Insomnia in Tourette Syndrome and Chronic Tic Disorder

Insomnia is common in Tourette syndrome (TS) and chronic tic disorder (CTD), but precise prevalence estimates are lacking.


Sleep difficulties are common in individuals with
Tourette syndrome (TS) or chronic tic disorder (CTD), 1 with studies reporting an extremely wide prevalence range (from 7% to 80%) of a broad variety of sleeprelated problems. 2,3 Overall, the most common sleep difficulties in this population are insomnia, excessive daytime sleepiness, disorders of arousal (eg, sleep walking, sleep talking, sleep terrors, and enuresis), persistence of tics during sleep, and presence of periodic limb movements during sleep. 3 Nonetheless, previously published studies have generally been small and control groups have often not been available for comparison. Additionally, the majority of studies reporting on subjective sleep-related symptoms have used self-reported or parent-reported questionnaires rather than clinician-reported diagnoses. Moreover, many of these questionnaires merge together a wide range of sleep problems. 2,3 Given that different sleep disorders may have different treatment indications, studying these disorders separately is clinically relevant.
Studies focusing specifically on TS/CTD and insomnia -as a clinical or self-reported diagnosis-have been generally small and generated imprecise prevalence estimates, ranging widely from 0.3% to 77%. 3 The handful of studies that included a control group also reported a higher prevalence of insomnia in those with TS/CTD than in controls. [4][5][6] The only exception to this is a Taiwanese population-based study including 1124 children and adolescents newly diagnosed with TS and 3372 matched unexposed controls from the general population, which found no significant differences in the prevalence of insomnia between the groups. 7 However, the analysis was severely underpowered and based on three cases of insomnia in the TS group (0.3%) and seven cases of insomnia in the control group (0.2%).
Hence, more precise estimates of the prevalence of insomnia in individuals with TS/CTD are needed. Additionally, whether insomnia is more prevalent in individuals with TS/CTD than in the general population and whether individuals whose tics persist or require clinical attention in adulthood have higher prevalence of insomnia requires further study.
Similarly, the knowledge about the role that psychiatric comorbidities play in the potential association between TS/CTD and insomnia is rather limited. A previous study reported a higher prevalence of primary insomnia in young individuals (age ≤21 years) with TS and comorbid attention-deficit/hyperactivity disorder (ADHD) (n = 48, 42%) than in those with TS only (n = 31, 32%). Moreover, 33% of individuals in the TS +ADHD group presented with insomnia that the authors considered to be secondary to ADHD medication. 8 ADHD has previously been associated to insomnia in its own right, 9 and specifically linked to the side effects of stimulant drugs, which are the first line treatment for ADHD. 10 Similarly, other psychiatric comorbidities, such as depression, anxiety or obsessive-compulsive disorder are known to be associated with both TS/CTD and insomnia. [11][12][13][14][15][16] Therefore, the specific contribution of psychiatric comorbidities to the association between TS/CTD and insomnia should be systematically evaluated.
This study aimed to provide more precise estimates of the prevalence of clinically diagnosed insomnia in a large population cohort of individuals with TS/CTD (n = 5877) and to estimate the magnitude of the association between TS/CTD and insomnia in the population. Additional discordant sibling models were used to control for a host of unmeasured familial confounders. We also explored whether TS/CTD chronicity was associated with a higher likelihood of insomnia. The role of psychiatric comorbidities was systematically assessed, with particular emphasis on ADHD and ADHD medication.

Methods
The study received ethical approval from the Stockholm Regional Ethical Review Board (register number 2013/862-31/5). Because of the register-based nature of the study and the fact that participants are not identifiable at any time, informed consent was waived.

Data Sources
In this total population cohort study, a number of nationwide administrative and health registers were linked by means of the personal identification number assigned to all Swedish residents. 17 Included registers were: (1) the Total Population Register, which contains information on all Swedish inhabitants since 1968 and provides demographic data for the cohort members 18 ; (2) the Migration Register, which contains records on every immigration into and emigration out of Sweden 18 ; (3) the Cause of Death Register, which covers records of all deaths in Sweden since 1952, including date and causes of death, based on International Statistical Classification of Diseases (ICD) codes 19 ; (4) the Multi-Generation Register, which connects every person born in Sweden since 1932 or ever registered as living in the country after 1960 to their parents 20 ; (5) the National Patient Register (NPR), which contains information on inpatient care (since 1969 for somatic disorders and since 1973 for psychiatric disorders) and outpatient specialist services (since 2001), with diagnoses based on ICD codes (ICD-8: 1969-1986, ICD-9: 1987-1996, and ICD-10: 1997 and onward) 21 ; and (6) the Prescribed Drug Register, which records all prescribed medications dispensed across pharmacies in Sweden since July 2005, using Anatomical Therapeutic Chemical (ATC) Classification System codes. 22

Study Cohort
We identified all individuals aged 3 or older living in Sweden anytime during the period ranging from January 1, 1997 (implementation of the ICD-10 codes in Sweden) to December 31, 2013 (end of the study period). Those that emigrated from the country during the study period and did not return were excluded from the cohort. Those with a diagnosis of organic brain disorder (ICD-8: 290, 292, 293, and 294, except 294.3; ICD-9: 290, 293, 294; ICD-10: F00-09) and/or epilepsy (ICD-8: 345; ICD-9: 345; ICD-10: G40, G41) registered in the NPR during the study period were also excluded. Individuals in the cohort were divided into TS/CTD-exposed and non-exposed. Further, the full siblings (ie, those sharing the same mother and father) of TS/CTD-exposed individuals were identified from the Multi-Generation Register to control for shared familial confounders.

Exposure
We defined the exposure as having a diagnosis of TS or CTD recorded at any time from January 1, 1973 (beginning of the registration of psychiatric disorders in the NPR) until the end of the study period, if diagnosed at the age of 3 years or older, as per prior research on these disorders. [23][24][25] TS/CTD cases were selected on the basis of an algorithm 26 that includes all cases with at least one diagnosis of tic disorder in ICD-8 (306.2) or ICD-9 (307C), and all cases in ICD-10 with at least one diagnosis of CTD (F95.1) or TS (F95.2), unless a diagnosis of transient tic disorder (F95.0) was recorded within the same year as the initial diagnosis. The diagnoses of "other tic disorders" (F95.8) and "tic disorders, unspecified" (F95.9) were included if at least one additional tic disorder diagnosis (F95.1, F95.2, F958 or F95.9) was also present, unless a final diagnosis of transient tic disorder within the same year had been recorded. This algorithm has been widely used in previous population-based studies using the Swedish registers [23][24][25] December 31, 2013 were also identified as having the outcome. This combined method to ascertain insomnia outcomes (ie, ICD codes plus medication with specific insomnia indication) results in better coverage of the outcome because insomnia is often managed in primary care by general practitioners and, therefore, not always captured in the NPR, which only includes specialist physician diagnoses.

Covariates and Additional Variables
Covariates included sex, birth year, birth country (Sweden or other), and somatic disorders diagnosed during the study period with a known association with insomnia and known for their immune dysregulation and inflammatory mechanisms, [27][28][29][30] which in turn are suggested to underlie the neurobiology of TS. 31,32 These included asthma, arthropathies, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), and other inflammatory liver diseases (see Supplementary Table S1 for ICD codes).
Persistence of the TS/CTD diagnosis was defined as those individuals who had at least two recorded diagnoses of TS/CTD after the age of 18 years (as a proxy for tic severity and chronicity of the tic disorder into adulthood); otherwise, TS/CTD were considered as non-persistent.

Data Analysis
The main analysis consisted of a logistic regression model used to compare TS/CTD-exposed individuals with their unexposed counterparts from the general population on the composite insomnia outcome. Results were expressed as odds ratios (OR) with 95% confidence intervals (CI). The initial model was adjusted for sex, birth year, and birth country (model 1). In a subsequent step, we additionally adjusted for the above-listed somatic disorders (model 2). These analyses were stratified by sex.
From the full cohort, a sub-cohort of all clusters of full siblings where at least one sibling had a diagnosis of TS/CTD was identified. Fixed-effects logistic regression models were implemented comparing individuals with TS/CTD to their unaffected siblings within families, where each family was considered a stratum. The models followed the same adjustment strategy as the main analysis. Sibling comparisons control for unmeasured familial environmental confounders shared by siblings (eg, parental socioeconomic status, parental education, parental history of somatic and psychiatric disorders, and rearing style) and partially for genetic factors, because full siblings share 50% of their genes. 33 To examine whether tic disorder persistence had an effect on the association with insomnia, the main analysis was repeated in the sub-cohort of those aged 18 or older where individuals with persistent tics and nonpersistent tics were compared with those without a TS/CTD diagnosis.
To explore the role of psychiatric comorbidities on the association between TS/CTD and insomnia, a number of analyses were performed. First, the fully adjusted analysis was repeated excluding different groups of comorbidities from the whole cohort (exposed and unexposed), one disorder group at a time. Second, to specifically investigate the role of ADHD comorbidity, we subdivided the individuals exposed to TS/CTD by their ADHD comorbidity status into two groups ("TS/CTD with ADHD" and "TS/ CTD without ADHD") and compared each of them to the general unexposed population by fitting logistic regression models fully-adjusted as in the main analysis. Additionally, we focused on the role of ADHD medication by using the sub-cohort of individuals living in Sweden during the period from July 2005 (start of the Prescribed Drug Register) to December 2013 (end of the study period) and who did not receive a record of insomnia before July 2005. In this subcohort, we ran the same fully adjusted models for individuals exposed to TS/CTD with ADHD who were on ADHD medication and individuals exposed to TS/CTD with ADHD who were not on ADHD medication, compared to TS/CTD-unexposed individuals from the general population.
Data management was performed using SAS, version 9.4 (SAS Institute, Cary, NC) and analyses were performed using Stata version 16.0 (StataCorp LLC, College Station, TX). All tests used 2-tailed significance set at P < 0.05 and robust standard errors.

Prevalence of Insomnia and Association between TS/CTD and Insomnia
The study cohort included 10,444,702 individuals, of which 5877 were TS/CTD-exposed. A total of 1890 individuals in the exposed cohort had at least one insomnia diagnosis or had been dispensed a medication to treat insomnia at least once during the study period, corresponding to a period prevalence of 32.16%, compared to 1,429,774 individuals with insomnia in the general population cohort, corresponding to a period prevalence of 13.70%. See Table 1 for further characteristics of the study cohort.
After adjusting for all relevant covariates, this corresponded to 6.7-times higher odds of insomnia in individuals with TS/CTD than in individuals from the general population (fully-adjusted OR [aOR] = 6.74 [95% CI, 6.37-7.15]) ( Table 2). In the analyses stratified by sex, the corresponding ORs for men were higher than the ORs for women ( Table 2). The sibling cohort consisted of all families (n = 2,656,561) with at least two singleton children, of which 3919 included clusters of full siblings discordant for TS/CTD. When comparing individuals with TS/ CTD (n = 3959) to their unaffected full siblings (n = 5859), the association between TS/CTD and insomnia remained statistically significant (aOR = 5.41 [95% CI, 4.65-6.30]), but the magnitude of the association was significantly reduced compared to the main analysis (non-overlapping CIs), suggesting that familial factors shared by siblings may explain a small part of the association between TS/CTD and insomnia ( Table 2).

Tic Persistence
In a sub-cohort of 8,847,343 individuals aged 18 and older, a total of 1650 individuals were classed as having persistent TS/CTD and 2264 as having non-persistent TS/CTD. In these groups, 757 (45.88%) and 599 (26.46%), respectively, met our insomnia definition. Individuals with persistent TS/CTD had an aOR of 7.95 (95% CI, 7.19-8.80), which was significantly higher than the corresponding estimates for nonpersistent TS/CTD (aOR = 3.63 [95% CI, 3.29-4.00]). Table 1 shows the distribution of psychiatric comorbidities in the study cohort. When we repeated the main analysis systematically excluding these groups of comorbidities one at a time (Table 3), we observed a slight attenuation in the ORs, compared to the main analysis. The only exceptions to this were the pervasive developmental disorders and learning disabilities group and ADHD. When excluding these groups of comorbidities from the whole cohort, the association between TS/CTD and insomnia remained statistically significant, but the magnitude of the association significantly decreased from an aOR = 6.74 (95% CI, 6.37-7.15) in the main analysis to 5.37 (95% CI, 5.00-5.76), and 3.60 (95% CI, 3.27-3.96), respectively (Table 3).

Role of Psychiatric Comorbidities and ADHD/ ADHD Medication
To focus specifically on the comorbidity with ADHD, we calculated the odds of insomnia in the "TS/CTD with comorbid ADHD" group (n = 3130, of which 1302 [41.60%] had insomnia), compared to the odds The study participants, both exposed and unexposed, may have more than one psychiatric comorbid disorder. Abbreviations: TS/CTD, Tourette syndrome/chronic tic disorder. in the general population unexposed to TS/CTD. This translated into an aOR of 11.49 (95% CI, 10.68-12.37). The corresponding calculations for the "TS/ CTD without ADHD" group (n = 2747, of which 588 [21.41%] had insomnia), compared to the general population unexposed to TS/CTD, resulted in an aOR of 3.30 (95% CI, 3.00-3.62) (Fig. 1, panel A). Next, we explored the contribution of ADHD medication to the observed associations in the sub-cohort restricted to individuals living in Sweden between July 2005 and the end of 2013 and who did not have an insomnia outcome before July 2005. Specifically, we estimated the likelihood of having insomnia among individuals with TS/CTD and ADHD who were on ADHD medication (n = 2568, of which 1170 [45.56%] had insomnia) and among those with TS/CTD and ADHD who were not on ADHD medication (n = 545, of which 119 [21.83%] had insomnia), compared to the general population unexposed to TS/CTD (n = 9,721,898, of which 1,421,752 [14.62%] had insomnia). Results showed a significant increase of the likelihood of having insomnia in both subgroups; however, the association was considerably stronger in individuals who were medicated for their ADHD (aOR = 17.33 [95% CI, 15.98-18.80]) than in individuals who were not on ADHD medication (aOR = 5.22 [95% CI, 4.26-6.40]) (Fig. 1, panel B).

Discussion
This population cohort study including 5877 individuals with TS/CTD is the largest to date to explore the association between tic disorders and insomnia. Results showed that 32.16% of individuals with TS/CTD had a record of insomnia during the study period. The corresponding period prevalence of insomnia among the individuals unexposed to TS/CTD was 13.70%, which is in line with the prevalence reported for the general population both in Sweden 27 and elsewhere. 34 The latter confirms that our combined outcome definition, including ICD diagnoses and dispensation of  drugs with specific indication for insomnia, resulted in adequate coverage of the outcome of interest. Individuals with TS/CTD had 6.7-fold increased odds of insomnia, compared to the unexposed population, which is in line with reports from previous clinical case-control studies. [4][5][6] Nonetheless, those studies were much smaller, mostly based on self-reported symptoms, and unable to control for other relevant variables. Our analyses adjusted for a number of somatic conditions with known association with insomnia and TS/CTD, which had not been done before. Our full sibling models produced attenuated estimates, compared to those in the main analysis, indicating that genetic and environmental factors shared by siblings may explain a small part of the association between tic disorders and insomnia. Nonetheless, even after adjusting for familial confounders, the likelihood of insomnia was still over 5-fold higher in the TS/CTD group than in the general population.
Individuals with chronic tics persisting and requiring medical attention beyond childhood (ie, multiple diagnoses of TS/CTD beyond age 18) had a particularly high likelihood of having insomnia. Therefore, clinicians should expect a relatively high prevalence of insomnia in adult patients with TS/CTD and should attempt to manage it to minimize its known negative impact on health.
Analyses exploring the role of major groups of psychiatric disorders suggest that TS/CTD are associated with insomnia in their own right, because the systematic exclusion of different groups of psychiatric disorders did not substantially alter the estimates. This was true for all groups of psychiatric disorders under study except for ADHD and, to a lesser extent, pervasive developmental disorders. Our results indicate that these neurodevelopmental comorbidities contribute to the observed association between tics and insomnia. However, their exclusion did not completely eliminate the association, which still showed an over 3-fold (after exclusion of ADHD cases) and over 5-fold (after exclusion of pervasive developmental disorders) increased likelihood of insomnia among the individuals with TS/CTD, compared to their unexposed counterparts. From a clinical perspective, our results highlight the need to systematically evaluate and manage insomnia in individuals with TS/CTD, particularly if they present with comorbid neurodevelopmental disorders.
Because ADHD and drugs commonly prescribed to manage it have been previously associated with sleeprelated problems, 9,10 we explored these variables more in depth. Ghosh et al 8 reported a higher prevalence of primary insomnia in TS patients with than in those without comorbid ADHD. Moreover, they considered that one third of the TS and ADHD sample had insomnia attributable to the medication for ADHD taken by these patients. In our study, prevalence figures followed the same pattern that those reported in Ghosh et al. 8 Further, we found a much higher likelihood of having insomnia in individuals with TS/CTD and comorbid ADHD (aOR = 11.89) than in individuals without this comorbidity (aOR = 3.38). Similarly, the likelihood of insomnia in individuals with TS/CTD and medicated ADHD was higher than that for those with TS/CTD with non-medicated ADHD (aOR = 17.83 and aOR = 5.26, respectively). These results suggest that the impact of TS/CTD and ADHD on sleep problems could be additive. 8,35 Previous studies using objective sleep measures show that tic disorders and ADHD have specific polysomnographic alterations that affect sleep patterns in different ways. 35,36 Further, because the prevalence of ADHD (and hence the likelihood of being on ADHD medication) is higher in men, the fact that ADHD and ADHD medication are associated to higher likelihood of insomnia could explain that, in the main analysis, TS/CTD was more strongly associated with insomnia among men (over 7-fold increase) than among women (over 5-fold increase), compared to their same-sex unexposed counterparts. This contrasts with the expected sex distribution of insomnia in the general population, which is higher in women than in men. 27 This study has several limitations. First, registerbased studies have intrinsic coverage issues. The NPR only includes individuals who sought help and that were seen on specialist settings by specialist physicians. Further, outpatient care was only introduced in 2001. These limitations might affect the generalizability of the results to milder forms of tic disorders. Second, the results should be interpreted in the context of potential surveillance bias, whereby the outcomes might be more likely to be detected in individuals who are already in the health system because of TS/CTD. Third, we used a combined method to ascertain insomnia cases, one based on individuals being diagnosed with insomnia and another one based on individuals using specific medications for insomnia as a proxy for the diagnosis. However, it was reassuring that the combined use of these methods led to similar prevalence rates of insomnia than those previously reported in Sweden and elsewhere. 27,34 Fourth, although our adjusted models accounted for a number of relevant somatic conditions with known association with TS/CTD and insomnia, we could not adjust for all possible confounding variables (eg, restless legs syndrome does not have its own ICD code). 37,38 Finally, for the comparison of TS/CTD and ADHD-exposed individuals with and without ADHD medication, it is important to consider that medication prescription does not occur at random and that the most severe or complex patients are more likely to be medicated. Hence, these results should be interpreted with caution.