Comment
Tourette’s syndrome is increasingly appreciated as a neural circuit disorder stemming from dysfunction within the cortical-striatal-thalamic-cortical loops that are crucial in human movement and behavior.1 Similar to other movement and neuropsychiatric disorders (including Parkinson’s disease and obsessive-compulsive disorder) linked to the same circuitry, the main manifestations of Tourette’s syndrome (motor and phonic tics) are amenable to treatment with deep brain stimulation (DBS).2 In The Lancet Neurology, Zinovia Kefalopoulou and colleagues3 present results from the first double-blind, randomised trial of anteromedial stimulation of the globus pallidus internus (GPi) in individuals with medication-refractory Tourette’s syndrome. The results showed small benefits in tic reduction in the largest cohort (n=15) studied in this blinded fashion. A growing interest in DBS for Tourette’s syndrome has guided the exploration of several targets, with various rationales for their selection.4 The bulk of previous experience relates to stimulation of the centromedianparafascicular complex (Cm/Pf) of the thalamus.5 Previous blinded, randomised trials of a single target both used Cm/Pf stimulation,6,7 which brought to light several challenges in trial design. Maciunas and colleagues6 enrolled five patients into a randomised trial with 7 day sequences of unilateral left, unilateral right, bilateral on, or bilateral off stimulation, and 3 month open-label bilateral stimulation. DBS parameters were selected during a single programming session before randomisation. The blinded bilateral on-stimulation condition yielded a video-based 53% reduction in motor tics and 70% reduction in phonic tics compared with baseline. After open-label stimulation, the motor tic reduction was 40%, while phonic tics increased by 21%. Ackermans and colleagues7 randomly assigned six patients to on stimulation versus off stimulation for 3 months after surgery, followed by a 3 month crossover and 6 months of open-label stimulation. Programming parameters were titrated over 3 weeks before randomisation. Four patients withdrew early from blinded sequences. Blinded on stimulation produced a 37% improvement in the Yale Global Tic Severity Scale (YGTSS), compared with the off-stimulation condition, whereas 49%
improvement occurred after open-label stimulation. In both studies, only some patients showed improvement. Open-label reports of GPi DBS in Tourette’s syndrome have been muddled because of variable GPi targeting. Some groups have studied stimulation of the posteroventral GPi, the motor subregion of the nucleus, whereas others (including Kefalopoulou and colleagues) have implanted within the anteromedial GPi or limbic subregion.5 Kefalopoulou and colleagues3 reported that bilateral anteromedial GPi DBS was associated with 15% tic improvement on the YGTSS during stimulation, compared with the off-stimulation condition, and 40% reduction in open-label follow-up (up to 36 months), using the same design as Ackermans and colleagues.7 Initial programming parameters were identified during a 1 week period before randomisation. Settings were intentionally subtherapeutic to avoid unblinding due to stimulation effects, but several patients already had reduced ratings at randomisation, probably from insertion of the DBS lead (microlesion effect). Despite allowance for stimulation adjustments or pseudoadjustments, three patients withdrew from the blinded phase of the trial. Electrode targeting differed from the original anteromedial GPi in two patients for whom investigators thought posteroventral GPi stimulation might be beneficial, because of a prominence of dystonic movements. Six patients had no clear benefit during blinded assessments but improved during openlabel stimulation after reprogramming. Why have blinded, randomised trials of DBS in Tourette’s syndrome failed to live up to the hype of openlabel experience, in which more than 50% tic reduction is often reported?5 One important consideration is trial design. Previously encou`ntered difficulties6,7 for which Kefalopoulou3 and colleagues provide further insight include how and whether to optimise stimulation before randomisation (not optimised in this study), optimum duration of stimulation sequences (3 months in each condition used in the present study), how best to account for microlesion effects and washout (Kefalopoulou and colleagues waited 6 weeks after electrode placement for assessment and programming and allowed 3 months between assessments during randomised sequences), whether to use video or YGTSS as an outcome measure (both collected), how to prevent patient unmasking of
www.thelancet.com/neurology Published online April 14, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00043-5
Vincent Moncorge/Look at Sciences/Science Photo Library
Design challenges for stimulation trials of Tourette’s syndrome
Lancet Neurol 2015 Published Online April 14, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00043-5 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(15)00008-3
1
Comment
For the Tourette Syndrome Association’s international database and registry see http://dbs.tsa-usa.org/
2
stimulation condition (use of subtherapeutic settings), how to account for variability in symptoms over time (stimulation adjustments or pseudo-adjustments were allowed during the randomised sequences), and how to enhance patient acceptance of blinded stimulation conditions (adjustments were allowed during randomised stimulation, and patients had the opportunity to proceed to an open-label phase). The relative ability of a trial to resolve these concerns without compromising efficacy or efficiency raises the question of whether a randomised, double-blind crossover design is best-suited to study the effects of DBS in Tourette’s syndrome. A delayed, blinded programming start with periods of brief reduction or withdrawal of stimulation could resolve some, but not all, concerns. Programming strategies for DBS in Tourette’s syndrome are not well defined and further investigation and experience of this approach will be informative for future trials. Much like DBS in dystonia, optimisation of DBS in Tourette’s syndrome could well take several months, and study designs will need to ensure that outcomes are measured after a steady state is achieved. Lastly, the choice of posteroventral GPi stimulation in two patients in this study underscores the uncertainty of target selection; as the investigators suggest, comparative studies are needed, although further insight might also come from neurophysiological investigations8 and the Tourette Syndrome Association’s international database and registry.
Despite the difficulties, the opportunity to show robust tic reduction through randomised, blinded studies of DBS in Tourette’s syndrome still exists. If these opportunities to enhance investigative efforts are pursued, more robust tic reduction might be shown in future randomised, blinded studies. Joohi Jimenez-Shahed Deep Brain Stimulation Program, Baylor College of Medicine, Parkinson’s Disease Center and Movement Disorders Clinic, Houston, TX 77030, USA [email protected] I have received consulting fees and honoraria from Medtronic. 1 2 3
4
5
6
7
8
DeLong M, Wichmann T. Changing views of basal ganglia circuits and circuit disorders. Clin EEG Neurosci 2010; 41: 61–67. Wichmann T, Delong MR. Deep-brain stimulation for basal ganglia disorders. Basal Ganglia 2011; 1: 65–77. Kefalopoulou Z, Zrinzo L, Jahanshahi M, et al. Bilateral globus pallidus stimulation for severe Tourette’s syndrome: a double-blind, randomised crossover trial. Lancet Neurol 2015; published online April 14. http://dx.doi. org/10.1016/S1474-4422(15)00008-3. Viswanathan A, Jimenez-Shahed J, Baizabal Carvallo JF, Jankovic J. Deep brain stimulation for Tourette syndrome: target selection. Stereotact Funct Neurosurg 2012; 90: 213–24. Schrock LE, Mink JW, Woods DW, et al. Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord 2014, published online Dec 5. DOI:10.1002/mds.26094. Maciunas RJ, Maddux BN, Riley DE, et al. Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome. J Neurosurg 2007; 107: 1004–14. Ackermans L, Duits A, van der Linden C, et al. Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome. Brain 2011; 134: 832–44. Maling N, Hashemiyoon R, Foote KD, Okun MS, Sanchez JC. Increased thalamic gamma band activity correlates with symptom relief following deep brain stimulation in humans with Tourette’s syndrome. PLoS One 2012; 7: e44215.
www.thelancet.com/neurology Published online April 14, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00043-5
Tourette’s syndrome is increasingly appreciated as a neural circuit disorder stemming from dysfunction within the cortical-striatal-thalamic-cortical loops that are crucial in human movement and behavior.1 Similar to other movement and neuropsychiatric disorders (including Parkinson’s disease and obsessive-compulsive disorder) linked to the same circuitry, the main manifestations of Tourette’s syndrome (motor and phonic tics) are amenable to treatment with deep brain stimulation (DBS).2 In The Lancet Neurology, Zinovia Kefalopoulou and colleagues3 present results from the first double-blind, randomised trial of anteromedial stimulation of the globus pallidus internus (GPi) in individuals with medication-refractory Tourette’s syndrome. The results showed small benefits in tic reduction in the largest cohort (n=15) studied in this blinded fashion. A growing interest in DBS for Tourette’s syndrome has guided the exploration of several targets, with various rationales for their selection.4 The bulk of previous experience relates to stimulation of the centromedianparafascicular complex (Cm/Pf) of the thalamus.5 Previous blinded, randomised trials of a single target both used Cm/Pf stimulation,6,7 which brought to light several challenges in trial design. Maciunas and colleagues6 enrolled five patients into a randomised trial with 7 day sequences of unilateral left, unilateral right, bilateral on, or bilateral off stimulation, and 3 month open-label bilateral stimulation. DBS parameters were selected during a single programming session before randomisation. The blinded bilateral on-stimulation condition yielded a video-based 53% reduction in motor tics and 70% reduction in phonic tics compared with baseline. After open-label stimulation, the motor tic reduction was 40%, while phonic tics increased by 21%. Ackermans and colleagues7 randomly assigned six patients to on stimulation versus off stimulation for 3 months after surgery, followed by a 3 month crossover and 6 months of open-label stimulation. Programming parameters were titrated over 3 weeks before randomisation. Four patients withdrew early from blinded sequences. Blinded on stimulation produced a 37% improvement in the Yale Global Tic Severity Scale (YGTSS), compared with the off-stimulation condition, whereas 49%
improvement occurred after open-label stimulation. In both studies, only some patients showed improvement. Open-label reports of GPi DBS in Tourette’s syndrome have been muddled because of variable GPi targeting. Some groups have studied stimulation of the posteroventral GPi, the motor subregion of the nucleus, whereas others (including Kefalopoulou and colleagues) have implanted within the anteromedial GPi or limbic subregion.5 Kefalopoulou and colleagues3 reported that bilateral anteromedial GPi DBS was associated with 15% tic improvement on the YGTSS during stimulation, compared with the off-stimulation condition, and 40% reduction in open-label follow-up (up to 36 months), using the same design as Ackermans and colleagues.7 Initial programming parameters were identified during a 1 week period before randomisation. Settings were intentionally subtherapeutic to avoid unblinding due to stimulation effects, but several patients already had reduced ratings at randomisation, probably from insertion of the DBS lead (microlesion effect). Despite allowance for stimulation adjustments or pseudoadjustments, three patients withdrew from the blinded phase of the trial. Electrode targeting differed from the original anteromedial GPi in two patients for whom investigators thought posteroventral GPi stimulation might be beneficial, because of a prominence of dystonic movements. Six patients had no clear benefit during blinded assessments but improved during openlabel stimulation after reprogramming. Why have blinded, randomised trials of DBS in Tourette’s syndrome failed to live up to the hype of openlabel experience, in which more than 50% tic reduction is often reported?5 One important consideration is trial design. Previously encou`ntered difficulties6,7 for which Kefalopoulou3 and colleagues provide further insight include how and whether to optimise stimulation before randomisation (not optimised in this study), optimum duration of stimulation sequences (3 months in each condition used in the present study), how best to account for microlesion effects and washout (Kefalopoulou and colleagues waited 6 weeks after electrode placement for assessment and programming and allowed 3 months between assessments during randomised sequences), whether to use video or YGTSS as an outcome measure (both collected), how to prevent patient unmasking of
www.thelancet.com/neurology Published online April 14, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00043-5
Vincent Moncorge/Look at Sciences/Science Photo Library
Design challenges for stimulation trials of Tourette’s syndrome
Lancet Neurol 2015 Published Online April 14, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00043-5 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(15)00008-3
1
Comment
For the Tourette Syndrome Association’s international database and registry see http://dbs.tsa-usa.org/
2
stimulation condition (use of subtherapeutic settings), how to account for variability in symptoms over time (stimulation adjustments or pseudo-adjustments were allowed during the randomised sequences), and how to enhance patient acceptance of blinded stimulation conditions (adjustments were allowed during randomised stimulation, and patients had the opportunity to proceed to an open-label phase). The relative ability of a trial to resolve these concerns without compromising efficacy or efficiency raises the question of whether a randomised, double-blind crossover design is best-suited to study the effects of DBS in Tourette’s syndrome. A delayed, blinded programming start with periods of brief reduction or withdrawal of stimulation could resolve some, but not all, concerns. Programming strategies for DBS in Tourette’s syndrome are not well defined and further investigation and experience of this approach will be informative for future trials. Much like DBS in dystonia, optimisation of DBS in Tourette’s syndrome could well take several months, and study designs will need to ensure that outcomes are measured after a steady state is achieved. Lastly, the choice of posteroventral GPi stimulation in two patients in this study underscores the uncertainty of target selection; as the investigators suggest, comparative studies are needed, although further insight might also come from neurophysiological investigations8 and the Tourette Syndrome Association’s international database and registry.
Despite the difficulties, the opportunity to show robust tic reduction through randomised, blinded studies of DBS in Tourette’s syndrome still exists. If these opportunities to enhance investigative efforts are pursued, more robust tic reduction might be shown in future randomised, blinded studies. Joohi Jimenez-Shahed Deep Brain Stimulation Program, Baylor College of Medicine, Parkinson’s Disease Center and Movement Disorders Clinic, Houston, TX 77030, USA [email protected] I have received consulting fees and honoraria from Medtronic. 1 2 3
4
5
6
7
8
DeLong M, Wichmann T. Changing views of basal ganglia circuits and circuit disorders. Clin EEG Neurosci 2010; 41: 61–67. Wichmann T, Delong MR. Deep-brain stimulation for basal ganglia disorders. Basal Ganglia 2011; 1: 65–77. Kefalopoulou Z, Zrinzo L, Jahanshahi M, et al. Bilateral globus pallidus stimulation for severe Tourette’s syndrome: a double-blind, randomised crossover trial. Lancet Neurol 2015; published online April 14. http://dx.doi. org/10.1016/S1474-4422(15)00008-3. Viswanathan A, Jimenez-Shahed J, Baizabal Carvallo JF, Jankovic J. Deep brain stimulation for Tourette syndrome: target selection. Stereotact Funct Neurosurg 2012; 90: 213–24. Schrock LE, Mink JW, Woods DW, et al. Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord 2014, published online Dec 5. DOI:10.1002/mds.26094. Maciunas RJ, Maddux BN, Riley DE, et al. Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome. J Neurosurg 2007; 107: 1004–14. Ackermans L, Duits A, van der Linden C, et al. Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome. Brain 2011; 134: 832–44. Maling N, Hashemiyoon R, Foote KD, Okun MS, Sanchez JC. Increased thalamic gamma band activity correlates with symptom relief following deep brain stimulation in humans with Tourette’s syndrome. PLoS One 2012; 7: e44215.
www.thelancet.com/neurology Published online April 14, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00043-5
