Background
Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterised by the presence of multiple motor and vocal tics, related to dysfunctional fronto-subcortical pathways involved in motor generation (Fig. 1). In the majority of patients, tics are associated with specific tic-related symptoms (echo-, pali- and coprophenomena, self-injurious behaviours, non-obscene socially inappropriate behaviours) and co-morbid psychiatric disorders, including attention deficit-hyperactivity disorder and obsessive-compulsive disorder (Table I). The presence of these tic-related symptoms and psychiatric co-morbidities is frequently accompanied by social impairment, which in turn reflects poor health-related quality of life. Treatment strategies for TS include pharmacological and behavioural therapy, plus invasive procedures such as deep brain stimulation (DBS) for severe, treatment-refractory cases (Table II, Figs. 2, 3). Despite being central to the eligibility of candidates for functional neurosurgery, the concept of “refractory patients” has never been adequately discussed and defined in TS. We set out to 1) review the available literature on the selection of treatment-refractory patients as candidates for DBS and 2) propose a pragmatic approach to the implementation of the concept of treatment refractoriness in the treatment algorithm for TS.
Methods
We systematically reviewed the scientific literature on treatmentrefractory patients with TS by using the search terms “refractory”, “resistant”, “tic”, “Tourette syndrome”. Results Treatment-refractory patients with TS are poorly defined in the scientific literature. The only papers dealing with this concept are studies on the efficacy and tolerability of innovative treatment strategies, namely DBS (Table III). The USA-TSA guidelines for DBS in TS recommend that candidates for DBS are refractory to conventional medical therapy, defined as non-responsive to trials of medications from three different classes – a-adrenergic agonists, dopamine antagonists (typical and atypical) and a benzodiazepine. In Europe, the Dutch-Flemish group, who pioneered DBS in TS, define treatment refractoriness as partial/ non-response or intolerance of side-effects, to three medication regimens of different classes (typical, atypical and experimental, e.g. pergolide), which have been tried for at least 12 weeks each and at adequate dosage. However, it is clear from the analysis of the work of other groups that there is no European consensus on the concept of “refractory patients” for this particular condition.
Conclusions
The concept of refractoriness is central and of practical importance in the management of patients with TS, especially in assisting decision making for referral to more invasive treatments (both off-label pharmacological interventions and DBS). At present, there is no general consensus on the definition of the “refractory patient” (e.g. potential candidate for DBS) in TS. Based on our clinical experience (18/38 case reports on DBS in TS are from this centre), we propose a pragmatic definition of “treatment-refractory TS” which takes into account the complex presentation of the behavioural spectrum of TS (Fig. 4). Patients with TS should be considered refractory to treatment if they show no significant improvement in health-related quality of life in response to trials of conventional (typical and atypical neuroleptics) and innovative (including dopamine depletors, such as tetrabenazine, and botulinum injections) anti-tic medications, plus selective serotonin-reuptake inhibitors (e.g. fluvoxamine) and tricyclics (clomipramine) for tic-related obsessive-compulsive symptoms.