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Usefulness of neurophysiologic techniques in stereotactic subthalamic nucleus stimulation for advanced Parkinson's disease
Clinical Neurophysiology 114 (2003) 1793–1799 www.elsevier.com/locate/clinph
Usefulness of neurophysiologic techniques in stereotactic subthalamic nucleus stimulation for advanced Parkinson’s disease J.L. Molinuevo, F. Valldeoriola*, J. Valls-Sole´ Institut Clı´nic de Malalties del Sistema Nervio´s, Hospital Clı´nic de Barcelona, Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain Accepted 6 May 2003
Abstract Objective: The objectives of this study are to determine the impact of neurophysiologic guidance on subthalamic nucleus (STN) targeting and to assess its safety and effectiveness. Methods: We have compared the initial theoretic anatomic target (TAT) of the STN with the final microrecording guided coordinates in 15 consecutive patients with bilaterally implanted electrodes in the STN. The clinical results and adverse effects are also reported. All comparisons were done through a paired Student’s t test and Pearson’s correlation test. Results: Neurophysiological guidance changed the target coordinates in 26 of the procedures. The mean correction applied to the TAT in order to place the electrode in its definite location was 0.4 mm (^0.8, range 0 – 3; P ¼ 0:03) in the medial-lateral axis, 1.6 mm (^ 1.2, range 0 – 5; P ¼ 0:01) in the anterior-posterior plane and 0.8 mm (^ 0.8, range 0 – 3; P ¼ 0:26) in the vertical axis. The mean number of microrecording tracks employed to localize each STN was 2.8 ^ 1.8 (range 1 – 8) tracks. After surgery, the total UPDRS motor score in the off medication condition improved by 65.9%; UPDRS-II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. No intraoperative hemorrhages occurred in this series. Conclusions: Neurophysiological guidance is a safe and useful tool in order to improve and confirm target localization. The correction applied in the target resulted in a significant clinical improvement 6 months after surgery. q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Subthalamic nucleus stimulation; Neurophysiological guidance
1. Introduction Microrecording techniques have recently been employed in stereotactic functional neurosurgery to improve target location. They allow the recording of the cellular activity present in the neurons of the distinct basal ganglia nuclei and thalamus (Hutchison et al., 1998; Lozano et al., 1996; Wichmann et al., 1994a,b). These techniques have been widely used in the performance of stereotactic posteroventral pallidotomy (Baron et al., 1996; Dogali et al., 1995; Lozano et al., 1995; Molinuevo et al., 2000a; Stefani et al., 1997; Sterio et al., 1994; Sutton et al., 1995), and some studies have confirmed their value in localizing the surgical * Corresponding author. Institut Clı´nic de Malalties del Sistema Nervio´s, Servei de Neurologia, Hospital Clı´nic Universitari, C/ Villarroel, 170, 08036 Barcelona, Spain. Tel.: þ34-93-2275750; fax: þ34-93-2275783. E-mail address: [email protected] (F. Valldeoriola).
target (Alterman et al., 1994; Molinuevo et al., 1999; Tsao et al., 1998). Bilateral subthalamic nucleus (STN) stimulation has been successfully performed in humans, proving to be an effective therapy for the amelioration of Parkinson’s disease (PD) motor symptomatology and drug-induced dyskinesias (Benabid et al., 1994; Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999; Molinuevo et al., 2000b). In addition, it has been shown to improve the frontal N30 component of somatosensory evoked potentials (Pierantozzi et al., 1999). The stereotactic target for the STN is located 0 –2 mm posterior to the mid commissural point, 10.5 – 12 mm lateral to the intercommissural line (ICL), and 5 mm ventral to the ICL (Hutchison et al., 1998). Neurophysiological guidance has been employed, in most reported studies, in order to localize the sensorimotor area of the STN to optimize the final position of the electrodes (Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999; Molinuevo
1388-2457/03/$30.00 q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00160-3
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et al., 2000b). The usefulness of these techniques to adequately locate the STN has not been precisely determined. The objectives of this study are to determine the impact of neurophysiologic guidance on STN targeting and to assess its safety and effectiveness.
2. Patients and methods 2.1. Patients Deep brain stimulation electrodes were bilaterally implanted in the STN of 15 PD patients between 1997 and 1998. All patients met the United Kingdom Parkinson’s Disease Society brain-bank clinical criteria for idiopathic PD (Hughes et al., 1992). Selection criteria were: age under 75 years, and the presence of disabling motor fluctuations and drug-induced dyskinesias refractory to medical therapy adjustments. Exclusion criteria were: presence of cognitive impairment, major depression or marked cerebral atrophy on neuroimaging studies. The patients were 10 males and 5 females, with a mean age of 60.9 (^ 6.8, range 52– 74) years, a mean disease duration of 15.8 (^ 9.2, 7 – 38) years and a mean off medication Hoehn & Yahr (H/Y) stage of 3.8 (^ 0.8, 2.5 – 5). All patients were treated with L -DOPA, 4 patients also used oral dopamine agonists and two used subcutaneous apomorphine. 2.2. Surgical procedure All patients gave their informed consent and the protocol was approved by the local ethical committee. Antiparkinsonian medication was withdrawn the night before surgery. A model G Leksell stereotactic frame was placed under local anesthesia. Images through the ICL were acquired at 1 mm thick slices obtained through cranial computerized tomography (CT). After selection of a slice with the anterior commissure (AC) and the posterior commissure (PC), the theoretic anatomic target (TAT) was placed 12 mm lateral to the ICL (x coordinate), 3 mm posterior (y coordinate) and 5 mm ventral to the midcommissural point (z coordinate). The first recording track was always directed to the TAT of the left STN. We approached the target with an anteriorposterior angle of 458 with respect to the ICL. The stereotactic coordinates were calculated with the help of a computer program containing a digitized brain atlas based on the Schaltenbrand and Wahren atlas (Schaltenbrand and Wahren, 1977). Under local anesthesia a single 15 mm burr hole was made in the skull 2 cm from the midline at the coronal suture. Recording of single unit neuronal activity was performed using a Neurological Registering Equipment (Neurorack). A platinum-iridium microelectrode (extended microelectrodes, 14-TDSC-CC; FHC, Inc., Bowdoingham,
ME) was inserted through the burr hole. Patients were induced with brief general anesthesia using intravenous propofol (2.5 mg/kg) during the procedure except when their collaboration was needed. Microelectrode recording was started 20 mm above the theoretic target and conducted by an electronic microdrive device. By means of the microelectrode recording the discharge pattern of the neurons of the thalamus, subthalamus and substantia nigra pars reticulata could be identified. With the anteriorposterior angle used for the target approach, thalamic cells mainly belonged to the reticular nucleus, characterized by high frequency bursts of activity. Other typical thalamic cells presented a low firing rate (10 – 20 Hz) with a low tendency to burst. Below the thalamus we usually found some cells with a low firing rate that probably belong to a thin strip of gray matter located between the thalamic and lenticular fasciculi, the Zona Incerta. After this low density cellularity area, we encountered a marked increase in the background noise, when entering the STN. Typical STN cells have a large amplitude and a non-tonic, irregular firing pattern with a firing rate of around 25 –50 Hz. Finally, without a clear border, the electrodes enter the substantia nigra characterized by the presence of neurons with high frequency and tonic discharges. The sensorimotor area of the STN was distinguished by modification of neuronal activity in response to active and passive movements or palpation and light touch of individual contralateral body parts (Hutchison et al., 1998; Limousin et al., 1997). A computer program (TPM. DAQ Analysis 3.0, National Instruments Espan˜a, Barcelona, Spain) was employed to quantify the firing rate to define cells as driving-responders or not. Microstimulation (bipolar pulses at 40– 80 mA, 300 Hz and 500 – 1000 ms duration) was also performed to determine the threshold for side effects. The first track was initially directed to the TAT and a minimum of one and a maximum of 8 parallel exploration tracks were needed for localization of the sensorimotor STN area and its anatomic boundaries. An electrode for long-term stimulation (DBS 3389 electrode, Medtronic, Minneapolis, MN) was inserted at the location previously defined through the neurophysiological techniques. An external stimulation device connected to the stimulation electrode was then employed to confirm that there were not any limiting side effects and there was a beneficial antiparkinsonian response. After the left STN electrode was fixed, we proceeded to implant symmetrically a lead in the right hemisphere, following the same procedure. Programmable pulse generators (Itrel II, Medtronic) were implanted in the subclavicular region ipsilateral to the electrode 1 week after surgery. 2.3. Calculation of target deviation The data presented in this study were prospectively collected in the operation room and retrospectively analyzed from our own operative records. We recorded the x, y and z coordinates of the original CT-derived target (designated
J.L. Molinuevo et al. / Clinical Neurophysiology 114 (2003) 1793–1799
TAT) and the x, y and z coordinates for the final location of the electrode (Tfinal). The absolute difference between both coordinates represents the correction in the x, y and z coordinates that the neurosurgeon made in order to achieve the optimal neurophysiological target, and therefore we called it ‘neurosurgical distance’. However, the ‘neurosurgical distance’ does not exactly correspond with the magnitude of the displacement of the tip of the electrode from the TAT, since our anterior-posterior angle with respect to the ICL is 458. Because we approach the target with a 458 angle any change in the target point along the trajectory alters the z and y coordinates of the Tfinal equally (slope ¼ 1). The following equation was used to calculate the magnitude of the change: p Dz ðand DyÞ ¼ 1=2 (distance of the tip of the electrode point from the z TAT coordinate)2 The resultant coordinates, after adjusting the increment derived from the angle, were denominated Treal. The absolute difference between TAT coordinates and the Treal coordinates (dx,dy,dz) represents the true distance between the tip of the electrode and the TAT, and therefore we called it ‘real distance’. In addition we calculated the 3-dimensional distance between the TAT and the tip of the electrode with the following formula: p 3-dimensional distance ¼ ðdx2 þ dy2 þ dz2 Þ Since the magnitude of the correction performed by the neurosurgeon (neurosurgical distance) is as important as the real change in the target (real distance), we decided to show both data in the results. We also recorded the number of patients in which the first recording track reached the STN and its sensorimotor area and the total number of microrecording tracks employed in each patient.
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To assess the effectiveness of STN stimulation, we compared the off medication scores obtained before surgery with the off medication/on stimulation scores after surgery, and the off medication/off stimulation with the off medication/on stimulation scores obtained after surgery. 2.5. Statistical analysis Statistical analysis to determine the significance of the clinical results and the difference between the coordinates of the TAT and the coordinates of Tfinal and Treal was carried out by means of the software SPSS-PC Windows 3.1 version. All comparisons were done through a paired Student’s t test. We employed Pearson’s correlation test to determine if the magnitude of the distance between the TAT and Treal or the number of microrecording tracks performed in each patient correlated with the amount of clinical improvement, which was calculated as the percentage of improvement of the UPDRS part III and the H/Y staging system after surgery. 2.6. Magnetic resonance imaging Magnetic resonance imaging (MRI) studies were performed during the week before surgery and 1 week after surgery before implanting the programmable pulse generators. All subjects were examined by a superconducting resonance magnet at a field of 1.5 T (Siemens Magnetom, Germany). The standard protocol consisted of T1-weighted axial, coronal and sagittal contiguous images to evaluate the location of the electrode. Coronal and axial images were 2.5 mm thick (TR ¼ 30, TE ¼ 6, FOV ¼ 25 cm, matrix ¼ 256 £ 256) and the sagittal images were 2.5 mm thick (TR ¼ 608, TE ¼ 14, FOV ¼ 23 cm, matrix ¼ 192 £ 256). T2-weighted axial images were contiguous, and 5.0 mm thick (TR ¼ 2500 ms, TE ¼ 90 ms, FOV ¼ 23 cm, matrix ¼ 192 £ 256).
2.4. Clinical assessment Clinical assessments were done following the CAPIT (Core Assessment Program for Intracerebral Transplantation) instructions (Langston et al., 1992) 4 days before surgery, 6 months after surgery, and 1 year after surgery in a few patients which have already completed this follow-up period. All assessments were carried out by means of the unified Parkinson’s disease rating scale (Fahn et al., 1987) (UPDRS) version 3.0. We grouped the items rising from a chair, gait, posture, postural reflexes, hypokinesia, facial expression, voice, axial rigidity and axial tremor under the term ‘axial symptoms’. Motor fluctuations were assessed through item 39 of the UPDRS. Patients were also graded according to the H/Y staging system (Hoehn and Yahr, 1967) and the Schwab & England (S/E) scale (Schwab and England, 1969). Dyskinesias were evaluated through the Abnormal Involuntary Movement Scale (AIMS, 12 items, maximum score 48, graded 0– 4) (Sweet et al., 1993).
3. Results 3.1. Deviation of the TAT from the sensorimotor area of the STN We did not identify the characteristic cell firing pattern of the STN in 11 out of the 30 electrodes implanted, therefore the TAT was located out of the STN in these procedures. In 19 proceedings the TAT was located in the STN, however in 5 of them it was located outside the sensorimotor area of the STN, since modification of neuronal activity to active or passive limb movements was not observed during the first microrecording track. Although in 14 procedures the TAT was located at the sensorimotor area of the STN, only 4 electrodes were placed in the initial TAT. Three of these electrodes were implanted in the left side and one in the right hemisphere. In contrast, 18 electrodes were located posterior with respect to the TAT and 8 were located
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Table 1 Number and percentage of patients whose initial target was accurately located and those who needed a correction
Patients (n) Percentage of patients
TAT located in the STN
TAT located in the SM
Anterior correction from TAT
Posterior correction from TAT
Medial correction from TAT
Lateral correction from TAT
Superior correction from TAT
Inferior correction from TAT
19 63.3
14 46.6
8 26.6
18 60
6 20
1 3.3
12 40
7 23.3
TAT, theoretic anatomic target (see text); STN, subthalamic nucleus; SM, sensorimotor area of the subthalamic nucleus.
anterior. In addition, 6 electrodes had also to be located medially in relation to the TAT and one laterally, and finally 12 were left superior to the TAT and 7 inferior (Table 1). The mean number of microrecording tracks employed to localize each STN was 2.8 ^ 1.8 (range 1– 8), and the mean time performing a microrecording track was 30 min. 3.2. Neurosurgical distance The mean final coordinates of the long-term stimulation electrode were 12.0 ^ 1 mm lateral to the ICL, 4.1 ^ 1.8 mm posterior, and 4.8 ^ 1.1 mm ventral to the midcommissural point. The mean correction applied to the TAT in order to place the electrode in its definite location was 0.4 mm (^ 0.8, range 0 –3; P ¼ 0:03) in the medial-lateral axis, 1.6 mm (^ 1.2, range 0 – 5; P ¼ 0:01) in the anteriorposterior plane and 0.8 mm (^ 0.8, range 0– 3; P ¼ 0:26) in the vertical axis (Table 2). We have also analyzed selectively those coordinates that were incorrect, since this measurement gives a better idea of the magnitude of the rectification that the neurosurgeon had to apply for those targets that were not accurate. The mean correction of the specifically wrong coordinates was 1.6 mm (^ 0.9, range 1– 2.5; P ¼ 0:01) in the medial-lateral axis, 1.9 mm (^ 1.1, range 0.5 – 5; P ¼ 0:01) in the anteriorposterior plane and 1.2 mm (^ 0.7, range 0.2– 3; P ¼ 0:27) in the vertical axis (Table 2). 3.3. Real distance The mean distance between the TAT and the final location of the electrode (Treal) was 0.4 mm (^ 0.8, range 0 –3; P ¼ 0:03) in the medial-lateral axis, 1.7 mm (^ 1.3, range 0– 5; P ¼ 0:01) in the anterior-posterior plane and
0.6 mm (^ 0.6, range 0 – 2.1; P ¼ 0:2) in the vertical axis (Table 2). The tridimensional distance between TAT and Treal was 2.1 ^ 1.3 mm. 3.4. Clinical response and MRI results At 6 months follow-up after surgery, the total UPDRS motor score in the off medication condition improved by 65.9%, and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1% and 81.1%, respectively. UPDRS-II scores were reduced by 71.8% and S/E scores improved by 45.3% (Table 3). L -DOPA was completely withdrawn in 8 patients and the overall L -DOPA dose was reduced by 80.4%. The time spent in the off condition was reduced by 89.7% and the intensity of dyskinesias by 80.6%. All results were statistically significant (P , 0:001). Postoperative MRI confirmed that all electrodes were located within the STN. There was no correlation between the degree of clinical improvement and the number of microrecording tracks employed to reach the optimal target (0.29; P , 0:05) or the magnitude of the distance corrected (0.22; P , 0:05). 3.5. Surgical complications No major adverse effects were seen as a consequence of the surgical procedure. Transient confusion, disorientation and abulia were observed during the first 2 weeks after surgery, but only in two patients both over 70 years of age. One of these patients developed mild postoperative depression, which still persisted at 6 months follow-up. Dysarthria and hypophonia affected two patients. These side effects were intense in one patient and mild in the other and remained 6 months after surgery.
Table 2 Mean distance between the tip of the electrode and the original TAT and mean correction from the TAT to the final location of the electrodes dx All electrodes Wrong electrodes Left electrodes Right electrodes
0.4 1.6 0.2 0.6
(0.8) (0.9) (0.6) (0.9)
dy
dz
3-D distance
Correc x
Correc y
Correc z
1.7 (1.3) 1.9 (1.3) 1.8 (1.2) 1.6 (1.4)
0.6 (0.6) 0.9 (0.5) 0.5 (0.7) 0.6 (0.4)
2.1 (1.3) 2.5 (1.2) 2.0 (1.3) 2.1 (1.4)
0.4 (0.8) 1.6 (0.9) 0.2 (0.6) 0.6 (0.9)
1.6 1.9 1.5 1.8
0.8 (0.8) 1.2 (0.6) 0.7 (1.0) 0.8 (0.6)
(1.2) (1.1) (0.9) (1.4)
dx, dy, dz, mean distance between the tip of the electrode and the original TAT in the lateral plane (x), in the anteroposterior plane (y) and in the dorsoventral plane (z). Correc x, Correc y, Correc z, mean correction applied for the final location of the electrodes in the lateral plane (x), in the anteroposterior plane (y) and in the dorso-ventral plane (z).
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Table 3 UPDRS total motor scores and subscores, activities of daily living, and Schwab & England and Hoehn & Yahr obtained before and after surgery in 15 patients who underwent bilateral STN stimulation
Maximal value Before surgery Off med On med After surgery* Off stim On stim
Motor UPDRS
Axial
Brad
Rigidity
Tremor
ADL
S/E
H/Y
108
36
32
16
24
52
100
5
49.6 (14) 20.1 (8)
17.1 (6) 8.1 (3)
17.7 (6) 8.1 (4)
8.5 (3) 3.2 (2)
6.3 (6) 0.7 (1)
26.7 (9) 10.6 (8)
51.1 (17) 16.9 (7)
16.0 (7) 5.9 (4)
17.9 (5) 7.0 (3)
7.6 (3) 2.9 (2)
9.5 (7) 1.2 (2)
n.a. 7.5 (6)
38.7 (14) 69.3 (13) n.a. 84 (11)
3.8 (0.7) 2.7 (0.6) 3.6 (0.9) 1.9 (0.5)
Numbers are the mean scores with the standard deviation in parentheses. *Eight patients were not taking any dopaminergic medication. The other 7 patients were evaluated in the morning after an overnight off. ADL, activities of daily living; Brad, bradykinesia; off med, off medication; on med, on medication; off stim, off stimulation; on stim, on stimulation; n.a., not applicable.
4. Discussion The results of this study suggest that neurophysiologic techniques are useful to correctly localize the functional STN, which requires millimeter accuracy in order to obtain good clinical effects (Molinuevo et al., 2000b; Valldeoriola et al., 2002). Only 4 electrodes were placed in the initial CT-derived target, while the guidance of microrecording techniques modified the target in 26 (87%) of the procedures. The mean magnitude of the correction was statistically significant in the medial-lateral and anteriorposterior axis and accounted for more than 1.5 mm in the latter. Furthermore, when we considered the mean extent of the correction for only the wrong coordinates they accounted for over 1.5 mm in the medial-lateral plane and almost 2 mm in the anterior-posterior axis, which represents a relevant figure due to the small size of the human STN (Hutchison et al., 1998). In addition, in less than 50% of the procedures the TAT coincided with the sensorimotor area of the STN. Taking into account that we are performing physiological procedures rather than pure anatomical ones it is mandatory to place the electrode not only in the right structure but in its segment which offers the best results. The mean 3-dimensional distance between the TAT and the tip of the electrode accounted for 2 mm, although in 10% of the procedures this was 4 mm or greater. This degree of error is in agreement with that shown by other groups (Alterman et al., 1994) during microelectrode guided pallidotomy, and it has been stated enough to justify the use of microrecording guidance to correctly place the target (Alterman et al., 1994). A recent study about the variability in lesion location after microelectrode guided pallidotomy has also shown the importance of the third ventricular variation in determining lesion placement (Gross et al., 1999), which may be even more substantial with structures, such as the STN, located more medial than the pallidum. In addition, there are other anatomical considerations, which further complicate the targeting of the STN. The dorsal-ventral axis of the STN is directed
from a lateral to a medial position in the brain and its anterior-posterior axis is arched presenting a characteristic kidney shape. Therefore, any displacement of the microelectrode in the medial-lateral axis is associated with an anterior-posterior correction, thus neurophysiological techniques are the only reliable method to confirm that you are within the target. The degree of clinical improvement in our patients is similar to that published by other groups (Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999). In our series of patients the mean L -DOPA dose was reduced by 80.4% and in more than 50% of the patients it was completely withdrawn; these clinical results suggest that the electrodes were correctly placed in the sensorimotor area of the STN. In addition, the lack of correlation between the distance between the TAT and Treal and the clinical results observed 6 months after surgery implies that the initial targeting error can be confidently amended through neurophysiological techniques. Detractors of the use of neurophysiologic techniques for mapping of cellular recording fields during the surgical procedure argue that it unbearably prolongs surgery (Kishore et al., 1997), however, this was not the case in the present series. Each recording track and subsequent mapping took an average of 30 min and the mean number of recording tracks needed to locate the sensorimotor STN was 2.8, so the mean overflowing time was less than 90 min for each STN. Life threatening adverse effects are not frequent in functional neurosurgery, and the largest series of STN stimulation patients (Limousin et al., 1998) disclosed one cerebral hemorrhage in 48 procedures. Among larger contemporary functional neurosurgery series, Lozano et al. (1996) reported a 1.4% incidence of hemorrhages employing neurophysiological guidance, whereas other authors (Iacono et al., 1995) reported an incidence of 1.5% of hemorrhages without the use of microrecording techniques. In this series, the incidence of cerebral hematomas was zero. Furthermore, only one intraoperative hemorrhage has occurred in 87 (1.1%) functional stereotactic procedures performed in our institution, including pallidotomies and
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STN stimulation. Therefore, the risk for intraoperative hemorrhages remains low when functional neurosurgery is performed with the aid of microrecording guidance. Our targeting could be improved using MRI instead of cranial CT, but this is also controversial since a recent report found relatively small differences between MRI- and CTderived target coordinates for pallidotomy (Holtzeimer et al., 1999). The absolute difference in targeting between MRI and CT, disclosed by this study, was only around 0.5 mm for each axis. In addition, imaging techniques are not able to discriminate the functional part of an anatomic structure, and therefore identification of the STN sensorimotor area can only be achieved with a neurophysiological approach. In summary, neurophysiological guidance is a useful tool in order to improve and confirm target localization. The correction applied in the target resulted in a significant clinical improvement 6 months after surgery. These data can be obtained safely and without an important increment of the operation time. Well designed studies, such as prospective randomized clinical trials, should be performed in order to assess the beneficial effects specifically derived from the correction performed in the target through microelectrode recording techniques.
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Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, Lozano AM. Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998;44: 622 –8. Iacono RP, Shima F, Lonser RR, Kuniyoshi S, Maeda G, Yamada S. The results, indications and physiology of posteroventral pallidotomy for patients with Parkinson’s disease. Neurosurgery 1995;36:1118–27. Kishore A, Turnbull IM, Snow BJ, de la Fuente-Fernandez R, Schulzer M, Mak E, Yardley S, Calne DB. Efficacy, stability and predictors of outcome of pallidotomy for Parkinson’s disease. Six months follow-up with additional 1-year observations. Brain 1997;120:729 –37. Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, Lang AE. Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998;51: 850 –5. Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, Watts R. Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992;7:2–13. Limousin P, Greene J, Pollack P, Rothwell J, Benabid AL, Frackowiak R. Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson’s disease. Ann Neurol 1997; 42:283–91. Limousin P, Krack P, Pollack P, Banazzouz A, Ardouin C, Hoffman D, Benabid AL. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339: 1105–11. Lozano AM, Lang AE, Galvez-Jimenez N, Miyasaki J, Duff J, Hutchinson WD, Dostrovsky JO. Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–7. Lozano A, Hutchinson W, Kiss Z, Tasker R, Davis K, Dostrovsky J. Methods for microelectrode guided posteroventral pallidotomy. J Neurosurg 1996;84:194–202. Molinuevo JL, Valldeoriola F, Rumia` J, Nobbe FA, Martı´nez R, Ferrer E, Tolosa E. Contribution of neurophysiological guidance to stereotactic posteroventral pallidotomy for Parkinson’s disease. Acta Neurochir 1999;141:1195–201. Molinuevo JL, Valldeoriola F, Nobbe FA, Rumia` J, Ferrer E, Tolosa E. Eficacia y seguridad de la palidotomı´a posteroventral en la enfermedad de Parkinson avanzada. Med Clin 2000a;114:205–8. Molinuevo JL, Valldeoriola F, Tolosa E, Rumia` J, Valls-Sole´ J, Ferrer E. Withdrawal of l-dopa after bilateral subthalamic nucleus stimulation in advanced Parkinson’s disease. Arch Neurol 2000b;57:983–8. Moro E, Scerrati M, Romito LMA, Roselli R, Tonali P, Albanese A. Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson’s disease. Neurology 1999;53:85–90. Pierantozzi M, Mazzone P, Bassi A, Rossini PM, Peppe A, Altibrandi MG, Stefani A, Bernardi G, Stanzione P. The effect of deep brain stimulation on the frontal N30 component of somatosensory evoked potentials in advanced Parkinson’s disease patients. Clin Neurophysiol 1999;110:1700–7. Schaltenbrand G, Wahren W. Atlas for stereotaxy of the human brain. Stuttgart: Thieme; 1977. Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson’s disease. In: Gillingham FJ, Donaldson IML, editors. Third Symposium on Parkinson’s Disease, Edinburgh: Livingstone; 1969. p. 152 –7. Stefani A, Stanzione P, Bassi A, Mazzone P, Vangelista T, Bernardi G. Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson’s disease: clinical score and internal globus pallidus activity. Short communication. J Neural Transm 1997;104: 895 –904. Sterio D, Beric A, Dogali M, Fazzini E, Alfaro G, Devinsky O. Neurophysiological properties of pallidal neurons in Parkinson’s disease. Ann Neurol 1994;35:586– 91. Sutton JP, Couldwell W, Lew MF, Mallory L, Grafton S, DeGiorgio C, Welsh M, Apuzzo ML, Ahmadi J, Waters CH. Ventroposterior medial
J.L. Molinuevo et al. / Clinical Neurophysiology 114 (2003) 1793–1799 pallidotomy in patients with advanced Parkinson’s disease. Neurosurgery 1995;36:1112 –7. Sweet RA, DeSensi EG, Zubenko GS. Reliability and applicability of movement disorder rating scales in the elderly. J Neuropsychiatry Clin Neurosci 1993;5(1):56 –60. Tsao K, Wilkinson S, Overman J, Koller WC, Batnitzky S, Gordon MA. Pallidotomy lesion locations: significance of microelectrode refinement. Neurosurgery 1998;43:506–12.
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Valldeoriola F, Pilleri M, Tolosa E, Molinuevo JL, Rumia` J, Ferrer E. Bilateral subthalamic stimulation in advanced Parkinson’s disease: long-term follow-up of patients. Mov Disord 2002;17:125 –32. Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus. I. Functional properties in intact animals. J Neurophys 1994a;72:494–506. Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophys 1994b;72:507–20.
Usefulness of neurophysiologic techniques in stereotactic subthalamic nucleus stimulation for advanced Parkinson’s disease J.L. Molinuevo, F. Valldeoriola*, J. Valls-Sole´ Institut Clı´nic de Malalties del Sistema Nervio´s, Hospital Clı´nic de Barcelona, Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain Accepted 6 May 2003
Abstract Objective: The objectives of this study are to determine the impact of neurophysiologic guidance on subthalamic nucleus (STN) targeting and to assess its safety and effectiveness. Methods: We have compared the initial theoretic anatomic target (TAT) of the STN with the final microrecording guided coordinates in 15 consecutive patients with bilaterally implanted electrodes in the STN. The clinical results and adverse effects are also reported. All comparisons were done through a paired Student’s t test and Pearson’s correlation test. Results: Neurophysiological guidance changed the target coordinates in 26 of the procedures. The mean correction applied to the TAT in order to place the electrode in its definite location was 0.4 mm (^0.8, range 0 – 3; P ¼ 0:03) in the medial-lateral axis, 1.6 mm (^ 1.2, range 0 – 5; P ¼ 0:01) in the anterior-posterior plane and 0.8 mm (^ 0.8, range 0 – 3; P ¼ 0:26) in the vertical axis. The mean number of microrecording tracks employed to localize each STN was 2.8 ^ 1.8 (range 1 – 8) tracks. After surgery, the total UPDRS motor score in the off medication condition improved by 65.9%; UPDRS-II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. No intraoperative hemorrhages occurred in this series. Conclusions: Neurophysiological guidance is a safe and useful tool in order to improve and confirm target localization. The correction applied in the target resulted in a significant clinical improvement 6 months after surgery. q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Subthalamic nucleus stimulation; Neurophysiological guidance
1. Introduction Microrecording techniques have recently been employed in stereotactic functional neurosurgery to improve target location. They allow the recording of the cellular activity present in the neurons of the distinct basal ganglia nuclei and thalamus (Hutchison et al., 1998; Lozano et al., 1996; Wichmann et al., 1994a,b). These techniques have been widely used in the performance of stereotactic posteroventral pallidotomy (Baron et al., 1996; Dogali et al., 1995; Lozano et al., 1995; Molinuevo et al., 2000a; Stefani et al., 1997; Sterio et al., 1994; Sutton et al., 1995), and some studies have confirmed their value in localizing the surgical * Corresponding author. Institut Clı´nic de Malalties del Sistema Nervio´s, Servei de Neurologia, Hospital Clı´nic Universitari, C/ Villarroel, 170, 08036 Barcelona, Spain. Tel.: þ34-93-2275750; fax: þ34-93-2275783. E-mail address: [email protected] (F. Valldeoriola).
target (Alterman et al., 1994; Molinuevo et al., 1999; Tsao et al., 1998). Bilateral subthalamic nucleus (STN) stimulation has been successfully performed in humans, proving to be an effective therapy for the amelioration of Parkinson’s disease (PD) motor symptomatology and drug-induced dyskinesias (Benabid et al., 1994; Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999; Molinuevo et al., 2000b). In addition, it has been shown to improve the frontal N30 component of somatosensory evoked potentials (Pierantozzi et al., 1999). The stereotactic target for the STN is located 0 –2 mm posterior to the mid commissural point, 10.5 – 12 mm lateral to the intercommissural line (ICL), and 5 mm ventral to the ICL (Hutchison et al., 1998). Neurophysiological guidance has been employed, in most reported studies, in order to localize the sensorimotor area of the STN to optimize the final position of the electrodes (Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999; Molinuevo
1388-2457/03/$30.00 q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1388-2457(03)00160-3
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et al., 2000b). The usefulness of these techniques to adequately locate the STN has not been precisely determined. The objectives of this study are to determine the impact of neurophysiologic guidance on STN targeting and to assess its safety and effectiveness.
2. Patients and methods 2.1. Patients Deep brain stimulation electrodes were bilaterally implanted in the STN of 15 PD patients between 1997 and 1998. All patients met the United Kingdom Parkinson’s Disease Society brain-bank clinical criteria for idiopathic PD (Hughes et al., 1992). Selection criteria were: age under 75 years, and the presence of disabling motor fluctuations and drug-induced dyskinesias refractory to medical therapy adjustments. Exclusion criteria were: presence of cognitive impairment, major depression or marked cerebral atrophy on neuroimaging studies. The patients were 10 males and 5 females, with a mean age of 60.9 (^ 6.8, range 52– 74) years, a mean disease duration of 15.8 (^ 9.2, 7 – 38) years and a mean off medication Hoehn & Yahr (H/Y) stage of 3.8 (^ 0.8, 2.5 – 5). All patients were treated with L -DOPA, 4 patients also used oral dopamine agonists and two used subcutaneous apomorphine. 2.2. Surgical procedure All patients gave their informed consent and the protocol was approved by the local ethical committee. Antiparkinsonian medication was withdrawn the night before surgery. A model G Leksell stereotactic frame was placed under local anesthesia. Images through the ICL were acquired at 1 mm thick slices obtained through cranial computerized tomography (CT). After selection of a slice with the anterior commissure (AC) and the posterior commissure (PC), the theoretic anatomic target (TAT) was placed 12 mm lateral to the ICL (x coordinate), 3 mm posterior (y coordinate) and 5 mm ventral to the midcommissural point (z coordinate). The first recording track was always directed to the TAT of the left STN. We approached the target with an anteriorposterior angle of 458 with respect to the ICL. The stereotactic coordinates were calculated with the help of a computer program containing a digitized brain atlas based on the Schaltenbrand and Wahren atlas (Schaltenbrand and Wahren, 1977). Under local anesthesia a single 15 mm burr hole was made in the skull 2 cm from the midline at the coronal suture. Recording of single unit neuronal activity was performed using a Neurological Registering Equipment (Neurorack). A platinum-iridium microelectrode (extended microelectrodes, 14-TDSC-CC; FHC, Inc., Bowdoingham,
ME) was inserted through the burr hole. Patients were induced with brief general anesthesia using intravenous propofol (2.5 mg/kg) during the procedure except when their collaboration was needed. Microelectrode recording was started 20 mm above the theoretic target and conducted by an electronic microdrive device. By means of the microelectrode recording the discharge pattern of the neurons of the thalamus, subthalamus and substantia nigra pars reticulata could be identified. With the anteriorposterior angle used for the target approach, thalamic cells mainly belonged to the reticular nucleus, characterized by high frequency bursts of activity. Other typical thalamic cells presented a low firing rate (10 – 20 Hz) with a low tendency to burst. Below the thalamus we usually found some cells with a low firing rate that probably belong to a thin strip of gray matter located between the thalamic and lenticular fasciculi, the Zona Incerta. After this low density cellularity area, we encountered a marked increase in the background noise, when entering the STN. Typical STN cells have a large amplitude and a non-tonic, irregular firing pattern with a firing rate of around 25 –50 Hz. Finally, without a clear border, the electrodes enter the substantia nigra characterized by the presence of neurons with high frequency and tonic discharges. The sensorimotor area of the STN was distinguished by modification of neuronal activity in response to active and passive movements or palpation and light touch of individual contralateral body parts (Hutchison et al., 1998; Limousin et al., 1997). A computer program (TPM. DAQ Analysis 3.0, National Instruments Espan˜a, Barcelona, Spain) was employed to quantify the firing rate to define cells as driving-responders or not. Microstimulation (bipolar pulses at 40– 80 mA, 300 Hz and 500 – 1000 ms duration) was also performed to determine the threshold for side effects. The first track was initially directed to the TAT and a minimum of one and a maximum of 8 parallel exploration tracks were needed for localization of the sensorimotor STN area and its anatomic boundaries. An electrode for long-term stimulation (DBS 3389 electrode, Medtronic, Minneapolis, MN) was inserted at the location previously defined through the neurophysiological techniques. An external stimulation device connected to the stimulation electrode was then employed to confirm that there were not any limiting side effects and there was a beneficial antiparkinsonian response. After the left STN electrode was fixed, we proceeded to implant symmetrically a lead in the right hemisphere, following the same procedure. Programmable pulse generators (Itrel II, Medtronic) were implanted in the subclavicular region ipsilateral to the electrode 1 week after surgery. 2.3. Calculation of target deviation The data presented in this study were prospectively collected in the operation room and retrospectively analyzed from our own operative records. We recorded the x, y and z coordinates of the original CT-derived target (designated
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TAT) and the x, y and z coordinates for the final location of the electrode (Tfinal). The absolute difference between both coordinates represents the correction in the x, y and z coordinates that the neurosurgeon made in order to achieve the optimal neurophysiological target, and therefore we called it ‘neurosurgical distance’. However, the ‘neurosurgical distance’ does not exactly correspond with the magnitude of the displacement of the tip of the electrode from the TAT, since our anterior-posterior angle with respect to the ICL is 458. Because we approach the target with a 458 angle any change in the target point along the trajectory alters the z and y coordinates of the Tfinal equally (slope ¼ 1). The following equation was used to calculate the magnitude of the change: p Dz ðand DyÞ ¼ 1=2 (distance of the tip of the electrode point from the z TAT coordinate)2 The resultant coordinates, after adjusting the increment derived from the angle, were denominated Treal. The absolute difference between TAT coordinates and the Treal coordinates (dx,dy,dz) represents the true distance between the tip of the electrode and the TAT, and therefore we called it ‘real distance’. In addition we calculated the 3-dimensional distance between the TAT and the tip of the electrode with the following formula: p 3-dimensional distance ¼ ðdx2 þ dy2 þ dz2 Þ Since the magnitude of the correction performed by the neurosurgeon (neurosurgical distance) is as important as the real change in the target (real distance), we decided to show both data in the results. We also recorded the number of patients in which the first recording track reached the STN and its sensorimotor area and the total number of microrecording tracks employed in each patient.
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To assess the effectiveness of STN stimulation, we compared the off medication scores obtained before surgery with the off medication/on stimulation scores after surgery, and the off medication/off stimulation with the off medication/on stimulation scores obtained after surgery. 2.5. Statistical analysis Statistical analysis to determine the significance of the clinical results and the difference between the coordinates of the TAT and the coordinates of Tfinal and Treal was carried out by means of the software SPSS-PC Windows 3.1 version. All comparisons were done through a paired Student’s t test. We employed Pearson’s correlation test to determine if the magnitude of the distance between the TAT and Treal or the number of microrecording tracks performed in each patient correlated with the amount of clinical improvement, which was calculated as the percentage of improvement of the UPDRS part III and the H/Y staging system after surgery. 2.6. Magnetic resonance imaging Magnetic resonance imaging (MRI) studies were performed during the week before surgery and 1 week after surgery before implanting the programmable pulse generators. All subjects were examined by a superconducting resonance magnet at a field of 1.5 T (Siemens Magnetom, Germany). The standard protocol consisted of T1-weighted axial, coronal and sagittal contiguous images to evaluate the location of the electrode. Coronal and axial images were 2.5 mm thick (TR ¼ 30, TE ¼ 6, FOV ¼ 25 cm, matrix ¼ 256 £ 256) and the sagittal images were 2.5 mm thick (TR ¼ 608, TE ¼ 14, FOV ¼ 23 cm, matrix ¼ 192 £ 256). T2-weighted axial images were contiguous, and 5.0 mm thick (TR ¼ 2500 ms, TE ¼ 90 ms, FOV ¼ 23 cm, matrix ¼ 192 £ 256).
2.4. Clinical assessment Clinical assessments were done following the CAPIT (Core Assessment Program for Intracerebral Transplantation) instructions (Langston et al., 1992) 4 days before surgery, 6 months after surgery, and 1 year after surgery in a few patients which have already completed this follow-up period. All assessments were carried out by means of the unified Parkinson’s disease rating scale (Fahn et al., 1987) (UPDRS) version 3.0. We grouped the items rising from a chair, gait, posture, postural reflexes, hypokinesia, facial expression, voice, axial rigidity and axial tremor under the term ‘axial symptoms’. Motor fluctuations were assessed through item 39 of the UPDRS. Patients were also graded according to the H/Y staging system (Hoehn and Yahr, 1967) and the Schwab & England (S/E) scale (Schwab and England, 1969). Dyskinesias were evaluated through the Abnormal Involuntary Movement Scale (AIMS, 12 items, maximum score 48, graded 0– 4) (Sweet et al., 1993).
3. Results 3.1. Deviation of the TAT from the sensorimotor area of the STN We did not identify the characteristic cell firing pattern of the STN in 11 out of the 30 electrodes implanted, therefore the TAT was located out of the STN in these procedures. In 19 proceedings the TAT was located in the STN, however in 5 of them it was located outside the sensorimotor area of the STN, since modification of neuronal activity to active or passive limb movements was not observed during the first microrecording track. Although in 14 procedures the TAT was located at the sensorimotor area of the STN, only 4 electrodes were placed in the initial TAT. Three of these electrodes were implanted in the left side and one in the right hemisphere. In contrast, 18 electrodes were located posterior with respect to the TAT and 8 were located
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Table 1 Number and percentage of patients whose initial target was accurately located and those who needed a correction
Patients (n) Percentage of patients
TAT located in the STN
TAT located in the SM
Anterior correction from TAT
Posterior correction from TAT
Medial correction from TAT
Lateral correction from TAT
Superior correction from TAT
Inferior correction from TAT
19 63.3
14 46.6
8 26.6
18 60
6 20
1 3.3
12 40
7 23.3
TAT, theoretic anatomic target (see text); STN, subthalamic nucleus; SM, sensorimotor area of the subthalamic nucleus.
anterior. In addition, 6 electrodes had also to be located medially in relation to the TAT and one laterally, and finally 12 were left superior to the TAT and 7 inferior (Table 1). The mean number of microrecording tracks employed to localize each STN was 2.8 ^ 1.8 (range 1– 8), and the mean time performing a microrecording track was 30 min. 3.2. Neurosurgical distance The mean final coordinates of the long-term stimulation electrode were 12.0 ^ 1 mm lateral to the ICL, 4.1 ^ 1.8 mm posterior, and 4.8 ^ 1.1 mm ventral to the midcommissural point. The mean correction applied to the TAT in order to place the electrode in its definite location was 0.4 mm (^ 0.8, range 0 –3; P ¼ 0:03) in the medial-lateral axis, 1.6 mm (^ 1.2, range 0 – 5; P ¼ 0:01) in the anteriorposterior plane and 0.8 mm (^ 0.8, range 0– 3; P ¼ 0:26) in the vertical axis (Table 2). We have also analyzed selectively those coordinates that were incorrect, since this measurement gives a better idea of the magnitude of the rectification that the neurosurgeon had to apply for those targets that were not accurate. The mean correction of the specifically wrong coordinates was 1.6 mm (^ 0.9, range 1– 2.5; P ¼ 0:01) in the medial-lateral axis, 1.9 mm (^ 1.1, range 0.5 – 5; P ¼ 0:01) in the anteriorposterior plane and 1.2 mm (^ 0.7, range 0.2– 3; P ¼ 0:27) in the vertical axis (Table 2). 3.3. Real distance The mean distance between the TAT and the final location of the electrode (Treal) was 0.4 mm (^ 0.8, range 0 –3; P ¼ 0:03) in the medial-lateral axis, 1.7 mm (^ 1.3, range 0– 5; P ¼ 0:01) in the anterior-posterior plane and
0.6 mm (^ 0.6, range 0 – 2.1; P ¼ 0:2) in the vertical axis (Table 2). The tridimensional distance between TAT and Treal was 2.1 ^ 1.3 mm. 3.4. Clinical response and MRI results At 6 months follow-up after surgery, the total UPDRS motor score in the off medication condition improved by 65.9%, and axial symptoms, bradykinesia, rigidity, and tremor improved by 65.8%, 60.4%, 66.1% and 81.1%, respectively. UPDRS-II scores were reduced by 71.8% and S/E scores improved by 45.3% (Table 3). L -DOPA was completely withdrawn in 8 patients and the overall L -DOPA dose was reduced by 80.4%. The time spent in the off condition was reduced by 89.7% and the intensity of dyskinesias by 80.6%. All results were statistically significant (P , 0:001). Postoperative MRI confirmed that all electrodes were located within the STN. There was no correlation between the degree of clinical improvement and the number of microrecording tracks employed to reach the optimal target (0.29; P , 0:05) or the magnitude of the distance corrected (0.22; P , 0:05). 3.5. Surgical complications No major adverse effects were seen as a consequence of the surgical procedure. Transient confusion, disorientation and abulia were observed during the first 2 weeks after surgery, but only in two patients both over 70 years of age. One of these patients developed mild postoperative depression, which still persisted at 6 months follow-up. Dysarthria and hypophonia affected two patients. These side effects were intense in one patient and mild in the other and remained 6 months after surgery.
Table 2 Mean distance between the tip of the electrode and the original TAT and mean correction from the TAT to the final location of the electrodes dx All electrodes Wrong electrodes Left electrodes Right electrodes
0.4 1.6 0.2 0.6
(0.8) (0.9) (0.6) (0.9)
dy
dz
3-D distance
Correc x
Correc y
Correc z
1.7 (1.3) 1.9 (1.3) 1.8 (1.2) 1.6 (1.4)
0.6 (0.6) 0.9 (0.5) 0.5 (0.7) 0.6 (0.4)
2.1 (1.3) 2.5 (1.2) 2.0 (1.3) 2.1 (1.4)
0.4 (0.8) 1.6 (0.9) 0.2 (0.6) 0.6 (0.9)
1.6 1.9 1.5 1.8
0.8 (0.8) 1.2 (0.6) 0.7 (1.0) 0.8 (0.6)
(1.2) (1.1) (0.9) (1.4)
dx, dy, dz, mean distance between the tip of the electrode and the original TAT in the lateral plane (x), in the anteroposterior plane (y) and in the dorsoventral plane (z). Correc x, Correc y, Correc z, mean correction applied for the final location of the electrodes in the lateral plane (x), in the anteroposterior plane (y) and in the dorso-ventral plane (z).
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Table 3 UPDRS total motor scores and subscores, activities of daily living, and Schwab & England and Hoehn & Yahr obtained before and after surgery in 15 patients who underwent bilateral STN stimulation
Maximal value Before surgery Off med On med After surgery* Off stim On stim
Motor UPDRS
Axial
Brad
Rigidity
Tremor
ADL
S/E
H/Y
108
36
32
16
24
52
100
5
49.6 (14) 20.1 (8)
17.1 (6) 8.1 (3)
17.7 (6) 8.1 (4)
8.5 (3) 3.2 (2)
6.3 (6) 0.7 (1)
26.7 (9) 10.6 (8)
51.1 (17) 16.9 (7)
16.0 (7) 5.9 (4)
17.9 (5) 7.0 (3)
7.6 (3) 2.9 (2)
9.5 (7) 1.2 (2)
n.a. 7.5 (6)
38.7 (14) 69.3 (13) n.a. 84 (11)
3.8 (0.7) 2.7 (0.6) 3.6 (0.9) 1.9 (0.5)
Numbers are the mean scores with the standard deviation in parentheses. *Eight patients were not taking any dopaminergic medication. The other 7 patients were evaluated in the morning after an overnight off. ADL, activities of daily living; Brad, bradykinesia; off med, off medication; on med, on medication; off stim, off stimulation; on stim, on stimulation; n.a., not applicable.
4. Discussion The results of this study suggest that neurophysiologic techniques are useful to correctly localize the functional STN, which requires millimeter accuracy in order to obtain good clinical effects (Molinuevo et al., 2000b; Valldeoriola et al., 2002). Only 4 electrodes were placed in the initial CT-derived target, while the guidance of microrecording techniques modified the target in 26 (87%) of the procedures. The mean magnitude of the correction was statistically significant in the medial-lateral and anteriorposterior axis and accounted for more than 1.5 mm in the latter. Furthermore, when we considered the mean extent of the correction for only the wrong coordinates they accounted for over 1.5 mm in the medial-lateral plane and almost 2 mm in the anterior-posterior axis, which represents a relevant figure due to the small size of the human STN (Hutchison et al., 1998). In addition, in less than 50% of the procedures the TAT coincided with the sensorimotor area of the STN. Taking into account that we are performing physiological procedures rather than pure anatomical ones it is mandatory to place the electrode not only in the right structure but in its segment which offers the best results. The mean 3-dimensional distance between the TAT and the tip of the electrode accounted for 2 mm, although in 10% of the procedures this was 4 mm or greater. This degree of error is in agreement with that shown by other groups (Alterman et al., 1994) during microelectrode guided pallidotomy, and it has been stated enough to justify the use of microrecording guidance to correctly place the target (Alterman et al., 1994). A recent study about the variability in lesion location after microelectrode guided pallidotomy has also shown the importance of the third ventricular variation in determining lesion placement (Gross et al., 1999), which may be even more substantial with structures, such as the STN, located more medial than the pallidum. In addition, there are other anatomical considerations, which further complicate the targeting of the STN. The dorsal-ventral axis of the STN is directed
from a lateral to a medial position in the brain and its anterior-posterior axis is arched presenting a characteristic kidney shape. Therefore, any displacement of the microelectrode in the medial-lateral axis is associated with an anterior-posterior correction, thus neurophysiological techniques are the only reliable method to confirm that you are within the target. The degree of clinical improvement in our patients is similar to that published by other groups (Kumar et al., 1998; Limousin et al., 1998; Moro et al., 1999). In our series of patients the mean L -DOPA dose was reduced by 80.4% and in more than 50% of the patients it was completely withdrawn; these clinical results suggest that the electrodes were correctly placed in the sensorimotor area of the STN. In addition, the lack of correlation between the distance between the TAT and Treal and the clinical results observed 6 months after surgery implies that the initial targeting error can be confidently amended through neurophysiological techniques. Detractors of the use of neurophysiologic techniques for mapping of cellular recording fields during the surgical procedure argue that it unbearably prolongs surgery (Kishore et al., 1997), however, this was not the case in the present series. Each recording track and subsequent mapping took an average of 30 min and the mean number of recording tracks needed to locate the sensorimotor STN was 2.8, so the mean overflowing time was less than 90 min for each STN. Life threatening adverse effects are not frequent in functional neurosurgery, and the largest series of STN stimulation patients (Limousin et al., 1998) disclosed one cerebral hemorrhage in 48 procedures. Among larger contemporary functional neurosurgery series, Lozano et al. (1996) reported a 1.4% incidence of hemorrhages employing neurophysiological guidance, whereas other authors (Iacono et al., 1995) reported an incidence of 1.5% of hemorrhages without the use of microrecording techniques. In this series, the incidence of cerebral hematomas was zero. Furthermore, only one intraoperative hemorrhage has occurred in 87 (1.1%) functional stereotactic procedures performed in our institution, including pallidotomies and
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STN stimulation. Therefore, the risk for intraoperative hemorrhages remains low when functional neurosurgery is performed with the aid of microrecording guidance. Our targeting could be improved using MRI instead of cranial CT, but this is also controversial since a recent report found relatively small differences between MRI- and CTderived target coordinates for pallidotomy (Holtzeimer et al., 1999). The absolute difference in targeting between MRI and CT, disclosed by this study, was only around 0.5 mm for each axis. In addition, imaging techniques are not able to discriminate the functional part of an anatomic structure, and therefore identification of the STN sensorimotor area can only be achieved with a neurophysiological approach. In summary, neurophysiological guidance is a useful tool in order to improve and confirm target localization. The correction applied in the target resulted in a significant clinical improvement 6 months after surgery. These data can be obtained safely and without an important increment of the operation time. Well designed studies, such as prospective randomized clinical trials, should be performed in order to assess the beneficial effects specifically derived from the correction performed in the target through microelectrode recording techniques.
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