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5/14/19 1 Could Your Child’s Behavior be PANS/PANDAS? National Autism Association Conference May 2019 Lindsey E. Wells, ND www.lindseywellsND.com What is PANS/PANDAS PANDAS = Pediatric Autoimmune Neuropsychiatric Disorder Associated with Strep PANS = Pediatric Acute-Onset Neuropsychiatric Syndromes PITANDS = Pediatric Infection-Triggered Autoimmune Neuropsychiatric Disorders Post-streptococcal Autoimmune Encephalitis (of the basal ganglia) Sydenham Chorea Post-Streptococcal Striatal Autoimmune Encephalitis 95% with emotional lability, 50-75% with OCD at initial presentation and 100% with recurrence (Russel Dale & colleagues)

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Page 1: Could Your Child’s Behavior be PANS/PANDAS?nac.nationalautismassociation.org/.../05/...PANDAS.pdf · PANS/PANDAS Swedo et al, Ped Ther, 2012 PANS/PANDAS • 1 in 150-200 children

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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)

Page 2: Could Your Child’s Behavior be PANS/PANDAS?nac.nationalautismassociation.org/.../05/...PANDAS.pdf · PANS/PANDAS Swedo et al, Ped Ther, 2012 PANS/PANDAS • 1 in 150-200 children

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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

Page 3: Could Your Child’s Behavior be PANS/PANDAS?nac.nationalautismassociation.org/.../05/...PANDAS.pdf · PANS/PANDAS Swedo et al, Ped Ther, 2012 PANS/PANDAS • 1 in 150-200 children

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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

Page 9: Could Your Child’s Behavior be PANS/PANDAS?nac.nationalautismassociation.org/.../05/...PANDAS.pdf · PANS/PANDAS Swedo et al, Ped Ther, 2012 PANS/PANDAS • 1 in 150-200 children

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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.

Page 20: Could Your Child’s Behavior be PANS/PANDAS?nac.nationalautismassociation.org/.../05/...PANDAS.pdf · PANS/PANDAS Swedo et al, Ped Ther, 2012 PANS/PANDAS • 1 in 150-200 children

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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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