Brain, Vol. 122, No. 3, 405-416,
March 1999
© 1999 Oxford University Press
Article |
Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson's disease
1 Department of Surgery, University of Toronto, Division of Neurosurgery, The Toronto Hospital, 2 Department of Psychology, 3 Movement Disorders Centre, The Toronto Hospital, 4 Department of Medicine, University of Toronto, Division of Neurology, The Toronto Hospital, 5 Departments of Anatomy and Cell Biology and of Psychology, University of Toronto, Toronto, Ontario, Canada
Correspondence to:
Dr R. E. Gross, Division of Neurosurgery, The Toronto Hospital, Western Division, 399 Bathurst Street, McL 2-433, Toronto, Ontario, Canada M5T 2S8
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Abstract |
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The purpose of this study was to examine the relationship between lesion location and clinical outcome following globus pallidus internus (GPi) pallidotomy for advanced Parkinson's disease. Thirty-three patients were prospectively studied with extensive neurological examinations before and at 6 and 12 months following microelectrode-guided pallidotomy. Lesion location was characterized using volumetric MRI. The position of lesions within the posteroventral region of the GPi was measured, from anteromedial to posterolateral along an axis parallel to the internal capsule. To relate lesion position to clinical outcome, hierarchical multiple regression analysis was used. The variance in outcome measures that was related to preoperative scores and lesion volume was first calculated, and then the remaining variance attributable to lesion location was determined. Lesion location along the anteromedial-to-posterolateral axis within the GPi influenced the variance in total score on the Unified Parkinson's Disease Rating Scale in the postoperative `off' period, and in `on' period dyskinesia scores. Within the posteroventral GPi, anteromedial lesions were associated with greater improvement in `off' period contralateral rigidity and `on' period dyskinesia, whereas more centrally located lesions correlated with better postoperative scores of contralateral akinesia and postural instability/gait disturbance. Improvement in contralateral tremor was weakly related to lesion location, being greater with posterolateral lesions. We conclude that improvement in specific motor signs in Parkinson's disease following pallidotomy is related to lesion position within the posteroventral GPi. These findings are consistent with the known segregated but parallel organization of specific motor circuits in the basal ganglia, and may explain the variability in clinical outcome after pallidotomy and therefore have important therapeutic implications.
Parkinson's disease; globus pallidus; pallidotomy; clinical outcome
GPe = globus pallidus externus; GPi = globus pallidus internus; UPDRS = Unified Parkinson's Disease Rating Scale; vMRI = volumetric MRI
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Introduction |
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Pallidotomy of the globus pallidus internus (GPi) has gained widespread acceptance over the last several years as an effective treatment for advanced-stage Parkinson's disease (Laitinen et al., 1992
; Dogali et al., 1995; Lozano et al., 1995; Baron et al., 1996; Lang et al., 1997). This is due in large measure to two important advances: (i) adjustment of the surgical target to the posteroventral region of GPi (Svennilson et al., 1960; Laitinen et al., 1992), and (ii) improved understanding of the subnuclear anatomy and physiology of the motor circuits involving cortical motor areas, basal ganglia and thalamus, and their roles in Parkinson's disease. Improved outcomes have been thought to be due to direct targeting of the sensorimotor region of GPi, which has been shown to be situated in the posteroventral pallidum in subhuman primates (DeLong et al., 1985; Hoover and Strick, 1993; Yoshida et al., 1993; Wichmann et al., 1994). However, controlled studies of patients with Parkinson's disease undergoing pallidotomy have yet to substantiate this hypothesis. In fact, recent studies have failed to show any relationship between lesion location within GPi and clinical outcome (Burns et al., 1997; Krauss et al., 1997).
We have used volumetric MRI (vMRI) to localize lesions postoperatively in a cohort of patients who underwent microelectrode-guided GPi pallidotomy for advanced stage Parkinson's disease (Gross et al., 1999). These patients were prospectively assessed preceding and at defined intervals following surgery (up to 2 years) with extensive neurological examinations (Lang et al., 1997). We demonstrated that the lesions are distributed from anteromedial to posterolateral, along an axis parallel to the obliquely oriented internal capsule, within the posteroventral region of GPi. Here we analyse the relationship between lesion location and outcome following pallidotomy.
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Clinical material
The patient group consisted of 33 unselected patients of the 40 participants in the initial prospective series examining the effects of microelectrode-guided pallidotomy (Lozano et al., 1996
) on Parkinson's disease, and has been described previously (Lang et al., 1997; Gross et al., 1999). All 33 patients underwent clinical assessments 6 months following surgery and 31 patients 12 months following surgery (the remaining two patients were excluded at this time point as a result of having had surgery on the contralateral side). Although 18 patients were assessed 24 months postoperatively, the small size of this group precluded statistical analysis and these data are therefore not included. Extensive neurological assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS) (Langston et al., 1992; Lang et al., 1995) and the modified Dyskinesia Rating Scale (Goetz et al., 1994), were performed in the unmedicated state (practically defined `off' period) and the medicated state (best `on' period). Separate dyskinesia scores were obtained for the ipsilateral and contralateral sides, as well as a total score which additionally incorporated axial dyskinesia. L-Dopa equivalents were calculated as described previously (Lang et al., 1997).
vMRI lesion characterization
vMRI was performed on all available patients from the prospective series (33 out of 40 patients). The remaining patients could not participate due to illness, inconvenience or implantation of a contralateral neurostimulation device. Imaging was performed between 1 day and 49 months following pallidotomy (mean = 18.6 months). Image processing was performed using a reformatting program (Silhouette, ISG, Missisauga, Ontario, Canada) on an UltraSPARC workstation (Sun Microsystems) to allow characterization of lesion location and volume, as previously described (Gross et al., 1999). Briefly, vMRIs (spoiled gradient volumetrically acquired images, 256 x 256 pixels; field of view, 20 cm) were reformatted to correct for head rotation, twist and tilt prior to generating triplanar data sets parallel and perpendicular to the intercommissural line. The position of the centre of the lesion with respect to the conventional commissural landmarks, as well as to the wall of the third ventricle (IIIrdV), was then measured and normalized to an intercommissural distance of 23 mm using the formula: measured distance (mm) x 23 mm/intercommissural distance (mm). This normalization allows comparisons of distances among patients with brains of different sizes, but assumes that scaling is equal in each dimension. Although the intervals between pallidotomy and imaging varied considerably, previous work has established that the position of the lesion centre is independent of scan interval (Gross et al., 1999).
Lesion volumes were calculated using segmentation analysis of the hyperintense ring seen on T1-weighted imaging (early scans) or the hypointense region seen on later T1-weighted scans, as previously described (Gross et al., 1999). Lesion volumes calculated in this way changed little between early and late scans obtained in the same patients, mitigating the effects of oedema on lesion volume.
Measurement of anteromedial-to-posterolateral distance of lesions
We previously noted significant variability of the position of the lesion centre in both the anterior–posterior dimension (with respect to the anterior commissure) and the medial–lateral dimension (with respect to the third ventricle wall), whereas variation in the dorsal–ventral dimension (with respect to the intercommissural line) was relatively small (Gross et al., 1999). Anterior–posterior and medial–lateral lesion positions were correlated, such that lesions were distributed from anteromedial to posterolateral within the posteroventral region of GPi, parallel to the internal capsule. Rather than separately examining the relationship of anterior–posterior and medial–lateral lesion locations to clinical outcome, we determined how far each lesion was located along the axis from anteromedial to posterolateral. To do this, lesions at all dorsal–ventral positions were projected onto a common axial plane (justifiable given the relatively small degree of variation in the dorsal–ventral dimension). Next, a regression line through the lesions was generated and perpendicular lines were drawn from the lesions to the regression line. The distances along the regression line where these lines intersected it were measured and denoted distanceam–pl, 0 being most anteromedial. Thus, a unique number could be used to describe how far from anteromedial to posterolateral each lesion was situated. The second-order term, distanceam–pl2, was calculated for use in the regression analysis described below.
Statistical analysis
Group outcome analysis
The performance of this subgroup of the patients from the original series was analysed for the effect of pallidotomy on the manifestations of parkinsonism. For this purpose, Wilcoxon's sign/rank test was used, comparing the groups at 6 and 12 months with preoperative performance. Bonferoni correction was used for multiple comparisons, and a stringent criterion of P < 0.001 was used to determine significance.
Multiple regression analysis of clinical outcome versus lesion location
Hierarchical multiple regression analyses were used to examine the relationship of lesion location to clinical outcome. In each hierarchical analysis, independent variables were entered in a stepwise manner, in an order determined by logical priority. The amount of the variance in the dependent variable (e.g. postoperative UPDRS score) accounted for by each independent variable was calculated in turn. In this way, the effects of previously entered variables (such as preoperative score) could be controlled for when examining the effects of subsequently entered variables (e.g. lesion location) on outcome measures. The independent variables and the order in which they were entered into the hierarchical multiple regression analyses were as follows.
- (i) Preoperative score: the effect of preoperative score on the postoperative score was evaluated first; this is more effective for evaluating postoperative changes than a percentage change score, since the latter is confounded by the size of the preoperative score.
(ii) Volume: the amount of variance accounted for by the lesion volume, calculated previously (Gross et al., 1999
), was determined next. The likelihood of a lesion ablating a `critical structure' is a combination of its location and size. Since variance in outcome scores will be affected by each of these parameters, both must be accounted for.
(iii) Distanceam–pl: the variance in the outcome scores accounted for by lesion location from anteromedial to posterolateral along the posterior region of GPi was determined next.
At each step in the hierarchical analysis, the increment in the proportion of the variance accounted for by the entered independent variable over that accounted for by all of the previously entered variables was determined; this represents the squared semipartial correlation coefficient (sr2). The significance of this relationship was then ascertained.
The above regression analysis was performed using linear regression, to analyse first-order (linear) relationships between the variables. To allow for the possibility of non-linear relationships between lesion position and outcome measures (e.g. that centrally located lesions may be more or less efficacious than anteromedial or posterolateral lesions), the final step of the multiple regression analysis was performed using quadratic regression. For this, the additional variance accounted for by simultaneously entering both the first-order term (distanceam–pl) and the second-order term (distanceam–pl2) over that accounted for by preoperative score and lesion volume was determined. The variance accounted for by these combined variables is reported.
Order of analyses
To minimize type I errors, statistical analyses were first applied to the total UPDRS score (`off' period) and total score (`on' period) to determine significance. When significant relationships were detected the analysis was extended to the individual motor items that contributed to the total scores to determine their contribution to the overall effect. Only `off' period UPDRS scores were examined, since previous studies have shown effects of pallidotomy mainly on `off' period findings (Lang et al., 1997).
Graphical display of lesion location versus outcome
For ease of graphical display, the percentage change from baseline score is shown as a function of linear distance along the anteromedial-to-posterolateral axis of lesion distribution. Statistical significance was not determined for percentage change scores, however, as described above. Curve-fitting was performed based on the multiple regression analysis: if a linear relationship was observed (i.e. a significant percentage of variance was accounted for by the linear regression with distanceam–pl), then a linear regression line was superimposed on the particular graph; if a non-linear relationship was observed (i.e. a significant percentage of variance was accounted for by the quadratic regression with distanceam–pl combined with distanceam–pl2, but not with distanceam–pl alone), then a quadratic linear regression line was superimposed. The r2 value reflects the fit of the curve to the percentage change data, but is unrelated to the sr2 values reported for the multiple regression analyses.
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Results |
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Overall outcome following pallidotomy
The clinical outcome for the 33 patients studied is shown in Table 1
. There was significant improvement in each of the areas of motor function during the `off' period (akinesia, rigidity, postural instability/gait disorder and tremor), and in `on' period drug-induced dyskinesia, at 6 and 12 months. Contralateral improvements were sustained in akinesia, rigidity, tremor and dyskinesia, whereas ipsilateral improvements were (i) present at 6 and 12 months (dyskinesia), (ii) present at 6 months with deterioration by 12 months (akinesia), (iii) not present at 6 months but statistically significant at 12 months (rigidity), or (iv) not present at either time point (tremor).
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Medication changes were modest in this cohort of patients. The preoperative L-dopa equivalent dose was 1013.79 ± 490.06 mg (mean ± SD) compared with 965.52 ± 427.43 mg at 6 months and 1027.59 ± 527.9 mg at 12 months. For each patient, the postoperative L-dopa equivalent dose was 107.4 ± 52.7% (mean ± SD) of the preoperative dose at 6 months and 116.0 ± 69.5% 12 months after surgery.
Lesion distribution following pallidotomy
Previously, lesion location has been characterized in relation to the anterior commissure in the anterior–posterior dimension, and the third ventricle wall in the medial–lateral dimension (Gross et al., 1999). Lesions were distributed predominantly from anteromedial to posterolateral within the posteroventral region of GPi along an axis parallel to the internal capsule. Little variation in the dorsoventral axis was observed. MRIs of representative patients, each with an anteromedial, central or posterolateral lesion, are shown in Fig. 1. Lesions were located in a nearly normal distribution along a distance of 11.7 mm (normalized to an intercommissural distance of 23 mm) from anteromedial to posterolateral (Fig. 2).
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Relationship of preoperative scores and lesion volumes to clinical outcome
In the first step of the hierarchical multiple regression analysis, the variance in postoperative scores attributable to the preoperative scores was analysed. The preoperative score accounted for a large percentage of the variance in each of the postoperative `off' period scores (9–60%): higher preoperative scores predicted higher postoperative scores (Table 2
). Lesion volume accounted for a very small amount of the variance in each postoperative score (0–12%), and was only rarely statistically significant (Tables 2 and 3). There was a trend for larger lesions to be associated with worse postoperative outcome scores in the `off' period, but better `on' period dyskinesia scores. In all subsequent analyses, the amount of variance accounted for by preoperative score and lesion volume was controlled for.
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Relationship of lesion location to clinical outcome
Total `off' period UPDRS score and lesion location
The relationship between lesion location and total `off' period UPDRS score is shown in Fig. 3
. Linear lesion location along the anteromedial to posterolateral axis (distanceam–pl) accounted for none (0–1%) of the variance in the postoperative total UPDRS scores (Table 2
). However, quadratic regression demonstrated that introducing the second-order term distanceam–pl2 accounted for a significant proportion of the postoperative variance at both 6 and 12 months (14–17%, P < 0.025) (Table 2). This reflects the non-linear relationship between lesion location and outcome (seen graphically in Fig. 3) such that lesions located centrally along the anteromedial to posterolateral axis were associated with better outcome on the UPDRS total score compared with anteromedial or posterolateral lesions.
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UPDRS scores relating to specific motor signs and lesion location
Since the total UPDRS score was significantly related to lesion location, we next examined the relationship between lesion location and specific motor items of the UPDRS. Because the main effects of unilateral pallidotomy are contralateral, we examined contralateral motor signs where possible.
Contralateral akinesia.
As with the total UPDRS score, there was greater improvement in patients with more centrally located lesions than in those with more anteromedial and posterolateral lesions (Fig. 4A). This relationship was only significant at 6 months, at which time the quadratic term accounted for 16% of the outcome variance (P < 0.05), whereas the linear term accounted for 1% of the variance (Table 2).
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Postural instability/gait disturbance.
As in akinesia, a significant non-linear relationship was observed between outcome on postural instability/gait disturbance scores and lesion location (Fig. 4B
and Table 2). At both 6 and 12 months, patients with centrally located lesions had significantly better outcomes (P < 0.025) than the anteromedial and postero- lateral groups. The quadratic term accounted for 10% of the variance at 6 months and 16% at 12 months (Table 2).
Contralateral rigidity.
In contrast to akinesia and postural instability/gait disorder, there was a linear relationship between lesion location and postoperative contralateral rigidity, such that anteromedial and central lesions were more effective than posterolateral lesions (Fig. 4C). This relationship was statistically significant at 12 months, when the linear term (distanceam–pl) accounted for 8% of the outcome variance (P < 0.04) and the quadratic term accounted for only 2% more variance (Table 2). At 6 months there was a trend towards a quadratic relationship (accounting for 6% of the outcome variance), central lesions being more effective.
Contralateral tremor.
Although most patients had improvement in contralateral tremor, posterolateral lesions were slightly more effective than anteromedial lesions at 6 months (Fig. 4D), when linear lesion position accounted for 10% of outcome variance (P < 0.03) (Table 2). By 12 months of follow-up, however, the effect of lesion location had abated.
Drug-induced dyskinesia and lesion location
Anteromedial lesion location was associated with greater improvement in both total (contralateral + ipsilateral + axial) and contralateral postoperative dyskinesia scores in the `on' period (Fig. 5). At 6 and 12 months, linear lesion position accounted for 23% (P < 0.005) and 14% (P < 0.03) of outcome variance in contralateral dyskinesia (Table 2).
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Ipsilateral effects in relation to lesion location
As shown in Table 1
, unilateral pallidotomy was associated with improvements on the ipsilateral side that, although significant, were less robust and shorter-lasting. In most cases, the relationship between lesion location and ipsilateral outcome on individual motor signs mirrored that seen for contralateral effects (Fig. 6 and Table 3). At 6 months, improvement in ipsilateral akinesia was greater with central lesions (P < 0.05). Ipsilateral rigidity was more favourably affected by anteromedial lesions, the effect not being observed until 12 months following surgery (P < 0.03), exactly mirroring the contralateral effects. The weak relationship between tremor and posterolateral lesion location was not observed for ipsilateral tremor (Table 3), and indeed little effect of pallidotomy was seen for ipsilateral tremor irrespective of lesion position (Table 1).
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Interestingly, the relationships of lesion location with ipsilateral and contralateral dyskinesia were markedly different. Whereas anteromedial lesion location was linearly related to improvement in contralateral dyskinesia (Fig. 5
and Table 2), a quadratic relationship was seen for ipsilateral dyskinesia (Fig. 6 and Table 3). At 6 months, 19% of outcome variance was attributable to the quadratic term (P < 0.025) and only 1% to the linear term (compare with contralateral dyskinesia, Table 2). Moreover, the direction of the relationship was opposite to that of the non-linear relationships observed for akinesia and postural instability/gait disturbance. For ipsilateral dyskinesia, centrally located lesions were associated with less improvement and occasional worsening compared with anteromedial and posterolateral lesions (Fig. 6). This inverted non-linear relationship was not observed for ipsilateral outcomes on any other measure. |
Discussion |
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Leksell was the first to observe that posteroventral pallidotomy lesions were associated with better outcomes than the previously performed anterodorsal lesions (Svennilson et al., 1960
). Since this seminal work there has been little further information on the relationship between lesion location and clinical outcome following pallidotomy, which thus remains an important issue. Recent studies characterizing postoperative lesion location with modern neuroimaging techniques have failed to demonstrate a relationship between outcome and location (Burns et al., 1997; Krauss et al., 1997). Samuel et al. (1998) reported a correlation between the most ventral extent of the lesion and improvement in bradykinesia, but did not detect a relationship with other parkinsonian features in 11 patients. In this report, we have used quantified lesion location information and married it to quantitative clinical outcome measures. We were thus able to demonstrate a significant relationship between clinical outcome and lesion location from anteromedial to posterolateral along the posteroventral region of GPi. The influence of lesion location from anteromedial to posterolateral within the posteroventral region of GPi has not been addressed previously.
For total `off' period UPDRS score, akinesia (contra- and ipsilateral) and postural instability/gait disturbance, lesions that were located centrally along the anteromedial-to-posterolateral axis were associated with better outcome scores in comparison with more anteromedial or posterolateral lesions. In contrast, anteromedial and central lesions preferentially improved rigidity (contra- and ipsilateral) and contralateral drug-induced dyskinesia. Greater improvement with posterolateral lesions was noted only for contralateral tremor. Although statistically significant, the sizes of the effects observed were modest. This may be related to the well-known daily variability of parkinsonian signs, or may reflect the influence of other factors in determining clinical outcome following pallidotomy. Such factors, however, have been difficult to identify. The influence of patient age on response to surgery has not been consistently demonstrated (Baron et al., 1996; Kishore et al., 1997; Uitti et al., 1997), but was not a statistically significant factor in the outcomes reported in the present study (data not shown). We and others have shown that the preoperative response to L-dopa is predictive of the response to pallidotomy (Kazumata et al., 1997; Samuel et al., 1997; A. E. Lang, unpublished observations). The response has also been correlated to preoperative measures of lentiform glucose metabolism using [18F]fluorodeoxyglucose PET (Kazumata et al., 1997).
The findings reported here suggest a dissociation in the effects of pallidotomy on different motor signs. Hypokinetic signs, such as bradykinesia and postural stability and gait, were preferentially improved with posteroventral GPi lesions that were centrally located, whereas `hyperkinetic' signs, such as drug-induced dyskinesia and rigidity, were more improved with anteromedial and central lesions. A further dissociation was noted in regard to ipsilateral and contralateral effects of lesions on dyskinesia. For parkinsonian motor signs, ipsilateral and contralateral findings were in general similarly related to lesion location, whereas central lesions that were effective for contralateral dyskinesia were less effective for ipsilateral dyskinesia.
Differential responses of individual motor signs are well-known manifestations of L-dopa therapy of Parkinson's disease, especially in advanced stages, and improvements in parkinsonian signs often go hand-in-hand with exacerbation of dyskinesia. Another type of dissociation has been demonstrated recently in response to surgical therapies. In this case, implantation of deep brain stimulating electrodes enabled the selective stimulation of subregions of the pallidum by activating different electrode contacts (Bejjani et al., 1997; Krack et al., 1998). In both studies, L-dopa-induced dyskinesia was improved by posteroventral stimulation while `on' period (Bejjani et al., 1997; Krack et al., 1998) and/or `off' period (Bejjani et al., 1997) akinesia was adversely affected. In contrast, the opposite effects were found with anterodorsal stimulation (which may have been within the external pallidal segment). In addition, one of the studies demonstrated amelioration of rigidity with anterodorsal stimulation (Bejjani et al., 1997) whereas the other showed benefits for rigidity with the posteroventral electrodes (Krack et al., 1998). There are important differences with the current study that make cross-comparisons difficult. First, the physiological relationship of ablative lesions to blockade accomplished via deep brain stimulation is unknown. Secondly, the trajectories by which deep brain stimulating electrodes are implanted allows comparisons to be made only between posteroventral and anterodorsal locations. In contrast, the consistent placement of our lesions within the posteroventral GPi but at different medial–lateral locations allowed testing along a different axis from that accomplished by deep brain stimulation. Thus, the data generated by each of these techniques is complementary but not directly comparable. Nevertheless, we have also observed a dissociation between dyskinesia and akinesia, in the case of anteromedially located lesions, where dyskinesia is markedly ameliorated while akinesia is less responsive. In contrast to pallidal stimulation studies (Bejjani et al., 1997), however, none of the patients with lesions in this region had a significant worsening of `off' period akinesia. We also did not observe a significant relationship between lesion location and `on' period akinesia (data not shown), as was observed with deep brain stimulation (Bejjani et al., 1997).
The finding that lesions in different regions of GPi are associated with effects on distinct motor signs of Parkinson's disease is in keeping with the current understanding of corticobasal ganglia–thalamocortical circuitry (Parent and Hazrati, 1995). Anatomical studies have revealed that these circuits, including the motor pathways, are organized into multiple segregated but parallel loops (Hoover and Strick, 1993). The motor loops have been shown to occupy the posterior two-thirds of the internal segment of the globus pallidus, over its entire medial to lateral extent (Hoover and Strick, 1993; Middleton and Strick, 1997). Moreover, physiological studies in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)–treated primates have demonstrated sensorimotor responses of recorded units located anteromedially, centrally and posterolaterally within the posteroventral GPi (Wichmann et al., 1994). However, specific circuits originating in the primary motor cortex, premotor cortex, and supplementary motor cortex have defined anatomical locations within GPi (Middleton and Strick, 1997). Hence, it is predictable that lesions that are located in different regions of GPi would have different effects related to selective interruption of one or more of the multiple output channels. Preliminary work in primates has indeed indicated differential magnitudes of antiparkinsonian effects with infusion of the GABA agonist muscimol in different subregions of the sensorimotor GPi (Wichmann et al., 1994). It is tempting to hypothesize that specific manifestations of Parkinson's disease are mediated by pathophysiological imbalances within circuits involving discrete cortical motor areas, and that amelioration of specific signs is related to interruption of the corresponding circuit. It is not possible at this time, however, to explain precisely the mechanism by which specific features of Parkinson's disease are affected by lesions in different locations. The response of particular motor signs to intraoperative local administration of pharmacological agents at different sites may be informative. Alternatively, functional imaging studies of patients following pallidal procedures may reveal distinct patterns of activation by lesions/electrical stimulation in different locations.
Consideration must also be given to non-GPi structures that may have been lesioned, such as the external segment of the globus pallidus (GPe) or projection tracts such as the ansa lenticularis and lenticular fasciculus. The role played by GPe in the pathophysiology of Parkinson's disease is uncertain (Chesselet and Delfs, 1996; Parent and Cicchetti, 1998). Whether GPe is hypoactive or not in Parkinson's disease, a matter that has not been resolved, its ablation would be predicted to either worsen or be ineffective in treating parkinsonism as a result of disinhibition of the subthalamic nucleus. Indeed, excitotoxic lesions of GPe in MPTP-treated subhuman primates have been shown to worsen parkinsonian signs and exacerbate drug-induced dyskinesia (Blanchet et al., 1994), and pallidotomy lesions involving GPe in Parkinson's disease patients have been observed to be ineffective (Krauss et al., 1997). It is possible that posterolateral GPi lesions may encroach on GPe, due to the narrowness of GPi and the proximity of the external segment in this region. Thus, involvement of GPe might partially explain the decreased effectiveness of posterolateral lesions on total UPDRS score, akinesia, rigidity, postural instability/gait disturbance and dyskinesia. However, tremor was more effectively treated by posterolateral lesions than by central and anteromedial lesions. Furthermore, dyskinesia, while more improved by anteromedial lesions, was also moderately improved by posterolateral lesions, in contrast to the findings in primates with GPe lesions (Blanchet et al., 1994). Nevertheless, we cannot entirely rule out the possibility that the generally poorer performance in the posterolateral lesion group was related to encroachment of the lesions on GPe. We have noticed, as have others (DeLong et al., 1998; Krauss et al., 1997), that pallidotomy lesions often encroach on GPe. It is difficult to discern reliably the internal medullary lamina separating GPe from GPi on postoperative MRI scans, especially for those performed in the presence of oedema. However, the incidence of GPe involvement does not seem to be greater for posterolateral compared with central or anteromedial lesions (R. E. Gross, unpublished observations).
Finally, the surgical implications of the findings reported here must be considered. Overall, the most beneficial target was the central region of the posteroventral GPi. However, anteromedial location was associated with improved outcomes for rigidity and dyskinesia. It is conceivable that lesions might be directed at specific targets for specific parkinsonian signs. Consideration of placing multiple small lesions, however, may be reasonable. Moreover, avoidance of the posterolateral region should be considered, because of the decreased effectiveness of lesions in this region on akinesia, rigidity, postural instability/gait disturbance and dyskinesia in comparison with more centrally located lesions. This type of selective targeting will require either (i) advances in the medial–lateral information generated during microelectrode mapping, and/or (ii) careful consideration of inter-individual anatomical variations, especially as regards the width of the third ventricle.
Conclusions
Following microelectrode-guided GPi pallidotomy, lesion location was related to improvement in specific clinical manifestations of Parkinson's disease. Lesions located centrally within the anteromedial to posterolateral extent of the posteroventral internal pallidum were associated with improvements in total UPDRS during the `off' period, as well as in akinesia and postural instability/gait disorder. Anteromedial lesions were more beneficial for rigidity and drug-induced dyskinesia. Posterolateral lesion position was related to improvement in contralateral tremor scores. Specific targeting or (more likely) targeting of lesions to more than one anteromedial to posterolateral location within the posteroventral GPi might be considered in the future for advanced-stage Parkinson's disease.
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Acknowledgments |
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This study was supported by Parkinson's Foundation of Canada grants and a Center of Excellence grant from the National Parkinson Foundation. A.M.L. is a Medical Research Council of Canada clinical scientist.
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Received June 1, 1998. Revised September 30, 1998. Accepted October 23, 1998.
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