Clinical Sleep Medicine Update: Year in Revie · Sleep Duration: Consensus Statement of AASM, AAP, NIH • Panel of 13 experts reviewed 864 relevant arIcles • Paruthi S et al 2016

Clinical Sleep Medicine Update:

Year in Review

CynthiaNichols,MDVirginiaSkiba,MD

Q.AfifaShamim-Uzzaman,MDNeerajKaplish,MD

MASMFall2016MeeIngOctober14,2016

OBJECTIVES

Reviewandunderstandkeymedicalliteraturepublishedinthefollowingtopicsbetween2015–2016,inordertoincorporatethemintomedicalpracIce:

•  Pediatrics•  Insomnia(includingpharmacological&non-

pharmacologicalmanagementopIons)•  SleepanditsrelaIonshiptoothermedicaldisorders•  AlternaIvetreatmentsforobstrucIvesleepapnea

Year in Review: Pediatric Sleep

CindyNichols,PhD,DABSM,FAASM,CBSMClinicalDirector

MunsonSleepDisordersCenterTraverseCity,MI

Conflict of Interest Disclosures for Speakers 1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR

2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients:

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support

Consultant

Speakers’ Bureaus

Financial support

Other

3. The material presented in this lecture has no relationship with any of these potential conflicts, OR

4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

1.

2.

3.

Review Process • SLEEPandJCSMItlesfromallvolumesandissuesin2015and2016werereviewed.

• ExpertopinionarIcleswithoutoriginaldatawereexcluded.

• ArIcleswithoriginaldatawerereviewedusingtheGRADEcriIcalappraisaltechnique.

• SystemaIcreviewandmeta-analyseswereincluded,butwereexcludedfromtheGRADEevaluaIon.

Results Review • SystemaIcreviewsand/ormeta-analysis:3

• Scoringupdate:1

Highlevelevidence:• RCT:2

Lowlevelevidence:

• Caseseries:3• ProspecIveobservaIonalstudies:4

• Pre-postdesign:3• Matchedcasecontroldesign:8

• CrosssecIonaldesign:6

• RetrospecIveobservaIonaldesign:1

Topics

• Mentalandbehavioralhealth:2

• Sleep-disorderedbreathing:10

• SleepduraIon:1• Insomnia:2• CPAPadherence:1• Generaldevelopment:4

• Infantsleepscoring:1• Narcolepsy/IHS:3

• SleepdeprivaIon:4• SleepandcogniIon:2• Circadianrhythm:1• Sleepinothermedicalillness:2

• SleepeducaIon:1

Sleep-Disordered Breathing

• WhileATreducestheAHIsignificantlyeveninobesechildren,obesechildrendonotloseweightaferundergoingupperairwaysurgery(ComGetal,2015).

• OSAisnotrouInelyscreenedforbyanesthesiaproviderspriortoambulatorypediatricsurgery,andparadoxically,paIentswithundiagnosedOSAwhowouldbenefitthemostfromscreeningweretheleastlikelytobescreened(IshmanSetal,2015).

• Adenotonsillarhypertrophycauseselevatedairwayresistance/upperairwayloadingthatmaycontributetotheincreasedfrequencyofrespiratorydiseasesinuntreatedchildrenwithOSA.AirwayresistanceloadingwashigherinchildrenwithOSAvs.normalcontrols,butbothgroupshadnormalspirometry.AirwayresistancedecreasedtothatofnormalcontrolsfollowingAT(TapiaIetal2016).


•  39%ofchildrentreatedwithAT,nasalsurgery,ornasalcorIcosteroidssIllhadsignificantSDB3yearsafertreatment(WalterL,etal2015).

• ObstrucIve,central,mixed,andtotalAHIwerenotsignificantlyhigherinobeseadolescentswithandwithoutmetabolicsyndrome(ErdimIetal2015).

• Pre-ATandpost-AThigh-sensiIvityC-reacIveprotein(aninflammatorybiolmarker)ispredicIveofresidualOSAfollowingAT(BhajacharjeeRetal2016).

•  66.4%prevalenceofOSAinchildrenwithDownsyndrome,andeventhosewitha“negaIve”historyforOSAsymptoms,prevalenceis53.8%(MarisMetal2016).


• Neckcircumference-heightraIomayimprovetheabilitytotriagechildrenandadultsatriskforOSA.Inchildren,theoddsraIoofAHI>2was3.47forNHR>0.25;however,inadultstheoddsraIoofAHI>5was18forNHR>0.25(HoA,etal2016).

• ObstrucIveeventsinchildrenage12-18aresIllpredominantlyinREMandinthesupineposiIon;AAadolescentshavemoreREMobstrucIveevents.El-KershK,etal2016.

• Childrenwithmicrognathia,butnotchildrenwithisolatedclefpalatepriortorepair(+/-cleflip)aremorelikelytohaveOSAwhencomparedtocontrols(CieloCetal2016).

PAP Adherence

•  FemalesandchildrenwithdevelopmentaldelayaremorelikelytobeadherentwithCPAP,parIcularlyfemaleswithDownsyndrome.

• Only49%ofpaIentsusedCPAPforatleast4hoursonatleast70%ofnights.

HawkinsSetal2016

Insomnia

• UseoftheJuStmethod(6groupsessions–5forchildren,1forparents;uIlizingcogniIveandbehavioralintervenIons(sleephygiene,SCtherapy,relaxaIon/guidedimagery/self-hypnosis,anxietymanagementtechniques,psychoeducaIon)waseffecIveforchildrenages11-16.Treatmenteffectsweremaintainedat3,6,and12monthfollowup(RoeserKetal2016).

• PubertalmaturaIonisassociatedwithaprogressiveincreaseinprevalenceofinsomniasymptomswiththeemergenceoffemalepreponderance(ZhangJ,ChanN,LamS2016).

Circadian Rhythms

•  EarlyMarchDSTonsetaffectedsleepandvigilanceinhighschoolstudents,withanaverageof32minuteslesssleeppernightduringtheweekfollowingDST,resulInginincreaseddayImesleepiness,reducedreacIonImes,andincreasedlapsesonthePVT.(MedinaDetal2015).

Narcolepsy and Idiopathic Hypersomnia • Childrenwithtype1narcolepsymayhaveflajeningofthecircadianrhythm,demonstraIngincreasedmotoracIvityduringthenightandbluntedacIvityintheafernoon(FilardiMetal2016).

• Childrenwithtype1narcolepsywerecomparedwithnormalcontrolsandchildrenwithidiopathicepilepsy.NarcolepIcchildrenhadworsepsychosocialhealth,increasedinternalizingproblems,andbehavioralproblemsthanchildrenwithepilepsyornormalcontrols.Theseproblemsweresignificantlycorrelatedwithsleepiness(RoccaFetal2016).

• ChildrenwithIHSconInuetoexperiencearangeofsignificantpsychosocialconsequences(academicperformance,QoL,wellness,sleepiness,parIcipaIoninextracurricularacIviIes)evenaferadiagnosishasbeenmadeandtreatmentsiniIated(AvisKetal2015).

Chronic Fatigue Syndrome

•  SystemaIcreviewof6case-controlledstudies;allwerelowqualityevidence

• MostfoundthatchildrenandadolescentswithCFShadmoresleepcomplaintswhencomparedtohealthycontrols.

•  FurtherresearchshouldfocusonidenIfyingspecificsleepsymptoms,consequencesofsleepdisturbance,andeffecIveintervenIonsinthispopulaIon

•  SnodgrassKetal2015

Mental and Behavioral Health

• DelayedschoolstartImes(45minutes)improvedtardinessanddisciplinaryissuesthatpersistedunIltheendoftheacademicyear,butattheendoftheyearstudentstotalsleepImereturnedtobaselinelevelswithadelayinbedIme(ThacherPetal2016).

• MetaanalysisofPSGin11studiesonsleepandADHDfoundfewdifferencesinsleepbetweenchildrenwithADHDandcontrols,withapossibletrendtowardmoreN1inchildrenwithADHD(Diaz-RomanAetal2016).

Sleep in Medical Illness

• CriIcallyillchildreninthePICU,venIlatedandtreatedwithopioidsandbenzodiazepines,didnotdemonstrateday-nightorganizaIonofsleepandhaddiminisheduntradianvariabilityinEEGpower(KudchadkarS,etal2015).

Sleep Duration: Consensus Statement of AASM, AAP, NIH

• Panelof13expertsreviewed864relevantarIcles•  ParuthiSetal2016

• RecommendedsleepduraIons(includenaps)•  4monthsto12months:12to16hours•  1to2years:11to14hours•  3to5years:10to13hours•  6to12years:9to12hours•  13to18years:8to10hours

Sleep Duration: Consensus Statement of AASM, AAP, NIH SleepingtherecommendedhoursonaregularbasisisassociatedwithbejerhealthoutcomesincludingimprovedajenIon,behavior,learning,memory,emoIonalregulaIon,qualityoflife,andmental/physicalhealth.

RegularlysleepingfewerthantherecommendedhoursisassociatedwithproblemsinajenIon,behavior,andlearning.Insufficientsleepalsoincreasesriskofaccidents,injuries,hypertension,obesity,diabetes,anddepression.

Insufficientsleepinteenagersisassociatedwithincreasedriskofself-harm,suicidalthoughts,andsuicideajempts.

Sleepingmorethantherecommendedhoursmaybeassociatedwithadversehealthoutcomessuchashypertension,diabetes,obesity,andmentalhealthproblems.

Sleepingtoolijleortoomuchmaybeassociatedwiththepresenceofasleepdisorder

General Development

•  OlderageisassociatedwithlowerpercentageofN3,higherN2,andhigherREMsleep.EEGpowerinhigherfrequencybandswaslowerinoldervs.youngeradolescents,withequaleffectsacrosselectrodes.Olderboys(butnotgirls)hadmorefrequentawakeningsandWASO(Bakeretal2016).

•  Sigmafrequenciesbecomelinearlyfasterwithageandsigmapowerdeclineswithacomplextrajectory,mostlikelyduetosynapIceliminaIon(CampbellIetal2016).

•  Bothadolescentsandpreadolescentswithacircadianpreferenceforeveningnesshaveimpairedsleepquality.Preadolescentsweremoreinvolvedingamingandtelevision,andadolescentsweremoreinvolvedininternet,phone,andsocialnetworkacIviIeswhentheywerenotsleeping(BruinO,etal2015).

•  PretermchildrenhaveshortersleepduraIonthantermchildrenevenatage5-12measuredbyacIgraphy.ParentalesImatesofsleepwereabout45minuteslongerthanacIgraphicesImates(BiggsSetal2016).

Cognition

• AdayImenapwasassociatedwithmoreeffecIvelearningofwordmeanings,includingforgetngofirrelevantinformaIon,intoddlers(HorvathKetal2016).

• AweekofparIalsleepdeprivaIon(5hrs/night)impairsawiderangeofcogniIvefuncIons,alertness,andmoodeveninhigh-performinghighschooladolescents.Evenafer2nightsofrecoverysleep(9hours/night),sleepinessandsustainedajenIondidnotreturntobaseline(LoJ,OngJetal2016).

Sleep Education

•  SystemaIcreviewevaluated“lessonslearned”from13studies,toidenIfyfactorscontribuIngtosuccessandtomakerecommendaIonsforimprovement.

• RecommendaIons:•  TeacherparIcipaIonisessenIal•  Parentandfamilyinvolvementmusthappen•  SleepeducaIonshouldbeginearlierthanhighschool•  MoIvaIonalcomponentsshouldbeincluded•  ConsideronlinedeliveryandinteracIveengagement•  Includingsleepdiariesishelpful•  Considerculturalimpact

BlundenS,etal

Scoring Sleep in Infants

•  Scorein30secondepochsasWake(W),REM(R),NREM(N),andtransiIonal(T).

• MinimumEEGmontageisF3-M2,F4-M1,C3-M2,C4-M1,O1-M2,O2-M1;C3-Cz,Cz-C4helptodetectearlyandasynchronousspindles.

•  SleeponsetismostofenRunIl2-3monthsposjerm• DrowsinessisbestscoredbyvisualobservaIon• WideopeneyesiscrucialdeterminantofW

• Regular/irregularrespiraIonisveryusefulforscoringsleepstages• Presenceofspindles=N•  ScoreRwithany4ormoreofthefollowing:lowchinEMG,eyesclosedwithatleast1REMandlowchinEMG,irregularrespiraIon,mouthing/sucking/twitchin,nospindles

Scoring Sleep in Infants

•  ScoreRwithany4ormoreofthefollowing:•  lowchinEMG•  eyesclosedwithatleast1REMandlowchinEMG•  irregularrespiraIon•  mouthing/sucking/twitching•  conInuousEEGpajernnospindles

•  ScoreNwithany4ormoreofthefollowing:•  regularrespiraIon•  EEGpajernoftracealternans,highvoltageslowacIvity,orspindles

•  eyesclosedwithnoeyemovement•  chintonepresent

•  ScoreTifepochcontains2ormorediscordantPSGstatesGrigg-DambergerM2016.

Reference List AvisK,ShenJ,WeaverP,etal.PsychosocialcharacterisIcsofchildrenwithcentraldisordersofhypersomnolenceversusmatchedhealthychildren.JClinSleepMed2015;11(11):1281-1288.BakerF,WilloughbyA,deZambotM,etal.Age-relateddifferencesinsleeparchitectureandelectroencephalograminadolescentsintheNaIonalConsorIumonAlcoholandNeurodevelopmentinAdolescencesample.Sleep2016;39(7):1429-1439.BhajacharjeeR,Kheirandish-GozalL,KadiIsA,etal.C-reacIveproteinasapotenIalbiomarkerofresidualobstrucIvesleepapneafollowingadenotonsillectomyinchildren.Sleep2016;39(2):283-291.BiggsS,MeltzerL,TapiaI,etal.Sleep/wakepajernsandparentalpercepIonsofsleepinchildrenbornpreterm.JClinSleepMed2016;12(5):711-717.

BlundenS,RigneyG.LessonslearnedfromsleepeducaIoninschools:areviewofdosanddon’t’s.JClinSleepMed2015;11(6):671-680.BruinO,SejeS,FontanesiL,etal.Technologyuseandsleepqualityinpreadolescenceandadolescence.JClinSleepMed2015;11(12):1433-1441.

Reference List CampbellI,FeinbergI.MaturaIonalpajernsofsigmafrequencypoweracrosschildhoodandadolescence:alongitudinalstudy.Sleep2016;39(1):193-201.

CieloC,TaylorJ,VossoughA,etal.EvoluIonofobstrucIvesleepapneaininfantswithclefpalateandmicrognathia.JClinSleepMed2016;12(7):979-987.

ComG,CarrollJ,TangX,etal.CharacterisIcsandsurgicalandclinicaloutcomesofseverelyobesechildrenwithobstrucIvesleepapnea.JClinSleepMed2015;11(4):467-474.

Diaz-RomanA,Hita-YanezE,Buela-CasalG.SleepcharacterisIcsinchildrenwithajenIon-deficithyperacIvitydisorder:systemaIcreviewandmeta-analysis.JClinSleepMed2016;12(5):747-756.

El-KershK,CavallazziR,PatelP,etal.EffectofsleepstateandposiIononobstrucIverespiratoryeventsdistribuIoninadolescentchildren.JClinSleepMed2016;12(4):513-517.

ErdimI,AkcayT,YilmazerR,etal.IsmetabolicsyndromeassociatedwithobstrucIvesleepapneainobeseadolescents?JClinSleepMed2015;11(12):1371-1376.

Reference List FilardiM,PizzaF,BruniO,etal.Circadianrest-acIvityrhythminpediatrictype1narcolepsy.Sleep2016;39(6):1241-1247.

Grigg-DambergerM.Thevisualscorigofsleepininfants0to2months.JClinSleepMed2016;12(3):429-445.

HawkinsS,JensenE,SimonS,etal.CorrelatesofpediatricCPAPadherence.JClinSleepMed2016;12(6):879-884.

HoA,MoulD,KrishnaJ.Neckcircumference-heightraIoasapredictorofsleeprelatedbreathingdisorderinchildrenandadults.JClinSleepMed2016;12(3):311-317.

HorvathK,LiuS,PlunkejK.AdayImenapfacilitatesgeneralizaIonofwordmeaningsinyoungtoddlers.Sleep2015:39(1):203-207.

IshmanS,TawfikK,SmithD,etal.ScreeningforpediatricobstrucIvesleepapneabeforeambulatorysurgery.JClinSleepMed2015;11(7):751-755.

Reference List KudchadkarS,YasterM,PunjabiA,etal.TemporalcharacterisIcsofthesleepEEGpowerspectrumincriIcallyillchildren.JClinSleepMed2015;11(12):1449-1454.LoJ,OngJ,LeongR,etal.CogniIveperformance,sleepiness,andmoodinparIallysleepdeprivedadolescents:theneedforsleepstudy.Sleep2016;39(3):687-698.MarisM,VerhulstS,WojciechowskiM,etal.PrevalenceofobstrucIvesleepapneainchildrenwithDownSyndrome.Sleep2016;39(2):699-704.MedinaD,EbbenM,MilradS,etal.AdverseeffectsofdaylightsavingImeonadolescents’sleepandvigilance.JClinSleepMed2015;11(8):879-884.ParuthiS,BrooksL,D’AmbrosioCetal.RecommendedamountofsleepforpediatricpopulaIons:aconsensusstatementoftheAmericanAcademyofSleepMedicine.JClinSleepMed2016;12(6):785-786.RoccaF,FiotE,PizzaF,etal.Psychosocialprofileandqualityoflifeinchildrenwithtype1narcolepsy:acasecontrolstudy.Sleep2016;39(&):1389-1398.

Reference List RoeserK,SchwerdtleB,KublerA,etal.FurtherevidencefortheJuStprogramastreatmentforinsomniainadolescents:resultsfroma1yearfollow-upstudy.JClinSleepMed2016;12(2):257-262.SnodgrassK,HarveyA,ScheinbergA,etal.SleepdisturbancesinpediatricchronicfaIguesyndrome:areviewofcurrentresearch.JClinSleepMed2015;11(7):757-764.TapiaI,MarcusC,McDonoughJ,etal.AirwayresistanceinchildrenwithobstrucIvesleepapneasyndrome.Sleep2016;39(4):793-799.ThacherP,OnyperS.LongitudinaloutcomesofstartImedelayonsleep,behavior,andachievementinhighschool.Sleep2016;39(2):271-281.WalterL,BiggsS,NisbetLetal.Long-termimprovementsinsleepandrespiratoryparametersinpreschoolchildrenfollowingtreatmentofsleepdisorderedbreathing.JClinSleepMed2015;11(10):1143-1151.ZhangJ,ChanN,LamS,etal.Emergenceofsexdifferencesininsomniasymptomsinadolescents:alarge-scaleschool-basedstudy.Sleep2016;39(8):1563-1570.

Year in Review: Insomnia

VirginiaSkiba,MDSeniorStaff

HenryFordSleepDisordersandResearchCenterDetroit,MI





Consultant

Speakers’ Bureaus

Financial support

Other



1.

2.

3.

Insomnia Update

• Pharmacologic:Suvorexant• Non-Pharmacologic:

• ThermalCooling• Web-basedCBT-I

Suvorexant

•  Belsomra•  ApprovedintheU.S.inAug2014•  ScheduleC-IVcontrolledsubstance

• MechanismofacIon:orexinreceptorantagonist• OrexinpathwayoriginatesinthelateralhypothalamusandprojectswidelythroughoutthebraintomediatetransiIonsbetweenwakefulnessandsleep

•  AntagonismoforexinreceptorsselecIvelydampensunwantedwakefulnessinterferingwithsleep

• Halflife:12hours•  Timetopeak:2hours

• Metabolism:primarilyhepaIcbyCYP3A

•  ExcreIon:primarilyinfeces

Suvorexant

• Efficacy:showntoimprovesleepefficiency• Michelsonetal.2014:

•  781paIentswithprimaryinsomniawererandomlyassignedtoreceivenightlysuvorexantorplaceboforoneyear,followedbyatwo-monthrandomizeddisconInuaIonphase.Thedoseofsuvorexantusedwas40mgforpaIents<65yoand30mgforpaIents≥65yo.

•  Atonemonth,paIentstreatedwithsuvorexanthadincreasedsubjecIvetotalsleepIme(39versus16minutes;difference23minutes,95%CI16-29)anddecreasedsubjecIveImetosleeponset(-18versus-8minutes,95%CI-15to-5)comparedwithplacebo.

•  ImprovementsinsubjecIvesleeppersistedatoneyear.•  Herringetal.2012:254subjectsreceiveddosesrangingfrom10to80mgnightlyfor4weeks

•  Comparedtoplacebo,suvorexantshowedimprovedsleepefficiencyofabout5-10%.IncreaseisTSTwasseenduetoincreaseinN2andREM.

Suvorexant

• Efficacy:showntoimprovesleepefficiency• Herringetal.2016:

•  AnalysisofpooleddatafromtwoidenIcalrandomized,double-blind,placebo-controlled,parallel-group,3-monthtrialsinnon-elderly(18–64years)andelderly(≥65years)paIentswithinsomnia.PaIentswererandomizedtosuvorexant20/15mg(non-elderly/elderly,N=493),suvorexant40/30mg(notreportedinthisarIcle),orplacebo(N=767).Efficacywasassessedbyself-reportedandpolysomnographysleepmaintenanceandonsetendpoints.

Differencebetweenplaceboandsuvorexantbetweenmeanchangefrombaseline:

Measure Week1/night1

1mo 3mos

sTST 15min 18.4min

16.0min

sTSO -6.1min

-5.6min

-5.9min

sWASO -5.3min

-6.6min

-4.7min

TST 44.8min

34.7min

27.5min

WASO -34.6min

-25.4min

-23.1min

LPS -11.2min

-9.1min

-4.6min

SE 9.3 7.2 5.7

ISI -- -1.4 -1.3

Suvorexant •  Sideeffects:

•  Somnolence(2-12%),morecommoninfemalesandwithhigherdoses•  ReboundinsomniacanbeseenwithdisconInuaIonofsuvorexant(instudiesof1yearbutnot1or3months)

•  MinimalpotenIaltoworsenrespiraIonsduringsleep•  Drivingisminimallyimpaired•  Headache(7%),dizziness(3%),abnormaldreams(2%),abnormalthinking/behaviorchanges,cough/URI(2%),sleepparalysis.Noreportedcasesofparasomniasorcataplexy.

•  Noevidenceforabuse.•  InteracIons:

•  SuvorexantismetabolizedbycytochromeP4503A4(CYP3A4),andthereispotenIalforincreasedtoxicitywhenusedincombinaIonwithCYP3A4inhibitors.

•  Dosing:•  Startat5mgandItrateasneededupto20mgoncedaily,takenwithin30minuteofgoingtobed,allowatleast7hrsinbed.

Thermal System for Insomnia

•  InMay2016,FDAapproveda“thermalsystemforinsomnia”–“aprescripIondeviceforuseinpaIentswithinsomniathatisusedtoapplyaspecifiedtemperature[14-16°C]totheskinsurface”.

•  CERÊVESLEEPSYSTEM

DeNovoSummary(DEN140032)hjp://www.accessdata.fda.gov/cdrh_docs/reviews/den140032.pdf.Accessed7/31/2016


•  “Ournoveltechnologyisdesignedtoworkdifferentlythanotherproductsandpills,byaddressingthesourceoftheproblem–calmingtheoveracIvemindthatisthoughttoberesponsibleforprevenIngusfromfallingasleepatnight.Bycalmingthismental“hyperarousal”,wecanturnoffourmindsandgettosleepfaster.”

h"p://cerevesleep.com/press-release.aspxAccessed7/31/2016

•  FrontalcorIcalhyperarousalininsomnia•  Thereisgrowingevidenceshowinghyper-metabolismduringsleepinthefrontalregions.

• MulIplestudiesshowincreasedbetaEEGpowerduringsleepandwakefulnessinthefrontalregions.


•  Efficacy:decreasedlatencytostage1andstage2sleep•  Randomized,mulI-centertrial,116primaryinsomniaadults,treatedfor2nights:nodifferencesforprimaryendpoint(sustainedsleep,sleepefficiency)butshoweddecreasedsleeplatencytostage1andstage2sleep

•  Cross-overtrialof145subjectstesIng2temperaturemodes,treatedfor5-7nights,nodifferencetopersistentsleeporsleepefficiency

•  32subjectsusedtreatmentathomefor30days,reportedimprovedself-reportedsleepquality,noseriousadverseeventswerereported

•  Labeling:“OtherthanreducIonofsleeplatencytoStage1andStage2sleep,theefficacyofothersleepmeasuresassociatedwithinsomniahasnotbeenestablishedbytheCerêveSleepSystemincontrolledclinicaltrials.“

•  Listedadverseevents:adverseskinreacIons,electricalsafety,thermalinjury

•  Adverseeventsnotedinstudies:headache

Web-based Cognitive Behavioral Therapy for Insomnia (CBT-I)

•  CogniIveBehavioralTherapyreceivedaStandardlevelofrecommendaIonbytheAASM(2006PracIceParameter)andisrecommendedastheiniIalintervenIonwhenappropriateandwhencondiIonspermit(2008clinicalguideline)

• However,therearefewtrainedprovidersandtherapymaybecostlyandnotavailableformanypaIents

•  SeveraltrialsshoweffecIvenessofweb-baseddeliveryofCBT-I•  Rijerbandetal.2009:22internetand22controlsubjects

•  MeanISIdecreasedfrom15.7to6.5,WASOdecreasedfrom66to29min,SEincreasedfrom77%to89%.At6months,ISIremainedlowat7.3intheinternetgroup

•  Espiteetal.2012:164subjectsassignedtoweb-basedCBT-I,web-basedcontrol(IRT)ortreatmentasusual

•  SEimprovedfrom63%to82%,SOLdecreasedfrom47to21min,WASOdecreasedfrom76to48min.Improvementsweresustainedat6months.

Web-based CBT-I •  Randomizedtrialsshowweb-basedCBT-IiseffecIve,butmaybelesseffecIvecomparedtoin-persontherapy

•  Lanceeetal.2016:guidedonline(withe-mailfeedback)andindividualface-to-faceCBT-Iwerecomparedtoawait-listcondiIon

•  Atpost-assessment,face-to-faceandonlineintervenIongroupsshowedsignificantlylargertreatmenteffectsthanthewait-listgrouponinsomniaseverityandsleepefficiency

•  Largertreatmenteffectwasseenintheface-to-facegroup,especiallyondepressionandanxietyoutcomes

Web-based CBT-I

•  Treatmenteffectsremainedgreaterfortheface-to-facegroupat3and6monthfollowup

Web-based CBT-I

• Web-basedCBT-Iismorecost-effecIvethanin-personCBT-I

•  DeBruinetal.2016:62parIcipants,aged12-19yo,randomizedtoweb-basedCBT-Iwithpersonalfeedback(IT)comparedtogroupCBT-I(GT)

•  Ateachmeasurementoccasion,parentsfilledoutretrospecIvecostquesIonnairesthatreportedonresourceusageoverthepast2months(e.g.,doctors’visits,useofmedicaIon,mentalhealthcarevisits,addiIonalhelpatschool/home,etc.)

•  IThadasmallercostposjreatmentat1year,mostlyduetothedifferencesiscostofthetherapy

•  TherewasnosignificantdifferenceinproporIonsofparIcipantsinITandGTwhohadSE≥85%:atposjreatment,87%forITand74%forGTandat1year90%forITand94%forGT

$300,1year

$135,16-weeks

Take home points

•  SuvorexantisaneffecIvepharmacologictreatmentofinsomnia,withminimalresidualsleepiness.

•  Thermalsystemforinsomniaiswelltoleratedbutprovidesminimalimprovementininsomniawithdecreasedlatencytostage1andstage2sleep.

• Web-basedCBT-IisaneffecIvealternaIvemethodofdeliveringCBT-Iatasmallercost.

References: Insomnia

•  Suvorexant•  FDANewsRelease.FDAapprovesnewtypeofsleepdrug,Belsomra.August13,2014.hjp://www.fda.gov/newsevents/newsroom/pressannouncements/ucm409950.htm.Accessed7/31/2016

•  HerringWJ,ConnorKM,SnyderE,SnavelyDB,ZhangY,HutzelmannJ,Matzura-WolfeD,BencaRM,KrystalAD,WalshJK,LinesC,RothT,MichelsonD.SuvorexantinpaIentswithinsomnia:pooledanalysesofthree-monthdatafromphase-3randomizedcontrolledclinicaltrials.JClinSleepMed2016;12(9):1215–1225.

•  HerringWJ,SnyderE,BuddK,HutzelmannJ,SnavelyD,LiuK,LinesC,RothT,MichelsonD.Orexinreceptorantagonismfortreatmentofinsomnia:arandomizedclinicaltrialofsuvorexant.Neurology.2012Dec;79(23):2265-74.Epub2012Nov28.

•  MichelsonD,SnyderE,ParadisE,Chengan-LiuM,SnavelyDB,HutzelmannJ,WalshJK,KrystalAD,BencaRM,CohnM,LinesC,RothT,HerringWJ.Safetyandefficacyofsuvorexantduring1-yeartreatmentofinsomniawithsubsequentabrupttreatmentdisconInuaIon:aphase3randomised,double-blind,placebo-controlledtrial.LancetNeurol.2014May;13(5):461-71.Epub2014Mar27.

•  SunH,PalczaJ,CardD,GipsonA,RosenbergR,KrygerM,LinesC,WagnerJA,TroyerMD.EffectsofSuvorexant,anOrexinReceptorAntagonist,onRespiraIonduringSleepInPaIentswithObstrucIveSleepApnea.JClinSleepMed.2016Jan;12(1):9-17

•  VermeerA,SunH,VuurmanEF,JongenS,VanLeeuwenCJ,VanOersAC,PalczaJ,LiX,LaethemT,HeirmanI,BautmansA,TroyerMD,WrishkoR,McCreaJOn-the-RoadDrivingPerformancetheMorningaferBedImeUseofSuvorexant20and40mg:AStudyinNon-ElderlyHealthyVolunteers.Sleep.2015;38(11):1803.


•  Thermalcoolingdevice•  DENOVOCLASSIFICATIONREQUESTFORCERÊVESLEEPSYSTEM.hjp://www.accessdata.fda.gov/cdrh_docs/reviews/DEN140032.pdf.Accessed7/31/2016

•  ClassificaIonOrder.hjp://www.accessdata.fda.gov/cdrh_docs/pdf14/den140032.pdf.Accessed7/31/2016.

•  Frontalac5va5onininsomnia•  ColomboMA,RamautarJR,WeiY,Gomez-HerreroG,StoffersD,WassingR,BenjaminsJS,TagliazucchiE,vanderWerfYD,CajochenC,VanSomerenEJW.Wakehigh-densityelectroencephalographicspaIospectralsignaturesofinsomnia.SLEEP2016;39(5):1015–1027

•  Fernandez-MendozaJ,LiY,VgontzasAN,FangJ,GainesJ,CalhounSL,LiaoD,BixlerEO.InsomniaisassociatedwithcorIcalhyperarousalasearlyasadolescence.SLEEP2016;39(5):1029–1036.

•  NofzingerEA;NissenC;GermainAetal.RegionalcerebralmetaboliccorrelatesofWASOduringNREMsleepininsomnia.JClinSleepMed2006;2(3):316-322.


•  CBT-I•  MorgenthalerT;KramerM;AlessiCetal.PracIceparametersforthepsychologicalandbehavioraltreatmentofinsomnia:anupdate.AnAmericanAcademyofSleepMedicinereport.SLEEP2006;29(11):1415-1419.

•  Schuje-RodinS;BrochL;BuysseD;DorseyC;SateiaM.ClinicalguidelinefortheevaluaIonandmanagementofchronicinsomniainadults.JClinSleepMed2008;4(5):487-504.

•  Web-basedCBT-Idelivery•  DeBruinEJ,vanSteenselFJ,MeijerAM.Cost-effecIvenessofgroupandinternetcogniIvebehavioraltherapyforinsomniainadolescents:resultsfromarandomizedcontrolledtrial.SLEEP2016;39(8):1571–1581.

•  EspieCA;KyleSD;WilliamsC;OngJC;DouglasNJ;HamesP;BrownJSL.Arandomized,placebo-controlledtrialofonlinecogniIvebehavioraltherapyforchronicinsomniadisorderdeliveredviaanautomatedmedia-richwebapplicaIon.SLEEP2012;35(6):769-781.

•  LanceeJ,vanStratenA,MorinaN,KaldoV,KamphuisJH.Guidedonlineorface-to-facecogniIvebehavioraltreatmentforinsomnia:arandomizedwait-listcontrolledtrial.SLEEP2016;39(1):183–191.

•  RijerbandLM,ThorndikeFP,Gonder-FrederickLA,MageeJC,BaileyET,SaylorDK,MorinCM.EfficacyofanInternet-basedbehavioralintervenIonforadultswithinsomnia.ArchGenPsychiatry.2009Jul;66(7):692-8.


•  Web-basedCBT-I•  hjps://www.sleepio.com/•  hjp://shuI.me/•  hjp://t2health.dcoe.mil/apps/CBT-i:adjunctforface-to-facecare;acollaboraIveeffortbetweenVA’sNaIonalCenterforPTSD,StanfordSchoolofMedicineandDoD’sNaIonalCenterforTelehealth&Technology.

•  hjp://cobaljx.com/cbt-online-insomnia-treatment.html•  hjp://www.sleeptutor.com/•  hjp://www.cb�orinsomnia.com/

Websitesaccessed7/31/2016and8/31/2016

Year in Review: Sleep & Medical

Disorders Q.AfifaShamim-Uzzaman,MD

Director,AAVASleepDisordersCenter

AssistantProfessor,UniversityofMichigan





Consultant

Speakers’ Bureaus

Financial support

Other



1.

2.

3.

Sleep & Kidney Disease

SubjectswithloweresImatedglomerularfiltraIonratewereolder,moreobese,moreofenfemale,hadworseobstrucIvesleepapneaandmoreco-morbidiIes

MarroneOetal.ChronickidneydiseaseinEuropeanpaIentswithobstrucIvesleepapnea:theESADAcohortstudy.SleepRes.2016May18.doi:10.1111/jsr.12426.

OSA & Psoriasis

P<0.001

N=12,336 N=24,008

OddsraIo=1.27(95%CI1.08–1.49,p<0.001)whenadjustedforage,sex,ethnicity,BMI,COPD,hypothyroidism,hyperlipidemia,andpepIcdisease.

ShalomG,DreiherJ,CohenA.PsoriarisandOSA.IntlJDerm;2016July15.

Non-Apnea Sleep Disorders & Auto-Immune Dysfunction

HsiaoYH,ChenYT,TsengCM,WuLA,LinWC,SuVY,PerngDW,ChangSC,ChenYM,ChenTJ,LeeYC,ChouKT.Sleepdisordersandincreasedriskofautoimmunediseasesinindividualswithoutsleepapnea.SLEEP2015;38(4):581–586.

PaIentswithnon-apneasleepdisordersareassociatedwithahigherriskfordevelopingautoimmunediseases.

OSA & Cancer

Nieto,Peppard,Young,etal.:Sleep-disorderedBreathingandCancerMortality.AmJRespirCritCareMed.2012Jul15;186(2):190–194.

MarshallNS;WongKK;CullenSR;KnuimanMW;GrunsteinRR.Sleepapneaand20-yearfollow-upforall-causemortality,stroke,andcancerincidenceandmortalityintheBusseltonhealthstudycohort.JClinSleepMed2014;10(4):355-362.

N=393

WisconsinSleepCohort

SleepMedicine15(2014)1016–1020

EuropeanRespiratoryJournal201443:1661-1668;DOI:10.1183/09031936.00115413

SleepMedicine15(2014)749–754

N=5.6million

SLEEP2016;39(8):1493–1500

Sleep, Stroke, & Stroke Recovery

SleepDisorderedBreathing•  SDBisanindependentpredictorofstroke•  StrokeriskincreaseswithincreasingAHI•  SDBmostsevereinacutestroke&improvedduringrecovery

•  53%ofpaIentshadAHI>10fourweekspoststroke

•  StrokepaIentsmayhavecombinaIonofOSA&CSA

•  InpaIentswithstroke,OSA(AHI>15orAHI>20)predictsdeathornonfatalcardiovascularevents(namelyrecurrentstroke)

Hypersomnia•  MostlyfoundafersubcorIcalandpontomesencephalicstroke

•  Althoughhypersomniaimprovesduringthefirstmonthspoststroke,faIguecanpersistforyears.

•  FaIgue2yearspoststrokeassociatedwithnursinghomereferralandpredictedmortalityinthefollowingyear

•  longsleep(8–9+hourssleep/nightinquesIonnaires),isanindependentpredictorofincidentstroke

•  EDSpredictsstroke&impairsstrokerecovery

HermannDM,BassetCL.Roleofsleep-disorderedbreathingandsleep-wakedisturbancesforstrokeandstrokerecovery.Neurology.2016Aug3.pii:10.1212/WNL.0000000000003037.[Epubaheadofprint]

Sleep, Stroke, & Stroke Recovery

•  12-13%ofStrokepa5entshadRLS15-30daysaSerstroke.•  ThosewithRLShadahigherneckcircumference,poorersleepquality,andhigherdiabetesprevalencethanpaIentswithoutRLS.

•  RBDprevalenceinischemicstrokepa5ents~11%.

•  46%ofpaIentswithRBDhadbrainsteminfarcts.

•  Duringthefirstmonthspoststroke,insomniaprevalencemaybeashighas50%.

•  Shortsleep(<5–6hourssleep/nightinquesIonnaires)andphysician-diagnosedinsomniaareindependentpredictorsofincidentstroke

•  Shortsleep(</=5hourssleep/night)predictedcardiovasculareventsonlywhensymptoma5c(i.e.,associatedwithdifficultyfallingasleep,difficultymaintainingsleep,earlymorningawakening,ornonrestoraIvesleep),butnotwhenasymptomaIc

HermannDM,BassetCL.Roleofsleep-disorderedbreathingandsleep-wakedisturbancesforstrokeandstrokerecovery.Neurology.2016Aug3.pii:10.1212/WNL.0000000000003037.[Epubaheadofprint]

HsuCYetal.TheAssociaIonBetweenInsomniaandIncreasedFutureCardiovascularEvents:ANaIonwidePopulaIon-BasedStudy.PsychosomMed.2015Sep;77(7):743-51.

SleepBreath2016;DOI10.1007/s11325-016-1393-1

N=3,162,083 27cohortstudies

HR1.28;95%CI0.96–1.69

HR1.19;95%CI0.86–1.65

HR2.13;95%CI1.94–3.85

HR1.86;95%CI,1.81–1.91


1.24(0.53–2.55)

2.05(0.57–5.47)2.73(1.94–3.85)

HR2.36;95%CI,1.22–4.57


CSA & HF (SERVE-HF) •  InternaIonal,mulIcenter,randomized,parallel-group,event-drivenstudy

•  InvesIgateeffectsofaddingASVtoguideline-basedmedicaltreatmentonsurvivalandCVoutcomesinpaIentswithHFrEFandpredominantlyCSA(withAHI>15)

•  Primaryendpoint=1stofunplannedhospitalizaIonworseningHF,lifesavingCVintervenIon,ordeath

•  Recruitedover5years+2yearfollowup.Target651events

SERVE – HF Baseline Characteristics

Early Discontinuation of Study

After SERVE-HF, AASM recommends

• AdapIveservo-venIlaIon(ASV)targetedtonormalizetheapnea-hypopneaindex(AHI)shouldnotbeusedforthetreatmentofCSASrelatedtoCHFinadultswithanejec5onfrac5on≤45%andmoderateorsevereCSApredominant,sleep-disorderedbreathing.(STANDARDAGAINST)

• AdapIveservo-venIlaIon(ASV)targetedtonormalizetheapnea-hypopneaindex(AHI)canbeusedforthetreatmentofCSASrelatedtoCHFinadultswithanejec5onfrac5on>45%ormildCHF-relatedCSAS.(OPTION)

Summary

• PaIentswithsleepapneaareatincreasedriskforCKDandESRDcomparedwiththegeneralpopulaIon.

•  ThosewithlowereGFRtendtobeolder,moreobese,moreofenfemale,andhaveworseobstrucIvesleepapneaandmoreco-morbidiIes

•  Insomniaisassociatedwithanincreasedriskoffuturecardiovascularevents(MI&Stroke)

• PaIentswithsleepapneaandnon-apneasleepdisordersareincreasedatriskforauto-immunedisorders

• AssociaIonsbetweensleepapneaandcancerappeartobeselecIveandaffectcertaintypesofsolidmalignanciessuchasmelanomaandthoseofthekidneyandpancreas

• ASVshouldNOTbeusedfortreatmentofCSAinpaIentswithHFrEF.

Year in Review: Updates on Non PAP Rx

for OSA NeerajKaplish,M.D.

President,MASM

MedicalDirector,UofMSleepLab

AssistantProfessor,Dept.ofNeurology





Consultant

Speakers’ Bureaus

Financial support

Other



1.

2.

3.

We Have Options. Do We ?

Life Style Modifications: Wt. Loss -OSA

•  RandomizedcontrolledtrialcomparedChineseOSApaIents(withAHI>15)toreceivedieIcianledLMPvsusualcare.

•  Followup-12months

•  LMPwasmoreeffecIveinreducing•  AHIfrombaseline(P=0.011)•  BMIfrombaseline(P<0.001)

•  MentalhealthandhealthiereaInghabitswerenotedat4monthsandsustainedat12months

SusannaS.S.Ngetal,CHEST2015;148(5):1193-1203

Medications-Weight Loss and OSA

•  32weeksofrandomized,double-blindtrialinOSApts(AHI>15)ofLiragluIdevs.Placebo,bothasadjuncttodietandexercise.

•  MeanAge-49.2•  Males-71.5%•  MeanAHI-49.2•  SevereOSA-67.1%•  BMIof39.1

•  LiragluIdearmshowedagreaterreducIonin

•  AHI(12.2vs6.1)P=0.015•  Weight(5.7%vs1.6%)P<0.0001•  HbgA1c•  SystolicBP

ABlackmanetal,IntJObes(Lond)2016Aug.4(8):1310-9(

Weight Loss Surgery and Sleep Apnea •  205OSApaIents(AHI>15)whounderwentRoux-en-YgastricbypasswhichunderwentpreandpostoperaIvePSG

•  MeanAHI-32.3•  MeanBMI-46•  Meanage-48.8years•  Women–63%

•  FollowUp(mean8.6months)showed•  MeanBMIdecreaseof12.2•  Excessweightlossof61.1%•  MeanAHIwas8.5

•  About25.9%sIllhadAHI>15

ChristelA.L.deRaffetal,SurgObesRelatDis2016Mar

PAP Compliance After Weight Loss Surgery

•  RetrospecIvecontrolledcohortstudystudiedcomplianceinsevereOSApts(s/pbariatricsurgery)vsmatchedcontrols.Followup-2yrs.

•  AsinglecenterstudyataTerIaryCenterinFrance.

•  Predictorsofnon-complianceonunivariateanalysisincluded

•  FemaleGender•  Absenceofco-morbidites•  GreaterWeightLoss•  LowerOSAseverity

•  NofactorswerepredicIveonmulIvariateanalysis

CAgostaetal,ObesSurg201626:2082-2088

STAR Trial- 3 Year Follow Up

Otolaryngol Head Neck Surg. 2016 Jan;154(1):181-8

STAR Trial- 3 Year Follow Up

Otolaryngol Head Neck Surg. 2016 Jan;154(1):181-8

THN Stimulation-6 Month F/U

N=46paIentsimplantedPrimaryOutcomes≥50%reducIoninAHI+AHI<20

RepeatPSGat6months15of43(35%)wereAHIrespondersAHI=35.7to8.528of43(65%)werenonAHIrespondersAHI=34.5remainedat34.5

PredictorsofsuccessAHI<65AI<30BMI<35ODI<15fordesaturaIons>10%

Laryngoscope. 2016 Mar 24. doi: 10.1002/lary.25909

Who’s Got better OA Compliance?

•  1yearadherencewithOAtherapy•  Arousers-85%•  Desaturators-55%(P=0.034)

•  AHIwasreducedinboth•  Arousers(14to3)•  Desaturaters(18to7)

•  Femalegenderwashigherarousers.

•  77%reportedsideeffectsbutmajoritysIllsaIsfied.

•  Despiteimprovementinindices,dayImesymptomsdidnotimprove

J Clin Sleep Med. 2016 Aug 15;12(8):1159-65

OA vs CPAP in P-OSA

• MaleOSApts(AHI>15)whohadP-OSAtreatedwithOAandCPAPwerecompared.

• P-OSAwasdefinedas•  Supine≥2xLateralAHI•  Lateralsleep>60min•  LateralREM>10min

• PrimaryendpointbeingAHI

J Clin Sleep Med. 2016 Aug 15;12(8):1113-9

OA Treatment Affects BP

•  ReducIonwasseeninBPbothSBPandDBPbutonlyDBPreducIonwassignificant

•  ReducIonwasmuchhigherforbothSBPanDBPiftherewashypertensionpriortoOAtherapy.

• MeanSBPreduc5onwas11.3mmHg

• MeanDBPwas6.4mmHg

StudypopulaIonwasJapanese Men188

Women49MeanAge54.7yearsMeanBMI24.6

BPwasmeasuredinclinicvisits

Clin Exp Hypertens. 2016;38(4):404-8

Who should get a UPPP ?

• Meta-analysisof15studies(tricklefromsearchof1257studies)showedfollowingaspredictorsof

•  Success–FriedmanStageI•  Failure-FriedmanStageIII

LowHyoidSuspension•  NotSignificant-AgeBMIPre-opera5veAHICephalometrics

Otolaryngol Head Neck Surg. 2016 Aug 2

Multilevel Surgery Risks ?

• ComparedUPPP,UPPP+NCandUPPP+BOTforcomplicaIons

•  Overall• Medical•  Surgical•  Readmission•  ReturntoOR•  Death•  HospitalStayLength

OtolaryngolHeadNeckSurg.2016Aug23

What about MMA ? • Meta-analysisof45studies(518paIents)showed

•  78%(wheredataavailable)hadgonepriorsurgery

•  AHIwasreducedby47.8

•  RDIwasreducedby44.4

•  PAwentfrom5.5to11.5mm

•  ESSreducedfrom13.5to3.3

• MeanMaxillaryAdvance-9mm

• MeanMandibularAdvance-10.2mm

JAMAOtolaryngolHeadNeckSurg.2016Jan;142(1):58-66

QUESTIONS

Documents

Clinical Sleep Medicine Update: Year in Revie · Sleep Duration: Consensus Statement of AASM, AAP, NIH • Panel of 13 experts reviewed 864 relevant arIcles • Paruthi S et al 2016