Low frequency subthalamic nucleus electrical stimulation relieves the symptoms of DYT1-dystonia: a case description

Introduction

Primary DYT1-dystonia is the most common form of hereditary dystonia. It is an autosomal dominant movement disorder caused by mutation of the TOR1A gene (1,2). Its response to drug therapy is usually transient and unsatisfactory, and botulinum toxin injections are rarely indicated (3,4). Many groups have reported the long-term efficacy of high frequency deep brain stimulation (DBS) on the globus pallidus internus (GPi) and subthalamic nucleus (STN) as a treatment for dystonia in pediatric patients, especially DYT1-dystonia patient (5-10). Two recent meta-analyses suggest that DBS targeting the GPi is effective in treating primary dystonia, especially early onset DYT1-dystonias (11,12). However, the efficacy of low frequency DBS, especially low frequency STN-DBS, has rarely been documented. Here, we report on a boy with primary DYT1-dystonia who was treated with 60 Hz STN-DBS after the failure of high frequency STN and GPi-DBS. The patient obtained remarkable improvement and now behaves normally in daily life. This is the first report of a beneficial effect of low frequency STN-DBS in patients with DYT1-dystonia, in view of the limited efficacy in the only report on the treatment of DYT1-dystonia with low frequency STN-DBS (13).

Case description

Our patient is an 11-year-old Chinese boy who is a primary school student. He experienced the first emergence of right arm spasm at the age of six, and a TOR1A gene mutation was detected in the same year, which presented as a 907_909delGAG heterozygous mutation. At present, his chief complaint was severe muscle spasm inflicting both arms, right leg, back, and waist, which made him lean to the left and involuntarily tilt his head backward (observable in Video S1). His face, throat, and left arm were spared. He experienced his worst period of disease the year before the operation, with a Burke-Fahn-Marsden dystonia rating scale (BFMDRS) score of 39. His walking and writing were heavily affected, which made him drop out of school. He did not receive any medical treatment prior to the operation. Neurological examination showed an intermittent increase in muscle tension in both upper limbs, waist, back, and right lower limb. There was no obvious abnormality in his medical and psychosocial history. No secondary causes such as trauma, infections (e.g., encephalitis), or medication adverse effects (e.g., tardive dyskinesia) were found. The patient’s father was also a DYT1-dystonia patient with the same TOR1A gene mutation, but his symptom was not so serious, that he can live a normal life (observable in Video S2). The diagnosis was made carefully by neurological physicians according to the patient’s typical symptoms, history of present illness, neurological examination, family history, and TOR1A gene mutation.

After rigorous preoperative assessments of his condition, the indication for a DBS procedure was confirmed by neurosurgeons experienced in hyperkinetic movement disorders. The operation was carried out by experienced neurosurgeons of the functional neurosurgery department in Beijing Tiantan Hospital. All procedures performed in this study were in accordance with the ethical standards of the ethics committee of Beijing Tiantan Hospital and the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient’s father for publication of this case report and the accompanying images and videos. A copy of the written consent is available for review by the editorial office of this journal. The patient underwent bilateral implantation of electrodes (3387 Medtronic, Minneapolis, MN, USA) into the GPi under local anesthesia using a Leksell microstereotactic system (Elekta Instrument AB, Stockholm, Sweden) working with preoperative magnetic resonance imaging (MRI) and computed tomography. Then, the implantable pulse generator (IPG) was implanted in the subclavicular area under general anesthesia. The coordinates of the left and right GPi were (115.3, 104.7, 109.1) and (81.2, 104.2, 109.3), respectively. The preoperative MRI was shown in Figure S1. The IPG was turned on one month after the operation. The programming parameters were adjusted according to his complaints. A standardized videotape assessment and validated rating scale BFMDRS were used to document dystonia severity. As shown in Table 1, the patient’s preoperative BFMDRS score was 39 (29 and 10 respectively for the movement scale and disability scale). After 8 months of high frequency GPi-DBS [left (L): C+2-3-, 3.0 V/90 us/130 Hz, right (R): C+9-10-, 3.0 V/90 us/130 Hz], his symptoms showed no improvement and had become more severe (43.5 in stim-off condition and 35 in stim-on condition), with the face and neck symptoms worsened. Furthermore, reconstruction of the electrodes using the Lead-DBS toolbox (14) showed a non-ideal electrode location, with implantation outside the GPi (Figure 1A).

Figure 1 Reconstruction images of electrode location in STN and GPi using the Lead-DBS toolbox. (A) Non-ideal electrode location of GPi-DBS. (B) Ideal electrode location of STN-DBS. Blue: GPe; green: GPi; yellow: STN; red: red nucleus. STN, subthalamic nucleus; GPi, globus pallidus internus; DBS, deep brain stimulation; GPe, external globus pallidus.

After careful deliberation, the original electrodes were removed. In the second operation (8 months after the first operation), we attempted to implant the electrodes into the GPi again, but we didn’t find typical GPi electrophysiological signals during microelectrode recording (Figure S2). During the temporary electrical stimulation, the patient showed facial paresthesia. Considering that more and more researches have confirmed the effectiveness of STN-DBS in the treatment of primary dystonia (6,15,16), and that STN-DBS enables lower power consumption, which is suitable for his non-rechargeable IPG. Bilateral STN-DBS surgery was performed, which obtained informed consent from the patient’s father. The coordinates of the left and right STN were (109.7, 101, 108.5) and (87.1, 101, 108.5), respectively. Electrode reconstruction showed an ideal electrode location (shown in Figure 1B). High frequency STN-DBS (L: C+0-3-, 1.85 V/60 us/135 Hz, R: C+8-11-, 1.5 V/60 us/135 Hz) sometimes greatly relieved the patient’s symptoms (8.5 on the BFMDRS), but the relief did not last, and his symptoms frequently recurred within a short time (22 on the BFMDRS), usually of several hours to several days. So, the patient has been in a state of repeated remission and recurrence of dystonia, which exhausted the patient and his families. After a long period (6 months) of unfavorable treatment attempts with high frequency STN-DBS, and in view of some favorable results using low frequency STN-DBS in Parkinson’s disease (PD) and dystonia (17,18), low frequency STN-DBS (L: C+0-3-, 2.3 V/60 us/60 Hz, R: C+8-11-, 2.3 V/60 us/60 Hz) was employed. This allowed stable improvement to be achieved (2 on the BFMDRS), which has been persisting for 2 years. In addition, stimulation-induced dyskinesia (SID) occurred in the early stage of stimulation. After many attempts of various monopolar and bipolar stimulation modes, the current double monopolar stimulation mode was employed, which can not only achieve satisfied dystonia improvement, but also avoid SID. No other surgery-related, stimulation-related, or device-related complication was reported. The patient obtained remarkable and persistent improvement and now behaves normally in daily life. The BFMDRS scores and videos of the patient at various follow-up time points (before and after DBS surgery) are presented in Table 1 and Video S1, respectively.

Discussion

An important finding in this case was that 60 Hz STN-DBS provided significant and continuous relief of dystonia, which has been persisting for 2 years. To the best of our knowledge, this is the first report of a beneficial effect of low frequency STN-DBS in patients with DYT1-dystonia. In this report, we not only confirm the efficacy of STN-DBS, but also provide evidence for the validity of low frequency STN-DBS in the treatment of DYT1-dystonia.

DYT1-dystonia is an autosomal dominant disease that typically begins at school age, with a mean onset of approximately 12 years old. Characteristically, it initially affects a unilateral arm or leg, then subsequently spreads to additional limbs and/or the trunk. Up to 50% of affected subjects may ultimately develop general involvement (1,2). Our patient was a typical DYT1-dystonia patient, presenting with typical clinical manifestations and a TOR1A gene mutation, and demonstrated general involvement with multiple body parts being implicated. GPi-DBS is now a mature treatment for DYT1-dystonia, with long-term efficacy of over 60% (19-21). STN-DBS has also been reported to be a valid treatment for several patients with primary dystonia (6,15,16). As in PD patients, high frequency stimulation is the traditional stimulation mode in dystonia, but low frequency stimulation has also been tried in a few studies. Merola et al. (17) reported an improvement in residual involuntary movement (including dyskinesia and dystonia) after switching stimulation frequency from 130 to 80 Hz in PD patients. However, a moderate worsening of parkinsonian symptoms was observed in a portion of patients, requiring a return to 130 Hz STN-DBS. Furthermore, Ostrem et al. (13) reported that high frequency STN-DBS was more effective than low frequency STN-DBS in primary dystonia (5 cranial cervical dystonia and 2 DYT1-dystonia patients). Thus, the efficacy of low frequency STN-DBS has not been confirmed. The patient in our case obtained a stable improvement of 95.4% on the BFMDRS (from 43.5 to 2), similar to that reported for high frequency STN-DBS (more than 50% on long-term follow-up) (6,15-17), and a higher improvement rate than achieved using low frequency STN-DBS in primary dystonia (16.6%) (13), which gives support to the validity of low frequency STN-DBS for DYT1-dystonia.

Along with the increasing application of low frequency DBS, there is growing interest in the effects of varying frequencies in basal ganglia DBS for the treatment of movement disorders, although the frequency-dependent mechanism of action has not been clarified. It may be that a specific frequency of stimulation interferes with the pathogenesis of dystonia, or it could be that the electrical activity of basal ganglia neural circuits could be differently modulated by different frequencies of stimulation (17). In the present case, GPi-DBS failed because of a non-ideal electrode location, which may be due to an error of stereotactic system or human operation error. Patients with dystonia had lower beta power but higher low frequency and high gamma power than PD, and its mean firing rate was lower compared to PD (22-24). Local field potential activity less than 10 Hz has been observed in coherence with dystonic movement (25,26). It has been hypothesized that stimulation frequencies exceeding the firing rate and the mean oscillatory activity of the target in dystonia (~50 Hz) would be enough to modulate this abnormal electrical activity and dystonic movements (25,26), which may be the reason why 60 Hz STN-DBS is effective for this patient. However, we cannot provide a reason for the limited success of the high frequency STN-DBS. This may be due to the individual specific local field potential and single unit activity in the patient’s cortico-basal ganglia-thalamic circuits. These electrophysiological activities responded well to low frequency STN-DBS, but not to high frequency STN-DBS. In addition, the double monopolar stimulation mode of this patient may also be one of the reasons for its different stimulation strategy.

The SID that occurred in the early stage of stimulation is a common stimulation-induced adverse effect of STN-DBS, which usually predicts better clinical outcomes on chronic stimulation and this dyskinesia generally disappears within several months. SID is usually caused by stimulating the ventral part of STN, while stimulating the area above the STN (zona incerta area) can exert a direct anti-dyskinesia effect (27,28).

Some limitations must be considered in this study. The results from a single case may not be applicable to patients in other settings. Besides, the rater who scored the BFMDRS was not blinded to the patient’s before and after DBS surgery status.

In conclusion, this case can serve as evidence that low frequency STN-DBS has promise for treating patients with DYT1-dystonia, and that it may be the direction of future programming for some patients with primary dystonia, although the underlying mechanism requires further study.

Acknowledgments

We deeply thank the patient and families for participating in this study. We also thank Liwen Bianji (Edanz) (https://www.liwenbianji.cn) for editing the language of a draft of this manuscript.

Funding: This study was funded by National Natural Science Foundation of China (Nos. 81971070, 81671104, 81830033, 61761166004) and the Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20150503).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-56/coif). FM reports that he receives funding from National Natural Science Foundation of China (81971070). JZ reports that he receives funding from National Natural Science Foundation of China (81671104, 81830033, 61761166004) and Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20150503). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the ethics committee of Beijing Tiantan Hospital and the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient’s father for publication of this case report and the accompanying images and videos. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Skogseid IM. Dystonia--new advances in classification, genetics, pathophysiology and treatment. Acta Neurol Scand Suppl 2014;13-9. [Crossref] [PubMed]
2. Lohmann K, Klein C. Update on the Genetics of Dystonia. Curr Neurol Neurosci Rep 2017;17:26. [Crossref] [PubMed]
3. Miri S, Ghoreyshi E, Shahidi GA, Parvaresh M, Rohani M, Saffari M. Deep brain stimulation of globus pallidus internus for DYT1 positive primary generalized dystonia. Med J Islam Repub Iran 2014;28:18. [PubMed]
4. Cif L, Vasques X, Gonzalez V, Ravel P, Biolsi B, Collod-Beroud G, Tuffery-Giraud S, Elfertit H, Claustres M, Coubes P. Long-term follow-up of DYT1 dystonia patients treated by deep brain stimulation: an open-label study. Mov Disord 2010;25:289-99. [Crossref] [PubMed]
5. Cury RG, Kalia SK, Shah BB, Jimenez-Shahed J, Prashanth LK, Moro E. Surgical treatment of dystonia. Expert Rev Neurother 2018;18:477-92. [Crossref] [PubMed]
6. Deng Z, Pan Y, Zhang C, Zhang J, Qiu X, Zhan S, Li D, Sun B. Subthalamic deep brain stimulation in patients with primary dystonia: A ten-year follow-up study. Parkinsonism Relat Disord 2018;55:103-10. [Crossref] [PubMed]
7. Torgerson LN, Munoz K, Kostick K, Zuk P, Blumenthal-Barby J, Storch EA, Lázaro-Muñoz G. Clinical and Psychosocial Factors Considered When Deciding Whether to Offer Deep Brain Stimulation for Childhood Dystonia. Neuromodulation 2021; Epub ahead of print. [Crossref] [PubMed]
8. Ramezani Ghamsari M, Ghourchian S, Emamikhah M, Safdarian M, Shahidi G, Parvaresh M, Moghaddasi M, Habibi SAH, Munhoz RP, Rohani M. Long term follow-up results of deep brain stimulation of the Globus pallidus interna in pediatric patients with DYT1-positive dystonia. Clin Neurol Neurosurg 2021;201:106449. [Crossref] [PubMed]
9. Xu W, Li H, Zhang C, Sun B, Wu Y, Li D. Subthalamic Nucleus Stimulation in Pediatric Isolated Dystonia: A 10-Year Follow-up. Can J Neurol Sci 2020;47:328-35. [Crossref] [PubMed]
10. Scaratti C, Zorzi G, Guastafierro E, Leonardi M, Covelli V, Toppo C, Nardocci N. Long term perceptions of illness and self after Deep Brain Stimulation in pediatric dystonia: A narrative research. Eur J Paediatr Neurol 2020;26:61-7. [Crossref] [PubMed]
11. Hale AT, Monsour MA, Rolston JD, Naftel RP, Englot DJ. Deep brain stimulation in pediatric dystonia: a systematic review. Neurosurg Rev 2020;43:873-80. [Crossref] [PubMed]
12. Elkaim LM, Alotaibi NM, Sigal A, Alotaibi HM, Lipsman N, Kalia SK, Fehlings DL, Lozano AM, Ibrahim GMNorth American Pediatric DBS Collaboration. Deep brain stimulation for pediatric dystonia: a meta-analysis with individual participant data. Dev Med Child Neurol 2019;61:49-56. [Crossref] [PubMed]
13. Ostrem JL, Markun LC, Glass GA, Racine CA, Volz MM, Heath SL, de Hemptinne C, Starr PA. Effect of frequency on subthalamic nucleus deep brain stimulation in primary dystonia. Parkinsonism Relat Disord 2014;20:432-8. [Crossref] [PubMed]
14. Horn A, Kühn AA. Lead-DBS: a toolbox for deep brain stimulation electrode localizations and visualizations. Neuroimage 2015;107:127-35. [Crossref] [PubMed]
15. Liu Y, Zhu G, Jiang Y, Wang X, Chen Y, Meng F, Zhang K, Yang A, Liu H, Zhang X, Zhang J. Comparison of Short-Term Stimulation of the Globus Pallidus Interna and Subthalamic Nucleus for Treatment of Primary Dystonia. World Neurosurg 2019;123:e211-7. [Crossref] [PubMed]
16. Ostrem JL, San Luciano M, Dodenhoff KA, Ziman N, Markun LC, Racine CA, de Hemptinne C, Volz MM, Heath SL, Starr PA. Subthalamic nucleus deep brain stimulation in isolated dystonia: A 3-year follow-up study. Neurology 2017;88:25-35. [Crossref] [PubMed]
17. Merola A, Zibetti M, Artusi CA, Rizzi L, Angrisano S, Lanotte M, Lopiano L, Rizzone MG. 80 Hz versus 130 Hz subthalamic nucleus deep brain stimulation: effects on involuntary movements. Parkinsonism Relat Disord 2013;19:453-6. [Crossref] [PubMed]
18. Xie T, Bloom L, Padmanaban M, Bertacchi B, Kang W, MacCracken E, Dachman A, Vigil J, Satzer D, Zadikoff C, Markopoulou K, Warnke P, Kang UJ. Long-term effect of low frequency stimulation of STN on dysphagia, freezing of gait and other motor symptoms in PD. J Neurol Neurosurg Psychiatry 2018;89:989-94. [Crossref] [PubMed]
19. Panov F, Gologorsky Y, Connors G, Tagliati M, Miravite J, Alterman RL. Deep brain stimulation in DYT1 dystonia: a 10-year experience. Neurosurgery 2013;73:86-93; discussion 93. [Crossref] [PubMed]
20. Markun LC, Starr PA, Air EL, Marks WJ Jr, Volz MM, Ostrem JL. Shorter disease duration correlates with improved long-term deep brain stimulation outcomes in young-onset DYT1 dystonia. Neurosurgery 2012;71:325-30. [Crossref] [PubMed]
21. Jahanshahi M, Torkamani M, Beigi M, Wilkinson L, Page D, Madeley L, Bhatia K, Hariz M, Zrinzo L, Limousin P, Ruge D, Tisch S. Pallidal stimulation for primary generalised dystonia: effect on cognition, mood and quality of life. J Neurol 2014;261:164-73. [Crossref] [PubMed]
22. Schrock LE, Ostrem JL, Turner RS, Shimamoto SA, Starr PA. The subthalamic nucleus in primary dystonia: single-unit discharge characteristics. J Neurophysiol 2009;102:3740-52. [Crossref] [PubMed]
23. Geng X, Zhang J, Jiang Y, Ashkan K, Foltynie T, Limousin P, Zrinzo L, Green A, Aziz T, Brown P, Wang S. Comparison of oscillatory activity in subthalamic nucleus in Parkinson's disease and dystonia. Neurobiol Dis 2017;98:100-7. [Crossref] [PubMed]
24. Piña-Fuentes D, van Dijk JMC, Drost G, van Zijl JC, van Laar T, Tijssen MAJ, Beudel M. Direct comparison of oscillatory activity in the motor system of Parkinson's disease and dystonia: A review of the literature and meta-analysis. Clin Neurophysiol 2019;130:917-24. [Crossref] [PubMed]
25. Paap M, Perl S, Lüttig A, Plocksties F, Niemann C, Timmermann D, Bahls C, van Rienen U, Franz D, Zwar M, Rohde M, Köhling R, Richter A. Deep brain stimulation by optimized stimulators in a phenotypic model of dystonia: Effects of different frequencies. Neurobiol Dis 2021;147:105163. [Crossref] [PubMed]
26. Baizabal-Carvallo JF, Alonso-Juarez M. Low-frequency deep brain stimulation for movement disorders. Parkinsonism Relat Disord 2016;31:14-22. [Crossref] [PubMed]
27. Wang N, Wang K, Wang Q, Fan S, Fu Z, Zhang F, Wang L, Meng F. Stimulation-Induced Dyskinesia After Subthalamic Nucleus Deep Brain Stimulation in Patients With Meige Syndrome. Neuromodulation 2021;24:286-92. [Crossref] [PubMed]
28. Fan SY, Wang KL, Hu W, Eisinger RS, Han A, Han CL, Wang Q, Michitomo S, Zhang JG, Wang F, Ramirez-Zamora A, Meng FG. Pallidal versus subthalamic nucleus deep brain stimulation for levodopa-induced dyskinesia. Ann Clin Transl Neurol 2020;7:59-68. [Crossref] [PubMed]