Association of Streptococcal Throat Infection With Mental Disorders: Testing Key Aspects of the PANDAS Hypothesis in a Nationwide Study.

Importance: Streptococcal infection has been linked with the development of obsessive-compulsive disorder (OCD) and tic disorders, a concept termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). However, previous studies of this association have been small, and the results have been conflicting. Objective: To investigate the risk of mental disorders, specifically OCD and tic disorders, after a streptococcal throat infection. Design, Setting, and Participants: A population-based cohort study was conducted using data from the nationwide Danish registers from January 1, 1996, to December 31, 2013, with up to 17 years of follow-up. The Danish National Health Service Register provided information on individuals with the registration of a streptococcal test. Data analysis was conducted from January 1, 2016, to February 28, 2017. Main Outcomes and Measures: Individuals were followed up in the nationwide Psychiatric Central Register for a diagnosis of any mental disorder, OCD, or tic disorders. Incidence rate ratios (IRRs) were calculated by Poisson regression analysis. Results: Of the 1 067 743 children (<18 years of age) included in the study (519 821 girls and 547 922 boys), 638 265 received a streptococcal test, 349 982 of whom had positive test results at least once. Individuals with a positive streptococcal test result had an increased risk of any mental disorder (n = 15 408; IRR, 1.18; 95% CI, 1.15-1.21; P < .001), particularly of OCD (n = 556; IRR, 1.51; 95% CI, 1.28-1.77; P < .001) and tic disorders (n = 993; IRR, 1.35; 95% CI, 1.21-1.50; P < .001), compared with individuals without a streptococcal test. Furthermore, the risk of any mental disorder and OCD was more elevated after a streptococcal throat infection than after a nonstreptococcal infection. Nonetheless, individuals with a nonstreptococcal throat infection also had an increased risk of any mental disorder (n = 11 315; IRR, 1.08; 95% CI, 1.06-1.11; P < .001), OCD (n = 316; IRR, 1.28; 95% CI, 1.07-1.53; P = .006), and tic disorders (n = 662; IRR, 1.25; 95% CI, 1.12-1.41; P < .001). Conclusions and Relevance: This large-scale study investigating key aspects of the PANDAS hypothesis found that individuals with a streptococcal throat infection had elevated risks of mental disorders, particularly OCD and tic disorders. However, nonstreptococcal throat infection was also associated with increased risks, although less than streptococcal infections for OCD and any mental disorder, which could also support important elements of the diagnostic concept of pediatric acute-onset neuropsychiatric syndrome.

Detección de anticuerpos antiestreptococos, anti-enolasa y antineurales en sujetos con trastornos psiquiátricos de inicio temprano / Detection of anti-streptococcal, anti-enolase, and anti-neural antibodies in subjects with earlyonset psychiatric disorders

Introducción. La infección por Estreptococo del grupo A puede ocasionar secuelas post-infecciosas entre las que se han reportado un espectro de trastornos obsesivos-compulsivos y tics de aparición en la edad pediátrica y origen autoinmune (PANDAS). No ha sido diseñada una prueba inmunológica que permita diagnosticar inequívocamente estos trastornos. En este trabajo se evaluó la detección en suero de anticuerpos contra Enolasa cerebral humana (AE), tejido neural (AN) y Estreptococo (AS) como herramienta de laboratorio para el diagnóstico de trastornos psiquiátricos de inicio temprano. Metodología. Los anticuerpos séricos contra Enolasa cerebral humana, proteínas totales del Estreptococo y proteínas totales cerebrales fueron detectados mediante la metodología de ELISA en 37 individuos con diagnóstico presuntivo de PANDAS y en 12 sujetos sanos de México y Cuba. Resultados. Los títulos de anticuerpos contra AE y AS fueron más elevados en el grupo de pacientes vs controles (t-student, tAE=-2.17, P=0.035; tAS=-2.68, P=0.01, n=12 y 37/grupo, gl=47, nivel de significación de 0.05), mientras que los títulos de anticuerpos AN no difirieron entre ambos grupos (P(t)=0.05). La seropositividad (títulos > mediacontrol + IC95) simultánea a los tres anticuerpos fue mayor (51.4 %) en los individuos del grupo de los pacientes comparado con los controles (8.3%) (X2 =5.27, P=0.022, gl=1, n=49). Conclusiones. La detección simultánea de los tres anticuerpos séricos podría brindar información útil para el diagnóstico etiológico de los individuos con trastorno obsesivo compulsivo de inicio temprano asociados con la infección por Estreptococo y en consecuencia para indicar una terapéutica adecuada

Introduction. Infection with group A Streptococcus (Strep A) can cause post-infectious sequelae, including a spectrum of childhood-onset obsessive-compulsive (OCD) and tic disorders with autoimmune origin (PANDAS, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). Until now, no single immunological test has been designed that unequivocally diagnoses these disorders. In this study, we assessed the detection of serum antibodies against human brain enolase (AE), neural tissue (AN) and Streptococcus (AS) as a laboratory tool for the diagnosis of early-onset psychiatric disorders. Methodology. Serum antibodies against human brain enolase, total brain proteins, and total proteins from StrepA were detected by ELISA in 37 patients with a presumptive diagnosis of PANDAS and in 12 healthy subjects from Mexico and Cuba. Results. The antibody titers against human brain enolase (AE) and Streptococcal proteins (AS) were higher in patients than in control subjects (t-student, tAE=-2.17, P=0.035; tAS=-2.68, P=0.01, n=12 and 37/group, df=47, significance level 0.05), while the neural antibody titers did not differ between the two groups (P(t)=0.05). The number of subjects (titers> mean control + CI95) with simultaneous seropositivity to all three antibodies was higher in the patient group (51.4%) than in the control group (8.3%) group (X2 =5.27, P=0.022, df=1, n=49). Conclusions. The simultaneous detection of all three of these antibodies could provide valuable information for the etiologic diagnosis of individuals with early-onset obsessive compulsive disorders associated with streptococcal infection and, consequently, for prescribing suitable therapy

Detection of anti-streptococcal, antienolase, and anti-neural antibodies in subjects with early-onset psychiatric disorders.

INTRODUCTION: Infection with group A Streptococcus (StrepA) can cause post-infectious sequelae, including a spectrum of childhood-onset obsessive-compulsive (OCD) and tic disorders with autoimmune origin (PANDAS, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections). Until now, no single immunological test has been designed that unequivocally diagnoses these disorders. In this study, we assessed the detection of serum antibodies against human brain enolase (AE), neural tissue (AN) and Streptococcus (AS) as a laboratory tool for the diagnosis of early-onset psychiatric disorders. METHODOLOGY: Serum antibodies against human brain enolase, total brain proteins, and total proteins from StrepA were detected by ELISA in 37 patients with a presumptive diagnosis of PANDAS and in 12 healthy subjects from Mexico and Cuba. RESULTS: The antibody titers against human brain enolase (AE) and Streptococcal proteins (AS) were higher in patients than in control subjects (t-student, tAE=-2.17, P=0.035; tAS=-2.68, P=0.01, n=12 and 37/group, df=47, significance level 0.05), while the neural antibody titers did not differ between the two groups (P(t)=0.05). The number of subjects (titers> meancontrol + CI95) with simultaneous seropositivity to all three antibodies was higher in the patient group (51.4%) than in the control group (8.3%) group (X2=5.27, P=0.022, df=1, n=49). CONCLUSIONS: The simultaneous detection of all three of these antibodies could provide valuable information for the etiologic diagnosis of individuals with early-onset obsessive-compulsive disorders associated with streptococcal infection and, consequently, for prescribing suitable therapy.

Challenges in the identification and treatment of PANDAS: a case series.

Paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), is characterized by childhood-onset obsessive-compulsive disorder (OCD) and Tic disorder that has been found to have a post infectious autoimmune-mediated etiology, where the onset and subsequent exacerbations of symptoms is temporally related to group A beta-hemolytic streptococci (GABHS) infection. In addition to the use of anti-tic and antiobsessional agents, the use of Penicillin during the acute phase and for prophylaxis, tonsillectomy, immunomodulatory therapies such as plasma exchange and intravenous immunoglobulin, etc. have all been reported to improve the symptoms. We describe five cases of neuropsychiatric symptoms triggered by streptococcal infection in an Arab population and highlight the challenges faced by clinicians in the identification and management of PANDAS.

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.

Association between streptococcal infection and obsessive-compulsive disorder, Tourette's syndrome, and tic disorder.

OBJECTIVE: Reports have suggested that streptococcal infection may be etiologically related to pediatric autoimmune neuropsychiatric disorders (PANDAS), but there are few good epidemiologic studies to support this theory. Using population-based data from a large West-Coast health maintenance organization, we assessed whether streptococcal infection was associated with increased risk for obsessive-compulsive disorder (OCD), Tourette's syndrome (TS), or tic disorder. METHODS: This is a case-control study of children 4 to 13 years old receiving their first diagnosis of OCD, TS, or tic disorder between January 1992 and December 1999 at Group Health Cooperative outpatient facilities. Cases were matched to controls by birth date, gender, primary physician, and propensity to seek health care. RESULTS: Patients with OCD, TS, or tic disorder were more likely than controls to have had prior streptococcal infection (OR: 2.22; 95% CI: 1.05, 4.69) in the 3 months before onset date. The risk was higher among children with multiple streptococcal infections within 12 months (OR: 3.10; 95% CI: 1.77, 8.96). Having multiple infections with group A beta-hemolytic streptococcus within a 12-month period was associated with an increased risk for TS (OR: 13.6; 95% CI: 1.93, 51.0). These associations did not change appreciably when limited to cases with a clear date of onset of symptoms or with tighter matching on health care behavior. CONCLUSION: These findings lend epidemiologic evidence that PANDAS may arise as a result of a postinfectious autoimmune phenomenon induced by childhood streptococcal infection.

Characterisation of group A streptococcal (GAS) isolates from children with tic disorders.

BACKGROUND & OBJECTIVES: An association between the onset or recrudescence of some neuropsychiatric disorders in children such as tic disorders and group A streptococcal (GAS) infections has been suggested. No information is available on the characterization of GAS strains associated with such disorders. The present study was undertaken to characterize the GAS strains isolated from children with tic disorders and to determine and correlate the antistreptolysin O (ASO) titre with the presence of GAS. METHODS: During 1996-2001, 368 children with tic disorders were investigated for possible exposition to streptococcal antigens. All children, at the time of the first visit and during the follow up visits were apparently healthy and showed no clinical evidence of streptococcal infections or post streptococcal sequelae. Blood and throat swab samples were collected and serological and bacteriological tests done. The isolates obtained were investigated for T pattern, M protein and emm type, as well as for the production of protease. RESULTS: Of the 800 throat swabs studied 100, corresponding to 67 patients, were positive for GAS; 49 children were found positive for GAS only once during the study, 18 had more than one sample positive for different serotypes, 8 were positive twice or more for the same type. ASO titres of these children were, in general, elevated. Five types, namely type M12, 3, 13, 11, 1, accounted for 39 per cent of the isolates, M12 being the most common, but a large number of different types were also found. A large number of isolates (62%) showed an elevated prodution of protease in the casein plate assay. INTERPRETATION & CONCLUSION: Despite the high level of ASO titres found, the results were not in favour of a particular virulence or invasivity of the isolates. Only a few colonies per sample were found indicating that factors different from the microbial virulence play a role in this type of disease.

Colour Doppler echocardiography in children with group A streptococcal infection related tic disorders.

BACKGROUND & OBJECTIVES: A possible relationship has been suggested between tic disorders and streptococcal infections. To understand the complex relationship between streptococcal infections and neuropsychiatric disorders in children the present study was done on colour Doppler echocardiography of patients with possible post-streptococcal tic disorders. METHODS: The patients were 23 children (22 males, 1 female) affected by tic disorders, who at the time of the observation presented (or had presented in the past) signs of streptococcal infections temporally related to the onset or recrudescence of tic disorders. Echocardiographic examination and laboratory tests were performed on these children. RESULTS: In 4 cases a mild mitral insufficiency and in 8 cases a minimal mitral insufficiency was seen, all haemodynamically not significant. Follow up studies (up to 1 yr) showed the consistency and persistence of these findings. Of the 12 patients with echocardiographic abnormalities, 10 displayed very high anti streptolysin O (ASO) titres, 5 showed positive cultures for GAS and 9 had abnormal ESR, even if no significant differences were found in respect to patients with tics and normal echocardiography. INTERPRETATION & CONCLUSION: With the caution due to the design of study and to low number of patients, our data seem to indicate that the pathophysiology of GAS-infection related tic disorders is similar to that SC, at least in some cases.

Anti-basal ganglia antibodies: a possible diagnostic utility in idiopathic movement disorders?

BACKGROUND: The spectrum of post-streptococcal brain disorders includes chorea, tics, and dystonia. The proposed mediators of disease are anti-basal ganglia (neuronal) antibodies (ABGA). AIM: To evaluate ABGA as a potential diagnostic marker in a cohort of UK post-streptococcal movement disorders. METHODS: Forty UK children presenting with movement disorders associated with streptococcal infection were recruited. ABGA was measured using ELISA and Western immunoblotting. To determine ABGA specificity and sensitivity, children with neurological diseases (n = 100), children with uncomplicated streptococcal infection (n = 40), and children with autoimmune disease (n = 50) were enrolled as controls. RESULTS: The mean ELISA result was increased in the post-streptococcal movement disorder group compared to all controls and derived a sensitivity of 82.4% and specificity of 79%. The Western immunoblotting method to detect ABGA derived a sensitivity and specificity of 92.5% and 94.7% respectively. There was common binding to basal ganglia antigens of 40, 45, and 60 kDa. Immunofluorescence localised the antibody binding to basal ganglia neurones. CONCLUSION: ABGA appears to be a potentially useful diagnostic marker in post-streptococcal neurological disorders. Western immunoblotting appears to be the preferred method due to good sensitivity and specificity and the ability to test several samples at once.

Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections.

BACKGROUND: It has been proposed that infection by group A beta-hemolytic streptococci (GABHS) can trigger acute symptom exacerbations among patients with Tourette's syndrome (TS) or obsessive-compulsive disorder (OCD), via autoimmune mechanisms. OBJECTIVE: To examine the temporal relationship between newly acquired GABHS infections (and other immunologic indices) and acute exacerbations of tics and obsessive-compulsive symptoms. METHODS: Pediatric patients (7-17 years of age) with TS and/or OCD (N = 47) and healthy control subjects (N = 19) were prospectively monitored for newly acquired GABHS infections, nonspecific markers of acute inflammatory responses, and D8/17-reactive cells (a marker of rheumatic fever). Objective monthly ratings of tic and obsessive-compulsive symptom severity were used to determine the timing of symptom exacerbations. RESULTS: The overall rate of acute exacerbations of neuropsychiatric symptoms was 0.56 exacerbations per patient per year. The average rate of new GABHS infections, using a stringent definition, was 0.42 infections per subject per year among patients, compared with 0.28 infections per subject per year for control subjects. The association between symptom exacerbations and new GABHS infections among patients was no greater than that expected on the basis of chance. At baseline, patients demonstrated significantly higher levels of D8/17-reactive cells and neopterin, compared with control subjects, but there was no consistent pattern of change when exacerbation time points were compared with baseline or follow-up time points. CONCLUSIONS: The results suggest no clear relationship between new GABHS infections and symptom exacerbations in an unselected group of patients with TS and/or OCD.

[Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A report of two cases]. / Popaciorkowcowe autoimmunologiczne zaburzenia neuropsychiatryczne u dzieci (PANDAS). Opis 2 przypadków.

AIM: To critically review the past years of research on paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in children and adolescents. METHOD: Literature on PANDAS published from 1995 onward was systematically reviewed. The review focuses on definition and diagnostic consideration aetiological and therapeutical issues. To illustrate the clinical characteristic of PANDAS authors present two cases of children with a severe course of obsessive-compulsive disorder and Tourette's syndrome. RESULTS: Post-streptococcal autoimmunity has been postulated as an aetiologic factor in the development of childhood-onset obsessive-compulsive disorder, tic disorders including Tourette's disorder. This hypothesis arose from a series of clinical observations including the documentation of obsessive-compulsive symptoms of children affected by Sydenham's chorea, a variant of rheumatic fever characterised by neurological dysfunction and also by concomitant investigations of childhood-onset OCD and Tourette's syndrome. CONCLUSION: Results of these studies led to the identification of children whose clinical course is characterised by abrupt and dramatic symptom exacerbations which are temporally related to group A beta-hemolytic streptococcal infections. The identification of such a subgroup will allow for testing of the model of pathogenesis as well as development of novel treatment and prevention strategies. Future research are needed to explore the nature of PANDAS and their relationship with different psychiatric disorders in children and adolescents.