Surgery for Tourette Syndrome

Key Concepts

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by vocal and motor tics, typically with a childhood-onset and significant symptom reduction in early adulthood. Studies have shown a neurodevelopmental deficit in these patients, especially regarding the cortical-striatal-thalamic-cortical loops.
First-line therapy for TS patients should be cognitive behavior therapy and pharmacologic treatment. A significant number of patients fail to experience a decline in tic severity on reaching adulthood and require continuous therapy. For a small subset of patients with severe TS refractory to conservative treatments, surgery can be considered.
Deep brain stimulation (DBS) is currently considered an effective and safe treatment option for TS patients with refractory symptomatology to conservative therapies. This therapy has shown to be effective in the reduction of both motor and vocal tics.
Several brain regions have been targeted for DBS on TS, including the medial part of the thalamus, the anteromedial and posteroventral segments of the globus pallidus internus, the globus pallidus externus, the internal capsule/nucleus accumbens, and the subthalamic nucleus, showing positive results on the reduction of symptoms in the majority of cases. The best target for neurostimulation in TS has not yet been established.
Documentation and registration of TS patients undergoing DBS surgery has improved in the past years, in particular thanks to projects like the International Deep Brain Stimulation Registry. The availability of this information, together with new technologies like adaptive stimulation and imaging techniques like tractography, will hopefully improve our knowledge about this therapy and ultimately lead to progress in patient benefit.

a Contributed equally to this work.

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by vocal and motor tics. TS develops characteristically during infancy, with a childhood prevalence of approximately 0.3% to 1% of the worldwide population. ^, Tics are sudden, rapid, involuntary movements or phonations that can be defined as simple or complex. Simple motor tics involve only one muscle group and can be divided into clonic (e.g., head jerking or blinking), dystonic (e.g., bruxism or torticollis), or tonic tics (e.g., muscle tensing without actual movement). Complex motors tics are coordinated movements that in many cases may appear purposeful but are inappropriately timed or intense. Simple vocal tics involve throat clearing, sniffing, coughing, or shouting. Complex vocal tics might display as coprolalia, echolalia, or palilalia. Tics are often temporarily suppressible and are usually accompanied by uncomfortable premonitory sensations or urges that are relieved after execution of the tic. The number, complexity, and frequency of tics fluctuate during the course of the disease. Symptoms usually start at around 5 to 7 years of age and peak at around 10 years of age. About 85% of TS patients are diagnosed with a further neuropsychiatric comorbidity, such as attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), depression, or anxiety disorders. TS is usually self-limiting, with more than one-half of patients becoming tic free or only displaying mild symptoms by the time they reach early adulthood. This waning pattern should be taken into consideration when choosing therapeutic strategies. Treatment options include psychotherapeutic approaches and primarily antidopaminergic drugs. For adult patients with persisting and severe tics affecting quality of life and level of functioning, which are refractory to cognitive behavior therapy (CBT) and pharmacologic treatment, surgical therapy can be considered.

Pathophysiology

First reported by Jean Itard in 1825 and then by Georges Gilles de la Tourette in 1885, the syndrome was originally described as a paroxysmal tic disorder. TS was considered for many years as a psychogenic disorder, and therefore it was not initially treated as an organic condition. The understanding of TS pathophysiology has developed in the past decades. However, many aspects of this disorder are still unclear. Anatomic and physiologic findings suggest dysfunction in frontostriatal networks involved in motor control, specifically the cortical-striatal-thalamic-cortical (CSTC) loops, which have also been associated with OCD and ADHD. ^, These circuits overlap and interact with each other forming a complex connection between the basal ganglia and the limbic, associative, and sensory-motor cortical networks. In TS patients, there seems to be an imbalance in the inhibitory and stimulating neurons between limbic and sensory-motor/associative loops. ^, Functional imaging studies showed that the activation of different brain regions in fMRI during tic generation follows the CSTC circuit, starting from cortical areas like the supplementary motor area or the primary motor cortex. Based on the early onset and decline in severity of symptoms in adulthood, it has been hypothesized that TS is a neurodevelopmental disorder. Supporting this, imaging studies have shown a higher functional disorganization with increased global integration, however, lower structural connectivity within the CSTC loops of TS patients, ^, signifying a delayed maturation. Furthermore, when comparing networks involved in task control, connectivity patterns of adolescent TS patients were shown to be more similar to those of younger healthy controls than those of age-matched controls.

Several neurotransmitters are involved in the circuitry of the CSTC loops and have therefore been considered to be associated with the development of TS. However, none of them emerged as a solitary pathologic factor responsible for the symptomatology. Evidence indicates that dysregulation in the tonic and phasic release of dopamine plays a major role in tic formation; however, abnormalities in the glutamate, GABA, norepinephrine, serotonin, acetylcholine, histamine, and endogenous opioids system have also been described. ^,

TS is a highly heritable disease; however, like in many other heritable neuropsychiatric disorders, there is no clear association to a single nucleoid polymorphism. Therefore, it is considered to have a polygenic and multifactorial pathogenesis, fitting the heterogenous development of TS patients.

Diagnostics

The diagnosis of TS is entirely based on clinical symptoms. Diagnostic criteria consist of childhood onset of multiple chronic motor tics and one or more phonic tics that persist for at least 1 cumulative year. If necessary, one should exclude other diseases (Wilson disease, cerebro-organic changes) with appropriate investigations. Children with TS often display symptoms of other accompanying neuropsychiatric disorders that can significantly delay diagnosis. On average, it takes around 5 years from first symptoms to diagnosis. Nevertheless, it is crucial to start psychological and medical support as early as possible, as these children often experience social exclusion and severe psychological distress if their environment is uninformed about their condition.

Treatment

Symptoms and objective impairment are very variable in TS patients. In many cases, psychoeducational support is sufficient for a good quality of life; therefore, only a small proportion of patients seek further medical treatment. Before starting therapy, it is required to evaluate whether there are existing comorbidities that should be prioritized for treatment, like ADHD or OCD. Most patients experience such a significant decrease in tics during adolescence, that eventually they do not require further treatment. However, about 20% to 30% of patients continue having symptoms in adulthood, and a small number may even experience tic worsening. Presently, there is no permanent cure for tics in TS; therefore, all therapies focus on reducing the intensity and duration of symptoms.

Noninvasive Treatment Options

CBT, especially habit-reversal training, is an effective treatment option with no known side effects. It can function as a solitary therapy in both adults and children, especially in mild or moderate cases, ^, but should be recommended to all patient groups as additional therapy. There are also several pharmacologic therapy options available. Typical antipsychotics, like haloperidol or pimozide, have been the longest prescribed medical treatment for tic reduction. However, severe adverse reactions like drowsiness, extrapyramidal motor reactions, anxiety, hyperprolactinemia, or weight gain may occur, especially with higher dosages and when administered over longer periods. Atypical antipsychotics, like risperidone, also show a good clinical effect. Adverse effects like the ones described for typical antipsychotics are less common; however, severe depression has been reported. Olanzapine or quetiapine have also shown significant tic reduction, with the most common adverse effect being drowsiness and weight gain. In the past decade, aripiprazole emerged as a promising alternative. It is relatively well tolerated by TS patients and has significantly fewer serious adverse effects. ^, It also seems to have a positive effect on the most common comorbidities like OCD, depression, and ADHD. α ₂ -Adrenergic agonists like clonidine are recommended for patients with ADHD as the dominant disorder.

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