“Super” high-frequency subthalamic stimulation for managing refractory dyskinesia in Parkinson’s disease

Chayut Kasemsuk; Genko Oyama; Fuyuko Sasaki; Satoko Sekimoto; Maierdanjiang Nuermaimaiti; Hirokazu Iwamuro; Atsushi Umemura; Nobutaka Hattori

doi:10.4103/AOMD.AOMD_11_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 5 | Issue : 3 | Page : 178-182

“Super” high-frequency subthalamic stimulation for managing refractory dyskinesia in Parkinson’s disease

Chayut Kasemsuk¹, Genko Oyama², Fuyuko Sasaki³, Satoko Sekimoto³, Maierdanjiang Nuermaimaiti³, Hirokazu Iwamuro⁴, Atsushi Umemura⁴, Nobutaka Hattori²
¹ Department of Neurology, Prasat Neurological Institute, Bangkok, Thailand; Department of Neurology, Juntendo University School of Medicine, Bunkyo City, Tokyo
² Department of Neurology, Juntendo University School of Medicine, Bunkyo City, Tokyo; Department of Neurodegenerative and Demented Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan; Home Medical Care System, based on Information and Communication Technology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Drug Development for Parkinson’s Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan; PRO-Based Integrated Data Analysis in Neurological Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan; Research and Therapeutics for Movement Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan
³ Department of Neurology, Juntendo University School of Medicine, Bunkyo City, Tokyo
⁴ Department of Neurosurgery, Juntendo University School of Medicine, Bunkyo City, Tokyo; Research and Therapeutics for Movement Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan

Date of Submission	24-Feb-2022
Date of Decision	13-Apr-2022
Date of Acceptance	06-May-2022
Date of Web Publication	14-Dec-2022

Correspondence Address:
Genko Oyama
Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113–8421
Japan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_11_22

Abstract

Objective: To evaluate and compare the effect of “super” high-frequency (SHF; >130 Hz) stimulation and conventional high-frequency (CHF; 100–130 Hz) stimulation on patients with dyskinesia. Methods: The patients were evaluated using the Abnormal Involuntary Movement Scale (AIMS) with SHF and CHF after levodopa infusion. The secondary outcomes included the Burke–Fahn–Marsden dystonia rating scale and the Unified Parkinson’s Disease Rating Scale part III scores. Result: Six patients were enrolled in this study. The AIMS scores were not significantly different between SHF and CHF (p=0.89, paired t-test). Three out of six patients (50%) had better AIMS scores when SHF was applied, the scores of two patients remained unchanged, and one patient had a score worse than that with CHF. No short-term adverse effects were observed. Conclusion: The results of our pilot study show that SHF is safe and tolerable. We believe that in appropriate cases SHF can be used for managing dyskinesia after conventional methods yield unfavorable results.

Keywords: deep brain stimulation, dyskinesia, high-frequency stimulation, movement disorders, Parkinson’s disease

How to cite this article:
Kasemsuk C, Oyama G, Sasaki F, Sekimoto S, Nuermaimaiti M, Iwamuro H, Umemura A, Hattori N. “Super” high-frequency subthalamic stimulation for managing refractory dyskinesia in Parkinson’s disease. Ann Mov Disord 2022;5:178-82

How to cite this URL:
Kasemsuk C, Oyama G, Sasaki F, Sekimoto S, Nuermaimaiti M, Iwamuro H, Umemura A, Hattori N. “Super” high-frequency subthalamic stimulation for managing refractory dyskinesia in Parkinson’s disease. Ann Mov Disord [serial online] 2022 [cited 2023 May 30];5:178-82. Available from: https://www.aomd.in/text.asp?2022/5/3/178/363461

Introduction

Deep brain stimulation (DBS) has potential to be a therapeutic option for levodopa-induced dyskinesia. It acts by reducing dopaminergic medications in the subthalamic nucleus (STN)–DBS and direct anti-dyskinesia effects in the globus pallidus interna–DBS.^[1] Some patients develop refractory dyskinesia, also called “brittle dyskinesia,” owing to a narrow therapeutic window.^[2] In addition, STN–DBS itself can cause stimulation-induced dyskinesia, resulting in difficulty in managing dyskinesia combined with levodopa-induced dyskinesia.^[3] Troubleshooting in case of dyskinesia after STN–DBS includes decreasing the amplitude or pulse width, adding dorsal contact, using bipolar settings, and interleaving stimulation, as well as adjusting the medications.^[4] Among these solutions, reducing the amplitude and dopaminergic medications are the first-line treatment options for improving dyskinesia. However, they may worsen cardinal parkinsonian motor symptoms. During amplitude reduction, frequency adjustment could be an option to keep the total electrical energy delivered (TEED) constant, maintaining motor symptoms.^[5]

The recommended rate/frequency of stimulation for Parkinson’s disease (PD) is approximately 130 Hz, based on the consideration of battery consumption and the “ceiling effect” for rigidity that frequency >130 Hz and up to 185 Hz did not remarkably improve rigidity. In contrast, tremor may be improved with higher frequency.^[6] To date, there is no published evidence regarding the efficacy of “super” high-frequency (SHF; >130 Hz) stimulation on dyskinesia compared to conventional high-frequency (CHF; 100–130 Hz) stimulation for PD; however, we observed that SHF stimulation eventually suppresses medically refractory dyskinesia in some cases. This was observed after a trial of multiple combinations of DBS settings in clinical situations in some cases. Therefore, this study aimed to compare the effect of SHF and CHF on dyskinesia. We hypothesized that SHF is superior to CHF in improving dyskinesia without compromising the motor symptoms.

Methods

Patients

The patients who underwent DBS (Medtronic Activa SC or Activa RC) via bilateral implantation in STN for PD at Juntendo University Hospital were screened. The inclusion criteria were as follows: 1) patients have to be diagnosed with PD and currently have dyskinesia, 2) patients were implanted with STN–DBS for more than 6 months, and the programming setting had been stabilized based on our standardized programming methods (including reducing medications/stimulation amplitude),^[4] and 3) written informed consent forms were obtained from patients after the research was completely explained. The exclusion criteria included 1) any remarkable psychiatric problems such as depression, 2) any current drug or alcohol abuse, 3) history of recurrent or unprovoked seizures, and 4) any medical condition that was likely to interfere with the study procedures or confound the evaluation of the study endpoints, including any terminal illness.

Study protocol

This was a single-center, randomized, double-blinded, cross-over study. Following the screening assessments, the patients visited our clinic after withholding antiparkinsonian medication for at least 12 hours before the evaluation. First, DBS was turned off for at least 30 minutes. The baseline of the patients was evaluated using the Abnormal Involuntary Movement Scale (AIMS), Burke–Fahn–Marsden dystonia rating scale (BFM–DRS), and the Unified Parkinson Disease Rating Scale (UPDRS) III. Furthermore, 200-mg levodopa was intravenously administered to the patients to induce the “supra-on” condition with dyskinesia. Thirty minutes after administering levodopa, all scores were evaluated with the first programming (CHF or SHF). Subsequently, DBS was turned off, and a second 200-mg levodopa injection was administered to the patients after they had rested for 4 hours following the first levodopa injection; this duration was the washout period considering the half-life of intravenous levodopa.^[7] Thirty minutes after the second injection, the patients were evaluated with the second programming (SHF or CHF). The order of administering CHF or SHF was randomized by selecting envelopes based on a previous computer-generated randomized list. The patients and examiner were blinded to the order of programming, and only a programmer could obtain information regarding the randomization. For CHF, the monopolar configuration was used, and DBS parameters, including amplitude and pulse width, were optimized at the best contact that was previously defined based on the monopolar review 1 week after the surgery. For SHF, the frequency was gradually increased until a maximally tolerable frequency, and the amplitude was then adjusted based on the TEED calculation (TEED (1 second) = voltage² × frequency × amplitude/impedance).^[5] Prior to the first programming, the programming of all patients was optimized using CHF, followed by the calculation for TEED. Furthermore, the frequency was adjusted to the designated group (CHF or SHF), and the amplitude was accordingly adjusted to maintain the TEED value. The primary outcome was the AIMS score for the evaluation of dyskinesia. The secondary outcomes included the UPDRS III and BFM–DRS scores to evaluate the parkinsonian motor outcomes and dystonia.

Statistical analysis

As this is a pilot study, we only performed descriptive statistics.

Results

Six eligible patients were enrolled in this study ([Table 1]). Five were women with ages ranging from 51 to 75 years (64 ± 9 years). The age at PD onset was 24–58 years (44 ± 12 years), and the time interval since DBS implantation was between 10 and 58 months (33 ± 16 months). Five out of the six patients had akinetic rigid-type PD, whereas one patient had tremor-dominant PD. Two patients experienced peak dose dyskinesia (patients 1 and 2), and four patients experienced diphasic dyskinesia (patients 3, 4, 5, and 6). The original DBS settings are described in [Table 1]. Four out of the six patients were given the SHF stimulation. All patients used dopaminergic medications. The levodopa-equivalent daily dose was 716 ± 524 mg (270–1698 mg).

Table 1: Baseline characteristics of all six patients enrolled in the study

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The stimulation settings applied for each patient and the outcome of the AIMS, BFM–DRS, and UPDRS III scores are listed in [Table 2]. No patient reported persistent severe side effects during and after the study. The AIMS and BFM–DRS scores did not show significant differences between SHF and CHF (p=0.89 and p=0.86, paired t-test). The UPDRS III score improved with both SHF and CHF compared to that with the baseline (p = 0.0022). However, there was no significant difference in the UPDRS III scores when compared between SHF and CHF (p=0.83).

Table 2: Stimulation settings and outcome of the AIMS, BFM–DRS, and the UPDRS III total scores in each patient

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After infusing levodopa, five patients developed dyskinesia. After switching DBS on, dyskinesia worsened in four patients who were given SHF (patients 1, 3, 4, and 6) and CHF (patients 1, 2, 3, and 6). When comparing the AIMS scores between SHF and CHF, three patients (patients 1, 2, and 6) had better AIMS scores, two patients (patients 3 and 5) had scores that remained unchanged, and the score of one patient (patient 4) had worsened when SHF was applied.

Discussion

In this study, there was no remarkable difference in the AIMS and UPDRS III scores between SHF and CHF stimulations. However, some patients treated with SHF had short-term beneficial effects against dyskinesia. To the best of our knowledge, ours is the first study to evaluate the effect of SHF on dyskinesia. Our study demonstrated that SHF may have benefits against dyskinesia. Of note, all peak-dose dyskinesia patients (patients 1 and 2) showed a better outcome with regard to AIMS scores when SHF was applied. Patients with peak-dose dyskinesia may respond well to SHF compared to diphasic dyskinesia patients. However, our study sample was small, and further studies with a larger group of patients is needed for robust results.

The mechanism of SHF stimulation that has an effect on dyskinesia is unknown. We hypothesize that a higher frequency stimulation changes the abnormal oscillation that is associated with dyskinesia.^[8] An increase in frequency has been reported to elevate the neuronal oscillatory power along with the neuronal activity of the basal ganglia in an animal model.^[9] It can be postulated that the oscillation spread to the pallidothalamic tract or zona incerta is pronounced with increased frequency, which may directly suppress dyskinesia.^[10] In addition, it is possible that the oscillation spread may affect the corticospinal tract, leading to spasticity and eventually slowing down dyskinetic movements. However, all participants did not show obvious pyramidal side effects. On the other hand, decreasing the amplitude may result in improvement of dyskinesia, because the amplitude was reduced along with an increase in frequency to maintain the same TEED. However, increasing the stimulation frequency may cause deterioration of bradykinesia.^[11],[12] However, these insights are highly speculative and require further studies to investigate the effect of frequency on bradykinesia.

Despite the promising findings, our study has several limitations. First, we could not recruit a large number of patients because of the complex study protocol. Second, the evaluation time in this protocol was limited to 1 day. Therefore, the levodopa wash-off period and the duration between the first and second programming were limited. In addition, the evaluation time and adequate levodopa dosage are important limitations. Furthermore, the medications taken by the patients prior to the study may be a confounding factor. We believe that these factors may have affected the results. Moreover, we did not clearly distinguish between the types of dyskinesia during the evaluation, e.g., peak-dose and diphasic dyskinesia. The mechanism and treatment of different types of dyskinesia may differ. Future studies should increase the time points for evaluation to assess the effect of diphasic dyskinesia (e.g., every 15 minutes), instead of only assessing before and after. Furthermore, we did not evaluate the effect of lead location and selected contact. Finally, this protocol could only evaluate the acute effect of stimulation on dyskinesia, although dyskinesia may appear hours or days after the stimulation changes.^[13] Therefore, long-term follow-up may be needed to thoroughly evaluate the effect of SHF and the long-term side effects of the treatment.

Conclusion

This study points toward the possible benefit of applying SHF (>130 Hz) stimulation in limited patients with refractory dyskinesia. In such cases, SHF stimulation may be a therapeutic option for suppressing dyskinesia after conventional approaches have failed. Future studies should investigate the methods to titrate frequency and evaluate the long-term efficacy and possible side effects of such a treatment.

Acknowledgement

None.

Author contribution

Chayut Kasemsuk, Genko Oyama, and Fuyuko Sasaki contributed towards study design, data collection, statistical analysis and discussion. Satoko Sekimoto and Maierdanjiang Nuermaimaiti contributed towards data collection and discussion. Hirokazu Iwamuro, Atsushi Umemura, and Nobutaka Hattori contributed towards concept and discussion.

Ethical compliance statement

This study was conducted according to ISO 14155: Clinical Investigation of Medical Devices for Human Subjects - Good Clinical Practice, whose ethical principles have their origins in the Declaration of Helsinki, and was approved by the institutional review boards of Juntendo University School of Medicine (#16–179). All participants provided a signed informed consent prior to participation. This trial is registered at the University Hospital Medical Information Network Clinical Trial Registry, number UMIN000025078. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Financial support and sponsorship

Financial disclosures for the previous 12 months: CK, FS, SS, and MN have no disclosed financial relationships. HI has received speaker honoraria from Medtronic. GO has been funded by grants from the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research. In addition, Dr. Oyama has received speaker honoraria from Medtronic, Boston Scientific, Otsuka Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Company Ltd., Kyowa Hakko Kirin Co. Ltd., and AbbVie GK. Employment: Juntendo University School of Medicine the Department of Neurodegenerative and Demented Disorders is a donated course from GLORY LTD, Kirin Company LTD, Mitsubishi UFJ Lease and Finance Company LTD. The Department of Home Medical Care System, based on Information and Communication Technology, is a donated course from Sunwels Co., Ltd.. The Department of Drug Development for Parkinson’s Disease, Juntendo University Faculty of Medicine, is a donated course from Ohara Pharmaceutical Co., Ltd. and PARKINSON Laboratories Co., Ltd.. Department of PRO-Based Integrated Data Analysis in Neurological Disorders, Juntendo University Graduate School of Medicine is a donated course from Takeda Pharmaceutical Company Ltd.. NH has received speaker honoraria from Dai-Nippon Sumitomo, Otsuka, Takeda, Kyowa Hakko- Kirin, Boehringer Ingelheim, FP, Eisai, Kissei, Nihon Medi-physics, Novartis, Biogen Idec Japan, AbbVie, Boston Scientific Japan, Sanofi, Alexion, Mylan N.V, and Daiichi Sankyo. NH has received consultancies and subcontracting from Dai-Nippon Sumitomo, Biogen Idec, Otsuka, Takeda, Kyowa Hakko- Kirin, Meiji Seika, Hisamitsu, Kao, and Ono.

Conflicts of interest

There are no conflicts of interest.

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