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SleepDisorders:WhatOptometrists

NeedtoKnowA.PaulChous,MA,OD,FAAO

Tacoma,WA

Disclosures•  Ihavespokenfor,beenonadvisoryboardsfororhavebeenpaidconsultantsfor:

Bausch&Lomb,Genentech,Konan,NovoNordisk,Optos,Optovue,Regeneron,VSP,Zeiss,ZeaVision

MyFocus•  Sleepproblemsareprevalent

•  Sleepproblemscontributetoeyedisease&systemicdiseasethatislinkedtoeyedisease

•  ECPscanhelppatientswithsleepproblemsgetdiagnosedandtreated

SleepDisorders–WhatWeThinkOf

It’sNOTJustSleepApnea•  BroaderDefinitionofSleepDisorders

– Parasomnia:episodicsleepeventsincludingsleepterrordisorder,sleepwalkingandnightmaredisorder

– -Dyssomnia:abnormalitiesintheamount,duration,qualityortimingofsleep;PrimaryvsSecondary

=MostPrevalent

Sleep Walking Talking

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Dyssomnia•  Primary:Primaryinsomnia,narcolepsy,circadianrhythmdisorders,andsleepdisorderedbreathingincludingsleepapnea(central,obstructive,mixedforms)

•  Secondary:sleepdisorderscausedbypsychosocialstressors,anxiety,depression,diet(caffeine/alcohol/nicotine),medications(anti-depressants)

Epidemiology•  Estimatedthat20-40%ofAmericansexperiencesleep

problemseachyear•  50%ofthose>50yearsold

•  25%offatalmotorvehicleaccidentsareduetosleepinessordriverfatigue

•  Sleepdeprivationsignificantlyincreasesriskofmedicalerrors– 100Kdeathsin2006;250,000in2016–  CommitteeonSleepMedicine,WashingtonD.C.,TheNationalAcademiesPress2006–  SleepReview,February27,2017

MMWRMorbMortalWklyRep.2014;63:557-562.

•  17-18.5hoursofwakefulnessimpairsmotorfunctiononaparwithormorethanabloodalcoholcontent(BAC)=0.05%

•  17.74-19.65hourswithoutsleepwasequivalenttoBAC=0.10%

SleepDurationAcrosstheLifespanSleepMedRev.2012Jun;16(3):199–201.

Insomnia•  Prolongedsleeplatencyand/orreduceddurationofsleep– Acute:30%ofAmericanseachyear(>1monthduration)–  ChronicInsomniaSyndrome:10%eachyear(>3monthsduration)

–  Ifadjustedfordepression,about6%/year–  Bydefinition,accompaniedbyinterferencewithwakefulactivity(e.g.excessivedaytimesleepiness=EDS)

JClinSleepMed.2007Aug15;3(5Suppl):S7–S10.

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Hyposomnia:ShortSleep(<7h)isCommon

•  BehavioralRiskFactorSurveillanceSystem2014•  35%ofUSadults

– 68%ofteensget<8hours(NSFrecommends8.5)

•  46%ofAfricanAmericans&NativeHawaiians•  SignificantlymorecommoninadultswithCAD,stroke,asthma,COPD,diabetes,CKD,depression

PrevalenceofShortSleepDurationbyState,2014CDCBRFSSData AverageSleepDurationinUSAdults

2hourreductionsince1960

Doyougetenoughsleepandisitimportant?

FewerpeoplereportingEnoughsleepovertime

Maximalwell-beingscoresAt8hourspernight

MyPatients•  50yopsychiatristwithT2DMandBMI=40Kg/m2

– GlaucomaSuspectinforthresholdvisualfield– Fallsasleep/snoring3Xduringperimetry

•  40yointernistjustoffof48hourhospitalshiftinforroutineeyeexam–  “Howareyoudoing?”–  Sobbingb/chescreamedathisfavoritenurse

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SleepApnea•  Cessationofbreathduringsleep•  About20%ofUSadults•  Roughly15%ofthesearesymptomatic

30-50%RestrictionofFlow80-100%RestrictionofFlow

SleepApnea•  MostcaseareObstructive(OSAS)

–  22%ofmen/17%ofwomen!22millionAmericans

–  Ratesincreasewithage&obesity!80%unDx•  <10%arecentral-<1%ofpopulation

–  Decreasedorabsentventilatoryeffort(neurologic)•  Apnea:temporarycessationofbreathing(>10seconds)

duringsleepwithreducedO2saturation•  Hypopnea:decreasedairflow>10secwithreducedO2

saturation(partialobstruction)–  ElevatedApnea-HypopneaIndex(AHI)

JThoracDis.2015Aug;7(8):1311–1322

AHIapneic+hypopneicepisodes

timeasleep(inhours)

•  AHI<5=normal•  AHI>5<15=mildapnea•  AHI>15<30=moderateapnea•  AHI>30events/hour=severeapnea

•  15%ofallOSAismoderateorworsebyAHI•  MilderOSAfarmorelikelytobepositional

EurRespJ2016;47:23-26 Chest2005Oct;128(4):2130-7

OtherSleepDisorders•  RestlessLegSyndrome:legdiscomfortcoupledwithcompulsivemovement;Symptomsworsewhenstationary;females>males;5.5%ofthepopulation

•  Narcolepsy:excessivedaytimesleepiness,sleepparalysis,hallucinations,+/-cataplexy;males<females;79.4casesper100,000

Sleep2018;41(suppl1):A227

SleepMed2011;12(7):623-34

.Neurotherapeutics.2012;9(4):776–790

•  Oftenworsenedbyantihistamines,melatonin,alcohol,SSRIs

•  RLSincreasestheriskofsuicideandself-harmbyupto4-foldafteralladjustments–  24+KRLSpatientsfollowedover8years

JAMANetwOpen.2019;2(8):e199966.Epub2019Aug2

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ToolsforAssessingSleepSymptoms•  EpworthSleepinessScale(ESS)

–  Questionsaboutsleepinessduringwakeactivity

•  PittsburghSleepQualityInventory(PSQI)–  Questionsaboutsleeplatency,quality,breathing

•  LittlecorrelationbetweenESS&PSQI•  Bothpoorpredictorsofmilderobstructivesleepapnea(OSA)

&othersleepdisorders

•  BerlinObstructiveSleepApneaSurvey•  STOP-BANGApneaQuestionnaire(snore/tired/observed/

pressure–BMI/age/neckcircumference/gender)

SleepMed.2014Apr;15(4):422-9.

IntJPrevMed.2018Mar9;9:28

Polysomnography(PSG)

•  Goldstandardfordiagnosisofmostsleepdisorders(exceptRestlessLegSyndrome)

•  Overnightmeasurementofbreathing,pulse,P02,EEG,REM,legmovements

•  Homesleepstudiesrecordpulse,P02,breathing–  GoodcorrelationwithPSGforDxofOSA–  Costsaretypically$200-500versus$1500-2000

Respirology.2010Feb;15(2):336-42

ESAP:EasySleepApneaPredictor•  100%specificityformildOSASinT2DM(n=43)when

comparedwithPSG•  Neckcircumference>17/16inchesinmales/femalesalso

100%specific•  BothmorespecificbutlesssensitivethanBMI>35and+

STOP-BANG•  ApositiveESAPwasdefinedasa1cmgapwhenapatient

encircledtheirhandsaroundtheneck

SleepDisord.2019;2019:3184382.

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SleepDisordersAssociatedwithRiskofMultipleSystemicPathologies

•  CardiovascularDisease•  Diabetes/InsulinResistance/Obesity•  IntestinalDysbiosis•  Hypertension

•  Sub-optimalresponsetotreatmentoftheabove

https://www.cdc.gov/sleep/about_sleep/chronic_disease.html

CVD•  ObstructivesleepapneaincreasestheriskofstrokeandMImorehan3-fold,butCPAPdoesn’tlowerriskofrecurrenteventspermultipleanalyses*

•  Meta-analysisshowssleepapneadoublestheriskofMACEafterstentplacement

•  UntreatedOSASincreassriskofheartfailureby140%viahypoxicdamagetocardiacmuscle

•  10-yearanalysisshowsInsomniaincreasesriskofMIandstrokeby13%

Medicine(Baltimore).2018Apr;97(17):e0621

EurJClinInvest.2018May;48(5):e12908.

*MOREonthisLATER

TexHeartInstJ.2018Jun;45(3):151–161

Neurology2019Dec3;93(23):e2110-e2120

Diabetes•  Shortsleep(<5.5hours)triplesthelikelihoodofT2DM

inobservationalstudiesafterallcontrols

•  Severeobstructivesleepapneaincreasedincidentdiabetes71%over13yearsindependentlyofadiposity

•  Bothshort(<5.5hrs)andlong(>9hrs)sleepdurationaresignificantlyassociatedwithadiposity&insulinresistance

CurrDiabRep.2018Aug17;18(10):82.

SleepMed.2016Sep;25:156-161

DiabetesResClinPract.2018May;139:195-202

DiabetesCare2015Mar;38(3):529-537480K+subjects

“SweetSpot”is7.7hours

ShortSleepèêLeptin(adipocytes)&éGhrelin(stomach)èéappetite/BMI

PLoSMed.2004Dec;1(3):e62 HTNandOSA•  50%ofhypertensivepatientshaveOSA•  Drug-resistantHTNishighlywassociatedsevereOSA

Hypertension.2014Feb;63(2):203–209.

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OSA+HighFatDiet!Dysbiosis,HTN•  Ratswithtrachealballoon-inducedapneaandhigh-fatdietdevelopsignificantdecreaseinbutyrate-producingbacterialfloraand29mmHgBPincreaseafter2weeks

•  Fecaltransplantationintonormalratsresultedina32mmHgincreaseinBPat2weeks

•  SuggestsacausalnexusforHTNbetweensleepapnea,dysbiosisandfatintake Hypertension.2016Feb;67(2):469–474.

ReductionsinbutyrateproducingbacteriaareprevalentinT2DM&HTN MedSci(Basel).2018Jun;6(2):32

Microbiome.2017;5:14.

GutMicrobiomeAffectsSleep•  Antibioticstotallyinactivatetryptophan-serontoninsignallinginmice

•  Highertryptophanbutlittleserotonin•  SignificantlymoreREMtonon-REMsleeptransitions

•  Improvingguthealth&diversity("saturatedfatand#fermentedfoods,probiotics)mayimprovesleep

Gutmicrobiotadepletionbychronicantibiotictreatmentaltersthesleep/wakearchitectureandsleepEEGpowerspectrainmice.ScientificReports,2020

PLoSOne.2019;14(10):e0222394.

SleepDisordersAssociatedwithMultiple,PrevalentEyeDiseases

•  OSA:normotensiveglaucoma,NAION,DR&DME,Poorresponsetoanti-VEGFTxinnvAMD&DME,FloppyEyelidSyndrome

•  Insomnia:AMD•  Hyposomnia:nvAMD,POAG,dryeye,myopia•  Hypersomnia(excessivesleepduration):Sight-threateningDR,AMDwithgeographicatrophy,POAG

ApneainDiabeticRetinopathy/DME•  STDRrateswere2-2.5XhigherinT2DMpatients(n=230)with

untreated/under-treatedOSAfollowedfor4yrs•  Afteralladjustments,OSAincreasedoddsofprogressingto

severeNPDR/PDR5-fold•  AHI>11.9vs<4.8increasedoddsofSTDR7.5-fold•  CSMEpatientswithconfirmedOSA&Txwithgridlasergainedan

extralineofVAiftreatedwithCPAP>2.5hrs/night@6months

•  DMEpatients(n=30receivingAvastin),theprobabilityofOSAsymptomswasdirectlyproportionaltothe#ofrequiredinjections

AmJRespirCritCareMed.2017Oct1;196(7):892-900.

Retina.2014Dec;34(12):2423-30

Respiration.2012;84(4):275-82

DR&Hypersomnia•  1231T2DMpatientsinSingapore•  Longsleepduration(>8hrs)&EDSwereindependentlyassociatedwithVTDR(3-fold)

•  Hypothesis:RetinalO2demandispredominantlydrivenbyrodmetabolism;increasedsleepmaybeahypoxicstimulustoworseningretinaldisease

PLoSOne.2018;13(5):e0196399

VTDRisProliferativeRetinopathy(PDR)orcenter-involvedmacularedema(CI-DME)

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A novel approach to DR n  InnerretinalhypoxiaisprimarilyresponsibleforDRandvisionloss

n  RodsareprimarilyresponsibleformostretinalO2consumptionduringdark

n  LimitingrodmetabolismwithagreenLEDreduceshypoxicstressinanimalsandimprovedDMEin17/26eyesversus3/26controleyes

Diabetic retinopathy and a novel treatment based on the biophysics of rod photoreceptors and dark adaptation. Editors In: Kolb H, Fernandez E, Nelson R, editors.

GeographicAtrophy•  Afteralladjustments,longsleep(>8hours)increasedtheriskofGA7.1timescomparedtopatientswithoutAMD–  1003consecutiveptsinaSanFranciscoretinapracticesurveyedaboutsleephistory

–  HourssleepingwasnotassociatedwithnvAMD

Retina.2016Feb;36(2):255-8.

?nvAMD•  InacaseontrolstudyofAMDptswithself-reportedshortsleep

(<6hours),relativeriskofCNVMwas3.29v.7-8hrs;2.25for6-7hrs;1.39for>8hrs(n=165)–  HR=3.1forshortsleepafterallcontrols(p<0.01)

In38patientswithnvAMDandOSAconfirmedbyPSG,CPAP+AvastinimprovedVA(20/40vs20/100),CSTby-78μandcutrequiredAVTinhalfcomparedtoAvastinalone(8vs16injections)

Retina.2016Apr;36(4):791-7.

OphthalmicEpidemiol.2016;23(1):20-6.

PoorResponsetoAVTinUntreatedOSA

Glaucoma•  POAGwasassociatedwithshort(<5hrs)andlong(>9hrs)sleepduration(p=0.07)

•  Whenstratifiedbyabdominalobesity&BMI,overweightsubjectswere2.4XmorelikelytohavePOAGifsleepdurationwas>9hrsor<7hrsafteradjustmentsforage/gender/IOP/HTN/smoking/drinking/income/depression(p=0.036)–  9400subjectsfromKNHANES2012

Medicine(Baltimore).2016Dec;95(52):e5704.

‘SweetSpot’’

SleepdurationsignificantlyassociatedwithPOAGinabdominallyobesesubjects

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NormotensiveGlaucoma

•  NTGappearstobemoreprevalentinOSAandviceversa

•  PresenceoffloppyeyelidsyndromeinptswithOSAassociatedwitha4-fold+increaseinglaucoma(NTG&POAG)– 23%vs5%p=0.04– 150FESpatients

JGlaucoma.2014Jan;23(1):e81-5.

JGlaucoma.2007Jan;16(1):42-6BMCOphthalmol.2014Mar10;14:27

MySimpletonConclusion•  Sickretinasandopticnervesneedtobreathe

•  Sickretinasandopticnervesneedadequatesleep,butnottoomuchortoolittlesleep

DryEye•  Shortandveryshortsleepdurationincreasedoddsofdryeyesymptoms–  HR=1.2(5hrs)and1.29(<4hrs)–  16KfomKNHANES

•  ClinicalandsubjectivedryeyesignificantlymorecommoninpatientswithpoorPSQIscores–  Osakastudyn=672Japaneseofficeworkers–  730ptsatTokyoeyeclinic

SleepMed.2015Nov;16(11):1327-133

ClinOphthalmol.2016;10:1015–1021.NeuropsychiatrDisTreat.2015;11:889–894

Mechanisms?•  Experimentalsleepdeprivation(mice)induceslacrimalglandhypertrophyandreducestearproductionafter10days–  Reversedafter14daysofrest

•  Sleepapneasignificantlyassociatedwithpersistent/severedryeyesymptomsinastudyof120USVeterans(3.8X)–  CPAPusenotreported

ExpMolMed.2018Mar2;50(3):e451

JAMAOphthalmol.2016Dec22.

SleepDeprivationDryEye(SDE)•  SDEresultsfromchangesinmorphologyofcornealepithelialmicrovilliandêtearstabilityresultingfrominhibitionoftheproteinPPAR-α (mousemodel)

•  Topicalfenofibrate(anti-lipidagentTricor™)activatesPPAR-α andnormalizesmicrovilli&tearfilmstability

InvestOphthalmolVisSci.2018Nov1;59(13):5494-5508

CPAPuse&OSD•  Conjunctivalsquamousmetaplasiaincreased&TBUTdecreasedinrighteyesonlyafter4monthsofCPAP(n=80)– Positionaleffect?(maskvshabitualsleepposition);maskleakage,maskdisplacement,nasolacrimalairflow

Cornea.2012Jun;31(6):604-8

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EyeEco’sEyeseals4.0.

SleepReview2016InterviewofArtEpstein,OD,FAAO

DoesCPAPIncreaseIOP?•  NodifferenceinmeanIOPatbaselineandafter7hoursin31subjectswOSA+/-CPAP

•  NocturnalIOPwassignificantlyhigherin21CPAPsubjectsmeasuredQ2h– Meantrough/peakspreadincreasedfrom6.7to9.0mmHgafter1month

– DecreasedIOPwasseenafter30minutesCPAPcessation

GraefesArchClinExpOphthalmol.2015Dec;253(12):2263-71

InvestOphthalmolVisSci.2008Mar;49(3):934-40.

Hyposomnia&Myopia•  3625Koreanadolescents(12-19yo)•  Myopiawasinverselyassociatedwithsleepdurationaftercontrols(0.1D/hour)

•  Comparedtosubjectsgetting<5hrs,ORformyopia>-0.50D<6.00Dinthosegetting>9hrswas0.59(p=0.006)

•  Norelationshipwasseenformyopia>6diopters

ActaOphthalmol.2016May;94(3):e204-10.

HowDoWe‘Fix’PoorSleep?

CombattingPoorSleep•  Removelocalfactors(quiet/darkroom;avoidcaffeine/

nicotine/alcohol&lightatnight)– Bluelightsuppressesmelatonin,impairssleeplatency,durationofREM–559studiesin5yrs

•  Identify&treatpsycho-socialstressors(anxiety/depression)•  Avoidnapping,shiftworkandvariablebed/wakingtimes

•  Physicalactivity•  Identify&treatOSA

NationalSleepFoundation

$DrugTherapyinsomnia!Sonata,Lunesta

nightterrors!clonazepam,prazosinRLS!carbidopa,gabapentin,Fe

AvoidLight-at-Night•  LANdisruptsthecircadianrhythmandmetabolism,increasingratesofobesityandmetabolicdisorders

•  Indoorandoutdoornightimelightingaffectssleepqualityandquantity

EndocrRev.2014Aug;35(4):648-70.

Sleep.2016Jun1;39(6):1311–1320

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SchoolStartTimes•  TheAmericanSocietyofPediatricsrecommendsthatmiddleandhighschoolsstartnoearlierthan8:30AM

•  Veryfewschoolsdoso

TreatingOSA•  CPAPisthegoldstandard,butcomplianceratesarelow(50%discontinuewithinthefirstyearandanother25%byyear3)

•  Females,>55yoandimproveddaytimesleepiness(ESS)predictcompliancepast6mos

•  CPAPdidNOTimproveMACEormortalityinptswithestablishedCVD(meannightlyuseonly3.3hrson70%ofnights)

RespirCare.2010Sep;55(9):1230-9

SleepApnea.NEnglJMed.2016Sep8;375(10):919-31

SAVETrial(n=2717)SleepApneacardioVascularEventstrial

Meannightlyusewasonly3.3hrson70%ofnights!

PtswithsevereO2desaturationAnddaytimesleepinesswereexcluded

Allsubjectshadestablishedcoronaryarteryand/orcerebrovasculardisease

DoseMayBeCriticalforCPAP•  TheSAVEStudydidshowa44%reductioninstrokeriskforthosewith‘goodcompliance’– >4hrson70%ofnights

•  CPAPuse>4hours/nightdoessignificantlyreduceMACEinmeta-analysis– 4RCTs,3780patientsp=0.02

AmJCardiol.2017Aug15;120(4):693-699

OtherOSATxOptions•  MandibularAdvancementDevices(MAD)

–  comparabletoCPAPformildOSA(50-60%lowerAHI)

•  Uvulopalatopharyngoplasty(UPPP)–  removaloftonsils,posteriorsoftpalate,uvula

•  TargetedHypoglossalNeurostimulation–  improvestonguemuscletonus

•  Playingadouble-reedinstrument(e.g.anoboe)–  lowerprevalenceofOSA

•  Playdidgeridoo-comparabletoCPAPformild-moderateOSA

•  WeightLoss

DtschArzteblInt.2018Mar;115(12):200–207MayoClinProc.2009Sep;84(9):795–800.Sleep.2015Oct1;38(10):1593–1598JClinSleepMed.2012Jun15;8(3):251–255BMJ.2006Feb4;332(7536):266–270

UPPP

THN OboeDidgeridoo

MAD

TongueBaseRadiofrequency GenioglossusAdvancement

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Excess Body Weight

Sleep Disorders NatSciSleep.2013;5:27–35

WeightLossImprovesDysomnia•  Overweight/ObeseT2DMpatients(meanBMI=36.7)andOSAwholost30lbsover1yearreducedtheirmeanAHIfrom23.2to13.5

•  ImprovedOSAscorespersistedafter4yrs(meanchangeAHI=-7.7)despite(mean=15lbs)weightgain

•  Decreasedvisceralfat(600Kcaldeficit+/-exercise)significantlyimprovedsleepsymptoms(insomnia,EDS,apnea)inoverweight/obese

ArchInternMed.2009Sep28;169(17):1619–1626.Sleep.2013May1;36(5):641-649A

BehavSleepMed.2016May-Jun;14(3):343–350.

Conclusions•  Sleepdisordersareprevalentandcontributetovisionlossandmortality

•  ECPsshouldaskpts/partnersaboutsleepquality/quantity(STOP-BANG)

•  ECPsshouldinitiatereferralforDxofhigh-riskpatients

•  ECPsshouldassess/treatocularsequelaeofsleepdisordersaswellaspossibleCPAP-relatedocularadverseevents

•  ECPsshouldeducateonsleephygiene&therapies

Summary

ThankYou!

PaulChous

dr_chous@diabeticeyes.com