PANDAS and PANS

Erica Greenberg, MD

Child and Adolescent Psychiatrist, MGH

Pediatric Psychiatry OCD and Tic Disorders Program, Director

Assistant Professor, Harvard Medical School

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Disclosures

My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose:

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Take-aways

• PANDAS (pediatric autoimmune neuropsychiatric disorder associated with strep) and PANS (pediatric acute-onset neuropsychiatric syndrome) are real conditions that require treatment
• Currently treatments have limited evidence
• When treating PANDAS/PANS, one should start with typical evidence-based symptom-targeting treatments
• Can add additional anti-inflammatory approaches

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PANDAS: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

Earthnworld.com

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Clinical Case

• 6 y/o male with no previous history of psychiatric illness, family hx of OCD/tics on Dad’s side, Mom has Hashimoto’s thyroiditis
• Independent, socially well adjusted, “cautious”

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• “Always sick” with 7 strep infections since age 2, and multiple ear infections

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Clinical Case - PANDAS

• “June 10^th”
• Woke up in middle of night and “appeared possessed,” increased urinary frequency, sudden separation anxiety, worsened hand-washing/symmetry, “mean and oppositional,” rage episodes, joint pain, eye rolling tics, and “baby-talk”
• Tested positive for strep by culture, 1m Augmentin… Symptoms improved immediately!

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• Initial visit in October
• No longer on antibiotics and close to baseline:
• Few eye tics, mild anxiety, occasional hand-washing

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PANDAS

• Rapid, new onset (or severe exacerbation) of obsessive-compulsive and/or tic symptoms in previously healthy child
• Symptom onset temporally associated with Group A Streptococcal (GAS) infection, that follows episodic course

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• Hypothesized to be a post-infectious autoimmune disorder (induced by a Group A Strep infection)
• Autoimmune cells cross-react with proteins in the brain – leading to OCD/tics/other behavioral changes (molecular mimicry)�
• First described by Dr. Susan Swedo and colleagues at NIMH investigating Sydenham’s chorea and OCD in the 1990s

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PANDAS - Clinical Criteria

1. Presence of DSM-based OCD, a tic disorder, or both
2. Pre-pubertal symptom onset
3. Episodic course of symptom severity
• Abrupt, explosive onset of symptoms or dramatic symptom exacerbations assigned to a specific day
4. Temporal association of symptom exacerbations with GABHS infection
• Positive throat culture or streptococcal titers
5. Presence of associated neurologic abnormalities
• Motoric hyperactivity and choreiform movements

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PANDAS - Historical Context

• Sydenham’s Chorea (SC) – “St. Vitus’s dance”
• Acute-onset movement disorder in children
• Cardinal symptom of rheumatic fever (post-strep autoimmune disease)
• Patients also have significant, new-onset OCD symptoms
• ~20% OCD and 50% OCB (da Rocha et al 2008)
• Those with SC often have:
• Variety of behavioral symptoms, OCD, emotional lability, ADHD symptoms

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Concerns with PANDAS

• Tics and OCD typically worsen during illness
• Conflicting literature
• Exacerbations during non-strep periods
• GAS with no symptom exacerbation
• PANDAS-like picture without strep
• Tics often present with sudden-onset

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• What population are we examining?
• Heterogeneous vs. homogeneous

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PANS: Pediatric Acute-Onset Neuropsychiatric Syndrome

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PANS Diagnostic Criteria

• Abrupt, dramatic onset of OCD or severely restricted food intake
• Symptoms not better explained by known neurologic/medical disorder
• Concurrent presence of additional severe/acute-onset neuropsychiatric symptoms from at least 2/7 categories:
• Anxiety
• Emotional (mood) lability and/or depression
• Irritability, aggression, severe oppositionality
• Regression – behavioral/developmental
• Attention/concentration changes
• Sensory/motor abnormalities
• Somatic signs/symptoms (e.g. sleep disturbances, enuresis/inc. urinary frequency)

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Neurocircuitry of Tourette syndrome (TS)�(Dysfunction of frontocortical-striatal-thalamo-cortical (CSTC) circuits networks)�

• Leads to disinhibition and dysregulation of motor (movement), cognitive (thinking), affective (emotion), motivation (reward-based) processes
• Manifestations include: Tics, OCD, ADHD, executive dysfunction, mood dysregulation, hair-pulling/skin-picking disorder, etc.
• Associated with difficulties with impulsivity and compulsivity
• Habit formation, affect regulation, reward processing and inhibitory control

Dr. Erica Greenberg 3/23/22

Beddows 2015 - http://scitechconnect.elsevier.com/neurobiology-basis-of-ocd/. Modified from original image, credits: Patrick J. Lynch and C. Carl Jaffe.

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Tourette Pathophysiology: Dysregulated�Cortico-striatal-thalamo-cortical (CSTC) Networks

Dr. Erica Greenberg 12/13/23

Basal Ganglia

Modified from Adapted from Haber & Knutson, 2010

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PANDAS/PANS Prevalence

• Jaspers et al 2017 (JCAP)
• To determine frequency and features of those with PANDAS/PANS symptoms
• 136 youth presenting at subspecialty pediatric OCD clinic (Canada)
• 5% (~1-10%) met proposed criteria

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• Features:
• Little pre-morbid pathology
• Greater family impact/more OCD-related impairment
• Increased (lifetime) association with strep infections
• Younger age of OCD onset
• Increased urinary incontinence
• Increased autoimmune illness

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Recent Research!

Orlovska et al (2017) JAMA Psychiatry

• Investigate link between OCD/tic disorders and infection
• 17y Danish cohort study with >1M youth
• Strep linked with increased OCD, tics, any mental disorder
• Non-strep throat infection linked with tics and any mental disorder

Kohler-Forsberg et al (2018) JAMA Psychiatry

• Investigate link between infections requiring treatment and risk for mental illness (same Danish cohort)
• Infections (hospitalization):
• Any mental illness diagnosis - HRR 1.8
• OCD: HRR 2.7; TS: HRR 3.3
• Infections (antibiotic):
• Any mental illness diagnosis - HRR 1.4
• OCD: HRR 2.4; TS HRR 3.1

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New Research Continued

• Mataix-Cols et al (2017) Molecular Psychiatry
• Swedish birth cohort of 7.5million individuals
• Individuals with OCD and TS had increased rates of autoimmune disorders (AD) (by 43% and 36% respectively)
• Familial link between AD and OCD/TS
• 76% biological relatives of 45 children with PANS had an autoimmune or inflammatory disorder! (Gromark et al 2019 JCAP)

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• OCD and TS may share genetic risk factors with autoimmune disease
• Immunological factors may play role in etiology some individuals with OCD/CTD

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New Research Continued

• Xu et al (2021) Am J Psychiatry
• 27 children with PANDAS; 23 w/o
• IgG antibodies in PANDAS bind to cholinergic interneurons (CINs) in striatum
• CINs (ACH neurotransmitter): link with tics, repetitive behaviors, habit learning
• More IgG binding to CINs than other neuron types, and more from PANDAS vs controls
• Pathophysiology hypothesis: CINs are critical cellular target in PANDAS

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New Research and General Insights

• Hyman S (2021) Am J Psychiatry
• Commentary on Xu et al findings
• Xu et al’s proposed immunologic mechanism increases validity for PANDAS; however…
• “Diverse genetic and pharmacologic manipulations of the basal ganglia … produce OCD-like symptoms”
• Binding of serum autoantibodies has not distinguished PANDAS or TS from controls
• Failed replications may represent heterogeneity in autoantibodies and target cells
• “One of many situations in which infection and immune mechanisms influence neuropsychiatric syndromes”

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Pittenger et al (2021): “The nature of this immune dysregulation, whether it exists in all patients or in a subset, whether it is causally associated with disease onset or progression, and whether it is a specific cause of disease, a nonspecific exacerbating factor, or an epiphenomenal consequence of other pathophysiological events remain unclear”

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Treatment

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Current Guidelines

Consensus guidelines published during Summer 2017

• Establish that PANS/PANDAS is the correct diagnosis (“diagnosis of exclusion”)
• Provide symptomatic relief with psychiatric medications/behavioral interventions
• Treat any underlying infections
• consider use of prophylactic antibiotics
• Treat any inflammatory components
• Evaluate effectiveness
• Stop treatment when symptoms resolve

Swedo et al (2017) JCAP

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Treatment Guidelines Continued

3-pronged approach

• Psychiatric medications and behavioral treatment for symptom relief
• Typical treatments for OCD are effective! (CBT, SSRIs)
• Antibiotics* to eliminate source of infection
• ?Anti-inflammatory
• Anti-inflammatories (or immune-modulating) treatments to help immune system

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• “Education, supportive and behavioral therapies, and psychoactive medications are the mainstays of symptomatic treatment for PANDAS. Antimicrobials and immunomodulatory therapies may also be indicated”
• Need more prospective studies!

Swedo et al (2017) JCAP

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Guideline highlights

• Psychiatric:
• OCD and other symptoms respond to same medications as in non-PANS
• Start low / go slow
• Psychoeducation and support

• Immunomodulatory:
• Start with NSAIDs for mild symptoms (up to 6 weeks)
• 5-10mg/kg bid naproxen
• 10mg/kg tid ibuprofen
• Consider early use of corticosteroids to abort or shorten flares

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Thienemann et al (2017) JCAP

Frankovich et al (2017) JCAP

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Guideline highlights

Antibiotics:

• Initial course of anti-strep treatment for newly diagnosed PANS and PANDAS patients (10 – 30d)
• *Amoxicillin/Augmentin, Keflex, Azithromycin
• Chronic secondary prophylaxis for children with severe symptoms/recurrent GAS
• If not GAS, prophylaxis (typically) not recommended
• Watch for other infections, but treat per standard guidelines
• Get standard immunizations(!)
• Get culture with symptom worsening if post-antibiotics
• Antibody levels (>50% change)

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Cooperstock et al (2017) JCAP

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Lab-work

• “Full laboratory work-up for clinical practice is currently limited”

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• Throat culture for active strep
• Strep antibodies (ASO / anti-DNAse B): Need multiple data points
• Mycoplasma antibodies
• Concern for false positives
• Other infectious causes:
• Only if clinical syndrome that’s consistent

• If multiple instances of infection, look for evidence of immune deficiency, inflammation, autoimmune markers
• IgA, IgG, IgM immunoglobulins
• IgG subclasses
• ANA
• ESR/CRP
• TSH/T4
• Vitamin D
• Iron/ferritin

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Gromark et al (2021) CPHD

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Recent treatment studies

• Antibiotics:
• Azithromycin vs. placebo in double-blinded study
• Better CGI-S, not CY-BOCS
• Murphy et al (2017) JCAP

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• Anti-inflammatories
• NSAIDS (ibuprofen, naproxen)
• Two retrospective studies with positive findings
• Flares shortened by 2.5-4 weeks
• Spartz et al (2017) JCAP
• Brown et al (2017) JCAP

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• Steroids:
• One positive study
• Course shortened by 3.5weeks (from 11.4wks); early better
• Brown et al (2017) JCAP

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• Immune-modulating
• IVIG (mixed results)
• Williams et al (2016) JAACP

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Systematic review – Treatment Studies to Date

• Limited studies thus far:
• 4 RCTs, 1 cross-over, 2 open trials, 4 observational, 1 survey
• Lots of case reports/series

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• Inconclusive evidence for:
• Antibiotics
• Therapeutic plasma exchange
• Tonsillectomy/adenoidectomy
• IVIG
• NSAIDs
• Corticosteroids

• Issues:
• Rigorously conducted research is scarce
• High risk of bias

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• Conclusion:
• “Insufficient evidence to clearly propose any treatment for PANDAS and related disorders” (Sigra et al 2018, p 62)

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• “Lack of evidence for treatment is based not on the inefficacy of the treatments, but on lack of systematic research” (Sigra et al 2018, p 62)

Sigra et al Neurosci and Biobeh Rev 2018

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Treatment

• Tailor treatment to the clinical severity of the patient
• Mild Symptoms
• Watchful waiting, CBT, NSAIDs
• Moderate Symptoms
• CBT, NSAIDs, +/-SSRIs, +/-Antibiotics
• Severe Symptoms
• CBT, typical psychiatric medications, NSAIDs, Antibiotics, ?steroids, ?other immune treatment

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Johnson et al: “Anti-inflammatory, antibacterial and immunomodulatory treatment in children … PANS: A systematic review.”

• PICO study:
• Review of literature 1998 to 2020
• 59 full-text reviewed; 7 included
• All studies had major risk of bias:
• Comparability uncertainty, unblinding for AEs, indirectness, imprecision
• Conclusion:
• “Available evidence neither supports nor excludes potential beneficial effects, but supports that such treatment can result in adverse effects”

Johnson M et al (2021) PLoS ONE

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2 - 5 year follow-up in youth with PANS!�Gromark C … Mataix-Cols D et al:

• 34 patients with PANS
• Onset 6.6y and follow-up 3.3y

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• “Significant reductions in clinician-rated PANS symptom severity and improved general function!” (85%)

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• Symptom profiles:
• Remitted (n=2); Relapsing-remitting (n=20); Chronic-static/progressive (n=12)
• *Chronic-progressive profile...

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• Co-occurring conditions:
• 32% autoimmune/inflammatory condition
• 82% family history of inflammatory /AD!
• 79% family history of psychiatric disorder

• Common follow-up symptoms:
• OCD (62%), Tics (50%)
• CY-BOCS median 8; YGTSS median 4.5
• ~33% Anxiety, ADHD, “behavioral difficulties,” depressive sx, sleep disorder, tired/fatigue
• Chronic group had more non-tic/OCD impairments
• Treatments:
• No antibiotics prescribed long-term or prophylactically
• Short-term after suspected/verified infection
• Lab findings:
• 36% elevated inflammatory markers
• IL-B, TNF-a, IgM elevated in chronic vs not
• 60% with active flare during assessment
• IL-B, TNF-a elevated vs asymptomatic

Gromark et al (2021) Child Psych + Hum Dev

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Treatment Studies to Date

• 12 treatment studies in PANS/PANDAS to date
• 4 double-blinded RCTs; 1 cross-over; 2 open-label; 4 observational
• 1 retrospective online self-report
• Treatments included: Penicillin, Azithromycin, IVIG, Therapeutic Plasma Exchange (TPE), Tonsillectomy, CBT, Steroids, NSAIDs
• 11/12 had moderate or high risk of bias
• Inconclusive evidence: Abx, TPE, IVIG, NSAIDs, CBT, steroids
• Evidence weak for tonsillectomy

Sigra et al (2018) Neurosci and Biobeh Rev

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Differentiating Pediatric-onset OCD

• Presentation differences vs adults:
• Children more likely to have poor insight
• More obsessions involving ‘fear of harm’ and separation
• May more often see compulsions without obsessions
• More rituals involving family members
• Reassurance seeking / checking (esp children)
• More common sexual and religious symptoms
• Adolescents > children and adults

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• OCD with tics:
• Symmetry writing/re-writing compulsions, aggressive/sexual-based obsessions
• “Tourettic OCD”

Pediatric OCD: Phenomenology and Course (Geller, D. Psych Clin N Am; 2006; 29 (2); 353-370)

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Adapted from Coffey BJ 2019 Pediatric OCD; Child and Adolescent Psychopharmacology Slides

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“…Baseline Clinical Features of the Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort …”

Gromark C, … Mataix-Cols D et al (2019) JCAP

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• 100 referrals from 2014-2018, 45 met strict PANS criteria
• Median age was 7.2 (3.0-13.1), 56% were male
• 93% had an infection in temporal relation to onset
• 24% had pre-existing autoimmune disease; 18% had pre-existing (neuro)psychiatric diagnoses
• 64% biological relatives had at least one psychiatric disorder
• 76% biological relatives of child with PANS had at least one autoimmune or inflammatory disorder!

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