Stimulative Implants in the Treatment ofTourette's Syndrome: A Short, ComprehensiveReview

Authors: Alexander Sheppert, Arnav Ghosh, Jake Graff, Andrew Romney

Introduction And Background

Tourette’s syndrome is a disorder that causes tics (compulsive, difficult to control sudden movements). These tics come in multiple forms: simple, which cause tics in one part of the body, and complex, which cause tics in one or more parts of the body [1]. Recent literature suggests that the most common cause of Tourette's syndrome is a dysfunction in the globus pallidus externus (GPe) [2]. A stimulative implant placed in the globus pallidus externus, anterior limb of internal capsule (ALIC), anteromedial or limbic globus pallidus internus (amGPi), centromedian-parafascicular complex (CM-Pf), Nucleus Accumbens (NAc), and

posteroventral globus pallidus internus (pvGPi), has the potential to inhibit these tics and other psychological and neurological symptoms associated with the disorder, effectively treating Tourette’s [3,4]. Most of these areas control sensory motor signals involved in Tourette’s pathologies. Stimulation of these areas has been shown to decrease tic frequency significantly [5]. Deep brain stimulation is promising for Tourette’s treatment as Tourette’s is characterized by abnormal impulses in the thalamus, globus pallidus internus, and globus pallidus externus. An implant placed in the globus pallidus externus can treat Tourette’s syndrome by inhibiting the tic generation network - a network identified to cause the tics

observed in Tourette’s syndrome [6]. In addition, under qualified medical supervision, DBS can be applied successfully to other tic disorders. [7]. Trials reveal that patients respond well to DBS implantation [8].

Review

Current Treatment of Tourette's

First-line Tourette’s treatment involves education and cognitive behavioral therapy [9]. Pharmaceutical Tourette’s treatment is primarily symptom based. Alpha-2 adrenergic agonists are commonly used. Antiepileptic drugs which have been shown to suppress tics are sometimes administered, although their effects aren’t often replicated in other studies [5,10]. Dopamine receptor blockers agents, which achieves tic suppression through striatal DA-D2 receptors, are also studied and used in clinical Tourette's treatment [10]. Procedural options including botulism toxin injections to prevent tics and neural stimulation are used in

severe cases. Neurosurgical treatment of Tourette’s is uncommon. Assuming that medication and other non-invasive treatments have been tried, Tourette’s can be treated using deep brain stimulation [11,12]. This treatment is most effective when care is taken: a local ethics community should be consulted, tics should be the main cause of disability, and malingering should be ruled out prior to DBS implantation [12].

Pathophysiology of the Globus Pallidus Externus

While the underlying physiology of Tourette’s has not been categorically determined, the physical manifestation of some symptoms are identifiable, and therefore physiological pathways have been proposed. The globus pallidus externus itself has connections to multiple striatal pathways, which can be controlled to limit the effects of Tourette’s [13]. The function of the globus pallidus externus is to control conscious and proprioceptive movements. A fMRI study also shows that this region is one of the more common causes of

Tourette’s syndrome [14]. An implant that regulates globus pallidus externus placed in the region has the potential to treat the tics observed in Tourette’s.

Implant Treatment of Tourette's

A stimulative implant procedure for Tourette's is done under general anesthesia and in a neurosurgical unit. After the patient is anesthetized, a neurosurgeon can use previous MRI scans and intraoperative CT scans to ensure accurate placement of the electrodes [15]. Follow-ups should be conducted frequently to ensure that the patient is not having any adverse side effects to the treatment. A recent study [16] shows deep brain stimulation’s efficacy in treating Tourette’s syndrome. The study consisted of a baseline measurement, and

recordings of Tourette’s syndrome symptoms using the Yale Tic Specifications battery at the 7 day, 3 month, and 12 month marks. The patient who received the implant noted significantly fewer tics in comparison to the patient who did not receive the treatment. Another study [17] with 185 patients conducted revealed the efficacy of deep brain stimulation. 62.4 percent of patients have a history of self-injurious behavior. The Yale Global Tic Severity Scale mean (SD) total score improved from 75.01 (18.36) at baseline to 41.19 (20.00) one year after implantation. DBS (P<0.001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) at 1 year (P<0.001), as did the Mean (SD) tic phonics improved from 16.82 (6.56) at

baseline to 9.63 (6.99) at 1 year (P<0.001) during this study. Severe side effects due to this treatment are unlikely - with intracranial hemorrhage occurring in 2 patients (1.3 percent), infection in 4 patients with 5 events (3.2 percent), and lead explantation in 1 patient (0.6 percent). The most common stimulation- induced adverse effects were dysarthria (10 [6.3 percent]) and paresthesia (13 [8.2 percent]). These results are unlikely to be attributed to chance, as a result, and more to the efficacy of the implant, as a consistent improvement in tic severity has been noted in the first and second studies. A follow-up study mentioned

that the therapeutic effect that DBS implantation provides for Tourette’s is widespread, as all targets reported a lower Yale Tic Specifications score at maximum follow-up [18]. Another study confirms the findings, as when the implant’s battery died, the therapeutic effect was significantly lessened [19]. A GPe-DBS implant has the potential to minimize side effects and drastically decrease tic frequency. Deep brain stimulation works by recognizing pathological brain activity and delivering stimulation to treat the neurological and psychological disorders associated with the abnormal neurological pattern [20]. The implant works via electrodes that sense abnormal brain activity and delivers a stimulus to either modulate or correct abnormal brain activity [21]. Other parts of the brain can be targeted as well, such as the centromedian nucleus, the substantia periventricularis, and the nucleus ventro-oralis internus [22]. However, it is imperative that people who undergo this procedure are committed to improving their case, as successful treatment of Tourette's with DBS requires long-term commitments to medication changes and programming of the DBS implant [23]. This procedure also may help in treating obsessive-compulsive comorbidities associated with Tourette’s syndrome [24].

Clinical Hesitancies of Deep Brain Stimulation

Surgical treatment of Tourette's is not widespread due to several procedural caveats. There is a risk of explantation and neurological symptoms such as paresthesia with this procedure [25]. However, these risks are acceptably low. Even with meticulous surgical planning, mild to moderate side effects such as electrode fractures, one electrode migration and one pulse-generator infection contribute to the hardware-related complication rate of 5 percent are present [26]. These risks are rare and range from mild to moderate, suggesting that DBS implantation is still a good option for Tourette’s syndrome. No sensorimotor or life threatening complications have been noted to date in any studies conducted. However, in order to minimize risks, the staff involved in performing the procedure should have relevant and up-to-date qualifications. A dedicated "Movement Disorder Team" consisting of neurologists, neurophysiologists, functional neurosurgeons, neuropsychologists and nursing specialists is essential for a successful performance of the procedure [27].

Conclusions

Surgical treatment for Tourette’s syndrome is a powerful option when used correctly and performed by medical professionals with appropriate qualifications. DBS implantation is recommended for people who have Tourette’s and don’t have any conflicts with the surgery. Any age is acceptable for DBS implantation, though if the patient is under 18, a local ethics community should be involved. After the procedure, the patient should have consistent and frequent follow-ups to ensure that the implantation was successful and that the implant is improving symptoms. The patient might experience side effects such as electrode fractures, electrode migration, and pulse-generator infection. In such cases, a reperformance of the surgery may be necessary to experience the symptomatic improvements of DBS implantation.

Additional Information

Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

References

1. Piedimonte F, Andreani JC, Piedimonte L, et al.: Behavioral and motor improvement after deep brain

stimulation of the globus pallidus externus in a case of Tourette's syndrome. Neuromodulation. 2013, 16:55-8. 10.1111/j.1525-1403.2012.00526.x

2. NIH Fact Sheet 2022 . (2022). https://www.ninds.nih.gov/tourette-syndrome-fact-sheet.

3. Temel Y, Visser-Vandewalle V.(2004) Surgery in Tourette syndrome: Mov. Disord. 19:3-14.

10.1002/mds.10649

4. Xu W, Zhang C, Deeb W, et al.: Deep brain stimulation for Tourette’s syndrome . Transl Neurodegener 9.

2020, 4:10.1186/s40035-020-0183-7

5. Baldermann JC, Schüller T, Huys D, et al.: Deep Brain Stimulation for Tourette-Syndrome: A Systematic

Review and Meta-Analysis. Brain Stimulation, Volume. 9:296-304. 10.1016/j.brs.2015.11.005

6. Bohlhalter S, Goldfine A, Matteson S, et al.: Neural correlates of tic generation in Tourette syndrome: an

event-related functional MRI study. Brain. 2006, 8:16520330. 10.1093/brain/awl050

7. Mink JW, Walkup J, Frey KA, et al.: Patient Selection and Assessment Recommendations for Deep Brain

Stimulation in Tourette Syndrome. Mov. Disord. 21: 1831-1838. 21:1831-1838. 10.1002/mds.21039

8. Servello D, Porta M, Sassi M, et al.: Deep brain stimulation in 18 patients with severe Gilles de la Tourette

syndrome refractory to treatment: the surgery and stimulation. Journal of Neurology, Neurosurgery and

Psychiatry. 2008, 79:136-142.

9. Pediatric tourette syndrome. Background, Pathophysiology, Etiology. . (2022). Accessed: 2022:

https://emedicine.medscape.com/article/289457-overview .

10. Cavanna AE, Nani A: Antiepileptic drugs and Tourette syndrome. Int Rev Neurobiol. . 2013, 112:373-89.

10.1016/B978-0-12-411546-0.00012-3

11. Kurlan RM: Treatment of Tourette syndrome . Neurotherapeutics. 2014, 11:161-5. 10.1007/s13311-013-

0215-4

12. Schrock LE, Mink JW, Woods, et al.: Tourette syndrome deep brain stimulation: A review and updated

recommendations. Movement Disorders. 30:448-471. 10.1002/mds.26094

13. Javed N, Cascella M: Neuroanatomy, Globus Pallidus. StatPearls, Treasure Island (FL); 2022.

14. Leckman JF, Bloch MH, Smith ME, Larabi D, Hampson M: Neurobiological substrates of Tourette's disorder. J

Child Adolesc Psychopharmacol. 2010, 20:237-47. 10.1089/cap.2009.0118

15. DBS Under General Anesthesia: Comparison To The Standard Technique. . (2016). Accessed: 2022:

https://clinicaltrials.gov/ct2/show/NCT01997398.

16. Kuhn J, Bartsch C, Lenartz D, et al.: Clinical effectiveness of unilateral deep brain stimulation in Tourette

syndrome. Transl Psychiatry. 1:52. 10.1038/tp.2011.51

17. Martinez-Ramirez D, Jimenez-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, 1:353-359.. 10.1001/jamaneurol.2017.4317. Erratum in: JAMA

18. Wehmeyer L, Schüller T, Kiess J, et al.: Target-Specific Effects of Deep Brain Stimulation for Tourette

Syndrome: A Systematic Review and Meta-Analysis. Front. Neurol. 12:769275. 10.3389/fneur.2021.769275

19. Piedimonte F, Andreani JC, Piedimonte L, et al.: Behavioral and motor improvement after deep brain

stimulation of the globus pallidus externus in a case of Tourette's syndrome. Neuromodulation. 2013, 16:55-

8. 10.1111/j.1525-1403.2012.00526

20. Lozano AM, Lipsman N, Bergman H, et al.: Deep brain stimulation: current challenges and future

directions. Nat Rev Neurol. 2019, 15:148-160. 10.1038/s41582-018-0128-2

21. Vissani M, Isaias IU, Mazzoni A.: Deep Brain Stimulation: A review of the Open Neural Engineering

challenges. Journal of Neural Engineering. 2020, 17:051002. 10.1088/1741-2552/abb581

22. Bajwa RJ, de Lotbinière AJ, King RA, et al.: Deep brain stimulation in Tourette's syndrome . Mov. Disord.

22:1346-1350. 10.1002/mds.21398

23. Tourette Association of America: Deep Brain stimulation. Tourette Association of America. 25, 5:2022.

24. Viswanathan A, Jimenez-Shahed J, Baizabal CJ, et al.: Deep Brain Stimulation for Tourette Syndrome:

Target Selection. Stereotact Funct Neurosurg. 2012, 90:213-224. 10.1159/000337776

25. Fenoy AJ, Simpson RK Jr: Risks of common complications in deep brain stimulation surgery: management

and avoidance. J Neurosurg. 2014, 120:132-9. 10.3171/2013.10.JNS131225

26. Chan DT, Zhu XL, Yeung JH, et al.: Complications of deep brain stimulation: a collective review . Asian J

Surg. 2009, 32:258-63. 10.1016/S1015-958460404-8

27. Essential tremor.. (2022). Accessed: 2022: https://www.mayoclinic.org/diseases-conditions/essential-

tremor/diagnosis-treatment/drc-20350539 .