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• Reducing Uncertainty and Expanding Patient Engagement in Deep Brain Stimulation Trials for Tourette Syndrome
  Kara A Johnson, Marwan Hariz, Thomas Foltynie, Ludvic Zrinzo, Aysegul Gunduz, Kelly D Foote, Michael S Okun, Joseph J Fins and Christopher R Butson
  Published on: 12 September 2019

• Published on: 12 September 2019

  Reducing Uncertainty and Expanding Patient Engagement in Deep Brain Stimulation Trials for Tourette Syndrome

  • Kara A Johnson, Graduate Research Fellow, Department of Biomedical Engineering, Scientific Computing & Imaging (SCI) Institute University of Utah
  • Other Contributors:
    • Marwan Hariz, Neurosurgeon
    • Thomas Foltynie, Neurologist
    • Ludvic Zrinzo, Neurosurgeon
    • Aysegul Gunduz, Associate Professor
    • Kelly D Foote, Neurosurgeon
    • Michael S Okun, Neurologist
    • Joseph J Fins, Professor
    • Christopher R Butson, Associate Professor

  We appreciate the editorial by Dr. Muller-Vahl [1] about our recent article [2]. The large, international study group who co-authored our paper collectively felt that it would be useful to provide clarification of a few important points regarding the International Tourette Syndrome (TS) Deep Brain Stimulation (DBS) Database and Registry, the International Neuromodulation Registry, and our published analysis.

  There is widespread agreement on the need for more randomized controlled trials (RCTs) to evaluate the efficacy of DBS for many indications, including TS, and there has been substantial discussion in the medical community about how these trials should be organized and carried out [3]. Our approach to overcome the challenges with the modest amount of data available for surgical therapies for TS has been to use symbiotic data sharing [4]. This approach encourages the broadening of investigative teams after publication of clinical studies to perform additional analyses and to develop new hypotheses. The key concept behind this approach is that new investigators work in a close, collaborative relationship with the teams that conducted the initial data collection. In addition, a recent viewpoint from the Food & Drug Administration in the United States reported that “For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of...

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  We appreciate the editorial by Dr. Muller-Vahl [1] about our recent article [2]. The large, international study group who co-authored our paper collectively felt that it would be useful to provide clarification of a few important points regarding the International Tourette Syndrome (TS) Deep Brain Stimulation (DBS) Database and Registry, the International Neuromodulation Registry, and our published analysis.

  There is widespread agreement on the need for more randomized controlled trials (RCTs) to evaluate the efficacy of DBS for many indications, including TS, and there has been substantial discussion in the medical community about how these trials should be organized and carried out [3]. Our approach to overcome the challenges with the modest amount of data available for surgical therapies for TS has been to use symbiotic data sharing [4]. This approach encourages the broadening of investigative teams after publication of clinical studies to perform additional analyses and to develop new hypotheses. The key concept behind this approach is that new investigators work in a close, collaborative relationship with the teams that conducted the initial data collection. In addition, a recent viewpoint from the Food & Drug Administration in the United States reported that “For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of the device without the need for conducting detailed trials. For the majority of devices, the benefits and risks are expected to be manifest through registries and evolve as clinical techniques are refined and the technologies themselves are rapidly modified and improved. Such a continuous improvement cycle would be impossible if every device iteration required a full trial to test its safety and efficacy” [5]. We believe that the candidate population for TS DBS therapy falls squarely within this description, particularly as new capabilities are being added to commercially available DBS systems (e.g. directional electrodes, current steering, and closed loop stimulation to name a few). Hence, the type of secondary data analysis we reported was intended to support, rather than circumvent, future RCTs.

  There is not a current consensus on how future RCTs should be designed. Enrollment can be challenging given so few cases are implanted, even at centers with extensive DBS experience. We have previously published post-hoc analyses of failed RCTs using neurostimulation devices. For example, one study strongly suggested the trial would have reached its primary endpoint if it was designed to better accommodate known sources of variability such as lead location, type of stimulation, or the length of time given to assess primary outcomes [6]. Our purpose in performing these types of analyses is not to be overly critical of past RCTs, but rather to make use of lessons learned in order to design more effective future trials. While much of the TS DBS registry data in our study was open label, and therefore we cannot rule out placebo response, only a few patients chose to be explanted for lack of effectiveness. Our 12 month data on the effectiveness and safety of DBS for TS [7] revealed that one patient was explanted and one patient underwent pulse generator removal. In addition, the therapeutic effect size in most of the responders was substantial and durable. Lastly, for a few cases in which the pulse generator battery was inadvertently depleted without the patient’s knowledge, the sudden recurrence of symptoms suggests positive and reversible effects of DBS. When combined with the positive outcomes of two successful RCTs of DBS for TS [8,9], we feel that our data provide sufficient evidence to support future studies. These studies should be designed to accommodate several known sources of variability identified through the analyses of the TS DBS registry. Hence, our goal was to report how DBS for TS has been applied across multiple international sites and to generate testable hypotheses to guide future studies.

  Our study revealed that the anatomical location of the applied stimulation did not fully explain the variability in clinical outcomes across patients. In an effort to further disentangle the complexities of this treatment, we are preparing a forthcoming paper that includes additional analyses on our cohort. The results suggest that there may be a common network that is correlated with clinical improvement across surgical targets, which could provide important insights on the underlying TS network and how neuromodulation can be refined. Importantly, this type of analysis would not be possible without a TS database and registry.

  In closing, we agree with the value of additional RCTs as suggested by Dr. Muller-Vahl; however we must also recognize the current logistical difficulties and be creative and pluralistic in our methodologic approaches. In addition, we suggest the greater inclusion of patient voice in driving the research agenda consistent with the disability rights adage, “nothing about us without us" [10]. Instead of the prescriptive critique of Muller-Vahl, we should strive to develop more adaptive patient-centered methodologies. Through this effort we will be better positioned to meet the needs of individuals with severe TS as they consider the risks and benefits of DBS.

  References

  1. Muller-Vahl KR. Deep brain stimulation in Tourette syndrome: the known and the unknown. J Neurol Neurosurg Psychiatry Published Online First: 12 July 2019. doi:10.1136/jnnp-2019-321008
  2. Johnson KA, Fletcher PT, Servello D, et al. Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study. J Neurol Neurosurg Psychiatry Published Online First: 25 May 2019. doi:10.1136/jnnp-2019-320379
  3. Fins JJ, Kubu CS, Mayberg HS, et al. Being open minded about neuromodulation trials: Finding success in our “failures”. Brain Stimul 2017;10:181–6. doi:10.1016/j.brs.2016.12.012
  4. Longo DL, Drazen JM. Data Sharing. N Engl J Med 2016;374:276–7. doi:10.1056/NEJMe1516564
  5. Faris O, Shuren J. An FDA Viewpoint on Unique Considerations for Medical-Device Clinical Trials. N Engl J Med 2017;376:1350–7. doi:10.1056/NEJMra1512592
  6. Pathak Y, Kopell BH, Szabo A, et al. The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. Brain Stimul 2013;6:254–60. doi:10.1016/j.brs.2012.07.001
  7. Martinez-Ramirez D, Jiminez-Shahed J, Leckman JF, et al. Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry. JAMA Neurol 2018;32607:1–7. doi:10.1001/jamaneurol.2017.4317
  8. 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;14:595–605. doi:10.1016/S1474-4422(15)00008-3
  9. 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. doi:10.1093/brain/awq380
  10. Charlton JI. Nothing About Us Without Us: Disability Oppression and Empowerment. Berkley: University of California Press 1998.

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  Conflict of Interest:
  M.S. Okun serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. M.S. Okun’s DBS research is supported by: R01 NR014852 and R01NS096008. M.S. Okun has previously received honoraria, but in the past >60 months has received no support from industry. M.S. Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, and Cambridge (movement disorders books). M.S. Okun is an associate editor for New England Journal of Medicine Journal Watch Neurology. M.S. Okun has participated in CME and educational activities on movement disorders (in the last 36) months sponsored by PeerView, Prime, QuantiaMD, WebMD, Medicus, MedNet, Henry Stewart, and by Vanderbilt University. The institution and not M.S. Okun receives grants from Medtronic, Abbvie, Allergan, and ANS/St. Jude, and the PI has no financial interest in these grants. M.S. Okun has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. C.R. Butson has served as a consultant for NeuroPace, Advanced Bionics, Boston Scientific, IntelectMedical, St. Jude Medical, Functional Neuromodulation and he holds intellectual property related to DBS.

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