Double-blind Clinical Trial of Thalamic Stimulation in Patients with Tourette Syndrome

Linda Ackermans; Annelien Duits; Chris van der Linden; Marina Tijssen; Koen Schruers; Yasin Temel; Mariska Kleijer; Pieter Nederveen; Richard Bruggeman; Selma Tromp; Vivianne van Kranen-Mastenbroek; Herman Kingma; Danielle Cath; Veerle Visser-Vandewalle

Disclosures

Brain. 2011;134(3):832-844. 

In This Article

Abstract and Introduction

Abstract

Deep brain stimulation of the thalamus has been proposed as a therapeutic option in patients with Tourette syndrome who are refractory to pharmacological and psychotherapeutic treatment. Patients with intractable Tourette syndrome were invited to take part in a double-blind randomized cross-over trial assessing the efficacy and safety of stimulation of the centromedian nucleus - substantia periventricularis - nucleus ventro-oralis internus crosspoint in the thalamus. After surgery, the patients were randomly assigned to 3 months stimulation followed by 3 months OFF stimulation (Group A) or vice versa (Group B). The cross-over period was followed by 6 months ON stimulation. Assessments were performed prior to surgery and at 3, 6 months and 1 year after surgery. The primary outcome was a change in tic severity as measured by the Yale Global Tic Severity Scale and the secondary outcome was a change in associated behavioural disorders and mood. Possible cognitive side effects were studied during stimulation ON at 1 year postoperatively. Interim analysis was performed on a sample of six male patients with only one patient randomized to Group B. Tic severity during ON stimulation was significantly lower than during OFF stimulation, with substantial improvement (37%) on the Yale Global Tic Severity Scale (mean 41.1 ± 5.4 versus 25.6 ± 12.8, P = 0.046). The effect of stimulation 1 year after surgery was sustained with significant improvement (49%) on the Yale Global Tic Severity Scale (mean 42.2 ± 3.1 versus 21.5 ± 11.1, P = 0.028) when compared with preoperative assessments. Secondary outcome measures did not show any effect at a group level, either between ON and OFF stimulation or between preoperative assessment and that at 1 year postoperatively. Cognitive re-assessment at 1 year after surgery showed that patients needed more time to complete the Stroop Colour Word Card test. This test measures selective attention and response inhibition. Serious adverse events included one small haemorrhage ventral to the tip of the electrode, one infection of the pulse generator, subjective gaze disturbances and reduction of energy levels in all patients. The present preliminary findings suggest that stimulation of the centromedian nucleus - substantia periventricularis - nucleus ventro-oralis internus crosspoint may reduce tic severity in refractory Tourette syndrome, but there is the risk of adverse effects related to oculomotor function and energy levels. Further randomized controlled trials on other targets are urgently needed since the search for the optimal one is still ongoing.

Introduction

Tourette syndrome is a neuropsychiatric disorder characterized by sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics) or sounds (phonic or vocal tics) (Mink, 2001; Leckman et al., 2006). Tics are often preceded by a premonitory urge or sensation. Onset is in early childhood and tic frequency and intensity usually wax and wane during the natural course of the disease (Mink, 2001; Leckman et al., 2006). Patients may also suffer from sleep disturbances, learning disorders, anxiety and depression (Robertson, 2000). Moreover, Tourette syndrome is often accompanied by behavioural disorders such as attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder and behaviour, as well as self-injurious behaviour (Leckman et al., 2006). Tics and associated disorders can have a serious impact on the overall quality of life. The occurrence of ADHD in patients with Tourette syndrome ranges from 21–90% (Leckman et al., 2006). Obsessive–compulsive behaviour may be present in up to 75% of patients with Tourette syndrome (Robertson, 2000). Obsessive behaviour in Tourette syndrome frequently involves sexual, violent, religious, aggressive and symmetrical themes, while compulsive behaviour is often related to checking, counting, forced touching and self-damage (Robertson, 2000). Over one-third of clinical patients with Tourette syndrome may suffer from self-injurious behaviour, with head banging being the most frequently reported type (Robertson et al., 1989).

Tourette syndrome is frequently a self-limiting disorder with remission or significant improvement around 20 years of age. However, in about 20% of patients, tics continue into adult life and require long-term treatment (Bloch and Leckman, 2009). Behavioural therapy and medication may provide temporary relief from symptoms but some patients remain refractory to medical therapy or experience unbearable side-effects. In 1999, deep brain stimulation was introduced as a new approach to treat intractable Tourette syndrome (Vandewalle et al., 1999). The target was located in the medial part of the thalamus at the centromedian nucleus-substantia periventricularis-nucleus ventro-oralis internus crosspoint of the thalamus. This was based on thalamotomies performed in patients with Tourette syndrome by Hassler and Dieckman (1970) and ideas about the role of this specific part of the thalamus within cortico-basal ganglia-thalamocortical circuits.

In a small case series (n = 3) (Visser-Vandewalle et al., 2003) a positive effect on both tics and associated disorders was observed and patients reported a better quality of life, postoperatively. Stimulation-induced side-effects included erectile dysfunction and reduced energy levels (Visser-Vandewalle et al., 2003; Temel et al., 2004). Long-term evaluation was performed in two patients at 6 and 10 years postoperatively. They demonstrated continued benefit of tic control, 78 and 92%, respectively (Ackermans et al., 2010). Clinical observations and neuroimaging suggest that dysfunction of the basal ganglia and related thalamocortical circuits form part of the pathophysiological basis of Tourette syndrome (Mink and Thach, 1993; Albin and Mink, 2006). The basal ganglia are thought to play a major role in the timing and sequencing of movement and behaviour by selecting desired programmes and suppressing unwanted ones (Singer, 1997). The basal ganglia thereby influence the (pre)frontal cortex, via the thalamus and modulate behavioural and/or motor responses. Uncontrolled movements and behavioural disorders in Tourette syndrome may therefore be the result of defective inhibitory mechanisms at the level of the basal ganglia circuits. Deep brain stimulation may act by modulating the relay functions of the thalamus between the basal ganglia and the cortex. Although Tourette syndrome is characterized by difficulty in suppressing involuntary behaviour, the ability to inhibit highly prepotent voluntary responses suggests impairment in response control mechanisms at the striatal rather than the cortical level (Watkins et al., 2005).

Since 1999, 10 different brain areas have been described as a target for deep brain stimulation in Tourette syndrome, including the centromedian nucleus - substantia periventricularis - nucleus ventro-oralis internus crosspoint of the thalamus (Bawja et al., 2007; Maciunas et al., 2007; Shield et al., 2008). The Milan group (Servello et al., 2008) targeted a similar area 2 mm more anterior. The Paris group (Houeto et al., 2005; Welter et al., 2008) targeted the centromedian nucleus, and the dorsomedial thalamus was targeted in a single patient (Vernaleken et al., 2009). Other targets outside the thalamus include the globus pallidus externus (Vilela Filho et al., 2007) and internus with both the ventroposterolateral motor and the anteromedial limbic part targeted in refractory Tourette syndrome (van der Linden et al., 2002; Diederich et al., 2005; Gallagher et al., 2006; Shahed et al., 2007; Dehning et al. 2008; Welter et al., 2008; Dueck et al., 2009). The nucleus accumbens (Kuhn et al., 2007; Zabek et al., 2008; Neuner et al., 2009; Servello et al., 2009; Burdick et al., 2010) and the anterior limb of the internal capsule (Kuhn et al., 2007; Shields et al., 2008; Servello et al., 2009; Burdick et al., 2010) have also been targeted in patients with Tourette syndrome, particularly in those suffering from obsessive–compulsive behaviour. Finally, an improvement of tics after deep brain stimulation of the subthalamic nucleus was noted in a patient suffering from Parkinson's disease and tics (Martinez-Torres et al., 2009).

The effect of centromedian nucleus - substantia periventricularis - nucleus ventro-oralis internus stimulation on tics and associated disorders was examined in a randomized double-blind cross-over trial comparing the effect of stimulation ON with that of stimulation OFF. Evaluation at 1 year follow-up with stimulation ON was also conducted. The primary outcome was a change in tic severity and the secondary outcome a change in associated behavioural disorders and mood. Cognition was tested during stimulation ON at 1 year postoperatively, in order to evaluate the safety of this procedure with regard to possible side-effects.

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