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PANDAS/PANSChild and Adolescent Psychopharmacology

March 16, 2019

Barbara J. Coffey, MD, MSDivision Chief, Child and Adolescent Psychiatry

Department of Psychiatry and Behavioral Sciences University of Miami Miller School of Medicine

Director, Uhealth Tics, OCD and Related Problems Program

Professor, Department of Psychiatry

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Disclosures (Past 12 Months)

• Abide Therapeutics: Scientific Advisory Board• American Academy of Child and Adolescent Psychiatry: Honoraria• Bracket: Honoraria• Cincinnati Children’s Hospital: Honorarium• Harvard Medical School: Honoraria• Neurocrine Biosciences: Research Support• Nevada Psychiatric Association: Honorarium• NIMH: Research Support• Partners Healthcare: Honoraria• Teva/Nuvelution: Research Support; Scientific Advisory Board• Tourette Association of America: Co-Chair, Medical Advisory Board; TAA-

CDC Partnership

• Off label indications will be discussed

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PANDAS/PANS

Learning Objectives

• At the end of this session, the participant should be able to:

• Review diagnostic criteria for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) and Pediatric Acute Onset Neuropsychiatric Syndrome (PANS)

• Discuss current controversies in scientific understanding of these disorders

• Recognize clinical presentation of children who may meet diagnostic criteria for PANDAS and PANS

• Consider treatment implications?

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Swedo, PANDAS: A “Controversial” Diagnosis

ALL CHILDHOOD-ONSET OCD & TIC DISORDERS

PANDAS

PITANDS

PANS

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Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS): Diagnostic Features (Swedo, S. Leonard, H. et al; Am J Psych 1998; 155; 2; 264-271)

• OCD and/or a tic disorder (lifetime)• Pre-pubertal onset (age 3-12)• Episodic course; abrupt, dramatic or explosive onset or

exacerbation of symptoms• Temporal association of symptom onset or exacerbation with

Group A Beta hemolytic streptococcus (GABHS) by positive throat culture and/or elevated anti-streptococcal antibody titers

• Neurological abnormalities: choreiform and adventitious movements; motoric hyperactivity

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Evidence For PANDAS: Antibiotic Studies (Snider, Lougee, Slattery, Grant and Swedo; Biol Psych 2005; 57;

788-792)

• Design: Double blind, randomized controlled trial of antibiotic prophylaxis

• Methods: 23 subjects with PANDAS enrolled. Prophylaxis with penicillin or azithromycin administered for 12 months

• Rates of strep infections and neuropsychiatric symptoms were compared between baseline year and over study year

• Results: Significant decreases in strep infections occurred during the study year: mean 0.1 per subject vs. baseline 1.9 in penicillin group, and 2.4 in azithromycin group (p<0.01).

• Significant decreases in tics/OCD during study year with mean 0.5 per subject in penicillin group and 0.8 in azithromycin group compared to baseline 2.0 in penicillin group and 1.8 in azithromycin group. (p<0.01).

• Conclusion: Both antibiotics were effective in decreasing strep infections and neuropsychiatric symptom exacerbations in PANDAS.

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Evidence for PANDAS:Association Between Streptococcal Infection and OCD, Tourette Syndrome (TS),

and Tic DisorderMell, L. Davis, R. Owens, R. Pediatrics 2005;116;56 DOI: 10.1542/peds.2004-2058

• Objective: Large West-Coast HMO assessment whether streptococcalinfection was associated with increased risk for OCD, TS, or tic disorder.

• Methods: Case-control study children age 4-13 with first diagnosis of OCD,TS, or tic disorder between 12/92-12/99.

• Cases matched to controls by birth date, gender, primary physician, andpropensity to seek health care.

• Results: Cases more likely than controls to have had prior streptococcalinfection (OR: 2.22; 95% CI: 1.05, 4.69) in 3 months before onset date. Riskwas higher in children with multiple streptococcal infections within 12months (OR: 3.10; 95% CI: 1.77, 8.96). Having multiple infections with GASwithin a 12- month period was associated with very high increased risk forTS (OR: 13.6; 95% CI: 1.93, 51.0)

• Conclusion: PANDAS may result from a post-infectious autoimmunephenomenon induced by childhood streptococcal infection

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Evidence Against PANDAS(Kurlan, R. and Kaplan, E.; Pediatrics; 2004: 113; 883-886)

• GABHS infection is very common in the school age period

• Rates of asymptomatic carriers are high

• Tics and OCD worsen during times of stress and can be worsened by otherprecipitants (fatigue, anxiety, etc.)

• For SC, choreoathetoid movements appear 3-5 months after GABHS;Swedo et al initially suggested infection up to 9 months before symptomonset may be acceptable for PANDAS diagnosis

• Variety of infectious agents have been implicated, ie Borrelia,mycoplasma, common cold.

• Most non-PANDAS TD patients have onset before puberty

• Clinical course: 53% of one series of 80 consecutively referred TS patientshad sudden, explosive worsening or onset of tics (Singer; Ped Neurol,2002)

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Streptococcal Infection and Exacerbations of Childhood Tics and Obsessive Compulsive Symptoms: A Prospective Blinded Cohort Study

(Kurlan R, Johnson D, Kaplan E, Tourette Ssyndrome Study Group. Pediatrics. 2008;121:1188-1197)

Streptococcal Upper Respiratory Tract Infections and

Exacerbations of Tic and Obsessive-Compulsive

Symptoms: A Prospective Longitudinal Study.

(Leckman, J. King, R. Gilbert, D. Coffey, B. et al. Journal of the

American Academy of Child and Adolescent Psychiatry;

2011; Volume 50; (2); 108-118).

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Summary: PANDAS Prospective Studies

(Kurlan, R. et al 2008; Leckman, J. et al 2011)

1) Streptococcus is a relatively weak, and not particularly unique, precipitant of tic and OCD exacerbations.

2) Conventional treatment of tics and OCD is recommended in children with PANDAS if symptoms cause distress or impairment

3) Antibiotic treatment of acute streptococcal infections is indicated, but prophylaxis is generally not recommended

4) NIMH Work group proposed new criteria (PANS)

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Hierarchy of PANS; (Swedo, S. et al. Pediatr Therapeut 2012;

2:2. 1000113)

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Diagnostic Criteria Proposed for Pediatric Acute-onset

Neuropsychiatric Syndrome (PANS) (Swedo, S. et al 2012)

Criterion Description

I Abrupt, dramatic onset of obsessive-compulsive disorder or severely

restricted food intake

II Concurrent presence of additional neuropsychiatric symptoms, with similarly

severe and acute onset, from at least two of the following seven categories:

1. Anxiety

2. Emotional lability and/or depression

3. Irritability, aggression and/or severely oppositional behaviors

4. Behavioral (developmental) regression

5. Deterioration in school performance

6. Sensory or motor abnormalities

7. Somatic signs and symptoms, including sleep disturbances, enuresis or

urinary frequency

III Symptoms are not better explained by a known neurologic or medical

disorder, such as Sydenham chorea, systemic lupus erythematosus,

Tourette’s disorder or others.

Note: The diagnostic work-up of patients suspected of PANS must be

comprehensive enough to rule out these and other relevant disorders. The

nature of the co-occurring symptoms will dictate the necessary assessments,

which may include MRI scan, lumbar puncture, electroencephalogram or

other diagnostic tests.

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Characterization of the PANS Phenotype(Murphy, T. et al. JCAP; 2015; 14-25)

Objective: PANS is a sub-type of OCD with abrupt onset or exacerbation of neuropsychiatric symptoms. Aim was to characterize presentation.

Methods: N=43 youth ages 4-14 who met criteria for PANS underwent comprehensive psychiatric evaluation.

Results: Youth with PANS had early age of onset (mean=7.84 years) and had moderate to severe OCD symptoms. All had comorbid anxiety and emotional lability, and reduced quality of life.

Youth with PANS and comorbid tics were more likely to have: school performance decline, visual-motor impairment, food restriction, hand writing deterioration and poorer quality of life vs. those without tics.

Conclusion: Findings are suggestive that PANS subgroup consists of sudden onset, severely impaired youth.

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Murphy, T. et al 2015

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Clinical Evaluation of Youth with PANS: Recommendations from 2013

Consensus Conference. Chang, K. et al. 2015; JCAP; 25 (1); 3-13

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Clinical Evaluation of Youth with PANS:

Recommendations from the 2013 Consensus

Conference. Chang, K. et al. 2015; JCAP; 25

(1); 3-13

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Clinical Evaluation of Youth with PANS: Recommendations from

the 2013 Consensus Conference. Chang, K. et al. JCAP;

DOI:10.1089/cap.2014.0084

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Considerations for PANDAS/PANS Diagnostic Evaluation Professor, Department of Psychiatry

OCD: Abrupt, dramatic, explosive, 24-48 hour onset or exacerbation of symptoms

General Evaluation:

Comprehensive psychiatric evaluation

Physical examination

Examination for choreiform (piano playing finger) movements

Laboratory workup:

48 hour plated throat culture (vs. rapid strep only)

CBC, ESR, CRP, Urinalysis

ASOT and Anti DNAse B

Mycoplasma and Borrelia (Lyme Disease) titers

ANA

EKG

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General Principles for Treating Pediatric Acute-Onset Neuropsychiatric Syndrome.

(Swedo, S. et al.; JCAP; 27, (7), 2017; 562-565)

1. Establish PANS is correct ‘‘diagnosis of exclusion’’ by completing a comprehensive diagnostic evaluation (Chang et al. 2015).2. Provide symptomatic relief with psychiatric medications and behavioral interventions, prioritizing treatment of symptoms causing the greatest distress and interference (Thienemann et al. 2017).3. Treat underlying infections and consider use of therapeutic or prophylactic antibiotics (Cooperstock et al. 2017).4. Treat symptoms resulting from neuroinflammation or postinfectiousautoimmunity with anti-inflammatory or immunomodulatory therapies, chosen on the basis of symptom severity and disease trajectory (Frankovich et al. 2017).5. Evaluate effectiveness of treatment at frequent intervals, making modifications as warranted by improvement or worsening of symptoms.6. Treatment can be tapered or stopped when symptoms resolve. However, treatment may be necessary again at some point in the future, given the relapsing–remitting nature of PANS symptoms……

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Treatment of Non-Streptococcal PANS (Swedo, S. et al.; JCAP; 27, (7), 2017; 562-565)

1. Long-term antibiotic prophylaxis against streptococcal infections is not recommended

2. Children with PANS often experience exacerbation of neuropsychiatric symptoms during intercurrent sinusitis or other non-streptococcal infections. These should be promptly evaluated and managed according to current standards of practice.

3. It is possible that GAS may initiate a symptom flare in children with non-streptococcal PANS. It is important to be vigilant for possible GAS infection in both the patient and close family members.

4. If the PANS patient or close contact has a sore throat, a throat swab should be obtained and treated promptly if GAS is identified.

5. If the PANS patient has a definite increase in PANS symptoms, careful physical evaluation for an inciting infection should be performed. Skin infection, including perianal dermatitis, would warrant appropriate cultures. A throat swab for GAS should be performed even in the absence of clinical pharyngitis. GAS serology (ASO and ADB), and a polymerase chain reaction test for Mycoplasma pneumoniae may be performed as well.

Mount Sinai / Presentation Slide / December 5, 2012

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PANS Treatment: Psychotropics and

Immunomodulation

(T. Murphy, M.D. AACAP, 10.25.13)

Psychotropic medications may exert neuropsychiatric effects via immunomodulation and support of neurogenesis

These agents have been found to have anti-inflammatory effects through suppression of pro-inflammatory cytokines (ie. IL-2, TNF-a, T cell proliferation, etc.)

Some were originally used as antimicrobialsAmoxicillin-clavulanate (Augmentin) is a B-lactamase inhibitor. CNS effects: readily crosses the blood brain barrier and has demonstrated anxiolytic properties in animal models, possibly due to glutamate transmission effects

CNS effects: Promote expression of glutamate transporterNeuroprotective role in vivo and in vitro (Rothstein et al Nature; 2005)

Beta-lactams: penicillin, cephalosporins

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Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders:

A Pilot Randomized Trial

(Murphy, T. et al JCAP 25 (1) 2015; 57–64; DOI:

10.1089/cap.2014.0010)

Methods:

20 children ages 4-13 with new onset of OCD/tics

– Did not require infectious trigger

– Dosed at 14mg/kg (max 600mg)/day with target length of RCT of 30 days

– Chosen for palatability, safety and efficacy for Group A Streptococcus

– Placebo matched for taste, color, consistency

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Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders:A Pilot Randomized Trial

(Murphy, T. et al JCAP 25 (1) 2015; 57–64; DOI: 10.1089/2014.0010)

Tanya Murphy, MD

3/8/2019

DemographicsALL

(N=20)PLACEBO (N=11) ANTIBIOTIC (N=9)

Age 7.3±1.9 7.4±1.9 7.2±2.0

Gender F 5 (25.0%)

M 15 (75.0%)

F 4 (36.4%)

M 7 (63.6%)

F 1 (11.1%)

M 8 (88.9%)

Diagnosis %

OCD 20%(n=4) 27% (N=3) 11.1% (N=1)

OCD/Tics 55% (n= 11) 55% (N=6) 56.6% (N=5)

Tics 25% (n=5) 18% (N=2) 33.3% (n=3)

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Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders:A Pilot Randomized Trial

(Murphy, T. et al JCAP 25 (1) 2015; 57–64; DOI: 10.1089/2014.0010)

TriggerALL

(N=20)

PLACEBO

(N=11)

ANTIBIOTIC

(N=9)

Infectious trigger 14 6 8

Recent URI 8 3 5

Positive GAS (culture/rapid strep)

6 3 3

No evidence of infectious trigger

6 5 1

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Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders:

A Pilot Randomized Trial

(Murphy, T. et al JCAP 25 (1) 2015; 57–64; DOI: 10.1089/2014.0010

Mean CYBOCS Scores

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Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders:

A Pilot Randomized Trial

(Murphy, T. et al JCAP 25 (1) 2015; 57–64; DOI: 10.1089/2014.0010

Mean CYBOCS Scores

YGTSS PLACEBO VS. CEFDINIR SCORE CHANGE

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Cefdinir for Recent-Onset Pediatric Neuropsychiatric Disorders:A Pilot Randomized Trial

(Murphy, T. et al JCAP 25 (1) 2015; 57–64; DOI: 10.1089/2014.0010.

Results: Tics: subjects on cefdinir had improvement in tic symptoms; 44.4% at least a

25% reduction in YGTSS (mean decrease = 9.5) scores vs. 9.1 placebo group (mean

decrease = 0.13).

No significant group differences for YGTSS (F [1, 13] = 4.03, p = 0.066)

OCD: subjects on cefdinir had improvement in OCD symptoms; 33.3% at least a 25%

reduction in CY-BOCS scores (mean decrease = 7.8)vs. 27.3% placebo group (mean

decrease = 4.7)

No significant differences CY-BOCS (F [1, 13] = 0.385, p = 0.546; d = 0.24).

Conclusion: Subjects on cefdinir had non-statistically significant improvement in tic

symptoms, vs.placebo group. There were some improvements in OCD symptoms,

although not significant.

Overall, cefdinir was well tolerated. Given preliminary results, a fully powered study is

warranted to explore efficacy of cefdinir as a therapeutic tool for new-onset pediatric

neuropsychiatric symptoms, particularly those

that appear to be precipitated by infection.

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Randomized, Controlled Trial of IntravenousImmunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated

With Streptococcal Infections

(Williams, K. et al. J Am Acad Child Adolesc Psychiatry 2016; 55(10):860–867).

Method: N= 35 children meeting criteria for PANDAS and moderate to severe

obsessive-compulsive disorder (OCD)

6-week trial of IVIG (1g/kg/day on 2 consecutive days), followed by optional

open-label treatment for non-responders, with follow-up at

12 and 24 weeks.

Primary outcome measures were CYBOCS and (CGI-I) rating. “

Responders” were defined, a priori, by a 30% decrease in CY-BOCS total

score, and a “much” or “very much” improved rating on CGI-I.

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Randomized, Controlled Trial of IVIG for Pediatric Autoimmune Neuropsychiatric Disorders Associated With

Streptococcal Infections (Williams, K. et al. J Am Acad Child Adolesc Psychiatry 2016;55(10):860–867).

• Results: DB: mean decrease in CY-BOCS score 24% (+- 31%) in the IVIG group and 12%(+- 27%) in the placebo group; 6 responders in IVIG group (35%)vs 4 (22%) in placebo group; not statistically significant.

• 24 participants met criteria for nonresponse to double-blind and received open-label IVIG at week 6. Among allparticipants, mean C-BOCS improvement frombaseline was 55%(+-33%) at week 12 and 62%(+- 33%) atweek 24.Conclusion: IVIG was safe and well tolerated. Between group differences weresmaller than anticipated, and DB comparison failed to demonstrate superiorityof IVIG over placebo.

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Randomized, Controlled Trial of IVIG for Pediatric Autoimmune Neuropsychiatric Disorders Associated With

Streptococcal Infections (Williams, K. et al. J Am Acad Child Adolesc Psychiatry 2016;55(10):860–867).

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EMTICS PANDAS/PANS Study Results (Hoekstra, P. et al. February 2019)

• EMTICS: a longitudinal observational European multicentre study involving 16 clinical centres with following objectives:

• to investigate association of environmental factors (GAS exposure and psychosocial stress primarily) with the onset and course of tics and/or obsessive–compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3–10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder)

• and affected individuals (COURSE cohort: 715 youth aged 3–16 years with a tic disorder)

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EMTICS PANDAS/PANS Study Results; February 2019

• The most significant result from the cohort studies is that we found no indication for a role of new GAS exposures in relation to exacerbations of tic disorders.

• We did find that new GAS exposures are very frequently occurring.

• Our data indicate that exposure to GAS at some point during childhood is nearly universal.

• Thus, it is quite understandable that a part of the children who come to clinics with a tic exacerbation have signs of a recent GAS exposure. Clinical observations of the co-occurrence of recent GAS exposures and tic exacerbation have led to the PANDAS concept.

• However, the EMTICS study indicates that the co-occurrence of tic exacerbations and recent new GAS exposures is most likely due to chance. …”

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PANDAS and PANS: Summary: What is GCP for

CAPs?

1. Comprehensive evaluation of children with acute onset OCD/tic symptoms is essential.

2. Some may have infectious, autoimmune or stress related precipitants, but at this time evidence is lacking for specific clinical or biological markers. The prevalence of these children is likely very low.

3. Children with acute, abrupt or explosive onset or exacerbation of OCD symptoms are candidates for evaluation of possible infectious etiologies

4. Longitudinal cohort studies, particularly the largest one to date from Europe with results just released, indicate there is no indication for a role of new GAS exposures in relation to exacerbations of tic disorders. 5. More investigation is certainly needed…..

Stay tuned!