Several studies have already showed that the COVID pandemic have a significant impact on the mental health of young people with TS, worsening both tics and emotional and behavioral symptoms. The social contexts for children and young people during this last year have been markedly different to what they had experienced before [
15,
30,
34] did not observed significant differences in tic symptom or severity between participants who were assessed before and during the pandemic [
15]. Conversely, since the onset of the COVID19 pandemic, it was reported an increase in tic symptoms in some children and adolescents who already had a diagnosis of a tic disorder [
8,
16] In a recent study, self-reported data on the impact of lockdown in school-age patients with tic disorders indicate perceived changes in tic severity, as well as restlessness and irritability, in about half of the cases [
41]. A worsening of tics in patients affected by TS, after the lockdown, has not been observed only in pediatric patients, but also in adults with TS/CTD [
10]. The increase and worsening of tics during the pandemic can be explained by the evidence that, psychosocial stress is largely implicated in the severity and frequency of tics [
7]. Considering the general abrupt growth in neuropsychiatric symptoms during the recent pandemic period, it was possible to hypothesize that the worsening of tics and associated comorbid symptoms is strongly related to lockdown measures, the psychological pressure of the pandemic, and the major vulnerability to emotional events in children and adolescents. Neurological and psychiatric symptoms of long COVID have been reported even in patients without a previous diagnosis of tic disorders. Abnormal movements, anxiety, emotional dysregulation and other neuropsychiatric symptoms were reported in a case series of five children from a few weeks to months after the resolution of the acute infection [
36]. Pavone et al. [
29] also reported on two unrelated children with new-onset paediatric acute onset neuropsychiatric syndroms (PANS) that started two weeks after a positive COVID-19 infection [
29]. Our results showed a more significant worsening of tics in TS patients that contracted SARS-CoV-2 infection, compared with TS patients without SARS-CoV-2 infection. This was supported by an increased score at YGTSS, that confirmed the data obtained from the administered questionnaire: TS patients with SARS-CoV-2 infection presented a mean YGTSS score at 3 months post-infection of 19.5 (SD 9.8), with a mean total increase of 1.3; in contrast, in the TS cohort without SARS-CoV-2 infection, patients showed a reduction in tic symptom severity, as assessed by YGTSS scores, at T1 (mean YGTSS score = 15.4, SD 7.35), with a mean total decrease in YGTSS at 3 months of 1.9. In general, patients of both groups reported an increase non only of tics but also of comorbid symptoms. The worsening of symptoms observed was more severe in patients of COVID + group compared on patients of COVID- group. Moreover, we can speculate that the decrease of tic symptoms observed at follow-up visit in patients without SARS-CoV-2 infection may be probably attributable to the minor severity of tics at baseline, and to the minor presence of other associated comorbidities that further complicate their clinical course., Long COVID symptoms occurred in 36.2% (
n = 25) of patients of COVID + group:, the most experienced symptom was fatigue in 21.7% (
n = 15), followed by headache and difficulty in completing daily activities both in 10.1% (
n = 7). To the best of our knowledge, no studies have been already focused on long COVID effects on patients with tic disorders. In general, children were less likely to develop long COVID when compared to adults [
42]. Instead, in a report conducted by Asadi‑Pooya et al. [
4], twenty-six (44·8%) children/adolescents reported symptoms/complaints of long COVID, including fatigue (21%), shortness of breath (12%), exercise intolerance (12%), weakness (10%), and walking intolerance (9%). In our study, we assessed tics, but also co-occurring conditions, including anxious and depressive symptoms, and behavioral disorders. Other literature studies conducted on paediatric samples observed similar results. Pasca et al. [
28] reported increased scores in CBCL questionnaire during the global pandemic caused by SARS-CoV-2 infection in pediatric patients with neuropsychiatric disorders. In another study, 25% of families reported during home quarantine the exacerbation of some behavioral problems, such as more frequent and intense episodes of non-collaboration, indifference, physical/verbal aggression, poorly targeted/organized play, screaming/crying, social iso- lation, provocative attitudes towards others, attempts to escape, and self-cutting ideation, in line with our study [
33]. In a meta-analysis conducted on 80,879 children, the pooled prevalence of depression and anxiety symptoms during pandemic has doubled compared to prepandemic estimates [
32]. These findings are consistent with previous studies that have shown that compared to adults, children and adolescents are at higher risk for depression and anxiety after natural disasters [
9,
42]. In our study, no statistically significant differences were observed between both groups in CBCL scores at T1: in fact, the mean score in the first group was 31.1 (SD = 22. 2), while in the second is 25 (SD = 18.4). As these scores showed, in both groups we observed an increase in the severity of behavioral, depressive and anxious symptoms: this increase, however, was more important in patients who contracted SARS-CoV-2 infection than in patients who did not contract it.
The underlying cellular and molecular mechanisms underlying the various clinical spectrum of long COVID are poorly understood. The proposed pathophysiological mechanisms for the development of long COVID seems to be include: hyperinflammatory state, chronic immune activation, renin-angiotensin system dysfunction leading to central and peripheral circulatory abnormalities, mast cell activation, virus persistence and organ damage, interference with fibrinolysis and promotion of micro-thrombi, and the development of auto-antibodies [
5,
27]. Lastly, infections or post-infections autoimmune effects-post-SARS-CoV-2 might play an important role [
40,
45]. The increase of tics observed in TS patients with SARS-CoV-2 infection could also in part be related to the virus pathogenesis: SARS-CoV-2 is directly neuro-invasive and causes a cytokine firestorm with consequences on the central nervous system (CNS); as a consequencee, cognitive and psychiatric follow-up of these patients will certainly be detected specifically in future. The altered immunological response seems to play a predominant role. Recently, the immunological differences between children recovered from the SARS-CoV-2 acute infection and children with post-acute sequelae (PASC) have been detected, including the possible predominant role of the innate immune system [
11]. Therefore, in the alveoli, after the initial damage to the blood–lung barrier, chronic inflammation with continuous production of pro-inflammator cytokines and reactive oxygen species (ROS) may occur, followed by their release into surrounding tissues and bloodstream [
13]. Abnormalities in coagulation can also increase the risk of microthrombosis in multiple organs but especially in alveolar capillaries, with an increased risk of thrombotic events. The blood–brain barrier dysregulation can then allow cytokines and leukocytes to infiltrate the brain parenchyma. Following SARS-CoV-2 infection, a “cytokine storm” from effector cells such as interleukin (IL)-6, IL-2, IL-17, interferons (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha, induces a neuroinflammatory response causing disruption of the blood–brain barrier (BBB), leading to peripheral immune cell transmigration into the brain and, in turn, causes imbalances in neurotransmission [
35]. Moreover, several studies suggested that microbiome/virome dysbiosis can impact initial SARS-CoV-2 risk and virulence, highlighting the importance of microbiome for the maintenance of symptoms [
31]. All these pathophysiological mechanisms can lead to the possible and various neurological manifestations recognized in patients with long COVID. Overall, patients affected by tic disorders shown possible abnormalities in the development of immune responses. Furthermore, a conspicuous number of studies have displayed hyperactive systematic immune-inflammatory responses in TS patients [
24,
18]. Post-mortem transcriptome analyses of the striatum of adults patients with TS compared with brain tissue from gender and age matched control group [
23] detected 309 downregulated genes, 822 upregulated genes, and 17 gene coexpression modules associated with TS. The top-scoring upregulated module included immune-related genes, consistent with these author’s observations [
23]. Recently, [
2] have investigated immune and inflammatory pathways in post-mortem brain tissue of individuals with Autism Spectrum Disorders (ASD) and TS and they reported enriched pathways involving inflammation, cytokines, signal transduction and cell signalling in ASD and TS brain transcriptome [
2]. Instead, our results confirms the risk of persistent symptoms in paediatric patients with long COVID, and highlight the importance of a long-term follow-up.
The current study has several limitations. First, our study had a short follow-up period, so an observation period longer than 3 months may be needed to show the onset of other symptoms of long COVID and worsening or improvement of the underlying pathology. Furthermore, considering the temporal pattern of tics, which are known to occur in bouts and wax and wane in severity [
21], a longer follow-up observation might represent important clues to the course and phenomenology of tics in our sample. Whether the increase of tics and associated symptoms observed in our sample of children with long COVID are the consequence of SARS-CoV-2 infection or are due to the tremendous impact resulting from the social isolation rules and lockdowns is still not clear. Second, our study did not include a non-TS control group infected by SARS-CoV-2. Considering these limitations, the results should be considered as preliminary rather than conclusive and may lay the groundwork for subsequent studies. On the other hand, this study also had several strengths, including carefully considered inclusion and exclusion criteria, the assessment of not only tics but also co-occurring conditions, the inclusion of a control group of children with TS without SARS-CoV-2 infection, and also the observation of long COVID symptoms. In conclusion, our results suggest that there was a significant increase in tics and also behavioral, depressive and anxious symptoms in TS patients with SARS-CoV-2 infection, compared with TS patients without the infection; in addition, long COVID symptoms were also observed in the infected patients.