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5/1/13
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PANDAS/PANS
A COMMON MODULATOR OF BEHAVIOR IN AUTISTIC SPECTRUM DISORDERS
DR. ROSARIO TRIFILETTI, MD PhD RAMSEY, N.J.
PDD 2000 • MOTHER SUSPECTS AUTISM AT 12 MOS
• TELLS PMD -‐-‐-‐ “IT’S NORMAL, LET’S WAIT”
• FURTHER SUSPICION OF AUTISM AT 15 MOS
• TELLS PMD -‐-‐-‐ “IT’S NORMAL, LET’S WAIT”
• CHILD STOPS TALKING AT 18 MONTHS, NO EYE CONTACT
• “LET’S REFER HIM FOR A DEVELOPMENTAL EVAL”
PDD 2000 • WAIT 3-‐6 MOS FOR DEVELOPMENTAL EVAL
• DIAGNOSIS OF AUTISM MADE AT 24 MOS
• “LET’S REFER HIM TO NEUROLOGIST” -‐WAIT 3 MORE MONTHS
• CHROMOSOMES, FRAGILE X, METABOLIC W/U -‐ NL
• “IT’S AUTISM, NOT MEDICAL, NOTHING TO DO
• PARENTS PURSUE ABA AND ALTERNATIVE MEDICINE
PDD 2013 – A NEW APPROACH • MOTHER SUSPECTS AUTISM AT 12 MOS
• ENTER “EARLY BIRD PROGRAM” – DESPITE PMD
• IMMEDIATE MEDICAL EVALUATION: • PANDAS/PANS • CHROMOSOME MICROARRAY • mtDNA/mitonucleomic SEQUENCING WITHIN ONE MONTH – ANSWERS
PERSONALIZED MEDICINE
PDD 2000 • WAIT 3-‐6 MOS FOR DEVELOPMENTAL EVAL
• DIAGNOSIS OF AUTISM MADE AT 24 MOS
• “LET’S REFER HIM TO NEUROLOGIST” -‐WAIT 3 MORE MONTHS
• CHROMOSOMES, FRAGILE X, METABOLIC W/U -‐ NL
• “IT’S AUTISM, NOT MEDICAL, NOTHING TO DO
• PARENTS PURSUE ABA AND ALTERNATIVE MEDICINE
• Pediatric • Autoimmune
• Neuropsychiatric
• Disorders
• Associated with
• Streptococcus
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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 dcs and/or OCD – 4. Temporally correlated with a Group A beta-‐hemolydc streptococcus (GABHS) infecdon
– 5. (Opdonal) Presence of choreiform signs
What are the symptoms?
Typical “textbook” case
– A 6 year old child is diagnosed with a strep throat – The child is treated with andbiodcs – One day, a few weeks later, a sudden change • Facial blinking and humming sounds • School phobia/avoidance • Separadon anxiety – need to visit parents in their bed at night, sleep problems
– Rapid improvement with ibuprofen – Sustained improvement with Amox/Clav
What are the symptoms? Variant case
– A 12 year old child is diagnosed with “walking pneumonia” – The child is treated with andbiodcs – A gradual steady change over the course of weeks
• Fear of vomidng or seeing other people vomit • Decrease appedte, eventual anorexia • Separadon 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)
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 sensidvity to sensory sdmuli • Repeddve, ritualisdc behavior (OCD) • A diagnosis of PDD-‐NOS is considered
– Rapid improvement with ibuprofen
What is PANDAS/PANS?
• In its inidal formuladon 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”
• Correcdon let to the re-‐definidon of PANDAS as PANS
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
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• Pediatric • Autoimmune ACUTE
• Neuropsychiatric
• Disorders SYNDROME
• Associated with
• Streptococcus
• Pediatric • Acute
• Neuropsychiatric
• Syndrome
PANS PANS
PANS What is the cause, or mechanism?
• Two compedng/complementary theories
– Molecular mimicry
– AlternaLve fever response
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Molecular mimicry PROs of molecular mimicry model
• Explains why PANDAS/PANS looks like rheumadc fever
• Explains the high incidence of auto-‐immune disease in padents with PANDAS/PANS and their families
• Explains the response of some cases to IVIG and PEX
• Leads to the potendal of discovery of specific molecular targets and thereby more refined immunotherapy
CONs of molecular mimicry model • Cannot explain why many unrelated pathogens, GABHS,
M.Pneumoniae, Coxsackie, EBV can trigger an idendcal syndrome • These agents are andgenically very different. It would be an
incredible coincidence for autoandbodies 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 andbodies in the brain
• No evidence of brain or peripheral dssue 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 autoandbodies
• Does not explain the full “pervasiveness” of the disorder ….
AlternaLve Fever Response
• Basic idea PANDAS is fever mechanism taking a wrong turn
• Locus of acdon in hypothalamus
• We can use what we know about fever to understand PANDAS
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.
AlternaLve Fever Response
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“PANS-‐PRONE” IMMUNOPHENOTYPE (PPI-‐1)
• LOW IgE, LOW IgG4 (G4E DYSREGULATION)
• LOW IgG2
• Low-‐absent basophils
• LOW HISTAMINE (ANTI-‐ANAPHYLACTIC) STATE
My study of 1000+ padents with PANDAS reveals a paqern:
ACUTE NEUROPSYCHIATRIC SYNDROME (aka “PANDAS/PITANDS”)
IgG3 deficiency
IgM deficiency with high IgA (males only)
IgG4/IgE Deficiency/ dysregulaLon
Mild WAS-‐like state?? (Wiskoq-‐Aldrich Syndrome)
Elevated IL-‐10 IL-‐4 or IL-‐13 pathway defects
TLR-‐4 , IL-‐10 pathway defects???
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
“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
“PANS-‐PRONE” IMMUNOPHENOTYPE (PPI-‐1) = LOW HISTAMINE
• LOW IgE, LOW IgG4 (G4E DYSREGULATION)
• LOW IgG2 (approx 50% reducdon)
• Low-‐absent basophils
• LOW HISTAMINE (ANTI-‐ANAPHYLACTIC) STATE
• Or perhaps beqer put: a defect in basophil histamine pool (shiu to neutrophil source?)
My study of 1000+ padents with PANDAS reveals a paqern:
HISTAMINE IS CRITICALLY IMPORTANT IN TS/OCD
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HISTAMINE IS CRITICALLY IMPORTANT IN TS/OCD
HDC AND TS/OCD A CriLcal Unifying Discovery
• There is only ONE HDC gene
• Therefore polymorphisms apply to basophils, neurons and all other cells!
• CONCLUSION – • DEFECTIVE BRAIN HISTAMINE SYNTHESIS = TS/OCD
• DEFECTIVE GUT HISTAMINE SYNTHESIS • DEFECTIVE IMMUNE SYSTEM HISTAMINE SYNTHESIS
HDC AND TS/OCD A CriLcal Unifying Discovery
• There is only ONE HDC gene
• Therefore polymorphisms apply to basophils, neurons and all other cells!
• CONCLUSION – • DEFECTIVE BRAIN HISTAMINE SYNTHESIS = TS/OCD
• DEFECTIVE GUT HISTAMINE SYNTHESIS • DEFECTIVE IMMUNE SYSTEM HISTAMINE SYNTHESIS
BRAIN HISTAMINE
ALL BRAIN HISTAMINE ORIGINATES
FROM ONE PLACE!!
VTN – the “SOUL” OF PANDAS
In the POSTERIOR HYPOTHALAMUS …. NOT THE BASAL GANGLIA!!
VTN – the “SOUL” OF PANDAS BRAIN HISTAMINE -‐ VTN
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PGE2 SENSITIVE BRAIN REGIONS PGE2 SENSITIVE AREA IN
ANTERIOR HYPOTHALAMUS MEDIATES FEVER
PGE2 SENSITIVE AREA IN POSTERIOR HYPOTHALAMUS
THE VTN !!
ALTERNATIVE FEVER MODEL TYPICAL SITUATION
INFECTION (GABHS, MP, MANY OTHERS)
INFLAMMATORY CYTOKINES
CENTRAL PGE2
VTN MnPO
FEVER/MALAISE PANDAS/PANS SYMPTOMS
ALTERNATIVE FEVER MODEL PPI-‐1 (LOW PERIPHERAL HISTAMINE)
INFECTION (GABHS, MP, MANY OTHERS)
INFLAMMATORY CYTOKINES
CENTRAL PGE2
VTN MnPO
FEVER/MALAISE PANDAS/PANS SYMPTOMS
ALTERNATIVE FEVER MODEL OF PANDAS/PANS
HYPOTHESES: PANDAS/PANS symptoms result in an esdmated 1-‐2% of children with a variant immunophenotype (associated with a low histamine, and-‐anaphylacdc state) encountering common organisms that in 98-‐99% of individuals simply produce fever and malaise. The cytokine milieu associated with this variant phenotype results in an imbalance of acdon of PGE2 on the MnPO and VTN, with an increase in effect on the laqer versus the former. Chronic over-‐sdmuladon of the VTN results in brain H3-‐receptor dysreguladon and dysreguladon of release of neurotransmiqers (i.e. dopamine, serotonin, norepinephrine, and others). Due to the widespread “pervasive” neuroanatomical connecdons of the VTN, one sees a “pervasive behavioral syndrome” following common infecdons. Autoandbodies play an ancillary role in this model.
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PROs of alternaLve fever model • Explains why many unrelated pathogens, GABHS, M.Pneumoniae,
Coxsackie, EBV can trigger an idendcal syndrome • These agents are andgenically very different, but trigger a
common immune response
• Readily explains the extraordinary response of the syndrome to cyclo-‐oxygenase inhibitors like ibuprofen.
• Fits with emerging genedc data implicadng the histaminergic system in the TS-‐OCD phenotype.
• Like fever, explains the reversibility of the disorder. No evidence of brain or peripheral dssue damage in vast majority of cases.
• Explains why many affected children do not have autoandbodies, especially early on.
CONs of alternaLve fever model
• Doesn’t yet clearly explain the improvement of syndrome with age
• Doesn’t clearly explain “pure genedc cases” or “geographical clusters” (like Leroy)
• As yet, no neuroimaging or electrophysiological data to support
• These deficiencies may be remedied but future anatomic, genedc and environmental studied.
• In fact, we already have substandal full mtDNA and mitoNucleome sequencing which indicates a small subset of risk genes.
PANDAS/PANS Genedc risk factors –pilot study
• 31 paLents with PANS (14) or PDD-‐PANS (17)
• Full sequence of the mitoNucleome (1100+ genes) • Analyze for relevant polymorphisms
– Precedent – Rarity – Strong evoludonary conservadon
• Study frequency of polymorphisms between geneLcally unrelated paLents to look for associaLon of disease with polymorphisms, with no pre-‐conceived noLons of what we are looking for …..
0
1
2
3
4
5
6
7
AAAS
AC
5M5
ACAD
SB
ACB8
AC
BC7
ACSM
5 AD
CK2
AKAP
1 ALDH
18A1
ALDH
5A
AMAC
R AS
S1
ATAD
3B
ATP1
0D
ATP5
0 AT
P5A1
AT
P5J
BAX
CCS1L
CDKL5
COQ6
COX1
5 CP
S1
CYB5
R3
CYP1
1A1
CYP2
7A1
DBT
DHTK1
DMGD
H DN
AJC1
1 EA
RS2
ECH1
EFHA
1 ETFB
EXOG
FAM82
A2
FKBP
8 GA
DD4L1P
1 GA
RS
GCDH
GL
UT1
GUF1
HAGH
LRRK
2 ME2
MRLP3
8 MRP
L21
MRP
L39
MRP
L55
MRP
L9
MRS2
MTC
H1
MUTYH
NDU
F64
NDU
FAF2
NDU
FS3
NEU
4 NNT
NUDT
8 OA2
3 OTC
PA
NK2
PC
CA
PCCB
PC
K2
PKLR
POLG
PO
LRMT
PRODH
RA
RS2
RNAS
EL
RRM2B
SD
HA
SECISSP2
SLC2
5A17
SLC2
5A47
TOP1
TO
P1MT
UBE
3A
UCP
3 UQCR
H WFS1
WWOX
PANS
PDDPANS
0
5
10
15
20
25
30
35
40
45
50
LRRK2 POLG WFS1 OTHER
PANS
PDD
POLYMORPHISMS IN THREE CRITICAL GENES IN 60-‐70% OF PANS CASES
PANDAS/PANS PERCENT PATIENTS WITH
POLYMORPHISMS GENE PANS PDD-‐PANS
LRRK2 28.5 23.5POLG 42.8 23.5WFS1 35.7 17.6>=1 64.2 52.9>=2 28.5 0
OTHERS 35.8 47.1
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PANDAS/PANS Genedc risk tesdng
100000 PTSINC PANS 0.02>=1 PANS-‐ 0.03
TEST+ TEST-‐PANS+ 1284 716PANS-‐ 2940 95060
SENS 64.20%SPEC 97%PPV 30.30%NPV 99.20%
• Assume incidence PANS 2% Assume each gene 1% polymorphism in general populadon TEST+ If LRRK2 or POLG or WFS1 polymorphisms present OTHERWISE TEST -‐
PREVENT AUTISM NOW?
RISK-‐REDUCED VACCINATION
• ASSUME 100, 000 NEWBORNS
• ASSUME ALL PANS+ PATIENTS HAVE VACCINE ISSUES
• SWAB CHEEK IN NURSERY AT BIRTH, RESULTS BACK IN 24 HRS
• IF TEST-‐, VACCINATE
• IF TEST+, DEFER VACCINATIONS
• REDUCE VACCINE ISSUES BY 64%
• UNDER-‐VACCINATE BY ONLY 3% -‐ NEGLIGIBLE EFFECT ON PUBLIC HEALTH
PANDAS/PANS Genedc risk factors –pilot study
PDD-‐PANS
PANS LRRK2 POLG WFS1
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HORIZONS
THE SPECTRUM EXPANDS …..
NEUROTYPICAL >> PANS >> PDD-‐NOS >> AUTISM
PDD-‐PANDAS
I can’t tell it beqer than this ….
hqp://www.youtube.com/watch?v=g26R0UjRIR0 And a happy ending ….
hqp://www.youtube.com/watch?v=AeM35yvkwns
PANDAS/PANS A FASCINATING DISORDER
• COMMON (1-‐2% OF POPULATION) • ACCOUNTS FOR MOST TS AND OCD CASES • PERVASIVE AND CHARACTERISTIC SYMPTOMS • CLOSE RELATIONSHIP TO AUTISM • “ALTERNATIVE FEVER RESPONSE” TO MANY COMMON ORGANISMS • CHARACTERISTIC IMMUNOPHENOTYPE WITH DYSREGULATION OF
HISTAMINE (peripheral and CNS) • ASSOCIATED WITH • Immunodeficiency -‐ early • Autoimmune disease/CFS -‐ late • MODY -‐late • Hypothalamic dysfuncdon – late
• GENETICS SUGGEST 3 MAIN RISK GENES • DEEP RELATIONSHIP TO PD
