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An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know

Open access
Hardin, Hannah, Shao, Wenhai, Bernstein, Jonathan A.·2023·Annals of Allergy, Asthma & Immunology
DOI 10.1016/j.anai.2023.08.022
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Abstract

Background: Pediatric acute-onset neuropsychiatric syndrome, further subcategorized as pediatric autoimmune neuropsychiatric disorders associated with streptococcus, is a form of idiopathic autoimmune encephalitis (IAE). Poststreptococcal autoimmunity seen in Idiopathic autoimmune encephalitis manifests as various neuropsychiatric symptoms such as obsessive rituals, tics, anxiety, depression, and many others. Idiopathic autoimmune encephalitis has clinically heterogeneous phenotypes that make accurate diagnosing difficult, although diagnostic testing such as the Cunningham Panel increases the likelihood of finding effective treatments. Current recommended treatments include psychiatric medication, behavioral intervention, antibiotics, anti-inflammatory therapy, and immunomodulating therapy. Objective: To provide an updated review on the diagnosis, management, and treatment of pediatric autoimmune neuropsychiatric disorder associated with streptococcus and pediatric autoimmune neuropsychiatric syndrome, also referred to as IAE. Results: Information from 47 sources was used to outline current knowledge of IAE pathophysiology, clinical manifestations, and epidemiology, and to outline diagnostic recommendations and current treatment guidelines. Gaps in knowledge, in addition to current controversy, were also outlined to provide a thorough background of this condition and future needs for IAE research. Conclusion: Owing to the complexity and variability in ways patients with IAE may present to the allergist/immunologist office, an interdisciplinary approach is imperative to provide patients with the best medical care. Still, more research is needed to further elucidate the mechanism(s) and optimal treatment algorithm for IAE to facilitate broader recognition and acceptance of this condition by the medical community. © 2023 American College of Allergy, Asthma & Immunology

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Crossref · 10.1016/j.anai.2023.08.022

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

47 of 101 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    An atypical presentation of IAE was reported in a 15-year-old girl who manifested impulsivity, seizure-like spells, auditory hallucinations, and catatonic movements.

    “An atypical presentation was recently reported involving a 15-year-old girl who also manifested impulsivity, “seizure-like” spells, auditory hallucinations, and catatonic movements.10”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Barzman, 2018, An atypical presentation of pediatric acute neuropsychiatric syndrome responding to plasmapheresis treatment, Case Rep Psychiatry source

      The Case Presentation reports a 15-year-old girl with impulsivity, “seizure-like” spells, auditory hallucinations, and catatonic movements. The Clinical Course identifies her condition as pediatric acute-onset neuropsychiatric syndrome (PANS), not IAE, so the symptoms are supported but the paraphrase’s IAE identification is not. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    A more recent study assessing children and adolescents with eating disorders revealed that 52% of the 52 participants met the IAE criteria.

    “A more recent study assessing children and adolescents with eating disorders revealed that 52% of the 52 participants met the IAE criteria.8”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Aman, 2022, Prevalence of pediatric acute-onset neuropsychiatric syndrome (PANS) in children and adolescents with eating disorders, J Eat Disord source

      The Results section (page unavailable) reports that 52% of 100 children and adolescents with eating disorders—52 participants—met PANS criteria based on parent questionnaires. The claim gets the percentage right but mistakes the 52 who met criteria for the total sample and calls the criteria IAE rather than PANS. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    The pathophysiology of IAE is believed to involve an autoimmune process that targets brain structures including the basal ganglia, leading to neuroinflammation and subsequent neuropsychiatric symptoms.

    “The pathophysiology of IAE is believed to involve an autoimmune process that targets brain structures including the basal ganglia, leading to neuroinflammation and subsequent neuropsychiatric symptoms.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [13] Galvin, 2000, Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin, J Clin Invest source

      The Introduction and Discussion describe cross-reactive antibodies in rheumatic carditis and possible inflammation of heart valves. The Introduction mentions chorea as a manifestation of rheumatic fever, but the copy does not address IAE, basal ganglia targeting, neuroinflammation, or the proposed pathway to neuropsychiatric symptoms (searched: IAE, brain structures, basal ganglia, neuropsychiatric symptoms). (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [14] Brimberg, 2012, Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders, Neuropsychopharmacology source
    • cites [15] Dileepan, 2016, Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells, J Clin Invest source

      The section “Why do T cells home to and persist in the brain?” proposes that repeated streptococcal infections may allow autoreactive antibodies into the brain and contribute to neuropsychiatric symptoms. But this is a proposed model for SC and PANDAS, not an account of IAE; the authors also report no extensive blood–brain barrier damage or IgG deposition in the basal ganglia of their mice. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Lysoganglioside GM1 is a neuronal surface antigen identified to be of interest in patients with IAE owing to cross-reactivity with human monoclonal antibodies derived from patients with Sydenham chorea.

    “Lysoganglioside GM1 is a neuronal surface antigen identified to be of interest in patients with IAE owing to cross-reactivity with human monoclonal antibodies derived from patients with Sydenham chorea.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Shimasaki, 2020, J Neuroimmunol source

      Section 1.1.1 (page unavailable) identifies lysoganglioside GM1 as a neuronal surface antigen and reports cross-reactivity with human monoclonal antibodies derived from patients with Sydenham chorea. The paper discusses its relevance to PANDAS/PANS, but does not establish its relevance specifically to patients with IAE. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Atorvastatin has been found to attenuate surgery-induced BBB disruption in an atorvastatin-treated mouse model, possibly through anti-inflammatory effects by decreasing TNF-a levels.

    “Interestingly, atorvastatin has been found to attenuate surgeryinduced BBB disruption in an atorvastatin-treated mouse model, possibly through anti-inflammatory effects by decreasing TNF-a levels.22”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Chen, 2022, Atorvastatin suppresses NLRP3 inflammasome activation in intracerebral hemorrhage via TLR4− and MyD88-dependent pathways, Aging (Albany NY) source

      The neuroinflammation results report that atorvastatin lowered TNF-α in mice with collagenase-induced intracerebral hemorrhage, and the brain-water-content results report reduced edema. The Animal model section says sham mice underwent the same surgery without collagenase; the paper does not report that atorvastatin attenuated surgery-induced blood–brain barrier disruption or measure that outcome. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 35

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Current recommended treatments for IAE include psychiatric medication, behavioral intervention, antibiotics, anti-inflammatory therapy, and immunomodulating therapy.

    “Current recommended treatments include psychiatric medication, behavioral intervention, antibiotics, anti-inflammatory therapy, and immunomodulating therapy.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Swedo, 2017, Overview of treatment of pediatric acute-onset neuropsychiatric syndrome, J Child Adolesc Psychopharmacol source

      The Abstract and the treatment summary near Fig. 1 recommend psychiatric medication, behavioral interventions, antibiotics, and anti-inflammatory or immunomodulatory therapy for pediatric acute-onset neuropsychiatric syndrome (PANS). The cited paper does not establish these as recommended treatments for IAE, as the contextualized claim states; it also says the treatment chosen depends on the child’s presentation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Atypical cases of IAE have manifested in adults.

    “Although classified as a rare condition, idiopathic autoimmune encephalitis (IAE) is estimated to affect up to 1 in 200 children, although atypical cases of IAE have also manifested in adults.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [10] Barzman, 2018, An atypical presentation of pediatric acute neuropsychiatric syndrome responding to plasmapheresis treatment, Case Rep Psychiatry source

      The Case Presentation describes a 15-year-old patient, and the Clinical Course discusses a suspected atypical autoimmune process in that patient. Neither those passages nor the Discussion reports atypical idiopathic autoimmune encephalitis in adults; searches for adult cases and atypical autoimmune encephalitis found no such passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [11] Kim, 2016, Obsessive-compulsive disorder related to mycoplasma-associated autoimmune encephalopathy with basal ganglia involvement, J Child Adolesc Psychopharmacol source
    • cites [12] Deshmukh, 2022, PANDAS in an adult?: A case report, Indian J Psychiatry source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Successful treatment recommendations for patients with IAE include psychiatric medications and behavioral interventions, antimicrobials, and anti-inflammatory and/or immunomodulating therapies such as intravenous immunoglobulin and plasmapheresis.

    “Successful treatment recommendations for patients with IAE include psychiatric medications and behavioral interventions, antimicrobials, and anti-inflammatory and/or immunomodulating therapies such as intravenous immunoglobulin and plasmapheresis.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Swedo, 2017, Overview of treatment of pediatric acute-onset neuropsychiatric syndrome, J Child Adolesc Psychopharmacol source

      The Abstract and the treatment summary under Fig. 1 recommend psychiatric and behavioral interventions, antimicrobials, and anti-inflammatory or immunomodulatory therapies for children with PANS. The cited paper does not establish these recommendations for patients with IAE or name intravenous immunoglobulin or plasmapheresis as examples in the passages found; it also describes the guidelines as best practices awaiting controlled trials, rather than established successful treatments. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PANDAS was first reported in 1998; researchers at the time used 5 clinical criteria, typically referred to as Swedo's criteria, to diagnose this disorder.

    “PANDAS was first reported in 1998; researchers at the time used 5 clinical criteria, typically referred to as “Swedo’s criteria” to diagnose this disorder: (1) evidence of a group A B-hemolytic Streptococcus (GABHS) infection; 2) abrupt onset of symptoms during the prepubertal period; 3) the presence of an OCD with or without a tic disorder; 4) association with neurologic abnormalities; and 5) an”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] Swedo, 1998, Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases, Am J Psychiatry source
    • cites [3] Swedo, 2015, Clinical presentation of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in research and community settings, J Child Adolesc Psychopharmacol source

  • May combine two claims.

    Premisecitation

    Patients with IAE may also experience hyperactivity, choreiform movements, fine motor skill loss, separation anxiety, and psychotic symptoms.

    “Aside from the above consensus diagnostic criteria, patients with IAE may also experience hyperactivity, choreiform movements, fine motor skill loss, separation anxiety, and psychotic symptoms.9”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Murphy, 2012, Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, J Pediatr source

      The Conclusion (page unavailable) lists hyperactivity, choreiform movements, fine motor skill loss, and separation anxiety as features of PANDAS. Table 1 in the Results (page unavailable) also records psychotic symptoms in 5 of 41 children classified with PANDAS. The paper studies PANDAS, however, and does not establish that this symptom list applies to patients with IAE generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Some patients with IAE have been found to have hypogammaglobulinemia (and less frequently, common variable immunodeficiency), but studies comparing the frequency of these incidental findings with the larger population have not been performed.

    “Still, some patients with IAE have been found to have hypogammaglobulinemia (and less frequently, common variable immunodeficiency), but studies comparing the frequency of these incidental findings with the larger population have not been performed.28”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Calaprice, 2018, Treatment of pediatric acute-onset neuropsychiatric disorder in a large survey population, J Child Adolesc Psychopharmacol source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One theory is that antibodies permeate through the blood-cerebrospinal fluid barrier, which normally is protected by a tight barrier formed from the choroid plexus but during disease states becomes more permeable to serum proteins, immune cells, and Abs.

    “One theory is that they permeate through the blood-cerebrospinal fluid barrier, which normally is protected by a tight barrier formed from the choroid plexus but during disease states becomes more permeable to serum proteins, immune cells, and Abs.24”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Platt, 2017, Hello from the other side: how autoantibodies circumvent the blood-brain barrier in autoimmune encephalitis, Front Immunol source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Other studies have reported that increased TNF-a levels were significantly associated with disease severity in IAE, possibly owing to disruption of the BBB, leading to increased permeability that allowed autoantibody and immune cell transmigration to occur.

    “Other studies have reported that increased TNF-a levels were significantly associated with disease severity in IAE, possibly owing to disruption of the BBB, leading to increased permeability that allowed autoantibody and immune cell transmigration to occur.21”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Cheng, 2018, TNFalpha disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice, Brain Behav Immun source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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    Premisecitation

    Although the pathogenesis of IAE is still not completely understood, it has been connected to other infection-linked disorders such as rheumatic fever (RF), which can progress to rheumatic heart disease when molecular mimicry and production of antimyocardial antibodies and streptococcal antigens cross-react.

    “Although the pathogenesis of IAE is still not completely understood, it has been connected to other infection-linked disorders such as rheumatic fever (RF), which can progress to rheumatic heart disease when molecular mimicry and production of antimyocardial antibodies and streptococcal antigens cross-react.13”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Galvin, 2000, Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin, J Clin Invest source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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    Premisecitation

    Tubulin is also important in inflammatory and demyelinating conditions owing to its role in cell signaling and overall cognitive function.

    “Tubulin is also important in inflammatory and demyelinating conditions owing to its role in cell signaling and overall cognitive function.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Shimasaki, 2020, J Neuroimmunol source

      Section 1.1.4 (Anti-tubulin; page unavailable) reports that tubulin autoantibodies have been identified in chronic inflammatory demyelinating polyneuropathy and Guillain-Barré syndrome. It does not explain tubulin’s relevance to those conditions through cell signaling or cognitive function; the discussion of signaling and cognitive impairment in section 1.1.2 concerns CaMKII instead. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Calcium modulin kinase II is essential to understanding the pathogenesis of IAE because it increases the activity of the enzyme tyrosine hydrolase, which helps convert tyrosine to the catecholamine dopamine.

    “Calcium modulin kinase II is also essential to understanding the pathogenesis of IAE because it increases the activity of the enzyme tyrosine hydrolase, which helps convert tyrosine to the catecholamine dopamine.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Shimasaki, 2020, J Neuroimmunol source

      Section 1.1.2 (page unavailable) states that CaMKII activation increases tyrosine hydrolase activity and dopamine output. The paper discusses this mechanism in PANDAS and related movement disorders, but does not establish that CaMKII is essential to the pathogenesis of IAE. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Group A streptococcal antibodies have been shown to cause CaMKII activation, and in the acute phase of IAE, CaMKII can be activated above baseline.

    “Group A streptococcal antibodies have been shown to cause CaMKII activation, and in the acute phase of IAE, CaMKII can be activated above baseline.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Shimasaki, 2020, J Neuroimmunol source

      Section 1.1.2 (page unavailable) reports evidence that group A streptococcal antibodies cause CaMKII activation and that activation was above basal levels during the acute phase in patients with Sydenham chorea or PANDAS. It does not establish the acute-phase finding for IAE specifically. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A more recent study from Shimasaki et al that compared pre-and posttreatment status of patients with a baseline Cunningham Panel revealed that overall accuracy of the test for diagnosis of IAE was 86%, with sensitivity and specificity being 88% and 83%, respectively.

    “A more recent study from Shimasaki et al that compared pre-and posttreatment status of patients with a baseline Cunningham Panel revealed that overall accuracy of the test for diagnosis of IAE was 86%, with sensitivity and specificity being 88% and 83%, respectively.19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Shimasaki, 2020, J Neuroimmunol source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The 2021 systematic analysis suggests a need for additional larger, well-designed studies of well-characterized patients with IAE to determine specific biomarkers that could identify those most likely to benefit from these therapies.

    “This suggests there is a need for additional larger, welldesigned studies of well characterized patients with IAE, to determine specific biomarkers that could identify those patients most likely to benefit from these therapies.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [50] Johnson, 2021, Anti-inflammatory, antibacterial and immunomodulatory treatment in children with symptoms corresponding to the research condition PANS (pediatric acute-onset neuropsychiatric syndrome): a systematic review, PLoS One source

      The Discussion calls for adequately designed future studies and says that a diagnosis with clear boundaries needs to be defined and verified. It also says reliable biomarkers for PANS have not been identified. The review concerns children with PANS-like symptoms, not patients with IAE, and does not propose biomarkers to identify who is most likely to benefit from treatment. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The CaMKII biomarker subsequently increased, which was associated with clinical deterioration of the patient's condition when IVIG was adjusted to every 6 weeks, suggesting this biomarker may be useful for monitoring dose adjustments for patients treated with IVIG.

    “The CaMKII biomarker subsequently increased, which was associated with clinical deterioration of the patient's condition when IVIG was adjusted to every 6 weeks, suggesting this biomarker may be useful for monitoring dose adjustments for patients treated with IVIG.31”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Connery, 2018, Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism, Transl Psychiatry source

  • May combine two claims.

    Premisecitation

    In that cohort, the Child Health Questionnaire Parent Form 50 revealed an average mental health/wellbeing score of 47.18 compared with the national average of 78.50, indicating a higher frequency of anxiety and depression.

    “The Child Health Questionnaire Parent Form 50 also measured the mental health/wellbeing of these patients from their parent's point of view, revealing an average score of 47.18 compared with the national average of 78.50, indicating that the subset of patients with IAE studied had a higher frequency of anxiety and depression.51”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [51] Murphy, 2015, Characterization of the pediatric acute-onset neuropsychiatric syndrome phenotype, J Child Adolesc Psychopharmacol source

      The ‘Impairment and quality of life in PANS youth’ section reports a CHQ-PF50 Mental Health (Well-Being) mean of 47.18 versus a national mean of 78.50 and interprets it as indicating more anxiety and depressive symptoms. However, the paper identifies its sample as PANS youth; it does not establish that these scores describe the cited sentence’s subset of patients with IAE. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A systematic analysis from 2021 of randomized controlled trials for IAE anti-inflammatory, antibacterial, or immunomodulating treatment found very low certainty of evidence in their beneficial effects and moderate certainty of evidence for adverse effects.

    “A systematic analysis from 2021 of randomized controlled trials for IAE anti-inflammatory, antibacterial, or immunomodulating treatment found very low certainty of evidence in their beneficial effects whereas there was moderate certainty of evidence for adverse effects.50”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [50] Johnson, 2021, Anti-inflammatory, antibacterial and immunomodulatory treatment in children with symptoms corresponding to the research condition PANS (pediatric acute-onset neuropsychiatric syndrome): a systematic review, PLoS One source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Interpretationnone given

    IAE remains controversial among physicians because of its heterogeneous phenotype, poor understanding of its pathogenesis, and lack of consensus for diagnosis and treatment.

    “Idiopathic autoimmune encephalitis remains controversial among physicians because of its heterogeneous phenotype, poor understanding of its pathogenesis, and lack of consensus for diagnosis and treatment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Cunningham Panel measures neuronal autoantibodies against dopamine receptors I and II, tubulin and lysoganglioside receptors, and calcium modulin kinase II.

    “Although there are no consensus diagnostic criteria for IAE, the PANDAS Physicians Network has posted a diagnostic flowchart to aid physicians in diagnosing and treating these patients, which includes the Cunningham Panel that measures neuronal autoantibodies against dopamine receptors I and II, tubulin and lysoganglioside receptors, and calcium modulin kinase II.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Moleculera labs. Cunningham Panel results. Available at: https://www.moleculeralabs.com/cunningham-panel-results-help-determine-treatment-plan-child-schizophrenic-like-symptoms/. Accessed June 5, 2023.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IAE is estimated to affect up to 1 in 200 children.

    “Although classified as a rare condition, idiopathic autoimmune encephalitis (IAE) is estimated to affect up to 1 in 200 children, although atypical cases of IAE have also manifested in adults.”
    • Also stated in: § Epidemiology · hedged
      “Although classified as a rare disorder, the PANDAS Network has estimated that this condition may be more common than realized, affecting as many as 1 in 200 children.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] PANDAS Network. PANDAS at a Glance. Available at: https://pandasnetwork.org/. Accessed June 6, 2023.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Children diagnosed with IAE are mostly observed between the ages of 1 to 13 years, with 60% diagnosed between ages 4 and 9 years and the peak onset of diagnosis at approximately 6.5 years of age.

    “They reported children diagnosed with IAE are mostly observed between the ages of 1 to 13 years, with 60% diagnosed between ages 4 and 9 years and the peak onset of diagnosis at approximately 6.5 years of age.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Texas pediatric acute onset neuropsychiatric syndrome advisory council. Available at: https://www.hhs.texas.gov/sites/default/files/documents/laws-regulations/reports-presentations/2021/pansac-report-sept-2021.pdf. Accessed June 5, 2023.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Pediatric acute-onset neuropsychiatric syndrome (PANS), further subcategorized as pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS), is a form of idiopathic autoimmune encephalitis (IAE).

    “Pediatric acute-onset neuropsychiatric syndrome, further subcategorized as pediatric autoimmune neuropsychiatric disorders associated with streptococcus, is a form of idiopathic autoimmune encephalitis (IAE).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Boys outnumber girls approximately 2:1 among children diagnosed with IAE.

    “Boys outnumber girls approximately 2:1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Texas pediatric acute onset neuropsychiatric syndrome advisory council. Available at: https://www.hhs.texas.gov/sites/default/files/documents/laws-regulations/reports-presentations/2021/pansac-report-sept-2021.pdf. Accessed June 5, 2023.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The National Institutes of Health developed working diagnostic criteria for PANS in July 2010, which are acute-onset obsessive-compulsive disorder (OCD) or restricted food intake; the presence of 2 additional neuropsychiatric symptoms from categories including anxiety, emotional lability/depression, irritability/aggression/severe oppositional behavior, behavioral regression, deterioration in学校?

    “The National Institutes of Health developed working diagnostic criteria for PANS in July 2010, which are acute-onset obsessive-compulsive disorder (OCD) or restricted food intake; the presence of 2 additional neuropsychiatric symptoms from categories including anxiety, emotional lability/depression, irritability/aggression/severe oppositional behavior, behavioral regression, deterioration in”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Chang, 2015, Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference, J Child Adolesc Psychopharmacol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    PANDAS is a subset of PANS, with a temporal association between Streptococcus infection and new-onset neurologic and psychological symptoms.

    “Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS) is a subset of PANS, with a temporal association between Streptococcus infection and new-onset neurologic and psychological symptoms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The estimate that IAE affects as many as 1 in 200 children is a lifetime prevalence based on research of OCD incidence and a Centers for Disease Control 2013 national surveillance report of emergency hospitalizations and comorbidities of mental health issues such as OCD, Tourette syndrome, and acute mood disorders.

    “This estimate is a lifetime prevalence based on research of OCD incidence and a Centers for Disease Control 2013 national surveillance report of emergency hospitalizations and comorbidities of mental health issues such as OCD, Tourette syndrome (TS), and acute mood disorders.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] PANDAS Network. PANDAS at a Glance. Available at: https://pandasnetwork.org/. Accessed June 6, 2023.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The investigators reported a significant increase in gene expression of NLRP3, which correlated with increased plasma levels of the cytokines (IL-1Ra, tumor necrosis factor [TNF], IL-6) and increased disease severity in patients vs matched controls.

    “The investigators reported a significant increase in gene expression of NLRP3, which correlated with increased plasma levels of the cytokines (IL-1Ra, tumor necrosis factor [TNF], IL-6) and increased disease severity in patients vs matched controls.20”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Hylen, 2020, Increased inflammasome activity in markedly ill psychiatric patients: an explorative study, J Neuroimmunol source

  • May combine two claims.

    Premisecitation

    Similarly to RF, some patients with IAE have been identified with DR+ cell surface markers on B lymphocytes recognized by the D8/17 monoclonal Ab, proposed to be a susceptibility marker in RF and poststreptococcal reactive arthritis, which, in 1 study, was found to be present in 85% of patients with IAE.

    “Interestingly, similarly to RF, some patients with IAE have been identified with DR+ cell surface markers on B lymphocytes recognized by the D8/17 monoclonal Ab, proposed to be a susceptibility marker in RF and poststreptococcal reactive arthritis, which, in 1 study, was found to be present in 85% of patients with IAE.26,27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Swedo, 1997, Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever, Am J Psychiatry source
    • cites [27] Harel, 2007, Presence of D8/17 B-cell marker in patients with poststreptococcal reactive arthritis, Rheumatol Int source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Normal ranges of brain dopamine are critical for normal motor control, as shown by the correlation between movement disorders such as Parkinson disease or essential tremors and low dopamine levels.

    “Normal ranges of brain dopamine are critical for normal motor control, as shown by the correlation between movement disorders such as Parkinson disease or essential tremors and low dopamine levels.18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Dirkx, 2017, Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus, Brain source

  • May combine two claims.

    Premisecitation

    IAE is believed to be caused by the production of cross-reactive antibodies to receptors on the basal ganglia produced in the peripheral circulation that cross a defective blood-brain barrier (BBB), causing inflammation in the central nervous system (CNS) manifesting as neuropsychiatric symptoms similar to those described for RF.

    “Idiopathic autoimmune encephalitis is believed to be caused by the production of cross-reactive antibodies to receptors on the basal ganglia produced in the peripheral circulation that cross a defective blood-brain barrier (BBB), causing inflammation in the central nervous system (CNS) manifesting as neuropsychiatric symptoms similar to those described for RF.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Brimberg, 2012, Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders, Neuropsychopharmacology source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of the choroid plexus in mice and humans, suggesting that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.

    “They found that the CCR6 ligand CCL20 was constitutively expressed in epithelial cells of the choroid plexus in mice and humans, suggesting that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS. 25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Reboldi, 2009, C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE, Nat Immunol source

  • May combine two claims.

    Premisecitation

    The presence of these antibodies correlates with the disease onset, symptom presentation, and clinical course.

    “The presence of these antibodies correlates with the disease onset, symptom presentation, and clinical course.14”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Brimberg, 2012, Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders, Neuropsychopharmacology source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Owing to the broad spectrum of IAE phenotypes, it is often mistaken for other disorders, including OCD, eating disorders, schizophrenia, severe TS, major depressive disorder, posttraumatic stress disorder, oppositional defiant disorder, and bipolar disease.

    “Owing to the broad spectrum of IAE phenotypes, it is often mistaken for other disorders, including OCD, eating disorders, schizophrenia, severe TS, major depressive disorder, posttraumatic stress disorder, oppositional defiant disorder, and bipolar disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The Cunningham Panel was developed to evaluate autoantibodies to CNS targets and aid in IAE diagnosis.

    “The Cunningham Panel (Moleculera Labs, Oklahoma City, Oklahoma) was developed to evaluate autoantibodies to these targets and aid in IAE diagnosis (Table 1).29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Moleculera labs. Cunningham Panel results. Available at: https://www.moleculeralabs.com/cunningham-panel-results-help-determine-treatment-plan-child-schizophrenic-like-symptoms/. Accessed June 5, 2023.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Although IAE has typically been diagnosed in children and adolescents, it can manifest in adults, as evidenced by a 2022 case study of a PANDAS-like syndrome developing in a 22-year-old man who presented with compulsive actions, anxiety, and a temporal relationship of symptom onset with a streptococcal infection.

    “Although IAE has typically been diagnosed in children and adolescents, it can manifest in adults, as evidenced by a case study in 2022 of a PANDAS-like syndrome developing in a 22-year-old man who presented with compulsive actions, anxiety, and a temporal relationship of symptom onset with a streptococcal infection.12”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Deshmukh, 2022, PANDAS in an adult?: A case report, Indian J Psychiatry source

  • May combine two claims.

    Interpretationcitation

    Given the caudate nucleus is important in voluntary skeletal motor function, and the lentiform nucleus is important in motor control and cognitive function, the neuroinflammation findings support the hypothesis of neuroinflammation leading to symptom patterns manifested by patients with IAE.

    “Given the caudate nucleus is important in voluntary skeletal motor function, and the lentiform nucleus is important in motor control and cognitive function, this study supports the hypothesis of neuroinflammation leading to symptom patterns manifested by patients with IAE.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Kumar, 2015, Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and Tourette syndrome: a positron emission tomographic (PET) study using 11C-[R]-PK11195, J Child Neurol source

  • May combine two claims.

    Interpretationcitation

    Despite poor accuracy in diagnosis, the Cunningham Panel may be useful in prognosis.

    “Despite poor accuracy in diagnosis, the Cunningham Panel may be useful in prognosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Discrepancies in the specificity of these markers among investigators may be secondary to patient selection, criteria for IAE diagnosis used, and methods used to measure the Ab biomarkers.

    “Discrepancies in the specificity of these markers among investigators may be secondary to patient selection, criteria for IAE diagnosis used, and methods used to measure the Ab biomarkers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the Pavone et al trial, a reduction or disappearance of motor symptoms was achieved for most patients (n = 29) after 1 or 2 cycles of IVIG treatment, although symptoms reappeared after the third IVIG cycle in 5 patients.

    “A reduction or disappearance of motor symptoms was achieved for most patients (n = 29) after 1 or 2 cycles of IVIG treatment, although symptoms reappeared after the third IVIG cycle in 5 patients.48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Pavone, 2018, Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS): clinical manifestations, IVIG treatment outcomes, results from a cohort of Italian patients, Neuropsychiatry (London) source

  • May combine two claims.

    Premisecitation

    In that longitudinal study, most children (72%) exhibited at least 1 IAE exacerbation during follow-up, but these events were generally mild and self-limiting after reinstitution of 1 of the initial treatment modalities.

    “Most children (72%) exhibited at least 1 IAE exacerbation during follow-up, but these events were generally mild and self-limiting after reinstitution of 1 of the initial treatment modalities.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Leon, 2018, Longitudinal outcomes of children with pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), Eur Child Adolesc Psychiatry source

  • May combine two claims.

    Premisecitation

    More frequent loose stools despite probiotics and a trend toward increased QTc intervals on electrocardiogram were observed for children receiving azithromycin.

    “However, more frequent loose stools despite probiotics and a trend toward increased QTc intervals on electrocardiogram were observed for children receiving azithromycin.42”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Murphy, 2017, A double-blind randomized placebo-controlled pilot study of azithromycin in youth with acute-onset obsessive-compulsive disorder, J Child Adolesc Psychopharmacol source

  • May combine two claims.

    Premisecitation

    In the Pavone et al open-label trial of 34 children with severe PANDAS, all patients manifested at least 1 psychiatric symptom, and many had tics and choreiform movements.

    “All patients manifested at least 1 psychiatric symptom, and many had tics and choreiform movements.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Pavone, 2018, Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS): clinical manifestations, IVIG treatment outcomes, results from a cohort of Italian patients, Neuropsychiatry (London) source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The improvement observed in the open-label part of the Williams et al 2016 trial suggested the need for trials with larger numbers of subjects that could help identify predictive biomarkers for patients responsive to IVIG.

    “Treatment was well tolerated, and the improvement observed in the open-label part of the trial suggested the need for trials with larger numbers of subjects that could help identify predictive biomarkers for patients responsive to IVIG.46”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Williams, 2016, Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, J Am Acad Child Adolesc Psychiatry source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Idiopathic autoimmune encephalitis is a heterogeneous condition overlapping with other neuropsychiatric conditions.

    “Idiopathic autoimmune encephalitis is a heterogeneous condition overlapping with other neuropsychiatric conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    For those patients with a PCN allergy based on a compelling history and confirmatory test results, additional options from the Infectious Diseases Society of America 2012 guide for GABHS include cephalexin, cefadroxil, clindamycin, azithromycin, or clarithromycin.

    “For those patients with a PCN allergy based on a compelling history and confirmatory test results, additional options from the Infectious Diseases Society of America 2012 guide for GABHS include cephalexin, cefadroxil, clindamycin, azithromycin, or clarithromycin.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Shulman, 2012, Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America, Clin Infect Dis source

  • May combine two claims.

    Premisecitation

    In the open-label part of the Williams et al 2016 trial, 24 participants who originally received IVIG or placebo and met criteria for nonresponse received open-label IVIG at week 6, and their mean CY-BOCS improvement from baseline was 55% ± 33% at week 12 and 62% ± 33% at week 24.

    “In total, 24 participants who originally received IVIG or placebo, meeting the criteria for nonresponse, received open-label IVIG at week 6, and their mean CY-BOCS improvement from baseline was 55% § 33% at week 12 and 62% § 33% (% change § SD) at week 24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Williams, 2016, Randomized, controlled trial of intravenous immunoglobulin for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, J Am Acad Child Adolesc Psychiatry source

  • May combine two claims.

    Study design and conductcitation

    Most research studies regarding IAE are small cohort studies and not double-blind, placebo-controlled clinical trials, limiting their generalizability.

    “Although many research studies have been conducted regarding IAE, most are small cohort studies and not double-blind, placebo-controlled clinical trials, limiting their generalizability.55”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Chiarello, 2017, An expert opinion on PANDAS/PANS: highlights and controversies, Int J Psychiatry Clin Pract source

  • May combine two claims.

    Premisecitation

    Overall, the uncontrolled Pavone et al study found that after IVIG, symptoms were alleviated in patients with IAE, but the response was variable.

    “Overall, this uncontrolled study found that after IVIG, symptoms were alleviated in patients with IAE, but the response was variable.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Pavone, 2018, Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS): clinical manifestations, IVIG treatment outcomes, results from a cohort of Italian patients, Neuropsychiatry (London) source
48 of 48

  • The paper relies on this without support.

    Many clinicians do not recognize PANDAS as a legitimate medical diagnosis and refuse to evaluate or treat these patients.

    “Unfortunately, owing to its poorly defined phenotype and underlying pathogenesis, many clinicians do not recognize PANDAS as a legitimate medical diagnosis and refuse to evaluate or treat these patients.”

  • The paper relies on this without support.

    Current incidence and prevalence data related to IAE are lacking.

    “Current incidence and prevalence data related to IAE are lacking.”

  • The paper relies on this without support.

    IAE can lead to a poor quality of life for patients in addition to a significant emotional and financial burden to their families.

    “Paired with the high frequency of comorbidities, IAE can lead to a poor quality of life for patients in addition to a significant emotional and financial burden to their families.”

  • The paper relies on this without support.

    Many psychiatric medications are often trialed but either are not effective or are associated with significant adverse effects, prompting caregivers to investigate other causes such as IAE.

    “However, many psychiatric medications are often trialed but either are not effective or are associated with significant adverse effects, prompting caregivers to investigate other causes such as IAE.”

  • The paper relies on this without support.

    The Cunningham Panel may not be covered by insurance, so patients often bear costs directly.

    “Because the Cunningham Panel may not be covered by insurance, patients often bear costs directly.”

  • The paper relies on this without support.

    OCD is a hallmark of IAE.

    “Given OCD is a hallmark of IAE, specifically CBT is an important consideration for treatment and has shown high efficacy for OCD intervention.43”

  • The paper relies on this without support.

    The natural history of IAE can be characterized by spontaneous improvement in a waxing and waning course.

    “Studies have been further challenged by the natural history of IAE, which can be characterized by spontaneous improvement in a waxing and waning course.”

  • The paper relies on this without support.

    Many patients with IAE experience cycles of symptoms remitting and relapsing after treatment, making the overall course of illness difficult to predict.

    “With many patients with IAE experiencing cycles of symptoms remitting and relapsing after treatment, it is difficult to predict the overall course of illness.”

  • The paper relies on this without support.

    Immunomodulating therapy for IAE is often a last resort prescribed by many physicians because it is expensive and often not covered by insurance, requiring prior authorization and peer-to-peer reviews.

    “Despite evidence that supports immunomodulating therapy for many patients with IAE, it is often a last resort prescribed by many physicians, given it is expensive and often not covered by insurance, requiring prior authorization and often peer-to-peer reviews, which is time-consuming and not feasible for many medical practices.”

  • The paper relies on this without support.

    IAE is often a diagnosis of exclusion, so treatment may be delayed.

    “Because IAE is often a diagnosis of exclusion, treatment may be delayed.”
10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 4 has conflicting source citations

    Minor

    The treatment discussion links Figure 4 to the IVIG and plasmapheresis study cited as reference 45, while the figure caption cites reference 38.

  • Figure 2 has conflicting source citations

    Minor

    The text attributes the diagnostic algorithm in Figure 2 to reference 33, but the figure caption cites reference 28.

  • Diagnostic criteria are described both as absent and as established

    Minor

    The abstract says there are no consensus diagnostic criteria for IAE, while the clinical manifestations section refers to consensus diagnostic criteria presented earlier in the review.

3 of 3

Cites

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Related

Authors
Hardin, H., Shao, W., & Bernstein, J. A.
Affiliations
  • Ohio University (US)
  • University of Cincinnati (US)
Corresponding author
Bernstein, Jonathan A.
ORCID
Bernstein, Jonathan A.
Venue
Annals of Allergy, Asthma & Immunology
Publisher
Elsevier BV
Published
2023-11
Volume
131
Issue
5
Pages
567-575
ISSN
1081-1206 (ISSN-L)
DOI
10.1016/j.anai.2023.08.022
OpenAlex
W4386171794
Cited by
7
References
54
Citations by year
2026: 1 · 2025: 4 · 2024: 1 · 2023: 1
FWCI
1.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Allergy Asthma & Immunology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
Keywords
PANDAS, PANDMC, pediatric acute-onset neuropsychiatric syndrome, obsessive-compulsive symptoms, tics, diagnostic testing, immunomodulatory therapy, treatment guidelines
MeSH terms
Allergists, Autoimmune Diseases, Child, Humans, Obsessive-Compulsive Disorder, Streptococcal Infections, Streptococcus

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

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