What are Pediatric Acute‑onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)?

PANS and PANDAS: Infection-Triggered Neuropsychiatric Syndromes

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) is a proposed syndrome characterized by abrupt-onset obsessive-compulsive disorder and/or tics following Group A Streptococcus infection, while PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) is the broader diagnostic category encompassing sudden neuropsychiatric symptoms triggered by various infections or other insults—though both remain controversial diagnoses of exclusion without validated biomarkers. 1

Core Definitions

PANDAS

PANDAS was first proposed in 1998 as a hypothesis that childhood OCD and/or tic disorders may arise from a post-streptococcal autoimmune process, similar to Sydenham chorea (a major manifestation of acute rheumatic fever). The proposed mechanism involves autoimmune responses that cross-react with brain tissue—specifically basal ganglia structures—following GAS infection. 2

Key clinical features include:

• Abrupt onset of obsessive-compulsive symptoms or tics
• Temporal association with documented Group A beta-hemolytic Streptococcus infection
• Neuropsychiatric symptoms that are dramatic and sudden rather than gradual
• Proposed involvement of anti-dopamine receptor antibodies (anti-D1R and anti-D2R) targeting basal ganglia circuits 3, 4

PANS

Research has shifted from the narrow PANDAS construct to the broader PANS category, which is characterized by:

• Sudden onset of obsessive-compulsive symptoms or severe food restriction
• Accompanying neuropsychiatric features including anxiety, depression, emotional lability, irritability, behavioral regression, deterioration in school performance, sensory or motor abnormalities, and somatic symptoms
• Symptoms triggered by various infections (not just streptococcal)—including Mycoplasma pneumoniae, influenza, Epstein-Barr virus, Borrelia burgdorferi, and SARS-CoV-2 5, 6
• Symptoms not better explained by another known neurologic or medical disorder 1

Critical Distinction from Sydenham Chorea

PANS/PANDAS must be differentiated from Sydenham chorea, which is a well-established major manifestation of acute rheumatic fever. The key differences are:

• Sydenham chorea presents with chorea (involuntary, irregular, purposeless movements), not tics
• Patients with Sydenham chorea typically have hypotonia or low muscle tone, including a rare paralytic form
• PANDAS/PANS present with tics and obsessive-compulsive symptoms, not true chorea
• In high-incidence rheumatic fever regions, Sydenham chorea would be the most likely etiology of acute chorea unless proven otherwise 7

The Controversy and Evidence Gaps

What the Guidelines Say

The 2009 American Heart Association scientific statement explicitly states that PANDAS should be considered only as a yet-unproven hypothesis. 2 The committee made clear Class III recommendations (meaning "not recommended"):

• Do NOT perform routine laboratory testing for GAS to diagnose PANDAS
• Do NOT use long-term antistreptococcal prophylaxis to prevent PANDAS
• Do NOT use immunoregulatory therapy (intravenous immunoglobulin, plasma exchange) to treat exacerbations until well-controlled studies establish a causal relationship

This remains the most authoritative guideline statement, though it predates more recent research.

Current State of Evidence

The 2019 Nature Reviews Disease Primers guideline notes that while advances have been made in formulating diagnostic criteria and investigating autoimmune mechanisms, research has shifted away from PANDAS specifically toward the broader PANS construct. 1

Major evidence gaps include:

• No validated biomarkers: ASO, anti-DNase B, anti-basal-ganglia antibodies, and the Cunningham Panel lack adequate diagnostic accuracy for individual patients 4
• Inconsistent biomarker replication across studies 3
• Prospective studies have not demonstrated consistent population-level associations between GAS infections and tic/OCD exacerbations 4
• High background prevalence of both GAS exposure and primary neurodevelopmental disorders creates conditions for incidental temporal co-occurrence 4
• Methodological heterogeneity and diagnostic overlap with primary psychiatric disorders 3

Diagnostic Approach

PANS/PANDAS remain diagnoses of exclusion requiring rigorous differential diagnosis. 5, 4

What to Look For Clinically

Hallmark presentation:

• Acute onset (literally overnight or within 24-48 hours) of severe OCD symptoms or dramatic food restriction
• Dramatic behavioral change that parents describe as "my child became a different person"
• Multiple concurrent neuropsychiatric symptoms: separation anxiety, emotional lability, irritability, aggression, behavioral regression, deterioration in handwriting or school performance
• Motor or sensory abnormalities: tics, choreiform movements, handwriting deterioration
• Somatic symptoms: urinary frequency, sleep disturbances

Critical Differential Diagnoses to Exclude

Before considering PANS/PANDAS, systematically rule out:

Primary psychiatric disorders:

• Primary OCD (typically gradual onset, family history common)
• Primary tic disorders (heritability 50-80%, 18-fold increased risk in first-degree relatives) 4
• Tourette syndrome
• Anxiety disorders
• Eating disorders

Neurological conditions:

• Sydenham chorea (presents with chorea, not tics; associated with rheumatic fever)
• Autoimmune encephalitis (anti-NMDA receptor, anti-LGI1, others)
• Wilson disease
• Huntington disease
• Neuroacanthocytosis
• Moyamoya syndrome
• Frontal lobe lesions 1, 7

Infectious/inflammatory:

• Encephalitis (viral, bacterial)
• Post-infectious encephalitis
• CNS vasculitis

Metabolic/genetic:

• Monogenic disorders of dyskinesia
• Mitochondrial disorders
• Inborn errors of metabolism

Diagnostic Testing Strategy

In low-incidence rheumatic fever regions (most developed countries), extensive workup is warranted:

• MRI brain with MR angiography to evaluate for structural lesions, cerebrovascular pathology
• Autoimmune panel: anti-NMDA receptor, anti-LGI1, other autoimmune encephalitis antibodies
• Metabolic screening as clinically indicated
• Genetic evaluation if family history or atypical features suggest monogenic disorder
• Streptococcal serology (ASO, anti-DNase B) may be obtained but cannot confirm or exclude the diagnosis 7, 4

In high-incidence rheumatic fever regions, if presentation is typical for Sydenham chorea with documented rheumatic fever, extensive testing may not be required. 7

Treatment Considerations

Evidence-Based First-Line Approaches

For acute neuropsychiatric symptoms:

• Psychiatric medications: SSRIs for OCD symptoms, alpha-2 agonists or antipsychotics for tics (standard evidence-based treatments for these symptoms regardless of etiology)
• Behavioral interventions: Cognitive-behavioral therapy with exposure and response prevention for OCD
• Treat documented infections: If active streptococcal pharyngitis is documented, treat with appropriate antibiotics per standard guidelines

Controversial/Unproven Interventions

The following lack adequate evidence and carry significant risks:

• Long-term antibiotic prophylaxis: Not recommended by AHA guidelines 2
• IVIG (intravenous immunoglobulin): Insufficient evidence, significant cost and risk
• Plasma exchange: Insufficient evidence, significant procedural risks
• Immunosuppressive therapy: May expose children to serious adverse effects while delaying evidence-based treatments 4

Clinical Pitfall

The major risk is diagnostic imprecision leading to inappropriate treatment. Children may receive immunomodulatory therapies with significant risk profiles (infection risk with IVIG, line complications with plasma exchange, bone marrow suppression with immunosuppressants) while evidence-based psychiatric treatments are delayed. 4

Primary tic disorders and OCD have strong genetic components (heritability 50-80% for tics), and the temporal co-occurrence with common childhood infections may be coincidental rather than causal. 4

Proposed Mechanisms (Research Stage)

Current mechanistic hypotheses include:

• Molecular mimicry: Streptococcal antigens cross-react with neuronal antigens
• Anti-dopamine receptor antibodies: Anti-D1R associated with OCD/tic phenotypes, anti-D2R with chorea phenotypes 3, 4
• Basal ganglia inflammation: Targeting cortico-striato-thalamo-cortical circuits
• Blood-brain barrier disruption: Allowing antibody access to CNS
• Cytokine-mediated neuroinflammation: Th17 responses, inflammatory amplification 5
• Gut-oral-brain axis: Microbiome alterations modulating neuroinflammation 6

None of these mechanisms has been validated as a diagnostic biomarker or treatment target in clinical practice. 3, 4

Bottom Line for Clinical Practice

Approach PANS/PANDAS as a clinical diagnosis of exclusion requiring:

1. Rigorous exclusion of alternative diagnoses (autoimmune encephalitis, primary psychiatric disorders, neurological conditions)
2. Multidisciplinary evaluation (neurology, psychiatry, immunology)
3. Cautious treatment escalation starting with evidence-based psychiatric interventions
4. Avoidance of unproven immunomodulatory therapies outside research protocols
5. Recognition that temporal association with infection does not prove causation given high background rates of both infections and neurodevelopmental disorders

Until prospective, controlled studies with validated biomarkers demonstrate clear benefit-risk ratios for immunomodulatory interventions, standard psychiatric and behavioral treatments remain the evidence-based approach for acute-onset neuropsychiatric symptoms in children. 2, 3, 5, 4