【景昱-神经科学专栏】| The Safety and Efficacy of a Novel DBS System
今天为大家分享的是“景昱—神经科学专栏”第四十三期，由上海瑞金医院功能神经外科中心孙伯民教授等带来的多中心随机双盲对照试验“The Safety and Efficacy of a Novel DBS System”，内容为刚发表的英文论文，非常精彩，欢迎阅读。
<Ref: Li D, Zhang C, Gault J, et al. Remotely Programmed Deep Brain Stimulation of the Bilateral Subthalamic Nucleus for the Treatment of Primary Parkinson Disease: A Randomized Controlled Trial Investigating the Safety and Efficacy of a Novel Deep Brain Stimulation System[J]. Stereotactic & Functional Neurosurgery, 2017, 95(3):174.>
摘要
评价无线程控DBS系统的安全性与有效性。64例原发性帕金森病患者，随机分为实验组与对照组，评价术后6个月、12个月UPDRS评分、开期时间和每日左旋多巴等效剂量。结果表明术后3个月，药物关期实验组UPDRS评分显著低于对照组（25.08±1.00 vs. 4.20±1.99）。说明无线程控DBS系统对于原发性帕金森病的运动症状控制安全有效。
Introduction
Parkinson disease (PD) is a common neurodegenerative disease affecting middle-aged and older adults, with more than 53 million cases and 103,000 deaths worldwide in 2013 [1,2]. A 2007 report by Dorsey et al. [3] projected
that in China, more than 2 million patients have been diagnosed with PD. Medication, surgery, and multidisciplinary management can provide relief from PD symptoms for many patients. However, when symptoms cannot be managed using medication, such as when an overall loss of drug effect throughout the course of the day (“wearing off”) or fluctuations in efficacy (“on-off” fluctuations)
occur, deep brain stimulation (DBS) surgery may provide relief [4]. To date, DBS is the most commonly recommended and performed surgical treatment for individuals with PD who experience inadequate control of motor fluctuations and tremor using medication. Patients who are intolerant to medication may also benefit from DBS, though the treatment is not recommended for patients with severe neuropsychiatric disturbances or dementia [5-7].
Though DBS technology was introduced in China around 1999, only approximately 1,000 people each year receive the implant surgery, which is inconsistent with the current trend of PD growth in China [8], mainly due to the high cost of DBS treatment. Although new DBS treatments have been developed in recent years [9], randomized controlled trials regarding the safety and efficacy of such treatment are rare. Therefore, we conducted a prospective, multicenter, randomized, single-blind, controlled clinical trial utilizing the SceneRay wireless programming DBS system (SceneRay, Suzhou, China) in patients with PD [10].
Methods
Study Design
The present clinical trial was performed at the following five centers from October 2012 to June 2013: Ruijin Hospital of Shanghai Jiaotong University, Tang Du Hospital of the Fourth Military Medical University, Shanghai Changhai Hospital, West China Hospital of Sichuan University, and the First Affiliated Hospital of
Guangzhou Medical University. After successful implantation, 64 participants were divided into a test group that received electrical stimulation 1 month after DBS surgery and a control group that received electrical stimulation 3 months after surgery. All patients were followed up at 3, 6, and 12 months after DBS surgery in order to assess the safety and efficacy of the treatment.
Randomization was performed at the Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, via an interactive web response system. The trial conformed to the Declaration of Helsinki, Good Clinical Practice guidelines, and was approved by the ethics committees of the five participating centers (Guangzhou [2013-08], Chengdu [2012-7], Shanghai Ruijin [2012-67], Xi’an
[2012009], and Shanghai Changhai [CHEC2012-044]). This study was performed under the supervision and instruction of both the ethics committees and clinical pharmacological centers of each hospital involved as well as the China Food and Drug Administration. Written informed consent was obtained from all patients prior to their participation in the trial. The study was listed by the China Food and Drug Administration according to the state policies and regulations prior to initiation of the trial (approved thereafter) and retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR-INR-16008951).
Patients underwent bilateral stereotactic surgery of the STN for the implantation of electrodes (Model 1200, SceneRay, Suzhou, China) and a pulse generator (Model 1180, SceneRay, Suzhou, China) within 2 weeks after randomization, using operative standards addressing local anesthesia, imaging, targeting, microelectrode recording, and confirmation of final electrode position. Data were collected and analyzed by the Medical Research and Biometrics Center in Beijing Fuwai Hospital.
Device Description
The SceneRay DBS device utilized in the present study is a double-channel device designed and manufactured by Suzhou Scene-Ray Medical Co., Ltd. The DBS system includes a dual-channel neurostimulator kit, lead kit, extension kit, clinician-operated wireless programmer, test stimulator, and patient controller
( Fig. 1 a). The external programmer wirelessly communicates with the implantable neurostimulator at 403 MHz [10] . The implan table pulse generator (IPG) is 68 × 60 × 12.5 mm in size, 82 g in weight, and 7,000 mAh in battery capacity. The lead (diameter = 1.27 mm) contains four stimulating contacts made of platinumiridium alloy. The length of each contact is 1.5 mm, and interval
spaces are 0.5 mm. This device shares the same basic principles utilized by Medtronic products, with unique wireless programming and electrode fixing designs ( Fig. 1 b). The amplitude (0–10 V), pulse width (60–960 ms), and frequency (1–1,600 Hz) can be programmed, and different frequencies may be utilized in the left and right hemispheres using this type of dual-channel IPG.
Wireless and Remote Programming
DBS patients are typically required to undergo three stages of programming: intraoperative, initial postoperative, and follow-up postoperative, during which conventional programming methods are deficient in a number of respects. First, during intraoperative programming, the programming probe must be in close contact with the IPG and test stimulator. However, the probe is not sterile and must therefore be wrapped in a sterile plastic bag before it can be attached to the IPG. Furthermore, when measuring the physical connectivity of the DBS product, the surgeon must halt the surgical procedure to make room for the attachment between the programming probe and IPG. Wireless programming technology enables the patient to move freely, while allowing for smooth parameter adjustment and real-time observation of its effects. Though various DBS systems available today enable wireless programming, the SceneRay system concurrently enables remote programming, allowing doctors to adjust postoperative stimulation parameters at any time in patients with network coverage, without necessitating patients to leave their homes. This system therefore holds significant advantages across all stages of programming compared to conventional methods. Patient convenience is markedly improved, while risk of infection and total treatment time are minimized,
benefitting both doctors and patients. A detailed description of this wireless and remote technology can be found in our previous work[10] . The system received was fully approved for use throughout China by the China Food and Drug Administration upon completion of this clinical trial.
Participants
A previous study [11] reported a 14-point difference in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores relative to baseline values at a 3-month follow-up visit after DBS surgery between a test group and a control group without the use of medication (95% confidence interval [CI]: 17.5–10.5) [12]. We therefore expected a 15-point decrease in UPDRS motor scores in the DBS-on group relative to the DBS-off group, with a conservatively estimated combined standard deviation of 20 points. Based on the aforementioned parameters and two-tailed significance set at the 5% level, the power of the test is 80%, requiring at least 28 cases in each group (56 cases in total). Taking into account a maximum dropout rate of 10% during the trial, we enrolled 32 patients in each group, for a total of 64 patients.
Patients with primary PD whose motor symptoms could not be controlled with medication were enrolled in the clinical trial. Inclusion criteria were as follows: (1) diagnosis of PD according to the UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria [13] for primary PD, (2) disease duration of ≥ 5 years, (3) age 18–75 years, (4) fitness for surgery, (5) significant decrease in the efficacy of levodopa accompanied by fluctuations in motor function/motor dysfunction, leading to reduced quality of life, (6) PD severity of Hoehn and Yahr stage 2.5–4 in off-medication states, (7) improvement after an acute levodopa challenge test no less than 30%, and (8) diary-recorded “off” period of ≥ 4 h each day.
Exclusion criteria were as follows: (1) Parkinsonism or Parkinson plus syndromes, (2) severe cognitive impairment due to dementia (Mini-Mental State Examination score: illiteracy <17, elementary school <20, junior high school or above <24) or inability to accurately record in a diary, (3) active psychosis or a history of psychosis, (4) serious heart, liver, or kidney diseases, (5) severe hypertension or orthostatic hypotension, severe diabetes, or diabetes accompanied by brain and cardiovascular diseases, (6) malignant cancer, brain injuries, epilepsy, or other unstable medical conditions, (7) pregnancy or plans to become pregnant, (8) severe alcohol dependence or drug abuse, or (9) electric shock treatment within 30 days before DBS surgery.
Randomization and Masking
Patients were randomly assigned to a group by an interactive web response system developed by the central trial office. Allocation (1: 1) to the test (stimulation on) and control groups (stimulation off) was performed using a computerized minimization procedure with the following categories: age at entry, years since diagnosis of PD, and Hoehn and Yahr stage in the “on” state. Patients and neurosurgeons were unmasked to treatment allocation. Blinded assessments were based on preoperative and postoperative faceto- face evaluation, which were scheduled at baseline and at 3, 6, and 12 months. A levodopa challenge test was performed at baseline.
Statistical Analysis
Descriptive analyses were carried out to describe the count data and measurement data. Statistical analysis of the baseline population was then performed, in which Yate’s continuity correction for χ² test was used for between-group comparisons of the count data. When the theoretical frequency in the four-fold table was less than 5, a Fisher exact test was used. A t test (two groups) or an ANOVA (multiple groups) was used to compare the normally distributed measurement data between groups. The Wilcoxon rank sum test was used for comparisons between groups. Similarly, for efficacy analysis, paired t tests were used to compare normally distributed measurement data within groups, and Wilcoxon signed rank tests were used to compare non-normally distributed measurement data. For between-group comparisons, covariance analysis was used to adjust for baseline effects and center effect. Furthermore, minimum mean square errors of the dependent variables and between groups, and 95% CI were calculated to test the null hypothesis. A Cochran Mantel-Haenszel χ² test that can adjust center effects was used for comparison of between-group count data.
The number and proportion of cases that were normal before treatment and abnormal after treatment are described in the test group and the control group, respectively. Adverse events were described using their numbers and incidences, and Yate’s continuity correction for the χ² test or Fisher exact test was used for the proportions. At the same time, the specific presentations, severity of all adverse events, and their relationships with the test devices that occurred in patients in each group were described in detail.
Primary Outcome for Efficacy Evaluation
Changes in motor function scores (UPDRS-III) were assessed for both the test and control groups in the off-medication state 3 months after surgery.
Secondary Outcome for Efficacy Evaluation
1. Changes in motor function scores (UPDRS-III) in both the test and control groups in the on-medication state 3 months after surgery.
2. Changes in daily living scores (UPDRS-II), mental, behavioral, and emotional situation scores (UPDRS-I), and complication scores (UPDRS-IV) in both the test and control groups in the on-medication state 3, 6, and 12 months after surgery.
3. Changes in “on” and “off” stimulation periods recorded in the diaries of both the test and control groups in the on-medication state 3, 6, and 12 months after surgery.
4. Changes in motor function scores (UPDRS-III) during the stimulation-on and stimulation-off periods in the test group in the off-medication state 3 months after surgery.
5. Changes in motor function scores (UPDRS-III) during the stimulation-on and stimulation-off periods in the test group in the on-medication state and off-medication state 12 months after surgery.
6. Evaluation of the surgery process.
7. Patient satisfaction.
Safety Evaluation Criteria
1. Number and proportion of patients exhibiting normal laboratory test results before treatment, but abnormal results after treatment.
2. Number and incidence of adverse events and severe adverse events (SAEs) that occurred during the clinical trial.
Results
Sixty-two of 64 (96.88%) patients received simultaneous bilateral implantation followed by complete randomization and follow-up ( Fig. 2 ). Baseline characteristics are presented in Table 1. Primary analyses revealed a mean baseline UPDRS-III score of 50.84 ± 12.89 for the test group, whereas patients in the offmedication state 3 months after DBS surgery scored 23.74 ± 11.64. The improvement rate was 53.30% (25.08 ± 1). In contrast, the mean baseline UPDRS-III score of patients in the control group was 49.47 ± 11.41, with an improvement rate of 8.19% (4.20 ± 1.99), leading to a difference of 20.88 points between the groups (95% CI: 26.28–15.48) (see Table 2 ).
In the on-medication state, UPDRS-III scores of the test group improved relative to baseline (16.32 ± 8.28 vs. 21.66 ± 11.38), while UPDRS-III scores in the control group decreased relative to baseline (22.55 ± 10.40 vs. 20.56 ± 9.87), and the difference in the score change between the groups was statistically significant (5.29 ± 8.88 vs. 9.21 ± 2.00, p = 0.0024). Additionally, 3 months after DBS surgery, UPDRS-III scores in the stimulation-on condition were significantly improved relative to those in the stimulation-off condition, regardless of medication state ( p < 0.0001). At the 6-month and 12-month followup time points, all patients had begun stimulation treatment, regardless of medication state. Scores in the stimulation- on condition were significantly improved relative to those in the stimulation-off condition ( p < 0.0001; Table 3 ).
In addition, the daily equivalent doses of levodopa in both control and test groups were reduced relative to baseline; the test group exhibited a significantly greater
reduction than the control group (383.4 ± 355.31 vs. 121.3 ± 331.05, p = 0.0036) (online suppl. Table 1; see www. karger.com/doi/10.1159/000475765 for all online suppl. material).
The “on” periods in both the test and control groups were increased relative to baseline, and this increase in duration was significantly longer in the test group than in the control group (3.88 ± 4.41 vs. 0.93 ± 2.69, p = 0.0025). Furthermore, the decrease in the “off” period relative to baseline was significantly greater in the test group than in the control group (4.41 ± 4.69 vs. 1.40 ± 2.50, p = 0.0028).
Regarding secondary outcomes, in the test group, daily living (UPDRS II) and treatment complications (UPDRS- IV) scores at 3, 6, and 12 months after DBS surgery significantly improved relative to baseline scores. In the control group, daily living (UPDRS-II) and treatment complications (UPDRS-IV) scores at 6 months and 12 months improved relative to baseline and 3-month follow-up scores. Mental, behavioral, and emotional state (UPDRS-I) scores were not significantly different between the two groups at any time point ( Fig. 3 ).
Fig. 3. Comparisons in changes in outcome assessment from baseline at different time points after the surgery between the test group and control group. a. Changes of UPDRS-III scores from baseline medication-off state. b. Changes of UPDRS-III scores from baseline medication-on state. c. Changes of UPDRS-I scores from baseline. d. Changes of UPDRS-II scores from baseline. e. Changes of UPDRS-IV scores from baseline. f. Changes of “on” period from baseline. g. Changes of “off” period from baseline. h. Changes of equivalent doses of levodopa from baseline.
Safety Results
No patient exhibited any changes from “normal” to “clinically significant/abnormal” in laboratory values obtained from blood examination, urinalysis, or electrocardiography.
During the trial, adverse events occurred in a total of 11 cases (16.9%). Among these cases, 9 (13.8%) involved SAEs; depression and mood disorders, which are common non-motor symptoms in PD, were noted in two cases. Among the SAEs, hemorrhagic infarction occurred in
one patient on the day of surgery, leading to motor and language impairments and exclusion from the trial (see Table 4 ).
Discussion
Surgical therapies are now widely accepted in the treatment of medically refractory PD and levodopa-related side effects. Neuromodulation using DBS is currently the most well-known and recommended surgical treatment[14], though much debate has centered around whether the optimal target for stimulation is the STN or the globus pallidus. Because the STN is easy to identify and stimulation in this region greatly reduces motor symptoms and levodopa dosage, it is currently the most frequently targeted brain area in China. Our results demonstrate that treatment with the wireless programming DBS system
developed and manufactured by SceneRay (SceneRay, Suzhou, China) effectively improves motor scores and reduces “off” duration and levodopa dosage in patients with primary PD whose motor disorders cannot be controlled
by medication. Our results further indicate that the treatment is safe, consistent with the results of previous studies of other DBS devices [12,15]. The wireless programming DBS system utilized in the present study is therefore a reliable alternative to the high-cost Medtronic device, which is currently the most popular device on the market.
Adverse Effects
DBS carries the risks of major surgery, with complication rates related to the experience of the surgical team. As with all surgeries, DBS surgery is accompanied by the risk of infection and bleeding both during and after the procedure, and major complications include hemorrhage (1–2%) as well as infection (3–5%) [15]. The foreign object may be rejected by the body, or calcification of the implant may occur. Furthermore, while DBS is helpful for
some patients, there is also the potential for neuropsychiatric side effects, including apathy, cognitive dysfunction, and depression. However, such side effects may be temporary and related to correct placement of electrodes and calibration of the stimulator, indicating that many cogni-tive side effects are potentially reversible [16]. Because the brain can shift slightly during surgery, it is also possible for the electrodes to become displaced or dislodged, resulting in more profound complications. However, electrode misplacement is relatively easy to identify using CT, as applied in the present study.
In the present study, of the 11 patients that experienced adverse events during the trial, 9 experienced SAEs, which were subsequently managed. Two patients had developed
mood disorders. Device failure was not reported during the study. Although infection was uncommon and all institutions involved in the present trial are experienced [14,15,17,18], wireless programming [10] may aid in reducing the occurrence of such adverse events.
Economic Issues
In 2006, we investigated the economic cost of patients with PD in Shanghai, China. Total cost was significantly associated with disease severity and frequency of outpatient visits. In addition, levodopa equivalent dose and
number of drugs taken were closely associated with drug therapy cost. These results indicate that the economic burden of Chinese patients with PD is heavy[19].
STN-DBS is an established and cost-effective treatment for advanced PD [20], and the overall cost of treatment depends on the lifespan of the IPG, replacement frequency, and the price of the device [20]. More costeffective
DBS systems are necessary, particularly in developing countries in which healthcare systems may not cover the cost of the device [21]. The high out-of-pocket expense required for the implantable hardware may be the chief obstacle in DBS implantation in such countries, including China, which is estimated to have 4.94 million patients with PD in 2030 [3].
Chronic use of levodopa, however, is often limited by the appearance of long-term side effects including an overall loss of drug effect throughout the course of the day (“wearing off”), fluctuations in efficacy (“on-off” fluctuations), and involuntary movements now recognized as levodopa-induced dyskinesia. These complications are observed in as many as 45% of patients treated with levodopa
for more than 5 years. Levodopa-induced dyskinesia and motor fluctuations can cause considerable disability in patients with PD and are a major reason for surgical treatment recommendation [14]. However, only approximately 10,000 patients in China have received DBS treatment since 1998 due to the high cost of the DBS system. Therefore, it is imperative to launch a more economical, functionally similar product, especially in developing countries.
Overall, the present study provides class III evidence that for patients with primary PD, STN-DBS reduces motor symptoms and is well tolerated. SceneRay’s DBS system (SceneRay, Suzhou, China) is expected to reduce costs of DBS surgery and improve convenience by allowing wireless programming. Nevertheless, the present study has some limitations. First, there was no direct comparison to the standard Medtronic device. Second, we did not perform neuropsychological assessment. Third, the follow-up period of the present study was only 1 year, and the placebo effect may have accounted for certain results due to the single-blinded design. Further studies utilizing larger sample sizes of patients with PD,
comprehensive assessment, and longer follow-up periods are required in order to corroborate and extend the findings of the present study.
Acknowledgments
The authors would like to acknowledge the contributions of Dr. Li Nan, Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China. Funding was provided by Shanghai Jiao Tong University School of Medicine (SHSMUION) Research Center for Brain Disorders, National Natural Science Foundation of China (81271518, 81471387 to B.S.), and SceneRay Co. Ltd.
Disclosure Statement
Dr. Bomin Sun and Dr. Wei Wang have received research support from SceneRay (donated devices for OCD). Dr. Guodong Gao has received research support from SceneRay (donated devices for addiction). Dr. Dianyou Li received travel sponsorship from Medtronic and PINS. Dr. Chencheng Zhang has served as a consultant for SceneRay and received travel sponsorship from PINS. The other authors report no conflict of interest.
References
Stereotact Funct Neurosurg 2017;95:174–182
DOI: 10.1159/000475765
【景昱-神经科学专栏】往期回顾