Deeper Dive: Streptococcal Involvement in PANDAS

Swedo S, Menendez CM, Cunningham MW. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) 2024 Jul 7 [Updated 2024 Sep 13]. In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes: Basic Biology to Clinical Manifestations [Internet]. 2nd edition. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2022 Oct 8. Chapter 26. Available from: https://www.ncbi.nlm.nih.gov/books/NBK607260/

Deeper Dive: Streptococcal Involvement in PANDAS

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a neuropsychiatric syndrome that develops after a Streptococcus pyogenes (group A strep) infection. It is marked by the sudden start or worsening of obsessive-compulsive symptoms and/or tics in prepubertal children, with symptoms that come and go and often appear suddenly across different areas. The chapter explains that much of the ongoing debate stems from challenges in research methods, including the prevalence of strep, silent infections, limited testing, and study design issues. At the same time, it brings together evidence from clinical observations, brain studies, immune markers, animal and lab research, treatment trials, and long-term studies that support a link between strep and a specific group of acute-onset cases. The main point is that accurately recognizing PANDAS depends on timing, symptom pattern, and careful infection screening, and that the way PANDAS develops is similar to other immune-related problems that follow strep infections.

 

  • PANDAS involves abrupt or newly worsening OCD and/or tics following Streptococcus pyogenes exposure, with a relapsing and remitting course. PANS and PANDAS share clinical features, but PANDAS requires a temporal link to streptococcal infection or exposure.
  • Diagnosis is complicated by the high prevalence of strep, frequent asymptomatic infection, and limitations of single-time-point testing. Research criteria emphasize longitudinal confirmation, requiring recurrent symptom exacerbations linked to streptococcal exposure.
  • Symptoms emerge suddenly across multiple domains and fluctuate far more dramatically than in typical OCD or tic disorders.
  • PANDAS shares clinical and biological features with Sydenham chorea, a well-established post-streptococcal autoimmune condition.
  • Evidence supports basal ganglia involvement and immune-mediated neuroinflammation, with abnormalities that may resolve during remission.
  • Cross-reactive antineuronal antibodies, dopamine receptor autoantibodies, and CaMKII signaling abnormalities support an immune mechanism, though no single biomarker is diagnostic.
  • Immunomodulatory and antibiotic treatment studies provide indirect evidence of immune involvement, particularly in carefully characterized cases.
  • Across clinical, imaging, immunologic, animal, epidemiologic, and treatment data, PANDAS is best understood as a post-streptococcal immune-mediated neuropsychiatric syndrome rather than a primary psychiatric disorder.

    Streptococcal Involvement in PANDAS

    Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is thought to be a complication that follows infection with Streptococcus pyogenes (group A streptococcus). It is marked by the sudden start or worsening of obsessive-compulsive symptoms and/or tics in prepubertal children, with symptoms that come and go. Besides OCD and tics, PANDAS often brings a rapid appearance of several psychiatric, behavioral, cognitive, sensory-motor, and physical symptoms. These can include anxiety (especially separation anxiety), mood swings, irritability, developmental setbacks, trouble paying attention, changes in thinking, sensitivity to sensory input, sleep problems, and urinary issues like frequent urination, urgency, or new bedwetting.

     

    • PANDAS follows infection with Streptococcus pyogenes
    • Symptoms begin abruptly or worsen suddenly from a stable baseline
    • OCD and/or tics are core features
    • Multiple neuropsychiatric and somatic symptoms emerge concurrently
    • The clinical course is relapsing and remitting

    PANDAS and PANS: Shared Presentation, Distinct Criteria

    PANDAS and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) have similar symptoms, but their diagnoses differ. PANS is diagnosed based on the sudden start or worsening of neuropsychiatric symptoms in several areas, without needing to find a specific cause. In contrast, diagnosing PANDAS requires proof that symptoms began or got worse around the time of a S. pyogenes infection or exposure. This difference helps doctors identify acute-onset cases, even though the exact cause may not always be clear right away.

     

    • PANS is defined by clinical presentation alone
    • PANDAS requires temporal association with S. pyogenes infection or exposure
    • Both involve abrupt symptom onset across multiple domains
    • PANDAS represents a post-streptococcal subgroup within acute-onset presentations
    Diagnostic Challenges Related to Streptococcal Infection
    Connecting the start of neuropsychiatric symptoms to S. pyogenes infection is challenging. Group A streptococcal infections are very common in school-aged children, and many can carry the bacteria without symptoms. Because of this, it is possible to mistakenly link infection and symptoms just by chance, which can lead to overdiagnosis. On the other hand, real connections may be missed if symptoms are caused by an infection that has no symptoms or by contact with someone who carries the bacteria but is not detected. These issues have led to ongoing debate about PANDAS and have made diagnosis and treatment more difficult for years.

    • S. pyogenes infections are common in children
    • Asymptomatic infection and carrier states are well documented
    • Chance associations may lead to overdiagnosis
    • Missed associations may occur with asymptomatic infection or exposure
    • These issues have contributed to controversy around PANDAS
    Research Criteria and Longitudinal Confirmation
    To address these challenges, research criteria for PANDAS require evidence of at least two episodes of neuropsychiatric symptoms that happen around the same time as a S. pyogenes infection or exposure. Because of this, doctors cannot make a definite diagnosis at the first visit. Instead, they may give a temporary diagnosis if there is recent evidence of streptococcal infection, and then watch the child over time to see if later episodes also match up with S. pyogenes. Tests may include throat or perianal cultures when needed, and repeated checks of anti-streptococcal antibody levels during symptom flare-ups.
    • At least two streptococcus-associated exacerbations are required for diagnosis
    • A definitive PANDAS diagnosis cannot be made at first presentation
    • Provisional diagnosis is often used initially
    • Longitudinal monitoring is essential
    • Cultures and serial antibody titers may support evaluation during flares

    Relationship to Sydenham Chorea

      Researchers focused on

    S. pyogenes as a trigger for PANDAS because of its similarities to Sydenham chorea, a neurological problem seen in acute rheumatic fever. Studies have shown that obsessive-compulsive symptoms often come before the movement problems in Sydenham chorea, suggesting that psychiatric symptoms are not just a reaction to motor issues. Both conditions have high rates of mood swings, trouble paying attention, and other neuropsychiatric symptoms, along with signs of basal ganglia involvement.

    • PANDAS shares clinical features with Sydenham chorea
    • Both are associated with S. pyogenes infection
    • OCD symptoms often precede chorea in Sydenham chorea
    • Psychiatric symptoms are not secondary reactions to motor impairment
    • Basal ganglia involvement is reported in both conditions

    Basal Ganglia Involvement and Immune-Mediated Mechanisms

     

    The fact that OCD, tics, and ADHD often appear together in PANDAS suggests the basal ganglia are a main area affected. Tests, brain scans, studies of brain chemicals, and treatment trials have all shown changes in the structure and function of the basal ganglia in OCD, tic disorders, ADHD, and PANDAS. In PANDAS, the basal ganglia can become larger during illness and return to normal after recovery. Other studies have found that immune cells in the basal ganglia are more active during symptoms, but this returns to normal after immune-based treatments.

    • The basal ganglia are implicated in OCD, tics, ADHD, and PANDAS
    • Phase-related structural and functional changes are observed in PANDAS
    • Imaging abnormalities normalize with clinical recovery
    • Microglial activation has been demonstrated during symptomatic periods
    • Findings support immune-mediated neuroinflammation

    Symptom Course: PANDAS Compared with OCD and Tic Disorders

     

    PANDAS has a relapsing and remitting pattern that is different from the usual ups and downs seen in most OCD and the typical waxing and waning of tic disorders. In OCD and tic disorders, symptoms usually change by about 10 to 25 percent over time. In PANDAS, however, symptoms can change much more, often by 50 to 100 percent, and can get much worse within 24 to 48 hours. Parents often remember the exact day or even time when their child’s symptoms started, which sets these cases apart from more gradual ones.

    • PANDAS follows a relapsing and remitting course
    • Severity shifts are large and abrupt
    • OCD and tic disorders typically show smaller fluctuations
    • Symptom onset in PANDAS often occurs within 24–48 hours
    • Parents can often pinpoint the exact onset

    Streptococcus as a Trigger Within a Broader Context

     

    Although S. pyogenes is a key factor in PANDAS, the chapter notes that infection alone does not fully explain how the disease develops. Genetics, differences between bacterial strains, and the person’s immune response all play important roles. These same factors also increase the risk of other conditions that follow streptococcal infections, such as acute rheumatic fever and rheumatic heart disease. The fact that autoimmune diseases and obsessive-compulsive conditions often run in families also supports the idea that a person’s vulnerability works together with streptococcal exposure to influence the disease.
    • S. pyogenes is a trigger, not a sole cause
    • Genetic predisposition influences susceptibility
    • Host immune response plays a critical role
    • Strain variability may contribute
    • Familial autoimmune patterns support host vulnerability

    Clinical Implications

     

    Overall, the evidence in this chapter supports the idea that PANDAS is a neuropsychiatric condition caused by the immune system after a streptococcal infection. It is marked by sudden or worsening symptoms and a pattern of symptoms that come and go. Making an accurate diagnosis requires close attention to when symptoms start, how they change, neurological exams, and tracking links to streptococcal infections over time. The chapter highlights the need to tell PANDAS apart from Sydenham chorea and from OCD or tic disorders that do not start suddenly, while also noting that these conditions share some biological pathways.

    Immune Biomarkers and Autoantibody Mechanisms in PANDAS

     

    A central focus of the chapter is the role of immune-mediated mechanisms in the pathogenesis of PANDAS, particularly the involvement of cross-reactive antineuronal antibodies after Streptococcus pyogenes infection, which contribute to PANDAS. Much of this understanding comes from years of research on Sydenham chorea (SC), where post-streptococcal autoimmunity is well known. These findings have been extended to PANDAS through studies in people, clinics, labs, and animals.

     

    Cross-reactive antineuronal antibodies and molecular mimicry
    Early foundational work demonstrated that antibodies generated in response to S. pyogenes can cross-react with host neuronal tissue through molecular mimicry. These antibodies are part of the normal immune response to the bacteria, but they become harmful when they recognize similar structures on the body’s own cells.

     

    Key points:
    • Cross-reactive (antineuronal) antibodies were first identified in Sydenham chorea.
    • These antibodies target neuronal tissue, particularly within the basal ganglia.
    • Reactivity is linked to molecular mimicry between streptococcal antigens and host neuronal epitopes.
    • Antibodies from SC differ from those seen in other autoimmune diseases by their absorption with S. pyogenes components, supporting a streptococcal origin.
    Recent studies have found a strong IgG2 antibody response against the group A carbohydrate N-acetyl-β-D-glucosamine (GlcNAc), which is common in acute rheumatic fever and Sydenham chorea. This response is much lower in simple streptococcal infections. Although GlcNAc-specific IgG2 may be a marker for post-streptococcal autoimmune risk, it has not yet been fully studied in PANDAS.

     

    Dopamine receptor autoantibodies and basal ganglia signaling
    Later research found that these cross-reactive antibodies target specific nerve cell structures. In Sydenham chorea, antibodies bind to parts of the basal ganglia and target dopamine receptors, especially the dopamine-2 receptor (D2R), which alters how nerve cells signal and release dopamine.

     

    Key findings include:
    • SC antibodies bind to D2R and induce downstream inhibitory signaling.
    • These antibodies provoke dopamine release and activate CaMKII signaling pathways.
    • Patient-derived monoclonal antibodies reproduce these effects in vitro, ex vivo, and in animal models.
    Children with PANDAS demonstrate overlapping but distinct autoantibody patterns:
    • PANDAS sera frequently contain antineuronal antibodies similar to those seen in SC.
    • Autoantibody-mediated CaMKII activation has been documented in a majority of PANDAS cases studied.
    • More recent data suggest PANDAS is primarily associated with dopamine-1 receptor (Newer data suggest that PANDAS is mainly linked to autoantibodies against the dopamine-1 receptor (D1R), while Sydenham chorea is more closely linked to autoantibodies against the D2R..
    These findings support the conceptualization of PANDAS and SC as related autoimmune basal ganglia encephalitides, distinguished by differences in receptor targeting and clinical expression.
     
    CaMKII signaling as a functional biomarker
    A common finding is that antibodies can activate calcium/calmodulin-dependent protein kinase II (CaMKII), a molecule that helps nerve cells communicate, release neurotransmitters, and adapt to changes.
    Evidence summarized in the chapter shows:
    • SC and PANDAS sera induce CaMKII activation in neuronal cells.
    • Removal of IgG from serum abolishes this signaling effect.
    • Elevated CaMKII activity correlates with symptom severity.
    • Reductions in CaMKII activity and dopamine receptor autoantibodies are associated with clinical improvement following treatment.
    These results suggest that CaMKII activation shows the immune system is actively affecting nerve cell signaling, not just that antibodies are present.
     
    Human, animal, and translational evidence
    The chapter emphasizes that immune-mediated mechanisms are supported across multiple experimental systems:
    • Human studies show antineuronal antibodies, receptor-specific autoantibodies, and signaling abnormalities.
    • Animal models replicate motor and behavioral changes following streptococcal immunization or passive antibody transfer.
    • Repeated streptococcal exposure is required to induce neuroinflammation, mirroring patterns seen in rheumatic fever models.
    • Th17 cell trafficking, blood–brain barrier disruption, microglial activation, and IgG deposition provide a pathway for immune access to the central nervous system.
    These findings collectively fulfill established criteria for defining an autoimmune disorder and support a causal role for post-streptococcal immune mechanisms in both SC and PANDAS.

     

    Clinical implications and evolving biomarkers
    While no single biomarker is sufficient for diagnosis, the authors emphasize converging signals:

    • Antineuronal antibodies, dopamine receptor autoantibodies, and CaMKII activation reflect disease biology.
    • Patterns of receptor targeting may help distinguish PANDAS from Sydenham chorea.
    • Emerging biomarkers, such as GlcNAc-specific IgG2, warrant further investigation in PANDAS populations.
    The chapter emphasizes that immune biomarkers should be considered along with the patient’s clinical picture and used as part of an evolving approach, not as final diagnostic tools.
    Recap
    • PANDAS involves immune-mediated mechanisms similar to Sydenham chorea
    • Cross-reactive antineuronal antibodies arise through molecular mimicry
    • Basal ganglia and dopamine receptor signaling are key targets
    • PANDAS is more strongly associated with D1R autoantibodies; SC with D2R
    • CaMKII activation reflects functional neuronal impact and correlates with severity
    • Animal and human studies support an autoimmune pathogenesis
    • Biomarkers are investigational and supportive, not standalone diagnostics

    Underlying Mechanisms: Autoimmunity, Genetics, and Immune Dysfunction Across Streptococcal Sequelae

     

    This section puts PANDAS in the broader context of diseases that follow strep infections, comparing it to acute rheumatic fever (ARF), rheumatic heart disease (RHD), and autoimmune diseases like lupus (SLE) and Sjögren’s syndrome (SS). The authors explain that linking S. pyogenes to PANDAS relies on evidence from many sources, including population studies, clinical groups, immune responses, genetics, and treatment results. They also note that research limitations have often made it hard to see real connections.
    Autoimmunity and overlap with systemic autoimmune disease
    The chapter highlights multiple immune-system intersections between streptococcal sequelae and systemic autoimmunity:
    • ANA positivity, common in SLE, is reported as positive in some cases of PANDAS.
    • Anti-idiotypic antibodies developed against ARF autoantibodies identified closely connected serum antibodies from SLE and SS, suggesting partially shared immune mechanisms across these conditions.
    • Sex-related immune effects are discussed in ARF/RHD, including evidence that estrogen can drive CD8+ T cells to upregulate perforin and granzyme in rheumatic valves, potentially contributing to why women show more valve disease in RHD.
    • Complement Factor C4 deficiencies are described as a genetic susceptibility trait in SLE and also identified in PANS/PANDAS, with the chapter noting an association with arthritis in that context.
    • The authors note an important contrast: PANDAS shows a male predominance (boys ~3:1), unlike many systemic autoimmune diseases where women are more frequently affected.
    Immune defects in rheumatic disease as a susceptibility context
    In ARF/RHD, the chapter describes immune alterations linked to repeated streptococcal infections/tonsillitis:
    • Repeated streptococcal infections were associated with alterations in the T follicular helper cell compartment, including smaller germinal centers and reduced antibody production against group A streptococcus.
    • These immune defects were noted in the context of HLA risk alleles, suggesting a “susceptibility background” where immune architecture and genetics may combine to influence outcomes following infection.
    Genetic susceptibility as a risk factor across ARF/RHD and related immune phenotypes
    Genetic susceptibility is presented as a major risk factor in ARF/RHD and potentially informative for understanding why immune responses become misdirected (heart/joints/brain):
    • Familial associations in ARF suggest inherited susceptibility with limited penetrance, not classic Mendelian inheritance.
    • Complement C4 copy-number deficiency, a known risk factor in SLE and some arthritis phenotypes, is also reported in PANS, and in the chapter is noted as mainly associated with arthritis.
    • Several lines connect ARF/RHD and SLE/SS immunologically and genetically, including:
      • Anti-idiotypic reagents against cardiac myosin autoantibodies detecting reactivity not only in ARF/RHD but strongly in SLE and SS.
      • A proposed connection between an idiotypic biomarker of RHD anti-cardiac myosin autoantibodies and immunoglobulin heavy chain (VH) gene associations reported in RHD risk across populations.
      • Experimental work in mice (streptococcal membrane immunization) producing anti-DNA autoantibodies, further linking group A streptococcal immune responses with autoimmune patterns relevant to SLE.
    HLA and other immune-related gene associations in ARF/RHD
    The chapter reviews susceptibility signals across HLA and other immune pathways (often varying by population):
    • HLA class II predisposition: different HLA alleles/haplotypes are associated with RHD susceptibility across ethnic populations; DR-7 is discussed in association with mitral valve disease in some cohorts and also linked in Brazilian, Egyptian, and Turkish populations.
    • The HLA class III region is described as a possible “hotspot” for susceptibility (noting replication across datasets), and the chapter highlights that this region also harbors complement genes relevant to pathogenesis.
    • Additional gene/pathway associations discussed include:
      • TLR2 polymorphism associated with ARF in a Turkish cohort, with the chapter noting related work identifying cardiac myosin/fragments as a TLR2 ligand capable of stimulating proinflammatory cytokines.
      • Mannose-binding lectin (MBL) gene O allele associated with aortic regurgitation; MBL’s role in bacterial clearance and complement interactions is emphasized.
      • FcR-gamma-IIA polymorphisms affecting IgG2 binding; failure to clear immune complexes is raised as a potential mechanism contributing to ongoing high-affinity antibody development.
      • Other reported genetic variation includes complement C4, TGF-beta1, MBL, and FcR loci, with the chapter treating these as relevant to inflammatory/immune responses against streptococcus and predisposition to sequelae.
    A separate biomarker thread is also described:
    • An integrative analysis identified an elevated IgG3–C4 response in ARF cases with high CRP that was not seen in controls, with the authors suggesting this pattern may help identify children at risk for early ARF/inflammation.
    Strain and environmental influences: host–streptococcus interaction matters
    Beyond host genetics, the chapter stresses that environmental and microbial factors are crucial:
    • Historical rheumatic-fever–associated strains are described as M-protein rich, heavily encapsulated, and highly virulent, with throat-associated strains implicated in certain outbreaks (including reference to WWII-era epidemics and a Utah outbreak).
    • In tropical climates, the epidemiology suggests greater strain diversity and possible dominance of skin-associated strains in ARF.

    Immunomodulatory treatment as evidence of immune dysfunction in PANDAS

     

    The chapter explains that immune problems in PANDAS may happen at several levels:
    • Local/targeted dysfunction linked to antineuronal antibodies
    • Regional abnormalities related to inflammation within neuronal tissues/vasculature of the basal ganglia
    • Systemic abnormalities in cytokine/chemokine production that may disrupt the blood–brain barrier and CNS function
    Treatment studies are described as ways to test the idea that antibodies are driving the illness:
    • A three-arm randomized controlled trial compared therapeutic plasmapheresis (TPE), IVIG, and sham IVIG. The chapter reports dramatic improvements in OCD symptom severity within one month for IVIG and TPE (45% and 58%), with no discernible effect for sham, and gains maintained for at least one year.
    • The chapter points out that TPE did not help children with OCD who did not have PANDAS, and IVIG did not help those with tic disorders not related to PANDAS. This suggests that the improvements seen were not just placebo effects from the procedures.
    • A later double-blind trial of IVIG vs placebo in carefully diagnosed PANDAS did not reach statistical significance at six weeks, but open-label IVIG was associated with a reported 50% reduction in OCD severity with persistence over follow-up; the chapter notes the open-label phase lacks a control group, while still calling the durability noteworthy.
    Clinical guidance in this section is framed around severity:
    • TPE/IVIG are described as recommended to be reserved for severely ill children, particularly those at risk for self-harm, while NSAIDs or corticosteroids may provide symptomatic relief in mild-to-moderate illness, alongside standard psychiatric/behavioral care and family supports.

    Epidemiologic and clinical evidence: why results conflict, and what methodology changes

     

    A main point here is that research on PANDAS has been limited because there is no specific diagnostic code for it. This has made researchers use “OCD” and “tic disorder” as stand-ins, which can dilute the results since PANDAS is only a small part of these groups.
    The chapter critiques widely cited negative findings by pointing to design limitations, including:
    • Age ranges extending far beyond the prepubertal onset requirement
    • Failure to assess acuity of onset
    • Long “intervals of interest” (2–5 years), obscuring temporal relationships
    • Broad “strep” code definitions including many irrelevant codes
    It also highlights potential ascertainment bias in later work where limiting access to antibiotics discouraged enrollment by families who perceived high risk and wanted treatment access.
    In contrast, multiple studies summarized in the chapter report stronger associations:
    • Large administrative/insurance datasets showing increased odds of prior S. pyogenes diagnoses preceding OCD/tic/TS diagnoses
    • School-based longitudinal observations linking seasonal peaks in S. pyogenes with behavior/tic-related observations and noting higher rates with repeated infections
    • Clinic-based longitudinal work where children with high symptom variability showed higher titers over time and correlations between titer changes and symptom severity changes
    A key methodological warning is repeated:
    • Standard ASO/anti-DNase B testing can miss immunologically active infections, and serology/titer interpretation is complicated by latency and decay curves.
    • The chapter emphasizes the value of serial titers rather than absolute thresholds and using at least two antibodies because responses vary by strain.
    • Culture technique matters: low colony counts and sampling technique can produce false negatives, and the chapter raises intracellular streptococci as a potential confounder for both testing and relapse patterns.

    Antibiotic treatment and prophylaxis: clinical observations and trial findings

     

    This section summarizes multiple lines of antibiotic-related evidence:
    • A prospective pediatric practice study described children presenting with acute-onset OCD and mild pharyngitis signs, with S. pyogenes confirmed by testing; antibiotic treatment eradicated infection and was associated with complete remission, with recurrences also reportedly tied to positive cultures and responsive to treatment.
    • Controlled antibiotic treatment trials are described, including a cefdinir vs placebo trial (improvement signals but underpowered) and azithromycin vs placebo for acute-onset OCD (reported superiority on CGI-S OCD and more responders; mild side effects, with QTc prolongation noted as non-significant).
    • A large Italian cohort receiving long-term benzathine benzylpenicillin prophylaxis is described as having prevention of S. pyogenes infections and reported clinical improvement in a substantial portion, while also noting relapses—often around nonspecific viral infections.
    Two NIMH prophylaxis trials are discussed:
    • An early cross-over penicillin trial struggled with adherence and did not prevent infections, limiting conclusions (with a secondary parent global rating showing perceived benefit).
    • A later prophylaxis trial using adherence supports reported large reductions in S. pyogenes infections and neuropsychiatric exacerbations during prophylaxis for both penicillin and azithromycin regimens.
    The authors explain that the use of antibiotics is still debated. Some groups strongly advise against antibiotics, while others support their use for acute-onset cases. They end with practical advice from the original NIMH guidance: when a child first presents with sudden, severe OCD or tics, take the right cultures and treat if the results are positive.

    Gabriella True

    Gabriella True

    Published : February 8, 2026
    Category : Blog, Clinicians, Symptoms

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