
Lithium
carbonate
B 600900mg
Lithiumlevels,renalfunction,
thyroidfunction
Diarrhea,tremor,polyuria
Topiramate B 50200mg Serumbicarbonate
Paresthesias,weightloss,cognitivedysfunction,fatigue,
dizziness,tastealteration
Valproicacid C 5002000mg CBC,liverfunction Weightgain,fatigue,tremor,hairloss,nausea
Melatonin C 10mg None Fatigue,sedation
Baclofen C 1530mg None Drowsiness,dizziness,ataxia,muscleweakness
Botulinum
toxin
Notrated 50units None Muscleweakness,injectionsitepain
Gabapentin Notrated 8003600mg CBC
Somnolence,fatigue,dizziness,weightgain,peripheral
edema,ataxia
Clonidine Notrated 0.20.3mg None Fatigue,hypotension
*SeeAppendixfordetailedguidelines.
AEs=adverseeffectsCBC=completebloodcountEFNS=EuropeanFederationofNeurologicalSocietiesEKG=electrocardiogram.
SecondlineTherapy
LithiumcarbonateisasecondlinetherapyformaintenanceprophylaxisofCH.Weconsiderlithiumasasecondlinetherapybecauseofitspotentialforcausing
numerousAEs,theneedforbloodtestmonitoringduringtherapy,anditspotentialforcausingseveraldruginteractions.Nonetheless,lithiumcarbonatehasbeen
demonstratedtoprovidesignificantbenefitinthetreatmentofCCH.ItsefficacyfortreatingCCHhasbeendemonstratedintheinvestigationdiscussedin"FirstLine
Therapy"andinastudyof8additionalCCHpatients.
[34,38]
Inthelatterstudy,all8patientshadatleasta75%improvementwithinthefirst2weeksoftherapy.
However,only1of3whowerefollowedlongtermhadcontinuedimprovementafter18monthsoftherapy.Theevidencefortheutilityoflithiumcarbonateforthe
treatmentofECHislessclear,withgenerallysmallstudiesprovidingcontradictoryresults.
[34,38,39]
Lithiumcarbonatedosesof600mgto900mgperdayaretypically
neededtoobtaintargettherapeuticserumlithiumlevelsof0.4to0.8mEq/L.Lithiumserumlevels,renalfunction,andthyroidfunctionshouldbemonitoredduring
lithiumtherapy.CommonAEstolithiumincludediarrhea,tremorandpolyuria.Symptomsandsignsoftoxicityincludenausea,vomiting,diarrhea,confusion,
nystagmus,extrapyramidalsigns,ataxia,andseizures.
Topiramate,indosesrangingfrom50mgto200mgperday,isconsideredsecondlinetherapyforCHprophylaxis.Althoughwehavedesignatedtopiramateas
secondlinetherapy,consistentwiththeGradeBrecommendationintheEuropeanFederationofNeurologicalSocietiesguidelines,topiramateuseforCHprophylaxis
hasbeeninvestigatedinopenlabelstudiesonly.
[4042]
CommonAEstotopiramateincludecognitivedysfunction,paresthesias,alterationintaste,weightloss,fatigue,
anddizziness.Patientswithahistoryofnephrolithiasisshouldnotreceivetopiramatebecauseofanincreasedriskofrecurrentstoneswhiletakingthismedication.
ThirdlineTherapy
Othertherapiesthatmaybeeffectiveformaintenanceclusterprophylaxisincludemethysergide,valproicacid,melatonin,gabapentin,baclofen,clonidine,and
botulinumtoxin.AlthoughmethysergideislikelyeffectiveforpreventingCH,itisnotavailableintheUSAandlongtermuseisassociatedwithfibroticcomplications.
Thus,wecannotrecommenditsuse.Valproicacidhasbeenshowntoprovidebenefitinopenlabelandretrospectivestudiesonly.
[43,44]
Adoubleblindplacebo
controlledstudyofsodiumvalproatedidnotsupportitsefficacyhowever,thismayhavebeenduetoanexceedinglyhighresponserateof62%intheplacebogroup.
[45]
Effectivedosesrangefrom500mgto2000mgdailyindivideddoses.CommonAEsincludeweightgain,fatigue,tremor,hairloss,andnausea.Monitoringwith
completebloodcountsandliverfunctiontestsarenecessaryduringvalproicacidtherapy.Limitedevidencesupportstheuseofmelatoninforclusterprophylaxis.Ina
doubleblind,placebocontrolledtrialof10mgmelatonin,5of10subjectsrandomizedtomelatoninhadclusterremissionwithin5dayswhilenoneofthe10subjects
takingplacebowentintoremission.
[46]
OpenlabelstudiesofgabapentinsuggestitsvalueinmaintenanceprophylaxisofCHindosesrangingfrom800mgto3600mg
perday.
[47,48]
GabapentinistypicallyawelltoleratedmedicationbutmorecommonAEsincludesomnolenceandfatigue,dizziness,weightgain,peripheraledema,
andataxia.Inasmallopenlabelstudyofbaclofen10mg3timesdaily,6of9subjectswentintoremissionwithin1weekandanadditional1subjecthadimprovement
followedbyremissionatweek2.
[49]
Althoughadverseeventswerenotreportedbysubjectsinthisstudy,morecommonAEstobaclofenincludedrowsiness,dizziness,
ataxia,andmuscleweakness.Clonidine,givenasa5mgto7.5mgtransdermalpatch(thatdeliversthedrugatarateof0.20.3mgdailyfor1week),hasbeen
studiedin2smallopenlabelstudies.
[50,51]
Inthefirst,whichincluded8ECHand5CCHpatients,thereweresignificantreductionsinmeanattackfrequency,pain
intensity,andattackduration.
[50]
However,asecondstudyincluding16ECHpatientsfailedtoconfirmthesepositiveresults.
[51]
Tirednessandreductioninblood
pressurewereAEsnotedinthesestudies.AnopenlabelstudyofbotulinumtoxintypeAasaddontherapyin3ECHand9CCHpatientshadmixedresults.
[52]
Fifty
unitsinjectedipsilateraltotheheadacheresultedinheadacheremissionin1CCHpatient,improvementinattackfrequencyandseverityinanadditional2CCH
patients,improvementinacontinuousbaselineheadachewithnochangeinsuperimposedclusterattacksinanadditional1CCHpatient,andnobenefitinthe
remaining8patients.MorecommonAEstobotulinumtoxintherapyincludeweaknessofinjectedmusclesandpainatinjectionsites.
TransitionalProphylaxis
Corticosteroidsareoftenprescribedconcurrentwithinitiationofmaintenanceprophylaxisinordertoquicklyobtainclustercontrol.Oralandintravenouscorticosteroids
maybothprovidebenefit.Varyingdosesoforalprednisone,rangingfrom10mg/dayto80mg/day,wereevaluatedinastudyof9episodicand10chroniccluster
patients.
[53]
Peakprednisonedosewasgivenfor3to10daysandtaperedover10to30days.CompleterelieffromCHwasseenin11patients,3had5099%relief,
3had2550%relief,and2patientshadnobenefit.TheECHandCCHpatientshadsimilarresponses.Investigatorsobservedthatprednisonedosesof40mgor
higherwereneededforbenefit.Headacherecurrencewascommonduringtheprednisonetaper.Otherstudiesoforalprednisonehavehadsimilarresults.
[54,55]
Intravenouscorticosteroids,sometimesfollowedbyoralsteroids,mayalsoprovidebenefitfortransitionalclustertherapy.
[56,57]
Asinglehighdoseofintravenous
methylprednisolone(30mg/kgbodyweightover3hours)deliveredontheeighthdayofanactiveclusterperiodprovided10of13treatedpatientswith2ormoredays
ofattackcessation.
[56]
Themeanintervalbetweensteroidtreatmentandattackrecurrencewas3.8days.Threepatientshadcompleteclusterremission.
Althoughadequatetrialssupportingtheirusearelacking,ergotaminetartrateandDHEmaybeusedfortransitionalprophylaxis.
[58,59]
Inanopenlabelstudy,23ECH
and31CCHpatientswereadmittedtothehospitalfortreatmentwithrepetitiveintravenousDHE.
[60]
AllpatientsbecameheadachefreewhilebeingtreatedwithIV
DHE:10patients(16%)afterthefirstdose,anadditional12(19%)duringthefirstdayofhospitalization,and22(34%)morebecameheadachefreebythesecondday
ofhospitalization.Byday3,greaterthan90%ofpatientswereheadachefreeandbyday5allwereheadachefree.At3monthsafterdischarge,>90%ofECH
patientsand44%ofCCHpatientsremainedheadachefree.Approximately83%ofpatientsreportednoAEsfromIVDHE.ReportedAEsincludednausea,noncardiac
chesttightness,andametallictaste.Ergotaminetartrate,34mgperdayindivideddoses,maybeadministeredfor2to3weeksfortransitionalprophylaxis.
[58,61]
Administrationjustbeforebedtimemayhelptopreventnighttimeattacks.
InvasiveProceduresforClusterHeadacheTreatment
Withanindividuallytailoredpharmacologictreatmentplan,themajorityofCHpatientswillachievesatisfactoryresults.Forthosewhoremainrefractorytomedical
treatment,anumberofinvasiveproceduresareavailable.Theseincludeperipheralnerveblocks,peripheralorcentralneurostimulationand,asalastresort,ablative
surgery.Peripheralnerveblock,mostlytargetingthegreateroccipitalnerve(GON),mayalsobeusedinlessrefractorypatients,asanadjuncttopharmacologic
therapy.
PeripheralNerveandSphenopalatineGanglionBlock
EfficacyofGONblockinCHtreatmentwassuggestedbyAnthonyinthe1980s.
[62]
Morerecently,theprocedurewasinvestigatedasCHtreatmentinanumberof
studies,withthemajorityshowingpositiveresults.
[6366]
PeresetalevaluatedtheeffectofGONblockin14patientswithCH.
[63]
PatientsreceivedGONblock
ipsilateraltotheheadpainusinglidocaine1%andtriamcinolone40mg.Patientswereevaluatedbeforeand1weekaftertheblock.Nine(64%)patientshadgoodor
moderateresponse.Theprocedurewaswelltolerated.Ambrosinietalevaluatedtheeffectofsuboccipitalinjectionoflidocaine2%withbetamethasone,compared
withlidocaineandsaline,in23CHpatientsinarandomized,controlledstudy.
[64]
TheCHattacksdisappearedwithin72hoursin85%ofthelidocaine+
betamethasonegroup(with61%remainingattackfreefor4weeks)comparedwithnoneinthelidocaine+salinegroup.Injectionswerewelltolerated.Afridietal
examinedtheefficacyofGONblock,usinglidocaine2%andmethylprednisolone,inpatientswithrefractorychronicdailyheadache.
[65]
Theirsampleincluded19
patientswithCHwhoreceived22injections.Thirteenoftheinjections(59%)resultedinacompleteorpartialresponse,withamediandurationof12and21days,for
completeandpartialresponse,respectively.Incontrasttotheseresults,Buschetalreportedononlyminorheadacheimprovementin60%of15CHpatientswho
receivedGONblockusingprilocaine.
[66]
Endoscopicallyguidedsphenopalatineganglion(SPG)blockadehasbeenevaluatedbyFelisatietalforCHtreatment.
[67]
Of20refractoryCCHpatientswho
underwenttheprocedure,11experiencedsignificant,albeittemporary,symptomrelief.
PeripheralNerveandSphenopalatineGanglionStimulation
PeripheralnervestimulationmaybeeffectiveandindicatedfortheprophylactictherapyofCCHpatientswhoarerefractoryorintoleranttomedicationtherapy.Several
smallstudieshavenowshownoccipitalnervestimulation(ONS)tobeapromisingtherapyforsuchpatients.EightpatientswithdrugresistantCCH,treatedwith
unilateralONS,werefollowedforanaverageof15.1months.
[68]
Atthetimeoflastfollowup,2of8patientswerepainfree,3hada~90%reductioninheadache
frequency,2had~40%reduction,and1patientderivednobenefit.Twopatientshadsideshiftoftheirclusterattacksrequiringtreatmentwithsuboccipitalsteroid
injection.Complicationsincludedelectrodemigration(n=1),leaddisplacementafterafall(n=1),andthoracicdiscomfortortingling(n=2).BilateralONSwas
investigatedin8patientswithmedicallyintractableCH.
[69]
Atmedianfollowupof20months,subjectiveselfassessmentofbenefitwasgradedassubstantial(90%)
in2patients,moderate(40%)in3,mild(25%)in1,andnilin2patients.SixpatientsreportedthattheywouldrecommendtheuseofONStoothersimilarcluster
patients.Complications,affecting4ofthepatients,included:excessivepainatincisionsite(n=1),electrodemigration(n=3),electrodefracture(n=1),andshock
likesensationbecauseofkinkingofwires(n=1).In2009,resultsfromextendedfollowupofthese8patientsandanadditional6patientstreatedwithbilateralONS
werereported.
[70]
Atamedianfollowupof17.5months,10of14patientsreportedimprovement,including3with>90%improvement,3with4060%improvement,
and4with2030%improvement.NinepatientsstatedthattheywouldrecommendONStootherpatients.Complications/AEsincludedleadmigration,painful
paresthesias,musclerecruitment,neckstiffness,skinpain,andinfection.Meanbatterylifewas15.1months.
TheSPGstimulationmayalsobeaneffectivetreatmentforrefractoryCH.FivepatientswithCCH,refractorytomoreconventionaltherapies,weretreatedwithSPG
stimulationduring18acuteclusterattacks.
[71]
Stimulationresultedincompleteattackresolutionfor11oftheattacks,greaterthan50%reductioninpainseverity
withoutcompleteresolutionfor3attacks,andminimaltonorelieffor4attacks.Benefitsfromstimulationwerenotedwithin1minuteto3minutesoftreatment
initiation.StimulationwaswelltoleratedwithonlymildAEsfromstimulatorplacement,includingtransientepistaxisandtransientmildfacialpain.Further
investigationsofSPGstimulationfortheacuteandprophylactictherapyofCHareneeded.
DeepBrain(Hypothalamic)Stimulation
Leoneetalreportedin2001ona39yearoldmanwithintractableCHwhoseattacksimprovedsignificantlyafterimplantationofastimulatingelectrodetotheposterior
hypothalamus,ipsilateraltothepain.
[72]
Sincethisfirstreport,severalstudieshavebeenpublishedontheefficacyandtolerabilityofhypothalamicstimulation(HS)for
CH.
[7375]
SchoenenetalexaminedtheeffectofunilateralHSin6refractoryCCHpatients.
[73]
Threepatientshad"excellent"results,whileanotherhadonlya
transientremission.In1patienttreatmenthadtobestoppedbecauseofAEs(autonomicdisturbancesandpanicattacks),and1diedofintracerebralhemorrhage
shortlyaftertheprocedure.Leoneetalreportedonthelongtermresultsof16previouslyrefractoryCCHpatientswhohadHS.
[74]
Atameanfollowupof23months,
majorimprovementinpain,orcompletepainelimination,wasobtainedin13(81%)patients.Themeantimetoheadachebenefitwas42days.Overall,theprocedure
waswelltolerated.Nohormonal,affectiveorsleeprelatedabnormalitieswereobserved.Onepatienthadanasymptomaticintracerebralhemorrhagethatsubsequently
resolved.TransientdiplopiawasacommonAEwithhighamplitudestimulation.Bartschetalreportedon6CCHpatientswhounderwentHS.
[75]
Atameanfollowup
of17months,3patientsrespondedwelltotreatment,beingalmostattackfree,while3patientsfailedtorespond.Theprocedurewaswelltolerated.Theauthors
concludedthatHSiseffectiveinasubsetofrefractoryCCHpatients.Interestingly,inanotherstudy,HSwasnoteffectiveinthemajorityofpatientswhenusedasan
acuteCHtreatment,suggestingthatthistreatmentaffectsCHthroughmorecomplexpainmodulatingmechanisms.
[76,77]
Insummary,HSisanemergingviabletreatmentforrefractoryCCH.Itappearstobeeffectiveinsome,butnotall,patients.Althoughthetreatmentisgenerallywell
tolerated,theriskofintraceberalhemorrhage,andevendeath,shouldbekeptinmindwhenconsideringthistreatmentoption.
AblativeSurgicalProcedures
WiththeemergenceofavarietyofpharmacologicandnonpharmacologictherapiesforCH,theroleofablativesurgeryinthisdiseasehasdeclined.
[1]
Candidatesfor
surgeryshouldhavestrictlyunilateral,sidelocked,CHattacks.Anumberofprocedureshavebeenusedwithsomesuccessforthisindication,includingradiofrequency
ablationofthetrigeminalganglion,trigeminalsensoryrhizotomy,gammaknifesurgery,andmicrovasculartrigeminalnervedecompression.
[1]
Radiofrequency
trigeminalgangliorhizolysishasbeenshownaseffectiveinupto75%ofrefractoryCCHpatients.
[78,79]
Inacaseseriesof27patientswhounderwentthisprocedure,2
developedanesthesiadolorosa.
[79]
Othercomplicationsincludedcornealanesthesia,keratitis,anddiplopia.Trigeminalrootsectionhasbeenreportedtobeeffectivein
88%of17patientswithrefractoryCCH,with76%experiencinglongtermpainrelief.
[80]
Complicationsincludedcornealabrasion,masticatorymuscleweakness,
anesthesiadolorosaandthedevelopmentofCHontheotherside.Onepatient,whounderwenttheproceduretwice,diedafterthesecondsurgery.Theauthors
concludedthattrigeminalnervesectionisaviabletherapeuticoptionforselectedrefractoryCCHpatients.Microvasculardecompressionofthetrigeminalnerve,withor
withoutsectionofthenervusintermedius,hasshownsomeefficacyinrefractoryCCHhowever,responseratedecreasedovertime.
[81]
Gammakniferadiosurgeryisa
relativelyrecenttherapeuticapproachforCH.
[82,83]
Despiteearlyencouragingresults,
[82]
morerecentdatashowedonlymodestlongtermpainreliefandhighrateof
AEs,includingdeafferentationpain.
[83]
AnothersurgicalapproachforCHtargetstheparasympatheticcomponentofthedisease,typicallybyblockingorablatingtheSPG.
[67,84,85]
In1study,radiofrequency
blockadeoftheSPGwasperformedin66CHpatients.
[84]
Completepainreliefwasachievedin61%and30%ofECHandCCHpatients,respectively.Inamore
recentstudy,15refractoryCCHpatientsweretreatedwithradiofrequencyablationoftheSPG.
[85]
Thetreatmentdecreasedsignificantlythemeanattackfrequency,
meanpainintensityandpainrelateddisability,andtheseeffectslastedfor1218months.
Insummary,ablativesurgicalproceduresshouldbereservedasthelastresortforrefractoryCHpatients.Theproceduresthatappeartobemoreeffectiveinthelong
termmanagementofthediseaseareradiofrequencytrigeminalganglionablationandtrigeminalrhizotomy.Itshouldbenoted,however,thatCHattackshavebeen
showntopersistaftertrigeminalrootsectioninacasereportofmanwithCH,supportingthehypothesisofacentralpaingeneratorinthisdisease.
[86]
Appendix
EuropeanFederationofNeurologicalSocieties(EFNS)guidelinesevidenceclassificationschemeforatherapeuticintervention
ClassI:Anadequatelypoweredprospective,randomized,controlledclinicaltrialwithmaskedoutcomeassessmentinarepresentativepopulationoranadequately
poweredsystematicreviewofprospectiverandomizedcontrolledclinicaltrialswithmaskedoutcomeassessmentinrepresentativepopulations.Thefollowingare
required:
a. Randomizationconcealment.
b. Primaryoutcome(s)is/areclearlydefined.
c. Exclusion/inclusioncriteriaareclearlydefined.
d. Adequateaccountingfordropoutsandcrossoverswithnumberssufficientlylowtohaveminimalpotentialforbias.
e. Relevantbaselinecharacteristicsarepresentedandsubstantiallyequivalentamongtreatmentgroupsorthereisappropriatestatisticaladjustmentfor
differences.
ClassII:Prospectivematchedgroupcohortstudyinarepresentativepopulationwithmaskedoutcomeassessmentthatmeetsaeorarandomized,controlledtrialina
representativepopulationthatlacks1criteriaae.
ClassIII:Allothercontrolledtrials(includingwelldefinednaturalhistorycontrolsorpatientsservingasowncontrols)inarepresentativepopulation,whereoutcome
assessmentisindependentofpatienttreatment.
ClassIV:Evidencefromuncontrolledstudies,caseseries,casereports,orexpertopinion.
Ratingofrecommendations:
LevelArating(establishedaseffective,ineffective,orharmful)requiresatleast1convincingclassIstudyoratleast2consistent,convincingclassIIstudies.
LevelBrating(probablyeffective,ineffective,orharmful)requiresatleast1convincingclassIIstudyoroverwhelmingclassIIIevidence.
LevelC(possiblyeffective,ineffective,orharmful)ratingrequiresatleast2convincingclassIIIstudies.
AdaptedwithpermissionfromBraininetal.GuidanceforthepreparationofneurologicalmanagementguidelinesbyEFNSscientifictaskforcesrevised
recommendations2004.EurJNeurol200411:577581.
Sidebar
StatementofAuthorship
Category1
a. ConceptionandDesign
AviAshkenazi
b. AcquisitionofData
AviAshkenaziToddSchwedt
c. AnalysisandInterpretationofData
AviAshkenaziToddSchwedt
Category2
a. DraftingtheManuscript
AviAshkenaziToddSchwedt
b. RevisingItforIntellectualContent
AviAshkenaziToddSchwedt
Category3
a. FinalApprovaloftheCompletedArticle
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AbbreviationsAEsadverseeffects,CCHchronicclusterheadache,CHclusterheadache,DHEDihydroergotamine,ECHepisodicclusterheadache,GONgreater
occipitalnerve,HBOhyperbaricoxygen,HShypothalamicstimulation,NBOnormobaricoxygen,ONSoccipitalnervestimulation,SPGsphenopalatineganglion
ConflictofInterestNone
Headache.201151(2):272286.2011BlackwellPublishing
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