Anti-dopamine D2 receptor antibodies in chronic tic disorders.

AIM: To investigate the association between circulating anti-dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs). METHOD: One hundred and thirty-seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4-16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti-D2R antibodies were evaluated using a cell-based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti-D2R antibodies was measured with McNemar's test and repeated-measure logistic regression models, adjusting for potential demographic and clinical confounders. RESULTS: At exacerbation, 11 (8%) participants became anti-D2R-positive ('early peri-exacerbation seroconverters'), and nine (6.6%) became anti-D2R-positive at post-exacerbation ('late peri-exacerbation seroconverters'). The anti-D2R antibodies were significantly associated with exacerbations when compared to baseline (McNemar's odds ratio=11, p=0.003) and conditional logistic regression confirmed this association (Z=3.49, p<0.001) after adjustment for demographic and clinical data and use of psychotropic drugs. INTERPRETATION: There is a potential association between immune mechanisms and the severity course of tics in adolescents with CTDs.

Inflammation in Tic Disorders and Obsessive-Compulsive Disorder: Are PANS and PANDAS a Path Forward?

This review and commentary is the product of an invited lecture called "Autoimmunity: PANS/PANDAS" presented at the 2018 Neurobiology of Diseases in Children Symposium in Chicago, IL. The talk addressed clinical and scientific questions and recently published data. At this time, among highly experienced and respected clinicians and researchers spanning relevant disciplines, there is substantial controversy regarding a role for inflammation in producing tics and obsessive-compulsive disorder. This commentary summarizes these controversies, discusses reasons for opposing views on best clinical practices, and concludes with suggestions for pathways forward.

Maternal thyroid autoimmunity associated with acute-onset neuropsychiatric disorders and global regression in offspring.

Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.

AUTOINMUNIDAD MATERNA TIROIDEA ASOCIADA CON TRASTORNOS NEUROPSIQUIÁTRICOS DE INICIO AGUDO Y REGRESIÓN GLOBAL EN LA DESCENDENCIA: Los estudios epidemiológicos, los modelos animales y los estudios de casos y controles indican que la activación inmune materna puede ser un factor importante involucrado en la expresión de la enfermedad del trastorno del espectro autista (TEA), el síndrome de Tourette y el trastorno obsesivo compulsivo (TOC). Informamos ocho niños (edad media 6 años de edad y 6 meses [rango 4-15 años]; 6 varones y 2 mujeres) remitidos durante un período de 2 años con al menos uno de estos trastornos del desarrollo neurológico más un historial materno de autoinmunidad tiroidea. Siete de ocho niños presentaron un inicio brusco de síntomas neuropsiquiátricos (TOC [n = 6], tics [n = 5] y / o psicosis [n = 1]), asociados con una regresión autista o global. Cuatro niños tenían un diagnóstico preexistente de TEA. Seis presentaciones fueron precedidas por infección, y los síntomas siguieron un curso de recaídas y remisiones en siete niños. Todos los niños respondieron al tratamiento inmunomodulador según lo indicado por una reducción en los síntomas psiquiátricos, y siete niños también fueron tratados con tratamiento convencional con una mejora adicional. Proponemos que la autoinmunidad materna puede activar la microglía fetal o alterar la transcripción de la vulnerabilidad del desarrollo neurológico y / o los genes inmunes en el útero, y es un factor ambiental que aumenta la expresión y la gravedad de los problemas del desarrollo neurológico, y la susceptibilidad a deterioros después de estímulos infecciosos o estresantes.

AUTOIMUNIDADE TIREÓIDE MATERNA ASSOCIADA COM DESORDENS NEUROPSIQUIÁTRICAS DE INÍCIO AGUDO E REGRESSÃO GLOBAL NA PROLE: Estudos epidemiológicos, modelos animais, e estudos de caso-controle indicam que a ativação imune materna pode ser um importante fator envolvido na expressão de doenças do transtorno do espectro autista (TEA), síndrome de Tourette, e transtorno obsessivo compulsivo (TOC). Reportamos oito crianças (média de idade 6a 6m [variação 4-15a]; 6 do sexo masculino e 2 do sexo feminino) encaminhadas em um período de 2 anos com pelo menos uma desordem neurodesenvolvimental e história de auto-imunidade tireóide materna. Sete das oito crianças apresentaram início agudo de sintomas neuropsiquiátricos (TOC [n=6], tiques [n=5], e/ou psicose [n=1]), associados com regressão autística ou global. Quatro crianças tinham diagnóstico pré-existente de TEA. Seis apresentações foram precedidas por infecção, e os sintomas seguiram um curso recorrência-remisão em sete crianças. Todas as crianças responderam ao tratamento imunomodulatório, indicado pela redução nos sintomas psiquiátricos, e sete crianças também foram abordadas com tratamento convencional, com melhora adicional. Nós propomos que a autoimunidade maternal pode ativar a microglia fetal ou alterar a transcrição de genes de vulnerabilidade neurodesenvolvimental e/ou imunes, e um fator ambiental pode aumentar a expressão e severidade de problemas neurodesenvolvimentais e suscetibilidade a deterioração após estímulo infeccioso ou estresse.

[Changes in T helper lymphocytes and their subsets in children with tic disorders].

OBJECTIVE: To explore the changes in T helper lymphocytes and their subsets in children with tic disorders (TD) and their clinical significance. METHODS: Flow cytometry was used to measure the percentages of T helper lymphocytes and their subsets in the peripheral blood of children with TD and healthy children (controls). RESULTS: The percentage of T helper lymphocytes was significantly lower in the TD group than in the control group (P<0.001). The abnormal rate of T helper lymphocytes in the TD group was significantly higher than that in the control group (68.7% vs 18.8%; P<0.001). The percentage of T helper lymphocytes was negatively correlated with Yale Global Tic Severity Scale score (r=-0.3945, P<0.001). As for the subsets of T helper lymphocytes, the TD group had a significantly higher percentage of Th1 cells and a significantly lower percentage of Th2 cells compared with the control group (P<0.001). CONCLUSIONS: The abnormality of T helper lymphocytes and the imbalance of their subsets may be associated with the pathogenesis of TD in children. The percentage of T helper lymphocytes can be used as an indicator for assessing the severity of TD.

Seroprevalance Anti-Toxoplasma gondii antibodies in children and adolescents with tourette syndrome/chronic motor or vocal tic disorder: A case-control study.

Toxoplasma gondii infection may be associated with psychiatric disorders due to its neurological effects. The purpose of this study was to investigate the relation between tic disorders in children and adolescents and Anti-Toxoplasma IgG. 43 children diagnosed with Tourette's syndrome(TS) and 87 with chronic motor or vocal tic disorder(CMVTD), and 130 healthy volunteers, all aged 7-18, were enrolled. Anti-Toxoplasma IgG antibody levels obtained from blood specimens were investigated. Toxoplasma IgG positivity was determined in 16(37.2%) of the patients with TS, in 27(31%) of those with CMVTD and in 12(9.2%) members of the control group. Anti-Toxoplasma gondii antibody positivity was 5.827-fold higher in subjects with TS and 4.425-fold higher in subjects with CMVTD compared to the control group. Correlation was determined between a diagnosis of TS or CMVTD and Anti-Toxoplasma gondii antibodies. We think that it will be useful for the neuropsychiatric process associated with Anti-Toxoplasma gondii antibodies to be clarified.

Anti-Basal Ganglia Antibodies and Streptococcal Infection in ADHD.

OBJECTIVE: Group A Streptococcus has been associated with ADHD, tic disorders (TD), and obsessive-compulsive disorder (OCD) through anti-basal ganglia antibodies (ABGA). METHOD: We investigated the association between ABGA and streptococcal exposure with behavioral, motor, and cognitive measures in 38 children with ADHD not comorbid to OCD or TD (nc-ADHD) and in 38 healthy children. An additional group of 15 children with TD and/or OCD was examined. RESULTS: ABGA titers were present in 3% of nc-ADHD patients and controls but in 27% of TD and/or OCD patients. Evidence of streptococcal exposure was similar between ADHD patients and controls living in the same urban area. Behavioral, motor, and cognitive measures were not associated with anti-streptococcal antibodies. CONCLUSION: ABGA do not distinguish nc-ADHD from controls. The differences in the frequency of streptococcal exposure in previous studies are determined by the dynamic nature of the infection rather than the behavioral phenotype of ADHD.

Cytokine correlations in youth with tic disorders.

BACKGROUND: Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder. METHODS: Twenty-one patients, ages 4-17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology. RESULTS: During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=-1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=-0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use. CONCLUSIONS: These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders.

On the connection between autoimmunity, tic disorders and obsessive-compulsive disorders: a meta-analysis on anti-streptolysin O titres.

Anti-streptolysin O (ASO) titration is useful in the context of autoimmune pathologies, including specific cases of tic and obsessive-compulsive disorders occurring after streptococcal infections. There is currently a lack of consensus on the use of ASO titres; therefore we performed a meta-analysis to systematise available data and clarify the role of ASO titres in the context of neuropsychiatric disorders. A meta-analysis was performed on ASO titration in neuropsychiatric patients, including tic disorders and obsessive-compulsive disorders. Included studies reported numbers of positive subjects, depending on a chosen threshold, or detailed ASO titrations. Three hundred and twenty nine studies were identified, of which 13 were eligible for meta-analysis. Due to limited available data, only tic disorders were evaluated. The odds ratio of finding an abnormal ASO titre in patients was 3.22 (95% C.I. 1.51-6.88) as compared to healthy controls and 16.14 (95% C.I. 8.11-32.11) as compared to non-psychiatric patients. Studies using different thresholds were generally concordant. ASO titres were also compared quantitatively, finding an overall difference of the means of 70.50 U/ml (95% C.I. 25.21-115.80) in favour of patients with tic disorders. Based on current evidence, tic disorders are associated with a significant increase in ASO titres, evident both in a threshold-level perspective and on a quantitative level. These results encourage the systematisation of ASO titration in the context of tic disorders.

Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

OBJECTIVE: To explore associated clinical factors in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). STUDY DESIGN: Children with tics, obsessive-compulsive disorder, or both (n=109) were examined with personal and family history, diagnostic interview, physical examination, medical record review, and measurement of baseline levels of streptococcal antibodies. RESULTS: Significant group differences were found on several variables, such that children in whom PANDAS (versus without PANDAS) were more likely to have had dramatic onset, definite remissions, remission of neuropsychiatric symptoms during antibiotic therapy, a history of tonsillectomies/adenoidectomies, evidence of group A streptococcal infection, and clumsiness. CONCLUSION: The identification of clinical features associated with PANDAS should assist in delineating risks for this subtype of obsessive-compulsive disorder/tics.

Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in identical siblings.

Termed pediatric autoimmune neuropsychiatric disorders associated with Streptococcus (PANDAS), these cases of childhood-onset obsessive compulsive disorder and tic disorders resemble the presentation of Sydenham chorea, in that they have an acute onset following a group A beta-hemolytic streptococcal infection (group A Streptococcus), with accompanying neurological signs, and an episodic or sawtooth course. Familial associations of this subgroup of patients remain understudied. This report provides phenotypic descriptions of three youth with PANDAS as well as their genetically identical siblings (in two cases of twins and one case of triplets). These cases highlight the potential for environmental influences for discordant presentations in genetically identical siblings. Despite identical genetics, presentations showed marked variation across siblings (from a full PANDAS presentation to asymptomatic). Further research into environmentally driven influences such as postinfectious molecular mimicry and epigenetic factors that may influence the manifestation of these pediatric neuropsychiatric disorders will promote our understanding of their prevention and treatment.

Cytokines and soluble adhesion molecules in children and adolescents with a tic disorder.

AIM: Dysregulation of the immune system may play a role in tic disorders. We screened for immune disturbances by investigating serum levels of cytokines and soluble adhesion molecules in patients with a tic disorder. METHODS: Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, soluble IL-2 receptor (sIL2R), tumor necrosis factor (TNF)-α, interferon (IFN)-γ, soluble vascular cell adhesion molecule-1 (sVCAM-1), and intercellular adhesion molecule-1 (sICAM-1) of 66 children and adolescents with a tic disorder and 71 healthy volunteers were compared. We also addressed possible relations between concentrations of the immune markers and severity of tics and comorbid obsessive-compulsive symptoms. RESULTS: Median serum concentrations did not differ significantly between patients and healthy subjects. Serum IL-2 concentrations were positively associated with tic severity ratings; serum IL-12 concentrations negatively with severity ratings of obsessive-compulsive symptoms. CONCLUSIONS: These preliminary findings do not reveal major immune activation in children with a tic disorder but may suggest more subtle disturbances related to disease expression.

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.

Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A beta-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and alpha-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood-brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.

Antineuronal antibodies in OCD: comparisons in children with OCD-only, OCD+chronic tics and OCD+PANDAS.

Autoimmunity associated with a streptococcal infection has been proposed as a pathogenic mechanism for obsessive-compulsive disorder (OCD) in children. Antibrain antibody profiles were compared in children with OCD-only (n = 13; 14.1 +/- 3.1 years), OCD+PANDAS (n = 20; 11.3 +/- 1.5 years), OCD+Chronic Tic Disorder (n = 23; 13.4 +/- 3.5 years), and controls (n = 29; 12.4 +/- 2.4 years) using ELISA (orbitofrontal (OFC) and dorsolateral prefrontal cortex (DLPFC), caudate (CD), cingulate gyrus (CG)), immunoblotting (four regions plus putative antigens), and immunohistochemistry. ELISA and immunohistochemistry showed no differences among groups. Immunoblot showed that a greater percentage of individuals in the OCD+PANDAS cohort had reactive bands at 27 kDa (CD, CG, DLPFC), 36 kDa (CD), and 100 kDa (CD, OFC) and increased peak height at 67 kDa (all regions). Immunoblotting studies using the putative antigens (pyruvate kinase M1, aldolase C, alpha- and gamma-enolase) did not differ among groups. ASO titers were similar in all groups and did not correlate with immunoassays. It remains controversial whether childhood OCD is associated with autoimmune mechanisms.

Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update.

PURPOSE OF REVIEW: To review recent developments related to the proposed entity Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococci (so-called 'PANDAS'). RECENT FINDINGS: The relationship between obsessive-compulsive disorder (OCD) or tics/Tourette's syndrome in childhood to antecedent group A streptococci (GAS) is unclear. One recent prospective cohort study found that more than 85% of clinical exacerbations in OCD/tic behavior in patients who met criteria for PANDAS had no relationship to GAS infection. Another study found no correlation between clinical exacerbations and changes in a variety of markers of brain autoimmunity, the proposed pathogenesis of PANDAS. A third recent study concluded that, compared with specialty clinic diagnoses, patients diagnosed with tics or Tourette's by physicians in the community were significantly more likely to be diagnosed with PANDAS without meeting the proposed criteria, most lacked supporting laboratory evidence of GAS infection, and they were more likely to be treated with unjustified short-term to chronic antibiotic and/or immunomodulatory therapy. SUMMARY: Despite continued research in the field, the relationship between GAS and specific neuropsychiatric disorders (PANDAS) remains elusive. It is possible that GAS infection may be but one of the many stressors that can exacerbate tic/Tourette's or OCD in a subset of such patients.

Plasma kynurenine and related measures in tic disorder patients.

OBJECTIVE: Increased plasma kynurenine has been reported in tic disorder patients, and this observation has been suggested to be indicative of immune dysregulation. In the present study, we examined plasma levels of kynurenine and related molecules in a group of tic disorder patients. METHODS: Plasma concentrations of tryptophan, kynurenine, cortisol, and neopterin were determined in Dutch tic disorder patients (N = 59), and healthy volunteers (N = 32). Group means were compared and age-controlled intra-individual correlations between tic severity and plasma levels of these molecules were examined. RESULTS: No significant differences were found between patient and control groups in plasma levels of tryptophan, kynurenine, and cortisol concentrations, nor in the kynurenine/tryptophan ratio. However, neopterin was significantly (p = 0.035) higher in patients (mean = 5.13 nmol/l) than in controls (mean = 3.30 nmol/l). Plasma levels of these molecules did not correlate with tic severity, with the exception of tryptophan (r = -0.289, p = 0.049). In patients, plasma neopterin correlated with kynurenine (r = 0.438, p = 0.002); in healthy subjects, tryptophan correlated with kynurenine (r = 0.670, p < 0.001). CONCLUSION: While the observed elevation in plasma neopterin is consistent with immune activation in a subset of tic disorder patients, metabolism of tryptophan through the kynurenine pathway appears to be unaltered in tic disorder patients.

Decreased numbers of regulatory T cells suggest impaired immune tolerance in children with tourette syndrome: a preliminary study.

BACKGROUND: Post-streptococcal autoimmune inflammation of basal ganglia was suggested to be an etiological factor in some cases of Tourette syndrome (TS). Since regulatory T (T reg) cells play a major role in preventing autoimmunity, we hypothesized that a defect in T reg cells may be present in children with TS. We also postulated that group A beta hemolytic streptococcal infections could promote autoimmune responses by releasing exotoxins (streptococcal pyrogenic exotoxins [SPE]). METHODS: We analyzed peripheral blood of TS patients and healthy age-matched control subjects by fluorescence-activated cell sorting (FACS) on multiple occasions and determined the numbers of CD4(+)CD25(+)CD69(-) T reg cells. Further, we quantified the number of CD4(+) and CD8(+) lymphocytes with regard to Vbeta chains to which SPEs are known to bind. RESULTS: A significant decrease in T reg cells was observed in patients with moderate to severe TS symptoms compared with healthy age-matched control children. A decrease in T reg cell number was also noted during symptom exacerbations in five out of six patients. Further, we found a significant decrease in numbers of CD8(+)Vbeta18(+) T cells in moderate to severe TS patients. CONCLUSIONS: These data support our hypothesis that at least some TS patients may have a decreased capacity to inhibit autoreactive lymphocytes through a deficit in T reg cells. Interactions of host T cell immunity and microbial factors may also contribute to the pathogenesis of TS.

Tic disorders: neural circuits, neurochemistry, and neuroimmunology.

The neuroanatomy and neurochemistry underlying tic disorders are thought to involve corticostriatothalamocortical circuits and dysregulation of their component neurotransmitter systems. Tourette syndrome is a tic disorder that begins in childhood and follows a waxing and waning course of tic severity. Although it is generally believed to have a genetic component, its etiology has not been fully elucidated. The clinical entity pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) has led some to suggest that the pathophysiology of tics in some individuals might involve a postinfectious autoimmune component. We review the neural circuits and neurochemistry of Tourette syndrome and evaluate the evidence for and against a role for autoimmunity in the expression of tics.

Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants.

Streptococcal infection in children is usually benign and self-limited. In a small percentage of children, prominent neurologic and/or psychiatric sequelae can occur. Sydenham chorea is the best defined and best recognized. PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive-compulsive disorder consistently exacerbate in temporal correlation to a group A beta-hemolytic streptococcal infection. PANDAS constitutes a subset of children with tics, Tourette syndrome, and obsessive-compulsive disorder. In addition to strictly defined PANDAS, we and others have recognized several PANDAS variants, including adult-onset variant, a dystonic variant, a myoclonic variant, and a "chronic" PANDAS variant. The nosology and classification of these entities are rapidly evolving. The recognition that some pediatric neurobehavioral syndromes have infectious and/or immunologic triggers points to important new avenues of disease treatment. In this review, we summarize this complex and rapidly evolving area of clinical research.