Group A Strep Not Associated with Tic Exacerbation

Multiple measures of group A Streptococcus (GAS) exposure were unrelated to tic exacerbations in children with chronic tic disorders (CTD), including Tourette syndrome, a prospective cohort study found.

“Specific work-up or active management of GAS infections is unlikely to help modify the course of tics in CTD and is therefore not recommended,” wrote Davide Martino, MD, PhD, of the University of Calgary in Canada, and co-authors in Neurology.

In 715 children with CTD who had mean age of 10.7 and who mostly (77%) were boys, researchers assessed tic, obsessive-compulsive symptoms, and attention deficit/hyperactivity disorder (ADHD) severity through weekly symptom diaries, regular clinic visits, and telephone calls over an average follow-up of 16 months. A clinical assessment visit was done when symptom worsening was reported.

Four definitions of GAS exposure based on pharyngeal swab and blood tests were investigated, ranging from restrictive to inclusive. Of 405 exacerbations occurring in 43% of participants, the proportion of exacerbations temporally associated with GAS exposure ranged by exposure definition from 5.5% (most restrictive) to 12.9% (most inclusive).

Although no association was seen between GAS exposure and tic exacerbation for any of the four definitions of exposure (odds ratios ranged from 1.006 to 1.235, with all P values >0.3), the group did find associated longitudinal changes of hyperactivity-impulsivity symptom severity.

“The research question addressed by this study is clinically important, in the light of potential practical implications,” wrote Andrea Cavanna, MD, PhD, of University of Birmingham in England, and Keith Coffman, MD, of Children’s Mercy Hospital in Kansas City, Missouri, in an accompanying editorial. “These findings suggest that GAS is unlikely to be the main trigger for immune activation in patients with chronic tic disorders.”

“It cannot be ruled out that other pathogens might exert a relevant contribution to immunological changes potentially altering the clinical course,” they added. “It is also possible that the interaction of psychosocial stress and GAS infections contributes more to tic exacerbations than psychosocial stress alone, as previously suggested.”

GAS has been studied for a relationship to CTD for over two decades, Martino and colleagues pointed out, stimulated by recognition of pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) syndrome, which is now considered as part of the broader pediatric acute neuropsychiatric syndromes (PANS) syndrome. “Neither population-based nor longitudinal clinical studies could definitively establish if tic exacerbations in CTD are associated with GAS infections,” they noted.

In this study, Martino and co-researchers drew on data from one arm of the multinational EMTICS study which explored relationships between CTD and environmental and genetic factors. The researchers included patients from the COURSE arm of the study, which focused on tic exacerbations. Patients were ages 3-16 and recruited through clinics, clinicians, and patient organizations from 2013 to 2016. Children with a clinical diagnosis of Tourette syndrome or chronic vocal or motor tic disorders were included.

Tic exacerbations were defined as an increase of 6 or more points on the Yale Global Tic Severity Scale, which ranges from 0-50 (higher scores imply greater severity). Blood tests included serum anti-streptolysin O (ASOT) and anti-DNAseB (ADB) antibody titers. Severity of attention-deficit/hyperactivity disorder was assessed with the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

“We used four definitions of GAS exposure, with definition 1 being the most conservative and definition 4 the most lenient,” the authors noted. These included new definite exposure (a positive throat swab alone), new possible exposure (throat swam negative or missing but increase of ASOT and/or ADB titer), ongoing definite GAS exposure (positive throat swab over at least two time points), and ongoing possible GAS exposure (increase of ASOT and/or ADB and one prior positive throat swab with second swab missing or negative).

The majority of participants (91%) had a diagnosis of Tourette syndrome. One exacerbation was reported in 218 patients, with two reported by 84 patients, three by 5 patients, and four by 1 patient.

Analysis was adjusted for concurrent antibiotic exposure as a surrogate for presence of overt GAS infection, and similar results were seen when the definition of tic exacerbation was defined as an 8 or more point increase on tic assessment.

GAS exposure, based on successively more lenient definitions was associated with a 17% to 21% increase in average SNAP-IV hyperactivity-impulsivity subscore.

“The negative findings of this study might lead to alternative explanations for tic exacerbations,” the editorialists observed. “For instance, if co-occurring psychosocial stress and infection-triggered immune activation are followed by an increase in tic severity, their interaction might not need to be related to any specific pathogen.”

“Future research addressing these hypotheses is likely to shed light on the neurobiological vulnerability to the development of tics and associated behaviors,” they added. “Specifically, the nature of the interaction between genetic and environmental factors active on immune and endocrine regulatory systems needs to be fully elucidated. Time will tell whether this study stands as another brick — a cornerstone? — in the wall that separates streptococcus from tics.”

Limitations include the study’s multicenter design with data from different European Union countries and Israel, and possible differences in clinical and microbiological assessments.

1. Multiple measures of group A Streptococcus (GAS) exposure were unrelated to tic exacerbations in children with chronic tic disorders (CTD), including Tourette syndrome, a prospective cohort study found.

2. These results suggest specific work-up or active management of GAS infections is unlikely to help modify the course of tics in CTD and is not recommended, according to the researchers.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Cat ID: 130

Topic ID: 82,130,730,190,130,138,192,925