- Email: [email protected]
Sleep, anxiety and psychiatric symptoms in children with Tourette syndrome and tic disorders
Accepted Manuscript Sleep, anxiety and psychiatric symptoms in children with Tourette syndrome and tic disorders Sergio Modafferi, Maddalena Stornelli, Flavia Chiarotti, Francesco Cardona, Oliviero Bruni, MD PII:
S1090-3798(16)30026-5
DOI:
10.1016/j.ejpn.2016.05.003
Reference:
YEJPN 2056
To appear in:
European Journal of Paediatric Neurology
Received Date: 5 December 2015 Revised Date:
25 April 2016
Accepted Date: 8 May 2016
Please cite this article as: Modafferi S, Stornelli M, Chiarotti F, Cardona F, Bruni O, Sleep, anxiety and psychiatric symptoms in children with Tourette syndrome and tic disorders, European Journal of Paediatric Neurology (2016), doi: 10.1016/j.ejpn.2016.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT SLEEP, ANXIETY AND PSYCHIATRIC SYMPTOMS IN CHILDREN WITH TOURETTE SYNDROME AND TIC DISORDERS.
Sergio Modafferia, Maddalena Stornellib, Flavia Chiarottic, Francesco Cardonad, Oliviero Brunie
of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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a Department
Email: [email protected] b Systems
Medicine Department, Child Neurology and Psychiatry Unit, Tor Vergata University
Hospital, Rome, Italy
c Department
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Email: [email protected]
of Cell Biology and Neuroscience, National Institute of Health, Rome, Italy
Email: [email protected]
of Pediatrics and Child Neuropsychiatry, Sapienza University, Rome, Italy
Email: [email protected]
Department of Developmental and Social Psychology, Sapienza University, Rome, Italy
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e
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d Department
Address correspondence to: Oliviero Bruni, MD
Department of Developmental and Social Psychology, Sapienza University
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Via dei Marsi 78 - 00185 Rome (Italy) email: [email protected]
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Tel. +39-0633775859.
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ACCEPTED MANUSCRIPT ABSTRACT Objective: The current study evaluated the relationship between tic, sleep disorders and specific psychiatric symptoms (anxiety, depression, obsessive compulsive symptoms). Methods: Assessment of 36 consecutive children and adolescents with tic disorders included: the Yale Global Tic Severity Scale (YGTSS) to assess the severity of tic symptoms; the Self-
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administered scale for children and adolescents (SAFA) to evaluate the psychopathological profile; a specific sleep questionnaire consisting of 45 items to assess the presence of sleep disorders.
An age and sex-matched control group was used for comparisons.
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Results: Sleep was significantly more disturbed in patients with tic disorders than in controls. Difficulties in initiating sleep and increased motor activity during sleep were the most frequent sleep disturbances found in our sample. Patients showed also symptoms of anxiety
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(SAFA A), depressed mood (SAFA D) and doubt-indecision (SAFA O). Additionally, difficulties in initiating sleep resulted associated with other SAFA subscales relative to obsessivecompulsive symptoms and depression symptoms. Furthermore, anxiety symptoms (SAFA A) resulted associated with increased motor activity during sleep.
Conclusions: Findings confirm literature studies reporting high frequency of sleep problems,
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anxiety and other psychopathological symptoms in patients with tic disorders, and support the hypothesis that intrusive thoughts and other emotional disturbances might disrupt the sleep onset of these patients. These results suggest the importance of a thorough assessment
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of sleep and psychiatric disturbances in patients with tic disorders.
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Keywords: Tourette syndrome, Tics, Sleep disorders, Anxiety, Psychiatric disorders
HIGHLIGHTS
Few studies evaluated the presence of sleep, anxiety and psychiatric disorders in patients with tic disorders
Sleep was significantly more disturbed in patients with tic disorders: difficulties in initiating sleep and increased motor activity during sleep were the most frequent sleep disturbances Difficulties in initiating sleep resulted associated with SAFA subscales relative to obsessivecompulsive symptoms and depression symptoms. Increased motor activity during sleep was associated with anxiety symptoms
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ACCEPTED MANUSCRIPT INTRODUCTION
Tic disorders (TicD) are the most frequent movement disorders in children: they have been estimated to be present in the 5-20% of children in the general population. TicD include different clinical conditions among which Tourette syndrome (TS) was the first described and
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the most studied in literature. TS is characterized by the presence of sudden, involuntary and repetitive movements or phonic utterances for a period longer than 1 year. Typically, children with TicD or TS show a wide variety of associated conditions, such as obsessive-compulsive disorder (OCD), attention deficit and hyperactivity disorder (ADHD), emotional and
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behavioural problems, and learning disabilities. 1
In his seminal paper 2 Gilles de la Tourette described the presence of sleep disorders in 2 out of his 9 patients with tics, but this finding was considered simply a coincidence. In the last
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thirty years, an increasing number of studies have investigated the psychopathological features of TS and, among others, sleep disorders. Overall, these studies have demonstrated a higher prevalence of sleep disturbances both in adults and in children with TS in comparison with the general population. 3-6
Notably, data from the Tourette Syndrome International Database Consortium showed the 3
The most
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presence of a history of sleep disorders in 25% of 5000 TS patients studied.
common problems are represented by disorders of arousal (sleep walking, pavor nocturnus),7-9 enuresis, sleep talking, difficulty with initiating and maintaining sleep, early morning awakenings, sleep-related anxiety, and restlessness during sleep. 4, 5
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Several lines of evidence indicate a meaningful association between OCD and TicD/TS including phenomenological overlap, evidence from family and genetic studies, and the
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potential involvement of basal ganglia circuitry and streptococcal infection in both conditions. OCD occurs in approximately 30% of TS patients, but up to 60% can experience obsessivecompulsive symptoms (OCS) at some point in their lifetime. 10-12 Since OCD is frequently comorbid with other psychiatric conditions, its association with TS has been correlated with a higher risk of other anxiety disorders. 13-16 Furthermore, several studies described a larger presence of anxiety in TS compared to controls ranging from 9 to 30%. 17-21 A bidirectional relationship seems to be present between anxiety and sleep disorders leading to a negative outcome on children’s neurobehavioral functioning. Anxiety is characterized as a state of hyper-vigilance or hyper-arousal and, as a result, is intimately tied with the regulation 3
ACCEPTED MANUSCRIPT of sleep.
22
Therefore, sleep and anxiety can be considered as opposite processes in the
arousal regulation. Abnormality in one of them claims for the evaluation of both, and of the arousal regulation system. 23 Interestingly, longitudinal studies showed that the presence of sleep problems during the childhood is predictive of anxiety disorders in adolescence or adulthood. 24, 25
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Moreover, sleep and anxiety disorders were found associated with severity of tic symptoms in patients with tics. 26, 27
At present, few studies evaluated the presence of sleep, anxiety and psychiatric disorders in the same group of patients. Aims of this study were: a) to evaluate the prevalence of sleep
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disorders, anxiety and other specific psychiatric conditions (depression and obsessivecompulsive symptoms) in a population of children with TicD or TS; b) to analyse the effect of clinical variables (severity of tics, ongoing drug treatment) on sleep disorders and specific
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psychiatric conditions; c) finally, to assess the association between sleep disorders and specific psychiatric conditions in TicD patients.
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MATERIALS AND METHODS
Patients
Between November 2010 and November 2012 a total of 36 consecutive subjects, that requested a consultation for tic disorders, was assessed at the Department of Paediatrics and
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Child Neuropsychiatry of the Sapienza University of Rome. Evaluation of all subjects included a complete medical history with particular regard to family
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history of tics, duration and clinical characteristics of tic symptoms; neurological and psychiatric examination.
Based on the diagnostic criteria established by the DSM-IV, the patients were classified as: Tourette's syndrome (TS), characterized by the presence of multiple motor and phonic tics, even not simultaneously, for a period longer than one year; Chronic motor or phonic Tic Disorder (CTD), characterized by the presence of multiple motor or phonic tics for a period longer than one year. All subjects were administered the Yale Global Tic Severity Scale (YGTSS) for the assessment of the severity of tic symptoms, the Self-administered scale for children and adolescents (SAFA) to evaluate the psychopathological profile, and a specific sleep questionnaire 4
ACCEPTED MANUSCRIPT consisting of 45 items that assess the presence of sleep disorders during the six months prior to the clinical evaluation, that has been previously used for prevalence studies in other diseases. 28
Controls
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In order to compare the prevalence of sleep disorders in our sample, a control group, age and sex matched, consisting of 266 children (191 males and 75 females) with a mean age of 11.5 years, was recruited in primary and secondary schools during a survey on sleep characteristics in childhood. All these subjects were typically developing children with no
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specific abnormalities.
The study was approved by the local Ethic Committee. All parents gave informed consent to
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the procedure.
Measures
1. Yale Global Tic Severity Scale (YGTSS)
This is the most widely used tool for assessing the severity of tics. Through a semi-structured interview, aimed at both children and parents, the clinician obtains information about the
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specific features and the anatomical distribution of tics that occurred during the past week. Based on the information gained from the interview is drawn up a list of motor and vocal tics; separately for motor tics and vocal ones, the severity of these tics is valued, by the clinician, through a 6-point scale which assesses each of the following five categories: the number,
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frequency, intensity, complexity, and interference with daily activities. The combined total is used as a measure of overall tic severity. The YGTSS also includes an overall impairment scale,
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rated from 0 to 50, that expresses the impact of tic disorder, as such, on the individual’s self esteem, family life, social acceptance, school functioning, and physical wellbeing.
2. Self-administered scale for children and adolescents (SAFA) SAFA is a psychometric test, processed at University of Cagliari and published in 2001, designed as a unitary instrument to a preliminary but sufficiently broad assessment of psychiatric conditions by means of different scales organized according to homogeneous criteria. It is structured as a self-report and presents a battery of six scales exploring a wide series of symptoms and psychiatric conditions: anxiety (SAFA A), depression (SAFA D),
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ACCEPTED MANUSCRIPT obsessive-compulsive symptoms (SAFA O), psychogenic eating disorders (SAFA P), somatic symptoms and hypochondria (SAFA S). For the purposes of this study, only the scales of anxiety (SAFA A) depression (SAFA D) and obsessive –compulsive symptoms (SAFA O) were administered and assessed. Three versions of each scale have been elaborated to adapt the test to the comprehension
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level of all age groups: version “e” for subject aged 8-10, version “m” for subject aged 11-13 and version “s” for those aged 14-18. Each scale is organized in sub-scales, relative to a specific aspect of the main disorder. The sub-scales are:
SAFA A: generalized anxiety, social anxiety, separation anxiety, school-related anxiety;
•
SAFA D: depressed mood, anhedonia and disinterest, touchy mood, sense of
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inadequacy and low self-esteem, insecurity, guilt, and hopelessness; •
SAFA O: obsessive thoughts, compulsions and rituals, rupophobia and contamination,
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order and control, and doubt and indecision.
The T score of SAFA defines different ranges: scores less than 30 indicate that the domain investigated is negated by the subject; scores between 30 to 39 that the subject tends to negate the symptoms; scores between 40 and 59 represent statistical normality; scores between 60 and 69 indicate that symptoms are basically pathological (borderline); finally,
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scores over 69 means that symptoms are clearly pathological. On the basis of the scores obtained, it is possible to build a general profile and/or individual profiles within the single scales, according to the main groups of the explored symptoms. In order to value the accuracy
subscale. 29, 30
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and the trustworthiness of the answers, a simulation scale is included in the SAFA D scale as a
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3. Sleep Disturbance Questionnaire (SDQ) This questionnaire, based on parental report, assesses the prevalence of sleep disorders and consists of 45 items in a Likert-type scale with values 1 to 5 (1=never; 2=occasionally; 3=often; 4=very often; 5=always) constructed to identify individual differences in sleep disorders. Items were based on clinical experience with sleep disorders in children, and from a review of previous sleep questionnaires reported in the literature. The items were grouped into eight components (duration of night-time sleep, sleep latency, bedtime difficulties, sleep quality, night awakenings, nocturnal symptoms, morning symptoms and daytime sleepiness). The first two components were defined by items 1 and 2 that pertained respectively to sleep duration (categorized as follows: 1=9-11 h; 2=8-9 h; 3 = 7-8 h; 4 = 5-7 h; 5 =less than 5 h) and 6
ACCEPTED MANUSCRIPT sleep latency (categorized as follows: 1 =less than 15 min; 2= 15- 30 min; 3=30-45 min; 4=4560 min; 5=more than 60 min). Instructions for completing the scale were always given to parents by the same investigator. The questionnaire, which took the parents 10-15 min to complete, assessed sleep behaviour and disorders observed during the last 6 months of the child's life. As cut-off for the presence of a sleep problem we considered the answer at Likert
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scale that was ≥ 3 (often, very often, always) as reported in the previous study. 28
Statistical analysis
We compared the whole sample of patients to the controls, and subgroups of patients across
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levels of two grouping variables: severity of tics (YGTSS >30 vs. ≤30), ongoing drug therapy at the time of the assessment (presence vs. absence). We assessed differences between groups
Statistical Software Release 8.1.
RESULTS
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using Fisher’s exact probability test. Statistical analyses were carried out using STATA
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The sample consisted of 30 males (83.3%) and 6 females (16.7%), aged 8 to 16.3 years (mean age: 11.7 years). The tic onset was between 3 to 10.5 years (mean age: 6.34). Based on the diagnostic criteria above mentioned, 28 patients (78%) were affected by TS and 8 patients (22%) by CTD.
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At the time of evaluation, YGTSS scores of patients ranged from 3 to 70 (mean: 28.25). In particular 16 patients (44.4%) obtained an YGTSS score above 30. Moreover, 11 patients were
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taking a neuroleptic therapy for tics at the time of assessment.
Sleep Disturbance Questionnaire Overall TicD vs. Controls
Prevalence analysis showed that the whole group of TicD patients had a higher percentage of sleep disturbances than controls. In particular, statistically significant differences were found in 15 items of the SDQ (table 1). Sleep duration lower than eight hours was more frequently reported in TicD patients than in the control group. TicD patients showed more bedtime problems than controls; in particular, they reported more difficulties getting to sleep at night and anxiety or fear when falling asleep. Significant differences were observed also for hypnic jerks and for fluids or drugs to facilitate sleep. Patients had more reluctance to go to bed, need 7
ACCEPTED MANUSCRIPT for light on or TV in the bedroom and need for a transitional object than controls. Regarding the nocturnal symptoms, TicD patients presented statistically higher prevalence of parasomnias, restless sleep, bruxism and snoring. Finally, TicD patients showed more daytime sleepiness than controls.
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TicD Subgroups vs. Controls In addition to the results described above, further significant differences were found comparing sub-groups of TicD patients with the control group (table 1). Interestingly, patients with YGTSS ≤ 30 showed a greater percentage of the following sleep problems compared to
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controls: sleep latency higher than 30 min., hypnagogic hallucinations, sleep talking, and nightmares. Additionally, patients not undergoing therapy were found having more sleep breathing difficulties and hypnagogic hallucinations than controls.
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No statistical significant differences were found comparing the two subgroups of patients.
SAFA
Data analysis showed that more than one half of patients (52.7%) reported pathological scores in the SAFA A (Anxiety) total score (table 2).
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Generalized anxiety resulted to be the most frequent anxiety trait, with 55.5% of patients obtaining pathological scores; pathological scores were also obtained in 33.3% of the patient for both social anxiety and separation anxiety, and in 36.1% for school-related anxiety. When considering the SAFA D, pathological scores were detected in more than 30% of
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patients in the total score and in many of the subscales: depressed mood, touchy mood, sense of inadequacy-low self esteem, insecurity, hopelessness.
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Significantly higher percentages of patients than controls obtained pathological scores in doubt-indecision (44.4%) and compulsion-rituals (33.3%) subscales of SAFA O. In the Simulation Scale, 19.4% of patients obtained pathological scores. From the subgroup comparison it resulted that patients with YGTSS scores ≤30 showed higher frequency of touchy mood than patients with YGTSS scores >30. No substantial differences were found between patients undergoing anti-tic therapy and patients not undergoing tic therapy (table 3).
Association: sleep problems/psychiatric symptoms
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ACCEPTED MANUSCRIPT To assess the association between sleep abnormalities and specific psychopathological conditions the sample was divided into two subgroups according to the SAFA scores. For each of the SAFA subscales we compared the frequency of sleep disorders between the group of patients with borderline + pathological score (T ≥60) vs. those with non-pathological score (T <60) (table 4).
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In particular, patients with borderline or pathological SAFA A or D scores had more frequently symptoms referring to abnormal movements just before or during sleep (hypnic jerks, rhythmic movements falling asleep, nocturnal hyperkinesia and unusual movements during sleep).
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Furthermore, patients with borderline or pathological SAFA O had more frequently symptoms interfering with falling asleep (reluctance to go to bed, anxiety/fear when falling asleep,
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bedtime variations) and reduced sleep duration.
DISCUSSION
In this study we found an increased prevalence of sleep disturbances in children with tic
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disorders compared to typically developing children, similarly to another recent study on the same topic 31 and previous evidences in literature. 3, 4, 6, 27, 32, 33, 34 Sleep problems in our sample consisted of shorter sleep duration, difficulties getting to sleep
sleepiness.
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at night and anxiety or fear when falling asleep, parasomnias, restless sleep and daytime
Problems when falling asleep were the most frequent sleep disorders in our sample; sleep
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seems to be disrupted mostly by reluctance, anxiety or fear and difficulty falling asleep. The same results were found in a similar study of 2004 which assessed sleep disturbances in 49 children with tic disorders using the same sleep questionnaire.
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Furthermore, difficulties
initiating sleep in patients with TS have been highlighted in several polysomnographic and non polysomnographic studies. 4, 5, 27, 33, 35 We found also a high prevalence of parasomnias (pavor nocturnus, bruxism and snoring) according to other reports. 4-9, 35 One of the most highlighted literature findings in TS patients was the presence of increased motor activity during both REM and NREM sleep compared to the control group;
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this
increased motor activity, has been interpreted as a sign of hyper-arousal and it seems 9
ACCEPTED MANUSCRIPT consistent with the reduced intra-cortical inhibition of the motor patterns demonstrated in TS.
6, 33
Accordingly, we found in our patients a higher rate of symptoms related to an
increased motor activity during sleep. From a psychological point of view, a high level of anxiety has been reported in TicD;
17-21
similarly, the SAFA assessment in our group of children with tic disorders showed
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pathological scores in several subscales of SAFA A, relative to generalized anxiety, social anxiety, separation anxiety and school-related anxiety.
Moreover, we found high frequencies of pathological scores also in SAFA D (depression) and SAFA O (obsessive-compulsive symptoms) subscales relative to depressed mood, touchy
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mood, sense of inadequacy/low self-esteem, compulsions/rituals and doubt/indecision. This is in accordance to the literature showing up to 60% of OCD-symptoms 12 and up to 78% of depression symptoms in children with tic disorders. 36
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To the best of our knowledge, this is the first work that analyzes a possible association between sleep and anxiety disorders in patients with tic disorders. The different studies showed higher frequencies of both disturbances in TicD patients than in the general population, without drawing a clear relationship. 3-9, 17-21, 27, 33, 34 Various Authors highlighted the co-occurrence of sleep problems in patients with anxiety
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disorders 37-40 and suggested a correlation between anxiety as a predictor or consequence of sleep problems 24, 25, 40 and of prolonged sleep latency. 41 The reluctance and difficulty falling asleep have been linked to the comorbid psychiatric conditions that often are associated with Tourette syndrome - mainly separation anxiety,
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specific phobias and obsessive thoughts. 42, 43
The psychopathological profile of our TicD patients, emerging from SAFA assessment, is
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consistent with this pattern of emotional disturbances which, according to some Authors, might enhance pre-sleep cognitive activity interfering with sleep and, particularly, with sleep onset. 23, 44, 45
In particular, Alfano et al.
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emphasized the importance of cognitive pre-sleep arousal in
children with anxiety disorder as predictor of sleep disruption. They reported, in patients with anxiety disorders, a correlation of an increased bedtime cognitive activity with reduced sleep duration and, more in general, with sleep problems, even though in their study there was not a specific correlation with difficullties in initiating sleep.
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ACCEPTED MANUSCRIPT Our data are in agreement with these results, given that we did not find an association between anxiety symptoms, as reported by the SAFA A subscales, and difficulties in initiating sleep, whereas anxiety resulted associated with increased movement during the night. Difficulties in initiating sleep were instead associated with SAFA subscales relative to DoubtIndecision, Order-Control and Depressed mood (SAFA O, SAFA D) suggesting that intrusive
onset of these patients. A similar association was already found in a previous study
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thoughts or more in general emotional disturbances could act as interference factors on sleep
in which Authors reported a
significant correlation between disturbances of initiating and maintaining sleep, and both
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“internalizing” and “thought problems” scales of the Child Behaviour Check List (CBCL). Finally, we analyzed the TicD subgroups in relation to the presence of sleep disturbances: sleep disorders were present in our sample irrespective of tic severity and ongoing therapy
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considering that we found no significant differences in the subgroup analysis. We can speculate that in tic disorders there is an alteration of arousal that occurs with a variable spectrum of clinical symptoms - anxiety symptoms, sleep disorders and tic symptoms - which might associate with each other.
Acknowledging the various clinical manifestations seen in TS, it has been hypothesized that
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tics and tic disorders associated with different comorbidities (sleep, anxiety, depression, etc.) might result from different neurotransmitters dysfunctions.46 As reported by neurobiological studies, beside dopaminergic hyperactivity, numerous neurotransmitter systems are involved in TS pathophysiology. Reduced serotoninergic
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activity has been related to both tics and insomnia of patients with TS; on the other hand, increased noradrenaline, which is considered a sign of hyperarousal in patients with
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insomnia, has been found in Tourette’s patients as well.27,46 According to a physiopathological model, patients with TS could present an intrinsic disorder of arousal as well as a lack of inhibition of the motor circuit: these two deficits would act synergistically creating a state of hyper-arousal that would make it more difficult to fall asleep resulting in an overall worsening of symptoms and the overall functioning of the patient 47 but independently from the anxiety. In this view, difficulties in initiating sleep might be regarded as alterations of the arousal control system during the delicate phase of transition from wakefulness to sleep. This phase, characterized by the switch from the prefrontal cortex and related executive functions predominance to the subcortical system prevalence, seems to be the most susceptible to the 11
ACCEPTED MANUSCRIPT obsessive thoughts rather than anxiety; disturbances of this phase can constitute the first signs of derangement of arousal system and its alteration might cause further sleep disorders. 23
These latter observations could be an important clue for the treatment in these patients. In fact, if chronic disruption of sleep onset processes leads to other changes in arousal and affect
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regulation, interventions focused on sleep onset may also have broader implications relevant to these disorders. This can be particularly true in some adolescent when cognitive influences
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significantly disrupt these physiological systems.
CONCLUSIONS
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The current study confirmed literature evidence reporting more frequent sleep disorders in paediatric patients with tic disorders compared with typically developing children, and the concomitant presence of anxiety, depression and obsessive-compulsive symptoms in these patients.
Moreover, anxiety symptoms were found associated with increased movement during the
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night. Difficulties in initiating sleep, which were the most common sleep problems in our sample, resulted correlated with the SAFA subscales relative to depression and obsessivecompulsive symptoms. This latter finding could suggest a role of the emotional disturbances of these patients as a trigger of their problems in falling asleep, which might worsen the
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overall symptoms. We suggest that sleep, anxiety and other psychiatric disturbances might represent variable expressions of the intrinsic arousal disorder in patients with tic disorders
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and, as frequent conditions that could affect the clinical course of tic disorders and the global functioning of these patients, they should be adequately assessed in order to customize the therapeutic approach.
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ACCEPTED MANUSCRIPT Table 1- Frequencies of occurrence of sleep problems in the overall sample of TicD and in the subgroups, and statistical comparison with the control group YGTSS>30
YGTSS≤30
Therapy (+)
Therapy (-)
Controls
1. Sleep duration 2. Sleep latency
36 % 36.1 *** 13.9
16 % 43.8 ** 0.0
20 % 30.0 25.0 *
11 % 45.5 * 9.1
25 % 32.0 * 16.0
266 % 14.7 6.0
DIFFICULTY IN INITIATING SLEEP 3. Go to bed reluctantly 4. Bedtime variations 5. Difficulty getting to sleep at night 6. Anxiety/fear when falling asleep 7. Drink stimulant beverages in the evening 8. Need for light on or TV 9. Need for a transitional object 10. Fluids or drugs to facilitate sleep 11. Hypnic jerks 12. Rhythmic movements falling asleep 13. Hypnagogic hallucinations 14. Falling asleep sweating
44.4 41.6 30.6 36.1 25.0 47.2 30.6 13.9 27.8 8.3 5.6 16.7
31.3 31.3 31.3 * 25.0 * 12.5 37.5 25.0 12.5 * 18.8 0.0 0.0 6.3
55.0 50.0 30.0 45.0 35.0 55.0 35.0 15.0 35.0 15.0 10.0 25.0
SLEEP QUALITY 15. Bad sleep quality
16.7
NIGHT AWAKENINGS 16. More than two awakenings per night 17. Waking up screaming in the night 18. Waking up to drink or eat in the night 19. Getting up to use to the bathroom 20. Waking up complaining of headache 21. Waking up with leg cramps 22. Difficulty to fall asleep after awakenings
8.3 13.9 * 5.6 * 5.6 2.8 2.8 11.1
NOCTURNAL SYMPTOMS 23. Nocturnal hyperkinesia 24. Unusual movements during sleep 25. Pains of unknown origin during sleep 26. Sleep breathing difficulties 27. Sleep apnea 28. Snoring 29. Night sweating 30. Sleepwalking 31. Sleep talking 32. Bed-wetting 33. Bruxism 34. Sleep terrors 35. Nightmares 36. Report of frightening dream 37. Convulsions during sleep
38.9 22.2 *** 0.0 11.1 0.0 27.8 * 30.6 5.6 22.2 0.0 19.4 ** 2.8 8.3 13.9 0.0
25.0 12.5 0.0 12.5 0.0 31.3 43.8 * 6.3 12.5 0.0 12.5 0.0 0.0 12.5 0.0
50.0 30.0 0.0 10.0 0.0 25.0 20.0 5.0 30.0 0.0 25.0 5.0 15.0 15.0 0.0
MORNING SYMPTOMS 38. Difficult to wake up in the morning 39. Variation of waking time 40. Restless sleep 41. Sleep paralysis 42. Hallucinations waking up in the morning
36.1 25.0 38.9 * 5.6 0.0
37.5 18.8 37.5 0.0 0.0
DAYTIME SLEEPINESS 43. Daytime somnolence 44. Falling asleep at school 45. Sleep attacks
19.4 ** 5.6 * 2.8
25.0 * 12.5 ** 0.0
*** ***
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* *** ** ** ** *** *
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* ** *** ***
**
12.5
6.3 0.0 6.3 6.3 0.0 0.0 6.3
18.2 18.2 27.3 18.2 27.3 36.4 0.0 18.2 ** 18.2 18.2 0.0 9.1
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*
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Number
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TicD Overall
56.0 52.0 32.0 44.0 24.0 52.0 44.0 12.0 32.0 4.0 8.0 20.0
**
** *** ** *** ** *** *
25.2 37.8 9.0 7.5 38.0 21.1 11.7 0.8 5.6 4.1 0.8 9.8
20.0
9.1
20.0
13.9
10.0 25.0 ** 5.0 5.0 5.0 5.0 15.0
9.1 9.1 0.0 0.0 0.0 0.0 9.0
8.0 16.0 * 8.0 8.0 4.0 4.0 12.0
7.5 4.9 19.6 13.9 0.7 0.7 5.3
36.4 18.2 0.0 0.0 0.0 18.2 27.3 0.0 18.2 0.0 18.2 0.0 9.1 9.1 0.0
40.0 24.0 0.0 16.0 0.0 32.0 32.0 8.0 24.0 0.0 20.0 4.0 8.0 16.0 0.0
33.5 5.6 1.5 4.9 0.7 14.3 16.2 3.4 13.1 2.3 4.1 1.1 2.3 8.3 0.4
35.0 30.0 40.0 10.0 0.0
45.5 9.1 36.4 0.0 0.0
32.0 32.0 40.0 * 8.0 0.0
15.0 0.0 5.0
27.3 * 18.2 ** 0.0
16.0 0.0 4.0
**
* ** **
** * *
**
38.0 24.4 21.8 2.6 0.0
5.6 0.4 1.5
Fisher exact test: * = p < 0.05; ** = p < 0.01; *** = p < 0.001 Significances refer to comparisons between each TicD group and the control group. No other statistically significant differences were found between the subgroups.
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SAFA O Total score Total critical items Obsessive thoughts Compulsions-rituals Rupophobia-contamination Order-control Doubt-indecision
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27.77 8.33 25.00 33.33 13.88 27.77 44.44
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19.44
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SIMULATION SCALE
30.55 13.88 38.88 19.44 33.33 33.33 30.55 16.66 30.55
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SAFA D Total score Total critical items Depressed mood Anhedonia-disinterest Touchy mood Sense of inadequacy-low self-esteem Insecurity Guilty Hopelessness
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Table 2. Percentages of borderline (60-69) and pathological (>69) T scores of SAFA test in the sample of TicD patients (n. 36). T ≥ 60 SAFA A Total score 52.77 Total critical items 27.77 Generalized anxiety 55.55 Social anxiety 33.33 Separation anxiety 33.33 School-related anxiety 36.10
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ACCEPTED MANUSCRIPT Table 3. Comparisons of pathological frequencies of SAFA subscales in the subgroups of TicD patients YGTSS>30 YGTSS≤30 Therapy (+) Therapy (-) 11
25
56.2 37.5 56.2 25 31.2 31.2
50 20 55 40 35 40
54.4 36.4 54.5 45.4 18.2 45.4
52 24 56 28 40 32
18.7 6.2 31.2 25 6.2 37.5
40 20 45 15 55* 30
27.3 9.1 27.3 18.2 27.3 36.4
25 12.5 18.7
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SAFA D Total score Critical items Depressed mood Anhedonia-Disinterest Touchy mood Sense of inadequacy-Low self-esteem Insecurity Guilty Hopelessness
20
35 20 40
36.4 18.2 27.3
28 16 32
27.3 9.1 36.4 27.3 0
28 8 20 36 20
9.1 36.4
36 48
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SAFA O Total score 25 30 Critical items 18.7 0 Obsessive thoughts 25 25 Compulsions-rituals 31.2 35 Rupophobia12.5 15 contaminations Order-control 25 30 Doubt-indecision 37.5 50 Fisher exact test: * = p < 0.05; ** = p < 0.01; *** = p < 0.001
32 16 44 20 36 32
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SAFA A Total score Critical items Generalized anxiety Social anxiety Separation anxiety School-related anxiety
16
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Number
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Table 4. Significant differences (Fisher exact test p -values) of frequencies in SDQ subitems' symptoms between patients with borderline + pathological SAFA scores (T ≥ 60) and those with normal SAFA scores (T < 60).
0.040
0.047
0.019
0.026 0.009
0.045
Doubt-Indecision
Order-Control
0.047
0.011
0.023
RupophobiaContamination
Obsessive thoughts
Critical Items
Total score
Hopelessness
Guilty
Insecurity
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SAFA O (Obsessive-Compulsive symptoms)
0.038
0.011 0.007 0.047 0.039* 0.039
0.031
0.023
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Go to bed reluctantly Bedtime variations Anxiety falling asleep Stimulant beverages Hypnic jerks Rhythmic movement falling asleep Hypnagogic hallucinations NIGHT AWAKENINGS Waking up screaming Diff. fall asleep after awaken NOCTURNAL SYMPTOMS Nocturnal hyperkinesia Unusual movements Breathing difficulties Snoring Sleeptalking Bruxism MORNING SYMPTOMS Variation of waking time
Touchy mood
Depressed mood
Critical Items
Tot Score
School-related
Separation
Social 0.025*
INITIATING
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IN
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DIFFICULTY SLEEP
SAFA D (Depression)
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Sleep duration
Generalized
Critical Items
Total score
SAFA A (Anxiety)
0.024
0.031 0.010 0.040
0.040 0.027 0.035*
0.040
0.039*
0.040 0.050
0.039*
Legenda: SDQ subitems’ symptoms were more frequent in patients with borderline + pathological SAFA scores than in patients with normal SAFA scores excepting those with pvalues evidenced with * in which, on the contrary, SDQ subitems were more frequent in patients with normal SAFA than in patients with borderline + pathological SAFA scores .
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ACCEPTED MANUSCRIPT REFERENCES
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1. Murphy TK, Lewin AB, Storch EA, Stock S; American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with tic disorders. J Am Acad Child Adolesc Psychiatry. 2013 Dec;52(12):1341-59. 2. Gilles de la Tourette G. Étude sur une affection nerveuse caractérisée par de l'incoordination motrice accompagnée d'echolalie et de coprolalie. Arch Neurol 1885 ; 9 :19-42 158-200.
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ACCEPTED MANUSCRIPT 14. Thibert AL, Day HI, Sandor P. Self-concept and self-consciousness in adults with Tourette syndrome. Can J Psychiatry 1995 Feb;40(1):35-9.
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21. Kurlan R, Como PG, Miller B, Palumbo D, Deeley C, Andresen EM, Eapen S, McDermott MP. The behavioral spectrum of tic disorders: a community-based study. Neurology 2002 Aug 13;59(3):414-20.
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23. Dahl RE. The regulation of sleep and arousal: Development and psychopathology. Dev Psychopathol 1996;8:3-27. 24. Gregory AM, O'Connor TG. Sleep problems in childhood: a longitudinal study of developmental change and association with behavioral problems. J Am Acad Child Adolesc Psychiatry. 2002 Aug;41(8):964-71. 25. Gregory AM, Caspi A, Eley TC, Moffitt TE, Oconnor TG, Poulton R. Prospective longitudinal associations between persistent sleep problems in childhood and anxiety and depression disorders in adulthood. J Abnorm Child Psychol. 2005 Apr;33(2):15763. 26. Lin H, Katsovich L, Ghebremichael M, Findley DB, Grantz H, Lombroso PJ, King RA, Zhang H, Leckman JF. Psychosocial stress predicts future symptom severities in children and adolescents with Tourette syndrome and/or obsessive-compulsive disorder. J Child Psychol Psychiatry 2007 Feb;48(2):157-66. 18
ACCEPTED MANUSCRIPT 27. Cohrs S, Rasch T, Altmeyer S, Kinkelbur J, Kostanecka T, Rothenberger A et al. Decreased sleep quality and increased sleep related movements in patients with Tourette’s syndrome. J Neurol Neurosurg Psychiatry 2001; 70:192-7. 28. Bruni O, Fabrizi P, Ottaviano S, Cortesi F, Giannotti F, Guidetti V. Prevalence of sleep disorders in childhood and adolescence with headache: a case-control study. Cephalalgia. 1997 Jun;17(4):492-8.
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31. Mol Debes NM. Co-morbid disorders in Tourette syndrome. Behav Neurol. 2013;27(1):7-14. 32. Allen RP, Singer HS, Brown JE, Salam MM. Sleep disorders in Tourette Syndrome: a primary or unrelated problem? Pediatr Neurol. 1992; 8: 275-80.
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35. Ghosh D, Rajan PV, Das D, Datta P, Rothner AD, Erenberg G. Sleep disorders in children with Tourette syndrome. Pediatr Neurol. 2014Jul;51(1):31-5.
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36. Robertson MM. Mood disorders and Gilles de la Tourette's syndrome: An update on prevalence, etiology, comorbidity, clinical associations, and implications. J Psychosom Res 2006: Sep;61(3):349-58. 37. Alfano CA, Ginsburg GA, Kingerly JN Sleep related problems among children and adolescents with anxiety disorders. J American Academy Child Adolescent Psychiatry 2007;46:224-232 38. Storch EA, Murphy TK, Lack CW, et al. Sleep related problems in pediatric ObsessiveCompulsive disorder. J Anxiety Disord. 2008; 22(5):877-885 39. Chase RM, Pincus DB. Sleep-related problems in children and adolescents with anxiety disorders. Behav Sleep Med. 2011;9(4):224-36 40. Alfano CA, Beidel DC, Turner SM, Lewin DS. Preliminary evidence for sleep complaints among children referred for anxiety. Sleep Med. 2006 Sep;7(6):467-73. 19
ACCEPTED MANUSCRIPT 41. Weiner CL, Meredith Elkins R, Pincus D, Comer J. Anxiety sensitivity and sleep-related problems in anxious youth. J Anxiety Disord. 2015 May;32:66-72. 42. Singer HS, Rosenberg LA. Development of behavioral and emotional problems in Tourette Syndrome. Pediatr Neurol. 1989;5:41-44.
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43. Kong RA, Scahill L. Emotional and behavioural difficulties associated with Tourette Syndrome. In: Cohen DG, Goetz CG, Jankovic J “Tourette Syndrome” Lippincot Williams and Wilkins, Philadelphia 2001; 79-88 44. Alfano CA, Pina AA, Zerr AA, Villalta IK. Pre-sleep arousal and sleep problems of anxiety-disordered youth. Child Psychiatry Hum Dev. 2010 Apr;41(2):156-67
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46. Felling RJ, Singer HS. Neurobiology of Tourette Syndrome: Current status and need for further investigation. J Neurosci., 2011 Aug 31;31(35)
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S1090-3798(16)30026-5
DOI:
10.1016/j.ejpn.2016.05.003
Reference:
YEJPN 2056
To appear in:
European Journal of Paediatric Neurology
Received Date: 5 December 2015 Revised Date:
25 April 2016
Accepted Date: 8 May 2016
Please cite this article as: Modafferi S, Stornelli M, Chiarotti F, Cardona F, Bruni O, Sleep, anxiety and psychiatric symptoms in children with Tourette syndrome and tic disorders, European Journal of Paediatric Neurology (2016), doi: 10.1016/j.ejpn.2016.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT SLEEP, ANXIETY AND PSYCHIATRIC SYMPTOMS IN CHILDREN WITH TOURETTE SYNDROME AND TIC DISORDERS.
Sergio Modafferia, Maddalena Stornellib, Flavia Chiarottic, Francesco Cardonad, Oliviero Brunie
of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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a Department
Email: [email protected] b Systems
Medicine Department, Child Neurology and Psychiatry Unit, Tor Vergata University
Hospital, Rome, Italy
c Department
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Email: [email protected]
of Cell Biology and Neuroscience, National Institute of Health, Rome, Italy
Email: [email protected]
of Pediatrics and Child Neuropsychiatry, Sapienza University, Rome, Italy
Email: [email protected]
Department of Developmental and Social Psychology, Sapienza University, Rome, Italy
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e
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d Department
Address correspondence to: Oliviero Bruni, MD
Department of Developmental and Social Psychology, Sapienza University
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Via dei Marsi 78 - 00185 Rome (Italy) email: [email protected]
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Tel. +39-0633775859.
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ACCEPTED MANUSCRIPT ABSTRACT Objective: The current study evaluated the relationship between tic, sleep disorders and specific psychiatric symptoms (anxiety, depression, obsessive compulsive symptoms). Methods: Assessment of 36 consecutive children and adolescents with tic disorders included: the Yale Global Tic Severity Scale (YGTSS) to assess the severity of tic symptoms; the Self-
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administered scale for children and adolescents (SAFA) to evaluate the psychopathological profile; a specific sleep questionnaire consisting of 45 items to assess the presence of sleep disorders.
An age and sex-matched control group was used for comparisons.
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Results: Sleep was significantly more disturbed in patients with tic disorders than in controls. Difficulties in initiating sleep and increased motor activity during sleep were the most frequent sleep disturbances found in our sample. Patients showed also symptoms of anxiety
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(SAFA A), depressed mood (SAFA D) and doubt-indecision (SAFA O). Additionally, difficulties in initiating sleep resulted associated with other SAFA subscales relative to obsessivecompulsive symptoms and depression symptoms. Furthermore, anxiety symptoms (SAFA A) resulted associated with increased motor activity during sleep.
Conclusions: Findings confirm literature studies reporting high frequency of sleep problems,
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anxiety and other psychopathological symptoms in patients with tic disorders, and support the hypothesis that intrusive thoughts and other emotional disturbances might disrupt the sleep onset of these patients. These results suggest the importance of a thorough assessment
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of sleep and psychiatric disturbances in patients with tic disorders.
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Keywords: Tourette syndrome, Tics, Sleep disorders, Anxiety, Psychiatric disorders
HIGHLIGHTS
Few studies evaluated the presence of sleep, anxiety and psychiatric disorders in patients with tic disorders
Sleep was significantly more disturbed in patients with tic disorders: difficulties in initiating sleep and increased motor activity during sleep were the most frequent sleep disturbances Difficulties in initiating sleep resulted associated with SAFA subscales relative to obsessivecompulsive symptoms and depression symptoms. Increased motor activity during sleep was associated with anxiety symptoms
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ACCEPTED MANUSCRIPT INTRODUCTION
Tic disorders (TicD) are the most frequent movement disorders in children: they have been estimated to be present in the 5-20% of children in the general population. TicD include different clinical conditions among which Tourette syndrome (TS) was the first described and
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the most studied in literature. TS is characterized by the presence of sudden, involuntary and repetitive movements or phonic utterances for a period longer than 1 year. Typically, children with TicD or TS show a wide variety of associated conditions, such as obsessive-compulsive disorder (OCD), attention deficit and hyperactivity disorder (ADHD), emotional and
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behavioural problems, and learning disabilities. 1
In his seminal paper 2 Gilles de la Tourette described the presence of sleep disorders in 2 out of his 9 patients with tics, but this finding was considered simply a coincidence. In the last
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thirty years, an increasing number of studies have investigated the psychopathological features of TS and, among others, sleep disorders. Overall, these studies have demonstrated a higher prevalence of sleep disturbances both in adults and in children with TS in comparison with the general population. 3-6
Notably, data from the Tourette Syndrome International Database Consortium showed the 3
The most
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presence of a history of sleep disorders in 25% of 5000 TS patients studied.
common problems are represented by disorders of arousal (sleep walking, pavor nocturnus),7-9 enuresis, sleep talking, difficulty with initiating and maintaining sleep, early morning awakenings, sleep-related anxiety, and restlessness during sleep. 4, 5
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Several lines of evidence indicate a meaningful association between OCD and TicD/TS including phenomenological overlap, evidence from family and genetic studies, and the
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potential involvement of basal ganglia circuitry and streptococcal infection in both conditions. OCD occurs in approximately 30% of TS patients, but up to 60% can experience obsessivecompulsive symptoms (OCS) at some point in their lifetime. 10-12 Since OCD is frequently comorbid with other psychiatric conditions, its association with TS has been correlated with a higher risk of other anxiety disorders. 13-16 Furthermore, several studies described a larger presence of anxiety in TS compared to controls ranging from 9 to 30%. 17-21 A bidirectional relationship seems to be present between anxiety and sleep disorders leading to a negative outcome on children’s neurobehavioral functioning. Anxiety is characterized as a state of hyper-vigilance or hyper-arousal and, as a result, is intimately tied with the regulation 3
ACCEPTED MANUSCRIPT of sleep.
22
Therefore, sleep and anxiety can be considered as opposite processes in the
arousal regulation. Abnormality in one of them claims for the evaluation of both, and of the arousal regulation system. 23 Interestingly, longitudinal studies showed that the presence of sleep problems during the childhood is predictive of anxiety disorders in adolescence or adulthood. 24, 25
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Moreover, sleep and anxiety disorders were found associated with severity of tic symptoms in patients with tics. 26, 27
At present, few studies evaluated the presence of sleep, anxiety and psychiatric disorders in the same group of patients. Aims of this study were: a) to evaluate the prevalence of sleep
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disorders, anxiety and other specific psychiatric conditions (depression and obsessivecompulsive symptoms) in a population of children with TicD or TS; b) to analyse the effect of clinical variables (severity of tics, ongoing drug treatment) on sleep disorders and specific
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psychiatric conditions; c) finally, to assess the association between sleep disorders and specific psychiatric conditions in TicD patients.
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MATERIALS AND METHODS
Patients
Between November 2010 and November 2012 a total of 36 consecutive subjects, that requested a consultation for tic disorders, was assessed at the Department of Paediatrics and
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Child Neuropsychiatry of the Sapienza University of Rome. Evaluation of all subjects included a complete medical history with particular regard to family
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history of tics, duration and clinical characteristics of tic symptoms; neurological and psychiatric examination.
Based on the diagnostic criteria established by the DSM-IV, the patients were classified as: Tourette's syndrome (TS), characterized by the presence of multiple motor and phonic tics, even not simultaneously, for a period longer than one year; Chronic motor or phonic Tic Disorder (CTD), characterized by the presence of multiple motor or phonic tics for a period longer than one year. All subjects were administered the Yale Global Tic Severity Scale (YGTSS) for the assessment of the severity of tic symptoms, the Self-administered scale for children and adolescents (SAFA) to evaluate the psychopathological profile, and a specific sleep questionnaire 4
ACCEPTED MANUSCRIPT consisting of 45 items that assess the presence of sleep disorders during the six months prior to the clinical evaluation, that has been previously used for prevalence studies in other diseases. 28
Controls
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In order to compare the prevalence of sleep disorders in our sample, a control group, age and sex matched, consisting of 266 children (191 males and 75 females) with a mean age of 11.5 years, was recruited in primary and secondary schools during a survey on sleep characteristics in childhood. All these subjects were typically developing children with no
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specific abnormalities.
The study was approved by the local Ethic Committee. All parents gave informed consent to
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the procedure.
Measures
1. Yale Global Tic Severity Scale (YGTSS)
This is the most widely used tool for assessing the severity of tics. Through a semi-structured interview, aimed at both children and parents, the clinician obtains information about the
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specific features and the anatomical distribution of tics that occurred during the past week. Based on the information gained from the interview is drawn up a list of motor and vocal tics; separately for motor tics and vocal ones, the severity of these tics is valued, by the clinician, through a 6-point scale which assesses each of the following five categories: the number,
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frequency, intensity, complexity, and interference with daily activities. The combined total is used as a measure of overall tic severity. The YGTSS also includes an overall impairment scale,
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rated from 0 to 50, that expresses the impact of tic disorder, as such, on the individual’s self esteem, family life, social acceptance, school functioning, and physical wellbeing.
2. Self-administered scale for children and adolescents (SAFA) SAFA is a psychometric test, processed at University of Cagliari and published in 2001, designed as a unitary instrument to a preliminary but sufficiently broad assessment of psychiatric conditions by means of different scales organized according to homogeneous criteria. It is structured as a self-report and presents a battery of six scales exploring a wide series of symptoms and psychiatric conditions: anxiety (SAFA A), depression (SAFA D),
5
ACCEPTED MANUSCRIPT obsessive-compulsive symptoms (SAFA O), psychogenic eating disorders (SAFA P), somatic symptoms and hypochondria (SAFA S). For the purposes of this study, only the scales of anxiety (SAFA A) depression (SAFA D) and obsessive –compulsive symptoms (SAFA O) were administered and assessed. Three versions of each scale have been elaborated to adapt the test to the comprehension
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level of all age groups: version “e” for subject aged 8-10, version “m” for subject aged 11-13 and version “s” for those aged 14-18. Each scale is organized in sub-scales, relative to a specific aspect of the main disorder. The sub-scales are:
SAFA A: generalized anxiety, social anxiety, separation anxiety, school-related anxiety;
•
SAFA D: depressed mood, anhedonia and disinterest, touchy mood, sense of
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•
inadequacy and low self-esteem, insecurity, guilt, and hopelessness; •
SAFA O: obsessive thoughts, compulsions and rituals, rupophobia and contamination,
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order and control, and doubt and indecision.
The T score of SAFA defines different ranges: scores less than 30 indicate that the domain investigated is negated by the subject; scores between 30 to 39 that the subject tends to negate the symptoms; scores between 40 and 59 represent statistical normality; scores between 60 and 69 indicate that symptoms are basically pathological (borderline); finally,
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scores over 69 means that symptoms are clearly pathological. On the basis of the scores obtained, it is possible to build a general profile and/or individual profiles within the single scales, according to the main groups of the explored symptoms. In order to value the accuracy
subscale. 29, 30
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and the trustworthiness of the answers, a simulation scale is included in the SAFA D scale as a
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3. Sleep Disturbance Questionnaire (SDQ) This questionnaire, based on parental report, assesses the prevalence of sleep disorders and consists of 45 items in a Likert-type scale with values 1 to 5 (1=never; 2=occasionally; 3=often; 4=very often; 5=always) constructed to identify individual differences in sleep disorders. Items were based on clinical experience with sleep disorders in children, and from a review of previous sleep questionnaires reported in the literature. The items were grouped into eight components (duration of night-time sleep, sleep latency, bedtime difficulties, sleep quality, night awakenings, nocturnal symptoms, morning symptoms and daytime sleepiness). The first two components were defined by items 1 and 2 that pertained respectively to sleep duration (categorized as follows: 1=9-11 h; 2=8-9 h; 3 = 7-8 h; 4 = 5-7 h; 5 =less than 5 h) and 6
ACCEPTED MANUSCRIPT sleep latency (categorized as follows: 1 =less than 15 min; 2= 15- 30 min; 3=30-45 min; 4=4560 min; 5=more than 60 min). Instructions for completing the scale were always given to parents by the same investigator. The questionnaire, which took the parents 10-15 min to complete, assessed sleep behaviour and disorders observed during the last 6 months of the child's life. As cut-off for the presence of a sleep problem we considered the answer at Likert
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scale that was ≥ 3 (often, very often, always) as reported in the previous study. 28
Statistical analysis
We compared the whole sample of patients to the controls, and subgroups of patients across
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levels of two grouping variables: severity of tics (YGTSS >30 vs. ≤30), ongoing drug therapy at the time of the assessment (presence vs. absence). We assessed differences between groups
Statistical Software Release 8.1.
RESULTS
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using Fisher’s exact probability test. Statistical analyses were carried out using STATA
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The sample consisted of 30 males (83.3%) and 6 females (16.7%), aged 8 to 16.3 years (mean age: 11.7 years). The tic onset was between 3 to 10.5 years (mean age: 6.34). Based on the diagnostic criteria above mentioned, 28 patients (78%) were affected by TS and 8 patients (22%) by CTD.
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At the time of evaluation, YGTSS scores of patients ranged from 3 to 70 (mean: 28.25). In particular 16 patients (44.4%) obtained an YGTSS score above 30. Moreover, 11 patients were
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taking a neuroleptic therapy for tics at the time of assessment.
Sleep Disturbance Questionnaire Overall TicD vs. Controls
Prevalence analysis showed that the whole group of TicD patients had a higher percentage of sleep disturbances than controls. In particular, statistically significant differences were found in 15 items of the SDQ (table 1). Sleep duration lower than eight hours was more frequently reported in TicD patients than in the control group. TicD patients showed more bedtime problems than controls; in particular, they reported more difficulties getting to sleep at night and anxiety or fear when falling asleep. Significant differences were observed also for hypnic jerks and for fluids or drugs to facilitate sleep. Patients had more reluctance to go to bed, need 7
ACCEPTED MANUSCRIPT for light on or TV in the bedroom and need for a transitional object than controls. Regarding the nocturnal symptoms, TicD patients presented statistically higher prevalence of parasomnias, restless sleep, bruxism and snoring. Finally, TicD patients showed more daytime sleepiness than controls.
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TicD Subgroups vs. Controls In addition to the results described above, further significant differences were found comparing sub-groups of TicD patients with the control group (table 1). Interestingly, patients with YGTSS ≤ 30 showed a greater percentage of the following sleep problems compared to
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controls: sleep latency higher than 30 min., hypnagogic hallucinations, sleep talking, and nightmares. Additionally, patients not undergoing therapy were found having more sleep breathing difficulties and hypnagogic hallucinations than controls.
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No statistical significant differences were found comparing the two subgroups of patients.
SAFA
Data analysis showed that more than one half of patients (52.7%) reported pathological scores in the SAFA A (Anxiety) total score (table 2).
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Generalized anxiety resulted to be the most frequent anxiety trait, with 55.5% of patients obtaining pathological scores; pathological scores were also obtained in 33.3% of the patient for both social anxiety and separation anxiety, and in 36.1% for school-related anxiety. When considering the SAFA D, pathological scores were detected in more than 30% of
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patients in the total score and in many of the subscales: depressed mood, touchy mood, sense of inadequacy-low self esteem, insecurity, hopelessness.
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Significantly higher percentages of patients than controls obtained pathological scores in doubt-indecision (44.4%) and compulsion-rituals (33.3%) subscales of SAFA O. In the Simulation Scale, 19.4% of patients obtained pathological scores. From the subgroup comparison it resulted that patients with YGTSS scores ≤30 showed higher frequency of touchy mood than patients with YGTSS scores >30. No substantial differences were found between patients undergoing anti-tic therapy and patients not undergoing tic therapy (table 3).
Association: sleep problems/psychiatric symptoms
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ACCEPTED MANUSCRIPT To assess the association between sleep abnormalities and specific psychopathological conditions the sample was divided into two subgroups according to the SAFA scores. For each of the SAFA subscales we compared the frequency of sleep disorders between the group of patients with borderline + pathological score (T ≥60) vs. those with non-pathological score (T <60) (table 4).
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In particular, patients with borderline or pathological SAFA A or D scores had more frequently symptoms referring to abnormal movements just before or during sleep (hypnic jerks, rhythmic movements falling asleep, nocturnal hyperkinesia and unusual movements during sleep).
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Furthermore, patients with borderline or pathological SAFA O had more frequently symptoms interfering with falling asleep (reluctance to go to bed, anxiety/fear when falling asleep,
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bedtime variations) and reduced sleep duration.
DISCUSSION
In this study we found an increased prevalence of sleep disturbances in children with tic
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disorders compared to typically developing children, similarly to another recent study on the same topic 31 and previous evidences in literature. 3, 4, 6, 27, 32, 33, 34 Sleep problems in our sample consisted of shorter sleep duration, difficulties getting to sleep
sleepiness.
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at night and anxiety or fear when falling asleep, parasomnias, restless sleep and daytime
Problems when falling asleep were the most frequent sleep disorders in our sample; sleep
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seems to be disrupted mostly by reluctance, anxiety or fear and difficulty falling asleep. The same results were found in a similar study of 2004 which assessed sleep disturbances in 49 children with tic disorders using the same sleep questionnaire.
6
Furthermore, difficulties
initiating sleep in patients with TS have been highlighted in several polysomnographic and non polysomnographic studies. 4, 5, 27, 33, 35 We found also a high prevalence of parasomnias (pavor nocturnus, bruxism and snoring) according to other reports. 4-9, 35 One of the most highlighted literature findings in TS patients was the presence of increased motor activity during both REM and NREM sleep compared to the control group;
27
this
increased motor activity, has been interpreted as a sign of hyper-arousal and it seems 9
ACCEPTED MANUSCRIPT consistent with the reduced intra-cortical inhibition of the motor patterns demonstrated in TS.
6, 33
Accordingly, we found in our patients a higher rate of symptoms related to an
increased motor activity during sleep. From a psychological point of view, a high level of anxiety has been reported in TicD;
17-21
similarly, the SAFA assessment in our group of children with tic disorders showed
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pathological scores in several subscales of SAFA A, relative to generalized anxiety, social anxiety, separation anxiety and school-related anxiety.
Moreover, we found high frequencies of pathological scores also in SAFA D (depression) and SAFA O (obsessive-compulsive symptoms) subscales relative to depressed mood, touchy
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mood, sense of inadequacy/low self-esteem, compulsions/rituals and doubt/indecision. This is in accordance to the literature showing up to 60% of OCD-symptoms 12 and up to 78% of depression symptoms in children with tic disorders. 36
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To the best of our knowledge, this is the first work that analyzes a possible association between sleep and anxiety disorders in patients with tic disorders. The different studies showed higher frequencies of both disturbances in TicD patients than in the general population, without drawing a clear relationship. 3-9, 17-21, 27, 33, 34 Various Authors highlighted the co-occurrence of sleep problems in patients with anxiety
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disorders 37-40 and suggested a correlation between anxiety as a predictor or consequence of sleep problems 24, 25, 40 and of prolonged sleep latency. 41 The reluctance and difficulty falling asleep have been linked to the comorbid psychiatric conditions that often are associated with Tourette syndrome - mainly separation anxiety,
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specific phobias and obsessive thoughts. 42, 43
The psychopathological profile of our TicD patients, emerging from SAFA assessment, is
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consistent with this pattern of emotional disturbances which, according to some Authors, might enhance pre-sleep cognitive activity interfering with sleep and, particularly, with sleep onset. 23, 44, 45
In particular, Alfano et al.
44
emphasized the importance of cognitive pre-sleep arousal in
children with anxiety disorder as predictor of sleep disruption. They reported, in patients with anxiety disorders, a correlation of an increased bedtime cognitive activity with reduced sleep duration and, more in general, with sleep problems, even though in their study there was not a specific correlation with difficullties in initiating sleep.
10
ACCEPTED MANUSCRIPT Our data are in agreement with these results, given that we did not find an association between anxiety symptoms, as reported by the SAFA A subscales, and difficulties in initiating sleep, whereas anxiety resulted associated with increased movement during the night. Difficulties in initiating sleep were instead associated with SAFA subscales relative to DoubtIndecision, Order-Control and Depressed mood (SAFA O, SAFA D) suggesting that intrusive
onset of these patients. A similar association was already found in a previous study
6
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thoughts or more in general emotional disturbances could act as interference factors on sleep
in which Authors reported a
significant correlation between disturbances of initiating and maintaining sleep, and both
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“internalizing” and “thought problems” scales of the Child Behaviour Check List (CBCL). Finally, we analyzed the TicD subgroups in relation to the presence of sleep disturbances: sleep disorders were present in our sample irrespective of tic severity and ongoing therapy
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considering that we found no significant differences in the subgroup analysis. We can speculate that in tic disorders there is an alteration of arousal that occurs with a variable spectrum of clinical symptoms - anxiety symptoms, sleep disorders and tic symptoms - which might associate with each other.
Acknowledging the various clinical manifestations seen in TS, it has been hypothesized that
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tics and tic disorders associated with different comorbidities (sleep, anxiety, depression, etc.) might result from different neurotransmitters dysfunctions.46 As reported by neurobiological studies, beside dopaminergic hyperactivity, numerous neurotransmitter systems are involved in TS pathophysiology. Reduced serotoninergic
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activity has been related to both tics and insomnia of patients with TS; on the other hand, increased noradrenaline, which is considered a sign of hyperarousal in patients with
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insomnia, has been found in Tourette’s patients as well.27,46 According to a physiopathological model, patients with TS could present an intrinsic disorder of arousal as well as a lack of inhibition of the motor circuit: these two deficits would act synergistically creating a state of hyper-arousal that would make it more difficult to fall asleep resulting in an overall worsening of symptoms and the overall functioning of the patient 47 but independently from the anxiety. In this view, difficulties in initiating sleep might be regarded as alterations of the arousal control system during the delicate phase of transition from wakefulness to sleep. This phase, characterized by the switch from the prefrontal cortex and related executive functions predominance to the subcortical system prevalence, seems to be the most susceptible to the 11
ACCEPTED MANUSCRIPT obsessive thoughts rather than anxiety; disturbances of this phase can constitute the first signs of derangement of arousal system and its alteration might cause further sleep disorders. 23
These latter observations could be an important clue for the treatment in these patients. In fact, if chronic disruption of sleep onset processes leads to other changes in arousal and affect
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regulation, interventions focused on sleep onset may also have broader implications relevant to these disorders. This can be particularly true in some adolescent when cognitive influences
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significantly disrupt these physiological systems.
CONCLUSIONS
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The current study confirmed literature evidence reporting more frequent sleep disorders in paediatric patients with tic disorders compared with typically developing children, and the concomitant presence of anxiety, depression and obsessive-compulsive symptoms in these patients.
Moreover, anxiety symptoms were found associated with increased movement during the
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night. Difficulties in initiating sleep, which were the most common sleep problems in our sample, resulted correlated with the SAFA subscales relative to depression and obsessivecompulsive symptoms. This latter finding could suggest a role of the emotional disturbances of these patients as a trigger of their problems in falling asleep, which might worsen the
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overall symptoms. We suggest that sleep, anxiety and other psychiatric disturbances might represent variable expressions of the intrinsic arousal disorder in patients with tic disorders
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and, as frequent conditions that could affect the clinical course of tic disorders and the global functioning of these patients, they should be adequately assessed in order to customize the therapeutic approach.
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ACCEPTED MANUSCRIPT Table 1- Frequencies of occurrence of sleep problems in the overall sample of TicD and in the subgroups, and statistical comparison with the control group YGTSS>30
YGTSS≤30
Therapy (+)
Therapy (-)
Controls
1. Sleep duration 2. Sleep latency
36 % 36.1 *** 13.9
16 % 43.8 ** 0.0
20 % 30.0 25.0 *
11 % 45.5 * 9.1
25 % 32.0 * 16.0
266 % 14.7 6.0
DIFFICULTY IN INITIATING SLEEP 3. Go to bed reluctantly 4. Bedtime variations 5. Difficulty getting to sleep at night 6. Anxiety/fear when falling asleep 7. Drink stimulant beverages in the evening 8. Need for light on or TV 9. Need for a transitional object 10. Fluids or drugs to facilitate sleep 11. Hypnic jerks 12. Rhythmic movements falling asleep 13. Hypnagogic hallucinations 14. Falling asleep sweating
44.4 41.6 30.6 36.1 25.0 47.2 30.6 13.9 27.8 8.3 5.6 16.7
31.3 31.3 31.3 * 25.0 * 12.5 37.5 25.0 12.5 * 18.8 0.0 0.0 6.3
55.0 50.0 30.0 45.0 35.0 55.0 35.0 15.0 35.0 15.0 10.0 25.0
SLEEP QUALITY 15. Bad sleep quality
16.7
NIGHT AWAKENINGS 16. More than two awakenings per night 17. Waking up screaming in the night 18. Waking up to drink or eat in the night 19. Getting up to use to the bathroom 20. Waking up complaining of headache 21. Waking up with leg cramps 22. Difficulty to fall asleep after awakenings
8.3 13.9 * 5.6 * 5.6 2.8 2.8 11.1
NOCTURNAL SYMPTOMS 23. Nocturnal hyperkinesia 24. Unusual movements during sleep 25. Pains of unknown origin during sleep 26. Sleep breathing difficulties 27. Sleep apnea 28. Snoring 29. Night sweating 30. Sleepwalking 31. Sleep talking 32. Bed-wetting 33. Bruxism 34. Sleep terrors 35. Nightmares 36. Report of frightening dream 37. Convulsions during sleep
38.9 22.2 *** 0.0 11.1 0.0 27.8 * 30.6 5.6 22.2 0.0 19.4 ** 2.8 8.3 13.9 0.0
25.0 12.5 0.0 12.5 0.0 31.3 43.8 * 6.3 12.5 0.0 12.5 0.0 0.0 12.5 0.0
50.0 30.0 0.0 10.0 0.0 25.0 20.0 5.0 30.0 0.0 25.0 5.0 15.0 15.0 0.0
MORNING SYMPTOMS 38. Difficult to wake up in the morning 39. Variation of waking time 40. Restless sleep 41. Sleep paralysis 42. Hallucinations waking up in the morning
36.1 25.0 38.9 * 5.6 0.0
37.5 18.8 37.5 0.0 0.0
DAYTIME SLEEPINESS 43. Daytime somnolence 44. Falling asleep at school 45. Sleep attacks
19.4 ** 5.6 * 2.8
25.0 * 12.5 ** 0.0
*** ***
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* *** ** ** ** *** *
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* ** *** ***
**
12.5
6.3 0.0 6.3 6.3 0.0 0.0 6.3
18.2 18.2 27.3 18.2 27.3 36.4 0.0 18.2 ** 18.2 18.2 0.0 9.1
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*
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Number
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TicD Overall
56.0 52.0 32.0 44.0 24.0 52.0 44.0 12.0 32.0 4.0 8.0 20.0
**
** *** ** *** ** *** *
25.2 37.8 9.0 7.5 38.0 21.1 11.7 0.8 5.6 4.1 0.8 9.8
20.0
9.1
20.0
13.9
10.0 25.0 ** 5.0 5.0 5.0 5.0 15.0
9.1 9.1 0.0 0.0 0.0 0.0 9.0
8.0 16.0 * 8.0 8.0 4.0 4.0 12.0
7.5 4.9 19.6 13.9 0.7 0.7 5.3
36.4 18.2 0.0 0.0 0.0 18.2 27.3 0.0 18.2 0.0 18.2 0.0 9.1 9.1 0.0
40.0 24.0 0.0 16.0 0.0 32.0 32.0 8.0 24.0 0.0 20.0 4.0 8.0 16.0 0.0
33.5 5.6 1.5 4.9 0.7 14.3 16.2 3.4 13.1 2.3 4.1 1.1 2.3 8.3 0.4
35.0 30.0 40.0 10.0 0.0
45.5 9.1 36.4 0.0 0.0
32.0 32.0 40.0 * 8.0 0.0
15.0 0.0 5.0
27.3 * 18.2 ** 0.0
16.0 0.0 4.0
**
* ** **
** * *
**
38.0 24.4 21.8 2.6 0.0
5.6 0.4 1.5
Fisher exact test: * = p < 0.05; ** = p < 0.01; *** = p < 0.001 Significances refer to comparisons between each TicD group and the control group. No other statistically significant differences were found between the subgroups.
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ACCEPTED MANUSCRIPT
SAFA O Total score Total critical items Obsessive thoughts Compulsions-rituals Rupophobia-contamination Order-control Doubt-indecision
SC
27.77 8.33 25.00 33.33 13.88 27.77 44.44
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19.44
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SIMULATION SCALE
30.55 13.88 38.88 19.44 33.33 33.33 30.55 16.66 30.55
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SAFA D Total score Total critical items Depressed mood Anhedonia-disinterest Touchy mood Sense of inadequacy-low self-esteem Insecurity Guilty Hopelessness
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Table 2. Percentages of borderline (60-69) and pathological (>69) T scores of SAFA test in the sample of TicD patients (n. 36). T ≥ 60 SAFA A Total score 52.77 Total critical items 27.77 Generalized anxiety 55.55 Social anxiety 33.33 Separation anxiety 33.33 School-related anxiety 36.10
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ACCEPTED MANUSCRIPT Table 3. Comparisons of pathological frequencies of SAFA subscales in the subgroups of TicD patients YGTSS>30 YGTSS≤30 Therapy (+) Therapy (-) 11
25
56.2 37.5 56.2 25 31.2 31.2
50 20 55 40 35 40
54.4 36.4 54.5 45.4 18.2 45.4
52 24 56 28 40 32
18.7 6.2 31.2 25 6.2 37.5
40 20 45 15 55* 30
27.3 9.1 27.3 18.2 27.3 36.4
25 12.5 18.7
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SAFA D Total score Critical items Depressed mood Anhedonia-Disinterest Touchy mood Sense of inadequacy-Low self-esteem Insecurity Guilty Hopelessness
20
35 20 40
36.4 18.2 27.3
28 16 32
27.3 9.1 36.4 27.3 0
28 8 20 36 20
9.1 36.4
36 48
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EP
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SAFA O Total score 25 30 Critical items 18.7 0 Obsessive thoughts 25 25 Compulsions-rituals 31.2 35 Rupophobia12.5 15 contaminations Order-control 25 30 Doubt-indecision 37.5 50 Fisher exact test: * = p < 0.05; ** = p < 0.01; *** = p < 0.001
32 16 44 20 36 32
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SAFA A Total score Critical items Generalized anxiety Social anxiety Separation anxiety School-related anxiety
16
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Number
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Table 4. Significant differences (Fisher exact test p -values) of frequencies in SDQ subitems' symptoms between patients with borderline + pathological SAFA scores (T ≥ 60) and those with normal SAFA scores (T < 60).
0.040
0.047
0.019
0.026 0.009
0.045
Doubt-Indecision
Order-Control
0.047
0.011
0.023
RupophobiaContamination
Obsessive thoughts
Critical Items
Total score
Hopelessness
Guilty
Insecurity
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SAFA O (Obsessive-Compulsive symptoms)
0.038
0.011 0.007 0.047 0.039* 0.039
0.031
0.023
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Go to bed reluctantly Bedtime variations Anxiety falling asleep Stimulant beverages Hypnic jerks Rhythmic movement falling asleep Hypnagogic hallucinations NIGHT AWAKENINGS Waking up screaming Diff. fall asleep after awaken NOCTURNAL SYMPTOMS Nocturnal hyperkinesia Unusual movements Breathing difficulties Snoring Sleeptalking Bruxism MORNING SYMPTOMS Variation of waking time
Touchy mood
Depressed mood
Critical Items
Tot Score
School-related
Separation
Social 0.025*
INITIATING
EP
IN
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DIFFICULTY SLEEP
SAFA D (Depression)
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Sleep duration
Generalized
Critical Items
Total score
SAFA A (Anxiety)
0.024
0.031 0.010 0.040
0.040 0.027 0.035*
0.040
0.039*
0.040 0.050
0.039*
Legenda: SDQ subitems’ symptoms were more frequent in patients with borderline + pathological SAFA scores than in patients with normal SAFA scores excepting those with pvalues evidenced with * in which, on the contrary, SDQ subitems were more frequent in patients with normal SAFA than in patients with borderline + pathological SAFA scores .
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