Stereotactic Staged Asymmetric Bilateral Radiofrequency Lesioning for Parkinson’s Disease

Today, the most common and effective method of surgical treatment for Parkinson’s disease (PD) is the implantation of electrodes for deep brain stimulation (DBS). DBS, used for the treatment of movement disorders, gained widespread acceptance at the end of the 20th century and has almost completely replaced ablative procedures [1, 2]. The main advantage of DBS is the ability to provide bilateral electrical stimulation of brain structures, which leads to excellent improvement in tremor, rigidity, akinesia, and dyskinesia. Another benefit is the possibility of non-invasive programming [3, 4].

Despite the low rates of overall complications, DBS treatment could be associated with a decrease in the patient’s quality of life. These complications include hardware-related and stimulation-induced adverse events, such as infection, skin erosion, seroma, lead migration or fracture, system malfunction, and battery exhaustion [5‒8]. The most common stimulation-induced adverse events include dyskinesia, gait disturbance, impulse control disorders, and some other psychiatric disturbances. Other disadvantages of DBS include the high cost of DBS devices and the requirement for complex follow-up.

In recent years, there has been a renewed interest in lesioning interventions in stereotactic neurosurgery for movement disorders. This can be explained by the significant achievements in neuroradiological, neurophysiological, and stereotactic software technologies. Ablative interventions are successfully used for PD, essential tremors, focal dystonia, and some psychiatric disturbances [9, 10]. Nowadays, radiosurgery, focused ultrasound ablation, and MRI-guided laser interstitial thermal therapy are widely used in addition to the classic radiofrequency (RF) lesioning technology [11‒13]. Several studies have found no significant difference in the improvement of motor symptoms after ablative treatment compared to DBS for PD in long-term follow-up [14‒18]. At the same time, other reports showed that thalamotomy may be considered as an option for treating patients who fail to respond to DBS or suffer from adverse effects of stimulation. In some cases, RF lesioning was successfully applied through DBS electrodes [19, 20]. Meanwhile, ablative interventions are relatively easier, have a shorter duration, patients do not need regular visits to doctors after treatment, and never lead to DBS withdrawal syndrome, which could develop after the sudden depletion of the implantable generator. Also, crucially for low- or lower-middle-income countries, ablative operations do not require significant expenses.

The issue of one-sided lesioning is generally accepted; however, bilateral ablative operations remain controversial. The purpose of this study is to evaluate the effectiveness of staged stereotactic bilateral asymmetric lesioning for PD.

We present a retrospective study of stereotactic bilateral ablative interventions for advanced PD. Among 446 consecutive patients undergoing stereotactic ablation between 2008 and 2017 at Romodanov Neurosurgery Institute, we identified 28 (6.3%) patients who underwent staged asymmetric bilateral ablation. These patients had bilateral motor symptoms, tremor, and rigidity-predominant motor features of PD, were unresponsive to medications, and experienced adverse effects of levodopa therapy. PD patients who had predominant hypokinesia and severe postural imbalance were not candidates for bilateral lesioning.

The patients’ age ranged from 43 to 72 years (mean 57.3 ± 1.5 years). There were 14 (50%) males and 14 (50%) females. Stereotactic thalamotomy and consecutive contralateral pallidotomy were performed in 16 (57.1%) patients (Vim-GPi group), while thalamotomy and consecutive contralateral lesion of subthalamic nuclei (STNs) were performed in 12 (32.9%) cases (Vim-STN group). Aggravation of symptoms in untreated limbs and low efficiency of drug therapy were considered indications for the second surgery. Thalamotomy was the first operation in all cases due to bilateral tremor in the overwhelming majority of patients, i.e., 27 out of 28. The choice of the subsequent intervention target was based on the clinical features of PD. Pallidotomy was applied for the patients who used high doses of levodopa and had dyskinesias, while subsequent STN lesion was provided for patients who only had bilateral tremor and rigidity. In this study, no patients underwent repeated lesions on the same side. The interval between the two operations ranged from 1 to 10 years (mean 3.5 ± 0.4 years). In the group Vim-STN, this interval was higher, but without significant difference (p value = 0.32).

Neurological and neuropsychological assessments were performed before the first surgery and 1 year after the second operation. Assessment included the following tests: Unified Parkinson’s Disease Rating Scale (UPDRS), modified Hoehn and Yahr scale, Schwab and England Scale, Mini-Mental State Examination (MMSE), Beck’s Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Rating Scale (HARS). For the assessment of the daily activities, UPDRS parts II (maximum score 52) were used, and for evaluating motor impairment, we used UPDRS parts III and IV (maximum scores 108 and 23, respectively). The severity of tremor was calculated by summarizing OFF state UPDRS III subscores Tremor at Rest (head, hands, legs) and Action or Postural Tremor of Hands (range, 0–28); rigidity subscore ranged from 0 to 20. We assessed the severity of hypokinesia by summarizing UPDRS III subscores Finger Taps, Hand Movements, Rapid Alternating Movements of Hands, Leg Agility and Rising from the Chair, Posture, Gait, Postural Stability, Body Bradykinesia, and Hypokinesia (range, 0–52), with higher values indicating severe motor symptoms.

The surgeries were performed under local anesthesia in the OFF state. For that reason, patients stopped antiparkinsonian therapy for 8 h before surgery and renewed the therapy after the intervention. Patients who used antiplatelet therapy stopped this treatment 3 days before surgery.

Operations were performed using a CRW stereotactic frame (Radionics Inc.). The ventrolateral intermedius (Vim) nucleus and the posteroventral area of the globus pallidus (GPi) were targeted for thalamotomy and pallidotomy, respectively. The sensorimotor region of the STN in its dorsolateral portion was targeted. The surgical targets were defined by MRI scan with contrast on a 1.5 Tesla machine. T1-weighted 1 mm thick contiguous axial MRI, T2-weighted axial images with a slice thickness of 2.0 mm, and proton density-weighted FSE axial and coronal images with a slice thickness of 2.0 mm were used. After frame placement, patients underwent CT scanning with contrast, and targeting was performed after MRI-CT fusion.

Vim was targeted by an indirect method based on AC, PC landmarks, and individual intercommissural distance (IC). The initial target was located at the level of the IC plane, 12–14 mm lateral to the midline. In order to calculate the point of the target on the IC plane, we divided it by three IC distances: from achieving the result, we subtracted 3 and obtained the final distance anterior to the PC. The STN and GPi (shown in Fig. 1) were identified by direct targeting based on the MRI scan (Table 1). Targets and trajectories were planned using different software: ImageFusion, AtlasPlan (Radionics Inc.), for 24 (43%) of operations, FrameLink, StealthStation (Medtronic), for 29 (52%) of procedures, and iPlan (Brainlab) for the last 3 (5%) operations.

Surgery was performed under local anesthesia. We used standard RF electrode (Cosman, USA) with a diameter of 2.1 mm and a 2.0 mm bare tip for lesioning Vim and GPi, while for STN lesioning, two types of RF electrodes were used: one electrode with a diameter of 2.1 mm and a 2.0 mm bare tip at first 6 cases, and another electrode with a diameter of 1.4 mm and a 3.0 mm bare tip for the following 6 cases. Treatment was provided without microelectrode recording. We used Radionics Inc.’s RF generator RFG-3C PLUS. In all cases, for delineating optimal lesion location, macrostimulation was performed at two different frequencies. The first test macrostimulation for thalamotomy was performed at a frequency of 100 Hz and a pulse width of 1 ms for assess regression of motor symptoms and sensory response; the second stimulation was performed at a frequency of 2 Hz and a pulse width of 1 ms to obtain motor thresholds. The current was gradually increased to 1.3–1.7 volts during high-frequency stimulation and to 1.5–3.5 volts during low-frequency stimulation. The GPi macrostimulation was aimed at avoiding speech dysfunction, damage to the optic tract, and damage to internal capsule. In contrast to the macrostimulation of Vim, stimulation of GPi improved motor symptoms not often. For STN lesions, the main aim of test stimulation was to assess regression of motor symptoms and to avoid internal capsule damage.

For thalamotomy and pallidotomy, we made two test lesions at 45°C and 55°C for 30 s each. For subthalamic nucleotomy, we made three test lesions at 45°C, 50°C, and 60°C for 10 s each. If a neurologic deficit was not obtained, a permanent lesion was made at 75°C for 60–65 s for thalamotomy and at 70°C for 50 s for subthalamic nucleotomy (shown in Fig. 2). We used the electrode with smaller diameter for decreasing the volume of STN ablation. For pallidotomy, we made two permanent lesions: the first at 75°C for 30 s. Then electrode was withdrawn to 3 mm above the target, and second lesion was made at 75°C for 90 s (shown in Fig. 3). A control CT scan was made within 24 h after operation in all cases.

Postoperative long-term follow-up lasted from 1 to 8 years (mean 4.8 ± 0.5 years). Patients were reviewed 3 months and 1 year after the second surgery. MRI scan was obtained in 19 (68%) patients 1 year after the second operation (shown in Fig. 4). Due to the small sample size of the observations, the Wilcoxon test was used to analyze the difference in clinical parameters. Proportions were compared using Fisher’s exact test. Results were considered statistically significant if p was less than 0.05. Software package SPSS Statistics 17.0 was used for statistical analysis.

The duration of the disease before the first surgery ranged from 4 to 21 years (mean 9.9 ± 0.8 years). The duration was higher in the Vim-GPi group (mean 11.6 ± 0.9 years) in comparison with Vim-STN group (mean 8.8 ± 0.6 years), but this difference was not statistically significant (p = 0.29). Most patients – 24 (85.3%) – used levodopa therapy before the first surgery. The duration of levodopa therapy ranged from 2 to 20 years (mean 6.9 ± 0.7 years). The mean dose of levodopa was 815.8 ± 98.1 mg/day in the Vim-GPi group and 527.8 ± 35.1 mg/day in the Vim-STN group; this difference was not significant as well (p value = 0.11). Twenty (71.4%) patients had motor side effects of levodopa therapy. In the Vim-GPi group, 4 (25.0%) patients suffered from motor fluctuations (MF), 5 (31.3%) patients had levodopa-induced dyskinesia (LID), and 3 (18.8%) patients had both MF and LID. In the Vim-STN group, patients did not have any LID; meanwhile, MF was observed in 8 (66.7%) cases. We did not make STN lesions in cases when the patient had LID because of the high risk of occurrence of hemiballism (Table 2). The duration of motor side effects was statistically higher in the Vim-GPi group (mean 4.4 ± 1.4 years), while in the Vim-STN group, it was 1.3 ± 0.3 years (p = 0.03).

All patients had a Hoehn and Yahr score of 2.5–4.0 (mean 3.24). The vast majority of patients – 19 (67.9%) had a tremor-rigidity form of PD, 7 (25.0%) patients had a tremor-akinetic-rigidity form, and isolated tremor was observed only in 2 (7.1%) cases.

Among 56 interventions in 3 (5.4%) cases, we had to perform repositioning of the electrode after intraoperative macrostimulation. One year after the second surgery, the overall mean tremor score improved from baseline, prior to the first operation, from 19.8 + 4.8 to 3.8 + 3.7 (p value <0.001). In the Vim-GPi group, tremor improved from 17.4 + 3.7 to 4.2 + 3.7, while in the Vim-STN group, the tremor improvement was more significant: from 22.8 + 4.5 to 3.3 + 3.9. The overall mean rigidity score improved from 11.0 + 2.9 to 3.7 + 2.4 (p value <0.001), with Vim-GPi group showing improvement from 11.8 + 2.1 to 3.6 + 2.5 and in the Vim-STN group from 10.0 + 3.5 to 3.9 + 2.3. Before the first operation, most patients had minimal signs of hypokinesia, with a baseline hypokinesia mean score of 14.8 + 4.6 out of a maximum 52. As was mentioned earlier, patients with severe hypokinesia or progressive hypokinesia after unilateral lesioning were not candidates for staged bilateral stereotactic lesioning. Nevertheless, mild improvement of hypokinesia was observed in both groups 1 year after the second operation. The hypokinesia mean score improved from 16.8 + 4.5 to 9.5 + 3.3 in group Vim-GPi and from 12.1 + 3.4 to 8.9 + 2.9 in the Vim-STN group (Table 3). The dose of levodopa therapy decreased on average by 43.4%, from a baseline 604.9 ± 78.3 mg/day to 342.6 ± 52.5 mg/day after the second operation. A more significant levodopa dose reduction was achieved in the Vim-STN group, with a reduction from a baseline of 397.5 ± 116.7 mg/day to 176.5 ± 94.4 mg/day (55.6% reduction), while in the Vim-GPi group, the levodopa dose decreased from 815.8 ± 98.1 to 512.8 ± 89.6 (37.1% reduction) (Table 4).

In the Vim-GPi group, the total UPDRS score in the OFF state improved from a baseline, prior to the first operation, of 96.7 to 51.2 (47.0% improvement) 1 year after the second operation and in the ON state from 76.0 to 41.1 (45.9% improvement). In the Vim-STN group, the total UPDRS mean score in the OFF state improved from a baseline of 102.1 to 56.4 (44.8% improvement) 1 year after the second operation and in the ON state from 85.6 to 41.4 (51.6% improvement). The results showed better improvement in UPDRS III motor subtype score in both groups. In the Vim-GPi group, the UPDRS III subscore in the OFF state improved from a baseline of 56.6 to 22.3 (60.6% improvement), and in the ON state, it improved from 40.3 to 18.4 (54.3% improvement). In the Vim-STN group, the UPDRS III score in the OFF state improved from a baseline of 64.8 to 28.5 (56.0% improvement) and in the ON state from 54.7 to 19.4 (64.5% improvement) (Table 5). In the Vim-GPi group, LID stopped in 6 out of 8 (75.0%) patients, and MF stopped in 4 out of 7 (57.1%) patients who had them before treatment. In the Vim-STN group, MF was abolished in 7 out of 8 (87.5%) patients. Regression of motor symptoms allowed for the improvement of general motor activity, functional independence, and quality of life, as confirmed by the improvement of mean Schwab and England daily living score from 52.5% to 72.7% in group Vim-GPi (38.5% improvement) and from 59.6% to 85.5% in group Vim-STN (43.5% improvement).

There were no adverse effects after the first operation. After the second intervention, surgical complication occurred in 4 cases (14.3%): two in Vim-GPi group and two in the Vim-STN group. In 1 (3.6%) case, local ischemia developed immediately after pallidotomy and induced permanent slight hypophonia, dysarthria, and contralateral weakness (Fig. 5). One more patient in the Vim-GPi group experienced transient motor weakness of the contralateral limbs that lasted for 3 weeks after the operation. Hemiballism occurred in 2 (7.2%) patients in the Vim-STN group after subthalamic nucleotomy and lasted for 2 and 6 months, respectively, after the operation. Overall, neurological deficit developed in 4 (14.3%) cases; among them, in 1 (3.6%) case, the deficit remained permanent.

Bilateral stereotactic lesioning had no apparent effect on cognitive function. We did not note significant changes in UPDRS mentation, behavior, and mood subscores after the second operation. The baseline, prior to the first surgery, the mean MMSE score was 26.5 ± 1.2, which corresponded to the minimal cognitive impairment. Mild impairments of attention and memory were noted before surgical treatment. One year after the second operation, cognitive function did not change significantly (mean MMSE score was 25.1 ± 0.9). Meanwhile, we noted a reduction of depression and anxiety in both groups after bilateral lesioning, but these differences were not statistically significant. BDI score improved from borderline clinical depression to mild mood disturbance (in the Vim-GPi group, from 19.2 ± 1.3 to 14.1 ± 0.9, and from 18.0 ± 1.1 to 15.6 ± 1.1 in the Vim-STN group). HDRS decreased from 15.8 to 11.7 in group Vim-GPi and from 14.9 to 11.6 in group Vim-STN). The rate of depression in the Vim-GPi group was higher in comparison to the Vim-STN group. LID affects the patient’s mood and quality of life, and in our opinion, it could be one of the factors contributing to depression. The baseline HARS score was 14.7 ± 2.1, which indicates mild anxiety severity. This score did not change in 1 year after the second operation (mean HARS score was 14.0 ± 2.6).

Despite the dominance of neurostimulation technology, ablative operations play a significant role in the treatment of PD and some other movement disorders in many neurosurgical units. This tendency can be explained by the high cost of DBS treatment and the relatively high risk of DBS complications, such as infection, electrode migration, lead fractures, skin erosions, and stimulation-induced adverse events [21‒26]. In recent years, there has been a rising interest in the MR-guided focused ultrasound and Gamma Knife treatments for PD. Also, RF ablations are favored in many neurosurgical units because of their relative straightforwardness, short duration of surgery, persistent effect, and low rate of complications [27, 28]. Furthermore, RF lesioning was successfully applied after ineffective DBS treatment [29] and even through DBS electrodes [19, 20].

Bilateral lesioning surgeries have faced criticism due to the development of postoperative balance or gait problems, speech disturbances, dysphagia, and other adverse effects. In most cases, such complications develop after bilateral thalamotomy caused by bilateral destruction of the corticothalamic fibers, corticobulbar, and cerebellothalamic tracts. However, recent advantages in neuroimaging, wide use of high-field MRI, and substantial improvements in planning software allow for the accurate identification of the anatomical details of the target and the creation of a safe surgical plan. Current experience with staged bilateral thalamotomy by Gamma Knife radiosurgery and MRI-guided focused ultrasound surgery demonstrates high efficiency and safety of bilateral lesioning [30, 31]. To eliminate the risk of adverse events, we proposed creating staged asymmetric lesions for advanced PD – thalamotomy and consecutive contralateral pallidotomy or thalamotomy and consecutive contralateral subthalamic nucleotomy.

The results of the current series show that staged RF asymmetric lesioning provides a significant improvement in motor symptoms of PD. One year after treatment, the total UPDRS score improved from baseline, prior to the first operation, in the Vim-GPi group by 47% in the OFF and 45.9% in ON states. In the Vim-STN group, the total UPDRS score improved by 44.8% in the OFF and 51.6% in ON states. Slightly more prominent improvement was evident in the motor UPDRS III score, which improved by 54.3% in the OFF and 60.6% in ON states in the Vim-GPi group and by 64.5% in the OFF and 56% in ON states in the Vim-STN group. Such significant improvement could be explained by careful patient selection for bilateral lesioning. This could be supported by the fact that during the same study period, 418 patients with advanced PD underwent unilateral RF lesioning (388 thalamotomy and 30 pallidotomy).

Some reports have described similar outcomes of RF lesioning for advanced PD. Alvarez et al. [32] noted a significant reduction of UPDRS III motor score at 12 (50%), 24 (30%), and 36 months (18%) after unilateral subthalamotomy. Less severe baseline clinical features and a notable improvement in rigidity and tremor on both sides 1 year after subsequent bilateral lesioning can be used to explain why our study’s results were more favorable in comparison with aforementioned report. The high efficacy of bilateral subthalamotomy in PD on long-term follow-up was described by the same group of authors. In this study, 7 patients underwent staged and 11 simultaneous bilateral subthalamotomy. In a long follow-up (ranging from 3 to 6 years), the authors demonstrated a notable improvement in UPDRS III motor score: 50% and 38% in the OFF and ON states, respectively, after staged bilateral subthalamotomy, and 49% and 33% in the OFF and ON states, respectively, after simultaneous subthalamotomy [33].

Another retrospective study demonstrated a significant motor benefit of staged bilateral pallidotomy in short- and long-term follow-up. York et al. [34] obtained 51% UPDRS score improvement in the ON and in the OFF states in the short-term follow-up (mean – 6.43 months). While in the long-term follow-up (mean – 3.7 years) UPDRS score improved by 29% in the ON state and 46% in the OFF state. In both short- and long-term follow-up, authors noted a more pronounced improvement in the motor UPDRS III score in the ON and OFF states. In contrast to the study by York et al. [34], the improvement of the UPDRS III motor score was slightly more prominent in our study. However, we have to take into account that in our study, evaluation was performed only 1 year after the second operation, whereas in York et al.’s [34] report, the mean follow-up after the second surgery was 3.7 years.

In the present study, the application of careful patient selection for staged bilateral lesioning allowed us to achieve significant improvement. The vast majority patients had a low rate of baseline hypokinesia, whereas patients who experienced progressive hypokinesis following their initial surgery (stereotactic RF thalamotomy) were not eligible for subsequent lesioning on the contralateral hemisphere. Suppression of the cardinal motor features of PD together with the elimination of LID and MF played a substantial role in the improvement of the UPDRS score 1 year after the second operation. We anticipate that the improvement in the UPDRS score may not be as evident in the extended postoperative period.

The results of present study indicate that stereotactic RF thalamotomy and consecutive contralateral pallidotomy for PD with levodopa-induced motor complications, especially dyskinesias, is an effective and well-tolerated treatment option. Following such treatment, tremor and rigidity were successfully suppressed in more than 80% of cases, and LID was eliminated in 6 out of 8 cases (75.0%): 2 (25.0%) unilaterally and 4 of 8 (50.0%) bilaterally.

The results obtained from the study enable us to recommend staged thalamotomy and contralateral subthalamic nucleotomy for patients with bilateral motor symptoms characterized by a tremor and rigidity-predominant type of PD and the absence of LID. RF lesion of Vim nuclei and STN leads to immediate relief of tremor and regression of MF in vast majority of cases. In this group, levodopa therapy decreased by 55.6%, which led to an additional promotion of the regression of MF and improvement of the total UPDRS score. Such an impressive reduction in levodopa therapy could be explained by the STN’s key influence on movement activity due to the involvement in circuitry between the cortex and basal ganglia. It’s also important to consider that patients in this group were using a low dose of levodopa before the operations (mean 397.5 ± 116.7 mg per day), and they did not exhibit the same degree of dependency on levodopa as observed in the patients in the Vim-GPi group.

Neurological complications were observed in 4 (14.3%) patients, with two cases in each group. Among these, adverse events were transient in 3 (10.7%) cases, while in 1 (3.6%) case, the complication was permanent. Transient hemiballism after subthalamic nucleotomy developed in 2 cases (16.7%). We could assume that a large volume of STN lesions and a short interval between surgeries (less than 4 years) can be considered favorable factors for hemiballism development. However, other authors have emphasized that only a preoperative high LID score associates with an increased risk of dyskinesias, whereas lesion volume is not a factor that determines the occurrence of hemiballism [35]. Taking these circumstances into account, we did not perform STN lesioning in patients who had LID.

The psychological examination did not find any cognitive decline 1 year after the second operation, while slight reduction of depression and anxiety were noted in both groups. The improvement in mood could potentially be attributed to the regression of cardinal motor symptoms of PD and the reduction of levodopa dose. This psychological improvement could serve as an additional argument over DBS for PD, particularly when considering the potential risk of developing neuropsychological complications following neurostimulation [23, 26].

In conclusion, it should be emphasized that the majority of patients presented of the study were well-suited candidates for DBS treatment. Given the substantial expense associated with DBS and the lack of assured medical coverage in numerous countries, PD patients exhibiting bilateral motor symptoms and an inadequate response to antiparkinsonian medical therapy encounter challenges in accessing treatment. Additionally, there is a small cohort of patients experiencing cognitive disturbances or immunodeficiency, making them unsuitable candidates for DBS treatment. In such situations, alternative neurosurgical options, like staged bilateral stereotactic ablation, may be taken into consideration. Despite the dominance of neurostimulation technologies in the present era, there exists a relatively modest level of interest in RF stereotactic lesioning within the medical community, especially among neurosurgeons and neurologists. This trend has also been influenced by the industrial promotion of DBS. Nevertheless, I hold the belief that RF stereotactic bilateral lesioning could still hold a position as one of the viable treatment options for PD, taking into account both clinical and financial considerations.

Despite the study’s limited sample size, our findings indicate that staged bilateral asymmetric stereotactic lesioning is a reliable and safe approach for managing PD in a highly selected group of patients. This modality improves overall motor function, augments the patient’s mobility, facilitates daily living activity, and ultimately contributes to an improved quality of life. Bilateral stereotactic lesioning enables a reduction in the levodopa dose, providing them greater independence from a complicated medication regimen. Thoroughly identifying and selecting patients for ablative surgery enables the attainment of optimal outcomes in treating PD with bilateral symptoms.

The study was conducted ethically and approved by Ethics Commission of Romodanov Neurosurgery Institute; head of Ethics Commission – Professor V. Rosumenko; members of commission: Professor A. Moroz, V. Biloshutsky, S. Litvak, and O. Biloshutsky. The study was approved by Ethics Commission in June 6, 2016, approval number 3.

Ethics Commission’s protocol accords to the World Medical Association Declaration of Helsinki for Human Studies. Ethics Commission’s protocol includes written information form and was signed by each patient enrolled in study.

Approved patient’s written information form includes the statement that results of the study can be used for publication. But this information form does not contain the statement that patient’s personal data would be disclosed for analysis abroad and publicly available.

The author has no conflicts of interest to declare.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Kostiantyn Kostiuk – conceptualization, methodology, supervision, visualization, and writing – reviewing and editing.

Patient’s written information form does not contain the statement that patient’s personal data would be disclosed for analysis abroad and publicly available. Taking into account the above circumstances all datasets cannot be shared. Further inquiries can be directed to the corresponding author.