Neuropsychiatric Effects of Bilateral Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease: Results at the 12-Month Follow-up

Abstract

Introduction:

It is aimed to report the effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on motor symptoms, neuropsychiatric symptoms, and quality of life in Parkinson’s Disease (PD) patients.

Methods:

The results of 22 patients with PD, who had undergone bilateral STN-DBS, were analyzed. The Unified Parkinson’s Disease Rating Scale (UPDRS) was applied to assess the patients’ clinical characteristics before surgery and 6-, and 12-month follow-up after surgery. The quality of life of the patients was evaluated with the Parkinson’s Disease Questionnaire (PDQ-39). Neuropsychological tests including Minnesota Impulse Control Disorders Interview (MIDI), Beck Depression Inventory-II (BDI), Hospital Anxiety and Depression Scale (HADS), Lille Apathy Rating Scale (LARS), and Mini-Mental State Examination (MMSE) were also routinely performed at baseline and 6 months and 12 months after surgery.

Results:

The mean age of patients was 57.3±8.8 years. Fourteen patients (63.6%) were male. Significant improvements were seen in UPDRS-part-II, UPDRS-part-III UPDRS-part-IV, and PDQ-39 in the follow-ups after the surgery. No significant change was observed in 6- and 12-month follow-up visits for BDI, HADS, MMSE, and LARS, compared to baseline. A depressive episode, requiring antidepressant treatment was recorded in four (18.1%) patients. Before DBS surgery, eight patients had at least one current impulse control behaviors (ICBs). Among these eight patients; ICBs disappeared in one patient, did not change in two patients, and worsened in five patients after STN-DBS treatment.

Conclusion:

In patients with a history of psychiatric disease, bilateral STN-DBS treatment may aggravate psychiatric symptoms such as depression, and ICBs.

INTRODUCTION

Parkinson’s disease (PD) is a progressive neurodegenerative disease that presents with the classic motor signs of tremor, rigidity, and bradykinesia, together with a wide variety of non-motor symptoms (NMS). Non-motor symptoms are observed in almost all patients with PD and have a negative impact on quality of life. Non-motor symptoms include different specific symptoms, such as cognitive dysfunction, neuropsychiatric symptoms, sleep disturbances, fatigue, autonomic dysfunction, olfactory dysfunction, gastrointestinal dysfunction, pain, and sensory disturbances. The disabilities caused by NMS are more likely to be difficult to treat than motor symptoms (1).

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced PD patients, who have motor symptoms, refractory to medicine and/or who show intolerable adverse effects to dopaminergic drugs. There is good evidence that STN-DBS has beneficial effects on motor symptoms, levodopa-induced motor complications, and health-related quality of life in PD patients (2). While a significant improvement in motor symptoms of STN-DBS has been reported, the effect of STN-DBS on NMS, especially neuropsychiatric symptoms, remains obscure. Subthalamic nucleus deep brain stimulation may have a negative impact on some of the NMS such as memory, attention, executive functions, psychomotor speed, and overall cognition (3). Behavioral disorders, such as impulse control behaviors (ICBs), may occur or worsen after STN-DBS (4). In contrast, ICBs may disappear as a result of reduced dopaminergic treatment following STN-DBS surgery (5). While some studies have found that STN-DBS rehabilitated depression and anxiety symptoms (3,6), some studies have found that depression symptoms could either develop or worsen following DBS surgery (7–9). Furthermore, most studies reported an increase in apathy (10–13), while a few studies reported no change in apathy after DBS surgery (14,15).

Highlights

• Subthalamic nucleus deep brain stimulation (STN-DBS) improved quality of life.

• STN-DBS did not change the depression and anxiety scores of the patients.

• Depressive episodes developed after surgery in some patients.

• STN-DBS did not change apahty score.

• STN-DBS aggravated ICBs in some patients with ICBs before surgery.

In conclusion, there is an ongoing debate in the literature about the effect of STN-DBS on neuropsychiatric symptoms. We aimed to report the effect of bilateral STN-DBS treatment on health-related quality of life, motor symptoms, and neuropsychiatric symptoms, such as depression, anxiety, apathy and ICBs in PD patients, who had undergone DBS surgery in our clinic.

METHODS

This retrospective study was approved by the University of Akdeniz Ethics Committee (KAEK-560, Date: 22.07.2020). In this study, 22 PD patients, who had undergone bilateral STN-DBS surgery at Akdeniz University, were enrolled. All patients had a diagnosis of idiopathic PD, troubling motor symptoms including motor fluctuations or dyskinesia despite best pharmacological treatment, and motor response to dopaminergic therapy.

Patients who had uncontrolled psychiatric diseases including depression, anxiety, and psychotic symptoms, and dementia were not enrolled for STN-DBS surgery. All surgeries were performed by the same neurosurgeon (T. U.). After DBS surgery, the DBS setting was made to provide maximum reduction in motor symptoms without adverse effects. All patients were routinely followed by a neurologist, neurosurgeon, and psychiatrist during the pre-operative and post-operative periods. All patients signed informed consent for data collection during the visits.

Demographic information such as sex, age, and time between diagnosis and surgery was collected from an electronic medical database. The patients’ medications for PD were evaluated using a levodopa-equivalent daily dose (LEDD). A modified Hoehn and Yahr scale and the Unified Parkinson’s Disease Rating Scale (UPDRS) were applied to assess the patients’ clinical characteristics at baseline, 6- and 12-month follow-up visits after surgery. The UPDRS has four parts: Part I concerns “non-motor experiences of daily life,” Part II concerns “motor experiences of daily life,” Part III is related to “motor examination,”, and Part IV concerns “motor complications.” The UPDRS part III was tested under two conditions; medication-ON (Med-ON) and medication-OFF (Med-OFF) conditions at baseline. Med-ON was considered to be at least an hour after taking their usual levodopa dose and Med-OFF was accepted as at least 12 hours without taking dopaminergic medications. During the 6- and 12-month follow-up visits after DBS surgery, the UPDRS part III and Hoehn and Yahr scale were performed in the Med-ON/stim-ON and Med-OFF/stim-ON conditions. Patients’ quality of life was evaluated with the Parkinson’s Disease Questionnaire (PDQ-39) (16). The total score of PDQ-39 is calculated by the following equation: the sum of all 39 item responses is divided by 4 (the maximal score for each question), divided by the total number of questions, and this result is multiplied by 100. The total score ranges between 0 and 100 on a linear scale, higher scores indicate more health problems.

During the preoperative and postoperative periods, all patients were evaluated with a Structured Clinical Interview for the DSM-5-Disorders-clinical version (SCID-5/CV) for psychiatric screening by a psychiatrist (17). At the same time, neuropsychological tests were also routinely performed at baseline, six months and 12 months after surgery. These tests were the Minnesota Impulse Control Disorders Interview (MIDI), Beck Depression Inventory-II (BDI), Hospital Anxiety and Depression Scale (HADS), Lille Apathy Rating Scale (LARS), Mini-Mental State Examination (MMSE). Beck Depression Inventory-II is a self-report psychometric test that assesses the presence and severity of depressive symptoms (18). The reliabilitiy and validity of Turkish BDI-II has been studied (19). It consists of 21 questions, with each answer being scored on a scale of 0 to 3. Higher global BDI-II scores show more severe depressive symptoms. Minnesota Impulse Control Disorders Interview is a clinical interview that provides screening for the diagnosis of impulse control behaviors (ICBs), including pathological gambling, compulsive buying, compulsive sexual behavior, compulsive exercise, kleptomania, trichotillomania, intermittent explosive disorder, and pyromania (20). Hospital Anxiety and Depression Scale is a self-assessment scale for determining the level of depression and anxiety in a hospital medical outpatient clinic setting (21). The validity study of the Turkish version scale was done by Özdemir et al. (22). It consists of 14 items, with half of the items related to anxiety. Each item in the questionnaire is scored between 0 and 3, meaning that the total score ranges between 0 and 21 for either anxiety or depression. The LARS is based on a semi-structured interview to screen and measure the severity of apathy (23). It includes 33 items, divided into nine below-mentioned domains: i) everyday productivity, ii) interests, iii) taking initiative, iv) novelty-seeking, v) voluntary actions, vi) emotional responses, vii) concern, viii) social life, and ix) self-awareness. The total score ranges between -36 and +36, with no apathy between -36 and -22; slight -21 and -17; moderate apathy -16 and -10; and severe apathy -9 and +36.

Statistical Analysis

For the statistical analysis, the Statistical Package for Social Sciences (SPSS) version 21.00 was used. A value of P less than 0.05 was deemed statistically significant. Friedman’s test was used to analyze the baseline variables as well as the sixth and 12th month after DBS surgery mean values. For the within group analysis, the amount of difference between the baseline, sixth, and 12th month results were calculated using the Wilcoxon test.

RESULTS

Twenty-two patients with PD with a mean age of 57.3±8.8 years, were included in this study. Fourteen patients (63.6%) were male. Mean disease duration between the diagnosis and the surgery was 11±4.6 years. Mean age of diagnosis of PD was 45.9±7.5 years. Mean duration of education was 7.7±4.6 years. Fifteen (68.2%) patients had only completed primary school, three patients had completed high school, four patients had graduated from a university. Nine patients were unemployed, nine patients were retired and four patients were working.

The score of UPDRS-part I was not significantly changed compared to baseline and the following-ups after surgery (p=0.58). The LEDD, UPDRS-part-II, UPDRS-part-III (both med-ON and med-OFF), UPDRS-part-IV, Hoehn-Yahr staging (both med-ON and med-OFF), PDQ-39 improved significantly in the follow-ups after the surgery. Post-hoc tests comparing baseline with 6-month follow-up resulted in significant improvements for the LEDD (p=0.002), UPDRS-part-II (p=0.006), UPDRS-part-III in both med-ON and med-OFF conditions (p=0.02, p=0.001 respectively), UPDRS-part-IV (p=0.002), and Hoehn-Yahr staging in both med-ON and med-OFF conditions (p=0.01, p=0.008 respectively) and PDQ-39 (p=0.018). Post-hoc tests comparing baseline with 12-month follow-up resulted in significant improvement for the LEDD (p=0.001), the UPDRS-part-II (p=0.002), the UPDRS-part-III and Hoehn-Yahr staging in the med-OFF condition (p=0.003, p=0.006 respectively), PDQ-39 (p=0.027) and the UPDRS-part-IV (p=0.001), but not for the UPDRS-part-III and Hoehn-Yahr staging in the med-ON condition (p>0.05). There was no significant change between 6-month follow-up and 12-month follow-up for LEDD, UPDRS, and PDQ-39. Table 1 shows the LEDD, UPDRS, and PDQ-39 of the patients at baseline, 6-month follow-up, and 12-month follow-up visits.

Table 1.

The clinical characteristics and quality of life of the patients at baseline, 6-month follow-up, and 12-month follow-up visits

	Baseline mean ± sd	Six-month follow-up mean ± sd	Twelve-month follow-up mean ± sd	p*	Post hoc tests
LEDD (mg)	1585±702	1054±377	973±329	0.001	ab
UPDRS-part I	9.1±702	7.3±6	8.6±6	0.678	-
UPDRS-part-II	19.2±8	12.2±8	12.2±7.7	0.008	ab
UPDRS-part-III (med-ON)	29.8±7	21.6±8	27.8±11	0.03	a
UPDRS-part-III (med-OFF)	63.2±16	39.06±15	47±17	<0.001	ab
UPDRS-part-IV	10.6±4	4.8±4	4.1±4.4	0.001	ab
Hoehn-Yahr (med-ON)	2.4±0.5	2.09±0.2	2.5±0.4	0.03	a
Hoehn-Yahr (med-OFF)	3.7±1.1	2.8±1	3.02±0.9	0.007	ab
PDQ39	42.3±22	26.7±19	27.1±22	0.02	ab

LEDD: levodopa-equivalent daily dose; Med-ON: medication-on conditions; Med-OFF: medication-off conditions PDQ-39: Parkinson’s Disease Questionnaire; sd: standard deviation; UPDRS: Unified Parkinson’s Disease Rating Scale.

^*Friedman test when non-parametric test criteria were fulfilled.

Post hoc comparisons (Wilcoxon signed rank):

— Baseline vs 6 months of follow-up: a, significant (P<0.05)

— Baseline vs 12 months of follow-up: b, significant (P<0.05)

— Six vs 12 months of follow-up: c, significant (P<0.05)

There were no significant differences in BDI and HADS scores between baseline and 6-month and 12-month follow-up visits. However, a depressive episode that required antidepressant treatment was recorded in four (18.1%) patients. These patients had scores of <17 in BDI and had not been receiving psychiatric treatment during the perioperative period. Yet, they had a medical history of depression and/or anxiety symptoms at some stage during the disease. None of the patients had suicidal behavior or new-onset suicidal thoughts. There was no significant change at 6-month and 12-month follow-up visits for MMSE compared to baseline (p=0.1). Total LARS scores did not significantly change six months and 12 months after DBS surgery (p=0.58). Severe apathy was observed in two patients prior to surgery and did not change after surgery. New-onset apathy did not develop after DBS surgery in 20 patients, who were non-apathetic prior to surgery. Table 2 summarizes BDI, HADS, LARS, MMSE scores of the patients before and after surgery.

Table 2.

The neuropsychiatric results of the patients at baseline, 6-month follow-up, and 12-month follow-up visits

	Baseline mean ± sd	Six-month follow-up mean ± sd	Twelve-month follow-up mean ± sd	p
BDI	12±6.7	11.8±9.7	11.2±9.8	0.6
HADS	12.5±6.9	11.4±7	11.06±7.6	0.2
LARS	-28.7±9.7	-24.8±19	-29.1±9	0.8
MMSE	27.4±2.2	27.5±2.1	27.7±2.2	0.6

BDI: Beck Depression Inventory-II; HADS: Hospital Anxiety and Depression Scale; LARS: Lille Apathy Rating Scale; MMSE: Mini-mental State Examination; sd: Standard deviation..

Before DBS surgery, eight (36%) patients had at least one current ICBs related to compulsive shopping, internet use, sexuality, and exercise. Seven of these eight patients with ICBs were male. Only one patient out of eight had full remission in his hypersexuality symptoms due to discontinuing dopamine agonist at 6-month visit after the surgery. Impulse control behavior symptoms in two patients did not change after STN-DBS treatment. The ICB symptoms of five patients worsened, which had serious socio-economic consequences following DBS surgery. Two of five patients with worsened ICB symptoms developed different new ICB symptoms after DBS surgery. None of the 14 patients without ICBs before the surgery had ICB at 6-month and 12-month follow-up visits.

DISCUSSION

The current study examined the effects of bilateral STN-DBS on motor symptoms, neuropsychiatric symptoms, and quality of life in PD patients. Subthalamic nucleus deep brain stimulation, as previously demonstrated, improved motor symptoms, levodopa-induced motor problems, and health-related quality of life (2).

According to a previous study, the total NMS burden as measured by the UPDRS Part-I did not change after STN-DBS treatment in this study (24). On the other hand, a study using the Non-Motor Symptom questionnaire scale (NMSQ) found a reduction of total NMS burden at one year following surgery, which correlated with quality-of-life improvements (25). A 36-month follow-up study found that patients treated with STN-DBS had a better outcome than patients treated with dopaminergic medication in terms of total NMS burden and specific NMS, such as sleep/fatigue, urinary symptoms, olfactory functions, and pain (26). A recent study has also shown that STN-DBS improved some of the NMS domains, such as sleep disturbance, but had a negative impact on cognitive performance, such as verbal fluency and executive function (2). Consequently, some of the NMS improve after STN-DBS, some are not influenced by DBS, and some deteriorate temporarily or permanently after DBS. In this study, we focused on the effect of STN-DBS treatment on neuropsychiatric symptoms of NMS, including depression, anxiety, apathy and ICBs.

In our study, a transient depressive episode was observed during the first year after surgery in four (18%) patients, who had a history of depression at any stage of the disease. They were treated with an antidepressant drug after DBS surgery. Previous studies have reported that depression developed in 20–25% of patients after STN-DBS surgery and such symptoms typically developed within the first two months after the surgery (7,8). A significant reduction of dopaminergic medication could have contributed to this postoperative depression. In contrast, the previous meta-analyses have found a significant reduction in depressive symptoms after STN-DBS surgery (3,6). A recent meta-analysis-of 47 studies has reported that the positive changes in depressive symptoms after DBS surgery were not associated with the quality of life or improved motor symptoms. As a result, they concluded that STN-DBS had an effect on the limbic system (27).

The current study revealed that DBS surgery had no effect on total apathy score as indicated in previous studies (14,15). In addition, neither new onset nor worsening apathy were recorded in our study. A recent meta-analysis involving 33 articles and 1,286 patients found that apathy increased after STN-DBS compared to pre-operative and PD patients on medication alone (12). Another study has also demonstrated that apathy increased in PD patients, who had undergone DBS surgery, but not in PD patients with medical treatment alone. Interestingly, also it has been also found that apathy increased following DBS was more common in middle-aged adults compared to older adults and this change in apathy after DBS was not related to motor severity, laterality of DBS, levodopa medication reduction, or motor changes after surgery (13).

In literature, there is an ongoing debate about the effects of bilateral STN-DBS on impulsivity and behavioral changes. Impulse control behaviors and behavioral addictions have been clearly linked to dopamine replacement therapy and especially to dopamine agonists in Parkinson’s disease (26). Several studies have reported that ICBs improved in correlation with reductions in dopaminergic drugs, especially dopamine agonists after STN-DBS treatment (5,29). In our study, since dopamine agonists, could be stopped after DBS surgery, only one patient’s ICBs symptoms were resolved. On the other hand, ICBs persisted in seven of eight patients. Moreover, four patients required treatment with antipsychotic drugs as a result of the worsening of ICBs. Lim, et al., have also reported that dopamine dysregulation syndrome (DDS), ICBs, and punding could develop for the first time or worsen following DBS surgery, despite the improvement of ICBs in a minority of patients (30). A study, involving 150 PD patients with approximately four years of chronic STN-DBS treatment has shown that, ICBs remitted in 69%, persisted in 31%, and new-onset ICBs developed in 7%. They also reported a significant improvement in hypersexuality, gambling and DDS, following DBS surgery (31). An observational study reported that ICBs disappeared in all patients with ICBs prior to DBS surgery; however, new-onset ICBs developed in seven patients within seven years after DBS surgery (32). A previous study has shown that post-operative worsening or a new-onset ICB was correlated with older age and a reduction in depression scores, but not with dopaminergic dose, although pre-operative ICBs were found to be in correlation with higher LEDD levels and lower MMSE scores. Thus, it has been concluded that different post-operative mechanisms, such as a side-effect of stimulation, may cause a new-onset or worsening ICBs (4).

The major limitation of this study was the small number of patients. Due to the small number of patients, we were unable to evaluate risk factors associated with psychiatric complications such as age, gender, social-economic troubles, disease duration, disease stage, dopaminergic medication dose. Since it was a retrospective study, patients could not be evaluated with more comprehensive and detailed neuropsychological tests. Patients were evaluated with only BDI, HADS, MMSE, and LARS scales, which were used routinely for pre-operative and post-operative follow-up. Nevertheless, the patients were followed closely by both a neurologist and a psychiatrist for one year in terms of psychiatric symptoms. Consequently, the present study demonstrated that STN-DBS treatment could aggravate ICBs and depressive episode, especially in patients with a history of psychiatric disease at any stage of PD. This means that the presence of psychiatric diseases before surgery is a main predictor of psychiatric complications after DBS surgery. A careful psychiatric interview is required before surgery and behavioral and mood disorders must be carefully monitored following DBS. In addition, multiple factors such as the reduction in dopamine replacement therapy after surgery, the location of active contacts, the setting of electrical stimulation and social support after surgery may also play a role in neuropsychiatric symptoms after DBS surgery. For this reason, post-operative management such as regulating dopaminergic medications, setting electrical stimulation, and maintaining social and psychiatric support is very important.