Eight‐year follow‐up outcome of subthalamic deep brain stimulation for Parkinson’s disease: Maintenance of therapeutic efficacy with a relatively low levodopa dosage and stimulation intensity

Abstract Aims This follow‐up study aimed to examine the 8‐year efficacy and safety of subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinson's disease (PD) in southern China. Methods The follow‐up data of 10 patients with PD undergoing STN‐DBS were analyzed. Motor symptoms were assessed before and 1, 3, 5, and 8 years after the surgery with stimulation‐on in both off‐medication (off‐med) and on‐medication (on‐med) status using the Unified Parkinson's disease Rating Scale Part III. The quality of life was assessed using the 39‐item Parkinson's Disease Questionnaire. The sleep, cognition, and emotion were evaluated using a series of nonmotor scales. Levodopa equivalent daily dose (LEDD) and stimulation parameters were recorded at each follow‐up. Results The motor symptoms were improved by 50.9%, 37.7%, 36.7%, and 37.3% in 1, 3, 5, and 8 years, respectively, in the off‐med / stimulation‐on status compared with the baseline. The quality of life improved by 39.7% and 56.1% in 1 and 3 years, respectively, but declined to the preoperative level thereafter. The sleep, cognition, and emotion were mostly unchanged. LEDD reduced from 708.1 ± 172.5 mg to 330 ± 207.8 mg in 8 years. The stimulation parameters, including amplitude, pulse width, and frequency, were 2.77 ± 0.49 V, 71.3 ± 12.8 μs, and 121.5 ± 21 Hz, respectively, in 8 years. Conclusion Long‐term therapeutic efficacy of STN‐DBS could be achieved even with relatively low stimulation intensity and medication dosage for PD patients in southern China. Motor improvement and medication reduction were maintained through the 8‐year follow‐up, but improvement in quality of life lasted for only 3 years. No definite changes was found in nonmotor symptoms after STN‐DBS.


| INTRODUC TI ON
Parkinson's disease (PD) is the most common neurodegenerative disease after Alzheimer's disease. As a surgical treatment, deep brain stimulation (DBS) has gained widespread popularity since it was introduced in the 1970s and become the treatment of choice for advanced PD. Recent years have seen breakthroughs in electrode and battery designs, new stimulation paradigms, adaptive closed-loop stimulation, and sensing technologies, which hold a promise for higher efficacy and tolerability of DBS. 1 The efficacy of DBS for PD is well-established for up to 1 or 2 years, but long-term outcome data are still limited. 2 Both short-term and long-term efficacies of DBS have been reported in Western countries. [3][4][5][6] However, the long-term efficacy of DBS has not been thoroughly studied in China, although China has the largest proportion of patients with PD worldwide. Furthermore, with the influence of racial, cultural, and probably genetic differences, patients with PD in China are characterized by lower body weight, lower dosages of levodopa, and lower prevalence of dyskinesia.
Whether these factors have an impact on the management, efficacy, and safety profiles of DBS in Chinese patients, especially in the long-term, is a practical but unclear problem for Chinese neurologists. This study aimed to report the findings of 1-, 3-, 5-, and 8-year follow-ups for 10 consecutive patients with PD, who underwent bilateral subthalamic nucleus (STN) DBS in the First Affiliated Hospital, Sun Yat-sen University.

| MATERIAL S AND ME THODS
A total of 20 patients diagnosed with PD according to the criteria of the United Kingdom Parkinson's Disease Society Brain Bank underwent bilateral STN-DBS in the center during 2008-2010. The inclusion and exclusion criteria for DBS surgery were as stated in a previous study. 7 A month before undergoing surgery, the antiparkinsonian drugs remained unchanged to keep the whole condition stable. The patients were evaluated preoperatively (baseline assessment) and in 1, 3, 5, and 8 years postoperatively (follow-up assessment). The "on" and "off" motor states were recorded on video at the baseline and each follow-up.

| Motor and nonmotor assessment
Preoperative motor function was evaluated with the Unified Parkinson's disease Rating Scale Part III (UPDRS III) in a levodopa challenge test. Details of the test were reported in our previous study. 7 Follow-up evaluations were performed in the off-med and on-med

| Surgical procedure
Before the surgery, each patient underwent a nonstereotactic brain magnetic resonance imaging scan and a stereotactic brain computed tomography (CT) scan, which were then fused together to facilitate trajectory planning. As previously reported, implantation of electrodes

| Programming
The IPG was switched on 1 month after the surgery, allowing for the microlesion effect to fade away. The procedure for initial programming was detailed in the previous report. 7 The initial stimulation parameters, including pulse width, frequency, and voltage, were set at 60 μs, 130 Hz, and 0.8-1.5 V, respectively, in a single monopolar configuration with the IPG as an anode and the optimal contact as a cathode. The patients were asked to return in 2 weeks for parameter adjustment. Thereafter, they made a programming appointment as needed. The stimulation parameters and medications were adjusted by experienced neurologists. Before each follow-up, the medications and parameters remained unchanged for at least 1 month.
Levodopa equivalent daily dose (LEDD), stimulation parameters, and adverse events (AEs) were recorded at each follow-up.

| Statistical analyses
Continuous variables were presented as mean ± standard devia-

| Study population
A total of 20 patients with PD (11 male and 9 female) who underwent bilateral STN-DBS were included in this study. Their mean age at surgery was 59.3 ± 8.7 years, and the disease duration was 9.6 ± 2.8 years. All of them achieved more than 30% improvement  Table 1). The average weight of the tracked group at the baseline and in 8 years was 63.0 ± 9.8 kg and 63.9 ± 12.7 kg (p = 0.610), and the average BMI was 22.6 ± 2.7 and 22.9 ± 3.7 (p = 0.623), respectively.

| Motor outcome
Compared with the preoperative off-med state, motor symptoms (evaluated with UPDRS III) significantly improved from the baseline to 1, 3, 5, and 8 years postoperatively by 50.9%, 37.7%, 36.7%, and 37.3%, respectively (Table 2). Tremor and rigidity showed a prominent and sustained improvement of more than 50% during the 8- year follow-up. However, the improvement in bradykinesia and axial symptoms lasted only for 5 and 3 years, respectively. As for the on-

| Medication
The mean LEDD decreased from 708.1 ± 172.5 mg at the baseline In 8 years, levodopa, dopamine agonists, selegiline, and amantadine was taken by eight, six, one, and two patients, respectively. One patient withdrew all medications starting from 1 year postoperatively, and one took only levodopa.

| Programming
Multiple stimulation settings were observed in 8 years, including single monopolar, double monopolar, bipolar, and interleaving configurations. The amplitude gradually increased from 1 to 8 years, while the frequency was stable in 1, 3, and 5 years but decreased in 8 years; the pulse width remained unchanged (

| AEs and safety
AEs observed during the 8-year follow-up were recorded for all patients. Troublesome dyskinesia, gait deterioration and falls, dysarthria, and drooling were the second most frequent AEs, following TA B L E 2 UPDRS scores at the baseline and in 1, 3, 5, and 8 years postoperatively in off-med / stimulation-on and on-med / stimulation-on Emotion HAMD 0-76 9.7 ± 6.5 5.7 ± 3.8 8.7 ± 7.8 7.9 ± 7.9 10.8 ± 8.5 HAMA 0-56 8.8 ± 4.9 5.2 ± 3.2 § §* 5.4 ± 6.2 6.3 ± 6.8 9.5 ± 6.9 Note: Values are presented as mean ± standard deviation. The ANOVA for repeated measures showed significant time effects for PDQ-39 SI  domestic studies, the motor benefit of STN-DBS still persisted after 5 years. [9][10][11] For patients with early-onset PD, axial symptoms were responsive to STN-DBS even at 13 years. 12 However, all these studies mainly focused on motor function. Nonmotor outcome were limited, although some short-term results has been reported. 13 To help fill the gap, we reported our 8-year follow-up data of STN-DBS after a thorough assessment of both motor and nonmotor symptoms.
The drop-out rate of our study was high in 8 years. The older patients tended to drop out more easily, probably because they had a higher risk of having other diseases that might worsen their mobility or lead to death. Postoperative weight gain has been reported in many studies. 14-16 However, no difference was found between weight at the baseline and that in 8 years, suggesting a reduction in weight as the disease progressed, offsetting the weight gain in the first few years.
According to the off-med motor scores, STN-DBS alone significantly improved motor symptoms up to 8 years postoperatively in this study. Tremor and rigidity showed the best response to STN-DBS while bradykinesia and axial symptoms showed a diminishing response, which was also found by other teams. 17,18 In the on-med state, the motor scores started to worsen after 5 years. One possible cause of the deterioration was decreased levodopa responsiveness. 19 With a longer follow-up, the disease progressed and levodopa-resistant symptoms, such as axial symptoms, developed. The dimension score of cognition, comprising four items including somnolence, concentration, memory, and distressing dreams/hallucinations, also worsened in 8 years, with the first and the fourth items as the main contributors. Other nonmotor symptoms, including sleep, cognition, and emotion, remained mostly stable over time.
Given the selection bias, deterioration of these nonmotor aspects, especially cognition, might be found in patients lost to follow-up, with age being a risk factor of dementia. Studies about changes in nonmotor symptoms after STN-DBS have provided conflicting results including improvements, a lack of changes, and worsening (for review, see Ref. 21 and 22). Improvement of nonmotor symptoms, for example, sleep, might be either directly or indirectly due to motor benefit or reduction of dopaminergic drug load. 21 Decline in postoperative executive function, especially verbal fluency, has been consistently reported. This adverse change might be due to insertion and location of the electrodes. 22 It has been shown that medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. 23 However, in most cases, this decline did not have a significant impact on the global cognitive function and the patients' quality of life. 24 In addition, dementia prevalence and incidence after STN-DBS were not higher than those reported in the general PD population. 25 Postoperative psychiatric complications, for example, depression, The limitations of this study included the small sample size, unblinded and monocenter study design, high drop-out rate, and lack of stimulation-off motor assessment due to the patients' intolerance of this condition.

| CON CLUS IONS
This study showed that the therapeutic efficacy of STN-DBS could be maintained for at least 8 years for patients with PD in southern

CO N FLI C T O F I NTE R E S T
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
The study was approved by the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University. Signed informed consent was obtained from all patients before their participation in the study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.