Subthalamic deep brain stimulation in patients with primary dystonia: A ten-year follow-up study

Accepted Manuscript Subthalamic deep brain stimulation in patients with primary dystonia: A follow-up of more than ten years Zhengdao Deng, Yixin Pan, Chencheng Zhang, Jing Zhang, Xian Qiu, Shikun Zhan, Dianyou Li, Bomin Sun PII:

S1353-8020(18)30256-6

DOI:

10.1016/j.parkreldis.2018.05.024

Reference:

PRD 3683

To appear in:

Parkinsonism and Related Disorders

Received Date: 18 January 2018 Revised Date:

3 May 2018

Accepted Date: 27 May 2018

Please cite this article as: 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 follow-up of more than ten years, Parkinsonism and Related Disorders (2018), doi: 10.1016/j.parkreldis.2018.05.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title Page Title: Subthalamic deep brain stimulation in patients with primary dystonia: A follow-up of more than ten years

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Running Title: Subthalamic deep brain stimulation for primary dystonia

Author: Zhengdao Deng*, Yixin Pan*, Chencheng Zhang, Jing Zhang, Xian Qiu, Shikun Zhan, Dianyou Li, Bomin Sun

of Medicine, Shanghai, China;

Corresponding author: Bomin Sun

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*these two authors contributed equally to this paper

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a Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School

Bomin Sun, MD, PhD, Functional Neurosurgery, Ruijin Hospital Affiliated to Shanghai JiaoTong

[email protected];

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University School of Medicine, Shanghai, China. Phone number: +8613817777401 Email:

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Number of words in the abstract: 207 Number of keywords: 3

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Number of words in the text: 2416 Number of tables: 3

Number of figures: 1

Number of references: 26

Keywords: Primary dystonia; subthalamic nucleus; deep brain stimulation.

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Abstract

Background: Subthalamic deep brain stimulation (STN-DBS) is a promising intervention for primary dystonia; however, evidence regarding its efficacy is lacking. Thus, a long-term follow-up is indispensable.

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Objective: This trial was designed to examine the efficacy and consistency of subthalamic deep brain stimulation in patients with primary dystonia over the long term.

Method: This was a retrospective study involving 14 patients with primary dystonia who underwent

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STN-DBS and consented to a follow-up of at least 10 years. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and 36-item Short-Form General Health Survey were employed, at five

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time points (pre-operation [baseline], 1 month post-operation, 1 year post-operation, 5 years postoperation, and last follow-up), to assess improvement of dystonic symptoms and changes in quality of life.

Outcomes: All patients gained extensive clinical benefits from STN-DBS therapy, without experiencing serious adverse effects. Improvements of 59.0% at 1 month, 85.0% at 1 year, and

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90.8% at 5 years after the operation, and up to 91.4% at the last follow-up, were demonstrated by movement evaluation with the BFMDRS. All patients achieved a substantial improvement in

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quality of life.

Conclusion: Subthalamic deep brain stimulation is an effective and persisting alternative to pallidal

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deep brain stimulation, and importantly, it is very safe even with extremely long-term chronic stimulation.

Introduction

Primary dystonia, a neurodegenerative movement disorder, is characterized by involuntary sustained or intermittent muscle contractions, which give rise to repetitive patterned movements or abnormal postures. Patients with primary dystonia are usually deprived of the ability to work, and feel social isolation due to the stigma attached to their embarrassing dystonic manifestations. Even worse, the medical interventions currently available are problematic, leading to adverse effects or

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unsustainable alleviation of symptoms. Deep brain stimulation (DBS) emerged as a mainstream surgical alternative or supplement to orthodox therapy for movement disorders, due to its flexibility and sustained efficacy. For primary dystonia, pallidal DBS is most commonly used[1], and its efficacy and safety have been confirmed[2]; however, dysarthria is frequently encountered as a

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stimulation-induced side effect[3], affecting from 12% to 33% of patients[2, 4, 5]. Its high energy consumption[6] is another concern. Thus, alternative targets are worth considering. Subthalamic DBS is a potential alternative[7], but its long-term efficacy has not been fully verified. We designed

stimulation over a follow-up of at least 10 years.

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Materials and Methods

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this trial with the aim of examining the efficacy and sustainability of subthalamic deep brain

The ethics committees of the Ruijin Hospital Shanghai Jiao Tong University School of Medicine approved this retrospective clinical research. Each patient and his/her family agreed to this trial and signed an informed consent form. Patients

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Fourteen patients with primary dystonia who had follow-up profiles of at least 10 years, and who underwent bilateral subthalamic DBS surgery at Ruijin hospital between 2002 and 2007,

Clinical evaluation

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participated in this study.

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All the patients involved were evaluated by an experienced neurologist (J.Z.) before surgery (Baseline), 1 month after the operation, 1 year after the operation, 5 years after the operation, and at the last follow-up (range: 11–15 years), with the evaluation centering on dystonic symptoms and quality of life (QoL).

Dystonic symptoms and signs were quantified by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS)[8], which comprises two sections, a disability score (BFMDRS-D) and a movement score (BFMDRS-M), assessing the extent to which the dystonia affected daily life and motor

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capability, with scores ranging from 0 to 120 and 0 to 30, respectively. Higher scores represent greater impairment. General quality of life (QoL) was evaluated with the 36-item Short-Form General Health Survey (SF-36)[9], which includes eight sections, on general health, physical functioning, role-physical

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functioning, role-emotional functioning, social functioning, bodily pain, vitality, and mental health, with the score for each section ranging from 0 to 100, and higher score indicating higher QoL. Surgical procedures

)

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(1) The surgical inclusion criteria were: I）patients were diagnosed with primary dystonia;

patients experienced dystonic symptoms that severely affected their motor function and social ) patients were intolerant of or failed to respond adequately to pharmacotherapy

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activities;

(e.g., anticholinergic drugs, benzodiazepines);

) patients without antipsychotic drug history;

) patients were willing to accept regular consulting visits and a long-term follow up. (2) The surgical exclusion criteria were: I) patients with dystonia resulting from any secondary

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cause; II) patients with prominent cognitive decline; II) patients with severe psychiatric disease (e.g., suicidal ideation, hallucinations); IV) patients with any contraindications to DBS surgery; V) patients with anatomical anomalies in the basal ganglia region.

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(3) Operative methods: We chosen the dorsal region of the subthalamus as the target. The location of the dorsal subthalamic nucleus was determined directly using T2 weighted magnetic

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resonance imaging (MRI), in which it was defined as 12–14 mm lateral and 2–3 mm posterior to the midpoint of the anterior commissure–posterior commissure line (AC-PC), and 4–6 mm below the AC-PC plane. The detailed procedure is described elsewhere[6]. A computed tomography (CT) brain scan was performed for each patient one week after the surgery to confirm the location of the electrodes. (Figure 1-A) Post-operative programming The current generator initially came into effect one week following the operation, with parameters of 60 µs, 130 Hz, and 1.5–2.0 V for pulse width, frequency, and amplitude, respectively. Patients

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underwent the first programming session one month after implantation, and paid regular consulting visits thereafter. Changes in parameters (Table 4), dystonic symptoms and post-operative side effects were charted. The electrode contacts nearest to the dorsal STN were chosen to be cathodal. Statistical methods

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The Kolmogorov-Smirnov test was initially applied to analyze the distribution of the grouped data. For the assessment of primary dystonia and QoL, the results for total score on the BFMDRS-M and BFMDRS-D, and for several sub-scores of the SF-36 (general health, physical functioning, vitality,

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mental health) were non-significant (p > 0.05), indicating that these data distributions did not deviate significantly from normality. Accordingly, a one-way repeated-measures ANOVA,

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including time as a within-subjects factor (5 levels: baseline, after 1 month, after 1 year, after 5 months, long-term follow-up), was performed to analyze whether significant differences in the mean scores for dystonic severity existed between the five periods. Follow-up pairwise comparisons, using post hoc Dunnett’s tests, were employed to determine whether the scores at baseline were significantly different from the scores observed at the four follow-up times. For the

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remaining SF-36 variables (role-physical functioning, role-emotional functioning, social functioning, bodily pain), the scores did not meet the normality requirement, and therefore

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nonparametric tests (the Kruskal-Wallis test and the Wilcoxon signed-rank test) were used. Statistical significance was set at p = 0.05 for the overall tests; a Bonferroni correction (p = 0.05/3 =

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0.0167) was utilized for the four post-hoc pairwise comparisons. The analyses were implemented using IBM® SPSS® Statistics, version 23 (SPSS, Inc., Chicago, IL). The results are presented as mean ± SD, unless stated otherwise. Results

Patient sample Fourteen patients (5 female and 9 male) were tracked for 12.7 years (range: 11–15 years). The age of the patients at dystonic symptom onset was 24.9 ± 18.7 years (range: 10–72 years), and the duration of symptoms was 4.6 ± 3.1 years (range: 1–12 years). (see Table 1)

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Postoperative battery replacement and depletion

The life span of the generator is about 6.4 ± 1.3 years. Nine patients received a battery replacement once, and three patients received one twice. The level of control of dystonic symptoms after replacement was the same as pre-replacement. Two patients sustained substantial benefits from the

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procedure, but did not agree to battery replacement, and no aggravation occurred of dystonic symptoms as their bilateral batteries depleted. One received 7 years of chronic stimulation therapy; the other received 4 years.

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Assessment of motor function

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All the patients showed substantial improvement at the last follow-up visit. The total BFMDRS-M score demonstrated a significant improvement at 1 month (59.0%, p < 0.01), 1 year (85.0%, p < 0.01), 5 years (90.8%, p < 0.01), and at the last follow-up (91.4%, p < 0.01) (Table 2). The total BFMDRS-D score exhibited substantial improvement at 1 month (50.0%, p < 0.01), 1

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year (79.1%, p < 0.01), 5 years (86.5%, p < 0.01) and at the last follow-up (88.5%, p < 0.01) (Table 2). There was a trend to maintain the motor improvement that was observed at 1 year over the years

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Assessment of QoL

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that followed (Figure 1-B).

All the patients showed a pronounced improvement at the last follow-up. As the SF-36 scores demonstrated, compared with the baseline values, each sub-score of the eight sections (general health, physical functioning, role-physical functioning, role-emotional functioning, social functioning, bodily pain, vitality, mental health) showed a significant change (p < 0.01) (Table 3) at the first month, and the sub-scores remained stable after 5 years of stimulation (Figures 1-C, 1-D). Adverse events

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Two patients (14%) experienced transient depression, and one patient suffered stimulation-induced dysarthria (7%), which could be improved by reducing the stimulus amplitude. Two patients (14%) encountered electrode displacement. One patient (7%) had a surgical incision-related scalp skin infection, and a bruise-induced extension-related infection occurred on the auricular-mastoid level

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half a year later, resulting in repetitive skin erosion. This patient had the bilateral generators and electrodes extracted, and received additional implants. One patient (7%) experienced a serious scalp skin infection that required the right electrode to be extracted because it was exposed directly to the

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air. One patient (7%) received aspiration because he experienced subcutaneous effusion at the right generator implantation site. No lethal or permanent side-effects were observed during the entire

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follow-up period. Discussion

To the best of our knowledge, this retrospective trial had the largest sample-size and the longest follow-up period of any study aimed at establishing the safety, efficacy, and reliability of

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subthalamic DBS for the treatment of primary dystonia. In this trial we included 14 patients with primary dystonia, and found that all of these patients achieved persisting and substantial

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amelioration of all types of dystonic manifestations. We observed that a large proportion of patients gained substantial motor improvement in the first

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month, which is consistent with our previous study[7]. This remarkable improvement may partly be attributable to the effects of micro-lesions induced by the electrodes[10], which are akin to thalamotomy. This initial improvement occasionally showed significant fluctuations or major symptomatic regression, but these gradually decreased in frequency over the first year. The benefits were maintained and continued to slowly accumulate over the following four years, finally reaching a plateau, indicative of the most stable phase of primary dystonia (Figure 1-B). Subthalamic DBS produced an immediate improvement of as much as up to 59.0%, as indicated by the BFMDRS-M, with is consistent with the results of other investigations[7, 11]. This differed from the outcomes

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observed during pallidal DBS treatment, which requires months or even longer to produce significant improvements in dystonic symptoms[2, 12]. This superiority over pallidal DBS made it possible to observe effects related to programming within a shorter period, which allowed the programming to be fine-tuned, and facilitated the patients obtaining the most satisfactory

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experiences with the least time spent on programming. Pallidal DBS has been established as a first-line treatment for patients with refractory primary dystonia[13], however, we found that the outcomes of subthalamic DBS, as demonstrated by

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assessment with BFMDRS-D and BFMDRS-M, were superior to those of pallidal DBS[2, 12, 14]. This finding is promising, and in combination with previous studies[15-17], suggests that

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subthalamic DBS may have the potential to evolve into an alternative to pallidal DBS for primary dystonia. A novel finding of our study was that two patients did not display noticeable dystonic symptoms even as the generator failed to work without replacement, and this stable state was maintained for nearly nine years without significant regression or aggravation. Similar events have

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been encountered elsewhere[6, 18]. Patients may experience an immediate symptomatic relapse[19] on cessation of pallidal DBS therapy, however, notably sustained effects after device failure, which was observed in subthalamic DBS therapy, was not yet seen for pallidal-DBS therapy. Theoretically

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the motor outputs of the globus pallidus pars interna (GPi) can be enhanced by the subthalamic nucleus (STN), and the STN itself also plays a pivotal role in motor regulation. Thus, subthalamic

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DBS may be more effective and quicker than pallidal DBS because of motor outputs that it activates independently[20]. However, further RCTs are warranted to determine the differences between these two targets.

In this cohort, we found that the longevity of the implantable pulse generator was much greater than that for pallidal DBS[21, 22], which may be explained by the fact that the GPi is larger than the STN, and therefore requires more energy for a given level of stimulation[2, 21-24]. Thus, subthalamic DBS is an energy-saving method, and can also be considered as an optimal selection for patients who do not wish to have a recharged generator implanted. In accordance with our

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programming experience in patients with Parkinson’s disease, we found that more positive outcomes trended to be observed as the contacts were positioned closer to the dorsal STN, in proximity to the zona incerta[25] as well as the cerebello- and pallidothalamic projections[26], which are associated with motor regulation. Thus, it is advisable to select dorsal contacts during the

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interrogation. Strikingly, all patients gained a marked enhancement in QOL, as reflected by SF-36 assessment. We observed that the QOL sub-scores showed a sharp increase within one month and then gradually plateaued; this was in accord with our previous study [7], and is very meaningful for

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patients with primary dystonia. The dystonic symptoms were the major deleterious sources leading to a poor QOL and disability, at either a psychiatric or physical level, thus the enhanced QOL can

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largely be credited to the great improvement in dystonic symptoms, and additionally, the rapid and effective improvement in QOL can strengthen the confidence of the patients to get rid of embarrassment and stigma, and further, to allow them to return to working, learning and social activities as soon as possible. Most importantly, this trial did not observe any permanent side effects

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or lethal neurosurgical complications (e.g., death, disability, aphasia). This trial demonstrated the efficacy, safety and reliability of subthalamic DBS. However, the sample size is still limited, and multi-center studies are warranted to determine whether the

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observed powerful therapeutic effects of subthalamic DBS can be confirmed in other research

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settings, in other samples of patients with primary dystonia. Conclusion

This ten-year-plus follow-up study found that patients with primary dystonia can achieve great benefits in terms of reduction in dystonic symptoms and enhancement in QOL following bilateral subthalamic DBS. Nevertheless, multi-center RCT trials are needed to confirm these observations owing to the small sample size of the current study. Most importantly, the approach detailed here appears to be safe and well-tolerated by patients. Acknowledgement

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This work was supported by National Key Research and Development Program of China Grant No. 2017YFC0803607 (to DYL); National Natural Science Foundation of China (81471387, 81271518, 81771482 to BMS); Shanghai Health and Family Planning Commission research project (201440504 to DYL); Shanghai JiaoTong University School of Medicine – Institution of

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Neuroscience Research Center for Brain Disorders. Financial Disclosures

Dr. Bomin Sun received research support from SceneRay (donated devices);

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Dr. Dianyou Li received travel sponsorship from Medtronic. Dr. Chencheng Zhang has received honoraria and travel expenses from the Deep Brain

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conflicts of interest to declare.

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Figure legends

Figure 1-A Brain T1 - weighted and T2 - weighted MRI images for a

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representative postoperative patient. A) T2 axial image: the targets highlighted with green show the location of the subthalamic nucleus; B) T1 axial image: the targets highlighted with green show the location of the subthalamic nucleus; C) T2 coronal image: this image shows the depth of the implanted electrodes. The targets highlighted with green show the location of subthalamic nucleus; D) The line in red is the surgical trajectory along which the right electrode was implanted.

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Figure 1-B Mean scores for the movement scale and the disability scale of the patients (N=14) at various time points before (baseline) and after operation. Error bars indicate standard deviations. Comparison with baseline, * p < 0.01. Figure 1-C Mean scores for the baseline and the last follow-up assessed by the 36-item Short-Form

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General Health Survey. The upper bars indicate the mean plus standard deviations of the scores. ** p < 0.01; GH=general health; PF=physical functioning; RP=physical-role functioning; RE=roleemotional functioning; BP=bodily pain; MH=mental health; SF=social functioning; VT=vitality.

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Figure 1-D GH=general health; PF=physical functioning; RP=physical-role functioning; RE=role-

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emotional functioning; BP=bodily pain; MH=mental health; SF=social functioning; VT=vitality.

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Table 1 Patients demographics( N=14)

76

4

Patient 2

M

15

17

2

Patient 3

F

10

20

10

Patient 4

M

8

20

12

Patient 5

F

25

EP 4

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29

Patient 6

M

48

49

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72

1

2

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M

Times for generator replacement

failed preoperative medication

generalized dystonia (spasmodic botulinum toxin, baclofen, torticollis, alprazolam, dystonia in trihexyphenidyl bilateral upper and lower limbs and trunk) early-onset generalized dystonia (spasmodic botulinum toxin, torticollis, trihexyphenidyl dystonia in bilateral upper and lower limbs and trunk) childhood-onset focal dystonia( L-levodopa, botulinum spasmodic toxin torticollis) childhood-onset generalized dystonia( taskspecific botulinum toxin, dystonia in right diazepam_trihexyphenidyl hand, dystonia in trunk, spasmodic torticollis) adult-onset generalized dystonia (Taskspecific focal dystonia in right botulinum toxin hand, spasmodic tortocollis, dystonia in left lower limb) adult-onset focal dystonia botulinum toxin (spasmodic torticollis)

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Patient 1

Clinical phenotype

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Age at Disease Gender Onset surgery course age

1

0*

1

2

1

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3

Patient 8

F

41

45

4

Patient 9

M

20

25

5

Patient 10

F

18

20

2

Patient 11

M

8

1

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17

1

SC

14

M AN U

F

1

1

EP

TE D

Patient 7

early-onset generalized dystonia (severe baclofen, tiapride, distonic, diazepam myoclonic signs in bilateral upper limbs and lower limbs) adult-onset segmental dystonia botulinum toxin, L(blepharospasm, levodopa oromandibular dystonia) early-onset generalized dystonia (spasmodic botulinum toxin, baclofen, dysphonia, tiapride, diazepam spasmodic torticollis, taskspecific dystonia in left hand) early-onset generalized dystonia (spasmodic torticollis, taskbotulinum toxin, baclofen specific dystonia in left hand, dystonia in left lower limb) childhood-onset generalized dystonia( diazepam, baclofen, Ldystonia in levodopa, haloperidol trunk, bilateral trihexyphenidyl upper and lower limbs) childhood-onset generalized dystonia( taskspecific botulinum dystonia in right toxin,diazepam, baclofen hand, dystonia in bilateral upper limbs) adult-onset generalized dystonia baclofen, (dystonia in diazepam_trihexyphenidyl upper limb and lower limbs)

2

AC C

10

Patient 12

M

6

12

6

Patient 13

M

33

39

6

1

2

1

ACCEPTED MANUSCRIPT

Mean ± STDEV

M

31

34

3

24.9 29.5 4.6± ± ± 3.1 18.7 17.9

botulinum toxin

0*

RI PT

Patient 14

adult-onset generalized dystonia (spasmodic torticollis, dystonia in trunk)

AC C

EP

TE D

M AN U

SC

M= male, F= Female, STDEV=standard deviation; * This patient did not consent to have the depleted generator to be replaced.

ACCEPTED MANUSCRIPT

Table 2 The outcomes for Burke-Fahn-Marsden Dystonia Rating Scale (N=14) Score( Mean ± SD) Movement scale 1 mo

1y

5y

10y

11.0±5.2

4.1±3.4

1.6±1.4

0.8±1.1

0.8±1.1

32.0±11.4

12.0±5.7

4.0±3.4

2.0±2.6

2.0±2.6

2.3±3.8

0.9±1.9

0.3±0.8

0.2±0.4

0.2±0.4

3.6±4.4 46.6±16.5

2.1±3.2 19.1±9.1**

1.0±1.5 7.0±4.6**

1.1±1.2 2.6±0.6 2.3±1.1

0.7±0.9 1.4±0.7 1.2±1.1

0.4±0.5 0.7±0.7 0.4±0.5

RI PT

Baseline

0.7±1.1 4.0±3.9**

0.4±0.5 0.4±0.6 0.3±0.5

0.3±0.6 0.4±0.6 0.3±0.5

SC

0.9±1.2 4.3±4.1**

M AN U

0.7±0.8 0.4±0.8 0.2±0.4 0.1±0.3 0.1±0.3 2.1±1.2 0.9±0.9 0.3±0.5 0.1±0.4 0.1±0.4 2.1±1.1 1.1±1.0 0.4±0.5 0.2±0.4 0.2±0.4 3.1±0.9 1.7±0.8 0.8±0.7 0.4±0.5 0.4±0.5 14.8±5.4 7.4±3.5** 3.1±2.1** 2.0±1.8** 1.7±1.8** One-way ANOVA test was used, comparisons with baseline, **p <0.01;

AC C

EP

TE D

Axis: Neck and trunk [0–24] Limbs: Lower, upper [0–64] Face: Eyes and mouth [0–16] Speech and swallowing [0–16] Total [0–120] Disability scale Speech [0–4] Writing [0–4] Feeding [0–4] Eating and swallowing [0–4] Hygiene [0–4] Dressing [0–4] Walking [0–6] Total [0–30]

1

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Table 3 The outcomes for 36-item Short-Form General Health Survey (N=14) Score( Mean ± SD) P -value SF-36 Subscale Baseline 1 mo 1y 5y 10 y 1 mo vs baseline 1 y vs baseline 5 y vs baseline General health 16±7 45±9 65±9 68±9 68±9 <0.001 <0.001 <0.001 Physical 21±22 57±24 75±19 85±18 85±18 <0.001 <0.001 <0.001 functioning Role physical 13±16 50±28 82±28 82±28 82±28 0.002 0.001 0.001 Role emotional 12±17 69±33 95±12 95±12 95±12 0.002 0.001 0.001 Social functional 21±8 45±9 65±12 68±11 68±11 0.001 0.001 0.001 Body pain 49±10 68±9 78±8 81±9 81±9 0.001 0.001 0.001 Vitality 34±9 61±7 78±9 80±8 80±8 <0.001 <0.001 <0.001 Mental health 33±11 55±12 72±12 80±7 80±7 <0.001 <0.001 <0.001 *According to Kruskal-Wallis or Wilcoxon tests using a Bonferroni corrected p-value of 0.0167 for significance.

1

F-value 10y vs baseline <0.001 <0.001

95.666 24.746

0.001 0.001 0.001 0.001 <0.001 <0.001

NA* NA* NA* NA* 123.926 55.56

ACCEPTED MANUSCRIPT Table 4 Parameters recorded in each follow-up session

1 month after surgery

2 1 . 7 4 0

1

2

3 1 . 7 1 0 5

Right side

Left side

Right side

Left side

Right side

Left side

Right side

v o l t a g e

v o l t a g e

v o l t a g e

v o l t a g e

v o l t a g e

v o l t a g e

v o l t a g e

2 1 . 8 4 0 5

3 1 . 7 2 0 5

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 5 ( ) 1 c 2 a 0 s e ( + ) , 2 ( ) , 3 ( -

f r e q u e n c ( y V ) ( H z )

2 1 5 0

i m p u l s e

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 0 ( ) 9 c 0 a s e ( + ) , 6 ( ) , 7 ( -

f r e q u e n c ( y V ) ( H z )

i m p u l s e

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 4 ( ) 1 c 2 a 0 s e ( + ) , 2 ( ) , 3 ( -

f r e q u e n c ( y V ) ( H z )

2 1 . 5 9 5

i m p u l s e

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 0 ( ) 9 c 0 a s e ( + ) , 6 ( ) , 7 ( -

f r e q u e n c ( y V ) ( H z )

1 1 . 6 9 0

2 1 . 5 1 5

3 1 6 5

2 1 . 5 8 0

i m p u l s e

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 4 ( ) 1 c 1 a 0 s e ( + ) , 2 ( ) , 3 ( -

f r e q u e n c ( y V ) ( H z )

2 1 5 5

2 1 . 6 9 5

i m p u l s e

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 0 ( ) 9 c 0 a s e ( + ) , 6 ( ) , 7 ( -

f r e q u e n c ( y V ) ( H z )

RI PT

i m p u l s e

SC

f r e q u e n c ( y V ) ( H z )

AC C

P a t i e n t

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 1 ( ) 9 c 0 a s e ( + ) , 6 ( ) , 7 ( -

last follow-up

M AN U

P a t i e n t

i m p u l s e

5 years after surgery

TE D

f r e q u e n c ( y V ) ( H z )

EP

Left side

v o l t a g e

1 year after surgery

2 1 . 5 1 0 5

2 1 . 5 8 0

2 1 . 5 1 5

2 1 . 6 9 5

i m p u l s e

e l e c t r o d w e i d c t o h n t ( a µ c s t ) s 6 c 0 a s e ( + ) , 4 ( ) 1 c 1 a 0 s e ( + ) , 2 ( ) , 3 ( -

ACCEPTED MANUSCRIPT

4

P a t i e n t

1 1 9 . 7 0 7 0

P a t i e n t

2 1 6 . 3 0 5 0 5

6

P

1 1 9 . 7 0 7 0

3 1 9 . 5 0 1 5 5

1 1 9 . 4 0 5 5 5

AC C

5

3 1 1 . 6 1 2 5 0 5

2 1 9

2 1 1 . 5 1 8 0 0

2 1 9 . 3 0 5 0 5

2 1 6

2 1 6 . 3 0 3 0 5

1 1 9

3 1 6 3 0 5

2 1 9 . 5 0 9 0

) c a s e ( + ) , 1 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 5 ( ) c a s e ( + ) , 1 ( ) c

3 1 6 3 0 5

1 1 9 . 5 0 6 5 5

2 1 9 . 3 0 4 0 5

2 1 6

1 1 9 . 4 0 5 5 5

2 1 6 . 1 0 2 0 5

2 1 9

) c a s e ( + ) , 5 ( ) c a s e ( + ) , 6 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 5 ( ) c

3 1 6 3 0 5

) c a s e ( + ) , 1 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 5 ( ) c a s e ( + ) , 1 ( ) c

3 1 6 3 0 5

RI PT

3 1 9 . 7 0 4 0 5

3 1 6 4 0 5

) c a s e ( + ) , 6 ( ) c a s e ( + ) , 6 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 6 ( ) c

2 1 9 . 5 0 8 0

2 1 9 . 5 0 9 0

SC

P a t i e n t

2 1 6 . 4 0 9 5

) c a s e ( + ) , 2 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 5 ( ) c a s e ( + ) , 2 ( ) c

M AN U

3

3 1 6 . 4 0 2 5 5

) c a s e ( + ) , 6 ( ) c a s e ( + ) , 6 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 6 ( ) c

TE D

3 1 6 . 4 0 2 5 5

) c a s e ( + ) , 2 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 5 ( ) c a s e ( + ) , 2 ( ) c

EP

P a t i e n t

1 1 9 . 5 0 6 5 5

2 1 9 . 1 0 3 0 5

2 1 6

1 1 9 . 4 0 5 5 5

2 1 6 . 1 0 2 0 5

2 1 9

2 1 9 . 5 0 8 0

1 1 9 . 5 0 6 5 5

2 1 9 . 1 0 3 0 5

2 1 6

) c a s e ( + ) , 5 ( ) c a s e ( + ) , 6 ( ) c a s e ( + ) , 1 ( ) c a s e ( + ) , 5 ( ) c

ACCEPTED MANUSCRIPT

P a t i e n t 9

P a t i e n t 1 0

2

. 1 0 a 1 5 s 5 e ( + ) , 2 ( ) , 3 ( ) 2 1 9 c . 4 0 a 0 0 s 5 e ( + ) , 7 ( ) 2 1 9 c . 2 0 a 2 5 s 5 e ( + ) , 2 ( ) 2 1 6 c . 5 0 a 6 0 s e ( + ) , 4 (

2 . 4 5

2 . 4 5

2 0 a 5 s e ( + ) , 4 ( ) , 6 ( ) 1 9 c 3 0 a 0 s e ( + ) , 2 ( ) 1 9 c 5 0 a 5 s e ( + ) , 7 ( ) 1 6 c 5 0 a 5 s e ( + ) , 2 (

. 1 0 a 1 5 s 5 e ( + ) , 2 ( ) , 3 ( ) 2 1 9 c . 4 0 a 0 0 s 5 e ( + ) , 7 ( ) 2 1 9 c . 2 0 a 2 0 s 5 e ( + ) , 2 ( ) 2 1 6 c . 5 0 a 6 0 s e ( + ) , 4 (

RI PT

2 0 a 5 s e ( + ) , 4 ( ) , 6 ( ) 1 9 c 3 0 a 0 s e ( + ) , 2 ( ) 1 9 c 5 0 a 5 s e ( + ) , 7 ( ) 1 6 c 5 0 a 5 s e ( + ) , 2 (

SC

. 1 0 a 1 5 s 5 e ( + ) , 2 ( ) , 3 ( ) 2 1 9 c . 5 0 a 0 0 s 5 e ( + ) , 7 ( ) 2 1 9 c . 3 0 a 3 5 s 5 e ( + ) , 2 ( ) 3 1 9 c 6 0 a 0 s e ( + ) , 4 (

2

M AN U

8

. 2 0 a 8 5 s e ( + ) , 4 ( ) , 6 ( ) 2 1 9 c . 3 0 a 1 5 s 5 e ( + ) , 2 ( ) 2 1 9 c . 6 0 a 5 5 s 5 e ( + ) , 7 ( ) 2 1 9 c . 5 0 a 8 5 s e ( + ) , 2 (

TE D

P a t i e n t

3 0 a 5 s e ( + ) , 2 ( ) , 3 ( ) 1 9 c 5 0 a 0 s e ( + ) , 7 ( ) 1 9 c 5 0 a 5 s e ( + ) , 3 ( ) 1 6 c 6 0 a 0 s e ( + ) , 4 (

EP

7

. 3 0 a . 2 5 s 3 5 e 5 ( + ) , 4 ( ) , 6 ( ) 2 1 9 c 2 . 5 0 a . 3 5 s 2 5 e 5 ( + ) , 3 ( ) 2 1 9 c 2 . 7 0 a . 8 5 s 5 5 e 5 ( + ) , 7 ( ) 2 1 6 c 2 . 6 0 a . 5 0 s 8 e ( + ) , 2 (

AC C

a t i e n t

2 . 3 5

2 . 4 5

ACCEPTED MANUSCRIPT

P a t i e n t 1 3

P a t i e n t 1 4

3 1 7 5 0 5

3 1 9 6 0 0

) ) 2 1 7 c 1 1 9 c . 4 0 a . 6 0 a 5 5 s 8 5 s e e ( ( + + ) ) , , 1 1 ( 0 ( ) ) 2 1 6 c 2 1 9 c . 5 0 a . 4 0 a 8 5 s 8 5 s e e ( ( + + ) ) , , 1 4 ( ( ) ) 2 1 6 c 2 1 6 c . 3 0 a . 3 0 a 5 0 s 5 0 s 5 e 5 e ( ( + + ) ) , , 3 7 ( ( ) ) 2 1 6 c 2 1 9 c . 4 0 a . 6 0 a 8 5 s 8 0 s 5 e 5 e ( ( + + ) ) , , 2 5 ( ( -

RI PT

1 1 9 . 6 0 7 5 5

) c a s e ( + ) , 1 0 ( ) c a s e ( + ) , 4 ( ) c a s e ( + ) , 7 ( ) c a s e ( + ) , 5 ( -

SC

3 1 1 . 5 0 1 5 0 5

) 1 7 c 5 0 a 5 s e ( + ) , 1 ( )

1 6 c 2 5 0 a . 5 s 8 e ( + ) , 1 ( ) 1 6 c 2 3 0 a . 0 s 5 e 5 ( + ) , 3 ( ) 1 6 c 2 4 0 a . 5 s 8 e 5 ( + ) , 2 ( -

1 9 4 0 5

M AN U

1 2

3 1 9 c . 6 0 a 2 0 s e ( + ) , 2 ( ) 2 1 6 c . 4 0 a 8 5 s e ( + ) , 3 ( ) 3 1 7 c . 5 0 a 2 5 s e ( + ) , 1 ( -

TE D

P a t i e n t

) ) 2 1 9 c 1 1 9 c 2 . 6 0 a . 6 0 a . 7 0 s 7 0 s 6 e e 5 ( ( + + ) ) , , 1 1 ( 0 ( ) ) 3 1 6 c 3 1 9 c 2 5 0 a 4 0 a . 5 s 5 s 8 e e ( ( + + ) ) , , 1 4 ( ( ) ) 2 1 6 c 2 1 7 c 2 . 3 0 a . 3 0 a . 6 5 s 8 5 s 5 5 e e 5 ( ( + + ) ) , , 3 7 ( ( ) ) 3 1 6 c 2 1 9 c 2 4 0 a . 6 0 a . 5 s 8 0 s 8 e 5 e 5 ( ( + + ) ) , , 2 5 ( ( -

EP

1 1

1 1 9 . 6 0 7 5 5

) c a s e ( + ) , 1 0 ( ) c a s e ( + ) , 4 ( ) c a s e ( + ) , 7 ( ) c a s e ( + ) , 5 ( -

AC C

P a t i e n t

) 2 1 9 c . 7 0 a 8 0 s 5 e ( + ) , 1 ( )

1 6 3 0 0

1 9 6 0 0

ACCEPTED MANUSCRIPT 7 7 . 9 ± 1 4 . 8

2 . 7 ± 0 . 5

1 5 6 . 8 ± 1 3 . 7

8 4 . 3 ± 1 9 . 5

2 . 5 ± 0 . 5

1 4 6 . 8 ± 1 1 . 9

7 7 . 1 ± 1 5 . 4

) 2 . 5 ± 0 . 5

1 4 7 . 5 ± 1 4 . 4

8 5 . 7 ± 1 7 . 9

) 2 . 5 ± 0 . 4

1 4 2 . 5 ± 1 4 . 2

7 3 . 6 ± 1 5 . 0

) 2 . 4 ± 0 . 4

1 4 2 . 9 ± 1 7 . 7

8 0 . 7 ± 1 6 . 9

) 2 . 4 ± 0 . 4

EP

TE D

M AN U

SC

1 5 7 . 9 ± 1 4 . 4

)

AC C

S T D E V

2 . 8 ± 0 . 5

)

1 4 1 . 4 ± 1 3 . 5

7 3 . 6 ± 1 5 . 0

) 2 . 4 ± 0 . 4

1 4 2 . 5 ± 1 8 . 2

RI PT

) M e a n ±

8 0 . 7 ± 1 6 . 9

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Highlights:

• Patients who underwent subthalamic DBS were followed up for over 10 years • The motor function was improved as much as 91.4% with ten-year-plus follow-up • All the patients gained extensive and persisting benefits

AC C

EP

TE D

M AN U

SC

RI PT

• None of the patients experienced serious adverse effects