Results of chronic subthalamic nucleus stimulation for Parkinson’s disease: a 1-year follow-up study

Movement Disorders Results of Chronic Subthalamic Nucleus Stimulation for Parkinson’s Disease: A 1-Year Follow-Up Study J. Vesper,* F. Klostermann,† F. Stockhammer,* Th. Funk,‡ and M. Brock* *Department of Neurosurgery and †Department of Neurology, University Medical Center Benjamin Franklin, Berlin, Germany, ‡Department of Neurosurgery, Frankfurt (Oder) Hospital, Frankfurt (Oder), Germany Vesper J, Klostermann F, Stockhammer F, Funk Th, Brock M. Results of chronic subthalamic nucleus stimulation for Parkinson’s disease: a 1-year follow-up study. Surg Neurol 2002;57:306 –313. BACKGROUND Deep brain stimulation (DBS) has been established as an alternative approach for the treatment of advanced Parkinson’s disease (PD). Recently, the subthalamic nucleus (STN) has been identified as the optimal target for DBS. METHODS Thirty-eight patients have undergone surgery for advanced PD since 1996. They include 12 females and 26 males with a mean age of 55.6 years. The mean stage on the Hoehn and Yahr Scale was 3.5 (off condition). Electrodes (Medtronic DBS 31389) were stereotactically implanted into the STN bilaterally. Targeting was performed using computerized tomography (CT) scans and ventriculography (VG). After 4 days of external stimulation, permanent neurostimulators were implanted. Patients were evaluated preoperatively and 1, 6, and 12 months postoperatively. Evaluations were performed in defined on and off states using the Unified Parkinson’s Disease Rating Scale (UPDRS) as well as the Hoehn and Yahr Scale, the dyskinesia scale, and the Activities of Daily Living (ADL) Scale. RESULTS Significant improvement of all motor symptoms was found in all patients (UPDRS motor score 32/48 preoperatively versus 15/30 at 12-month follow-up, p ⬍ 0.001). Daily off-times were reduced by 35%. Dyskinesias also improved markedly (UPDRS IV: 3.2/3.1 [on/off] vs. 0.9/1.3 at 12 months follow-up). Postoperative L-dopa medication was adjusted (mean reduction: 53%). Complications occurred in two patients (5%) who developed infections, leading to system removal. Systems were replaced after 6 months. Two patients (5%) had a permanent worsening of a previously known depressive state and developed progressive dementia. Address reprint requests to: Dr Jan Vesper, Department of Neurosurgery, University Medical Center Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. Received February 5, 2001; accepted January 7, 2002. 0090-3019/02/$–see front matter PII S0090-3019(02)00691-2 CONCLUSION STN stimulation is a relatively safe procedure for treating advanced PD. The possibility of readjusting the stimulation parameters postoperatively improves the therapeutic outcome and reduces side effects in comparison to ablative methods. © 2002 by Elsevier Science Inc. KEY WORDS Parkinson’s disease, deep brain stimulation, stereotaxy, subthalamic nucleus, movement disorders. C hronic high-frequency stimulation has become a widely used procedure for the management of extrapyramidal movement disorders. Since the earliest application of this procedure for the stimulation of the ventrolateral thalamus in the treatment of disorders with predominant tremor, the indication has been extended to subthalamic nucleus (STN) and the globus pallidus internus (GPi) for akinetic rigid Parkinson’s disease (PD) [4,7,17,22]. Because the GPi was the target of ablative surgery in patients suffering from akinetic rigid conditions, it initially was the target of stimulation procedures as well. Because of its high rate of permanent adverse effects, pallidotomy is no longer recommended [14,16,18 –21,24,31,36,38,40,41]. Various theories have been proposed to explain the mechanism of deep brain stimulation (DBS). According to the model of Alexander the STN has an inhibitory function within the basal ganglia loops [1,35], which is increased in PD. This STN overactivity is shown by the discharge patterns of spontaneous activity recorded by microelectrodes in the target area during surgery [11,46]. When the effects of GPi stimulation turned out to be limited primarily to dyskinesia, there was a ris© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Chronic STN Stimulation for Parkinson’s 1 Surg Neurol 307 2002;57:306 –313 Target Points for Deep Brain Stimulation ESSENTIAL TREMOR VIM CEREBELLAR TREMOR PD TREMOR VIM (VOA/VOP) STN (VIM) ing interest in STN as a new target. To date, however, little long-term data are available on the results and adverse effects of chronic high-frequency stimulation of the STN. The present study was designed as a clinical follow-up evaluation of patients to identify parameters for the outcome of surgery and the intraoperative determination of target points. Materials and Methods A total of 84 patients have been operated on for various forms of extrapyramidal disorders since 1996. They suffered from different types of tremor (n ⫽ 41), from torsion dystonia (n ⫽ 3), as well as from Parkinson’s disease (n ⫽ 40). The follow-up study included 38 PD patients who were examined before surgery as well as 1, 6, and 12 months postoperatively. Thirty patients had a primarily akinetic rigid PD, 8 suffered from tremordominant Parkinson’s disease (26 male, 12 female, mean age 55.6 years, range 47 to 72 years). Because of the Hoehn and Yahr classification, patients were in stage 3.5 (max. 5, min. 3 points) in their off condition with a mean duration of 13 years (max. 25, min. 3 years) at the time of surgery. Pre- and postoperatively as well as at the 6-month follow-up, the patients were evaluated in their “on” and “off” states using the Unified Parkinson’s Disease Rating Scale (UPDRS, part I to IV) [13]. The patients were assessed under four conditions (on/off medication, on/off stimulation). Their quality of life was assessed with the Activities of Daily Living Scale of Schwab-England and their overall condition with the Hoehn and Yahr Scale. Exclusion criteria for surgery were psychosis, considerable dementia, a negative response to L-dopa test (change of clinical state within two hours after administration of the individual L-dopa dose plus 50 mg), abnormal brain anatomy on preoperative computed tomography (CT) scan or magnetic resonance imaging (MRI). Suspected multi-system atrophy or severe accompanying disease also led to exclusion from surgery. Patients were included if they were severely impaired in their quality of life despite optimized drug treatment for a minimum period of 6 months before surgery. No age limit was imposed. PD AKINETIC/ RIGID STN DYSTONIA GPi Initially the ventral intermediate nucleus (VIM) was the target in patients with tremor-dominant PD. When it became obvious that tremor but not rigidity and akinesia could be ameliorated, STN stimulation became the method of choice in the remaining patients (Table 1) [7,23,44]. Surgery was performed under analgesia and sedation. Intraoperatively, target determination was performed using CT scan and ventriculography (VG), by test stimulations, X-ray controls, and microrecordings. The validity of microrecordings was low regarding placement of the final electrode. Only in 13 cases was the site of optimal effect identical to the site of maximal spontaneous discharges. The Riechert-Mundinger stereotactic surgical system (Leibinger Inc., Freiburg, Germany) was used. The target coordinates were based on the SchaltenbrandtWahren atlas. In addition, the system allows for precise postoperative recalculation of the position of the electrodes relative to the posterior commissure (PC). Therefore, the coordinates of the PC were defined as “0” in the x-, y-, and z-dimension (Figure 1). Accuracy of target setting with 3D recalculation of final electrode positions in relation to the PC (coordinates of PC defined as x ⫽ y ⫽ z ⫽ 0). 1 308 Surg Neurol 2002;57:306 –313 2 On/off times (hours postoperative). Vesper et al per day; 12 months After external stimulation for an average of 4 days, a permanent pulse generator was implanted in all cases. This was conducted to confirm the intraoperative stimulation effect. Stimulators were implanted infraclavicularly (Itrel®II). Since October 1998 we have used the Kinetra™ system (Medtronic Inc., Minneapolis, MN, USA) because it offers the option of bilateral stimulation and external programming by the patient. Statistical evaluation included multivariance analysis with the one way ANOVA rank sum test (Sigmastat 1.0, Jandel Scientific Inc, Chicago, IL, USA). Results The evaluation based on the Hoehn and Yahr Scale showed a significant improvement in the patients’ off state under stimulation (mean scores: 3.5 preoperatively, 2.9 postoperatively, 2.7 at 6 months, 2.8 at 12 months, p ⬍ 0.001). Assessment by the Activities of Daily Living Scale of Schwab-England showed similar results (scores: 47% preoperatively, 63% postoperatively, 65% at 6 months, 66% at 12 months; p ⬍ 0.001). 3 Mean daily dose of L-dopa equivalents (12 months postoperative p ⬍ 0.001). 4 UPDRS score (medication on; p ⬍ 0.001). Off times were reduced by 35% (max. 60%, min. 10%) (Figure 2). The dose of L-dopa could be lowered by 53% (max. 100%, min. 0%) (Figure 3). In one patient with tremor-dominant Parkinson’s disease it was possible to dispense with medication. The motor subscores of the UPDRS (Part III) were significantly improved with L-dopa both on and off (Figures 4 and 5). According to the UPDRS, part IV dyskinesias were reduced from 3.2/3.1 (on/off) to 0.9/1.1 at 6 months and 0.9/1.3 at 12 months follow-up (p ⬍ 0.05 between pre- and postoperative state). The deviations of calculated versus final active electrode position in the three planes (x, y, z) ranged between 0.75 mm and 2.0 mm (Table 2, Figure 1). The final STN stimulation parameters were set gradually over the first 6 months with a parallel adjustment of medication. After 6 months, the parameters were only rarely changed (Table 3). Serious complications were infrequent. Two patients (5%) developed subcutaneous infections in the stimulator pocket. In these cases, the stimulators had to be removed and were replaced after 6 months. The exchange did not impair the effects of stimulation. Ten patients (30%) developed confu- 5 UPDRS score (stimulation on; p ⬍ 0.001) Chronic STN Stimulation for Parkinson’s 2 Surg Neurol 309 2002;57:306 –313 Accuracy of Targeting (mean distance between calculated and final electrode positions) [MM] STN VG STN CT VIM VG VIM CT x y z 0.75 1.65 1.97 2.15 1.40 2.03 2.02 1.72 1.85 2.17 2.08 1.50 sion postoperatively, which differed in duration and severity, requiring drug treatment in four patients (10%). In two cases (5%) symptoms did not resolve. An association with stimulation could not be identified. Discussion In the present study, improved motor functions could be confirmed (Figures 4 and 5), consistent with findings in smaller series [7,17,27,28,30,32–34, 37]. Moreover, Parkinson medication was significantly lowered (Figure 3) and daily off-times were considerably reduced. The results correspond to those found in recent publications (Table 4). With the evolution of DBS, the ventrolateral thalamus, in particular the ventral intermediate nucleus, has become the target for the management of movement disorders with tremor as the predominant symptom [23,44]. However, because stimulation of the VIM nucleus had little effect on other motor symptoms, parkinsonian patients with a predominance of tremor were stimulated in the subthalamic nucleus, where all symptoms of PD can be treated [23,25,30,33]. The accuracy of target setting was verified by recalculating the coordinates of the active electrode used after 6 months in relation to the posterior commissure. In the same way, the calculated targets were compared with the actual targets (active electrode contact after 6 months) on CT and VG (Table 2, Figure 1). Both the GPi and the STN have a crucial role in regulating extrapyramidal motor function. The generally accepted model proposed by Alexander as- 3 4 Overview of Recent STN Stimulation Results AUTHOR PATIENTS UPDRS III IMPROVEMENT (%) L-DOPA REDUCTION Benabid et al [7], 1998 Krack et al [27], 1998 Kumar et al [28], 1999 Pinter et al [37], 1999 Vesper et al 2001 51 75 30–50 8 71 56 7 58 40 9 45 — 38 52 53 (%) sumes that the lack of dopaminergic neurotransmission in PD leads to overactivity of the GPi innervated by a hyperactive STN [2,3,11], which has also been proven by recent positron emission tomography (PET) studies [9,10]. The GPi has for a long time been the standard target of ablation in the management of parkinsonian syndrome. However, this procedure is associated with a number of serious adverse effects, such as visual impairment resulting from lesions in the optical tract and behavioral and cognitive disturbances [16,18 –20,45]. With the introduction of deep brain stimulation (DBS), it has become possible to reduce many of these complications. However, DBS is less effective and particularly the long-term results of chronic high-frequency stimulation of the GPi appear to be less promising than those of pallidotomy [8,27,29]. A marked improvement was found for dyskinesias while there was only limited effect on akinesia and freezing phenomena. The effect on tremor in parkinsonian patients was poor and inconstant. Furthermore, it was not possible to achieve a significant reduction of the daily L-dopa dose [5,27–29, 36]. Because of the size of the globus pallidus and its inhomogeneous internal organization, it is not possible to produce all effects of pallidotomy with chronic high-frequency stimulation. It has even been reported that different parts of the GPi have to be stimulated for optimal results [6,26]. In contrast, STN Stimulation Parameters (12-month follow-up) Intraoperative 1 month 6 month 12 month FREQUENCY [HZ] PULSE WIDTH [␮S] AMPLITUDE [V] OUTPUT [␮A] IMPEDANCE [⍀] 134 134 133 133 108 109 86 98 2.5 2.3 3.0 3.1 40 53 58 1055 960 997 310 Surg Neurol 2002;57:306 –313 5 Vesper et al GPi Stimulation Parameters (12-month follow-up), Datas According to Brock et al [8] FREQUENCY [HZ] PULSE WIDTH [␮S] AMPLITUDE [V] OUTPUT [␮A] IMPEDANCE [⍀] 163 139 164 156 263 248 382 203 4.9 3.2 4.4 3.1 197 372 140 1031 1093 724 Intraoperative 1 month 6 month 12 month stimulation of the much smaller STN can be performed with a relatively small electrical field (Tables 3 and 5). The GPi requires a very high power output for effective stimulation, which reduces battery life and reduces the possibility of postoperative adjustment of stimulation parameters. In STN, stimulation parameters, especially the output, can be kept low [7,8]. Therefore, a randomized trial comparing both STN and GPi would be difficult to perform. Severe complications of the procedure are infrequent. The most common problem is the frequently observed, though mostly transient, deterioration of the patients’ psychic state. Similar observations have already been reported for lesioning operations as well as for stimulation procedures in both the GPi and STN [12,15,28,39,42,43,45]. Therefore, careful patient selection and preoperative neuropsychological testing over an extended period are of utmost importance. Conclusion In conclusion, STN deep brain stimulation has proven to be a safe and long-term effective procedure. It has been established as the method of first choice for managing advanced Parkinson’s disease. DBS in the STN has convincing advantages compared to GPi stimulation. However, careful selection of surgical candidates is required, especially with respect to pre-existing psychic disorders. 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The results obtained are interesting in that they confirm what has already been published, and they stress one of the important points of this method: its reproducibility in the hands of experienced teams who follow the basic rules of good practice in functional neurosurgery. The strength of the method depends on the techniques used and the teams using them. Even if there are differences be-