{'fraction_non_alphanumeric': 0.03273573430641494, 'fraction_numerical': 0.016129885239832883, 'mean_word_length': 5.337131367292225, 'pattern_counts': {'":': 0, '<': 4, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 2, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Clinical features and neuropsychiatric comorbidities in pediatric patients with tic disorders: a retrospective chart review study from South Korea

Background Tic disorders are childhood-onset neuropsychiatric disorders characterized by multiple motor or vocal tics with frequent comorbidities and a broad spectrum of phenotypic presentations. In this study, we aimed to investigate the clinical characteristics and comorbid neuropsychiatric conditions in pediatric patients with tic disorders. Methods We retrospectively reviewed the medical records of 119 pediatric patients (89 males, 30 females) who were diagnosed with tic disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) at Uijeongbu St. Mary’s Hospital, Republic of Korea, between January 2012 and July 2019. Results The mean age of tic onset was 6.9 years (range, 1–14) and the mean age at diagnosis was 8 years (range, 1–17). The mean lag between tic onset and diagnosis was 13.3 months (range, 0.25–132). The most common, first-presenting tics were eye blinking (50.4%), followed by jaw or lip movement (29.4%) and throat clearing (29.4%). Thirty-seven (31.1%) patients had at least one co-occurring neuropsychiatric disorder at the time of tic diagnosis. Subtypes of tic disorders, types of initial tics, and presence of neuropsychiatric comorbidities were not associated with tic severity. Tic severity was associated with greater functional impairment and tic noticeability (p < 0.05). A relatively shorter time to diagnosis was associated with tic severity (Spearman’s ρ = − 0.14, p = 0.11). Conclusions The evolving nature of tic expression and severity, high prevalence of neuropsychiatric comorbidities, and associated functional impairments emphasize the importance of comprehensive assessment during the disease course for determining and prioritizing goals of treatment.


Background
Tics are involuntary, stereotyped, nonrhythmic movements or vocalizations that are usually sudden and rapid [1,2]. A broad spectrum of phenotypes ranging from mild to severe and involving any muscle group characterizes the disorders [3]. Tics are categorized as either motor or vocal, and simple or complex, based on their quality and degree of complexity [4]. They can appear isolated or in combination and may coexist or occur in orchestrated sequences. The average age of onset for tic disorders is 4-6 years, peaking between 10 and 12 years, and declining throughout adolescence [5][6][7].
The precise etiology of tic disorders remains undetermined; however, there is strong agreement that their presence is associated with both polygenic and environmental factors [8]. Although several susceptibility genes have been suggested, no definitive causative gene mutation or risk allele has been identified, due to various factors such as the phenotypic and genotypic heterogeneity, variations in polygenic burden, rare mutations, epigenetic factors, and gene-environment interactions [9]. Environmental factors such as prenatal exposure, perinatal complications, infections, altered immune regulation, and psychosocial stressors are implicated in the development of tic disorders [10].
Tic disorders are usually associated with mental, behavioral, and developmental comorbidities, with previous studies demonstrating that approximately 80-90% of individuals with tic disorders also present other concurrent neuropsychiatric symptoms [5,11,12]. Attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) are the most commonly reported comorbidities, followed by depression [5,[13][14][15]. O'Hare et al. [16] noted that children with tic disorders and co-occurring neuropsychiatric comorbidities tend to have a lower global quality of life and more severe functional impairment. Considering the impact of associated psychopathology on the well-being of patients, an early diagnosis may allow prompt interventions that can improve quality of life, aid social skills, and facilitate academic achievement [17].
Tic disorders are clinically diagnosed on the basis of a detailed history and a neurological and psychiatric examination [4]. However, diagnostic difficulties can arise in certain circumstances because of the waxing and waning nature of tics and the variability of symptoms [18], which may impede initiating timely and appropriate interventions. The mean estimated interval between onset of tics and diagnosis is relatively long [19], with previous studies reporting a lag period ranging from 3 to 11.9 years [5,[20][21][22].
In this study, we aimed to investigate the clinical features and comorbid neuropsychiatric disorders in pediatric patients with tic disorders. In addition, we evaluated the effects of demographic and clinical factors on the timing of tic disorder diagnosis and on clinical outcomes.

Methods
We retrospectively reviewed the medical charts of pediatric patients who were diagnosed with tic disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) at Uijeongbu St. Mary's Hospital, Republic of Korea, between January 2012 and July 2019. Those who did not meet the diagnostic criteria or those who were lost to follow-up were excluded from this study.
Demographic and clinical data included gender, age of tic onset, age at diagnosis, types and duration of tic symptoms, tic severity at the initial clinical visit and at the most recent follow-up, and the presence of neuropsychiatric comorbidities. The diagnosis of neuropsychiatric comorbidities such as ADHD, OCD, depression, and anxiety were documented by a pediatric neurologist or a psychiatrist based on a psychiatric interview, according to the DSM-5 criteria. Developmental delay and intellectual disability were diagnosed based on the Bayley Scales of Infant Development, 3rd edition and Korean Wechsler Intelligence Scale for Children, 4th edition, respectively. The time to diagnosis of tic disorders was defined as the interval between the reported onset of tic symptoms and the timing of tic disorder diagnosis by a physician.
All statistical analyses were performed with SPSS 21.0 for Windows (IBM Corp., Armonk, NY, USA). Fisher's exact test, Pearson's chi-square test, and Student's t-test were used to compare the clinical outcomes by baseline demographics. In addition, Spearman's rank correlation coefficient (ρ) and the Kruskal-Wallis test were used to analyze the relationship between the time to diagnosis of tic disorders and other variables. Univariate and multivariate logistic regression analyses were performed to identify potential predictor variables and to assess the associations between the variables and tic severity. Statistical significance was defined at p < 0.05.
Ethical approval for this retrospective study was provided by the Institutional Review Board of Catholic Medical Center (IRB UC19RASI0149).

Tic severity and associated impairment
Seventy-six (63.9%) children in the sample were reported to have mild symptoms, thirty (25.2%) had moderate symptoms, and the remaining thirteen (10.9%) had severe symptoms. A comparison of demographic and clinical characteristics of patients with mild tics and those with moderate to severe tics is shown in Table 3. No significant differences were found between patients diagnosed with mild tics compared to moderate/severe tics with regard to gender, age at symptom onset, age at diagnosis, or time between symptom onset and diagnosis. Subtypes of tic disorders, types of initial tics, and presence of neuropsychiatric comorbidities were not associated with tic severity. Based on multivariate regression analysis, gender, age at symptom onset, age at diagnosis, time between symptom onset and diagnosis, subtypes of tic disorders, types of initial tics, and presence of neuropsychiatric comorbidities, were not significantly related to tic severity (Table 4). However, patients with moderate to severe tics were significantly more likely to have tics that  were noticeable to strangers and that interfered with their daily functioning, compared to those with mild tics. When the patients were divided into three groups according to subtypes of tic disorders, no significant differences in gender, age at symptom onset, age at diagnosis, time between symptom onset and diagnosis, types of initial tics, and presence of neuropsychiatric comorbidities were observed between patients with different tic severities. Compared to those with mild tics, patients with provisional tic disorder and those with moderate to severe tics, were significantly more likely to have tics that were noticeable to strangers and that interfered with their daily functioning.

Factors influencing time to diagnosis
The mean lag time from when tics were first noticed to diagnosis of tic disorders was 13.3 months (range, 0.25-132). Gender differences in lag time to diagnosis were observed, 10.0 months for females compared to 8.0 months for males (p = 0.05). No significant difference was found in the time to diagnosis between patients with  the presence of neuropsychiatric comorbidities, and those without (p = 0.91). In addition, age at symptom onset was not correlated with the time to diagnosis (Spearman's ρ = − 0.14, p = 0.11). The mean time to diagnosis was shorter in patients whose initial tics were motor tics only, compared to those with vocal tics only and combined motor and vocal tics, with a mean of 5.6 months (range, 0.25-24), 21.3 months (range, 0.25-96), and 18.9 months (range, 0.25-132), respectively (p < 0.05). Tic severity was negatively correlated with diagnostic lag time (Spearman's ρ = − 0.18, p < 0.05), that is, the more severe the tics, the less time that elapsed before a diagnosis.

Predictors of follow-up outcomes
The patients were followed up for an average of 20.2 months (range, 0.1-88.5) after the diagnosis of tic disorders. Of 119 patients, ninety-nine (83.2%) reported a greater than 50% reduction in tic severity, and twenty (16.8%) reported no changes in the tic symptoms at follow-up. To determine the factors related to favorable outcomes, we compared the characteristics of patients who achieved more than 50% reduction in symptoms with those who had no change in tic severity. Gender, age of onset, age at diagnosis, time interval between onset and diagnosis, subtypes of tic disorders, initial symptoms, tic severity at diagnosis, presence of neuropsychiatric comorbidities, and treatment utilization did not influence likelihood of favorable outcomes (Table 5). Based on multivariate regression analysis, gender, age of onset, age at diagnosis, time interval between onset and diagnosis, subtypes of tic disorders, initial symptoms, tic severity at diagnosis, presence of neuropsychiatric comorbidities, and treatment utilization, were not significantly related to clinical outcomes (Table 6). When the patients were divided into three groups according to subtypes of tic disorders, no significant differences regarding gender, age of onset, age at diagnosis, time interval between onset and diagnosis, initial tic symptoms, tic severity at diagnosis, presence of neuropsychiatric comorbidities, or treatment utilization were observed between patients who showed different outcomes.

Discussion
Isolated and transient tics are fairly common in childhood, ranging from 11 to 20% in different studies [24][25][26]. Diagnostic issues may arise in certain circumstances due to the waxing and waning nature and heterogeneity of tic symptom presentation [18]. Additionally, only a few studies have evaluated how many children with transient tics would become cases of Tourette syndrome or chronic tic disorder over time [27]. Therefore, in this study we tried to delineate the clinical features of tic disorders and characterize the demographic and clinical factors influencing the timing of tic disorder diagnosis and clinical outcomes. We found that the mean age of 6.9 years for the onset of tics was higher than that reported in other studies, which ranged between 4 and 6 years for onset [5][6][7]. Mild tic symptoms may initially go unrecognized by caregivers and become noticeable only with increasing severity, which may account for the higher mean age at onset in this study. Consistent with previous studies by Robertson et al. [28], we found a higher proportion of tic disorders in males than females in our study. With regard to initial tic symptoms, eye blinking was observed most frequently, accounting for more than half of tic symptoms in patients (50.4%). Previous studies have also noted that tics usually begin in the head and face, with eye blinking being the first and the most common tic [29,30].
Children with tic disorders have a higher likelihood of concomitant neuropsychiatric conditions [31]. An analysis of shared heritability in 23 different neurologic and psychiatric disorders demonstrated that a significant proportion of polygenic heritability in tic disorders is shared with OCD and ADHD [32]. Our results identified ADHD as the most commonly reported comorbid neuropsychiatric disorder, a finding consistent with previous research [33]. Tics are often not the most enduring or impairing problem in children with tic disorders; other coexisting neuropsychiatric conditions are often a greater source of impairment than the tics themselves [34]. Comorbid ADHD symptoms may have an undesirable impact on social, academic, and behavioral functions and can negatively impact quality of life and global psychosocial functioning [35][36][37]. Carter et al. [38] found that children with ADHD and tic disorders have more behavioral problems and poorer social adaptation compared to children with tic disorders only. Moreover, it has been postulated that the presence of ADHD in patients with tic disorders is correlated with higher rates of other neuropsychiatric comorbidities, such as OCD, anxiety disorders, anger control disorders, mood disorders, and personality disorders [5]. Our data noted a similar trend in that children with moderate to severe tics had more co-occurring neuropsychiatric disorders than those with mild tics, although the differences were not statistically significant. At a more general level, our results align with previous research showing that children with tic disorders may have increased healthcare needs and require supplemental mental health or educational services and support [39]. Therefore, clinical assessment of pediatric patients with tic disorders warrants a thorough evaluation for coexisting ADHD and other neuropsychiatric problems.
In our study, a relatively short lag time to diagnosis following the onset of tic symptoms was observed, with a mean duration of 13.3 months. This lag is significantly shorter than the 3 to 8 years delay reported in previous studies [5,21]. The shorter time to diagnosis identified in our study is comparable to findings from more recent studies [19,40]. In addition, time lag from when tics were first noticed to diagnosis was negatively correlated with tic severity. Growing awareness of tic symptoms among physicians and the availability of health information to patients and their families may be important factors in shortening the time to diagnosis [19]. Timely  [40]. We also found that patients with motor tics as the initial manifestation experienced less time to diagnosis than those with vocal tics. Patients with only vocal tics experienced relatively longer times to diagnosis compared to those with only motor tics or combined motor and vocal tics. Because throat clearing, sniffling, coughing, and grunting are the most common types of vocal tics, patients with vocal tics can often be misdiagnosed as having common pediatric conditions such as a cold, asthma, or allergy, which may contribute to diagnostic delay [4,19].
With regard to follow-up outcomes, the vast majority of patients (83.2%) reported improvement in their tics over time in our study. Tics reach their apex early in the second decade of life and then usually improve during adolescence [30]. According to Bloch et al. [6], more than three-quarters of children with childhood tic symptoms had fewer tics or were completely tic-free at follow-up, while less than a quarter had moderate or greater tics at follow-up. Though questions regarding the clinical predictive factors of follow-up outcomes arise frequently in clinical practice, previous studies have not successfully identified reliable predictors of followup outcomes. Prognostic issues can be difficult to address clinically because tic disorders have a complex range of possible symptom combinations and comorbidities [41]. In our study, we attempted to delineate the demographic and clinical factors that could be used to predict the future course of tic disorders. There were, however, no associations between future tic severity and gender, age of tic onset or diagnosis, lag time to diagnosis, subtypes of tic disorders, types of initial tic symptoms, tic severity at diagnosis, presence of neuropsychiatric comorbidities, or treatment utilization. Although we did not uncover robust clinical predictors of the course of tic disorders, our findings may provide a useful platform for further long-term follow-up studies regarding this issue.
Our study is limited by its retrospective nature. Drawing our patient sample from a single referral center likely influenced the lack of statistical significance. Thus, larger prospective studies or collaborative trials are warranted to elucidate the complex interaction of tic severity, comorbidities, and tic-related impairment and reveal the predictors of long-term follow-up outcomes.

Conclusions
The findings of this study suggest that motor tics as the initial manifestation and greater tic severity are associated with a shorter time to diagnosis. Although robust clinical predictors of the course of tic disorders were not identified, our findings extend previous research and provide potential explanations regarding the clinical features or neuropsychiatric comorbidities that influence the time to diagnosis and predict clinical outcomes in pediatric patients with tic disorders. We also noted heterogeneity in the initial presentation of tics and a higher likelihood of concomitant neuropsychiatric conditions. Thus, this study provides a better understanding and greater insight into the complexities of tic disorders. The evolving nature of tic expression and severity, high prevalence of neuropsychiatric comorbidities, and associated functional impairments reinforce the importance of comprehensive assessment during the disease course for determining and prioritizing goals of treatment. Furthermore, better recognition among parents, teachers, and health care providers of potential challenges related to either tic disorders or co-occurring conditions would help to best support the patient's future health and well-being.