Safety and accuracy of incisionless transcranial MR-guided focused ultrasound functional neurosurgery: single-center experience with 253 targets in 180 treatments

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  • Sonimodul Center for Ultrasound Functional Neurosurgery, Solothurn, Switzerland
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OBJECTIVE

Since the first clinical application of the incisionless magnetic resonance–guided focused ultrasound (MRgFUS) technology only small series of patients have been reported, and thus only extrapolations of the procedure-related risks could be offered. In this study, the authors analyze side-effects and targeting accuracy in 180 consecutive treatments with MRgFUS for chronic therapy-resistant idiopathic Parkinson’s disease (PD), essential tremor (ET), cerebellar tremor (CT), and neuropathic pain (NP), all performed in their dedicated center.

METHODS

A total of 180 treatments with MRgFUS for chronic therapy-resistant idiopathic PD, ET, CT, and NP were prospectively assessed for side-effects and targeting accuracy. Monitoring for later side-effects was continued for at least 3 months after the procedure in all but 1 case (0.6%); in that single case, the patient was lost to follow-up after an uneventful early postoperative course. The surgical targets were the pallidothalamic tract (pallidothalamic tractotomy, n = 105), the cerebellothalamic tract (cerebellothalamic tractotomy, n = 50), the central lateral nucleus (central lateral thalamotomy, n = 84), the centrum medianum (centrum medianum thalamotomy, n = 12), and the globus pallidus (pallidotomy, n = 2). Cognitive testing was performed before, 1–2 days after, and 1 year after the procedure. The Mini–Mental State Examination (MMSE) was used for the first 29 cases and was then replaced by the Montreal Cognitive Assessment (MoCA). Lesion reconstruction and measurement of targeting accuracy were done on 2-day posttreatment MR images for each performed target. To determine targeting accuracy measurement, 234 out of the 253 lesions depicted in the 2-day postoperative MR examination could be 3D-reconstructed.

RESULTS

The mean MoCA score was slightly improved 2 days postoperatively (p = 0.002) and remained stable at 1-year follow-up (p = 0.03). The mean MMSE score was also slightly improved 2 days postoperatively and at 1-year follow-up, but the improvement was not statistically significant (p = 0.06 and p = 0.2, respectively). The mean (± SD) accuracy was 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for the mediolateral, anteroposterior, and dorsoventral dimensions, respectively. The mean 3D accuracy was 0.73 ± 0.39 mm. As to side-effects, 14 events over 180 treatments were documented. They were classified into procedure-related (n = 4, 2.2%), effect on neighboring structures (n = 3, 1.7%), and disease-related (n = 7, 3.9%). There was no bleeding.

CONCLUSIONS

The incisionless transcranial MRgFUS technology demonstrates a higher targeting accuracy and a lower side-effect profile than techniques requiring cerebral penetration. In the absence of penetration brain shift, this technique avoids the placement of a thermolesion away from the chosen target, thus suppressing the need for reversible therapeutic energy application. With the use of proper physiopathology-based targets, definitive therapeutic effects can be coupled with sparing of sensory, motor, and paralimbic/multimodal thalamocortical functions. Clinical efficacy, not analyzed in this investigation, will ultimately rest in proper target selection and optimized thermolesional coverage of the target.

ABBREVIATIONS AC = anterior commissure; AP = anteroposterior; CLT = central lateral thalamotomy; CMT = centrum medianum thalamotomy; CT = cerebellar tremor; CTT = cerebellothalamic tractotomy; DBS = deep brain stimulation; DV = dorsoventral; ET = essential tremor; MoCA = Montreal Cognitive Assessment; ML = mediolateral; MMSE = Mini–Mental State Examination; MRgFUS = MR-guided focused ultrasound; NP = neuropathic pain; PC = posterior commissure; PD = Parkinson’s disease; PTT = pallidothalamic tractotomy; RF = radiofrequency.

OBJECTIVE

Since the first clinical application of the incisionless magnetic resonance–guided focused ultrasound (MRgFUS) technology only small series of patients have been reported, and thus only extrapolations of the procedure-related risks could be offered. In this study, the authors analyze side-effects and targeting accuracy in 180 consecutive treatments with MRgFUS for chronic therapy-resistant idiopathic Parkinson’s disease (PD), essential tremor (ET), cerebellar tremor (CT), and neuropathic pain (NP), all performed in their dedicated center.

METHODS

A total of 180 treatments with MRgFUS for chronic therapy-resistant idiopathic PD, ET, CT, and NP were prospectively assessed for side-effects and targeting accuracy. Monitoring for later side-effects was continued for at least 3 months after the procedure in all but 1 case (0.6%); in that single case, the patient was lost to follow-up after an uneventful early postoperative course. The surgical targets were the pallidothalamic tract (pallidothalamic tractotomy, n = 105), the cerebellothalamic tract (cerebellothalamic tractotomy, n = 50), the central lateral nucleus (central lateral thalamotomy, n = 84), the centrum medianum (centrum medianum thalamotomy, n = 12), and the globus pallidus (pallidotomy, n = 2). Cognitive testing was performed before, 1–2 days after, and 1 year after the procedure. The Mini–Mental State Examination (MMSE) was used for the first 29 cases and was then replaced by the Montreal Cognitive Assessment (MoCA). Lesion reconstruction and measurement of targeting accuracy were done on 2-day posttreatment MR images for each performed target. To determine targeting accuracy measurement, 234 out of the 253 lesions depicted in the 2-day postoperative MR examination could be 3D-reconstructed.

RESULTS

The mean MoCA score was slightly improved 2 days postoperatively (p = 0.002) and remained stable at 1-year follow-up (p = 0.03). The mean MMSE score was also slightly improved 2 days postoperatively and at 1-year follow-up, but the improvement was not statistically significant (p = 0.06 and p = 0.2, respectively). The mean (± SD) accuracy was 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for the mediolateral, anteroposterior, and dorsoventral dimensions, respectively. The mean 3D accuracy was 0.73 ± 0.39 mm. As to side-effects, 14 events over 180 treatments were documented. They were classified into procedure-related (n = 4, 2.2%), effect on neighboring structures (n = 3, 1.7%), and disease-related (n = 7, 3.9%). There was no bleeding.

CONCLUSIONS

The incisionless transcranial MRgFUS technology demonstrates a higher targeting accuracy and a lower side-effect profile than techniques requiring cerebral penetration. In the absence of penetration brain shift, this technique avoids the placement of a thermolesion away from the chosen target, thus suppressing the need for reversible therapeutic energy application. With the use of proper physiopathology-based targets, definitive therapeutic effects can be coupled with sparing of sensory, motor, and paralimbic/multimodal thalamocortical functions. Clinical efficacy, not analyzed in this investigation, will ultimately rest in proper target selection and optimized thermolesional coverage of the target.

ABBREVIATIONS AC = anterior commissure; AP = anteroposterior; CLT = central lateral thalamotomy; CMT = centrum medianum thalamotomy; CT = cerebellar tremor; CTT = cerebellothalamic tractotomy; DBS = deep brain stimulation; DV = dorsoventral; ET = essential tremor; MoCA = Montreal Cognitive Assessment; ML = mediolateral; MMSE = Mini–Mental State Examination; MRgFUS = MR-guided focused ultrasound; NP = neuropathic pain; PC = posterior commissure; PD = Parkinson’s disease; PTT = pallidothalamic tractotomy; RF = radiofrequency.

The first clinical study with incisionless transcranial MR-guided high-intensity focused ultrasound in the field of functional neurosurgery was published by Martin et al. in 2009. Since publication of this first trial, around 200 treatments have been reported. As each reported series has small numbers,8,11,12,14,19,20,24,26,28,40,41,44 no procedure-related risk profile can be reliably inferred yet. To assess risks, one also needs an analysis of targeting accuracy, which is directly related to the risk of damage to neighboring structures.

We thus report side-effects and target accuracy in 180 treatments performed in our dedicated center between April 2011 and November 2016 for patients with Parkinson’s disease, essential tremor, and cerebellar tremor, as well as neuropathic pain conditions, all chronic and therapy resistant.

Historically, the uncertainty due to brain shift during radiofrequency (RF) electrode insertion and consequent neurological deficits produced by misplaced thermolesions has been of great importance in the development of deep brain stimulation (DBS) techniques. Numerous reports have described clinical results of DBS in Parkinson’s disease and essential tremor, accompanied by significant procedure-related risks, however. The main procedure-related side-effects of DBS are bleeding45 and infection2–4,9,13,16,17,22,36,37,43 as well as hardware-related complications with return to the operation room for electrode repositioning and various material-related malfunctions or replacements. A removal or revision rate of up to 34% was reported by Rolston et al.,39 and an 8.4% hardware-related complication rate per electrode-year was reported by Oh and collaborators.35

The incisionless MR-guided high-intensity focused ultrasound technique has the potential to revolutionize the field of stereotactic functional neurosurgery as long as high targeting accuracy, a low side-effect profile, and sparing of neurological functions are provided. Symptom relief depends on targeting accuracy, the chosen target, and its thermolesional coverage. In this report, we concentrate on targeting accuracy and side-effects.

Methods

We report on 180 consecutive treatments for chronic therapy-resistant idiopathic Parkinson’s disease (PD), essential tremor (ET), neuropathic pain (NP), and cerebellar tremor (CT) in 136 patients. Two of the 180 treatments were aborted. One PD patient with cognitive reductions could not cope emotionally with the treatment procedure, which had to be interrupted before ultrasound application. Only 1 procedure had to be aborted because it was not possible to achieve therapeutic heat application in the target. No patient was excluded from treatment on the basis of preoperative bone density analysis. Thus 178 treatments were completed in 134 patients. Analysis of the skull density ratio (SDR) was not available at the beginning of this series. More recently, we have only measured these values irregularly, in cases where a semi-quantitative analysis of CT Hounsfield units was unfavorable. The patients were seen by neurologists or pain specialists who confirmed the diagnosis and the resistance to drug treatment. They were evaluated by an internist to identify any contraindication to surgery. No patient took anticoagulant or antiplatelet drugs within 10 days before the procedure. Laboratory blood studies were performed preoperatively, and all patients had normal electrolyte and coagulation status.

Monitoring for late side-effects was continued for at least 3 months following the procedure for all patients except 1 ET patient who was lost to follow-up after an uneventful early postoperative course with 90% contralateral tremor relief. In the preoperative assessment, the Mini–Mental State Examination (MMSE) was replaced after the first 29 cases by the Montreal Cognitive Assessment (MoCA). These cognitive tests were performed before, 1–2 days after, and 1 year after the procedure; postoperative test results were compared to preoperative test results to identify statistically significant differences. All patients signed an informed consent form after having been fully informed about the treatment, its potential results, and its risks.

The focused ultrasound procedure has been already described in previous studies.28,32,33 The different surgical targets used, as identified in the stereotactic atlas of the human thalamus and basal ganglia of Morel,30,31 were the pallidothalamic tract (pallidothalamic tractotomy [PTT], n = 105), the cerebellothalamic tract (cerebellothalamic tractotomy [CTT], n = 50), the central lateral nucleus (central lateral thalamotomy [CLT], n = 84), the centrum medianum (centrum medianum thalamotomy [CMT], n = 12), and the globus pallidus (pallidotomy, n = 2). All procedures were performed in a 3-T MRI system (GE Discovery 750, GE Healthcare) using the ExAblate Neuro device (InSightec). The patient’s head was immobilized by fixation in a Radionics (Integra Radionics) MR-compatible stereotactic frame. MRI was performed for co-registration preoperatively and at day 2 after surgery32,33 for target assessment and reconstruction, respectively. Peroperatively (Fig. 1), on T2-weighted midsagittal images, a line passing through the center of the anterior and posterior commissures (AC and PC, respectively) is used to create the axial dorsoventral “zero” plane, represented as the intercommissural line (ICL) on the midsagittal image. On the selected axial image, the positions of the 2 commissures are determined and the anteroposterior and mediolateral coordinates are measured to position the chosen target. Because of significant variations of the width of the third ventricle, the mediolateral “zero” point is set on the thalamoventricular border.

FIG. 1.
FIG. 1.

Measurement of targeting accuracy on T2-weighted MR images obtained on postoperative day 2. Upper: Screenshot of the mediolateral (ML) and anteroposterior (AP) accuracy measurements on a T2-weighted axial image, using PACS viewer software (Synedra). The intercommissural line (ICL, red line) is drawn first, and then the anterior commissure (AC) and posterior commissure (PC) lines are drawn perpendicular to that line. Finally, the midcommissural line (MCL) is drawn at an equal distance from the AC and PC. The geometrical center of the lesion is then estimated by drawing 2 diameters (omitted for clarity). The ML coordinate (blue line) is measured from the border of the ventricle to that center and the AP coordinate from the MCL to that center. Lower: Screenshot of dorsoventral (DV) accuracy measurement on a sagittal T2-weighted scan. The ICL is drawn on the midsagittal scan and then reported to the sagittal slice where the lesion is the largest. The height (positive direction, blue line) and depth (negative direction, white line) of the lesion are measured and added, and the result is halved: this gives the DV coordinate of the center of the lesion. B = lesion extension above the ICL; C = lesion extension below ICL; E = AC-PC distance; F = midcommissural distance; H = distance of the center of the lesion to the thalamic border. Figure is available in color online only.

The center of the realized thermolesion was measured on MR images obtained 2 days postoperatively using a 32-channel head coil (GE Signa MR750, General Electric). We used axial and sagittal T2-weighted, fast spin echo (FSE) series (TR 3627 msec, TE 101.44 msec, slice thickness 2 mm, gap 0 mm, field of view 220 × 220 mm, resolution 512 × 512, 27 slices centered on AC-PC line). On those 2 series, the relative coordinate system was first reconstructed, based on 3 anatomical landmarks, the anterior and posterior commissures (AC and PC) and the thalamoventricular border. The mediolateral (ML) and anteroposterior (AP) axes were determined on the axial series and the dorsoventral (DV) and AP axes on the sagittal series. The geometrical center of the visible lesion was reconstructed and placed on this coordinate system. ML as well as AP positions were measured on the axial series, and then DV was measured and AP verified on the sagittal series. Those measurements with an estimated 0.5-mm target reconstruction error were then compared with the coordinates of the chosen atlas target to obtain an accuracy determination. Figure 1 illustrates the main steps of our accuracy test procedure. The complete method has already been described elsewhere.32,33 Our procedural error assessment was as follows: 1) our mean test/retest and inter-examiner variability (D.M., D.J., and M.N.G.) was 0.2 mm, 2) the determination of the center of the anterior and posterior commissures was also 0.2 mm, and 3) the determination of the center of the thermolesion was 0.4 mm. All measurements were performed by transfer by hand from atlas coordinates onto postoperative MR images, similar to the intraoperative procedure. There is in this context no additional error due to co-registration merging. The choice of 2 mm is based on an optimized visualization of the relevant structures; its placement error is the one under point 2 (i.e., the error of the determination of the center of the 2 commissures to place the intercommissural 2-mm-thick slice). All measurements were performed by one author (D.M.) and checked by another (D.J.). Figure 2 displays the 4 main targets as seen at the 2-day postoperative MRI (T2) examination. Statistical analysis was performed with Microsoft Excel and XL Toolbox for Excel. Statistical significance was fixed at p < 0.05 (https://www.xltoolbox.net).

FIG. 2.
FIG. 2.

The 4 main targets displayed on axial T2-weighted MR images obtained 2 days after treatment. A: For central lateral thalamotomy—the posterior part of the central lateral nucleus (CLp) 6 mm dorsal to the intercommissural plane (D6). B: For pallidothalamic tractotomy—the pallidothalamic tract (indicated in this image by PTT) at DV0 (intercommissural plane). C: For centrum medianum thalamotomy—the centrum medianum (CM, centromedian nucleus) at D2. D: For cerebellothalamic tractotomy—the cerebellothalamic tract (indicated in this image by CTT) 4 mm below DV0 (V4). Figure is available in color online only.

Results

Characteristics of the treatments are described in Table 1. Of a total of 180 treatments in 136 patients, 2 treatments (in 2 patients) were aborted, as described in Methods. Thus 178 treatments were performed in 134 patients.

TABLE 1.

Characteristics of the treatments

CharacteristicValue
No. of pts136
Aborted treatments2
 Due to skull US absorption1
 Before start of sonications1
Retreatment to increase lesion size
 Target previously treated by MRgFUS
  No. of targets37
  No. of treatments29
 Target previously treated by RF
  No. of targets2
  No. of treatments2
Pt sex
 Female52
 Male128
Ethnicity
 Caucasian173
 African American1
 Asian1
 Arabic2
 Hindu3
Treatment of PD
 No. (%) of treatments90/178 (51%)
 No. of pts treated58
Treatment of ET
 No. (%) of treatments39/178 (22.3%)
 No. of pts treated33
Treatment of NP
 No. (%) of treatments46/178 (26.3%)
 No. of pts treated41
Treatment of CT
 No. (%) of treatments3/178 (1.1%)
 No. of pts treated2
Surgical targets253
 PTT105 (41.5%)
 CLT84 (33.2%)
 CTT50 (19.8%)
 CMT12 (4.7%)
 Pallidotomy2 (0.8%)
No. of pts w/ bilateral targets
 Total73
 Pts w/ PD19
 Pts w/ ET13
 Pts w/ NP41
No. of treatments w/ 2 targets during a single session75
Mean symptom duration (yrs)
 All pts16.2 ± 14
 Pts w/ PD10 ± 4.7
 Pts w/ ET31 ± 16.5
 Pts w/ NP16 ± 13.6
 Pts w/ CT21 ± 19.8
Mean age at treatment
 All pts65.5 ± 11
 Pts w/ PD66.3
 Pts w/ ET68.7
 Pts w/ NP61.9
 Pts w/ CT45.0
Duration of sonications (secs)
 Mean20 ± 6
 Range10–31
Mean applied power (W)890 ± 227
Mean max energy (J)18,250 ± 7460
Mean final temperature (°C)56.6 ± 1.5
Mean no. of sonications14.5 ± 6

Max = maximum; pt = patient; US = ultrasound.

Cognitive Status

The mean preoperative scores (calculated per treatment) on the MMSE and MoCA were 29.0 ± 1.2 (n = 29) and 27.1 ± 2.7 (n = 149), respectively. The mean postoperative (1 to 2 days after the procedure) MMSE score was 29.5 ± 0.8 (n = 29) (p = 0.06, vs preoperative score), and the mean postoperative MoCA score was 28.1 ± 2.1 (n = 147) (p = 0.002). At 1-year follow-up, the mean MMSE score was 29.4 ± 1.3 (n = 25) (p = 0.2) and the mean MoCA score was 28.0 ± 2.8 (n = 82) (p = 0.02). In 23 cases, the MoCA score improved by 3 points or more from the preoperative assessment to the assessment 2 days after the procedure, and in 14 of these cases, the patients reached a postoperative MoCA score in the normal range (26–30/30). Seven patients suffered a drop of 3 points or more at 2 days. For 2 of these patients, this meant a final MoCA score below 26 points.

Targeting Accuracy

Of a total of 253 thermal lesions, 234 could be reconstructed postoperatively. The other 19 lesions could not be reconstructed because of insufficient imaging quality (due to patient movements) or insufficiently sharp delineation of the lesion.

Figure 3 shows the measured accuracy for each direction (ML, AP, and DV) as well as the mean and standard deviation. We obtained a mean accuracy of 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for ML, AP, and DV dimensions, respectively. The mean 3D accuracy (Euclidian vector) was 0.73 ± 0.39 mm. Figure 4 shows that the centers of the 234 reconstructed lesions (depicted in black) are all located inside the ellipsoid (red) of 4 mm diameter and 6 mm height representing the average volume of our targets as determined from the stereotactic atlas of Morel.30,32 Nine measurements in ML (3.8%), 5 in AP (2.1%), and 19 in DV (7.9%) were 1 mm or greater, and 12 3D measurements were 1.5 mm or greater.

FIG. 3.
FIG. 3.

Measured accuracy. We obtained a mean (± SD) accuracy of 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for ML, AP, and DV dimensions, respectively. The mean 3D accuracy was 0.73 ± 0.39 mm. Figure is available in color online only.

FIG. 4.
FIG. 4.

Dimensions of the 234 reconstructed lesions (depicted in black) in the axial, coronal, and sagittal planes. All of the reconstructed lesions are located inside the ellipsoid (red) of 4 mm diameter and 6 mm height, representing the average volume of our targets as determined from the stereotactic atlas of Morel.30,32 Nine measurements in ML (3.8%), 5 in AP (2.1%), and 19 in DV (7.9%) were 1 mm or greater, and 12 3D measurements were 1.5 mm or greater. Figure is available in color online only.

Hospital Stay

From April 2011 to June 2013 (n = 48), patient stay was planned first for 3 and later for 2 days. Since July 2013 (n = 132), patient stay was organized in an ambulatory setting with an overnight stay as the rule, except in 8 cases (6%), in which the patients stayed between 2 and 4 nights. In all these cases, the reason for the delayed discharge was the preoperative general condition of these PD patients. In 2 cases (1.1%) the patients were not discharged home but transferred to the local hospital. At first follow-up, both of these patients were independent at home again. One patient was hospitalized in his local hospital 1 week after discharge due to combined drug abuse and was later discharged to a rehabilitation center. Three months postoperatively he was living independently at home.

Head Pain During Sonications

After each application of sonic energy (sonication), patients were specifically asked to rate their pain (range 0–4) during that sonication. Only the strongest pain rating for each patient is reported here (no mean values). Little or no pain (0–1) was reported by 48.3% of patients, 14% experienced moderate pain (2), and 37.6% experienced brief (less than 10 seconds) but strong pain (3–4), localized mostly frontally. No procedure had to be stopped because of sonication-related head pain. In all but one of the cases, the patients’ head pain subsided, with the paracetamol treatment, 1 to 2 hours after the end of the treatment. In the remaining case, the patient’s pain lasted 2 days.

Side-Effects

We defined and differentiated side-effects as follows: 1) general, nonneurological; 2) procedure-related, due to the application of any technique during the intervention (i.e., frame fixation, MRI, and FUS techniques); and 3) due to brain tissue damage, comprising 3a) thermal and edema-related effects on neighboring structures and 3b) disease-related effects (i.e., due to pre-existing neurological/cognitive deficits; see Discussion). There was no bleeding or infection. We report 19 side-effects that occurred during the first 3 months following the procedure.

General

There were 5 general, nonneurological side-effects, including 1 lung embolism 10 days after the procedure, 1 cardiac decompensation (4 days after the treatment) in a patient with known heart disease, 1 bladder infection in a patient with a urinary catheter, and 1 mild case of hiccups, which lasted 1 day (the first day after the treatment). One patient had a fall at home 1 week after the procedure and broke her elbow.

Procedure-Related

Four side-effects were classified as procedure-related. There were 2 cases of benign subcutaneous swelling of the face that resolved within a week. One patient reported short episodes of right-sided frontal headache on day 1, which resolved spontaneously on day 2 after the procedure. Another patient experienced temporary unilateral blindness during frame fixation after induction of supra-orbital local anesthesia. On 3D reconstruction of the bony orbita on the planning CT scan, an aberrant extension of the lateral orbital fissure was retrospectively identified. The temporary blindness was explained by bupivacaine passive inflow into the orbita through this anatomical variation. There was some small petechial bleeding on the retina, treated later by laser surgery, and the patient recovered his eyesight completely.

Effect on Neighboring Structures

Three side-effects were classified as effects on neighboring structures. In 1 case, an extension of the thermal lesion beyond the target (centrum medianum) caused slight hypesthesia on the lower lip and slight reduction of gustation, which were absent at the 3-month follow-up evaluation. In a second case, paresthesias around the mouth on the left and on the left hand (without somatosensory deficits) appeared on day 2 after a centrum medianum thalamotomy and lasted a few weeks before fully resolving. These events were most probably due to pressure on the ventroposterior thalamic nucleus due to lesional and/or perilesional edema, as seen in the MRI from postoperative day 2. A postoperative decompensation of mnestic functions was seen in one parkinsonian patient. His MoCA score was 24/30 preoperatively and 22/30 on postoperative day 2. Intraoperative thermal maps and postoperative MR images indicate, among other factors, possible partial thermal effect and/or an edema-related compression on the mammillothalamic tract.

Disease-Related

There were 7 disease-related side-effects. One PD patient suffering from Gaucher disease and with a significantly strained emotional and social history as well as significant preoperative cognitive deficits (MoCA 22/30) made a suicide attempt 2 months after an uneventful one-sided PTT while he was hospitalized in a psychiatric environment. During the following 18 months he did not show any signs of suicidality. Cognitive difficulties were seen over the course of a few weeks in 1 patient with advanced PD, who also showed preoperative cognitive deficits. At 1 year’s follow-up, he had nearly completely recovered to his preoperative baseline (MoCA 21/30 at 1 year after PTT vs 23/30 before PTT). Another PD patient had severe fatigue and apathy after PTT and was therefore hospitalized in a rehabilitation center for a few weeks. At 3 months’ follow-up, he was living independently in his own house again. Two patients who had hypophonia prior to treatment showed a significant postoperative symptom increase without dysarthria. Two patients suffering from severe forms of ET with preoperative cerebellar deficits had mildly slurred speech (1/4) 2 days after the procedure. In the first, slurring was barely detectable at 3 months, and in the second, slurring was only detectable 2 days after the procedure by the family of the patient in his mother language but not in English.

Discussion

Accuracy and Effects on Neighboring Structures

Our targeting accuracy stands between 0.29 and 0.44 mm in the 3 dimensions of space. As discussed by Moser et al.,32,33 such low values, particularly in the DV dimension, cannot be obtained with any technique involving brain penetration.5 Over the 234 accuracy measurements performed, no single thermal lesion was placed outside the target. Only 9 measurements in ML (3.8%), 5 in AP (2.1%), and 19 in DV (7.9%) were 1 mm or greater, and only 12 3D measurements were 1.5 mm or greater. As shown in Fig. 4, thermolesions were always placed on target, with a more or less complete degree of target coverage, thus reducing the risk of significant (or even complete) damage to a neighboring structure. Risk of significant damage to a neighboring structure can be attributed to the following:

  • MR thermal spots can be shifted or misshapen due to thermal image artifacts, causing the application by the neurosurgeon of an inadequate focal point correction.
  • A misshapen ultrasound thermal lesion can occur due to uneven thermal conduction in the target tissue (e.g., because of local vascular anomalies) or suboptimal focalization of yet unrecognized technical origin. Such a case is exemplified (see Results, Effect on Neighboring Structures) in the patient who experienced a postoperative temporary slight trigeminal deficit due to the extension of her thermal lesion into the ventroposterior thalamic nucleus. In the patient with postoperative decompensation of mnestic functions, there is the possibility of a partial thermal effect on the mammillothalamic tract, but an edema-related compression must also be considered, and this in the context of significant preoperative cognitive deficit (see below). The second patient with somatosensory neighboring effect experienced transient paresthesias without somatosensory deficits 2 days after the intervention, clearly suggesting an edema-related effect, especially as the patient did not have a misshapen thermal lesion.

Procedure-Related Side-Effects

We report no bleeding over 253 targets in this series. The single published instance of bleeding in the literature on MR-guided focused ultrasound (MRgFUS) in functional neurosurgery was reported by Jeanmonod et al. in 2012.19 Since the proposed recommendation of a limitation of final temperatures at 60° and the installation of a cavitation detector, no bleeding has been reported (worldwide). As expected from an incisionless technique, there were no infections.

Strong skull absorption can represent a limit to optimal thermal lesioning. In 1 case in the present series, temperatures above 50°C could not be reached at all. When high ultrasound energies were required, sonications at final temperatures were painful for 37.6% of patients. No treatment had to be aborted due to pain. A power or energy threshold for pain production could not be determined, probably because of interindividual variability: acute intraoperative stress management and thus pain experience in awake patients can indeed vary significantly, as shown by pain response, from absent to very strong, during local anesthesia. In 2 cases in which the patients received high amounts of energy, a local subcutaneous, mainly frontal swelling appeared, reached its maximum size 2 days after treatment, and resolved within a week.

Disease-Related Side-Effects, Thalamocortical Reserves, and Restabilization

Concerning the 5 PD patients described in Results under Disease-Related Side-Effects, and the last (PD) patient mentioned under Effect on Neighboring Structures, we propose that preoperative significant atrophy of thalamic and cortical structures, demonstrated by pre-existing hypophonia or lower MoCA scores, played a primary role in the appearance of these side-effects. This represents a causality that is unrelated to the target itself, to the applied technology, or to the accuracy of thermal lesion placement. We test preoperatively, clinically and anatomically, the state of the thalamocortical network, which is the main output system of the basal ganglia, using the MoCA and an MRI examination. The thalamocortical system, just like any complex system, enjoys a large amount of organizational redundancy, which can provide the necessary adaptability, or plasticity, when a functional change is imposed by the surgical act. Significant atrophies inside this system can reduce its reserves at disposition to integrate this change. Preoperative deficits are the markers of a reduction of these reserves, a warning of the possibility of postoperative difficulties.

As described by Aufenberg and collaborators,1 the post-PTT course over the months after treatment is characterized by symptom reduction along a progressive and fluctuating curve, with an average of 3 months for tremor control. Manifestations of increased sleepiness can be seen during the first days, indicating a restabilization of the thalamocortical network after liberation from pallidal overinhibition. This phenomenon can become stronger in the case of thalamocortical reserve reduction, which was most probably the case of the patient presenting purely transient fatigue and apathy. Concerning the 5 other patients, deficits in motor (voice) and cognitive functions were evident preoperatively. In all other PD patients in this series (n = 53), who had sufficient reserves, all motor and cognitive functions remained stable or were even improved, thanks to the surgical sparing of the thalamocortical network (see below).

Two patients presented a postoperative slurred speech of slight intensity and regressive over time after CTT. This relates to the fact that they both had severe essential tremor forms with preoperative cerebellar deficits, providing again evidence for the relevance of reduced preoperative reserves, this time at the cerebellar and/or thalamocortical level. This side-effect did not correlate with bilaterality of CTT, as one patient underwent unilateral CTT and the other underwent bilateral CTT. In essential tremor patients with normal cerebellar functions, a slight short-lasting and fully reversible gait imbalance in the sense of a motor neglect can be seen,14 which we interpret as a readjustment of the thalamocortical system after the abrupt surgical liberation from the pre-existing increased cerebellothalamic input.

Thalamic Sparing

In the context of sufficient thalamocortical reserves, 73 patients could be treated bilaterally without appearance of the dreaded neurological (mainly dysarthria) and cognitive side-effects associated with bilateral thalamotomies.6,10,15,18,21,23,29,38,42 MoCA performed 1 or 2 days after the treatment in fact showed slight improvement as compared with the patients’ preoperative values. So early after the intervention, this result is of high relevance and demonstrates the sparing capacity of our targets on thalamocortical functions. As the preoperative testing was performed from months to days before the treatment, a certain learning effect cannot be ruled out in some patients, but it would be unlikely to result in more than the mentioned slight postoperative improvement. Interestingly, the follow-up MoCA results showed no decline over time. The MoCA score does not allow a complete and in-depth neuropsychological assessment, but it covers the main cognitive fields relevant to the question of postoperative deficits and their effects on everyday life and quality of life.

These results question the well-established caveat issued from past experience that thermolesions cannot be performed bilaterally due to unacceptable neurological and cognitive deficits. This was indeed the prime motivation for the development of DBS for the treatment of PD and ET. Two risk factors existed then which can be set aside now. First, there was the possibility of placing a thermolesion in the internal capsule due to brain shift during electrode penetration and thus causing corticospinal and cognitive deficits, or in the subthalamic nucleus, which could result in ballism. Such a lesion misplacement is no longer a concern with MRgFUS thanks to the absence of electrode penetration and associated mechanical brain shift, and the MRgFUS accuracy within half a millimeter supports this claim. Secondly, lesioning of the specific (motor or premotor) thalamic nuclei surely weakens the related thalamocortical network dynamics, which is at the source of all input, output, and internal cognitive functions.25 The PTT, placed below the thalamus and thus sparing it, allows bilateral treatments: it in fact liberates the thalamocortical dynamics from pallidal overinhibition.27 Interestingly, a review of the “Golden Age” earliest literature of our field reveals that authors having obtained good results with bilateral “thalamotomies” were probably also performing, with unclear frequency, PTTs accompanied by only a minimal ventral thalamic lesion.7,10,23,34

Conclusions

The large series presented here, with an absence of infection and bleeding and a very low amount of untoward effects on neighboring structures (3 in 180 treatments), provides clear evidence that the incisionless transcranial high-intensity MR-guided focused ultrasound technology is accurate and safe. The technology-specific skull absorption–related difficulties will surely somewhat limit the applicability of the technique, but no technique is entirely free of limitations. The 2 subcutaneous swellings in our case series were fully benign and transient and were due to the application of particularly high ultrasound energy. The peroperative head pain, although sometimes strong, was short-lasting as a rule and never caused interruption of the treatment. The remaining 7 side-effects were due to disease-related factors causing reduced thalamocortical reserves and had nothing to do with the technology per se.

The final efficiency and safety of any technique is determined not only by the technological qualities of the given system but also by the experience of the hands and brains using it. Every procedure in this series was conducted by the same dedicated team, working regularly with the system. The targeting and monitoring during sonications were always performed in the presence of a senior neurosurgeon (D.J.) providing the team with his 30 years of uninterrupted experience in the field of lesional functional neurosurgical work. Although the primary handling of the focused ultrasound system is fairly simple, optimal targeting and optimization of target coverage require a long learning curve and long-term experience in lesional functional neurosurgery. During the last 2 decades, DBS dominance has led to a lack of training in the neurosurgical community for placing safe lesions inside the human brain; this will have to be reinstated in training programs. The art of lesional functional neurosurgery resides in proper pathophysiological basis leading to adequate (i.e., efficient and sparing) targets, applying therapeutic lesions with optimal target coverage. The chosen technique should then provide increased safety and accuracy to achieve the best clinical results. The incisionless transcranial MRgFUS technology demonstrates indeed a higher targeting accuracy and a lower side-effect profile than techniques involving cerebral penetration. In the absence of penetration brain shift, this technique avoids the placement of a thermolesion away from the chosen target, thus eliminating the need for reversible therapeutic energy application. Together with the use of proper physiopathology-based targets, definitive therapeutic effects can be coupled with sparing of thalamocortical, sensory, motor, and paralimbic/multimodal functions. Clinical efficacy, not analyzed in this investigation, will ultimately rest in proper target selection, optimized target identification/localization, and optimized thermolesional target coverage.

Acknowledgments

We thank Mrs. Franziska Rossi for coordination and administrative organization; Mrs. Tanja Thalmann for intraoperative patient support and monitoring; Dr. Milek Kowalski and Dr. Alexander Arnold for internal medicine evaluations; Dr. Anouk Magara, Dr. Maja Strasser, and Dr. Robert Bühler for neurological evaluations; Dr. Payam Pourtherani and Dr. Mike Fitze and colleagues of Rodiag Diagnostic Centers for CT and MR imaging; and Mrs. Roxanne Jeanmonod for physical therapy support.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Gallay, Jeanmonod. Acquisition of data: all authors. Analysis and interpretation of data: Gallay, Jeanmonod. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Gallay. Statistical analysis: Gallay. Administrative/technical/material support: Moser. Study supervision: Jeanmonod.

References

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    Beric A, Kelly PJ, Rezai A, Sterio D, Mogilner A, Zonenshayn M, : Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg 77:7378, 2001

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    Bhatia S, Zhang K, Oh M, Angle C, Whiting D: Infections and hardware salvage after deep brain stimulation surgery: a single-center study and review of the literature. Stereotact Funct Neurosurg 88:147155, 2010

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    Bjerknes S, Skogseid IM, Sæhle T, Dietrichs E, Toft M: Surgical site infections after deep brain stimulation surgery: frequency, characteristics and management in a 10-year period. PLoS One 9:e105288, 2014

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  • 5

    Bourgeois G, Magnin M, Morel A, Sartoretti S, Huisman T, Tuncdogan E, : Accuracy of MRI-guided stereotactic thalamic functional neurosurgery. Neuroradiology 41:636645, 1999

    • Crossref
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    • Search Google Scholar
    • Export Citation
  • 6

    Bravo G, Mata P, Seiquer G: Surgery for bilateral Parkinson’s disease. Confin Neurol 29:133138, 1967

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    Bravo G, Parera C, Seiquer G: Neurological side-effects in a series of operations on the basal ganglia. J Neurosurg 24:640647, 1966

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    Chang WS, Jung HH, Kweon EJ, Zadicario E, Rachmilevitch I, Chang JW: Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes. J Neurol Neurosurg Psychiatry 86:257264, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Chen T, Mirzadeh Z, Lambert M, Gonzalez O, Moran A, Shetter AG, : Cost of deep brain stimulation infection resulting in explantation. Stereotact Funct Neurosurg 95:117124, 2017

    • Crossref
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    • Search Google Scholar
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    Cooper IS: Parkinsonism: Its Medical and Surgical Therapy. Springfield, IL: Charles C. Thomas, 1961

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    Elias WJ, Huss D, Voss T, Loomba J, Khaled M, Zadicario E, : A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 369:640648, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, : A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 375:730739, 2016

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    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Fenoy AJ, Simpson RK Jr: Management of device-related wound complications in deep brain stimulation surgery. J Neurosurg 116:13241332, 2012

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    Gallay MN, Moser D, Rossi F, Pourtehrani P, Magara AE, Kowalski M, : Incisionless transcranial MR-guided focused ultrasound in essential tremor: cerebellothalamic tractotomy. J Ther Ultrasound 4:5, 2016

    • Crossref
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    • Search Google Scholar
    • Export Citation
  • 15

    Gillingham FJ, Kalyanaraman S, Donaldson AA: Bilateral stereotaxic lesions in the management of parkinsonism and the dyskinesias. BMJ 2:656659, 1964

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    Hamani C, Lozano AM: Hardware-related complications of deep brain stimulation: a review of the published literature. Stereotact Funct Neurosurg 84:248251, 2006

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    Hariz MI, Rehncrona S, Quinn NP, Speelman JD, Wensing C: Multicenter study on deep brain stimulation in Parkinson’s disease: an independent assessment of reported adverse events at 4 years. Mov Disord 23:416421, 2008

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    • Search Google Scholar
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    Hassler R, Mundinger F, Riechert T: Correlations between clinical and autoptic findings in stereotaxic operations of parkinsonism. Confin Neurol 26:282290, 1965

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    Jeanmonod D, Werner B, Morel A, Michels L, Zadicario E, Schiff G, : Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg Focus 32(1):E1, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Jung HH, Kim SJ, Roh D, Chang JG, Chang WS, Kweon EJ, : Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study. Mol Psychiatry 20:12051211, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Kalyanaraman S, Ramamurthi B: Simultaneous bilateral stereotaxic lesions in the diencephalon. Confin Neurol 26:310314, 1965

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    Kondziolka D, Whiting D, Germanwala A, Oh M: Hardware-related complications after placement of thalamic deep brain stimulator systems. Stereotact Funct Neurosurg 79:228233, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Krayenbuhl H, Wyss OA, Yasargil MG: Bilateral thalamotomy and pallidotomy as treatment for bilateral Parkinsonism. J Neurosurg 18:429444, 1961

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    Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, : MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol 12:462468, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Llinás R, Ribary U, Contreras D, Pedroarena C: The neuronal basis for consciousness. Philos Trans R Soc Lond B Biol Sci 353:18411849, 1998

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    Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D: First experience with MR-guided focused ultrasound in the treatment of Parkinson’s disease. J Ther Ultrasound 2:11, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Magnin M, Morel A, Jeanmonod D: Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience 96:549564, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B: High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann Neurol 66:858861, 2009

  • 29

    Matsumoto K, Shichijo F, Fukami T: Long-term follow-up review of cases of Parkinson’s disease after unilateral or bilateral thalamotomy. J Neurosurg 60:10331044, 1984

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Morel A: Stereotactic Atlas of the Human Thalamus and Basal Ganglia. Boca Raton: CRC Press, 2007

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    Morel A, Magnin M, Jeanmonod D: Multiarchitectonic and stereotactic atlas of the human thalamus. J Comp Neurol 387:588630, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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    Moser D, Zadicario E, Schiff G, Jeanmonod D: Measurement of targeting accuracy in focused ultrasound functional neurosurgery. Neurosurg Focus 32(1):E2, 2012

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    Moser D, Zadicario E, Schiff G, Jeanmonod D: MR-guided focused ultrasound technique in functional neurosurgery: targeting accuracy. J Ther Ultrasound 1:3, 2013

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    • Crossref
    • Search Google Scholar
    • Export Citation
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    Riechert T: Long term follow-up of results of stereotaxic treatment in extrapyramidal disorders. Confin Neurol 22:356363, 1962

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If the inline PDF is not rendering correctly, you can download the PDF file here.

Contributor Notes

Correspondence Marc Gallay: Center for Ultrasound Functional Neurosurgery, Solothurn, Switzerland. marc.gallay@sonimodul.ch.

INCLUDE WHEN CITING Published online May 25, 2018; DOI: 10.3171/2017.12.JNS172054.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • View in gallery

    Measurement of targeting accuracy on T2-weighted MR images obtained on postoperative day 2. Upper: Screenshot of the mediolateral (ML) and anteroposterior (AP) accuracy measurements on a T2-weighted axial image, using PACS viewer software (Synedra). The intercommissural line (ICL, red line) is drawn first, and then the anterior commissure (AC) and posterior commissure (PC) lines are drawn perpendicular to that line. Finally, the midcommissural line (MCL) is drawn at an equal distance from the AC and PC. The geometrical center of the lesion is then estimated by drawing 2 diameters (omitted for clarity). The ML coordinate (blue line) is measured from the border of the ventricle to that center and the AP coordinate from the MCL to that center. Lower: Screenshot of dorsoventral (DV) accuracy measurement on a sagittal T2-weighted scan. The ICL is drawn on the midsagittal scan and then reported to the sagittal slice where the lesion is the largest. The height (positive direction, blue line) and depth (negative direction, white line) of the lesion are measured and added, and the result is halved: this gives the DV coordinate of the center of the lesion. B = lesion extension above the ICL; C = lesion extension below ICL; E = AC-PC distance; F = midcommissural distance; H = distance of the center of the lesion to the thalamic border. Figure is available in color online only.

  • View in gallery

    The 4 main targets displayed on axial T2-weighted MR images obtained 2 days after treatment. A: For central lateral thalamotomy—the posterior part of the central lateral nucleus (CLp) 6 mm dorsal to the intercommissural plane (D6). B: For pallidothalamic tractotomy—the pallidothalamic tract (indicated in this image by PTT) at DV0 (intercommissural plane). C: For centrum medianum thalamotomy—the centrum medianum (CM, centromedian nucleus) at D2. D: For cerebellothalamic tractotomy—the cerebellothalamic tract (indicated in this image by CTT) 4 mm below DV0 (V4). Figure is available in color online only.

  • View in gallery

    Measured accuracy. We obtained a mean (± SD) accuracy of 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for ML, AP, and DV dimensions, respectively. The mean 3D accuracy was 0.73 ± 0.39 mm. Figure is available in color online only.

  • View in gallery

    Dimensions of the 234 reconstructed lesions (depicted in black) in the axial, coronal, and sagittal planes. All of the reconstructed lesions are located inside the ellipsoid (red) of 4 mm diameter and 6 mm height, representing the average volume of our targets as determined from the stereotactic atlas of Morel.30,32 Nine measurements in ML (3.8%), 5 in AP (2.1%), and 19 in DV (7.9%) were 1 mm or greater, and 12 3D measurements were 1.5 mm or greater. Figure is available in color online only.

  • 1

    Aufenberg C, Sarnthein J, Morel A, Rousson V, Gallay M, Jeanmonod D: A revival of Spiegel’s campotomy: long term results of the stereotactic pallidothalamic tractotomy against the parkinsonian thalamocortical dysrhythmia. Thalamus Relat Syst 3:121132, 2005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Beric A, Kelly PJ, Rezai A, Sterio D, Mogilner A, Zonenshayn M, : Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg 77:7378, 2001

  • 3

    Bhatia S, Zhang K, Oh M, Angle C, Whiting D: Infections and hardware salvage after deep brain stimulation surgery: a single-center study and review of the literature. Stereotact Funct Neurosurg 88:147155, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Bjerknes S, Skogseid IM, Sæhle T, Dietrichs E, Toft M: Surgical site infections after deep brain stimulation surgery: frequency, characteristics and management in a 10-year period. PLoS One 9:e105288, 2014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Bourgeois G, Magnin M, Morel A, Sartoretti S, Huisman T, Tuncdogan E, : Accuracy of MRI-guided stereotactic thalamic functional neurosurgery. Neuroradiology 41:636645, 1999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Bravo G, Mata P, Seiquer G: Surgery for bilateral Parkinson’s disease. Confin Neurol 29:133138, 1967

  • 7

    Bravo G, Parera C, Seiquer G: Neurological side-effects in a series of operations on the basal ganglia. J Neurosurg 24:640647, 1966

  • 8

    Chang WS, Jung HH, Kweon EJ, Zadicario E, Rachmilevitch I, Chang JW: Unilateral magnetic resonance guided focused ultrasound thalamotomy for essential tremor: practices and clinicoradiological outcomes. J Neurol Neurosurg Psychiatry 86:257264, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Chen T, Mirzadeh Z, Lambert M, Gonzalez O, Moran A, Shetter AG, : Cost of deep brain stimulation infection resulting in explantation. Stereotact Funct Neurosurg 95:117124, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Cooper IS: Parkinsonism: Its Medical and Surgical Therapy. Springfield, IL: Charles C. Thomas, 1961

  • 11

    Elias WJ, Huss D, Voss T, Loomba J, Khaled M, Zadicario E, : A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 369:640648, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, : A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med 375:730739, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Fenoy AJ, Simpson RK Jr: Management of device-related wound complications in deep brain stimulation surgery. J Neurosurg 116:13241332, 2012

  • 14

    Gallay MN, Moser D, Rossi F, Pourtehrani P, Magara AE, Kowalski M, : Incisionless transcranial MR-guided focused ultrasound in essential tremor: cerebellothalamic tractotomy. J Ther Ultrasound 4:5, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Gillingham FJ, Kalyanaraman S, Donaldson AA: Bilateral stereotaxic lesions in the management of parkinsonism and the dyskinesias. BMJ 2:656659, 1964

  • 16

    Hamani C, Lozano AM: Hardware-related complications of deep brain stimulation: a review of the published literature. Stereotact Funct Neurosurg 84:248251, 2006

  • 17

    Hariz MI, Rehncrona S, Quinn NP, Speelman JD, Wensing C: Multicenter study on deep brain stimulation in Parkinson’s disease: an independent assessment of reported adverse events at 4 years. Mov Disord 23:416421, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Hassler R, Mundinger F, Riechert T: Correlations between clinical and autoptic findings in stereotaxic operations of parkinsonism. Confin Neurol 26:282290, 1965

  • 19

    Jeanmonod D, Werner B, Morel A, Michels L, Zadicario E, Schiff G, : Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg Focus 32(1):E1, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Jung HH, Kim SJ, Roh D, Chang JG, Chang WS, Kweon EJ, : Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study. Mol Psychiatry 20:12051211, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Kalyanaraman S, Ramamurthi B: Simultaneous bilateral stereotaxic lesions in the diencephalon. Confin Neurol 26:310314, 1965

  • 22

    Kondziolka D, Whiting D, Germanwala A, Oh M: Hardware-related complications after placement of thalamic deep brain stimulator systems. Stereotact Funct Neurosurg 79:228233, 2002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Krayenbuhl H, Wyss OA, Yasargil MG: Bilateral thalamotomy and pallidotomy as treatment for bilateral Parkinsonism. J Neurosurg 18:429444, 1961

  • 24

    Lipsman N, Schwartz ML, Huang Y, Lee L, Sankar T, Chapman M, : MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study. Lancet Neurol 12:462468, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Llinás R, Ribary U, Contreras D, Pedroarena C: The neuronal basis for consciousness. Philos Trans R Soc Lond B Biol Sci 353:18411849, 1998

  • 26

    Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D: First experience with MR-guided focused ultrasound in the treatment of Parkinson’s disease. J Ther Ultrasound 2:11, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Magnin M, Morel A, Jeanmonod D: Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients. Neuroscience 96:549564, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B: High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann Neurol 66:858861, 2009

  • 29

    Matsumoto K, Shichijo F, Fukami T: Long-term follow-up review of cases of Parkinson’s disease after unilateral or bilateral thalamotomy. J Neurosurg 60:10331044, 1984

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Morel A: Stereotactic Atlas of the Human Thalamus and Basal Ganglia. Boca Raton: CRC Press, 2007

  • 31

    Morel A, Magnin M, Jeanmonod D: Multiarchitectonic and stereotactic atlas of the human thalamus. J Comp Neurol 387:588630, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Moser D, Zadicario E, Schiff G, Jeanmonod D: Measurement of targeting accuracy in focused ultrasound functional neurosurgery. Neurosurg Focus 32(1):E2, 2012

  • 33

    Moser D, Zadicario E, Schiff G, Jeanmonod D: MR-guided focused ultrasound technique in functional neurosurgery: targeting accuracy. J Ther Ultrasound 1:3, 2013

  • 34

    Mundinger F: Stereotaxic interventions on the zona incerta area for treatment of extrapyramidal motor disturbances and their results. Confin Neurol 26:222230, 1965

  • 35

    Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM: Long-term hardware-related complications of deep brain stimulation. Neurosurgery 50:12681276, 2002

  • 36

    Patel NK, Heywood P, O’Sullivan K, McCarter R, Love S, Gill SS: Unilateral subthalamotomy in the treatment of Parkinson’s disease. Brain 126:11361145, 2003

  • 37

    Pepper J, Zrinzo L, Mirza B, Foltynie T, Limousin P, Hariz M: The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure. Stereotact Funct Neurosurg 91:5665, 2013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Riechert T: Long term follow-up of results of stereotaxic treatment in extrapyramidal disorders. Confin Neurol 22:356363, 1962

  • 39

    Rolston JD, Englot DJ, Starr PA, Larson PS: An unexpectedly high rate of revisions and removals in deep brain stimulation surgery: analysis of multiple databases. Parkinsonism Relat Disord 33:7277, 2016

    • Crossref
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