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Abstract
Purpose The ventral intermediate nucleus of thalamus is the standard target for deep brain stimulation (DBS) in essential tremor (ET). However, favourable data have recently highlighted the caudal zona incerta (cZi) as an alternative target. Reports concerning the long-term results are however lacking, and we have therefore evaluated the long-term effects in our patients with ET and cZi DBS.
Methods 18 patients were evaluated using the Essential Tremor Rating Scale (ETRS) before and on-/off-stimulation at 1 and 3–5 years after surgery (mean 48.5±10.6 months). Two patients were operated on bilaterally but all electrodes were evaluated separately. The stimulation parameters were recorded and the stimulation strength calculated.
Results A baseline total ETRS mean score of 46.0 decreased to 21.9 (52.4%) at the final evaluation. On the treated side, tremor of the upper extremity (item 5 or 6) improved from 6.1 to 0.5 (91.8%) and hand function (items 11–14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in stimulation strength over time.
Conclusion cZi DBS is a safe and effective treatment for the long term suppression of ET.
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Introduction
Essential tremor (ET) is the most common adult movement disorder.1 The majority of patients either do not need or refrain from seeking medical care, but among those who do, up to 50% do not respond adequately to drug therapy. Stereotactic neurosurgical procedures are alternative treatments, and deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (Vim) is mostly used at the present time.2–4 In recent years, several studies have presented good results for DBS in the posterior subthalamic area (PSA), including the caudal zona incerta (cZi) and the prelemniscal radiation (Raprl).5–12 Reports of long-term results are lacking, although four patients were recently reported on by Plaha and colleagues.5 The short term results of DBS in this area may be promising but it is also of great importance to evaluate the long term effect and safety of this lifelong functional treatment. In this study we present the long-term results of our patients with cZi DBS for ET.
Patients and methods
The 1 year outcome for the 18 patients in this study has been previously presented in a study of 21 patients.11 Three of the patients from the original study did however not complete the long term follow-up. One patient died of causes not related to surgery and two patients did not wish to participate owing to old age, declining health and long travelling distances. Twelve patients were men and six were women. Mean age at operation was 62.6 years (range 34–62) and the duration of disease was 20.3±13.9 years. Fourteen patients had left-sided, two right-sided and two bilateral implants.
Informed consent was obtained according to the Declaration of Helsinki and the study was approved by the ethics committee at the University of Umeå.
Surgical technique
The surgical technique has been described in detail previously.11 The operations were frame based stereotactic implantations of the DBS electrode 3387 or 3389 (Medtronic, Minneapolis, Minnesota, USA) in the cZi. A preoperative stereotactic 1.5 T MRI and a postoperative CT were performed. The target was identified anatomically on T2 weighted transaxial MRI images as slightly posterior and medial to the posterior tip of the subthalamic nucleus at the horizontal level of the maximal diameter of the red nucleus. The procedures were performed under local anaesthesia and the effect and side effects were evaluated using macrostimulation through the permanent electrode. No microelectrode recording was made.
Evaluation
The stereotactic coordinates for each contact were calculated from a postoperative stereotactic CT. The stimulation parameters were optimised 6 weeks after the implantation and thereafter controlled and adjusted on an annual basis, or more often if necessary. Patients were evaluated before and off-/on-stimulation after 1 year, and at the final evaluation after 3–5 years using the Essential Tremor Rating Scale (ETRS).13 The evaluation off-stimulation was performed after the DBS had been deactivated during the night. The two patients with bilateral stimulation were evaluated separately for each electrode.
Statistics
The results are presented as mean±SD and range where applicable. Friedman's non-parametric test was used for discrete values and the Wilcoxon signed ranks test was used as a post hoc analysis. ANOVA for repeated measurements with the Bonferroni test as a post hoc test was used for continuous variables. A p value ≤0.05 was considered significant.
Results
Eighteen patients with 20 DBS electrodes were evaluated at the final evaluation 3–5 years (mean 48.5±10.6 (range 34–62) months) after surgery. The contacts used for chronic stimulation were localised 12.0±1.5 mm lateral to the midline, 6.3±1.5 mm posterior to the midcommissural point and 2.2±2.3 mm inferior to the intercommissural line. The contacts used for chronic stimulation are illustrated in figure 1, a three-dimensional model based on the axial slides of the stereotactic atlas of Morel that displays the target area and the anatomical structures in the vicinity of the PSA.14
(A, B) Illustration demonstrating the location of all contacts in the PSA used for chronic stimulation in these patients and adjacent structures that outline the area. (A) Superior view. (B) Posterior view. Both illustrations were made by plotting the contacts on the axial images of the stereotactic atlas of Morel and a three-dimensional atlas was created using Matlab 7.0 (The MathWorks, Inc, USA) software. RN, nucleus ruber; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, nucleus subthalamicus; VLp, nucleus ventralis lateralis posterior thalami.
Tremor assessment
The total ETRS score and selected subscores are presented in table 1 and figure 2. The percentual improvement on-stimulation at both postoperative evaluations is compared in table 2.
Essential Tremor Rating Scale scores for 18 patients evaluated separately for each of the 20 electrodes before surgery and off-/on-stimulation at 1 year and at the final evaluation after 3–5 years (mean 48.5 months)
Total Essential Tremor Rating Scale (ETRS), upper extremity tremor and hand function scores at the different evaluations (with error bars).
On-stimulation scores compared with off-stimulation scores at each follow-up and improvement (%) with stimulation
Total ETRS score was 46.0±8.7 at baseline and decreased to 38.7±4.8 (p=0.033) for off-stimulation after 1 year, but this decrease was not seen at the final evaluation (45.1±16.0). For on-stimulation, the total ETRS score was 17.6±8.2 after 1 year and 21.9±10.0 at the final evaluation, representing improvements of 61.7% (p<0.001) and 52.4% (p<0.001), respectively. The differences between the 1 year and final evaluation was significant for both off and on scores (p=0.022 and p=0.002, respectively) (tables 1 and 2).
Tremor scores (items 5 or 6) of the treated upper extremity were significantly decreased in the off-stimulation state after both 1 year (5.1±2.0, 16.4%, p<0.001) and at the final evaluation (4.7±2.3, 23.0%, p<0.001). For on-stimulation, the same ETRS items improved by 96.7% (p<0.001) after 1 year and by 91.8% (p<0.001) at the final evaluation. There were no significant changes in tremor scores between the first and the final follow-ups, except for action tremor where a slight increase from 0.2±0.4 to 0.5±0.6 on-stimulation (p=0.034) was seen at the final follow-up.
A slight but significant improvement was also seen for ipsilateral tremor (item 5 or 6) in the on- compared with the off- state, after both 1 year (p=0.026) and at the final evaluation (p<0.001). Subscores for hand function (items 11–14) of the treated side were 9.1±3.2 at baseline and improved by 90.1% to 0.9±1.0 (p<0.001) after 1 year and by 78.0% to 2.0±2.1 (p<0.001) at the final evaluation. The scores were significantly increased at the final follow-up compared with the first on- and off-stimulation (p=0.004 and p=0.006, respectively).
Items 15–21, which evaluate activities of daily living, were improved for on-stimulation by 64.1% (p<0.001) after 1 year and by 65.8% (p<0.001) at the final evaluation.
Stimulation parameters
Mean stimulation parameters are presented in table 3. Pulse effective voltage (PEV) was used as a measurement of stimulation strength (√(U2 × pps × pw, where U=voltage (V), pps=pulses per second (Hz) and pw=pulse width (μs)).15 There were no statistically significant differences in the stimulator settings at any point.
Stimulator settings 6 weeks after surgery, at 1 year and at the final evaluation after 3–5 years (mean 48.5 months)
Complications and battery replacement
The mainly mild and transient complications that occurred during the first year after surgery have been presented previously.11 One patient was operated on during the current follow-up with bilateral revision of the extension cables due to strain in the neck. The implantable pulse generator was replaced simultaneously although it was not yet depleted. There were no additional complications or battery replacements during the long term follow-up.
Discussion
Long term effect and efficacy of cZi DBS in ET
This study evaluated 18 patients treated with cZi DBS for ET after a mean of 4 years. The satisfying results on-stimulation seen after 1 year were mainly sustained at the final evaluation. The improvement in the off-state, the microlesional effect, was withheld only for tremor of the upper extremity at the final evaluation. There was some degree of decreased improvement on-stimulation compared with the 1 year results, as seen in tables 1 and 2. This is probably to a large extent due to a reduced microlesional effect and progression of tremor. This assumption is supported by a previous study which indicated that the more tremor a patient had off-stimulation, the more residual tremor the patient would have on-stimulation.16 Furthermore, with the exception of action tremor, all significant increases from 1 year to the final evaluation on-stimulation were accompanied by corresponding increases off-stimulation. Neither was any late treatment failures observed in this population. Considering these facts, development of tolerance seems to have been limited. This is further supported by the lack of increase regarding stimulation parameters, as discussed below.
Interestingly, there was an improvement in on-stimulation compared with off-stimulation for tremor of the ipsilateral upper extremity. There are indications that the Zi has bilateral connections which could explain this effect.17 It is, however, also possible that this was caused by decreased spread of oscillations from the treated side of the body during stimulation.
Previous reports concerning the long term effects of PSA DBS are limited to four patients with bilateral implants in whom the total ETRS score was improved by 72.6% after a follow-up period of 4 years or more.5 The published reports on cZi/PSA DBS for ET are summarised in table 4 (for a review of stereotactic functional procedures in this area, see Blomstedt et al 2009).7 With regard to the long term studies of Vim DBS, it is often difficult to compare different studies because many involve mixed bilateral and unilateral procedures and because the ETRS data are presented in various ways. The European and American multicentre studies with 5–6 years of follow-up reported 50–75% tremor reduction in the treated arm after unilateral Vim DBS.18 19 In our experience of 19 cases with Vim DBS evaluated at a mean of 7 years after surgery, tremor of the contralateral upper extremity was reduced by 60.3% and hand function was improved by 35.4%.20
Schematic table displaying the published data of caudal zona incerta/posterior subthalamic area deep brain stimulation for essential tremor
No batteries were replaced due to depletion and no significant increase in stimulation strength was seen from the follow-up after 6 weeks to the final follow-up (PEV 0.20 vs 0.21 V). In our long term study of Vim DBS, PEV increased from 0.15 V after 1 month to 0.24 V after 5 years and 0.29 V after 7 years. Other long term studies of Vim DBS report values of 0.27–0.48 V.15 18–22 In the four patients with long term cZi DBS reported by Plaha et al, PEV was 0.36 V.5
Development of tolerance to stimulation over time, making it necessary to increase the stimulation parameters and also in some cases causing stimulation failure, is reported quite frequently after Vim DBS.20 21 23–26 This can be a major problem, and Plaha et al have suggested that this might be due to properties of Vim itself.5 The long lasting treatment effects in this series of cZi DBS appear to be achieved at a low stimulation strength compared with other reports and without any apparent development of tolerance.
Rationale and future of PSA DBS for ET
Vim DBS is currently the surgical treatment of choice in ET and most often it is a safe and effective treatment. However, lack of effect, development of tolerance and troublesome adverse effects do sometimes constitute a problem.18 20 21 23 24 27 28
Alternative targets have therefore been suggested and, among them, the PSA.5 7 10–12 The PSA contains the Zi and the prelemniscal radiation, the area is situated below Vim, superior to the substantia nigra, lateral to the red nucleus, posteriomedial to the subthalamic nucleus and medial to the internal capsule. During the lesional era, many considered the PSA to be the optimal target in the treatment of tremor.7 29–31 Current theories indicate that the cZi might play a key role in transmitting GABAergic input from the basal ganglia to the cerebello-thalamo-cortical circuits and that DBS stimulation might therefore alter or inhibit abnormal oscillations.7 10 In addition, it has been postulated that the white matter tracts of the PSA may be regarded as a ‘bottle neck’ of axons projecting to the thalamus, and that stimulation of this white matter would be more potent than stimulation of nuclear structures such as the thalamus itself.7 32 33
Since 2000, case series with PSA DBS have indicated good results in ET and studies with evaluation of the contact location in DBS with Vim as the intended target have demonstrated favourable effects using contacts below Vim in the PSA.5 6 9–12 32 33 No randomised studies have been conducted, however, and the long term results have only been reported for four patients.5
This long term follow-up of 18 patients indicates that cZi DBS is a safe and effective treatment for ET— also in the long run. More studies on PSA DBS are warranted, especially long term evaluations.
Conclusion
PSA DBS is a safe and markedly effective treatment for the long term suppression of ET. The PSA should be further evaluated as an alternative DBS target for suppression of tremor.
Acknowledgments
Neurologist Jan Linder, PhD, and specialist nurse, Anna Fredricks, are acknowledged for the skilful management of these patients.
References
Footnotes
Funding This work was supported by funding from Umeå University and the Foundation for Clinical Neuroscience at the University Hospital of Umeå.
Competing interests None.
Ethics approval The study was approved by the ethics board at the University Hospital of Umeå (04-123M).
Provenance and peer review Not commissioned; externally peer reviewed.