Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson's disease.
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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. (+info)
Anticonvulsant-induced dyskinesias: a comparison with dyskinesias induced by neuroleptics.
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Anticonvulsants cause dyskinesias more commonly than has been appreciated. Diphenylhydantoin (DPH), carbamazepine, primidone, and phenobarbitone may cause asterixis. DPH, but not other anticonvulsants, may cause orofacial dyskinesias, limb chorea, and dystonia in intoxicated patients. These dyskinesias are similar to those caused by neuroleptic drugs and may be related to dopamine antagonistic properties possessed by DPH. (+info)
SR146131: a new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. II. In vivo pharmacological characterization.
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SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK1) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED50 of 66 and 2.7 micrograms/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3-10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 microgram/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans. (+info)
From off-period dystonia to peak-dose chorea. The clinical spectrum of varying subthalamic nucleus activity.
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The effect of chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) on levodopa-induced dyskinaesias was investigated in eight patients with fluctuating Parkinson's disease complicated by functionally disabling off-period dystonia. All of the patients also had severe diphasic and peak-dose chorea, so that it was possible to study the effect of high-frequency stimulation on the different types of levodopa-induced dyskinaesias. Off-period fixed dystonia was reduced by 90% and off-period pain by 66%. After acute levodopa challenge, high-frequency stimulation of the STN reduced diphasic mobile dystonia by 50% and peak-dose choreic dyskinaesias by 30%. The effect of bilateral high-frequency stimulation of the STN on the Unified Parkinson's Disease Rating Scale motor score had the same magnitude as the preoperative effect of levodopa. This allowed the levodopa dose to be reduced by 47%. The combination of reduced medication and continuous high-frequency stimulation of the STN reduced the duration of on-period diphasic and peak-dose dyskinaesias by 52% and the intensity by 68%. Acute high-frequency stimulation of the STN mimics an acute levodopa challenge, concerning both parkinsonism and dyskinaesias, and suppresses off-period dystonia. Increasing the voltage can induce repetitive dystonic dyskinaesias, mimicking diphasic levodopa-induced dyskinaesias. A further increase in voltage leads to a shift from a diphasic-pattern dystonia to a peak-dose pattern choreodystonia. Chronic high-frequency stimulation of the STN also mimics the benefit of levodopa on parkinsonism and improves all kinds of levodopa-induced dyskinaesias to varying degrees. Off-period dystonia, associated with neuronal hyperactivity in the STN is directly affected by stimulation and disappears immediately. The effect of chronic high-frequency stimulation of the STN on diphasic and peak-dose dyskinaesias is more complex and is related directly to the functional inhibition of the STN and indirectly to the replacement of the pulsatile dopaminergic stimulation by continuous functional inhibition of the STN. Chronic high-frequency stimulation of the STN allows a very gradual increase in stimulation parameters with increasing beneficial effect on parkinsonism while reducing the threshold for the elicitation of stimulation-induced dyskinaesias. In parallel with improvement of parkinsonism, the levodopa dose can be gradually decreased. As diphasic dystonic dyskinaesias are improved to a greater degree than peak-dose dyskinaesias, both direct and indirect mechanisms may be involved. Peak-dose choreatic dyskinaesias, associated with little evidence of parkinsonism and thus with low neuronal activity in the STN, are improved, mostly indirectly. Fixed off-period dystonia, mobile diphasic dystonia and peak-dose choreodystonia seem to represent a continuous clinical spectrum reflecting a continuous spectrum of underlying activity patterns of STN neurons. (+info)
Bromocriptine in Parkinsonism: long-term treatment, dose response, and comparison with levodopa.
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Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature. (+info)
Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.
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In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD. (+info)
Improvement of levodopa induced dyskinesias by thalamic deep brain stimulation is related to slight variation in electrode placement: possible involvement of the centre median and parafascicularis complex.
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OBJECTIVE: To define the reason why two teams using the same procedure and the same target for deep brain stimulation (DBS) obtained different results on levodopa induced dyskinesias, whereas in both, parkinsonian tremor was improved or totally suppressed. METHODS: Deep brain stimulation can replace lesions in the surgical treatment of abnormal movements. After 10 years of experience with DBS in Parkinson's disease, a comparison of results between the teams of Lille (A) and Grenoble (B) was carried out, for as long as they used intraoperative ventriculography. Both teams aimed at the same target, the ventralis intermedius nucleus of the thalamus (VIM), but team A found a clear improvement of choreic peak dose dyskinesias, whereas team B did not consistently. Therefore all teleradioanatomical data of both teams were re-examined and compared with the therapeutic effects. Location of 99 monopolar electrodes of thalamic stimulation applied to treat parkinsonian tremor has been retrospectively measured (team A included 21 patients, 22 electrodes; team B included 52 patients, 74 electrodes). Peak dose levodopa dyskinesias were suppressed by DBS in all nine patients of team A, four of which were severely disabling. Only eight out of 32 patients from team B experienced a moderate (four) or clear (four) improvement of dyskinesias, whereas in the remaining 24 patients, dyskinesias were unchanged with stimulation. RESULTS: The mean centre of team A's electrodes was on average 2.9 mm deeper, more posterior and medial than team B's (t=8.05; p<0.0001). This does not correspond to the coordinates of the VIM, but seems to be closer to those of the centre median and parafascicularis complex (CM-Pf), according to stereotaxic atlases. Considering only the dyskinetic patients, significant differences were found in the electrode position according to the therapeutic effects on levodopa dyskinesias, but they were not related to the team membership. Improvement in levodopa dyskinesias was significantly associated with deeper and more medial placement of electrodes. CONCLUSION: The retrospective analysis of patients treated with DBS using comparable methodologies provides important information concerning electrode position and therapeutic outcome. The position of the electrode is related to the therapeutic effects of DBS. The results support the hypothesis that patients experiencing an improvement of dyskinesias under DBS are actually stimulated in a structure which is more posterior, more internal, and deeper than the VIM, very close to the CM-Pf. These results are consistent with neuroanatomical and neurophysiological data showing that the CM-Pf is included in the motor circuits of the basal ganglia system and receives an important input from the internal pallidum. This suggests that the CM-Pf could be involved specifically in the pathophysiology of levodopa peak dose dyskinesias. (+info)
Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys.
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The antiparkinsonian and antidyskinetic profile of two N-methyl-D-aspartate (NMDA) receptor antagonists, a competitive antagonist, (R)-4-oxo-5-phosphononorvaline (MDL 100,453), and a novel noncompetitive allosteric site antagonist, 4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piper idi ne (Co 101244/PD 174494), was assessed in six levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine-lesioned parkinsonian monkeys. The effects on motor function of these two drugs, alone and in combination with levodopa, were then correlated with NMDA subtype selectivity and apparent affinity for four diheteromeric NMDA receptor subunit combinations expressed in Xenopus oocytes. MDL 100, 453 (300 mg/kg s.c.) by itself increased global motor activity (p =. 0005 versus vehicle) and administered 15 min after a low dose of levodopa/benserazide s.c., MDL 100,453 (50, 300 mg/kg s.c.) showed dose-dependent potentiation of antiparkinsonian responses and also produced dyskinesias. Following injection of a fully effective dose of levodopa, MDL 100,453 (300 mg/kg s.c.) also produced a 25% increase in mean dyskinesia score (p =.04). In contrast, Co 101244 did not change motor activity by itself and only showed a tendency to potentiate the antiparkinsonian response when given in combination with a low dose of levodopa, which did not attain statistical significance. However, with a high dose of levodopa, Co 101244 (0.1, 1 mg/kg s.c.) displayed antidyskinetic effects (67 and 71% reduction, respectively) while sparing levodopa motor benefit. In vitro, MDL 100,453 was an NMDA glutamate-site antagonist, with approximately 5- to 10-fold selectivity for the NR1A/NR2A subtype combination (K(b) = 0.6 microM) versus NR1A in combination with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed approximately 10,000-fold selectivity for the NR1A/NR2B (IC(50) = 0.026 microM) versus the other three subunit combinations tested. Taken together, the data suggest that the NR2 subunit selectivity profile of NMDA receptor antagonists can play an important role in predicting behavioral outcome and offer more evidence that NR2B-selective NMDA receptor antagonists may be useful agents in the treatment of Parkinson's disease. (+info)