Tourette's syndrome

doi:10.1016/S0140-6736(02)11526-1

The Lancet

Volume 360, Issue 9345, 16 November 2002, Pages 1577-1586

https://doi.org/10.1016/S0140-6736(02)11526-1 Get rights and content

Summary

As our knowledge of Gilles de la Tourette's syndrome increases, so does our appreciation for the pathogenic complexity of this disorder and the challenges associated with its treatment. Advances in the neurosciences have led to new models of pathogenesis, whereas clinical studies have reinvigorated early hypotheses. The interdependent roles of genes and environment in disease formation have yet to be fully elucidated. Results of epidemiological studies have prompted debate on how best to characterise and diagnose this disorder. Absence of ideal anti-tic drugs, combined with knowledge that uncomplicated cases of childhood Tourette's syndrome frequently have a favourable outcome, has led to striking changes in care and treatment of patients. This seminar focuses on these changing views and offers a new perspective on our understanding of the pathogenesis of Tourette's syndrome and on principles for treatment of patients with this disorder.

Section snippets

Symptoms and natural history

The cardinal features of Tourette's syndrome are motor and phonic tics that wax and wane in severity.² Motor tics usually begin between the ages of 3 and 8 years, with transient periods of intense eye blinking or some other facial tic. Phonic tics, such as repetitive bouts of sniffing or throat clearing, can begin as early as 3 years of age, but typically they follow the onset of motor tics by several years.³ In uncomplicated cases, severity of motor and phonic tics peaks early in the second

Epidemiology and genetics

Once thought to be a rare disorder,¹² the prevalence of Tourette's syndrome is presently estimated to be between 31 and 157 cases per 1000 in children aged 13–14-years.¹³ Frequency of the disorder varies by age, sex, source of sample, and method of assessment. For example, studies on direct classroom observation and that use multiple informants consistently yield substantially higher prevalence estimates than do other assessment methods. Many patients identified with these techniques have mild

Neural substrates of habit formation and tics

Habits are assembled routines that link sensory cues with motor action. Ideas at present have suggested neural substrates of habit formation are crucial for a better understanding of Tourette's syndrome38, 39, 40, 41, 42 (Figure 3, Figure 4, Figure 5).

Neuroscientists who are interested in learning and habit formation have focused on the motor, sensorimotor, association, inhibitory, and limbic (motivational and threat detection) neural circuits that course through the basal ganglia.39, 40, 41, 42

Developmental models

Future progress in elucidation of the pathogenesis and treatment of Tourette's syndrome could be greatly accelerated with development of animal models. Thus far, the use of psychomotor stimulants, direct dopamine receptor agonists, behavioural stress sensitisation conditioning paradigms, and immune-based challenges to induce different levels of stereotypy in rats and other species seem to offer the greatest promise in modelling key components of the disorder's phenotype.48, 58, 59, 60

If tics,

Assessment and diagnosis

Clinical examination of a child with tics should include an assessment of the child or adolescent as a whole not merely as someone with tics.62, 63 During the examination, the full range of difficulties and competencies should be charted: the clinician, family, and child must collaborate to reconstruct the child's history, tic symptoms (onset, progression, waxing and waning, and factors that have worsened or ameliorated tic status), and present functioning. An important question is the extent

Treatment

Multimodal treatment for Tourette's syndrome is usually indicated.⁶⁹ As noted above, this approach includes educational and supportive interventions appropriate for any chronic disease. Panel 2 outlines possible protective factors for the disorder. The various manifestations of the disorder are best treated in the context of a long-term relationship with a clinician who can help the patient, family, and school deal with the changing manifestations of the disorder through the years. Because

Future prospects

Present ideas about Tourette's syndrome have been shaped by advances in the neurosciences and our emerging understanding of the role of the basal ganglia in learning and habit formation. Although evidence that the same mechanisms have a role in habit formation and tics is circumstantial, progress has set the stage for a major advance in our understanding of this disorder. Continued success in these areas will lead to molecular insights into functioning of neural networks, complexities of

Search strategy and selection criteria

A computerised and manual search on PubMed of published work was done to identify studies about the pathogenesis of Tourette's syndrome and its treatment, with particular focus on original reports published over the past 5 years. Selection criteria included a judgment about novelty and importance of studies and their relevance to the well-informed general medical doctor. In the case of treatment studies, only those interventions whose efficacy has been supported by at least one randomised,

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Cited by (531)

Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome
2023, Neurobiology of Disease
Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron‑sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.
The histamine H3 receptor modulates dopamine D2 receptor–dependent signaling pathways and mouse behaviors
2023, Journal of Biological Chemistry
The histamine H3 receptor (H3R) is highly enriched in the spiny projection neurons (SPNs) of the striatum, in both the D1 receptor (D1R)–expressing and D2 receptor (D2R)–expressing populations. A crossantagonistic interaction between H3R and D1R has been demonstrated in mice, both at the behavioral level and at the biochemical level. Although interactive behavioral effects have been described upon coactivation of H3R and D2R, the molecular mechanisms underlying this interaction are poorly understood. Here, we show that activation of H3R with the selective agonist R-(−)-α-methylhistamine dihydrobromide mitigates D2R agonist–induced locomotor activity and stereotypic behavior. Using biochemical approaches and the proximity ligation assay, we demonstrated the existence of an H3R–D2R complex in the mouse striatum. In addition, we examined consequences of simultaneous H3R–D2R agonism on the phosphorylation levels of several signaling molecules using immunohistochemistry. H3R agonist treatment modulated Akt (serine/threonine PKB)–glycogen synthase kinase 3 beta signaling in response to D2R activation via a β-arrestin 2–dependent mechanism in D2R-SPNs but not in D1R-SPNs. Phosphorylation of mitogen- and stress-activated protein kinase 1 and rpS6 (ribosomal protein S6) was largely unchanged under these conditions. As Akt–glycogen synthase kinase 3 beta signaling has been implicated in several neuropsychiatric disorders, this work may help clarify the role of H3R in modulating D2R function, leading to a better understanding of pathophysiology involving the interaction between histamine and dopamine systems.
Abnormal dynamics of brain functional networks in children with Tourette syndrome
2023, Journal of Psychiatric Research
Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by the presence of multiple motor and vocal tics. Research using resting-state functional magnetic resonance imaging (rfMRI) have found aberrant static functional connectivity (FC) and its topological properties in the brain networks of TS. Our study is the first to investigate the dynamic functional connectivity (dFC) in the whole brain network of TS patients, focusing on the temporal properties of dFC states and the temporal variability of topological organization. The rfMRI data of 36 male children with TS and 27 matched healthy controls were collected and further analyzed by group spatial independent component analysis, sliding windows approach based dFC analysis, k-means clustering analysis, and graph theory analysis. The clustering analysis identified three dFC states. Of these states, state 2, characterized by increased inter-network connections in subcortical network (SCN), sensorimotor network (SMN), and default mode network (DMN), and decreased inter-network connections between salience network (SAN) and executive control network (ECN), was found to have higher fractional window and dwell time in TS, which was also positively correlated with tic severity. TS patients also exhibited higher temporal variability of whole-brain-network global efficiency and local efficiency, and higher temporal variability of nodal efficiency and local efficiency in SCN, DMN, ECN, SAN, and SMN. Additionally, temporal variability of the efficiency and local efficiency in insula was positively correlated with tic severity. Our findings revealed abnormal temporal property of dFC states and temporal variability of topological organization in TS, providing new insights into clinical diagnoses and neuropathology of TS.
Chinese patent medicine - New treatment for tic disorder
2022, Pharmacological Research - Modern Chinese Medicine
As a complex neuropsychiatric disease, tic disorder has a more and more significant impact on children's quality of life. Currently, the existing treatment methods mainly include non-drug and drug treatment, and good results have been achieved in clinic. However, limited to the patient's age and adverse events, other effective and safe treatment methods still need to be sought. Existing studies have shown that Chinese patent medicine have a good curative effect and high safety, which may become a new choice for the treatment of tic disorder.
Effectiveness of Low-Frequency Pallidal Deep Brain Stimulation at 65 Hz in Tourette Syndrome
2022, Neuromodulation
Pallidal deep brain stimulation (DBS) for refractory Tourette syndrome (TS) is often applied using a high frequency. The effectiveness of low-frequency long-term stimulation is unknown. We aimed to evaluate the clinical efficacy of low-frequency DBS applied to the globus pallidus pars internus (GPi) at 65 Hz for the treatment of TS, with long-term follow-up, to provide data for the optimization of stimulation parameters.
A total of six patients with refractory TS were implanted with electrodes in the GPi and were assigned to receive low-frequency (65 Hz) DBS programming. Assessments were performed pre-DBS and at 3, 12, and a median of 34 (range 26–48) months post-DBS. The primary outcome was tic severity, as assessed by the Yale Global Tic Severity Scale (YGTSS), and the secondary outcomes were comorbid behavioral disorders, mood, functioning, and quality of life.
We noted significant differences in the YGTSS scores between the baseline and the post-DBS follow-ups (p = 0.01). At the final follow-up, four of six (66.6%) patients had a greater than 50% reduction in the YGTSS score, whereas the remaining two patients showed a mild worsening of tic severity. The secondary outcome measures also showed remarkable improvements in associated behavioral disorders, mood, functioning, and quality of life. Stimulation-induced adverse effects were not reported, although a device-related complication (an uncomfortable feeling in the neck) occurred in one patient.
The results of this study indicated that low-frequency DBS represents an effective and practical treatment for refractory TS with comparable efficacy to high-frequency DBS.
Altered dynamic functional and effective connectivity in drug-naive children with Tourette syndrome
2024, Translational Psychiatry

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SeminarTourette's syndrome

Summary

Section snippets

Symptoms and natural history

Epidemiology and genetics

Neural substrates of habit formation and tics

Developmental models

Assessment and diagnosis

Treatment

Future prospects

Search strategy and selection criteria

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Psychoneuroendocrinology

Biol Psychiatry

Neuropsychopharmacol

Biol Psychiatry

J Neuroimmunol

Neuron

Neuron

Biol Psychiatry

Lancet

J Neuroimmunol

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Psychiatry

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Behav Res Ther

Pediatr Neurol

Biol Psychiatry

A cursing brain? The histories of Tourette syndrome

Tourette syndrome, associated conditions and the complexities of treatment

Brain

Tics and tic disorders

Course of tic severity in Tourette's syndrome: the first two decades

Pediatrics

Sensory experiences of Gilles de la Tourette syndrome

Arch Gen Psychiatry

Disentangling the overlap between Tourette's disorder and ADHD

J Child Psychol Psychiatry

Social and emotional adjustment in children affected with Gilles de la Tourette's syndrome: associations with ADHD and family functioning

J Child Psychol Psychiatry

Quality of life (QOL) of patients with Gilles de la Tourette's syndrome

Acta Psychiatr Scand

The Great Smoky Mountains Study of Youth: goals, design, methods, and the prevalence of DSM-III-R disorders

Arch Gen Psychiatry

The prevalence of Tourette syndrome in 13–14-year-olds in mainstream schools

J Child Psychol Psychiatry

Prevalence of tics in schoolchildren and association with placement in special education

Neurology

Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance

Am J Hum Genet

A complete genome screen in sib-pairs affected with Gilles de la Tourette syndrome

Am J Hum Genet

Further evidence for linkage of Gilles de la Tourette syndrome (GTS) susceptibility loci on chromosomes 2p1 1, 8q22 and 11q23–24 in South African Afrikaners

Am J Med Genet

Clinical and molecular genetics of ADHD and Tourette syndrome: two related polygenic disorders

Ann N Y Acad Sci

Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities

Arch Gen Psychiatry

Prenatal and perinatal risk factors for Tourette disorder

J Perinat Med

A double-blind, placebo-controlled, crossover trial of an antiandrogen in the treatment of Tourette's syndrome

J Clin Psychopharmacol

Environmental factors and related fluctuation of symptoms in children and adolescents with Tourette's disorder

J Child Psychol Psychiatry

Antineural antibodies in movement disorders

Pediatrics

Antibodies against human putamen in children with Tourette syndrome

Neurology

Antibodies against striatal, nuclear, cytoskeletal and streptococcal epitopes in children and adults with Tourette's syndrome, Sydenham's chorea, and autoimmune disorders

Biol Psychiatry

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases

Am J Psychiatry

Tourette's syndrome and ‘PANDAS’: will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

Neurology

Seminar
Tourette's syndrome