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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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slide1

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

slide2

Pediatric

  • Autoimmune
  • Neuropsychiatric
  • Disorders
  • Associated with
  • Streptococcus
what are the symptoms
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
what are the symptoms1
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
what are the symptoms2
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)
what are the symptoms3
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
what is pandas pans
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
problems with strict pandas model
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
slide9

Pediatric

  • AutoimmuneACUTE
  • Neuropsychiatric
  • Disorders SYNDROME
  • Associated with
  • Streptococcus
pandas pans institute p p i database

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)

slide14

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”
slide15

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)
slide16

“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”
slide18

Anti-streptolysin O

(LC subset)

ASO not normally distributed

Shows “low strep responder” group

slide23

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 !!
slide24

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….

slide25

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)

slide27

IgG4 and IgE are strongly correlated in patients with PANS

(“G4-E dysregulation”)

Log(IgE)

r2 = 0.557 (p<.0001)

Log(IgG4)

slide28

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”

slide29

PANS-prone immunophenotype (PPI-1)

IL-5

IL-3

Basophilpool

IL-4, IL-13

Mast cell pool

IL-10

HISTAMINE

NORMAL

slide30

PANS-prone immunophenotype (PPI-1)

IL-5

IL-3

Basophilpool

Mast cell pool

IL-4, IL-13

IL-10

HISTAMINE

PANS

“Anti-anaphylactic state”

slide31

Low IL-10

is a powerful STIMULATOR of

Inflammatory mediators

IL-1b

IL-6

(TNF)-a

what is the cause or mechanism
What is the cause, or mechanism?
  • Two competing/complementary theories
    • Molecular mimicry
    • Alternative fever response
pros of molecular mimicry model
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
cons of molecular mimicry model
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 ….
alternative fever response
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
slide37

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.

pans prone immunophenotype ppi 1
“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
slide40

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”)

normal immunophenotype
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
“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
“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?)
slide44

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

slide45

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

slide46

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 ….

slide47

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 ….

slide48

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 ….

slide49

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 ….

hdc and ts ocd a critical unifying discovery
HDC AND TS/OCDA Critical 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 critical unifying discovery1
HDC AND TS/OCDA Critical 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
BRAIN HISTAMINE

ALL BRAIN HISTAMINE ORIGINATES

FROM ONE PLACE!!

VTN – the “SOUL” OF PANDAS

In the POSTERIOR HYPOTHALAMUS ….

NOT THE BASAL GANGLIA!!

alternative fever model typical situation
ALTERNATIVE FEVER MODELTYPICAL SITUATION

INFECTION (GABHS, MP, MANY OTHERS)

INFLAMMATORY CYTOKINES

CENTRAL PGE2

MnPO

VTN

FEVER/MALAISE

PANDAS/PANS

SYMPTOMS

alternative fever model ppi 1 low peripheral histamine
ALTERNATIVE FEVER MODELPPI-1 (LOW PERIPHERAL HISTAMINE)

INFECTION (GABHS, MP, MANY OTHERS)

INFLAMMATORY CYTOKINES

CENTRAL PGE2

VTN

MnPO

PANDAS/PANS

SYMPTOMS

FEVER/MALAISE

alternative fever model of pandas pans
ALTERNATIVE FEVER MODEL OF PANDAS/PANS

HYPOTHESES:

PANDAS/PANS symptoms result in an estimated 1-2% of children with a variant immunophenotype (associated with a low histamine, anti-anaphylactic 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 action of PGE2 on the MnPO and VTN, with an increase in effect on the latter versus the former.

Chronic over-stimulation of the VTN results in brain H3-receptor dysregulation and dysregulation of release of neurotransmitters (i.e. dopamine, serotonin, norepinephrine, and others).

Due to the widespread “pervasive” neuroanatomical connections of the VTN, one sees a “pervasive behavioral syndrome” following common infections.

Autoantibodies play an ancillary role in this model.

slide66

HIGH INCIDENCE OF LARGE SCALE dup/dels IN PANS

65/180 (36%) ABNORMAL MICROARRAYS IN PANS (60% OF THOSE HAVE PDD-PANS)

6/65 (9%) ARE WITHIN THE 15q11.2,

4 in the BP1-BP2 PERI-ANGELMAN REGION (NON-IMPRINTED)

mitochondria in pans
Mitochondria in PANS
  • 225+ patients
  • Next gene sequencing
    • mtDNA (deep heteroplasmy)
  • Mitonucleome
    • 1200+ nuclear genes that encode for the mitochodria ….
slide72

SUMMARY

  • PANS is a common disorder of childhood
  • Wide range of manifestations – ACUTE onset OCD, tics, other symptoms
  • At least 4 different clinical sub syndromes
  • Remarkable response to PGE2 inhibitors such as ibuprofen
  • MANY different triggers : especially GABHS, M.Pneumoniae, Coxsackie B
  • Mechanism: early on, “alternative fever response” – cytokines
  • Also molecular mimicry with some triggers
  • Later on, auto-antibodies become more important
  • Dysimmunity, immunodeficiency and eventually autoimmunity common
  • Peripheral and central histaminergic mechanisms seem important in pathogenesis
  • Several genes implicated – probably multifactorial