could your child’s behavior be...
TRANSCRIPT
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Could Your Child’s Behavior be PANS/PANDAS?
NationalAutismAssociationConference
May2019
LindseyE.Wells,NDwww.lindseywellsND.com
What is PANS/PANDAS
• PANDAS=PediatricAutoimmuneNeuropsychiatricDisorderAssociatedwithStrep
• PANS=PediatricAcute-OnsetNeuropsychiatricSyndromes• PITANDS=PediatricInfection-TriggeredAutoimmuneNeuropsychiatricDisorders• Post-streptococcalAutoimmuneEncephalitis(ofthebasalganglia)• SydenhamChorea
• Post-StreptococcalStriatalAutoimmuneEncephalitis• 95%withemotionallability,50-75%withOCDatinitialpresentationand
100%withrecurrence(RusselDale&colleagues)
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PANS/PANDAS
Swedoetal,PedTher,2012
PANS/PANDAS
• 1in150-200childrendiagnosedwithPANS• SubgroupofthosechildrenwithOCD(which
represents2%ofpopulation)• Atleast25-30%ofOCDandTicdisordersare
acuteonset• Moreprevalentinmalesthanfemales(2.6:1)• Increasedoccurrencewithfamilyhistoryofautoimmunedisease
• 64%have1stdegreerelativewithinflammatorydisease
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DIAGNOSTIC CRITERIA
• ACUTEONSETofDRAMATICOCD(oranorexiaand/orsevere,restrictiveeatingdisorder)inadditiontoTWOofthefollowingneuropsychiatricsymptoms(withsevereandacuteonset):• SeparationAnxiety• Emotionallability• Behavioral/developmentalregression• Sensory/motorabnormalities–handwritingdeterioration
• Deteriorationofschoolperformance• Urinarysymptoms(urgency,frequency,enuresis)
• Sleepdisturbance(difficultyfallingasleep,REMdisinhibition/restlesssleep)
• Symptomsnotbetterexplainedbyanotherdisorder
Swedoetal,2012,PediatricTherapeu;Frankovichetal,JchildAdolPsychopharm,2015
CLINICAL OBSERVATIONS • Aggression60%• SleepDisorders80%• Insomnia,nightterrors,inabilitytosleepalone
• BehavioralRegression• Separationanxiety98%• LearningDifficulties60%• Hyperactivity;Inattentiveness70%
• Inabilitytoconcentrate90%• EatingDisorder20%
• Hallucinations10%• TerrorStrickenlookorHyper-alertappearance80%
• UrinaryFrequency,urgency,urinaryaccidents90%
• Handwritingdeterioration90%• Tics70%• Short-termmemoryloss60%• Sensory-hypersensitiveorinsensitive40%
• HistoryofrepeatedUTIsorsinusitis
Toufexisetal,,JACP,2015
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ADDITIONAL OBSERVATIONS
Buckley et al, NIH, J Clin Sleep Med, 2016
• Margin Drift (left sided neglect) • Shortened attention span • Difficulty with memory • Loss of math visuospatial skills • Dysgraphia/clumsiness • Patterns of executive function deficit different
than those children with Tourette’s • EEG – 17% show spikes (4/42) or diffuse
slowing (3/42) consistent with autoimmune encephalitis
• Sleep study – 85% show nonspecific REM motor disinhibition
ADDITIONAL OBSERVATIONS
• Studiesrevealthat80%ofpatientsdiagnosedwithPANShavepost-infectiousautoimmunityand/orneuroinflammation(Swedoetal,2015)
• Neuroinflammationseeninthecaudate/putamen(Kirvanetal,2003)
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DIFFERENTIAL DIAGNOSIS
• Sydenhamchorea(acuterheumaticfever)• Otherformsofencephalitis,cerebralvasculitis• Childabuse,sexualabuse,psychological
trauma• Toxins,medications,illicitdrugs• Tumors,strokes• Tourette’s,OCD–notACUTE
PATHOGENESIS
GroupAStrep
• GeneticSusceptibility
• HLA-Balleles
Mis-directedImmuneResponse
• MolecularMimicry
• AntiGASAbsRecognizeHost
SC/PANDAS
• RheumaticFever
• Carditis,PolyarthritisErythemaMarginatum
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MOLECULAR MIMICRY
• Processthatoccurswhenourimmunesystemmistakenlyattacksnormalbodytissuesbecauseofthestructuralsimilaritiesbetweenaparticularmoleculeonaninfectiousagentandthemoleculesinourownbodytissues.
• Exampleofmolecularmimicry=Rheumaticfever• Immunesystemistriggeredtoattackheartvalvesafterastrepinfection
• SimilarprocessoccursinPANSandPANDAS,whereantibodiesaretriggeredtoattacktheBasalGangliacausingmovementandbehavioralmanifestations
TH17
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TH17
Agalliu,etal.GroupAStreptococcusintranasalinfectionpromotesCNSinfiltrationbystreptococcal-specificTh17cells.JClinicalInvestestigation.2016;126(1)303-17
HLA SUSCEPTIBILITY
• IncreaseincidenceofPANSinsubjectswhichhadthefollowingHLA-Balleles:
• HLA-B55• HLA-B38• HLA-B52
• Associatedwithvasculitis(i.eBehcets)
• Showsgeneticpredispositiontovulnerability
Frankovich,2016
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CAM KINASE II
• Calcium-dependentCalmodulinProteinKinaseII
• CamKinaseIIisanenzymethatisinvolvedintheupregulationofmanyneurotransmitters(i.edopamine)
• Knowntoincreasethesensitivityandresponsivenessofneurologicreceptorstoneurotransmitters
• ThismarkeriselevatedinPANDAS
DIAGNOSIS
• PANS/PANDAS is a CLINICAL DIAGNOSIS
• Based on History and Physical Exam • Clinical Diagnosis of ACUTE onset
symptoms • Evidence of infection/inflammation
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HISTORY
• Recentillnessbeforetheonsetofsymptoms• Historyoffamilymembersbeingillaroundtheonsetofsymptoms
• IMPORTANTTONOTE:Ourkidswillnotalwayspresentwiththetypicalacuteillnesssymptomsandmayjustpresentwithbehavioralissues
HISTORY
• Strep:• Sorethroat• Fever• Foodrefusal–duetopainonswallowing• Nauseaorvomiting• Headache• ScarlatinaRash
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HISTORY
• Mycoplasma:• Fever(usuallylowgrade)• Respiratorysymptoms(cough)• Fatigue• Headache• Earinfections• Croup• Anxiety/depression
HISTORY
• Viral• Fever• GIsymptoms• Vomiting• ViralRash• Fatigue/lethargy• Nasaldischarge• RespiratorySymptoms
• Parasites• Worseningaroundthefullmoon• Grindingofteeth• Itchingofbuttocks
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PHYSICAL EXAM
• ChoreiformMovements(“pianoplayingfingers”)
• Strep(PANDAS)• Redanalring• Peelingfingers• Tongue• Palatepetechiae• Damagednailbed vasculature
PHYSICAL EXAM
• Other:• ErythemaMigrans–BORRELIA• Striaethatblanches–BARTONELLA• Swollen/tenderglands• Tendernesstopalpationofsinuses• Whitenessontongue–YEASTOVERGROWTH
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DIAGNOSIS
• Culture of possible sites of infection: • Throat (rapid test – high false negative rate) • Tonsils and Adenoids (surface/core) • Urinary Tract • GI Tract/Perianal (Toufexis et al, JCAP, 2013) • Sinuses - cryptic, recalcitrant (Mahoney et al, J Ped Otorhinolar, 2017)
DIAGNOSIS
• Laboratoryevidence• Strepmarkers–ASO,antiDNaseBAb
• 6-8weeksforriseintiterspostinfection• Theseantibodiesonlymeanthatthechildhas
hadapreviousstrepinfection.ItdoesNOTmeanthechildhasPANDAS
• About40%ofchildrenwithdocumentedGASinfectionsdonotshowariseintiters–leadingtofalsenegatives.
• Otherinfectiousmarkers:• MycoplasmaIgG/IgM• LymeandCoinfections(Babesia,Bartonella,
Ehrlichia)• Viralmarkers–influenza,EBV,CMV,etc.
• Inflammatorymarkers–CRP,ESR,ANA• ANAispositivein>56%(Coxetal,JACP,2015)
• CaMKinase–Molecularalabs• Testingmaybehelpfulwhenchildinaflare
ornotclassicalclinicalpicture
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DIAGNOSIS
• MOLD–mycotoxinprofile• Chemicalexposures• Immunizations
EnvironmentalExposures:
• FoodAllergies• Celiacscreen• Thyroidabs• CerebralFolateDeficiency• Metabolicmarkers• Endocrinemarkers
AdditionalMarkers:
TREATMENT
• Treating the symptoms with supportive interventions (CBT, supplements, psychoactive medications)
• Removing the source of the infection – treating with antimicrobials (natural and pharmaceutical)
• Treating immune disturbances with immunomodulatory and/or anti-inflammatory interventions
Swedoetal,JChildAdolPsychopharm,2017
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PRINCIPLES OF TREATMENT
Establish the correct diagnosis
Provide symptomatic relief –comprehensively treat symptoms causing the most distress (Thienemann et al, J Child Adol Psychopharm, 2017)
Treat infections – therapeutic and prophylactically (Cooperstock et al, J Child Adol Psychopharm, 2017)
Treat neuroinflammation and post-infectious autoimmunity with anti-inflammatory and immunomodulatory interventions (Frankovich, J Child Adol Psychopharm, 2017)
Evaluate effectiveness of treatment, modifying as warranted by relapsing and remitting symptoms (Swedo et al, J Child Adol Psyhopharm, 2017)
TREATMENT FOR SYMPTOMS
OCD
Tics
Anxiety
Aggression/Irritability
SleepDisturbances
ADHD
EatingDisorders/Restrictions
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OCD
• NATURAL INTERVENTIONS • N-Acetyl Cysteine (NAC) • Inositol
• 18 grams/day found to decrease OCD (Palatnik et al, J Clin Psychopharm, 2001)
• CBD (Hemp Oil) – Cannabidiol • Reverses mCPP-induced marble burying in mice
(Nardo et al, 2013; Delana et al, Psychopharm, 2012) • Lithium Orotate (O’Donnell et al, Eur Neuropsychopharm,
2003) • Passionflower – helps to calm of mind of repetitive thoughts • Ashwagandha
• Comparable efficacy in mice models to fluoxetine (Asian Pac J Trop Med, 2012)
• GABA • Modulates glutamate that has been found to be
significantly higher in CSF of subjects with OCD compared to controls(Pittenger et al, 2011)
• Mindfulness (Hansteded et al, J Nerv Ment Dis, 2008) • Exercise (Otto et al Oxford Univ Press, 2011)
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OCD • Pharmaceuticals
• SSRI’s (Selective Serotonin Reuptake Inhibitors) prescribed for OCD • Low dose with slow titration (Coffey, 2007) • Study found that 30% of patients have treatment-refractory
(Goddard et al., 2008) • Reason to implement natural interventions! • Possible benefit from additional treatment that addresses other
neurochemical pathways (i.e dopamine and glutamate) • Memantine (Namenda)
• NMDA receptor antagonist and regulates glutamate (excitatory neurotransmitter)
• Study showed improvement in OCD and impulsivity (Ghaleiha et al, 2013)
• Animal models show anti-inflammatory benefits • Amantadine
• NMDA receptor antagonist that decreases glutamate to help with OCD (Hosenbocus and Chahal, 2013)
ANXIETY
• 5-HTP• GABA• L-Theanine• B6• Bcomplex• Magnesium• Probiotics• Multi-mineral• EFA
• L-MTHF(ifMTHFRmutationORCFD)• Ashwagandha• LemonBalm• Motherwort• Passionflower• MimosaBark• Hempoil• EXERCISE• Meditation• ClassicalHomeopathy
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ANXIETY
• DosagesbasedonTDchildren• Startatlowdosageandslowlytitrateup• SSRIsmostsuccessfultreatmentforTDyouthwithanxiety
• SSRIsusedinASDpopulationbutlackofdouble-blindplacebocontrolledtrials• DatafromSSRItrialsreportbehavioralactivation(increasedactivity,impulsivity,insomnia,etc.)inchildrenwithASD(WalkupandLabellarte,2001).
ANXIETY
• ModifiedCBT(MCBT)isaneffectivetreatmentofchildrenandadolescentswithhigh-functioningASDandanxietydisorders
• Canbeadministeredindividuallyorinagroupandoftenincludesparentalinvolvement
• Thistherapyincludesaffectiveeducation,cognitiverestructuring,reducingavoidancebehaviors,relaxation,modeling,andexposuretothefearedstimuli(withresponseprevention)
Thoughts
EmotionBehavior
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SLEEP DISTRUBANCES • Herbals:
• Passionflower• Skullcap• Oat• Chamomile• Valerian• ChineseSkullcap• Kava• Lavender• Ashwagandha
• Nutrients:• Melatonin• GABA• Magnesium• 5-HTP• L-theanine
• Homeopathy:• ConstitutionalRemedy• CoffeaCruda30c
TICS
• OralorIVMagnesium(Garica-Lopezetal,2009)
• GABA• L-Theanine• B6(Garica-Lopezetal,2009)• Essentialfattyacids(Gabbayetal,2012)• CBD(SeifKanaanetal,2017)• Homeopathy
• ConstitutionalHomeopathy• AgaricusMuscaris
• Exercise• Acupuncture(Maetal,2006)
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FOOD RESTRICTIONS
• ZINC• Increasingproteinindiet(i.eproteinpowders)• MCTOIL• Digestivebitters
• Ginger• Gentian• Anise
ANTIMICROBIAL TREATMENT
• SubjectswithnewonsetofPANDASandpositiverapidstreptest/throatculturestreatedwithappropriateantibiotics–theirOCDresolved.
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ANTIMICROBIAL TREATMENT Antibiotics
• IMBicillin• Penicillin,Amoxicillin-Clavulanate,Azithromycin,Clarithromycin,
Cephalexin,Cefadroxil,Clindamycin(Shulmanetal,ClinInfDis,2012)• Cefdinir
• RandomizedTrialofCEFDINIRvs.PlacebofoundthattheCefdinirgroupwithsignificantimprovementinticsandOCDoverplacebogroup(Murphyetal.JofChild&AdolPsychopharm,2015)
• Azithromycin• ForlongtermusemusthaveEKGtoruleoutprolongedQTinterval• IseffectiveagainstMycoplasmaandhasimmunomodulatoryproperties
(Obregonetal,Neuropsych,2012;Murphyetal,JAntimicrobChemoth,2008)
• AntibioticProphylaxiswithPenicillinorAzithromycin
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ANTIMICROBIAL HERBS FOR
STREP
• Usnea • Activity against strep species (Abachi et al, 2016)
• Taiga – Pine needle extract • Antimicrobial/antifungal activity (Lee et al, 2005)
• Berberine (Goldenseal) • Berberine sulfate blocks adherence of Streptococcus
pyogenes to epithelial cells, fibronectin, hexadecane (Sun D et al, 1988)
• Neem • Neem extract effective against four Streptococcus
species responsible for causing dental caries (Chava et al., 2012).
• OreganoOil
ANTIMICROBIAL HERBS FOR
STREP
• Cordyceps• Medicinalmushroomcontainingmyceliumwhichshowedto
protectagainststrepinanimalmodels(Kouetal.,2005)
• Alliumsativum• Effectiveagainstmulti-drugresistantbacteriaincludingstrep
species(Iwalokunetal.,2004)
• Coptis• Antimicrobialpropertiesagainststrepmutans(Choietal.,
2007)
• Capsicum(CichewiczandThorpe,1996)
• Achillea(Candanetal,2003)• Ligusticum(Xiaoetal,2004)
• StrepThroatFormula-Hydrastis,Echinacea,Myrrha,andPhytolacca
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ANTIMICROBIAL INTERVENTIONS
FOR MYCOPLASMA
• Silvercillin• Goldenseal• Houttuynia• Isatis• Resihi• Pomegranatejuice• BrazilNuts• HomeopathicMycoplasmaNosode
ANTIMICROBIAL INTERVENTIONS
FOR VIRUSES
• VitaminA• VitaminD
• VitaminC• L-Lysine
• aminoacidthatdecreasesviralload
• Monolaurin• Interfereswithvirusassemblyandviralmaturation• Donotuseifcoconutallergy
• Zinc• Elderberry
• Hemagglutininproteinhasbeenshowntostopavirus'capabilitytoreplicatebyinhibitingitsabilitytopenetratethecellwall(SerkedjievaJandManolovaN,1999)
• Donotconsumerawelderberries-containcyanogenicglycosidesandmustbecookedsufficientlytoavoidriskofcyanidetoxicity
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ANTIMICROBIAL INTERVENTIONS
FOR VIRUSES
• Glycyrrhiza(Licorice)• Glycyrrhizicacidpresentintheplantinhibitsvirusgrowthand
inactivatesvirusparticles(AroraR.etal,2011)
• Ginger• increaselevelsofantioxidantenzymes,includingsuperoxide
dismutaseandglutathioneperoxidaseandTNF-alpha
• OliveLeaf• Preventsvirusshedding,budding,andassemblyofcell
membranes
• LemonBalm• inhibitsvirusreplication(Pourghanbarietal,2016)
• Echinacea• Toincreaseantibodyproduction,increaseandstimulatethe
activityofwhitebloodcells(Brinkebornetal,1998)
• Implementacuteviralprotocolsatonsetofviralillnesses(i.evitaminA,D,Zinc,L-lysine,enzymedefense,etc)
OTHER INTERVENTIONS
• VitaminD• Deficiencyassociatedwithincreasedfrequency
infections(Thorntonetal,2013)• Downregulateautoimmuneprocesses(Rolfetal,
2014)• Ibuprofen/NSAIDS(Spartzetal,2017)• Xylitol
• InhibitsgrowthofstrepmutansandStreptococcuspneumoniae(Tapianienetal,2001)
• Probiotics• BLISK12• EssentialOils
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IMMUNOMODULATORY TREATMENT
• Steroids(oralvsIV;lengthofcoursedependsonsymptomseverity)• Shortburst–usedtherapeuticallyanddiagnostically• Temporaryfixinsome;needtodofor30dayswithtaper+/-pulses• Transientworseningtypical
• HelminthTherapy–immunotherapywiththeuseofHDCs• www.biomerestoration.com• helminthictherapywiki.org
• Plasmophoresis–processthatfiltersthebloodandremovesharmfulantibodies• severe-extremedisease(Dalmauetal,2011)
• Rituximab–worksbyturningoffapartoftheimmunesystemthatisnotworkingproperlyinautoimmunedisease
• Deteriorating,moderate-extremedisease&previousresponsiveness&autoimmunity(Changetal,2015)
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IMMUNOMODULATORY TREATMENT
• IVIG – use of intravenous immunoglobulins to support immune system
• No improvements in control group; significant decrease in OCD severity in IVIG and plasmaphoresis groups after 1 month (Perlmutter et al,1999)
• One to six month course in moderate-severe (Frankovich et al, 2017)
• > 60% reduction in symptoms in children with prophylactic antibiotics followed by open label IVIG (sustained > 6 mths)
• High ANA and Cam Kinase activation predictive of symptoms improvement à Antibiotics therapeutic when these elevated
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IMMUNOMODULATORY TREATMENT
• ProbioticsandPrebiotics• Lactobacillus,Bifidobacterium,Bacillius• SaccharomycesBoulardii
• EssentialFattyAcids–Omega3(EPA/DHA)&6(GLA)• EatSardines!• Modulationofinflammatoryreactions,loweringtriglycerides,nerve
transmission• (Belluzzietal,1996)
• Aloe• Anti-oxidantpropertiestodecreaseROS(Landmeadetal,2004)
• Curcumin• Efficacyofcurcumin,andasaffron/curcumincombinationforthe
treatmentofmajordepression:Arandomized,double-blind,placebo-controlledstudy.
• (Loprestietal,2017)• CBDOil
• suppressionofcytokinesandchemokinesatinflammatorysitesandupregulationofFoxP3+regulatoryTcells(Nagarkattietal,2009)
• Flavonoids-Quercetin,Luteolin,Rutin• Potentmastcellstabilizerinhibitsreleaseofhistamine&
inflammatorymediators• Preventsexcessivereleaseofhistamine(Chuenkityanaonetal,2010)
CLOSING REMARKS
PANS/PANDASisaCLINICALDIAGNOSIS
ThinkPANS/PANDASwithACUTEonsetofsymptoms(tics,OCD,anxiety,regression,etc.)
Noteverychildwillpresentwithallofthesesymptoms
Treatmentplanshouldincludeantimicrobialinterventions,immunomodulatoryinterventions,andtherapy
Relapsingandremittingcourseofsymptoms
Besttocombineconventionalandnaturalinterventions
TAKECAREOFYOURSELF–YOURCHILDSHEALTHDEPENDSONIT!
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THANK YOU!
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