Pediatric Pharmacology: What It Means To Your Clinical ... · Pediatric Pharmacology: What It Means...

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PediatricPharmacology:WhatItMeansToYourClinicalPractice

SuzanneTinsleyPhD,PT,NCSAssistantDeanforDevelopment

ParksEndowedProfessorshipinNeurologicalRehabilitationAssociateDirectorNeurorehabilitationServices– CenterforBrainHealth

DepartmentofRehabilitationSciencesDepartmentofNeurology

LouisianaStateUniversityHealth-Shreveport

MarieVazquezMorganPT,PhDAssociateProfessor

DepartmentofRehabilitationScienceLouisianaStateUniversityHealth- Shreveport

Outline

• PharmacologyinthePediatricPopulation• OverviewofImportantPharmacologyPrinciples• CommonPediatricDrugClasses• ImpactofDrugTherapyonDevelopment,AcademicsandTimingofInterventions

• ImpactofNutritiononNeurodevelopmentalDisorders

• ImpactofOpioidEpidemiconChildren• Development• NeonatalAbstinenceSyndrome

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InternationalClassificationofFunctioning,DisabilityandHealth- ICF

Health Condition (disorder or disease)

Body Functions & Structures

Activity Participation

Environmental FactorsPersonal Factors

Contextual Factors

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GeneralPrinciples

• SideEffects/AdverseDrugReactions• HalfLife• PotencyvsEfficacy• Pharmacotherapeutic DifferencesinPediatricPopulations

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Definitions

• Therapeuticeffect – intendedordesiredeffectofthedruggiven.• Sideeffect/adversedrugreactions(SE/ADR)

• Effectsotherthanthedesiredeffects.• Anyunintendedorunwantedeffectofadrugthatmayoccuratacceptabledoselevels.(WHO)

• Toxiceffects – sideeffectsthatarepotentiallyharmfulorlife-threatening.• Theappearanceoftoxiceffectsusuallyrequiresthatthedosebereducedorthedrugstopped.

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• ThreetypesofSE/ADR• Mechanismbased

• Usuallydoserelated• Samereceptororreceptortypesinthegiventissueorindifferenttissues

• Off-targetbased• Notaconsequenceofthedrug�sprimarymechanismofactionbutaconsequenceoftheparticulardrugmolecule.

• Idiosyncraticinnature• Interactionofthedrugwithuniquehostfactors

• Mechanismbased• Off-targetbased

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• ThreetypesofSE/ADR• Mechanismbased

• Bronchoconstrictionwithanon-selectiveβ-blocker• Sedationwithananti-histamine

• Off-targetbased• Hepatotoxicityofacetaminophen

• Idiosyncraticinnature• Mechanismbased

• AngioedemaseenwithACEinhibitors• Off-targetbased

• Anaphylaxistopenicillin

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• Reasonsaremany• Age• Inadequatehistory• Drugselectivity

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• Elimination• Half-life

• Thetimerequiredforthebloodorplasmaconcentrationofthedrugtofalltohalfofitsoriginallevel.

• Itisdeterminedbybiotransformation/metabolismandexcretion.

• 4-5half-livesfor>90%ofthedrugtobeeliminatedfromthebody.

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Dose– ResponseRelationship• Dose-Response-Curve – therelationshipbetweenthedosageofadrugandaspecificresponsetothedrug.

• Thresholddose• CeilingeffectorMaximalefficacy

Re

sp

on

se

Dose ( log scale )

Threshold

dose

Ceiling effect

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BasicConceptsinPharmacology

Potency – itisameasureofthestrength,orconcentration,ofadrugrequiredtoproduceaspecificeffect.

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Decre

ase in M

ean A

rterial P

ressure

(5)

Dose

25

50

Drug A

Drug B

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13

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BasicConceptsinPharmacology

PatientAhashypertensionaveraging150/90– Whichdrugwouldworkbestforhim?PatientBhashypertensionaveraging190/100– Whichdrugwouldworkbestforhim?

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Decre

ase in M

ean A

rte

rial P

ressure

(5)

Dose

25

50

Drug A

Drug B

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• Gradeddose-responsecurvesfor3drugsdifferinginmaximalefficacyandpotency.(Emax =maximumeffect)

Re

sp

on

se

Dose (log scale)

A

B

CEmax Drug A

Emax Drug B

Relative

efficacy

Relative potency

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• Gradeddose-responsecurvesfor2drugs,differinginmaximalefficacyandpotency,usedtotreatpain.

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Dose mg (log scale)

\

Level of effects

of

reducin

g p

ain

A

B

Min.

Mod.

Severe

Ceiling effect

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Pharmacotherapeutic DifferencesinPediatricPopulations

Pharmacologic effect

Clinical Response

Toxicity Efficacy

Drug concentration in

system circulation

Dose of drug

administered

Drug Concentration

at site of action

Drug in tissues of distribution

Drug metabolized or excreted

PK

PD

Absorption

Elimination

Distribution

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• ClinicalRelevanceofTheseBasicPrinciples• IndividualVariation

• Age• Geneticmake-up• Bodyweight&composition• Physiologicalvariables

• Druginteractions• Pathologicalfactors

• Disease

• Thephysiologiccontextsinwhichthesepharmacologicalprinciplesoperatearedifferentinrapidlymaturinginfants,children,adults,andtheelderly.

• Pharmacokinetics• Pharmacodynamics

DrugTherapyinInfantsandChildren

• Drugabsorption• Bloodflow• GIfunction

• Drugdistribution• Neonate70-75%bodyweightiswater• Adult50-60%bodyweightiswater

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Oraldrugabsorption(bioavailability)ofvariousdrugsintheneonatecomparedwitholderchildrenandadults

• Acetaminophen• Ampicillin• Diazepam• Digoxin• Penicillin• Phenobarbital• Phenytoin• Sulfonamides

• Decreased• Increased• Normal• Normal• Increased• Decreased• Decreased• Normal

• DrugMetabolism• Allacrosstheboard• Neonateshaveadecreaseinliverenzymesearly• Children(toddlers)haveanincreaseinliverenzymeactivityforsomedrugsandadecreaseforothers.

• Doseofdigoxinintoddlersismuchhigherthanadults.

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Approximateeliminationhalf-livesofvariousdrugsinneonatesandadults.

DRUGS Neonatal Age

Neonatal half-life

(hrs)

Adult half-life

(hrs)Acetaminophen

2.25 0.9-2.2

Diazepam 25-100 40-50Phenobarbital

0-5 days5-15 days1-30 months

20010050

64-140

Phenytoin 0-2 days3-14 days14-50 days

80186

12-18

• DrugExcretion• GFRismuchlowerinnewbornsthaninolderinfants,children,oradults.• GFRreachesadultvalueby6-12months.

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• PediatricDrugAdministration• Astandardmedicationdosageisnearlynonexistentinpediatrics.• Amountofmedicationsareusuallyorderedbodysurfacearea.• Weightalone shouldnotbeused.

• Childrenarenotsmalladults.

• BodySurfaceArea• Calculatedfromheightandweight• Standardnomogram

• Approximatepediatricdose=BSAXAdultdose/1.73

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PolypharmacyDefinitionnToomanymedicationsoruseofunnecessarydrugsnUseofmorethanonemedicationtotreataspecificpathophysiologynWorldHealthOrganization

• FiveormoremedicationsusedempiricallyvPolypharmacy (>5)

• Excessivepolypharmacy (>10medicines)

AutismSpectrumDisorder

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ASD• DiagnosticandStatisticalManualofMentalDisabilities(5th edition)–includesautism,Asperger’sdisorder,and“pervasivepersonalitydisordernototherwisespecified”

• Symptomsappearbetweentheagesof2-3yearscharacterizedbydifficultyindevelopingsocial,speechandbehavioralskills

• Behavioraltherapyisusuallythefirst-linetreatment,withdrugtherapyaddedtohelppatientsfunctions

• DrugTherapy:Approvedandoff-labelpharmacotherapiesoptionsforthevarioussymptomsofASD

ASDDrugClasses

• Anti-psychoticDrugs• risperidone,aripiprazole,clozapine,haloperidol

• CNSStimulants• methylphenidate

• Anti-Depressants• venlafaxine,fluoxetine,mirtazapine,citalopram

• EndogenousHormone• Oxytocin,secretin,melatonin

• Cholinergics (ACHesteraseAntagonists)

• rivastigmine

• Glutamatergics (NMDAAntagonists)

• memantine

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Anti-psychoticDrugs

• PsychoticBehaviors- groupofdisorderswhichinclude:• breakdownofthepersonality• thoughtdisturbances• impairedperceptionofreality• inappropriatebehavior– Irritability,aggression,

• Schizophrenia• Bipolaraffectivedisorder• Severedepression

Psychosis• disorderedthinking,

emotionalwithdrawal,delusions,hallucinations

• Relativeexcessoffunctionalactivityofdopamineinthebasalganglia

SN

STRIATUM

FRONTAL CORTEX

DA

GLU

-

+

GABA-

-

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AntipsychoticDrugs• �Neuroleptics�• blockdopaminergicreceptors(D2)andserotoninreceptors(5-HT2)inthelimbicsystemandstriatum• adverseeffects

• CNS• extrapyramidaleffects• sedation

• ANS• anticholinergic(e.g.,drymouth,constipation)• posturalhypotensionduringinitializationoftherapy(duetoα receptorblocking)

• Weightgain

Antipsychotics,extrapyramidaleffects

• acutedystonia--musclespasmsofface,tongue,neck,back• akathisia--motorrestlessness• Pseudo-Parkinsonism--rigidgait,tremors• TardiveDyskinesia

• occursafterlong-termtherapy• repeatedchoreiform movements--involuntarymovementsoflips,jaws,tongue,extremities

• irreversible

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AntipsychoticDrugs,typical• Haloperidol(Haldol®)

• haloperidolwasmoreeffectivethanthesecond-generationantipsychoticdrugs(atypical)atreducingaggressioninchildrenwithautism(ages2- adult)(McDonaldetal2010,Clintonetal1987)

• Mosteffectivetotreatprominentsymptomsofirritability,anger,anduncooperativeness

• MOA:highlypotentandselectiveD2receptorantagonist.• AE:acutedystonicreactions,dyskinesias,andsedation,severeextrapyramidaleffects

AntipsychoticDrugs,atypical

• Risperidone(Risperdal®)• firstdrugapprovedbytheFDA(2006)totreatautism-relatedirritability.4

• It’sapprovalappliedtochildren5yearsofageandolder.–• Usefulintreeating ASDaccompaniedbyseveretantrums,aggression,orself-injuriousbehavior.

• MOA:antagonizesDA(D2)andserotonin5-HT2receptors• AE:increasedappetite,dizziness,drooling,drowsiness,andfatigue

• Veryfewextrapyramidalsideeffects

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AntipsychoticDrugs,atypical

• Clozapine(Clozaril®)• usedforaggressionandtantrums(widelyusedpriortotheaproval ofnewer2nd generationdrugs

• MOA:fewextrapyramidaleffectsbecauseblocksDA(D2)primarilyinlimbicbrainregionsand5HTactivity.Thedrugalsoactsasanantagonistatadrenergic,cholinergic,histaminergic,andotherdopaminergicandserotonergicreceptors.13

• AE:weightgain,metabolicsyndrome,tachycardiaandagranulocytosis(bonemarrowsuppression).Inhighdosagesmayalsocauseseizures

• Notcurrentlyusedasafirstlinedrugfortreatmentinchildren

AntipsychoticDrugs,comboMOA

• Aripiprazole(Abilify®)• Indicatedforthetreatmentofirritabilityinchildren(ages6to17years)withASD.

• MOA:unknownbutmayinvolveacombinationofpartialagonistactivityatdopaminetype2(D2)andserotonintype1A(5-HT1A)receptorsandantagonistactivityat5-HT2A receptors.

• AE:weightincrease,extrapyramidalsystems,increasedappetite,pyrexia,fatigue,andinsomnia

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AntipsychoticDrugs

• RisperidoneVersusHaloperidolforAberrantSocialBehavior• Miral etal(2008)reportedrisperidonewasmoreeffectivethanhaloperidolintreatingsocialbehavior,althoughbothdrugshadsignificanteffectsonthechangefrombaselineinchildrenages8-18.

• MeasuredbytheAberrantBehaviorChecklist• However,thehaloperidolgrouphadsignificantly(P=0.0477)morereportsofthedevelopmentorworseningofextrapyramidalsymptoms.

ASDDrugClasses

• Anti-psychoticDrugs• risperidone,aripiprazole,clozapine,haloperidol

• CNSStimulants• methylphenidate

• Anti-Depressants• venlafaxine,fluoxetine,mirtazapine,citalopram

• EndogenousHormone• Oxytocin,secretin,melatonin

• Cholinergics (ACHesteraseAntagonists)

• rivastigmine

• Glutamatergics (NMDAAntagonists)

• memantine

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CNSStimulants• Methylphenidate(Ritalin ®,Novartis ®,Concerta ®,Janssen ®)

• MildCNSstimulantindicatedforattention-deficitdisordersandnarcolepsyassociatedwithASD

• Methylphenidatewassuperiortoplaceboontheteacher- ratedhyperactivitysubscaleoftheABC(2008PediatricPsychopharmacologyAutismNetworkTrial)

• MOA:blocksthereuptakeofnorepinephrineanddopamineintothepresynapticneuronandincreasesthereleaseofthesemonoaminesintotheextraneuronal space.

• AE:decreasedappetite,increasedirritability, andsocialwithdrawal,

Anti-DepressantDrugs

• PathogenesisofMajorDepression• AmineHypothesisofMood

• afunctionaldecreaseintheactivityofNEand5-HTisthoughttoresultindepression

• AfunctionalincreaseinactivityoftheseNTsresultsinmoodelevation

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Anti-DepressantDrugs

• MedicationsusedtoTreatDepression

• MonoamineOxidaseInhibitors(MAOIs)

• AmineUptakeBlockers• Tricyclics(TCAs)– nonselective• SelectiveSerotoninReuptakeInhibitors(SSRIs)

• α2 Blockers

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Anti-DepressantDrugs

• Venlafaxine(Effexor®)• Fluoxetine(Prozac®)• Citalopram(Celexa®)• Mirtazapine(Remeron®)

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Anti-DepressantDrugs

• Venlafaxine(Effexor®)• Traditionallyforthetreatmentofmajordepressivedisorder,generalizedanxietydisorder,socialanxietydisorder,andpanicdisorder.

• Carminatietalshowedlow-dosevenlafaxine,inadditiontothepatient’scurrentantipsychoticregimen,couldimproveself-injuriousbehaviorandADHD-likesymptoms.

• MOA:serotoninandnorepinephrinereuptakeinhibitor(SNRI)• AE:

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Anti-DepressantDrugs• Fluoxetine(Prozac®)

• Traditionallyindicatedforacuteandmaintenancetreatmentofmajordepressivedisorder,obsessivecompulsivedisorder,bulimianervosa,andpanicdisorder.

• Showntoimprovementinrepetitivebehaviorsamongadults(18-60yo)withASD(Hollanderetal2015)

• IntheStudyofFluoxetineinAutism(SOFIA-2015),alow-dose,melt-in-the-mouthformulationofthefluoxetinewasfoundtobenomoreeffectivethanplacebointreatingrepetitivebehaviorsinchildrenandadolescents(5to17yearsofage)withASD.

• MOA:selectiveserotoninreuptakeinhibitor(SSRI)• AE:mild-to-moderateinsomnia,headache,anddrymouth.

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Anti-DepressantDrugs• Citalopram(Celexa®)

• Traditionallyindicatedforthetreatmentofdepression• OftenprescribedinchildrenwithASDforthetreatmentofrepetitivedisorder• Kingandcolleagues(2009)foundthatcitalopramwasineffectiveintreatingchildren(5to17yearsold)withASD,includingAsperger’sdisorderandunspecifieddevelopmentaldisorders.

• MOA:selectiveserotoninreuptakeinhibitor(SSRI)• AE:(SeeninchildrenwithASD)increasedenergylevel,impulsiveness,decreasedconcentration,hyperactivity,stereotypy,diarrhea,insomnia,anddryskinorpruritus.

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Anti-DepressantDrugs

• Mirtazapine(Remeron®)• tetracyclicantidepressantthatenhancescentralnoradrenergicandserotonergicactivity

• Poeandcolleaguesshowedthatmirtazapinewaseffectiveinimprovinginsomniachildren,adolescents,andyoungadults(4to24yearsofage)withASDandotherdevelopmentaldisorders.

• Thetreatmentalsosignificantlyimprovedaggression,self-injury,andirritability

• MOA:serotoninandnorepinephrinereuptakeinhibitor(SNRI)• AE:increasedappetiteandtransientsedation.

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WithdrawalSyndrome

• Occurswithabruptcessationofdrugtherapyfromtricyclics&SSRIs• Nausea,dizziness,anxiety,palpitations

• Ifyouaregoingtostoptakingthesemedicationsyoumustweanoffthedrugsslowly

• Thesesymptomscanoccurwithmissingasingledose

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Anti-DepressantDrugs&Children• Ingeneral,antidepressantshavebeenassociatedwithanincreasedrisk,comparedwithplacebo, ofsuicidalthinkingandbehaviorinchildren,adolescents,andyoungadultsinshort-termstudiesofsubjectswithmajordepressivedisorderandotherpsychiatricdisorders.Therefore,thisriskmustbebalancedwiththepatient’sclinicalneedwhenanyantidepressantisusedinchildren,adolescents,oryoungadults.

• Parents&caregiversshouldbeawareofwarningsigns• Agitation,irritability,suddenchangesinbehavior

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ASDDrugClasses

• Anti-psychoticDrugs• risperidone,aripiprazole,clozapine,haloperidol

• CNSStimulants• methylphenidate

• Anti-Depressants• venlafaxine,fluoxetine,mirtazapine,citalopram

• EndogenousHormone• oxytocin,secretin,melatonin

• Cholinergics (ACHesteraseAntagonists)

• rivastigmine

• Glutamatergics (NMDAAntagonists)

• memantine

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EndogenousHormones

• Oxytocin(Pitocin)• Secretin• Melatonin

EndogenousHormones• Oxytocin(Pitocin)

• Oxytocinplaysamajorroleinrelationshipformationandsocialfunctioninginbothhumansandanimals

• Gordonetal(2015)measuredchangesinbrainactivityduringjudgmentsofsociallyandnon-sociallymeaningfulpicturesin17childrenwithASDaftertreatmentwithintranasaloxytocin.Theyfoundthatoxytocinenhancedbrainfunctioninthesesubjectsandappearedtoimprovetheirevaluationsofthesociallymeaningfulstimuli.

• ASystemtic review(2014)identified“potentiallypromising”findingsinmeasuresofemotionrecognitionandeyegaze,whichareimpairedearlyinthecourseofASDandmightdisruptthelearningofsocialskillsindevelopingchildren.Theauthorsconcludedthatlong-termoxytocinnasalsprayappearedtobeapromisingtreatmentforthesocialimpairmentsofASD.

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EndogenousHormones

• Secretin• Secretinregulatesexocrinesecretionsinthestomach,pancreas,andgallbladder.Italsoactsasaneuropeptideinthecentralnervoussystem(CNS).Itishypothosized totreatsocialaberrantbehavior

• 2systematicreviewsdemonstratednosignificantlygreaterimprovementsinmeasuresoflanguage,cognition,orautisticsymptomscomparedwithplacebo.

• TheyconcludedthatsecretinshouldnotberecommendedoradministeredasanASDtreatment.

EndogenousHormones

• Melatonin• Highlyrecognizedtobeusefulininducingandmaintainingsleep• MelatoninimprovedsleeplatencyinchildrenwithASD

• Regimin suggest1-3mg30minbeforebedtime.• CortezetalandMalow etal

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Cholinergics (ACHesterase Antagonists)

• Rivastigmine (Exelon,Novartis)• isindicatedforthetreatmentofmild-to-moderatedementiaoftheAlzheimer’stypeandmild- to-moderatedementiaassociatedwithParkinson’sdisease.

• Chezetal(2004)foundsignificantimprovementsfrombaselineincognitionwereseenintheCARSscoresin32children(ages3to12years)

• MOA:it’saacetylcholinesteraseinhibitor.Itisthoughttoexertitstherapeuticeffectsbyenhancingcholinergicfunction

• AE:similartothosereportedinadultstreatedwithrivastigmine (e.g.,nausea,diarrhea,irritability,andhyperactivity).

Glutamatergics (NMDAAntagonists)

• Memantine (Namenda)• Memantine isanN-methyl-D-aspartate(NMDA)receptorantagonistindicatedforthetreatmentofmoderate-to-severedementiaoftheAlzheimer’stype.PersistentactivationofNMDAintheCNSisbelievedtocontributetothesymptomsofAlzheimer’sdisease

• Owley etalshowedasignificantimprovementfrombaselinewasnotedinamemoryevaluation(P=0.021).However,therewerenosignificantdifferencesfrombaselineonmeasuresofexpressivelanguage,receptivelanguage,andnonverbalIQ.

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DrugTherapyvsASDBehavioralSymptoms

• IrritabilityandAggression• risperidone,aripiprazole,clozapine,haloperidol,sertraline

• AberrantSocialBehavior• risperidone,haloperidol,oxytocin

• ADHD/HyperactivityandInattention

• Methylphenidate,Venlafaxine

• CognitiveDisorder• Memantine,rivastigmine

• RepetitiveBehaviors• fluoxetine,Citalopram,Bumetanide

• Insomnia• Mirtazapine,melatonin

ADHD/ADDMedications

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• ADHD• Poorlydefinedandover-diagnosedbehavioralsyndromeconsistingofshortattentionspan,hyperkineticphysicalbehavior,andlearningproblems

SympathomimeticDrugs

• CNSEffects• Mildalerting***• Improvedattentionstoboringtasks***• Elevationofmood• Insomnia• Euphoria• Anorexia• Full-blownpsychoticbehavior

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SympathomimeticDrugs

• AmphetaminevariantswithefficacyinchildrenwithADHD• Methylphenidate(Ritalin®)• Pemoline (Cylert®)• Modafinil (Provigil®)

• Methylphenidate(Ritalin®)andPemoline (Cylert®)• Amphetaminevariantswhosemajorpharmacologicaleffectsandabusepotentialaresimilartothoseofamphetamines

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• Modafinil (Provigil®)• Newamphetaminesubstitute• Effectscentral⍺-1receptorsaswellasappearstoaffectGABAergic,glutaminergic andserotonergicsynapses

• Fewerdisadvantagesthatamphetamine

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• ADR/SideEffects• Excessivemoodchanges• Insomnia• Weightloss• Abusepotential

ImpactofADHDMedicationonAcademics• Currieetal(2016).ExaminedwhethertheincreaseinADHDmedicationusewasassociatedwithimprovementsinemotionalfunctioningoracademicoutcomesamongchildrenwithADHD.Theyfoundlittleevidenceofimprovementineitherthemediumorthelongrun.Theysuggestthatexpandingmedicationinacommunitysettinghadlittlepositivebenefitandmayhavehadharmfuleffectsgiventheaveragewaythesedrugsareusedinthecommunity.

• NIMHsponsored theMultimodalTreatmentofADHD(MTA)study(2009).CombinationtreatmentandmedicationmanagementalonewerebothsignificantlysuperiortointensivebehavioraltreatmentaloneandtoroutinecommunitycareinreducingADHDsymptoms.

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TheGutà BrainConnectionASD,ADD/ADHD

MarieVazquezMorganPTPhDAssociateProfessor

LSUHealthShreveportDepartmentofRehabilitationSciences

MitochondrialDysfunctionandDisease

• Autism• Bipolard/o• Depression• Parkinson’sDisease• Asthma• GIdisorders

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TriggersforMitochondrialDysfunction

• Genemutations

• Shortagesofkeyvitaminsandmineralsindiet

• Chemicals,heavymetalsanddrugs

• Bacteriaandviruses

• Stress

AgentsforMitochondrialDysfunction

• Vitamins• C,D.E,thiamin,riboflavin

• Minerals• Magnesium,calcium,phosphate

• Lipids• Membranephospholipids,unsaturatedfattyacids

• Antioxidants• CoQ 10,alphalipoic acid

• Herbs• Curcumin

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TheGut

• Microbiome• Allorganismsandgeneticmaterialinbody

• Microbiota• Populationsofmicroorganismspresentinecosystemsi.e.gut

• Humangutmicrobiota– morethan1,000speciesandover7,000subspeciesofmicroorganisms

ImportanceofGI Health

• Immune:– Physicalbarrierofdefenseagainstbacteria,viruses, etc.– Largestpartoftheimmunesystem(70%)foundinthe gut

• Neurotransmitters:– Greatestamount(90%)ofthe“brainchemical”serotoninisfoundintheGI tract– Aminoacids(absorbedfromproteindigestion)areprecursorsforneurotransmitters

• Fullbody function:– Vitamins/mineralsabsorbedinthegutarecofactorsforenzymereactions,metabolism,conversionofnutrientsand fat

�Alldiseasebeginsinthe gut�--Hippocrates,thefatherofmodernmedicine

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Gut- BrainConnection

Gut- BrainConnection

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LeakyGutDefined..

• Conditionof“hyperpermeableintestine”or“increasedintestinalpermeability”

• Lininghasbecomemoreporous

• Screeningoutprocessisnolongerfunctioningappropriately

Prevalence?

• IntroductionofGMFs• Currently,80%offoodsinmainstreamgrocerystoresaregeneticallymodified

• Glyphosate(RoundUp)isthemostwidelyusedherbicideintheworld.• WhenGlyphosategetsintogut,itcanbindthebeneficialmineralsthatareneededtomaintainthathealthygutfloraandmakesthesemineralsunavailable.ThiscreatestheprocessofDysbiosis

• Throughdysbiosis,thebadbacteriacreatesholesintheliningofthewallsofthesmallintestineandcreatesaleakygut

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PercentageofgeneticallymodifiedcropsintheU.S.in1997and2018,bytype(aspercentoftotalacreage)

TriggersforLeakyGut

• Stress• Antibioticandanti-inflammatorydrugs(NSAIDs)• Extendeduseofantacids• Gluten/Casein

• Increaselevelsofaprotein,whichopenupthespacesbetweentheintestinalcells

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Body�s Effect on BrainADHD • Autism • ADD • Allergies • Anxiety

IMMUNE

Gut Inflammation

Poor pathogen fighting

Food sensitivities

DIGESTION

Leaky gut

Dysbiosis

Less nutrient absorption

DETOXIFICATION

Decreased detoxification

Food additives

NEUROLOGY

Brain Inflammation

Microbial toxins

Neurotransmitters

Nutrient deficiencies

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Autismstudies

• SauerAK1,BockmannJ2,SteinestelK3,BoeckersTM4,GrabruckerAM5,6,7AlteredIntestinalMorphologyandMicrobiotaCompositionintheAutismSpectrumDisordersAssociatedSHANK3MouseModel. IntJMolSci.2019Apr30;20(9).

• EshraghiRS1,Deth RC2,MittalR3,Aranke M3,KaySS4,Moshiree B1,EshraghiAA3.EarlyDisruptionoftheMicrobiomeLeadingtoDecreasedAntioxidantCapacityandEpigeneticChanges:ImplicationsfortheRiseinAutism. FrontCellNeurosci.2018Aug15;12:256.

• VuongHE1,HsiaoEY2.EmergingRolesfortheGutMicrobiomeinAutismSpectrumDisorder. BiolPsychiatry.2017Mar1;81(5):411-423.

ADHD/OtherStudies• SandgrenAM1,Brummer RJM2ADHD-originatinginthegut?Theemergenceofanewexplanatorymodel.MedHypotheses.2018Nov;120:135-145.

• deMagistris L1,Familiari V,Pascotto A,Sapone A,Frolli A,Iardino P,Carteni M,DeRosaM,Francavilla R,Riegler G,Militerni R,Bravaccio C.Alterationsoftheintestinalbarrierinpatientswithautismspectrumdisordersandintheirfirst-degreerelatives.JPediatrGastroenterol Nutr.2010Oct;51(4):418-24.

• Prehn-KristensenA1,ZimmermannA1,2,Tittmann L2,Lieb W3,SchreiberS2,4,BavingL1,FischerA2.ReducedmicrobiomealphadiversityinyoungpatientswithADHD. PLoSOne.2018Jul12;13(7):e0200728.

• deTheije CG1,Bavelaar BM,LopesdaSilvaS,Korte SM,OlivierB,Garssen J,KraneveldAD.Foodallergyandfood-basedtherapiesinneurodevelopmentaldisorders. PediatrAllergyImmunol.2014May;25(3):218-26.

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How Diet Can PossiblyHelpSupport Digestion & Biochemistry

• LeakyGutandGut Inflammation• Removefoodsthatinflame gut• Addfoodsthatreduceinflammationandheal• Addfoodsthatsupplybeneficialbacteria

• Nutrient Deficiencies• Increasethequalityoffoodand digestibility

• YeastOvergrowth• Remove sugars• Reducerefinedflourproductsand starches• Addprobiotic--rich foods

• ToxicityandPoor Detoxification• Avoidfood additives• Avoidtoxinsinfoodsupplyandmeal preparation

Parents Report withNutritionalInterventions

• GIproblems relieved• Diarrhea&constipation lessens• Improvedlanguageskillsand learning• Greaterfocusand attention• Reducedhyperactivity• Eyecontact• Moreappropriatebehavior• Better sleeping• Skinrashesoreczemaclearup

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ADD/ADHD

DietHistoryADD/ADHD

• BenjaminFeingold-1970’s• Artificialfoodadditives(colorings/flavors)• Salicylaterichfoods

• Keyofflimitfoods/ingredients:• Artificialfoodcolors/dyes/flavors• Artificialfragrancesfoods/lotions/airfresheners• Artificialsweeteners• FoodpreservativesBHA,BHT,etc• Salicylates

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HighSalicylates• Fruits: Raisins,prunes,apricots,blackberries,blueberries,cherries,cranberries,grapes,pineapples,plums,oranges,tangerines,strawberriesandguava.

• Vegetables:Broccoli,cucumbers,okra,chicory,endive,radish,zucchini,watercress,alfalfasprouts,eggplant,squash,sweetpotato,spinach,artichokesandbroadbeans.

• Spices:Curry,aniseed,cayenne,dill,ginger,allspice,cinnamon,clove,mustard,cumin,oregano,pimiento,tarragon,turmeric,paprika,thymeandrosemary.

• Othersources: Tea,rum,wine,cordials,vinegar,gravies,mints,almonds,waterchestnuts,honey,licorice,jam,chewinggum,pickles,olives,foodcolorings,savory-flavoredchipsandcrackersandfruitflavorings.

FeingoldDiet

• Phase1:Childavoidsfoodsorproductsthathaveingredientsonthelist.

• Phase2:Childcanbegintotrythesesamefoodsoneatatimetoseeifsymptomscomeback.

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FeingoldDietEffectiveness

Trasande L,ShafferRM,Sathyanarayana S(2018).FoodAdditivesandChildHealth.Pediatrics,2018Jul23.

“Artificialfoodcolors,commoninchildren’sfoodproducts,maybeassociatedwithworsenedattention-deficit/hyperactivitydisorder(ADHD)symptoms.StudiescitedinthereportfoundasignificantnumberofchildrenwhocutoutsyntheticfoodcoloringsfromtheirdietsshoweddecreasedADHDsymptoms.”

FeingoldDietEffectiveness

• Vojdani&Vojdani, Immunereactivitytofoodcoloring. AlternativeTherapiesinHealthandMedicine,2015;21Suppl 1:52-62.

• “consumptioncanactivatetheinflammatorycascade,canleadtocross-reactivities,autoimmunities,andevenneurobehavioraldisorders.”

• “TheCentersforDiseaseControl(CDC)recentlyfounda41%increaseindiagnosesofADHDinboysofhigh-schoolageduringthepastdecade.“

• “MoreshockingisthelegalamountofartificialcolorantsallowedbytheFDAinthefoods,drugs,andcosmeticsthatweconsumeanduseeveryday.Theconsumingpublicislargelyunawareoftheperiloustruthbehindthedeceptiveallureofartificialcolor.”

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3dietaryInterventionsHistoricallyTested

1. Restrictedeliminationdiets(RED)— referredtoastheFewFoodDiet.

• WhenreductioninADHDbehaviorsresults— (generallyoccurwithin2–3weeks)ifthedietisgoingtohaveapositiveeffect— newfoodscanbeaddedbackoneatatimetoseeiftheyarewell-toleratedorleadtoanincreaseinproblembehaviors.

• Alternatively,particularfoodsthataresuspectedtoexacerbateachild’ssymptomsmayberemovedoneatatimetoseeifthechild’sbehaviorimproves.

Gluten/Casein

• Proteins– deregulatorsofpermeabilityinintestine

• Iftestpositiveforglutensensitivity/lactoseintolerance=eliminatefromdiet

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Sugar

• Feeds yeast

• Depressestheimmune system

• Contributestoinflammation

• Higherreleaseofextracellulardopamine- desensitizationofreceptorsovertime

• Dopaminergicsignalingdysfunction-impactsfrontallobecontrolmechanisms– areadirectlyrelatedtoneurobiologyofADHD

Sugar

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3dietaryInterventionsHistoricallyTested

2.Artificialfoodcoloringexclusion(AFCE)- removeallartificialfoodcoloringsfromchild’sdiet,i.e.,Yellow #6,Yellow#5,SodiumBenzoate,Blue#2,etc.,andobservingwhetherthisisassociatedwithareductioninADHDbehaviors.

• CarefullyconductedtrialshavedemonstratedthatAFC’s– inamountschildrencouldtypicallyconsume– canincreaseADHDsymptomsinmanychildren.

3dietaryInterventionsHistoricallyTested

3.Essentialfattyacidsupplementation— Certainfattyacids,e.g.,Omega3andOmega6,promoteneuralfunctioning.

• Thesefattyacidsarecalledessentialbecausetheyarenotsynthesizedinthebodyandmustbeingested.

• ChildrenwithADHD-lowerlevelsofessentialfattyacidsrelativetopeersandseveralstudieshavedemonstratedalinkbetweenlowlev-elsofEFAsandtheseverityofADHDsymptoms.

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Evidence

• RED — Threedifferentmeta-analysesexaminingtheimpactofREDonchildrenwithADHDreport-edsignificantpositiveeffects.Themagnitudeofthiseffectvariedconsiderablyacrossthediffer-entstudies.

• restrictedeliminationdiets,ifimplementedproperly,haveasignificanteffectthatislikelytobeinthesmalltomoderaterange.Anaverageeffectinthesmalltomoderaterangereflectsthefactthatsomechildrenarelikelytoshowsubstantialbenefitswhilemanyothersmayshownobenefitsatall.

• AFCE — SmallbutsignificanteffectsofeliminatingAFC’sfromchildren’sdiethavebeenreport-ed.

• AswithRED,areasonableconclusionatthistimeisthat,onaverage,childrenwithADHDwillderivemodestbenefitswhenAFCsareremovedfromtheirdiet.SomechildrenmayshowlargereductionsinADHDsymp-tomswhileothersmayshownodiscerniblereductionsatall.

• Fattyacidsupplementation— Resultsfrommultiplemeta-analysesconvergeontheirbeingamodestbutsignificantbenefitoffattyacidsupplementationonADHDsymptoms.

• AswithREDandAFCE,somechildrenarelikelytodisplaysubstantialbenefitsfromthisapproachwhileforothers,theimpactonADHDsymptomswillbeminimalornon-existent.Eveninthesecases,however,therearegeneralhealthbenefitsthatmayaccruefromfattyacidsupplementation.

HowtobestimplementwithADD/ADHD…

• First,theeasiestofthe3dietaryinterventionstoimplementwouldbefattyacidsupplementation.

• Doesn’trequirerestrictingchildren’sfoodintakeinanyspecificway,canhavegeneralhealthbenefitsregardlessofhowitimpactsADHDbehaviors,andplacesmuchmorelimiteddemandsonchildrenandparents.

• Restrictedeliminationdietscanbedifficulttoimplement/sustain— effortstosignificantlylimitthefoodsachildeatsmayleadtoconflictsthatcreateimportantproblemsintheirownright.

• So,unlessfoodallergiesarepresent,adietrestrictingonlyAFCsmaybeabetterchoiceasthiswouldbeeasiertoimplement

• .However,giventheubiquitousnatureofartificialfoodcoloringsanddyes,thiscanalsobechallenging.

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Supplementsto Consider ADHD

• IncreasedlevelsofoxidativestressinADHD• VitaminB/C/D/E• C0Q10

• Magnesium• Omega-3fattyacids-Ofthestudiesidentified,13reportedfavorablebenefitsonADHDsymptomsincludingimprovementsinhyperactivity,impulsivity,andattention

ASD

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LeakyGutandDiet

• RemoveGluten,Casein

• Moreantioxidantsandanti-inflammatoryfoods

• Probioticrichfoods

• Prebioticrichfoods

Fermented FoodsRichin Probiotics

• Functionsofgood bacteria–Regulateperistalsisandbowel movements–Breakdownbacterial toxins–Helpbreakdownsugars,lactose,and oxalates– Supportimmunesystemandincreasenumberofimmune cells–Balanceintestinal pH–Protectagainstenvironmentaltoxins:mercury,pesticides,pollution

• Rawfermentedfoodscontain billionsof bacteria/serving!

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ProbioticRichFoods

PrebioticRichFoods

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ASD

• 2018interventiontrial(41autisticchildrenmeanage8y/o)displayedthatsupplementationofdietwithprebioticresultedinsignificantimprovementinanti-socialbehavior,GIhealthcomparedtobaseline.

Grimaldi,R.,Gibson,G.R.,Vulevic,J.etal.Aprebioticinterventionstudyinchildrenwithautismspectrumdisorders(ASDs).Microbiome(2018)6:133.

Top Diets**GFCF (Gluten--free and Casein--free) No gluten(wheat, rye, barley, spelt, kamut, and oats) or casein(dairy)

FoodSensitivityElimination/RotationEliminatingallotherfoodsensitivities:Soy,corn,eggs,citrus,peanuts,chocolate,canesugar

SCD(SpecificCarbohydrate Diet)/GAPSRestrictscarbohydratestoonlyfruits,non--starchyvegetables,andhoney.Nograins,starchyvegetables,ormucilaginousfiber

*Ketogenic– LowGlycemicMeat,fruit,vegetables,fatandnuts.Nograinsorbeans.Onenremovespotatoesanddairytoo.

LowOxalateDietRestrictshighoxalatefoods(nuts,beans,greens)

LowFODMAPS DietLowinfermentable,poorlyabsorbedcarbssuchasfructose,lactoseandFOS.

**Feingold/FAILSAFE DietsRestrictshighphenolicfoods,includingallartificialingredientsandhighsalicylatefruits(and more)

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GFCF

• Allowedfoods:• Beans,seeds,nutsinunprocessedform• Fresheggs• Freshmeats• Fruits/Vegetables

AllowedGrains/Starches- GFCF

• Rice• Corn/maize• Potato• Tapioca/cassava• Arrowroot• Quinoa• Millet

• Buckwheat• Sago• Lentil/pea• Amaranth• Lupin• Teff

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Avoid- GFCF

• Barley• Rye• Wheat• Triticale

GFCF

• AGF/CFdietisnoteasytofollow.• GlutenandcaseinareabigpartofUSdiet.Becausethedietdoesnotcontainmilkproducts,ormanybreadsandcereals,childmaynotgetenough:

• calcium• fiber• vitaminsA,D,andBcomplex• calories

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GFCF

• BecausecalciumandvitaminDarelimitedonthisdiet,encourageothercalcium-richbeverages/foods,suchas:

• calcium-fortifiedpotatomilk

• calcium-fortifiedricemilk

GFCFEffectiveness

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GFCF Effectiveness

• LangeKW1,HauserJ,Reissmann A.Gluten-freeandcasein-freedietsinthetherapyofautism. CurrOpin Clin Nutr Metab Care.2015Nov;18(6):572-5.

• 20-29%oftheparentsreportedsignificantimprovementsontheASDcoredimensions

• Thefindingsofanotherrecentinvestigationsuggestedthatageandcertainurinecompoundsmaypredicttheresponseofautismsymptomstoagluten-freeandcasein-freediet

• Agluten-freeandcasein-freedietshouldonlybeadministeredifanallergyorintolerancetonutritionalglutenorcaseinisdiagnosed

SCD(SpecificCarbohydrate Diet)• Nutrient-densedietthatisfreeofgrainsandextremelylowinsugar,includinglactose

• Dr.SidneyHaas,apediatricgastroenterologist,developeditinthe1920sasatreatmentforCeliacdisease

• Allowsalmostallfruits,vegetablesthataren’tcannedorfrozen,nuts,nut-derivedflours,meats,eggs,butter,andoils

• Exclusionsincludeallformsofgrains,sucrose,maltose,lactose,potatoes,okra,corn,fluidmilk,soy,cheesescontaininghighamountsoflactose,aswellasmostfoodadditivesandpreservatives

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GFCFvsSCDHowIsItDifferentFromGFCF?

• SCDisglutenfree,butdoesnot allowstarchandsugar.SCDincludesdairythatisvirtuallylactosefreeandcontainsdenaturedcasein,butnotrequiredindiet

HowSuccessfulIsSDC?

• Anecdotalreportsindicateasuccessrateofabout80-85%• ParentsandteachersofautisticchildrenonSCDreportachangeintheirattitude,increasesinskillsandresponsiveness.Insomeofthesecasesitoccursonlyafewweeksafterbeginningthediet

Gut&PsychologySyndrome(GAPSDiet)

• Dr.NatashaCampbell-McBride2004,basedonhertheorythatmanyofthemedicalissuesaffectingthebrainarecausedbyaleakygut

• SimilartoSCD

• BigdifferencebetweenSCDandGAPSisdairyproducts.• Dairy,attherighttimeandtherightforms,playsanimportantpartintheGAPSprogram

• Also,GAPSismuchmorerestrictiveandmeantasamulti-yeardietthateventuallyallowspeopletotransitionbacktoafuller,traditionalfoodsdiet

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GAPstages

Asyet,nostudieshaveexaminedtheeffectsoftheGAPSdietaryprotocolonthesymptomsandbehaviorsassociatedwithautism.

Candida/Sugarfreediet

• Limitorcompletelyexcludefoodsthatmaypromotecandidagrowth.• Non-starchyvegetables,includingallcolorsofvegetable.

• Nostarchyvegetableslikepeas,potatoes,beets,andwintersquash

• Low-glycemicfruitslikecitrusandberries• Healthyfatsincludingavocado,nutsandseeds

• Asyet,nostudieshaveexaminedtheeffectsoftheCandidafreedietonASDsymptoms

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Feingold/FAILSAFE Diets

• Feingold- Removesphenolsandsalicylates• FAILSAFE- Alsoremovessalicylates,aswellasaminesandglutamates(otherrelatedfoodchemicals)

• Phenols -artificialcoloring,artificialflavoring,andartificialpreservatives• Salicylates-chemicalsthatoccurnaturallyinplants– particularlyinmanyfruitssuchasapples,grapes,andberries

• Amines- comefromproteinbreakdownorfermentation.Largeamountsarepresentincheese,chocolate,wines,beer,yeastextractsandfishproducts

• Glutamate- foundnaturallyinmostfoods• Puremonosodiumglutamate(MSG)canalsobeusedasanadditivetoincreasetheflavorofsoups,sauces,Asiancookingandsnackfoods.

Phenols, Salicylates, and Amines

Can cause:• Hyperactivity• Red cheeks/ears• Itchy skin• Upset stomach• Asthma• Headaches• Bedwepng• Fatigue• Diarrhea

• Depression• Irritability• Aggression• Defiantbehavior• Sleepissues• Cravingsforsalicylates,amines,and/orglutamates.

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High Phenol/Salicylates

• Almonds• Apples• Apricots• Berries,raspberries, cherries• Chili powder• Ciderandcider vinegar• Coffee• Coladrinks• Cucumbersand pickles• Curry powder

• Grapes,raisins, currants

• Honey• Nectarinesand peaches• Orangesand oranges• Paprika• Peppers(belland chili)• Pineapple• Plumsand prunes• Radishes• Tea• Tomatoes• Wineandwine vinegar

FeingoldDiet

• Phase1:Childavoidsfoodsorproductsthathaveingredientsonthelist

• Phase2:Childcanbegintotrythesesamefoodsoneatatimetoseeifsymptomscomeback

• AutismResearchInstitute– reportsthat56%of899familieswhohadtrieddietfounditwashelpfulwiththeirchild

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LowOxalateDiet• NewerdietforASD-observationfromparentsthatfoodshighinoxalateswereproblematicfortheirchildren.

• Oxalatesaresharpcrystalsandareresponsibleforcertainformsofkidneystones.

• Oxalatecrystalscanbeinflammatoryanddamagingtoachild’sdelicatebiochemistryandthelowoxalatedietreducesthesecompounds.

• ChildrenwithASDhavemuchhigherurineoxalatelevels.

HighOxalateFoods

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TreatingOxalates

• Increasecalcium• LimitVitaminC• Increasefluid• Adequateprotein• Reducesodium

• KonstantynowiczJ1,Porowski T,Zoch-Zwierz W,Wasilewska J,Kadziela-Olech H,KulakW,OwensSC,Piotrowska-Jastrzebska J,KaczmarskiM.Apotentialpathogenicroleofoxalateinautism. EurJPaediatrNeurol.2012Sep;16(5):485-91.

Ketogenic

• Low-carbohydrate,moderateprotein,high-fatdiet

• TheKetogenicDiet,becauseofitsveryrestrictedcarbohydratesandlimitedproteins,forcesthebodytousefatratherthanglucoseasanenergysourceandthusproducesametabolicstatesimilartofasting

• Havebeenusedsuccessfullytotreatepilepsyinpeoplesince1921andepilepsyiscommoninwithASD

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Ketogenic• LeeRWY,CorleyMJ,PangA,etal.Amodifiedketogenicgluten-freedietwithMCTimprovesbehaviorinchildrenwithautismspectrumdisorder.PhysiolBehav.2018;188:205–211.

• Forty-fivechildrenaged3-8yearsdiagnosedwithASDbasedonDSM-5criteriawereenrolledinthisstudy.

• Patientswereequallydividedinto3groups,firstgroupreceivedketogenicdietasmodifiedAtkinsdiet(MAD),secondgroupreceivedglutenfreecaseinfree(GFCF)dietandthethirdgroupreceivedbalancednutritionandservedasacontrolgroup.

• Allpatientswereassessedintermsofneurologicalexamination,anthropometricmeasures,aswellasChildhoodAutismRatingScale(CARS),AutismTreatmentEvaluationTest(ATEC)scalesbeforeand6monthsafterstartingdiet.

• BothdietgroupsshowedsignificantimprovementinATECandCARSscoresincomparisontocontrolgroup,yetketogenicscoredbetterresultsincognitionandsociabilitycomparedtoGFCFdietgroup.

• Dependingontheparametersmeasuredinourstudy,modifiedAtkinsdietandglutenfreecaseinfreedietregimensmaysafelyimproveautisticmanifestationsandcouldberecommendedforchildrenwithASD.

NutritionalDeficienciesASD

• VitaminD

• Calcium

• Potassium

• Choline

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Deficienciesstem from…

• Poorqualityfoodconsumption

• Pickyandrestrictive eating

• Poordigestionorabsorption(innateor acquired)

• Intestinaldysbiosis andlackofbeneficial bacteria

• Medicationinducednutrient depletion

Choline

• Essentialforbraindevelopment

• Sourcesinclude:liver,eggs,salmon

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VitaminD

• Mayplayroleingutinflammationandserotoninlevels• Maternaldeficiencymayplayarole

SupplementsASD

• Melatonin– 50-80%insomnia(dosing25-75mg)

• Probiotics

• CoQ 10– 50mgBID– improveoxidativestress

• Omega3fattyacids– (1000-1500mg)Decreasedhyperactivity?

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OthernutritionalConsiderations…

Juicing

• Stored and pasteurized juices contain significantly less nutrients: zinc,iron, calcium, vitamins B1, B5, and B6

• Freshandrawvegetablejuicecontainmanytimesmorevitamins&phytonutrientsthan bottled

• Getnutrientswithoutneedingtoeat/chewvegetables

• Childrenthatlikeliquids,juicesand smoothies

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Food and Nutrition Strategy

Food intolerances?

Histamines

Food

sensitivities

Feingold/

phenols

glutamates

Nourishing Diet

Child�s Diet

GFCF

SCD/GAPS

Yeast/dysbiosis/inflammation?

Juryisstillout…

• Todate,availableinterventionsforthemaintenanceandrepairofgutbarrierarehoweverfew,evenifpromising.

• Abetterunderstandingofhowthegutimpactshealthanddiseaseinchildrenwithneurodevelopmentaldisordersisneeded.

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PharmacologyofToneManagementSkeletalMuscleRelaxants

NMJPharmacology

MYOFIBRILS

ACh

Motor End Plate

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SkeletalMuscleRelaxantsselectively inhibit neuromuscular function

PERIPHERAL

nondepolarizers

depolarizers

Direct Muscle Relaxants

Indirect NMJ Blockers

CENTRAL Indirect Muscle Relaxants

SkeletalMuscleRelaxants

• Neuromuscularblockers• �paralytics�• peripherallyacting• interferewithtransmissionattheneuromuscularend-plate

• inhibitmusclecontraction• adjunctingeneralanesthesia• Curare&Succinylcholine

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SkeletalMuscleRelaxants

• Musclerelaxants--�spasmolytics�• centrallyacting• blockconductionwithinthespinalcordtonormalizehyperexcitableskeletalmuscle

• spasticity• exaggeratedmusclestretchreflexatamotorneuron

• musclespasms• increasedmuscletensionfollowinginjuryorinflammation

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SkeletalMuscleRelaxants

• CentrallyActing/Indirect/Spasmolytics• Benzodiazepines• PolysynapticInhibitors• Baclofen• Gabapentin(Neurotin)• Tizanidine(Zanaflex)

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AgentsUsedtoTreatMuscleSpasms1. Diazepam(Valium)

- Centrallyacting• enhanceeffectsofGABAatGABAA-diazepam

1. PolysynapticInhibitors- carisoprodol (Soma,Vanadom),chlorphenesin carbamate(Maolate),

chlorzoxazone (Paraflex,Parafon Forte),cyclobenzaprine(Flexeril),metaxalone (Skelaxin),methocarbamol(Robaxin),&orphenadrine citrate(Antiflex,Norflex)

- Centrallyacting- Mechanismofactionnotwellunderstood

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AgentsUsedtoTreatSpasticity

• Baclofen• Diazepam(Valium®)• Dantrolene (Dantirum®)• Gabapentin(Neurontin®)• Tizanidine (Zanaflex®)

AgentsUsedtoTreatSpasticity

Centrally-actingSkeletalMuscleRelaxants

depressrefleximpulseconductionwithinthespinalcordreducesthenumberofimpulsesavailabletoproducecontraction

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AgentsUsedtoTreatSpasticity

• Baclofen• GABAagonistatGABAB--baclofen

GABA

K-+ 2nd messengers

GABAB

increase K

• Baclofen• HasaninhibitoryeffectonAMNactivitywithinthespinalcordatspecificsynapses

• Bothpostsynapticinhibitionandpresynapticinhibition&incombination.

Usedtotreatspasticityassociatedwithlesionsofthespinalcord&MS

AdverseEffect:Drowsiness,generalizedmuscleweakness

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• IntrathecalBaclofen• Usedtotreatsevere,intractablespasticity• Deliversthedrugdirectlyintothesubarachnoidspace.• Increasesdrugeffectivenesswithmuchsmallerdoses&fewersystemicsideeffects

• Problemsoccuronlywithpumpmalfunction

• Diazepam(Valium®)• IncreasestheinhibitoryeffectsofGABA• UsedinpatientswithspasticityresultingfromSCIandCP• AE:

• sedationoccurswithdoseseffectiveinproducingmusclerelaxation

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• Dantrolene (Dantirum®)• blocksreleaseofCa++ fromthesarcoplasmicreticulum

Ca++SR

muscle contraction

Ca++ Ca++

muscle relaxation

troponintroponin

• Dantrolene (Dantirum®)• blocksreleaseofCa++ fromthesarcoplasmicreticulum• usefultoRxmalignanthyperthermia• spasmolytic• usefulinmultiplesclerosis,cerebralpalsy,spinalcordinjuries

• AE• dizziness,vomiting,fatigue• hepatoxicity

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• Gabapentin(Neurontin)• Originallydevelopedasananti-seizuremedication• EnhancestheinhibitoryeffectsofGABAintheSCbyeitherincreasingGABAreleaseorbystimulatingGABA-likereceptorsonspinalneurons

• DecreasesspasticitybyincreasingGABA-mediatedinhibitionoftheAMN• UsedtotreatspasticityassociatedwithSCI&MS• Veryeffectivewhenusedincombinationwithotherdrugs(baclofen)• AE:

• Sedation,fatique,dizziness&ataxia

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• Tizanidine (Zanaflex)• Classifiedasanalpha-2agonist• Alpha-2receptorsareauto-receptors• Stimulationofalpha-2receptorsinhibitsfiringoftheinterneuronsthatrelayinformationtotheAMN

• UsedtotreatspasticityassociatedwithSCI,MSandCVA• AE:

• Milderside-effectsthanbaclofen&valium• Sedation,dizziness,&drymouth

XXX

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SkeletalMuscleRelaxants– SE/ADR

• GeneralizedMuscleWeakness• DecreasedMuscleTone• Sedation• Dizziness,Ataxia

InterferencewithFunctionalOutcomes

• MotorControlProblems• FunctionalDecline• Alertness• Problemsattheimpairment,strategy&functionallevel.• Theydonotfixtheproblemwhenrelatedtomuscleinjuryorinflammation.

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PossibleSolutions

• Scheduletherapywhensedationisless.• DiscusswithPhysicianweaknessimplicationsastheyeffectfunctionaloutcomes

• Intensetherapytofacilitatenormalphysiologicmotorcontrolforthepreviouslyusedspastictone.

• Intensetherapytoreducethestructuralorbiomechanicalproblemthatleadtotheoccurrenceofmusclespasm.

Chemodenervation UsedtoTreatSpasticity

• BotulinumToxin• ChemicalNeurolysis

• Implicationsaremany• SCI,TBI,CP,MS,PD,Stroke,Pain

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• BotulinumToxin• Entersthepresynmaptic terminalattheskeletalNMJandbindsstronglytopresynatpic ACHvesicles

• Onceboundbythetoxin,thesevesicalareunabletoreleaseACHintothesynapticcleft.

• DecreasesmuscleexcitationbydisruptingsynaptictransmissionattheNMJ• Affectsmusclesundergosomedegreeofparesis&subsequentrelaxationbecausethetoxinblocksthereleaseofACH

• DOESNOTCURESPASTICITY• AE:

• Auto-immuneresponsewherebyantibodiesaresynthesizedagainstthetoxin• Temporaryeffects

PharmacologyofSeizureDisorderinChildren

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• AntiepilepticDrugs• Barbiturates• Benzodiazepines• Hydantoins• Lamotrigine• Succinimides• Carbamazepine(Tegretol)• Gabapentin(Neurotin)• Topiramate (Topomax)• Levetiracetam (Keppra)• Valporic Acid(Depakene)

Anti-SeizureDrugs

Hydantoins

• blocksodiumchannel• prolonginactivationofNa+ channels• decreaseneuronalexcitability

• phenytoin(Dilantin®)• ethotoin (Peganone®)• mephenytoin (Mesantoin®)

membrane

Na+

Phenytoin

inner

outer

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Lamotrigine

• blocksodiumchannel• prolonginactivationofNa+ channels• decreaseneuronalexcitability

• Maysuppressthereleaseofglutamateandaspartate,twoofthedominantexcitatoryneurotransmittersintheCNS

• Additionalactions– broaderspectrumthanothersodiumchannelblockers

• Sigmareceptoractivity

• AE:fewersideeffectsanddruginteractions

Succinimides

• Increaseseizurethresholdandlimitthespreadofelectricalactivityinthebrain

• MechanismofAction– theyreducelow-thresholdcalciumcurrents• Ethosuximide(Zarontin)

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Carbamazepine

• prolongsinactivationoftheNa+ channel• similartophenytoininefficacy

• Tergretol®

Gabapentin

• StructurallyverysimilartotheGABANThoweverdoesnotinteractwiththeGABAreceptor.

• Mechanismofactionunknown• Usedextensivelytotreatneuropathicpain• Neurotin®

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Topiramate

• Blocksrepetitivefiringofspinalcordneurons• Mechanismofactionistri-fold

• BlocksvoltagedependentNachannels• PortentiatestheinhibitoryeffectsofGABA• DepressesexcitatoryactionofAMPAreceptors

• Off-labeluseextensivelyforweightloss• Topomax®

Levetiracetam

• Theexactmechanismbywhichlevetiracetamactstotreatepilepsyisunknown.However,thedrugbindstoasynapticvesicleprotein,SV2A,whichisbelievedtoimpedenerveconductionacrosssynapses

• Theywork• Keppra®

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Valproic Acid

• Blockshigh-frequencyfiringofneuronsviaNa+channels• MayalsoblockNMDAreceptor-mediatedexcitation.• Mayalsoincreasepotassiumconductance(hyperpolarizingtherestingmembranepotential)athighconcentrations

• Depakene®,Depakote®,Depacon®

AntiepilepticDrugs– SE/ADR• Barbiturates

• sedation,hepaticmicrosomalenzymeinduction

• Benzodiazepines• Sedation,weakness

• Hydantoins• dizziness,visualdisturbances,posturalimbalance

• Lamotrigine• Dizziness,diplopia

• Carbamazepine• dizziness,drowsiness,ataxia,blurredvision,waterretention,inductionofDMMS

• Gabapentin• Sedation,dizziness

• Topiramate• Weightloss

• Levetiracetam• Asthenia,dizziness

• Valproic Acid• GIdistress,inhibitionofdrugmetabolism

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InterferencewithFunctionalOutcomes

• DecreasedArousal/Alertness• PosturalImbalance/Ataxia• Uncontrolledseizureactivity

PossibleSolutions

• ExploreoptionswithPhysiciansastotherisk/benefitsofthemedication

• UnderstandOutcomesmaybeeffected• Bodystructure&function,activity,&participationlevels

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PotentiationofFunctionalOutcomesSecondarytoDrugTherapy

• Somepeoplewithseizurescanbecomeseizure-freebyusingoneormoreanti-seizuremedications

• Inothers,anti-seizuremedicationscandecreasethefrequency&intensityofseizures

• Eithersituation,theymayenablepatientstomeetrehabilitationgoals.

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ImpactofOpioidEpidemiconChildren

TheProblem.• Krans etal(2016)found27.47%femalesofchild-bearingage withMedicaid ans 39.4%femalesofchild-bearingagewithprivateinsurance,filledanoutpatientprescriptionforanopioid

• Inaddition,oneoutoffiveofthosewithMedicaidinsurancewhofilledaprescriptionforanopioidwerepregnant.

• Theriseinopioidusebypregnantwomeniscorrelatedtoanincreaseinadverseneonataloutcomes. IntheUnitedStates, ababywithdrugwithdrawalisbornevery30minutes.

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TheProblem

• Therewasalmosta“4-foldincrease(from7to27per1,000admissions)ininfantadmissionstotheneonatalintensivecareunitwithadiagnosisofneonatalabstinencesyndromebetween2004and2013.(Skolnick2017)

• Opioiddependenceduringpregnancyleadstovariouscomplicationsforbothmotherandbaby,includingincreasedmorbidityandmortality

OpioidEpidemicandNeonates

• ImpactofDrugsonFetalDevelopment• MedicalIssuesatBirth• NeonatalAbstinenceSyndrome• EffectsLaterinLife

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• ImpactofDrugsonFetalDevelopment• Intheearlyweeksofgestationduringembryonicdevelopment,opioiddrugs

cancausesignificantabnormalitiesofphysiologicaldevelopment.

• Oncethefetalperiodhasbeenreached,theeffectsofdrugabusebecomemoresubtle,includingabnormalgrowthand/ormaturation,alterationsinvariousneurotransmittersandreceptors,andbrainorganization.

• Indirectaffectofopioidaddictiononthefetusthroughthemotherincludedecreasedbraingrowthandcelldevelopment.

• MedicalIssuesatBirth• Prenatalopiateexposureisrelatedtofetalgrowtheffects,whichisoneof

theleadingcausesoflowbirthweight.• Bada etal.(2013)reported“lowerbirthweightinopiateexposednewborninfantsborn

at33weeks’orgreatergestation,independentofuseofotherdrugs,prenatalcare,orothermedicalriskfactors”

• Low-birthweightissignificantasitincreasesthechancesofhealthproblemsasopposedtonormal-birthweightinfants.

• Possiblecomplicationsfortheinfantincludebreathingproblems,suchasrespiratorydistresssyndrome,intraventricularhemorrhaging,patentductusarteriosus,necrotizingenterocolitis,retinopathyofprematurity,jaundice,andinfectionduetoanunderdevelopedimmunesystem.

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• NeonatalAbstinenceSyndrome• Describedasageneralizeddisorderwithsignsofcentralnervoussystemhyperirritability,respiratorydistress,gastrointestinaldysfunction,andvariousautonomicsymptomswhichmayincludebutarenotlimitedtothefollowing:yawning,sneezing,mottledskin,andfever.

• Theseissuesariseasaresultoftheinfant’sbodygoingthroughwithdrawalfromtheopioidstheywerepreviouslyexposedtointhewomb.

• Theonsetofthesewithdrawalsymptomscanrangefromjusthoursafterbirthtotwoweekslater,butmostsymptomswilltypicallypresentwithinthefirst72hoursafterbirth.5

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• NeonatalAbstinenceSyndrome• Thisonsetcanbeinfluencedbynumerousfactors:

• thetypeofsubstancesusedbythemothers,• thetiminganddoseofthelastdrugtakenbeforedelivery,• thecharacteroflabor,• thetypeandamountofanesthesiaoranalgesiaprovidedpriortolabor,and

• thematurity,nutrition,andpresenceofintrinsicdisease”inthechild.

• Withdrawalsymptomscanrangefrommild,withthechildonlydemonstratingsymptomswhendisturbed,tosevere,withsymptomonsetoccurringspontaneously.

• Fortunately,thesymptomsofneonatalabstinencearetreatablewithouttheconcernoflingeringeffectswithproperpharmacotherapeutic management.

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• NeonatalAbstinenceSyndrome• Throughoutthewithdrawalprocessinfantsshouldbeassessedwithanabstinencescoringsystemtodetermineonset,progression,andlongevityofsymptoms.2

• Additionally,theneonateshouldbecontinuallymonitoredforoverallcomfort.

• Kaltenbach etal.(2015)statesswaddling,usingapacifierforexcessivesucking,frequentdiaperchanges,softsheet,andpositioningareallimportantinmanagingtheinfant’ssymptomsthroughoutthewithdrawalprocess.

• EffectsLaterinLife• Theimpactsofopioidexposurearenotlimitedtoachild’sfirstyearsoflife.

• Whilethefulleffectsonlong-termneurodevelopmentalfunctionarestillbeingstudied,ingeneralchildrenexposedtoopioidsare“morelikelytohaveADD,disruptivebehavior,andtheneedforcomprehensivepsychiatricreferrals.”(Stoveretal2016)

• Caritis andPanigraphy (2019)statethat“animals,humanneuraltissue,adultbrains,thebrainsofchildrenandnewbornsdemonstratethatopioidsadverselyaffectthehumanbrain,primarilythedevelopingoligodendrocyteandtheprocessesofmyelinization connectivitybetweenpartsofthebrain.”

• Multiplebrainregionsareeffectedincludingthebasalganglia,thalamus,andcerebellarwhitematter.Whilethelong-termimpactsoftheseeffectshaveyettobeunderstood,researcherssuggesttheyareofsignificantconcern.

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• EffectsLaterinLife• Otherknownmedicalissuesmaystemfromalowbirthweight.

• Evenintheirlateryears,childrenbornwithlowbirthweightsareatanincreasedriskfordevelopingadditionalmorbiditiescomparedtobabiesbornatanormalbirthweight:

• diabetes,heartdisease,highbloodpressure,intellectualanddevelopmentaldisabilities,metabolicsyndromes,andgeneralobesity.4

IsTheiraLinkBetweenOpioidExposureandASDand/orADHD?• Sandtory etal(2018)lookedatschool-agedchildrenprenatallyexposedtoopiatesandotherillicitsubstances(n=171)

• PrenatallyexposedchildrenhadsignificantlyhigherSNAP-IVscoresassociatedwithADHDsymptomsinbothareasofinattentionandhyperactivity/impulsivity

• HigherASSQscorerelatedtoanincreasednumberofsymptomsassociatedwithASD,comparedwiththereferencegroup

• Conclusion:prenatallyexposedchildrenhadmorementalhealthsymptomsassociatedwithADHDandASDcomparedtothecontrolgroup

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IsTheiraLinkBetweenOpioidExposureandASDand/orADHD?• Nygaard,etal.(2016)conductedalongitudinalstudylookingatbehaviorandattentionproblemsineight-yearoldchildrenwithprenatalopiateandpoly-substanceexposure.

• Theycompared72childrenwhowereprenatallyexposedtoheroinanddifferentdrugswithagroupof58childrenwithoutexposure.

• Thechildren’sbehaviorandattentionwerebasedoffwhatcaregiversandteachersreportontheChildBehaviorCheckListandADHDRatingScale.

• Teachersreportedproblemsintheexposedchildrenaround4½yearsofagewherecaregiversreportedproblemsinexposedchildrenaround8½yearsofage.

• Conclusion:childrenwhowereexposedtodrugsprenatallyhaveincreasingmoreproblemsinmanyareasrelatedtobehaviorfrompreschooltoatleast8½yearsofage.

FutureStudies• BridgingResearchonAutisminNeurodevelopment(BRAiN)

• PilotDataProject:AutismSpectrumDisorders• 1)testthehypothesisthattheriskofphenotypicdiseasecategoryisassociatedwithsocioeconomicstatusandprenatalfactors.

• 2)testthehypothesisthatmarkersofoxidativestressandDNAmethylationareconsistentacrossbio-samples

• CenterforBrainHealthDevelopmentPlan• ASDInterventionProgram

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• SuzanneTinsleyPhD,PT,NCS• stinsl@lsuhsc.edu• 318-813-2942

• MarieVazquezMorganPhD,PT• mvazqu@lsuhsc.edu• 318-813-2944