Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride.

PURPOSE: Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. METHODS: Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. RESULTS: In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97-19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. CONCLUSIONS: This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).

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.

New insights into the role of neuron-specific enolase in tic disorders.

OBJECTIVE: Neuron-specific enolase (NSE) has been suggested for demonstrating brain metabolism in neuropsychiatric disorders. This study assessed serum NSE levels in patients with tic disorders (TD). METHODS: In this retrospective case-control study, we investigated whether NSE levels were increased in TD patients. Then, the influencing factors and correlations between NSE levels and clinical features were analyzed. Finally, we tested its diagnostic value for identifying tic severity. RESULTS: NSE levels were increased in TD patients, although no statistically significant difference was present between transient TD, chronic TD, and Tourette syndrome. Factors influencing NSE levels assessed by multiple linear regression were the Yale Global Tic Severity Scale (YGTSS) global severity scores and gender. There were significant correlations between NSE levels and tic severity. The optimal cut-off value to distinguish mild tics from moderate-severe tics estimated by receiver operating characteristics curve was 24.95 ng/ml (AUC = 0.683). CONCLUSION: Our findings suggested that NSE may be a significant biomarker in TD but should be confirmed in further investigation.

Serum 25-hyroxyvitamin D levels and tic severity in Chinese children with tic disorders.

The aim of this study is to evaluate serum 25-hydroxyvitamin D[25(OH)D] levels in children with tic disorders and to explore the relationship between serum 25(OH)D level and tic severity. Children (n = 179, 31 females, 148 males, mean age at diagnosis: 8.0 ± 2.7 years old, age ranged from 3 to 14.5 years old) who were diagnosed with a tic disorder were enrolled as case group, 189 healthy children were recruited as control group. Serum level of 25(OH)D of each child was measured by high performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). Yale Global Tic Severity Scale (YGTSS) was used to assess tic severity. Mean serum level of 25(OH)D in the case group was significantly lower than that of the control group. The serum 25(OH)D level was significantly associated with tic severity after adjusting for age and body mass index (BMI). This study identified a high prevalence of vitamin D insufficiency or deficiency in children with tic disorders, and there was a negative correlation between the serum 25(OH)D level and tic severity. In the future, large sample size studies are urgently needed to further clarify this correlation.

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.

[Serum levels of 25-hydroxyvitamin D in children with tic disorders].

OBJECTIVE: To examine serum 25-hydroxyvitamin D levels in children with tic disorders (TD) and to explore the relationship between vitamin D level and TD. METHODS: One hundred and thirty-two children who were diagnosed with TD between November 2016 and May 2017 were enrolled as the TD group, including 8 cases of Tourette syndrome, 32 cases of chronic TD, and 92 cases of transient TD. One hundred and forty-four healthy children served as the control group. Peripheral venous blood samples were collected from each child. Serum levels of 25-hydroxyvitamin D were measured using HPLC-MS/MS. The categories of vitamin D status based on serum 25-hydroxyvitamin D level included: normal (>30 ng/mL), insufficiency (10-30 ng/mL) and deficiency (<10 ng/mL). RESULTS: Mean serum level of 25-hydroxyvitamin D in the TD group was significantly lower than that in the control group (P<0.01). The rate of vitamin D insufficiency or deficiency in the TD group was significantly higher than in the control group (P<0.01). Mean serum level of 25-hydroxyvitamin D in the transient tic group was higher than in the TS group (P<0.05). CONCLUSIONS: Vitamin D insufficiency or deficiency might be associated with the development of TD, and the level of serum 25-hydroxyvitamin D might be related to the classification of TD.

Serum Ferritin Levels Are Lower in Children With Tic Disorders Compared with Children Without Tics: A Cross-Sectional Study.

OBJECTIVES: Alteration in peripheral iron indices has been reported in a number of movement disorders, particularly Parkinson's disease. We hypothesized that iron stores may be diminished in children at an early stage of tic disorder. METHODS: Using data retrieved from electronic medical records, we compared serum ferritin levels, an indicator of body iron store balance, in drug-naive children diagnosed for the first time with tic disorder (study group; N = 47, 32 boys/15 girls, aged 8.66 ± 3.17 years) compared to age- and sex-matched children with headaches (comparison group, n = 100, 62 boys/38 girls, aged 9.51 ± 3.15 years) treated in the same pediatric neurological clinic. RESULTS: Mean serum ferritin levels were significantly lower (-32%, p = 0.01) in the tic disorder group compared to the headache group. No significant differences were detected in circulatory hemoglobin, iron, transferrin, and platelet count between the two groups. CONCLUSION: Our findings suggest that body iron stores may be reduced in children with recent-onset tic disorder.

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.

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.

[Epidemiological investigation of tic disorders among pupils in the Shunde Longjiang area, and their relationship to trace elements].

OBJECTIVE: To investigate the epidemiological characteristics of tic disorders (TD) among pupils in the Shunde Longjiang area, and their relationship to trace elements. METHODS: A cross-sectional study of 4062 children aged 6-12 years, who were selected from the Shunde Longjiang area by stratified cluster sampling to investigate the epidemiological characteristics of TD, was conducted, and blood concentrations of trace elements in children with TD were determined. Forty normal children were selected as controls. RESULTS: The overall prevalence rate of TD was 2.98%; the prevalence rates of transient tic disorder, chronic motor or vocal tic disorder and Tourette's syndrome were 3.62%, 2.39% and 1.21% respectively. Boys had a significantly higher prevalence rate of TD than girls (3.92% vs 1.96%; P<0.05). There were no significant differences in blood copper, manganese and magnesium levels between children with TD and normal children (P>0.05), however, children with TD had a significantly increased blood lead level and significantly decreased blood zinc and iron levels compared with the normal children (P<0.05). No significant differences in trace elements were found between children with different subtypes of TD (P>0.05). CONCLUSIONS: TD is common in children aged 6-12 years and more prevalent in boys than in girls. High blood lead level and zinc and iron deficiencies may be one of the causes of TD, and thus should be considered during therapy.

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.

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.

Increased seroreactivity in tic disorder patients to a 60 kDa protein band from a neuronal cell line.

In tic disorders, increased seroreactivity against neuronal antigens has been demonstrated, without performing molecular characterization of antigens. Here, unselected patients with a tic disorder were compared with healthy controls, autistic disorder (AD), and obsessive-compulsive disorder (OCD) patients. Seroreactivity against neuroblastoma cells was analyzed by Western blot. Anti-60 kDa binding occurred significantly more frequently in tic disorder patients (67.1%) than in AD (40.0%), OCD (40.0%) and healthy controls (41.9%). Sequence analysis of the 60 kDa protein band identified this as a ubiquitous heat shock protein. However, the involvement of other autoantigens with a molecular weight of 60 kDa cannot be excluded.

Whole blood serotonin in juvenile obsessive-compulsive disorder.

Whole blood serotonin (5-HT) concentration was assessed in 16 children and adolescents with severe obsessive-compulsive disorder (OCD) and in 14 normal adolescent controls. There was no difference in blood 5-HT content between the OCD patients and the normal controls. However, the OCD patients with a family history of OCD had significantly higher blood 5-HT levels than did either the OCD patients without a family history of OCD or the normal controls. Blood 5-HT content was not associated with a history of major depressive disorder or chronic tic disorder. These preliminary results suggest that studies of serotonergic functioning in OCD may need to control for family history of OCD and that blood 5-HT may be a useful biochemical measure in family-genetic studies of OCD.

[Haloperidol. Plasma monitoring and hormonal effects of treatment]. / Halopéridol. Surveillance plasmatique et incidence hormonale du traitement.

Therapeutic plasma monitoring of haloperidol, a major neuroleptic, measured by radioimmunoassay, has shown a rather good correlation between plasma level and dosage but with large interindividual variation in children as in adults; age seems not to have any effect on haloperidol metabolism. 80% of subjects present a concomitant prolactin levels variation, whereas in 20% no prolactin response is found. During acute kinetics of either a 10 mg oral haloperidol administration or a 250 mg intramuscular haloperidol decanoate injection, a parallel elevation of prolactin, cortisol, immunoreactive bêta-endorphin and bêta-lipotropin plasma levels occur, at the same time as haloperidol plasma levels. Those rise with a good equivalence between the two doses of the two forms.