pans-pandas an update on research and clinical...
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PANS-PANDAS An Update on Research and Clinical
Management
Kyle Williams, MD PhDDirector, Pediatric Neuropsychiatry and
Immunology ProgramMassachusetts General Hospital
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Clinical Case-PANDAS
• 10 y.o. male with no previous history of psychiatric illness, no family hx of OCD/Tics– Independent, A student, socially well adjusted
• Feb: School letter advising 6 “Strep throat” infections in pt’s classroom
• Feb: Pt ill with sore-throat, high fever, throat swab positive for Streptococcus pyogenes (Group A Strep)– Treated with antibiotics; full recovery
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Clinical Case-PANDAS
• March-April: Mother notices severe stuttering not present the day prior, shortly after:– Pt expresses fear over not pronouncing words “exactly”
– New onset frequent hand-washing and showering rituals
– Extreme avoidance of door-knobs and “dirty surfaces”
– Pt’s blinking more pronounced, new “grunting” noise
• March-April: Symptoms become disabling, severe disruption at home/school, school performance declines to C’s/D’s
• Acute deterioration in handwriting
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Clinical Case-PANDAS
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Clinical Case-PANDAS
• Neurology evaluation: MRI normal, EEG normal– Diagnosed with Tic disorder – Started on Guanfacine for tic disorder
• Child Psychiatry evaluation:– Diagnosed with Obsessive Compulsive Disorder– Started on Sertraline– Cognitive Behavioral Therapy referral
• 12 weeks later, medications have minimal effect; symptoms remain severe, meds discontinued for excessive sedation
• Referral to NIMH
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Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS)
• 1. Presence of a tic and/or Obsessive Compulsive Disorder
• 2. Pediatric onset• 3. Abrupt symptom onset and an episodic course
of symptom severity• 4. Association with Group A Streptococcal
infection • 5. Neurological abnormalities (“choreiform”
movements, hyperactivity, psychomotor agitation)
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PANDAS
• Rapid, new onset of Obsessive-Compulsive and/or tic symptoms in previously healthy child
• Symptom onset temporally associated with Group A Streptococcal (GAS) infection
– Hypothesized to be an autoimmune disorder induced by a GAS infection
– Autoimmune cells cross-react with CNS proteins
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PANDAS
• “All kids get Strep throat”
• OCD is a common psychiatric disorder in children
• 1+1=3?
– Why OCD and not depression, psychosis, etc?
– Why GAS and not influenza, staphylococcus, etc?
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PANDAS-Historical Context
• GAS infections are associated with a variety of autoimmune disorders
• Sydenham’s Chorea (St. Vitus’s Dance): – Acute onset movement disorder in children
– Follows a GAS infection
– Patients also have significant, new-onset OCD symptoms
– Hypothesized to be the result of autoimmune antibodies against the basal ganglia
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PANDAS-Historical Context
• Dr. Susan Swedo and colleagues at NIMH investigating Sydenham’s chorea and OCD in the 1990s
• Described a subset of children who did not meet criteria for Sydenham’s Chorea but showed:
– Rapid onset OCD behaviors following GAS infections
– New-onset tics (as opposed to chorea)
– Relapsing-remitting course of illness
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PITANDSPANDAS
PITANDSPediatric Infection
Triggered Autoimmune Neuropsychiatric
Disorders
Allen, Leonard, Swedo, JAACAP, 1995
Symptoms may be triggered by any infectious agent(Bacteria/Virus)
PANDASPediatric Autoimmune
Neuropsychiatric Disorder Associated with Streptococcal
infections
Symptoms triggered by Group A Streptococcal infections (Streptococcus pyogenes)
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PANSPITANDSPANDAS
PANSPediatric Acute
Onset Neuropsychiatric
SyndromeSwedo, Leckman, Rose,
Pediatric &Therapeutics, 2012
Infectious Triggers
(PITANDS)
Non-infectious Triggers
EnvironmentalFactors, Metabolic Disorders
PANDAS(Streptococcal
Triggered)
Other Microbes(Lyme,
Mycoplasma, etc)
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PANS Diagnostic Criteria
• Pediatric Acute Onset Neuropsychiatric Syndrome:– Abrupt, dramatic onset of obsessive-compulsive disorder or severely
restricted food intake – Concurrent presence of additional neuropsychiatric symptoms, (with
similarly severe and acute onset), from at least two of the following seven categories: • Anxiety • Emotional lability and/or depression • Irritability, aggression, and/or severely oppositional behaviors • Behavioral (developmental) regression • Deterioration in school performance (related to attention-deficit/hyperactivity
disorder [ADHD]-like symptoms, memory deficits, cognitive changes) • Sensory or motor abnormalities • Somatic signs and symptoms, including sleep disturbances, enuresis, or urinary
frequency
– Symptoms are not better explained by a known neurologic or medical disorder
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First 50 Cases-Swedo et al., 1998 (Am J Psych)
• Mean age of onset 7.4 (±2.7)– Boys > girls at earlier ages of onset
• OCD Symptoms:• Contamination most prevalent obsession (50%)• Washing/cleaning most prevalent compulsion (42%)
• ADHD (40%), MDD (36%), Separation Anxiety (20%)
• ~6 week time difference between GAS infection and symptom onset/exacerbation
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Evidence for Streptococcal Infections as a trigger for OCD/Tics
• Danish Health Registry Study analyzing >1 million children in Denmark, followed for up to 17 years
• Analyzed the incidence of new psychiatric diagnoses following testing for Group A Streptococcal infections
– Positive streptococcal test was inferred from the filling of an antibiotic prescription in the 8 days following a streptococcal test
Orlovska et al., JAMA Psych, 2017
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Orlovska et al., JAMA Psych, 2017
• Children with a positive streptococcal test had an 18% increased rate for any psychiatric disorder
• Children with a negative test had a 28% and 25% increased risk for OCD and tics, respectively
Evidence for Streptococcal Infections as a trigger for OCD/Tics
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Orlovska et al., JAMA Psych, 2017
• Children with a positive streptococcal test had an 51% increased rate for an OCD diagnosis
• Children with a positive streptococcal test had an 35% increased rate for a tic disorder diagnosis
• Sibling pair analysis showed a 94% increased risk for OCD with a positive streptococcal result
Evidence for Streptococcal Infections as a trigger for OCD/Tics
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Translational Evidence for PANDAS?
• 34 PANDAS subjects vs. 82 healthy controls
– 8% increased caudate volume
– 7% increase pallidalvolume
– 5% increased putaminal volume
• No difference in thalamic volume or total brain volume
Giedd et al., Am J Psych, 2000
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Diagnosis and Treatment
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Diagnosis
• How do we separate children with OCD/Tic Disorders and those with PANDAS/PANS?
– No defined temporal criteria between the time of infection and onset of symptoms
– PANDAS Diagnostic criteria are difficult to operationalize in clinical practice
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Diagnosis
• Step 1: Stick to the diagnostic criteria
– General principles: Rapid onset (24-48h) is crucial
• Should be the “first episode” of either OCD/Tics
• Evidence of GAS infections in the preceding 6-8 weeks (as a general guideline)– Minimally elevated GAS titers (ASO/DNAseB not very useful)
• Look for the presence of potential ancillary symptoms
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Diagnosis
• Ancillary symptoms:– Acute handwriting deterioration
– New onset separation anxiety
– Urinary frequency/bedwetting
– Anorexia
– Sleep disturbance
– Emotional lability/impulsive aggression
– Developmental regression
– Concentration difficulty
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Diagnosis
• Pilot studies suggest that– Separation anxiety– Urinary frequency– ODD– Inattention/Hyperactivi
ty– Choreiform movements– Handwriting
deterioration– Decline in school
performance
• May distinguish PANDAS from Peds OCD
Bernstein et al., JAACAP, 2010
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Diagnosis
• Pilot studies also show the following symptoms differentiate PANDAS vs. Peds OCD:– Sudden onset
– Definite periods of symptom remission
– Remission during antibiotic therapy
– Clumsiness
• The most discriminating characteristics:– Rising GAS titers/culture+dramatic onset (Risk Ratio: 3.5)
– Rising GAS titers/culture+remissions (Risk Ratio 2.2)
– Rising GAS titers+dramatic onset+remissions (Risk Ratio:4.5)
Murphy et al., J. Pediatrics, 2012
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Treatment
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A word on antibiotics…
• 2 pilot studies of prophylactic antibiotic therapy in PANDAS:– Garvey et al., Biol Psych, 1999
• Penicillin therapy failed to present GAS infections in PANDAS patients; failed study
– Snider et al., Biol Psych, 2005• 33 Subjects with PANDAS randomized to azithromycin vs. penicillin
for 12 months
• Both antibiotics significantly decreased GAS infections in the study period compared to previous year
• Both antibiotics significantly decreased symptom exacerbations in the study period compared to the previous year
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Immune Modulating Therapy
• 2 types have been studied:– Intravenous Immunoglobulin (IVIG)
– Therapeutic Plasma Exchange (PEX)
• One randomized trial (Perlmutter et al., Lancet, 1999)
– PANDAS subjects assigned to• IVIG
• PEX
• Placebo
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Williams et al., JAACAP 2016
• 35 PANDAS Subjects, blinded, randomized, multicenter trial between the NIMH and Yale Child Study Center
– 1200+ Potential patients screened
• 18 Randomized to Placebo
• 17 Randomized to IVIG
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Williams et al., JAACAP, 2016
Williams et al., JAACAP 2016
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• No significant observed effect of IVIG vs placebo in the blinded phase
• 10% Mean decrease in CYBOCS score for placebo group
• 23% Mean decrease in CYBOCS score for IVIG group
Williams et al., JAACAP, 2016
Williams et al., JAACAP 2016
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Conclusions
• Intriguing evidence for PANDAS as a unique diagnostic entity
– No “smoking gun”
– No definitive biological tests available
• No clear treatment guidelines exist
– Unclear objective evidence on antibiotic effectiveness
– Immunomodulatory benefit unclear
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Autoreactive Antibodies in PANDAS?
• When serum from PANDAS patients is infused into mouse brain, binding to Cholinergic Acetyl Transferase Neurons (ChAT) is observed
Frick, Williams, Pittenger, et al, Brain Behavior and Immunity, 2018
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Treatment
• Special Issue on PANS/PANDAS Treatment Consensus Guidelines: Journal of Child and Adolescent Psychopharmacology, Sept., 2017
• Psychiatric Management: Part 1
• Immunomodulatory Therapies: Part 2
• Treatment and Prevention of Infections: Part 3
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Treatment
• You’ve made the diagnosis, now what?
– Do they have an active GAS infection?
• Pharyngeal
• Skin
• Anal/Vaginal
• -Rule out Sydenham’s Chorea
– Echocardiogram/referral to Infectious Disease
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Treatment
• Labwork:
– If multiple instances of infection, look for evidence of immune deficiency
• IgA, IgG, IgM immunoglobulins
• CBC
• ANA
• ESR/CRP
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Treatment
• Moderate Symptoms
– CBT or SSRI
– CBT/SSRI
– Anti-inflammatories
• NSAIDs/Short Course Steroids
– Antibiotics?
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Treatment
• Severe symptoms:
• CBT/SSRIs/Antibiotics/Anti-Inflammatories
• IVIG?
• Prophylactic antibiotic management may be warranted in children with immune deficiencies or repeated infections
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Resources
• www.ocdinkids.org
– International Obsessive Compulsive Disorder Foundation
– Special Issues on Pediatric Acute Onset Neuropsychiatric Syndrome (PANS)/PANDAS
• Journal of Child and Adolescent Psychopharmacology, Vol 25(1), 2015 and Volume 27(7) Sept., 2017
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Thank You!
Questions