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P ediatric A utoimmune N europsychiatric D isorder s A ssociated with S treptococcus

PANDAS/PANS A COMMON MODULATOR OF BEHAVIOR IN CHILDREN DR. ROSARIO TRIFILETTI, MD PhD RAMSEY, N.J. trifmd@gmail.com. P ediatric A utoimmune N europsychiatric D isorder s A ssociated with S treptococcus. What are the symptoms?. ORIGINAL DEFINITION (1996) “ PANDAS ” “SWEDO CRITERIA”

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P ediatric A utoimmune N europsychiatric D isorder s A ssociated with S treptococcus

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  1. PANDAS/PANSA COMMON MODULATOR OF BEHAVIOR IN CHILDRENDR. ROSARIO TRIFILETTI, MD PhDRAMSEY, N.J.trifmd@gmail.com

  2. Pediatric • Autoimmune • Neuropsychiatric • Disorders • Associated with • Streptococcus

  3. What are the symptoms? • ORIGINAL DEFINITION (1996) “PANDAS” • “SWEDO CRITERIA” • 1. Onset of symptoms between age 3 and 11 • 2. Acute onset • 3. Of motor/vocal tics and/or OCD • 4. Temporally correlated with a Group A beta-hemolytic streptococcus (GABHS) infection • 5. (Optional) Presence of choreiform signs

  4. What are the symptoms? Typical “textbook” case • A 6 year old child is diagnosed with a strep throat • The child is treated with antibiotics • One day, a few weeks later, a sudden change • Facial blinking and humming sounds • School phobia/avoidance • Separation anxiety – need to visit parents in their bed at night, sleep problems • Rapid improvement with ibuprofen • Sustained improvement with Amox/Clav

  5. What are the symptoms? Variant case • A 12 year old child is diagnosed with “walking pneumonia” • The child is treated with antibiotics • A gradual steady change over the course of weeks • Fear of vomiting or seeing other people vomit • Decrease appetite, eventual anorexia • Separation anxiety – need to visit parents in their bed at night, sleep problems • Rapid improvement with ibuprofen • NO response to Amox/Clav • Sustained response to Macrolides (azith-, clarithro-mycin)

  6. What are the symptoms? Yet another variant • A 2 year old child is diagnosed with an asthma-like illness • An abrupt change over the course of weeks • Marked increase in motor restlessness, “manic” • Increased sensitivity to sensory stimuli • Repetitive, ritualistic behavior (OCD) • A diagnosis of PDD-NOS is considered • Rapid improvement with ibuprofen

  7. What is PANDAS/PANS? • In its initial formulation by Swedo and colleagues • PANDAS was viewed as “Sydenham Chorea Lite” • This was a good guess, but not quite correct • In part, it lead to the “PANDAS controversy” • Correction let to the re-definition of PANDAS as PANS

  8. PROBLEMS WITH “STRICT” PANDAS MODEL • Not just a “pediatric disease” • Infants <3 • Adolescents • Adults • Many other symptoms • Not just strep • Onset not always acute Common denominator : INFLAMMATION • Rapid improvement with ibuprofen

  9. Pediatric • AutoimmuneACUTE • Neuropsychiatric • Disorders SYNDROME • Associated with • Streptococcus

  10. PANS

  11. PANS

  12. PANS

  13. PANDAS/PANS INSTITUTE (P/P-I) DATABASE 92% of my practice is PANS/PANS personally interviewed and examined Opened 11/2009 n=2007 LCsubset (n=674) Q subset (n=511) Non-LC/Q subset (n=822)

  14. It has several presentations in different age groups • Early infantile syndrome = autism • Infantile mania syndrome – • mimics mania, severe ADHD. Many children end up with PDD-NOS. • Very atypical response to stimulants and SSRI’s. • Juvenile onset - Swedo syndrome – classic PANDAS • -mimics TS/OCD . Outcome likely good. • Adolescent-onset PANS • Kovacevic syndrome – pure OCD, anxiety • Leroy syndrome – pure motor tics • Readily confused for “conversion disorder” • Often “star” student/athlete that falls off the “face of the earth” • Acute crises – the “Exorcist syndrome”

  15. PANDAS VARIANTS • “CHRONIC PANS” • PANS OVERLAP SYNDROMES: • 1. OVERLAP WITH HASHIMOTO ENCEPHALOPATHY • 2. OVERLAP WITH NEUROSARCOIDOSIS • 3. OVERLAP WITH OTHER AUTOIMMUNE ENCEPHALOPATHIES • NMDAR ENCEPHALITIS • LUPUS AND RELATED CONDITIONS (ESP. SJOGREN SX)

  16. “PANDAS PLUS” • PANS OVERLAP SYNDROMES: • OVERLAP WITH KLEINE-LEVIN SYNDROME • HYPERSOMNOLENC • HYPERPHAGIA • HYPER-SEXUAL (BOYS) / DEPRESSION (GIRLS) • 2. OVERLAP WITH EHLERS-DANLOS SYNDROME • A. MAINLY EDS3, HYPERMOBILITY ONLY TYPE • B. ARNOLD-CHIARI MALFORMATION • C. MAST CELL ACTIVATION DISORDER • 3. “POTS and PANS”

  17. N=674

  18. Anti-streptolysin O (LC subset) ASO not normally distributed Shows “low strep responder” group

  19. SEROLOGICAL DATA – LC SUBSET

  20. ACUTE INFECTION MARKERS – LC SUBSET

  21. Coxsackie B - GABHS co-infection: a particularly bad combination ??

  22. INFECTIOUS TRIGGER << VS. >> HOST

  23. ABNORMALITIES IN HUMORAL IMMUNITY IN PANS – TOTAL IgG LEVELS • 25% of children with PANS have one or more abnormal immunoglobulin level(excluding IgE) • 9.2% are hypogammaglobulinemic (age corrected) • 12% are low in IgA, and 0.4% absent in IgA • Among males , 1:30 show a markedly elevated IgA and low IgM (IgA/IgM >10 ;This is the “Wiskott-Aldrich syndrome -like” (WAS-like) immunophenotype) • 5.2% meet criteria for CVID - THESE are the children that definitely need IVIG !!

  24. IgE abnormalities in PANS LOW IgE subgroup 30% of PANS patients are in the low-IgE subgroup (IgE<15) There is a rarer (2%) hyper-IgE subgroup – this is not secondary to allergies it seems to be a formefruste of HIES … it is a “PANS-plus” subgoup …. Overall, there is a high incidence of DYSREGULATION of IgE in PANS….

  25. IgG subclass deficiency and dysregulation in PANS PANS – LC subset (n=777) PANS – LC subset compared to PID and normal children IgG subclass deficiency in PANS is comparable to children with primary immunodeficiency(reflects cytokine imbalances)

  26. IgG4 and IgE are strongly correlated in patients with PANS IgE

  27. IgG4 and IgE are strongly correlated in patients with PANS (“G4-E dysregulation”) Log(IgE) r2 = 0.557 (p<.0001) Log(IgG4)

  28. IL-4 and IL-13 promote IgG4 AND IgE class switching IL-10 potentiates IL-4/13 effect on IgG4 but inhibits IL-4 effect on IgE In PANS – low IL-4, low IL-13, and low IL-10 ….. Low IgG4 and IgE “anti-allergy or anti-anaphylactic state”

  29. PANS-prone immunophenotype (PPI-1) IL-5 IL-3 Basophilpool IL-4, IL-13 Mast cell pool IL-10 HISTAMINE NORMAL

  30. PANS-prone immunophenotype (PPI-1) IL-5 IL-3 Basophilpool Mast cell pool IL-4, IL-13 IL-10 HISTAMINE PANS “Anti-anaphylactic state”

  31. Low IL-10 is a powerful STIMULATOR of Inflammatory mediators IL-1b IL-6 (TNF)-a

  32. What is the cause, or mechanism? • Two competing/complementary theories • Molecular mimicry • Alternative fever response

  33. Molecular mimicry

  34. PROs of molecular mimicry model • Explains why PANDAS/PANS looks like rheumatic fever • Explains the high incidence of auto-immune disease in patients with PANDAS/PANS and their families • Explains the response of some cases to IVIG and PEX • Leads to the potential of discovery of specific molecular targets and thereby more refined immunotherapy

  35. CONs of molecular mimicry model • Cannot explain why many unrelated pathogens, GABHS, M.Pneumoniae, Coxsackie, EBV can trigger an identical syndrome • These agents are antigenically very different. It would be an incredible coincidence for autoantibodies against them to affect the same areas of brain. • Cannot easily explain the extraordinary response of the syndrome to cyclo-oxygenase inhibitors like ibuprofen. • Cannot readily explain the lack of evidence of BBB breakdown or antibodies in the brain • No evidence of brain or peripheral tissue damage in vast majority of cases, unlike ARF, now with 15+ yr follow-up; it’s not ARF-lite. • Many affected children do not have autoantibodies • Does not explain the full “pervasiveness” of the disorder ….

  36. Alternative Fever Response • Basic idea PANDAS is fever mechanism taking a wrong turn • Locus of action in hypothalamus • We can use what we know about fever to understand PANDAS

  37. FEVER (1 mi ahead) PANS (1 mi ahead) I shall be telling this with a sigh Somewhere ages and ages hence Two roads diverged in a wood, and I— I took the one less traveled by, And that has made all the difference.

  38. Alternative Fever Response

  39. “PANS-PRONE” IMMUNOPHENOTYPE(PPI-1) My study of 1000+ patients with PANDAS reveals a pattern: • LOW IgE, LOW IgG4 (G4E DYSREGULATION) • LOW IgG2 • Low-absent basophils • LOW HISTAMINE (ANTI-ANAPHYLACTIC) STATE

  40. Elevated IL-10 IL-4 or IL-13 pathway defects Mild WAS-like state?? (Wiskott-Aldrich Syndrome) TLR-4 , IL-10 pathway defects??? IgG4/IgE Deficiency/ dysregulation IgM deficiency with high IgA (males only) IgG3 deficiency ACUTE NEUROPSYCHIATRIC SYNDROME (aka “PANDAS/PITANDS”)

  41. NORMAL IMMUNOPHENOTYPE + • TRIGGERS • STREP PYOGENES • MYCOPLASMA PNEUMONIAE • COXSACKIE A • LYME AND LYME-LIKE AGENTS • EBV • H1N1 VACCINE (IN IGG2 DEFICIENT PATIENTS • PRETTY MUCH ANYTHING THAT MIGHT PRODUCE FEVER …. = FEVER, MALAISE

  42. “PANS-PRONE” IMMUNOPHENOTYPE + • TRIGGERS • STREP PYOGENES • MYCOPLASMA PNEUMONIAE • COXSACKIE A • LYME AND LYME-LIKE AGENTS • EBV • H1N1 VACCINE (IN IGG2 DEFICIENT PATIENTS • PRETTY MUCH ANYTHING THAT MIGHT PRODUCE FEVER …. = PANS

  43. “PANS-PRONE” IMMUNOPHENOTYPE(PPI-1) = LOW HISTAMINE My study of 1000+ patients with PANDAS reveals a pattern: • LOW IgE, LOW IgG4 (G4E DYSREGULATION) • LOW IgG2 (approx 50% reduction) • Low-absent basophils • LOW HISTAMINE(ANTI-ANAPHYLACTIC) STATE • Or perhaps better put: a defect in basophil histamine pool (shift to neutrophil source?)

  44. RATIONAL TREATMENT PANDAS/PANS HAS “STAGES” STAGE 1 – CYTOKINE DOMINANT PHASE (FEVER-LIKE, ALTERNATIVE FEVER RESPONSE) STAGE 2 - AUTO-INFLAMMATORY PHASE STAGE 3- AUTOANTIBODY DOMINANT PHASE STAGE 4- IRREVERSIBLE BRAIN INJURY IMPORTANT QUESTION STAGE 1 >>> STAGE 2 >>> STAGE 3 >> STAGE

  45. STAGE 1 – CYTOKINE DOMINANT PHASE (FEVER-LIKE, ALTERNATIVE FEVER RESPONSE) 1. CUNNINGHAM TEST: CAM2K ELEVATED, LOW AUTOANTIBODIES 2. EPISODES LINKED TO INFECTION ….CLEAR TRIGGERS STAGE 2 - AUTO-INFLAMMATORY PHASE CUNNINGHAM TEST : CAM2K ELEVATED, LOW-MODERATE AUTOANTIBODIES EPISODES LESS CLEARLY LINKED TO INFECTION MAY START TO SEE OTHER AUTOANTIBODIES – POSITIVE ANA, ANTI-THYROID STAGE 3- AUTOANTIBODY DOMINANT PHASE CUNNINGHAM TEST: CAM2K ELEVATED, HIGH LEVELS OF AUTOANTIBODIES NOT LINKED TO INFECTION, ALTHOUGH INFECTIONS STILL EXACERBATE HARDER TO REVERSE STAGE 4- IRREVERSIBLE BRAIN INJURY BASAL GANGLIA AND THALAMUS SEEN TARGETS OFTEN TAKES YEARS TO DEVELOP

  46. RATIONAL TREATMENT STAGE 1– CYTOKINE-DOMINANT (ALTERNATIVE FEVER RESPONSE) PHASE USUALLY MEANS IT HAS BEEN GOING ON FOR A FEW MONTHS. MOST “FIRST EPISODE” CASES HAVE THIS ANTIBIOTICS WORK AMAZINGLY, ONCE YOU FIND THE RIGHT ONE! “TREAT IT LIKE AN FEVER” PROVIDE ACUTE RELIEF NSAID’S – i.e. MOTRIN, ALEVE, CELEBREX, ?NATUROPATHICS FIND THE TRIGGER, TREAT THE TRIGGER Antibiotics Antivirals Others PREVENT IT FROM HAPPENING AGAIN – RATIONAL PROPHYLAXIS AVOID NEUROPSYCHIATRIC AGENTS IF POSSIBLE, MAY NOT BE POSSIBLE ….

  47. RATIONAL TREATMENT STAGE 2– AUTO-INFLAMMATORY PHASE USUALLY MEANS IT HAS BEEN GOING ON FOR A FEW YEARS “ANTIBIOTICS USED TO WORK, BUT NOW THEY STOPPED WORKING” “TREAT IT LIKE AN INFLAMMATORY DISEASE” PROVIDE ACUTE RELIEF NSAID’S – i.e. MOTRIN, ALEVE, CELEBREX, ?NATUROPATHICS FIND THE TRIGGER, TREAT THE TRIGGER ONCE ACUTE INFECTIONS TREATED, MILD IMMUNOMODULATORY RX IVIG, ESPECIALLY IF CVID-LIKE PICTURE ORAL OR INTRAVENOUS STEROIDS AVOID NEUROPSYCHIATRIC AGENTS IF POSSIBLE, MAY NOT BE POSSIBLE ….

  48. RATIONAL TREATMENT STAGE 3– AUTO-ANTIBODY PHASE USUALLY MEANS IT HAS BEEN GOING ON FOR A FEW YEARS “ANTIBIOTICS USED TO WORK, BUT NOW THEY STOPPED WORKING” “TREAT IT LIKE AN AUTO-ANTIBODY DISORDER (EX. MYSASTHENIA GRAVIS) PROVIDE ACUTE RELIEF NSAID’S – i.e. MOTRIN, ALEVE, CELEBREX, ?NATUROPATHICS FIND THE TRIGGER, TREAT THE TRIGGER ONCE ACUTE INFECTIONS TREATED, STRONGER IMMUNOMODULATORY RX IVIG, ESPECIALLY IF CVID-LIKE PICTURE OTHER AGENTS: CELLCEPT, RITUXIMAB – IMMUNOSUPPRESSION AVOID NEUROPSYCHIATRIC AGENTS IF POSSIBLE, MAY NOT BE POSSIBLE ….

  49. RATIONAL TREATMENT STAGE 4 – TERMINAL PHASE USUALLY MEANS IT HAS BEEN GOING ON FOR AT LEAST 5 YEARS “ANTIBIOTICS USED TO WORK, BUT NOW THEY STOPPED WORKING” “NOBODY KNOWS WHAT TO DO …..” LAST-DITCH EFFORT – LOOK FOR METABOLIC DISEASE MIMIC PROVIDE ACUTE RELIEF NSAID’S – i.e. MOTRIN, ALEVE, CELEBREX, ?NATUROPATHICS FIND THE TRIGGER, TREAT THE TRIGGER ONCE ACUTE INFECTIONS TREATED, STRONGER IMMUNOMODULATORY RX IVIG, ESPECIALLY IF CVID-LIKE PICTURE OTHER AGENTS: CELLCEPT, RITUXIMAB – IMMUNOSUPPRESSION AVOID NEUROPSYCHIATRIC AGENTS IF POSSIBLE, MAY NOT BE POSSIBLE ….

  50. MY HUMBLE ABODE ….

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