This randomized clinical trial compares deep brain stimulation surgery in the subthalamic nucleus for Parkinson disease under general anesthesia with surgery under local anesthesia.
Key Points
Question
Is deep brain stimulation (DBS) surgery in Parkinson disease under general anesthesia associated with less cognitive, mood, and behavioral adverse effects than DBS under local anesthesia, while being equally effective for motor improvement?
Findings
In this single-center randomized clinical trial including 110 patients with Parkinson disease, frame-based microelectrode-guided asleep DBS was associated with similar cognitive, mood, and behavioral adverse effects compared with awake DBS. Both groups showed equal improvement in motor function; surgery under general anesthesia was faster and less burdensome.
Meaning
An asleep microelectrode-guided bilateral subthalamic nucleus DBS approach had similar outcomes to awake surgery; the incidence of cognitive, mood, and behavioral effects after surgery under local anesthesia was not higher than after general anesthesia in this cohort.
Abstract
Importance
It is unknown if there is a difference in outcome in asleep vs awake deep brain stimulation (DBS) of the subthalamic nucleus for advanced Parkinson disease.
Objective
To determine the difference in adverse effects concerning cognition, mood, and behavior between awake and asleep DBS favoring the asleep arm of the study.
Design, Setting, and Participants
This study was a single-center prospective randomized open-label blinded end point clinical trial. A total of 187 persons with Parkinson disease were referred for DBS between May 2015 to March 2019. Analysis took place from January 2016 to January 2020. The primary outcome follow-up visit was conducted 6 months after DBS.
Interventions
Bilateral subthalamic nucleus DBS was performed while the patient was asleep (under general anesthesia) in 1 study arm and awake in the other study arm. Both arms of the study used a frame-based intraoperative microelectrode recording technique to refine final target placement of the DBS lead.
Main Outcomes and Measures
The primary outcome variable was the between-group difference in cognitive, mood, and behavioral adverse effects as measured by a composite score. The secondary outcomes included the Movement Disorders Society Unified Parkinson’s Disease Rating Scale, the patient assessment of surgical burden and operative time.
Results
A total of 110 patients were randomized to awake (local anesthesia; n = 56; mean [SD] age, 60.0 (7.4) years; 40 [71%] male) or to asleep (general anesthesia; n = 54; mean [SD] age, 61.3 [7.9] years; 38 [70%] male) DBS surgery. The 6-month follow-up visit was completed by 103 participants. The proportion of patients with adverse cognitive, mood, and behavioral effects on the composite score was 15 of 52 (29%) after awake and 11 of 51 (22%) after asleep DBS (odds ratio, 0.7 [95% CI, 0.3-1.7]). There was no difference in improvement in the off-medication Movement Disorders Society Unified Parkinson’s Disease Rating Scale Motor Examination scores between groups (awake group: mean [SD], −27.3 [17.5] points; asleep group: mean [SD], −25.3 [14.3] points; mean difference, −2.0 [95% CI, −8.1 to 4.2]). Asleep surgery was experienced as less burdensome by patients and was 26 minutes shorter than awake surgery.
Conclusions and Relevance
There was no difference in the primary outcome of asleep vs awake DBS. Future large randomized clinical trials should examine some of the newer asleep based DBS technologies because this study was limited to frame-based microelectrode-guided procedures.
Trial Registration
trialregister.nl Identifier: NTR5809
Introduction
Deep brain stimulation (DBS) of the subthalamic nucleus is an established effective treatment for patients with Parkinson disease and disabling motor response fluctuations despite optimal pharmacological treatment.1,2,3 Implant of the electrodes is usually performed under local anesthesia with intraoperative clinical observations during test stimulation to determine the optimal location of electrode placement. This procedure is very burdensome for patients because they frequently experience pain during stereotactic frame placement and during the surgery despite local anesthesia. Furthermore, patients have to endure a prolonged period of off-medication symptoms while experiencing anxiety and exhaustion due to clinical testing.4,5 Intraoperative test stimulation is only one of several elements used to determine optimal electrode placement in the target nucleus. Improvements in magnetic resonance imaging (MRI) enable direct visualization of the subthalamic nucleus,6,7,8,9,10 and neurophysiological target confirmation by intraoperative microelectrode recordings can also be performed under general anesthesia. This has led to a growing trend of surgery under general anesthesia.11,12,13 Many centers abolished microelectrode recordings as well,14 whereas many others continue to perform these under general anesthesia.15 Here we report the results of the General Anesthesia vs Local Anesthesia in Stereotaxy (GALAXY) randomized clinical trial, which aimed to compare DBS surgery in the subthalamic nucleus for Parkinson disease under general anesthesia with surgery under local anesthesia, using stereotactic frame-based MRI and microelectrode recordings for target determination in both groups.
Postoperative confusion after awake surgery is reported to occur in up to 20% of patients,16,17 and we expected that the burden of undergoing awake surgery could contribute to the risk of adverse effects concerning cognition, mood, and behavior. We hypothesized that DBS implantation under general anesthesia would reduce the cognitive, mood, and behavioral adverse effects that occur after local anesthesia surgery in patients with Parkinson disease, while being equally effective in obtaining motor improvement.
Methods
Study Design
The GALAXY study is a single-center prospective randomized open-label blinded end point trial that was conducted in the Amsterdam University Medical Centers in the Netherlands. The trial design was published previously18 and is available, along with the statistical analysis plan, in Supplement 1. The study was approved by the institutional ethics committee at Amsterdam University Medical Centers. The trial was conducted according to the Declaration of Helsinki,19 Dutch Medical Research Involving Human Subjects Act, and Good Clinical Practice. An independent data safety and monitoring board monitored the study, with a special focus on safety. The trial was registered at the Netherlands Trial Registry (NTR5809).
Patients
Patients with Parkinson disease who were referred to our center for DBS were trial candidates if they met all inclusion criteria: idiopathic Parkinson disease with bradykinesia, tremor and/or rigidity, and at least 1 of the following symptoms despite optimal pharmacological treatment: (1) severe motor response fluctuations, (2) dyskinesias, or (3) painful dystonia. Exclusion criteria were (1) previous Parkinson disease–related neurosurgery or (2) contraindications for DBS surgery, such as severe cognitive impairment indicated by a Mattis dementia rating scale score of 120 or lower, current depression or psychosis in psychiatric evaluation, or a physical disorder making surgery hazardous. Patients were recruited from May 2015 to March 2019, and all patients provided written informed consent.
Randomization and Masking
Included patients were randomly (1:1) assigned using a web-based system with allocation concealment to general or local anesthesia, stratified by 40% improvement in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)20 Motor Examination score in response to a suprathreshold levodopa dose administered in the off-medication condition.
Procedures
DBS electrodes were placed bilaterally in the dorsolateral part of the subthalamic nucleus. Dopaminergic medication was stopped on the evening before surgical procedure in all patients.
Surgery Under Local Anesthesia
The stereotactic frame was applied to the head under local anesthesia, after which a frame-based 1.5-T MRI scan was obtained. This was fused with a preoperative 3-T MRI scan. Using both MRI scans, the target was identified and stereotactic coordinates were calculated. After transfer to the operating room and surgical preparation, burr holes were made, and one side after the other, microelectrode recordings were carried out, in 2 or 3 simultaneous parallel tracks per side, starting at 6 mm above the calculated target depth, depending on the visibility of the target nucleus on the MRI scans. After outlining the superior and inferior borders of the subthalamic nucleus by microelectrode recordings, macroelectrode stimulation was performed in the track with the longest section or most powerful signal of subthalamic activity, testing for reduction of symptoms and for adverse effects of stimulation. Then followed implantation of the permanent electrodes under fluoroscopic guidance in a position with good therapeutic effect and a high threshold for adverse effects. The procedure was then repeated contralaterally. No sedation was used throughout this procedure. Then the frame was removed and the patient was immediately placed under general anesthesia for connection of the electrodes to extension cables and the infraclavicular subcutaneous implantable pulse generator (Vercise Deep Brain Stimulation system; Boston Scientific).
Surgery Under General Anesthesia
The patient was placed under general anesthesia using only remifentanil and propofol, together with an ultrashort-acting muscle relaxant for endotracheal intubation. Then the stereotactic frame was applied and the patient was transported to the 1.5-T MRI scanner, where a frame-based MRI was obtained. After fusion with a preoperative 3-T MRI, target identification and coordinate calculations were done. After returning to the operating room, burr holes were made and propofol was stopped for 20 minutes for subthalamic nucleus activity to return. Then one side after the other, microelectrode recordings were performed in 2 or 3 simultaneous tracks for each side, starting at 6 mm above target depth, followed by electrode implantation under fluoroscopic guidance in the track with the longest section or most powerful signal of subthalamic nucleus activity. Propofol cessation lasted maximally 45 minutes, while high-dose remifentanil was continued under careful observation of vital parameters and possible patient movements to ensure that wake-up did not occur. Immediately after electrode implantation on the second side, propofol was resumed and the surgical procedure continued with removal of the frame and repositioning and implantation of extension cables and the implantable pulse generator. Confirmation of electrode placement was performed by fusing a direct postoperative computed tomography scan with the planning MRI.
Outcomes
The primary outcome was a stringent composite score of cognitive, mood, and behavioral adverse effects up to 6 months after surgery. The score was composed of findings in 4 areas: (1) a clinically significant worsening on 3 or more cognitive tests based on a Reliable Change Index21 of −1.645 or less in more than 1 domain (language, memory, executive function, visuospatial function, attention, working memory) of the neuropsychological examination after 6 months compared with baseline; (2) any period of psychosis, depression, or anxiety as defined by the Mini-International Neuropsychiatric Interview22 psychiatric assessment up to 6 months; (3) the loss of professional activity, work, or job, all measured 6 months after the implantation; or (4) postoperative delirium assessed with the Confusion Assessment Method23 during the hospital admission for the surgery. Patients in whom at least 1 of these effects occurred were considered to have a positive composite score. This score was developed for another recent nationwide comparative surgical trial for Parkinson disease.24
The secondary outcomes investigated motor symptoms measured by the MDS-UDPRS Motor Examination and the Clinical Dyskinesia Rating Scale25 and adverse events. All baseline and follow-up motor examinations were performed by the same specialized trial nurse who was blinded to treatment allocation. The off-drug score was taken after withholding antiparkinsonian medication for 12 hours overnight. The on-drug score was then taken 1 hour after a suprathreshold levodopa dose, based on calculation of the levodopa equivalents of the patient’s morning medication. The same doses were used for baseline and follow-up assessment. Stimulators were turned on at the follow-up assessments. In addition, health-related functioning in daily life was measured by MDS-UPDRS Experiences of Daily Living and the Amsterdam Linear Disability Score.26 Quality of life was assessed with the Parkinson Disease Questionnaire–39.27 Other secondary outcome measures were the experienced burden of surgery and the satisfaction about the surgical outcome after 6 months, for which patients filled in 7-point Likert-type scale scores. Operative time was measured starting from the application of local anesthesia for frame mounting in the awake patients and from the start of general anesthesia in the other group and ending after removal of the tube after stimulator placement in both groups. To evaluate the effect on Parkinson disease medication, the Levodopa Equivalent Daily Dose was calculated.28
Statistical Analysis
Based on results in a previous large trial on DBS in Parkinson disease, we calculated that 110 patients were needed, 55 in each treatment group, for the current study to have 80% power to detect a relative reduction of 50% in the composite score of cognitive, mood, and behavioral adverse effects.24 We used the intention-to-treat principle for all outcomes. The analysis of the primary outcome, the proportion of patients with a composite score of 1 or more, was performed with the χ2 test. Additionally, we analyzed the treatment effect on the composite score using multivariable logistic regression, adjusting for the stratification variable and clinically relevant baseline imbalances. P values of less than .05 were considered statistically significant.
The differences between treatment groups for the secondary outcomes were analyzed with χ2 test, Fisher exact test, t test, or Mann-Whitney tests, as appropriate. Analyses were performed with SPSS statistics software, version 25 (IBM). Analysis took place from January 2016 to January 2020.
Results
A total of 110 patients were enrolled. Fifty-six patients were randomized to the awake group (local anesthesia) and 54 patients were randomized to the asleep group (general anesthesia). The groups were balanced with respect to baseline characteristics (Table 1). Primary outcome data were available for 103 patients because 3 patients were withdrawn from follow-up and 4 patients did not undergo repeated neuropsychological examination after 6 months. Secondary outcome measures were available for 107 patients (Figure).
Table 1. Baseline Characteristicsa.
| Characteristic | Local anesthesia (n = 56) | General anesthesia (n = 54) |
|---|---|---|
| Age, mean (SD) [range], y | 60.0 (7.4) [36-73] | 61.3 (7.9) [41-75] |
| Age at onset of Parkinson disease, mean (SD), y | 49.1 (7.2) | 50.7 (8.8) |
| Male, No. (%) | 40 (71) | 38 (70) |
| Female, No. (%) | 16 (29) | 16 (30) |
| Duration of Parkinson disease, mean (SD), y | 10.8 (5.3) | 10.6 (5.0) |
| Duration of use of medication for Parkinson disease, mean (SD), y | 10.4 (5.1) | 10.3 (4.7) |
| On-drug phase Hoehn and Yahr stage, No. (%)b | ||
| 1 | 1 (2) | 0 |
| 2 | 47 (84) | 43 (80) |
| 3 | 5 (9) | 10 (19) |
| 4 | 3 (5) | 1 (2) |
| 5 | 0 | 0 |
| Levodopa equivalent daily dose, mean (SD) | 1567.6 (555.2) | 1550.6 (599.4) |
| Difference in MDS-UPDRS ME score in on vs off-drug phase >40%, No. (%)c | 50 (89) | 48 (89) |
| Mattis Dementia Rating Scale, mean (SD)d | 139.7 (3.1) | 139.9 (2.5) |
Abbreviation: MDS-UPDRS ME, Movement Disorders Society Unified Parkinson’s Disease Rating Scale Motor Examination.
Percentages might not total 100 because of rounding.
Hoehn and Yahr scale: stage 1: unilateral involvement only; stage 2: bilateral involvement without impairment of balance; stage 3: mild to moderate bilateral disease, some postural instability, and physically independent; stage 4: severe disability, still able to walk or stand assisted; stage 5: wheelchair bound or bedridden unless aided.
A higher score indicates more motor symptoms.
The maximum score is 144, with a higher score indicating better cognition.
Figure. CONSORT Flow Diagram.
aAll 30 patients received deep brain stimulation; 26 had a preference for local anesthesia, and 4 had a preference for general anesthesia.
bFive patients had previous unilateral subthalamic nucleus or bilateral globus pallidus internus deep brain stimulation, 1 patient lived abroad, and 1 patient decided against surgery.
cOne patient was not eligible for deep brain stimulation and withdrew from follow-up after randomization owing to a new comorbidity.
dFour patients refused to undergo neuropsychological examination after 6-month follow-up.
There was no difference in the primary outcome, a composite score of 1 or more representing cognitive, mood, or behavioral adverse effects 6 months after surgery, between the general and local anesthesia group. A composite score of 1 or more occurred in 15 of 52 patients (29%) in the local anesthesia group and in 11 of 51 patients (22%) in the general anesthesia group (odds ratio, 0.7; 95% CI, 0.3-1.7; Table 2). Multivariable regression did not change the results (adjusted odds ratio, 0.7; 95% CI, 0.3-1.7). In the additional analysis as treated, results were equal to the intention-to-treat analysis with a composite score of 1 or more after local anesthesia in 15 of 51 patients (29%) and after general anesthesia in 11 of 52 patients (21%) (odds ratio, 0.6; 95% CI, 0.3-1.6; multivariable regression analysis adjusted odds ratio, 0.6; 95% CI, 0.3-1.6).
Table 2. Primary Outcome at 6 Months.
| Outcome | Local anesthesia (n = 52) | General anesthesia (n = 51) | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| Score for cognitive, mood, and behavioral adverse effects ≥1 | 15 (29) | 11 (22) | 0.7 (0.3-1.7) | .40 |
| Cognitive decline | 8 (15) | 4 (8) | 0.5 (0.1-1.7) | .23 |
| Loss of professional activity, hobby, or job | 7 (13) | 5 (9) | 0.7 (0.2-2.4) | .56 |
| Postoperative delirium | 2 (4) | 1 (2) | 0.5 (0-5.7) | >.99 |
| Psychosis | 1 (2) | 2 (4) | 0.5 (0-5.5) | .62 |
| Depression | 0 (0) | 3 (6) | NA | .12 |
| Anxiety | 2 (4) | 0 (0) | NA | .50 |
Abbreviation: NA, not applicable.
The mean (SD) improvement in motor symptoms, reflected by change from baseline to 6 months in MDS-UPDRS Motor Examination score during the off-medication phase, was not different between the groups: −27.3 (17.5) points (52% improvement) in the local anesthesia group compared with −25.3 (14.3) points (50% improvement) in the general anesthesia group (mean difference between groups, −2.0; 95% CI, −8.1 to 4.2). For the separate subscores of tremor, rigidity, bradykinesia, and gait and balance, there were also no differences in improvement between the groups (Table 3). Multivariable regression analysis did not change the main results (β = 1.1; 95% CI, −3.7 to 5.9). The improvement in the mean (SD) Amsterdam Linear Disability Score was higher in the general anesthesia group (22.9 [17.9] points) than in the local anesthesia group (15.7 [19.2]; mean difference between groups: 7.2; 95% CI, 0-14.3). The median (interquartile range) experienced burden of surgery was 5.0 (2.0-7.0) in the local anesthesia group compared with 1.0 (1.0-2.5) in the general anesthesia group on a 7-point Likert-type scale score (P < .001), with a higher score representing a greater burden. The median (interquartile range) satisfaction about the outcome of DBS after 6 months was 6.5 (6.0-7.0) in the local anesthesia group compared with 7.0 (6.0-7.0) in the general anesthesia group on a 7-point Likert-type scale score (P = .23), with a higher score representing a greater satisfaction. The mean (SD) operative time was longer in the local anesthesia group (323 [47] minutes) compared with the general anesthesia group (297 [53] minutes; P = .007). The number of microelectrode tracks used for the recordings was not different between the 2 groups (Mann-Whitney U = 1370.50; Z = −0.774; P = .44). The results of the secondary outcomes are shown in Table 3.
Table 3. Secondary Outcome Measurements.
| Outcome | Baseline | 6 mo | Change at 6 mo from baseline | |||||
|---|---|---|---|---|---|---|---|---|
| Local anesthesia (n = 56) | General anesthesia (n = 54) | Local anesthesia (n = 54) | General anesthesia (n = 53) | Local anesthesia (n = 54) | General anesthesia (n = 53) | Difference (95% CI) | P value | |
| Off-drug phase | ||||||||
| MDS-UPDRS III (ME), mean (SD)a | 52.6 (17.5) | 50.6 (15.6) | 25.2 (16.1) | 25.2 (12.7) | −27.3 (17.5) | −25.3 (14.3) | −2.0 (−8.1 to 4.2) | .53 |
| Tremor, median (IQR) | 8.0 (0 to 12.0) | 4.0 (0 to 9.3) | 0 (0 to 4.0) | 0 (0 to 1.8) | −3.5 (−10.0 to 0) | −3.5 (−8.0 to 0) | 0 (−3.0 to 0) | .30 |
| Rigidity, median (IQR) | 9.0 (6.0 to 11.0) | 7.0 (5.0 to 10.3) | 0 (0 to 4.0) | 0 (0 to 2.0) | −6.0 (−9.0 to −3.0) | −6.0 (−9.8 to −2.0) | 0 (−2.0 to 1.0) | .59 |
| Bradykinesia, median (IQR) | 21.5 (16.0 to 28.8) | 22.0 (17.8 to 27.0) | 11.5 (6.0 to 16.0) | 12.0 (7.3 to 19.0) | −9.0 (−14.3 to −4.8) | −8.5 (−13.8 to −4.3) | 0 (−4.0 − 2.0) | .75 |
| PIGD, median (IQR) | 2.0 (1.3 to 5.0) | 3.0 (2.0 to 6.3) | 1.0 (0 to 2.0) | 1.0 (0 to 2.0) | −1.0 (−3.0 to −1.0) | −1.0 (−3.0 to 0) | 0 (−1.0 to 1.0) | .90 |
| ALDS, mean (SD)b | 57.8 (23.6) | 53.0 (22.0) | 73.4 (19.7) | 76.5 (16.0) | 15.7 (19.2) | 22.9 (17.9) | −7.2 (−14.3 to 0) | .049 |
| On-drug phase | ||||||||
| MDS-UPDRS I (nM-EDL), mean (SD)c | 12.6 (6.0) | 11.4 (5.7) | 9.4 (4.9) | 8.4 (4.6) | −3.3 (5.8) | −3.0 (4.5) | −0.4 (−2.4 to 1.7) | .71 |
| MDS-UPDRS II (M-EDL), mean (SD)d | 16.9 (7.7) | 15.8 (5.7) | 11.7 (7.1) | 10.8 (5.8) | −5.1 (9.1) | −4.9 (5.2) | −0.2 (−3.2 to 2.8) | .88 |
| MDS-UPDRS III (ME), mean (SD)a | 19.0 (11.1) | 19.1 (10.3) | 15.7 (11.9) | 15.9 (9.4) | −3.2 (10.6) | −3.1 (7.8) | −0.1 (−3.7 to 3.5) | .94 |
| Tremor, median (IQR) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | .88 |
| Rigidity, median (IQR) | 1.0 (0 to 3.0) | 1.0 (0 to 3.0) | 0 (0 to 1.0) | 0 (0 to 1.0) | 0 (−3.0 to 0) | 0 (−2.0 to 0) | 0 | .72 |
| Bradykinesia, median (IQR) | 9.5 (6.0 to 14.8) | 9.0 (6.0 to 13.0) | 7.0 (3.0 to 13.0) | 7.0 (3.5 to 13.5) | −2.0 (−5.0 – 1.3) | −2.0 (−4.5 – 2.5) | 0 (−2.0 to 2.0) | .70 |
| PIGD, median (IQR) | 1.0 (0 to 2.0) | 1.0 (0 to 2.0) | 0 (0 to 1.0) | 1.0 (0 to 2.0) | 0 (−1.0 – 0) | 0 (0 to 0.5) | 0 (−1.0 to 0) | .05 |
| MDS-UPDRS IV (MC), mean (SD)e | 10.2 (3.1) | 10.8 (3.9) | 3.2 (3.6) | 3.7 (3.7) | −6.9 (4.0) | −7.1 (5.5) | 0.2 (−1.6 to 2.0) | .83 |
| ALDS, mean (SD)b | 82.9 (10.6) | 81.8 (12.7) | 83.1 (9.9) | 83.2 (10.1) | 0.7 (10.2) | 1.4 (14.0) | −0.7 (−5.4 to 4.0) | .59 |
| CDRS, mean (SD)f | 5.7 (4.1) | 7.0 (4.7) | 2.9 (3.1) | 3.7 (3.6) | −2.8 (4.9) | −3.2 (4.5) | 0.4 (−1.4 to 2.2) | .65 |
| PDQ-39, mean (SD)g | 31.6 (12.8) | 31.9 (10.6) | 22.7 (14.6) | 21.8 (12.9) | −8.8 (12.2) | −10.5 (12.0) | 1.7 (−3.1 to 6.6) | .48 |
| Medication, operation duration, tracks used for microelectrode recording, mean (SD) | ||||||||
| LEDD, mg | 1567.6 (555.2) | 1550.6 (599.4) | 667.5 (338.0) | 587.0 (290.8) | −908.4 (400.1) | −954.9 (547.2) | 46.5 (−136.9 to 230.0) | .62 |
| Operative time, min | 323.3 (46.7) | 297.4 (52.9) | NA | NA | NA | NA | 25.9 (7.1 to 44.7) | .007 |
| No. of MER tracks left + right side (tracks: patients) | ||||||||
| 2 | 3 | 1 | NA | NA | NA | NA | NA | .44 |
| 3 | 1 | 0 | NA | NA | NA | NA | NA | |
| 4 | 20 | 19 | NA | NA | NA | NA | NA | |
| 5 | 3 | 4 | NA | NA | NA | NA | NA | |
| 6 | 28 | 30 | NA | NA | NA | NA | NA | |
Abbreviations: ALDS, Amsterdam Linear Disability Score; CDRS, Clinical Dyskinesia Rating Score; IQR, interquartile range; LEDD, Levodopa Equivalent Daily Dose; MDS-UPDRS, Movement Disorders Society Unified Parkinson’s Disease Rating Scale; MC, Motor Complications; ME, Motor Examination; M-EDL, Motor Aspects of Experiences of Daily Living; MER, microelectrode recording; nM-EDL, Non-Motor Aspects of Experiences of Daily Living; NA, not applicable; PDQ-39, Parkinson Disease Questionnaire–39; PIGD, postural instability and gait disturbance.
The MDS-UPDRS score range is 0 to 132; the tremor score was calculated from MDS-UPDRS (ME) items 3.15 to 3.18; rigidity score, MDS-UPDRS (ME) item 3.3; bradykinesia score, MDS-UPDRS (ME) items 3.4 to 3.8; and postural instability and gait disturbance, MDS-UPDRS (ME) items 3.10 to 3.12.
The ALDS range is 0 to 100.
MDS-UPDRS (nM-EDL) range is 0 to 104.
MDS-UPDRS (M-EDL) range is 0 to 52.
MDS-UPDRS (MC) range is 0 to 24.
CDRS score range is 0 to 28.
PDQ-39 score range is 0 to 100.
One symptomatic intracerebral hemorrhage (2%) occurred in the local anesthesia group vs 4 (7.5%) in the general anesthesia group (Table 4). The symptoms due to intracerebral hemorrhage were dysphasia (n = 3, including 1 patient with hemorrhage in the local anesthesia group), delirium (n = 1), and delirium with an altered state of consciousness (n = 1). All these symptoms were resolved after 6-month follow-up. One patient in the general anesthesia group died 4 months after DBS surgery from urosepsis following surgery for a hip fracture. In 1 patient allocated to local anesthesia, the surgery was aborted because of intraoperative non–ST-elevation myocardial infarction. The patient underwent DBS surgery under general anesthesia without problems 2 months later.
Table 4. Serious Adverse Events.
| Adverse event | No. of events | No. of patients (%) | ||
|---|---|---|---|---|
| Local anesthesia | General anesthesia | Local anesthesia (n = 55) | General anesthesia (n = 54) | |
| Reoperation | 5 | 6 | 5 (9) | 5 (11) |
| Wound revision | 1 | 0 | 1 (2) | 0 |
| Decubitus IPG site | 1 | 0 | 1 (2) | 0 |
| Infection | 0 | 1 | 0 | 1 (2) |
| Hematoma IPG | 1 | 4 | 1 (2) | 4 (8) |
| Pain IPG | 1 | 0 | 1 (2) | 0 |
| Material dysfunction | 0 | 1 | 0 | 1 (2) |
| Othera | 1 | 0 | 1 (2) | 0 |
| Symptomatic intracerebral hemorrhage | 1 | 4 | 1 (2) | 4 (7.5) |
| Death | 0 | 1 | 0 | 1 (2) |
Abbrevation: IPG, implantable pulse generator.
Non–ST-elevation myocardial infarction during local anesthesia deep brain stimulation.
Discussion
The outcome of DBS under general anesthesia is comparable with DBS under local anesthesia. The incidence of cognitive, mood, and behavioral adverse effects after surgery under local anesthesia was not higher than after general anesthesia, which we had postulated. Motor improvement was the same in both groups. These conclusions are reflected in the comparable subjective patient satisfaction with the outcome of the therapy in both treatment groups, despite the large difference in experienced burden of surgery, which heavily favors general anesthesia.
The finding that improvement in motor function after DBS under general anesthesia was comparable with the improvement achieved in the local anesthesia group matches the results of 3 meta-analyses comparing the efficacy of DBS under general anesthesia vs local anesthesia.11,12,13 The GALAXY study provides added value because of the randomized nature of this trial, compared with the cohort studies analyzed in the meta-analyses. The 50% to 52% improvement in MDS-UPDRS Motor Examination score and the 28% to 33% improvement in Parkinson Disease Questionnaire–39 score in the GALAXY trial are in line with motor improvement and quality-of-life improvements in the literature.1,24
We investigated whether the abolishment of intraoperative testing would lead to less cognitive and behavioral effects, as postoperative confusion is frequently seen in patients after awake DBS surgery.16,17 We expected that prolonged abstinence from dopaminergic medication while being awake and undergoing the burdensome surgery, increasing the patients’ complex neurotransmitter imbalance, would contribute to postoperative cognitive, mood, and behavioral changes, but we did not find support for this in our data.
We continued the use of microelectrode recordings for neurophysiological confirmation of the dorsal and ventral borders of the nucleus under general anesthesia. Propofol was stopped for the time required to do this, but with continuation of sufficiently high-dosed opiates, patients remained unconscious. Patients were carefully monitored for signs of awakening, which we never observed. Owing to the recordings, the invasiveness of the actual surgery was therefore similar under general anesthesia compared with local anesthesia, and surgical morbidity from hemorrhage could be expected to be similar as well. Nevertheless, symptomatic intracerebral hemorrhages occurred more often during general anesthesia than under local anesthesia. We believe this is a random effect given the similar invasiveness of surgery in both groups, but our study was not powered to detect or exclude treatment allocation as a risk factor for hemorrhage. The opposite was found in the largest meta-analysis of retrospective data, where a lower incidence in intracerebral hemorrhages was reported in DBS under general anesthesia compared with local anesthesia.9 The total incidence of 4.5% of symptomatic intracerebral hemorrhages in this study of microelectrode recording–assisted DBS was higher than expected, compared with our overall risk of transient symptomatic deficit due to hemorrhage of 2% in our prospective data collection throughout the past 20 years. Earlier reports estimated the risk of symptomatic intracerebral hemorrhage around 2%29 and the overall risk of symptomatic and nonsymptomatic intracerebral hemorrhage was reported as 3.0% to 3.9%.30,31 It is likely that the risk for inducing intracerebral hemorrhage can be reduced by using fewer brain penetrations with only single-channel recordings. Abolishing the recordings altogether in a targeting procedure only based on imaging is also an increasingly common surgical strategy.30
Mortality in DBS studies is unusual and we believe that the death from urosepsis after hip fracture surgery in the present series was unrelated to the treatment group allocation.
There was also a difference in the incidence of a postoperative hematoma at the site of implantation of the pulse generator between the groups 1:4 in favor of local anesthesia, but we cannot explain this in relation to general or local anesthesia for the electrode implantations because the surgical procedure for pulse generator placement was the same for both groups.
The operative time of DBS implantation under general anesthesia was shorter than the operative time of DBS implantation under local anesthesia, as published previously.32 The time saved is attributable to the elimination of the clinical assessments during electrical macrostimulation. Also, surgical proceedings are slower in awake patients, with whom frequent interactions occur during the proceedings. Even more time will be gained in workflows with stereotactic imaging in the operating room fused to a preoperative MRI because intraoperative transport to the MRI scanner as we did takes considerably longer in patients under general anesthesia than in awake patients.
Another advantage of performing surgery under general anesthesia is that patients with extreme restlessness, anxiety, or painful off-dystonia who cannot endure DBS surgery under local anesthesia can be eligible for surgery under anesthesia.
Limitations
Frame-based microelectrode-guided surgery was performed in all patients in this study, both in awake and in asleep procedures. Therefore, it remains uncertain if these results also apply to some of the newer asleep-based implantation procedures without guidance of microrecordings or to frameless DBS procedures. Future randomized clinical trials should examine some of the newer asleep-based DBS technologies because this study was limited to frame-based microelectrode-guided procedures.
Conclusions
In conclusion, the GALAXY trial results indicate that microelectrode recording–guided DBS of the subthalamic nucleus in Parkinson disease under general anesthesia and under local anesthesia do not have a difference in outcome with regard to cognitive, mood, and behavioral adverse effects. Our study was not designed or powered to determine whether abandoning clinical testing has a meaningful influence on final electrode placement, but abandoning awake clinical testing does not lead to less motor improvement. The procedure under general anesthesia is much more patient friendly and faster.
Trial protocol and statistical analysis plan
Data Sharing Statement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol and statistical analysis plan
Data Sharing Statement.