CME Author: Zeena Nackerdien
Study Authors: Gustaf Brander, Kayoko Isimura et al.
Target Audience and Goal Statement: Neurologists, Psychiatrists/Psychologists, and Primary Care Physicians
The goal was to learn more about a Swedish, longitudinal population-based cohort study which incorporated a full sibling comparison design to investigate the risk of metabolic and cardiovascular disorders among persons with Tourette syndrome (TS) or chronic tic disorder (CTD).
Study investigators posed the following questions:
- Could the risk of cardiometabolic disorders be identified in almost 8,000 persons with TS or CTD?
- What was the contribution of attention deficit-hyperactivity disorder (ADHD) to the risk of cardiometabolic issues in TS or CTD cases?
- Was pharmacologic treatment with antipsychotics associated with the risk of cardiometabolic disorders in patients with TS or CTD?
Synopsis and Perspective:
Persons whose primary symptoms include motor and vocal tics are diagnosed with TS, a neuropsychiatric disorder that may be inherited.
Tics that begin before the age of 18, persist for more than one year, and that are not attributable to other medical or drug-related causes are referred to as CTD. Individuals can have one or more motor or vocal tics, but not both.
To date, there are no reliable estimates for TS and other tic disorders in the U.S. But over 500,000 American children may be affected by a tic disorder that could, in some cases, persist into adolescence and adulthood. Overall, TS and CTD affect about 1% of the population and are more common in males.
Since only 10%-15% of patients with TS or CTDs present exclusively with primary disease symptoms, surveillance and active management of these individuals extend beyond treatment of tics. Among TS patients with comorbidities, the most common psychiatric conditions included ADHD and obsessive compulsive disorders (OCD). Of all the comorbid conditions, metabolic syndrome and cardiovascular issues have received the most attention.
Results from literature evaluations of cardiometabolic conditions in TS and CTD (mainly conducted to assess potential adverse outcomes of pharmacologic treatment) were not readily generalizable due to methodological limitations (e.g., a lack of control groups of unexposed persons). There was an unmet need to conduct a longitudinal study, incorporating a matched control group, to investigate the association between TS and CTD and cardiometabolic disorders and to assess whether antipsychotic usage was associated with a risk of these conditions in diagnosed patients.
Analyses in the current investigation were based on data from several Swedish nationwide administrative registers (1973-2013) representing patients who were followed for a mean duration of 22.2 (SD 13.7) years. Most of the 7,804 eligible individuals were males (76.4%) who were diagnosed with TS or CTD in specialist care (median age at first diagnosis = 13.3 years). Lorena Fernandez de la Cruz, PhD, of Karolinska Institutet in Stockholm, and colleagues further identified 2,675,482 families with at least two singleton full siblings and of these families, 5,141 included siblings who were discordant for TS or CTD.
Registered diagnoses of obesity, dyslipidemia, hypertension, type 2 diabetes, and cardiovascular diseases (including ischemic heart diseases, arrhythmia, cerebrovascular disease and transient ischemic attack, and arteriosclerosis) served as the main outcomes and measures, according to the researchers.
Compared with the general population, persons with TS or CTD had a higher risk of any metabolic or cardiovascular disorder (hazard ratio adjusted by sex and birth year [aHR] 1.99; 95% CI 1.90-2.09). The aHR for any disorder was also higher in sibling controls (1.37; 95% CI 1.24-1.51). Risks for patients with TS or CTD were specifically increased in:
- Obesity (aHR 2.76; 95% CI 2.47-3.09)
- Type 2 diabetes (aHR 1.67; 95% CI 1.42-1.96)
- Circulatory system diseases (aHR 1.76; 95% CI 1.67-1.86)
Risks were already present during childhood (significant difference by age 8) and were significantly reduced with the exclusion of individuals with ADHD (aHR 1.52; 95% CI 1.42-1.62). Additionally, patients with TS or CD who took antipsychotics for more than a year had significantly lower risks of metabolic and cardiovascular disorders.
But drawing conclusions from this data may be problematic, said Donald Gilbert, MD, director of the Tourette Syndrome Clinic at Cincinnati Children’s Hospital Medical Center.
“There is ample reason for skepticism in using this paper to inform either clinical practice or public policy,” Gilbert, who was not part of the study, told MedPage Today.
Because the researchers included only patients who were hospitalized or treated in outpatient specialty clinics, “complex patients with multiple diagnoses — for example, both tic disorders and obesity — are likely over-represented compared to the general population, and patients with obesity or heart disease alone may be under-represented,” he said. “This could make associations between two conditions — like Tourette and heart disease — appear more common than they are in the general population.”
And recognition of TS was increasing during the study period while the overall incidence of obesity also was increasing. “Tic disorders may have been more likely to be diagnosed in children and adults receiving extra healthcare visits for obesity or cardiovascular disease,” Gilbert added.
Specialty clinic doctors also may have more rapidly discontinued antipsychotics in children who gained weight, Gilbert said.
Some of Gilbert’s opinions, to the effect that the observational findings were not readily generalizable, were echoed by Fernandez de la Cruz and colleagues. Besides the observational nature, the study has other limitations, the authors noted. It was not representative of all patients with TS or CTD. It also does not include information about behavioral variables that might affect cardiometabolic health — sedentary lifestyle, unhealthy eating habits, or smoking, for example — or non-drug strategies to manage them, they added. In addition, they pointed out that people with mild tics usually did not seek out help and that patients diagnosed in primary care were not included in the registries.
They were equally cautious in interpreting their exploratory findings which showed that long-term (>1 year) antipsychotic use was linked to a lower risk of metabolic and cardiovascular disease versus those who were not taking antipsychotics. Fernandez de la Cruz’s group wrote: “Because this is an observational study, we are careful not to ascribe the reduction of the risk to the medication itself.” Caveats included the likelihood that results were indirect evidence of greater medical vigilance and the need to continue to exercise caution when administering antipsychotics to this patient group.
Source Reference: JAMA Neurology, Jan. 14, 2019; DOI: 10.1001/jamaneurol.2018.4279
Study Highlights: Explanation of Findings
“Until recently, we knew very little about the physical health of individuals with Tourette syndrome and chronic tic disorders, particularly in the long run,” Fernandez de la Cruz told MedPage Today. “The Swedish registers, which have full coverage of the population’s medical health records for over 40 years, offered a unique opportunity to examine the long-term health status of these patients.” Persons with a TS or CTD diagnosis were nearly twice as likely to develop at least one cardiometabolic disorder (52.5%) versus persons from the general population without TS or CTD (29.5%) by the end of follow-up.
Risks for obesity, circulatory system disease, and type 2 diabetes were significantly higher in the TS/CTD cohort. Risks for cardiometabolic disorder were significantly higher in males than in females. The probability for any disease was already significantly elevated from childhood. Nearly half of the persons with TS or CTD also had ADHD. Nevertheless, after excluding individuals with ADHD from the cohort, the remaining individuals with TS or CTD still had a 52% higher risk of developing cardiometabolic issues. This finding suggests that ADHD adds to the observed study risk.
Risks were reduced but not eliminated during the sibling comparison analysis (from 1.99 to 1.37 for any cardiometabolic disorder). The presence of a 37% higher risk for patients with TS or CTD, even after controlling for familial factors, suggests that at least part of the observed health complications might be attributable to the tic disorders themselves, according to Fernandez de la Cruz and colleagues.
Taken together, the researchers concluded that “TS and CTD were linked to a substantial risk of cardiometabolic problems, even after taking into account a number of covariates and shared familial confounders and excluding relevant psychiatric comorbidities.”
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco