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.

Cefdinir for recent-onset pediatric neuropsychiatric disorders: a pilot randomized trial.

OBJECTIVE: Previous studies suggest that the unexplained sudden and severe onset of obsessive-compulsive disorder (OCD) and/or tics may be infection or immune precipitated. Beta lactam antibiotics may be neuroprotective beyond their antimicrobial efficacy. We examine the preliminary safety and efficacy of cefdinir in reducing obsessive-compulsive and/or tic severity in children with new-onset symptoms. METHOD: Twenty subjects were randomized to receive placebo or cefdinir for 30 days for the treatment of recent-onset OCD and/or tics. The placebo group received a comparable inactive treatment matched for taste, color, and consistency. The Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and Yale Global Tic Severity Scale (YGTSS) were the primary outcome measures utilized. RESULTS: Subjects receiving cefdinir saw notable improvements in tic symptoms, with 44.4% showing at least a 25% reduction in YGTSS (mean decrease=9.5) scores compared with 9.1% of the placebo group (mean decrease=0.13). Despite improvements, significant group differences were not observed for YGTSS (F [1, 13]=4.03, p=0.066) although there were moderate differences between group treatment effects (d=0.72). For OCD symptoms, subjects receiving cefdinir saw improvements in OCD symptoms, with 33.3% showing at least a 25% reduction in CY-BOCS scores (mean decrease=7.8) compared with 27.3% of the placebo group (mean decrease=4.7), but there were also no significant differences for CY-BOCS (F [1, 13]=0.385, p=0.546; d=0.24). CONCLUSIONS: Subjects assigned to cefdinir exhibited notable, albeit nonstatistically significant, improvements in tic symptoms, compared with the placebo group. There were also some improvements in OCD symptoms, although these were not significant. Overall, cefdinir was well tolerated. Given these preliminary results, a fully powered study is warranted to explore the efficacy of cefdinir as a therapeutic tool for new-onset pediatric neuropsychiatric symptoms, particularly those that appear to be precipitated by infection.

Characterization of the pediatric acute-onset neuropsychiatric syndrome phenotype.

OBJECTIVE: Pediatric acute-onset neuropsychiatric syndrome (PANS) is a subtype of obsessive compulsive disorder (OCD) marked by an abrupt onset or exacerbation of neuropsychiatric symptoms. We aim to characterize the phenotypic presentation of youth with PANS. METHODS: Forty-three youth (ages 4-14 years) meeting criteria for PANS were assessed using self-report and clinician-administered measures, medical record reviews, comprehensive clinical evaluation, and laboratory measures. RESULTS: Youth with PANS presented with an early age of OCD onset (mean=7.84 years) and exhibited moderate to severe obsessive compulsive symptoms upon evaluation. All had comorbid anxiety and emotional lability, and scored well below normative means on all quality of life subscales. Youth with elevated streptococcal antibody titers trended toward having higher OCD severity, and presented more frequently with dilated pupils relative to youth without elevated titers. A cluster analysis of core PANS symptoms revealed three distinct symptom clusters that included core characteristic PANS symptoms, streptococcal-related symptoms, and cytokine-driven/physiological symptoms. Youth with PANS who had comorbid tics were more likely to exhibit a decline in school performance, visuomotor impairment, food restriction symptoms, and handwriting deterioration, and they reported lower quality of life relative to youth without tics. CONCLUSIONS: The sudden, acute onset of neuropsychiatric symptoms, high frequency of comorbidities (i.e., anxiety, behavioral regression, depression, and suicidality), and poor quality of life capture the PANS subgroup as suddenly and severely impaired youth. Identifying clinical characteristics of youth with PANS will allow clinicians to diagnose and treat this subtype of OCD with a more strategized and effective approach.

Utility of the diagnostic interview schedule for children for assessing Tourette syndrome in children.

OBJECTIVE: The Diagnostic Interview Schedule for Children IV (DISC) has been used extensively in research and screening. Despite wide use, little information exists on the validity of the DISC for diagnosing tic disorders. METHODS: Participants were 181 youth with expert clinician-diagnosed Tourette syndrome (TS). RESULTS: Using expert clinician-diagnosed TS as the gold standard, the sensitivity of the DISC-Y (youth, 0.27) and DISC-P (parent, 0.44) was poor. The DISC-Y identified 29.7% of youth with diagnosed TS whereas the DISC-P identified 47.4% of cases. Only 54% of cases of TS were detected by either the DISC-Y or -P. Diagnostic agreement between the DISC and expert clinician diagnosis was poor. The DISC-Y/P results did not differ as a function of tic severity. CONCLUSIONS: Despite utility for assessing child psychiatric disorders, the sensitivity of the DISC for detecting TS appears poor. This study suggests that DISC has low agreement with expert clinician diagnosis of TS. Findings highlight the need for modification of the DISC and/or the identification and development of more sensitive measures for TS screening.

Tonsillectomies and adenoidectomies do not prevent the onset of pediatric autoimmune neuropsychiatric disorder associated with group A streptococcus.

BACKGROUND: In children presenting with obsessive compulsive disorder (OCD) and/or tics, especially those with a temporal association with streptococcal pharyngitis (eg, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), there is speculation about whether tonsillectomy/adenoidectomy might improve the child's neuropsychiatric course. Our objective was to examine whether removal of the tonsils and/or adenoids impacted streptococcal antibody titers, the timing of onset of OCD and/or tics and the clinical severity of these symptoms. METHODS: Study participants (N = 112; average age = 9.2 ± 2.4; 44 women) were recruited as part of a prospective investigation of neuropsychiatric phenomena with temporal association to streptococcal pharyngitis and examined by family history, diagnostic interview, physical examination, medical record review, psychological testing and streptococcal antibodies and divided into surgical or nonsurgical groups. The surgical group consisted of children having previously had a tonsillectomy and/or adenoidectomy (n = 32). The remaining children were categorized as nonsurgical group (n = 76). Measures of OCD and tic severity, streptococcal antibody titers and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus classification were compared between both groups. RESULTS: There were no significant differences as determined by streptococcal antibody titers, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus classification and OCD or tic severity between the surgical and nonsurgical groups. Most participants had surgery before the onset of neuropsychiatric symptoms and surgery did not affect symptomology. CONCLUSIONS: Streptococcal antibodies and neuropsychiatric symptom severity did not differ on the basis of surgical status. From these data, we cannot infer that tonsillectomy and adenoidectomy are likely to impact positively the course of OCD/tics or streptococcal antibody concentrations.

Maternal immune activation and autism spectrum disorder: interleukin-6 signaling as a key mechanistic pathway.

An emerging area of research in autism spectrum disorder (ASD) is the role of prenatal exposure to inflammatory mediators during critical developmental periods. Epidemiological data has highlighted this relationship showing significant correlations between prenatal exposure to pathogens, including influenza, and the occurrence of ASD. Although there has not been a definitive molecular mechanism established, researchers have begun to investigate this relationship as animal models of maternal infection have support- ed epidemiological findings. Several groups utilizing these animal models have found that activation of the maternal immune system, termed maternal immune activation (MIA), and more specifically the exposure of the developing fetus to maternal cytokines precipitate the neurological, immunological and behavioral abnormalities observed in the offspring of these animals. These abnormalities have correlated with clinical findings of immune dysregulation, neurological and behavioral abnormalities in some autistic individuals. Additionally, researchers have observed genetic variations in these models in genes which regulate neurological and immunological development, similar to what is observed clinically in ASD. Altogether, the role of MIA and cytokine dysregulation, as a key mediator in the neuropathological, behavioral and possibly genetic irregularities observed clinically in autism are important factors that warrant further investigation.