Introduction
In advanced Parkinson’s disease (PD), there is strong evidence that deep brain stimulation (DBS) of the subthalamic nucleus (STN) outperforms best medical treatment in controlling motor symptoms and drug-induced complications and improving quality of life in short- and long-term follow-up [
1,
2]. Accurately placing of leads into the targeted deep nucleus is an essential step for successful DBS therapy [
3]. Misplacement of leads is one of the most common causes of DBS failure, resulting in unsatisfactory improvement and/or adverse stimulation effects [
4]. In order to minimize failures and side effects, a full multidisciplinary preoperative assessment is mandatory; moreover, the neurosurgeon should take into consideration possible variables, such as brain shift during stereotactic implantation [
5].
In most centers, the procedure is performed using a stereotactic frame where the patient’s skull is fixed [
6]. During the surgical procedure, the reference frame can be coupled with a CT/MRI visible adapter, depending on the imaging modality used for targeting and for registering the images to patient’s head [
7]. These systems also require a CT or MRI scan to be taken immediately after the placement of frame. The process of frame placement, image acquisition, calculation, and then translation of the coordinates for the frame can take a significant amount of time, and not only increases patients’ discomfort but also use valuable operative room resources and time. Furthermore, frame placement on patients awake who are off their medications can be challenging, and patients may have difficulty to tolerate the frame during a procedure that severely limits range of motion, lasts several hours, and requires active participation [
8].
Frameless stereotaxy reduces the duration of surgical procedure, as imaging can be performed well in advance of surgery, avoiding a preoperative imaging after that the frame has been fixed, and reduces patients’ discomfort, because they are able to move their heads and reposition themselves during surgery. This is a disposable and sterile system, which does not need periodic recalibration of frame and arc. It also provides the possibility to target posterior areas of the brain without the need of inverting the frame, and minor adjustments can be made in multiple planes to the entry point without adjustment of frame and coordinates. Moreover, without the frame, intraoperative examination of the patient and eventual access to the airway are easier [
9].
Some studies reported that frameless technique slightly lessened lead placing accuracy as compared with frame-based technique, without influencing clinical results of DBS [
10,
11]. Conversely, other studies did not found significant differences between frameless and frame-based technique in lead placement accuracy [
12‐
14]. These inconsistencies may be explained, at least partially, by different procedural experience in various centers, which influence the targeting accuracy. In fact, the learning curve of frameless procedure shows a twofold improvement of accuracy with increasing experience of the surgical team. Notably, after the first procedures, frameless accuracy is comparable with frame-based system accuracy [
11].
Although several studies have investigated the targeting accuracy of frameless stereotaxy [
9], only a few studies reported clinical outcomes, with data of short-term follow-up [
15,
16]. In this retrospective study, we report 1- and 3-year clinical follow-up of PD patients who underwent STN-DBS with a manual adjustable frameless system.
Discussion
In this study, we report the longest clinical follow-up of PD patients undergone bilateral STN-DBS with frameless stereotaxy and single-track multipass MER.
DBS allowed the reduction of dopaminergic therapy (31.2% and 31.7% at 1- and 3-year follow-up, respectively), while off-med UPDRS III score was improved (30.1% and 11.1% at 1- and 3-year follow-up, respectively). It has to be highlighted that comparison between preoperative and postoperative off-med UPDRS III scores at 3-year follow-up failed to reach significant difference either from a statistical or clinical point of view. This is a relevant observation; in fact, in other long-term follow-up studies, the UPDRS III improvement was sustained at least up to 5 years after DBS [
2,
22]. While in these studies the patients had a high baseline UPDRS III score (ranging from 50.2 to 59.5), that remained substantially stable during the follow-up, in our study, the baseline UPDRS III score was lower and it worsened after 3 years (from 29.8 ± 10.2 to 41.6 ± 14.1). The different progression of motor scores among these populations might be explained by different severity of disease at baseline, being PD clinical progression rate higher in milder than in advanced stages [
23]. Thus, selecting for DBS patients with milder motor impairment, in line with recent evidences [
24], we found a worsening of baseline motor score after 3 years, as expected [
23]. Therefore, considering the underlying disease progression, we compared postoperative off-med on-stim and postoperative off-med off-stim UPDRS III score at 3-year follow-up, founding a significant DBS motor efficacy of 36.3%.
Although the beneficial effects of STN-DBS on appendicular motor symptoms are well recognized, the response of axial disability to this intervention is more difficult to predict [
25]. We specifically evaluated axial symptoms with the axial subscore of UPDRS III: an improvement of 36.4% was found at 1-year follow-up; at 3-year follow-up, the axial subscore was impaired of 11.5% compared with preoperative off-med condition, but it was significantly improved of 23.6% compared with postoperative off-med off-stim condition, probably because of the underlying disease progression (axial subscore impairment from 6.1 ± 3.0 preoperatively to 8.9 ± 4.3 postoperatively).
Our data at 1- and 3-year follow-up are in line with frame-based stereotaxy studies. For the large randomized-controlled studies with frame-based stereotaxy, at 6–12 months of follow-up, the reduction of off-med UPDRS III varied between 28.6 and 41%, and the levodopa equivalent dosage was reduced by 23–50% [
1,
24,
26‐
28]. In long-term follow-up studies with frame-based stereotaxy, these benefits were sustained at 3-year follow-up, similar to our study [
2,
22].
In this study, we achieved excellent results in terms of safety, as we did not have major adverse events surgery-related. No infection, suicide attempt, or death occurred during the 3-year follow-up. Only minor stimulation-related side effects (dysarthria, blepharospasm, apraxia of eyelid opening, seizures) and one device-related side effect (malfunction of one lead contact) were reported in long-term follow-up. One patient, a 61-year-old man with a multi-domain mild cognitive impairment before the intervention, developed dementia 2 years after the intervention. The low rate of major adverse events with frame-based stereotaxy calls for precaution when comparing these studies with ours, for the low number of patients included [
29]. However, in terms of safety, frameless technique seems not to increase the risk of adverse events, compared with frame-based stereotaxy.
Therefore, frameless DBS has clinical efficacy and safety as comparable with frame-based stereotaxy, with several advantages for clinicians and patients. This approach can reduce patients’ discomfort during the intervention, allowing them to move and adjust their position, with less muscular tension and pain, and better tolerance for the procedure. Moreover, the application of fiducial markers prior to surgery, avoiding a preoperative imaging after that the frame has been fixed, makes surgery time shorter than with conventional frame, sparing valuable operative room resources and time, and allowing patients to spend less time in the uncomfortable off-medication state [
12,
16]. Further advantages of this technique, as compared with the frame-based one, are the easier intraoperative examination of the patient and eventual access to the airway, the possibility to make minor adjustment in multiple planes to the entry point without adjustment of a frame and coordinates, and the absence of periodic recalibration of frame and arc, necessary with frame-based stereotaxy. On the other hand, potential disadvantages of frameless procedure are a more limited access and visualization of the bur hole, compared with frame-based approach, and the need of procedural experience, which has been shown to be necessary to improve the targeting accuracy [
9].
The accuracy plays a key role in DBS efficacy, and has been investigated in several studies. It depends on several factors: brain shift during the surgery, procedural experience, technical errors in lead placement, intrinsic stability of the platform, CT-MRI imaging fusion errors, and fiducial localization discrepancies [
9]. On this latter issue, a prospective study has demonstrated that repeated CT imaging of stationary bone fiducials resulted in a localization discrepancy of 0.7 mm on average [
30]. However, while for bone fiducials the accuracy is in an acceptable submillimeter range, skin fiducial markers or surface tracing, used in other frameless systems, do not provide sufficient accuracy for DBS surgery [
31]. Finally, with broad procedural experience, frameless technique has equivalent lead placing accuracy to frame-based stereotaxy. It is in a range of 1 to 3 mm on average for both the procedures [
10‐
14].
In the last years, other surgical strategies have been developed to improve DBS accuracy. MRI-guided DBS, with intraoperative imaging control, allows to avoid frame-based co-registration and image fusion, and MRI relies on an anatomical target under real-time guidance, taking into account the brain shift during the procedure. MRI-guided approach showed a good accuracy, in average within a range of 0.6 to 2 mm, reducing to submillimeter error in most cases [
32‐
34]. Moreover, robotic-assisted techniques have recently emerged to improve accuracy and precision of DBS lead placement. Interestingly, these procedures showed submillimeter accuracy using both frame-based and frameless systems [
35‐
37], and demonstrated greater accuracy when compared with classic manual procedures [
38,
39]. Future large studies should evaluate if MRI-guided and/or robotic-assisted techniques may further improve clinical DBS outcomes, compared with classic manual procedures.
This study has several limitations: the main one is the lack of a control group. In our center, we use only frameless technique, so, being this a single-center retrospective study, we do not have an available control group of patients operated with frame-based technique. The second limit of the study is the small size of the sample, which limits the statistical significance of the results. The third limit is the retrospective design of the study. The forth limit is the lack of targeting accuracy data, not available because of the retrospective nature of the study. Future large prospective controlled studies would be advisable to strengthen our findings.
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