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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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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• [email protected]• 318-813-2942
• MarieVazquezMorganPhD,PT• [email protected]• 318-813-2944