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Levodopa has long been the standard of care for Parkinson disease (PD); however, the eventual onset of motor fluctuations and levodopa-induced dyskinesia (LID) complicates its utility in advanced PD. Current neurosurgical interventions remain some of the best options for LID. Deep brain stimulation (DBS) is currently the procedure of choice for patients with advanced PD, patients refractory to medical management, and patients with motor complications from levodopa therapy. Significant progress has been achieved in recent years, however, as newer techniques are making their way through preclinical and clinical studies. Use of interventional magnetic resonance imaging (iMRI) and a skull-mounted aiming device to guide electrode placement has improved accuracy in recent DBS studies. Adaptive "closed-loop" DBS represents another exciting advancement in the field, in which real-time feedback allows dynamic modulation of the stimulation delivered to the basal ganglia. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel approach to creating precise lesioning in the brain that has shown promising results in preliminary studies for various movement disorders, including dyskinesias, and may transform the neuroablation field. Transcranial magnetic stimulation, which can induce local and distant effects in cortical and subcortical areas, has shown efficacy in managing certain PD and LID symptoms in early studies. Finally, direct stimulation of the motor cortex and the cerebellum has shown therapeutic effects in PD and LID patients in certain studies. Taken together, many of these new techniques have shown great promise in early studies and may eventually be preferred treatment options for LID patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim - to evaluate the efficacy of stereotactic pallidotomy and bilateral deep brain stimulation (DBS) of subthalamic nuclei (STN) in patients with Parkinson disease with motor fluctuations and levodopa-induced dyskinesias. 36 patients (age range 31-73 years (mean age 56.2±3.2 years) were enrolled in study. Mean duration of PD was 9.8±1.1years. All patients used levodopa-drugs, mean levodopa dose was 1075±304.1 mg/day. Mean duration of motor fluctuations and levodopa-induced dyskinesias before surgery was 2,18±0,8 years. Patients = were divided into 2 groups - 22 patients underwent stereotactic unilateral pallidotomy and 14 patients underwent bilateral DBS (STN target). Neurological and psychological status assessed before and after treatment by: UPDRS II, Hoehn and Yahr scale, Schwab and England scale, MMSE, Beck's Depression Inventory, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale and PDQ-39. Surgery performed on CRW stereotactic system. Postoperative follow-upranged from 1 to 8.5 years (mean 4.1±1.1 years). Regression of tremor, rigidity, bradykinesia and levodopa-induced dyskinesia observed in most patients after stereotactic interventions. The best results were achieved in patients who underwent DBS. In this group UPDRS II score improved by 74% in ON period and by 63% in OFF period. After pallidotomy UPDRS II score improved by 55% in ON period and by 47% in OFF period. Levodopa-induced dyskinesia stopped in 21 from 22 (95.5%) patients who had it before surgery after unilateral pallidotomy and in 11 from 12 (91.7%) patients after DBS. Surgical complications occurred in 3 (13.6%) case after pallidotomy, which induced transient neurological deficit. Our results demonstrate that both stereotactic interventions - pallidotomy and DBS are effective and safe methods of treatment of PD with levodopa-induced dyskinesias and motor fluctuations. Both surgeries improve overall motor function, increased patient's mobility and improve quality of life.

Aim: To evaluate the efficacy of deep brain stimulation in the subthalamic nucleus (DBS STN) in patients with Parkinson's disease (PD) using different methods of targeting according to the dynamics of motor symptoms of PD., Material and Methods: The study involved 90 patients treated with DBS STN. In 30 cases intraoperative microelectrode recording (MER) was used. MER was not performed in 30 patients of the comparison group. The control group consisted of 30 patients with PD who received conservative treatment. Hoehn and Yahr scale, Tinetti Balance and Mobility Scale (TBMS), Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Quality of Life-39 Scoring System (РDQ-39), Schwab & England ADL Scale were used. Levodopa equivalent daily dose (LEDD, 2010) was calculated for each patient., Results and Conclusion: The effect of DBS STN using intraoperative microelectrode recording on the main motor symptoms, motor complications, walking as well as indicators of quality of life and daily activities was shown. In both DBS STN groups, there was a significant reduction in the LEDD and marked improvement of the control of motor symptoms of PD. A significant reduction in the severity of motor fluctuations (50%) and drug-induced dyskinesia (51%) was observed. Quality of life and daily activity in off-medication condition were significantly improved in both DBS STN groups of patients, irrespective of the method of target planning (75-100%), compared with the control group.

Objective: to determine the efficacy of unilateral posteroventral pallidotomy (PVP) in the treatment of drug-induced dyskinesia (DID) in Parkinson's disease (PD)., Material and Methods: We analyzed surgical treatment of 14 patients with PD complicated by DID who underwent unilateral PVP at the Research Center of Neurology in the period between 2012 and 2015. The clinical type of DID was mainly represented by peak-dose choreoathetoid dyskinesia, more pronounced in the distal limbs, and predominantly unilateral. The severity of drug-induced dyskinesia was assessed on the UPDRS scale (part IV-A) before surgery and at 1 week and 6 months after surgery., Results: One week after pallidotomy, all of the 14 patients had a regression of contralateral dyskinesia by 68.3±9.7%; 50% of patients had a regression of ipsilateral dyskinesias by 43%, on average. In 50% of cases, the dose of levodopa was reduced by 15%, on average. On examination at 6 months after surgery, regression of contralateral dyskinesia was 55.7±8.8%, and the severity of ipsilateral DID returned to the preoperative level. The use of pallidotomy significantly improved the indicators of daily activity and quality of life of patients. There were no significant postoperative complications. Three patients had mild speech disorders in the form of dysarthria, which regressed 2-3 weeks after surgery.

Object: Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys., Methods: The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys., Results: The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTP-induced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor-specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor-specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP., Conclusions: These results implicate glutamate receptors in the previously observed benefits of unilateral subthalamotomy to improve motor control.

Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson's disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6-8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.

Dyskinesia seen in the off-state, referred as graft-induced dyskinesia (GID), has emerged as a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. Although the mechanism underlying the appearance of GID is unknown, in a recent clinical study the partial 5-HT(1A) agonist buspirone was found to markedly reduce GID in three grafted patients, who showed significant serotonin (5-HT) hyperinnervation in the grafted striatum in positron emission tomography scanning (Politis et al., 2010, 2011). Prompted by these findings, this study was performed to investigate the involvement of serotonin neurons in the appearance of GID in the rat 6-hydroxydopamine model. L-DOPA-primed rats received transplants of DA neurons only, DA plus 5-HT neurons or 5-HT neurons only into the lesioned striatum. In DA cell-grafted rats, with or without 5-HT neurons, but not in 5-HT grafts, GID was observed consistently after administration of amphetamine (1.5mg/kg, i.p.) indicating that grafted DA neurons are required to induce GID. Strikingly, a low dose of buspirone produced a complete suppression of GID. In addition, activation of 5-HT(1A) and 5-HT(1B) receptors by 8-OH-DPAT and CP 94253, known to inhibit the activity of 5-HT neurons, significantly reduced GID, whereas induction of neurotransmitter release by fenfluramine administration significantly increased GID, indicating an involvement of the 5-HT system in the modulation of GID. To investigate the involvement of the host 5-HT system in GID, the endogenous 5-HT terminals were removed by intracerebral injection of 5,7-dihydroxytryptamine, but this treatment did not affect GID expression. However, 5-HT terminal destruction suppressed the anti-GID effect of 5-HT(1A) and 5-HT(1B) agonists, demonstrating that the 5-HT(1) agonist combination exerted its anti-GID effect through the activation of pre-synaptic host-derived receptors. By contrast, removal of the host 5-HT innervation or pre-treatment with a 5-HT(1A) antagonist did not abolish the anti-GID effect of buspirone, showing that its effect is independent from activation of either pre- or post-synaptic 5-HT(1A) receptors. Since buspirone is known to also act as a DA D(2) receptor antagonist, the selective D(2) receptor antagonist eticlopride was administered to test whether blockade of D(2) receptors could account for the anti-dyskinetic effect of buspirone. In fact, eticlopride produced complete suppression of GID in grafted animals already at very low dose. Together, these results point to a critical role of both 5-HT(1) and D(2) receptors in the modulation of GID, and suggest that 5-HT neurons exert a modulatory role in the development of this side effect of neuronal transplantation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The transplantation of dopamine-rich tissue into the putamen of patients with Parkinson's disease shows much potential for use as a therapeutic strategy. However, a number of grafted individuals subsequently developed a set of abnormal involuntary movements (AIMs), unrelated to the dyskinesia caused by L-DOPA treatment, which have been termed graft-induced dyskinesia. Given the small number of patients, pre-clinical modeling of graft-induced dyskinesia in animal models will be critical to determine the underlying mechanisms and amelioration potential of this technique. Here we show that abnormal involuntary movements of the limbs, trunk and face can be observed in transplanted hemi-parkinsonian mice following amphetamine administration, similar to those previously described to model graft-induced dyskinesias in rats. C57Bl6 and CD1 mice were first rendered hemi-parkinsonian with 6-hydroxydopamine, treated with L-DOPA for 21 days until dyskinetic, and then transplanted with a single cell suspension of embryonic ventral mesencephalon (VM E12.5) tissue from corresponding strains into the denervated striatum. At 16 weeks post-transplantation, a single injection of amphetamine-elicited dyskinesia in a subgroup of mice of both strains, behavioural pattern not observed pre-transplantation. The number of surviving dopaminergic cells in the graft did not differ between those that developed AIMs and those that did not. The movements were phenotypically comparable to those seen in the rat model and parallels can be drawn to the human form of the movements, although the mouse model maybe less reproducible than the rat equivalent. This mouse model will facilitate assessment of graft-induced dyskinesia with mouse-derived stem cell lines and exploration of mechanisms using transgenic mice in future studies.

Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.

Many patients treated chronically with l-dopa for Parkinson disease (PD) become functionally disabled by l-dopa-induced dyskinesias (LID). Evolved from early empirical procedures, modern stereotactic surgical lesioning techniques and deep brain stimulation (DBS) can effectively treat LID while simultaneously improving the cardinal motor symptoms of PD. Here we review the common surgical targets used to treat LID, and compare their relative efficacy. We explain the anti-dyskinetic action of surgery at each of these targets based on evolving models of basal ganglia function. Finally, we discuss the appropriate selection of patients with LID for surgery and address relevant technical and management issues in these patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose of Review: We review recent experiments conducted using embryonic tissue and stem cell transplants in experimental models of Parkinson's disease. We also highlight the challenges which remain to be met in order for cell therapy to become clinically effective and safe., Recent Findings: The outcome of previous clinical transplantation trials was variable in terms of motor recovery. We discuss whether transplants can mitigate L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias and consider the risk factors which predispose to graft-induced dyskinesias. In addition, we introduce Transeuro, a new European Union-funded multicenter consortium which plans to perform transplantation trials.Stem cells have emerged as an alternative source for the generation of dopaminergic precursors. We briefly outline progress made in the use of human embryonic stem cells and focus predominantly on the emerging field of induced pluripotency. We conclude by introducing the exciting and novel method of direct reprogramming which involves the conversion of fibroblasts to neurons without inducing a pluripotent state., Summary: The area of cell transplantation has been revitalized by the identification of parameters which predispose patients to graft-induced dyskinesias and by the emergence of novel methods of generating dopaminergic neurons. Hopefully, the Transeuro clinical trials will give further impetus and act as a stepping stone to future trials employing stem-cell-derived neurons.

Unilateral pallidotomy has been effectively used to treat parkinsonism and reduce levodopa induced dyskinesia (LID). We sought to determine the long-term effects of pallidotomy on LID in 10 patients who had initial benefit from pallidotomy but went on to require DBS surgery for symptom progression. The Dyskinesia Rating Scale (DRS) was used to rate and quantify LID in a blinded fashion. Though sample size was small, there was a trend towards a reduction in LID lasting up to 12 years suggesting that posteroventral pallidotomy may provide sustained benefit in reducing LID., ((c) 2010 Movement Disorder Society.)

Transplantation of embryonic dopaminergic neurones has shown promise for the treatment of Parkinson's disease (PD), but this approach is limited by the poor survival of the transplanted cells. Exogenous dopaminergic neurotrophic factors such as growth/differentiation factor 5 (GDF5) have been found to enhance the survival of transplanted dopaminergic neurones. However, this approach is limited by the rapid degradation of such factors in vivo; thus, methods for long-term delivery of these factors are under investigation. The present study shows, using optimised lipid-mediated transfection procedures, that overexpression of GDF5 significantly improves the survival of dopaminergic neurones in cultures of embryonic day (E) 13 rat ventral mesencephalon (VM) and protects them against 6-hydroxydopamine (6-OHDA)-induced toxicity. In another experiment, E13 VM cells were transfected with GDF5 after 1 day in vitro (DIV), then transplanted into 6-OHDA-lesioned adult rat striata after 2 DIV. The survival of these E13 VM dopaminergic neurones after transfection and transplantation was as least as high as that of freshly dissected E14 VM dopaminergic neurones, demonstrating that transfection was not detrimental to these cells. Furthermore, GDF5-overexpressing E13 VM transplants significantly reduced amphetamine-induced rotational asymmetry in the lesioned rats. This study shows that lipid-mediated transfection in vitro prior to transplantation is a valid approach for the introduction of neurotrophic proteins such as GDF5, as well as lending further support to the potential use of GDF5 in neuroprotective therapy for PD.

Bilateral pallidotomy was performed in a schizophrenic patient with severe jaw-opening dystonia developed after chronic neuroleptic treatment. The dystonia led to sustained mandibular joint dislocation, and tracheotomy was performed after suffocation. The jaw-opening dystonia disappeared immediately following pallidotomy; the tracheotomy was closed, and he regained eating and speech ability. Analysis of the neuronal firing of the globus pallidus revealed low neuronal firing rates in the internal pallidum (GPi) and an irregular burst pattern of the GPi cells compared to those in Parkinson's disease. These results suggest that pallidotomy is a treatment option for tardive jaw-opening dystonia and that dystonia of this type is driven by abnormal neural activities in the GPi., ((c) 2010 S. Karger AG, Basel.)

The motor complications associated with levodopa therapy, namely, fluctuations in motor response and dyskinesias, occur in the majority of Parkinson's disease patients. These complications can impair a patient's quality of life and even cause pronounced disability. "Off" states that result in freezing of gait and falling are disabling for many patients. Dyskinesias most commonly occur at peak dose and typically alternate with the wearing-off state. Once these problems appear, they usually persist, and the physician needs to make continual adjustments in medications to minimize these problems. Medical treatments should be attempted before treatments such as deep brain stimulation are considered because of the potential adverse effects that are associated with surgery. The timing of surgery, however, is also important because younger patients and less advanced patients tend to have a better outcome. There is thus a need for experienced and knowledgeable physicians and surgeons who are able to handle these motor complications. This review discusses available medications and surgical approaches, and their outcomes.

Objective: To assess the impact of different surgical targets and techniques, such as ablation and deep brain stimulation, to treat patients with L-dopa-induced dyskinesia (LID), a major therapeutic complication of Parkinson's disease., Methods: This review analyzes the effects of early surgical procedures to treat hyperkinesia and the current methods and targets used to combat LID in Parkinson's disease, which are mainly thalamotomy, pallidotomy, and deep brain stimulation of the globus pallidus internus and the subthalamic nucleus., Results: Available information indicates that surgery of the globus pallidus internus and thalamus (the pallidal receiving area) and of the subthalamic nucleus has a pronounced antidyskinetic effect. This effect is associated with a concomitant improvement in the parkinsonian ("off"-medication) state. Although it is more profound with pallidal and subthalamic surgery, such an effect can also be observed to some extent with thalamic surgery. The latter is attributable to the fact that surgery of the ventralis intermedius is primarily effective for treating tremor. An integral pallidothalamic pathway is needed for dyskinesia to be expressed. Thus, LID is less frequent after subthalamotomy or deep brain stimulation of the subthalamic nucleus through a functional effect mediated by the physiological normalization of the motor system and by an indirect effect associated with a reduction in the daily dose of L-dopa., Conclusion: Surgery is the only treatment available for Parkinson's disease that can predictably improve both the parkinsonian motor syndrome and LID. The exact mechanisms involved in these effects are not well understood. Pallidal and thalamic surgery affecting pallidal relays reduce LID frequency by disrupting the pallidothalamic circuit, probably eliminating the neuronal activity associated with dyskinesia. Alternatively, the antidyskinetic effect of subthalamic nucleus surgery may in part be attributable to a reduction in the L-dopa dose as well as to the stabilization of the basal ganglia circuits after the surgical procedure.

Altered glutamatergic neurotransmission is central to the expression of Parkinson's disease (PD) symptoms and may underlie l-DOPA-induced dyskinesias. Drugs acting on glutamate metabotropic receptors (mGluR) of group I can modulate subthalamic nucleus (STN) overactivity, which plays a pivotal role in these phenomena, and may counteract dyskinesias. To address these issues, we investigated the effects of a 3-week treatment with mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), or of a subthalamic lesion, on abnormal involuntary movements (AIMs) and associated striatal expression of transcription factor FosB/Delta FosB caused by chronic l-DOPA administration, in rats with a nigrostriatal lesion. MPEP virtually abolished AIMs and reduced, dramatically, striatal expression of FosB/Delta FosB. Reduced FosB/Delta FosB expression, coupled with nonsignificant reduction of AIMs, was also observed in STN-lesioned rats. Our data confirm the role of glutamatergic neurotransmission in the pathogenesis of dyskinesias and the potential of mGluR5 antagonists in the treatment of l-DOPA-induced dyskinesias.

Deep brain stimulation (DBS) can be remarkably effective in treating movement disorders such as Parkinson's disease, dystonia, and essential tremor. Yet these effects remain essentially unexplained, even paradoxical. Equally challenging is the fact that DBS of motor targets in the basal ganglia appears to reverse abnormalities of movement without any obvious deleterious effects on remaining aspects of movement. Here, we explore the extent to which the noisy signal hypothesis might help solve some of these apparent paradoxes. Essentially the hypothesis, first tentatively advanced by Marsden and Obeso (1994), suggests that disease leads to a pattern of basal ganglia activity that disrupts local and distant function and that surgery acts to suppress or override this noisy signal. Critical to the success this theory is that different disease phenotypes are associated with different patterns of noisy signal, and we survey the evidence to support this contention, with specific emphasis on different types of pathological synchronization. However, just as DBS may suppress or override noisy signals in the basal ganglia, it must equally antagonize any remaining physiological functioning in these key motor structures. We argue that the latter effect of DBS becomes manifest when baseline motor performance is relatively preserved, i.e., when pathological activity is limited. Under these circumstances, the deleterious effects of DBS are no longer obscured by its therapeutic actions in suppressing noisy signals. Whether true, oversimplified or simply incorrect, the noisy signal hypothesis has served to focus attention on the detailed character of basal ganglia discharge and its variation with disease and therapy., (2007 Movement Disorder Society)

Deep brain stimulation (DBS) has the unique characteristic to very precisely target brain structures being part of functional brain circuits in order to reversibly modulate their function. It is an established adjunctive treatment of advanced Parkinson's disease and has virtually replaced ablative techniques in this indication. Several cases have been published relating effectiveness in neuroleptics-induced tardive dyskinesia. It is also investigated as a potential treatment of mood disorders. We report on the case of a 62 years old female suffering from a treatment refractory major depressive episode with comorbid neuroleptic-induced tardive dyskinesia. She was implanted a deep brain stimulation treatment system bilaterally in the globus pallidus internus and stimulated for 18 months. As well the dyskinesia as also the symptoms of depression improved substantially as measured by the Hamilton Rating Scale of Depression (HRSD) score and the Burke-Fahn-Marsden-Dystonia-Rating-Scale (BFMDRS) score. Scores dropped for HRSD from 26 at baseline preoperatively to 13 after 18 months; and for BFMDRS from 27 to 17.5. This case illustrates the potential of deep brain stimulation as a technique to be investigated in the treatment of severe and disabling psychiatric and movement disorders. DBS at different intracerebral targets being actually investigated for major depression might have similar antidepressant properties because they interact with the same cortico-basal ganglia-thalamocortical network found to be dysfunctional in major depression.

Clinical trials in patients with Parkinson's disease have shown that transplants of fetal mesencephalic dopamine neurons can form a new functional innervation of the host striatum, but the clinical benefits have been highly variable: some patients have shown substantial recovery in motor function, whereas others have shown no improvement and even a worsening in the 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinetic side effects. Differences in the composition of the grafted cell preparation may contribute to these discrepancies. In particular, the number of serotonin neurons contained in the graft can vary greatly depending on the dissection of the fetal tissue. Importantly, serotonin neurons have the ability to store and release dopamine, formed from exogenously administered L-DOPA. Here, we have evaluated the effect of transplants containing serotonin neurons, or a mixture of dopamine and serotonin neurons, on L-DOPA-induced dyskinesias in 6-hydroxydopamine-lesioned animals. As expected, dopamine neuron-rich grafts induced functional recovery, accompanied by a 60% reduction in L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks. Rats with serotonin-rich grafts with few dopamine neurons, in contrast, showed a progressive worsening of their L-DOPA-induced dyskinesias over time, and no functional improvement. The antidyskinetic effect of dopamine-rich grafts was independent of the number of serotonin neurons present. We conclude that serotonin neurons in the grafts are likely to have a detrimental effect on L-DOPA-induced dyskinesias in cases in which the grafts contain no or few dopamine neurons.

Intrastriatal transplantation of fetal ventral mesencephalon (VM) tissue provides the potential to alleviate motor symptoms of Parkinson's disease (PD) and levodopa-induced dyskinesia (LID). However, the degree of recovery varies among individuals with an incidence of "off-phase", graft-induced dyskinesia (GID) in some patients. We hypothesised that this variability is due to the heterogeneous nature of dopaminergic neurons in the transplant. We therefore investigated this in the unilateral 6-hydroxydopamine-lesioned rat model of PD. These animals were primed to develop LID and then transplanted with fetal VM into the caudal aspects of the striatum. No GID was observed but in a significant number of animals the transplants ameliorated LID. There was a correlation between the degree of behavioural and LID recovery with the number of A9 dopaminergic neurons in the transplant, based on their expression of a G-protein-coupled inward rectifying current potassium channel (Girk2). Furthermore, we showed that LID development is related to an abnormal expression profile of cyclin-dependent kinase 5 (Cdk5) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the striatum and that intrastriatal VM transplants normalised both Cdk5 expression and DARPP-32 phosphorylation in animals exhibiting functional improvement. These results suggest that an A9 dopaminergic neuron-enriched transplant may be the key to an effective PD cell replacement therapy through normalisation of the altered striatal expression of Cdk5/DARPP-32.

Context: Tardive dyskinesia (TD) is a common and potentially disabling disorder induced by use of antipsychotic drugs for which medical treatment often gives disappointing results., Objective: To assess the efficacy of bilateral deep brain stimulation of the internal part of the globus pallidus to treat severe TD., Design: Prospective phase 2 multicenter study., Setting: Six French university hospitals. Patients Patients with severe TD refractory to medical treatment were studied to evaluate the severity of abnormal involuntary movements before and after 6 months of bilateral globus pallidus deep brain stimulation. A 2-step open Fleming procedure was used to avoid unnecessary accrual of patients. A successful outcome was defined as a decrease of more than 40% in the main outcome measure at 6 months. The early stopping rule was invoked if the number of successful outcomes in 10 patients was fewer than 2, or 5 or more. A double-blind evaluation in the presence and absence of stimulation was performed at 6 months after surgery. Main Outcome Measure Change in score on the Extrapyramidal Symptoms Rating Scale., Results: At 6 months after surgery, the Extrapyramidal Symptoms Rating Scale score had decreased compared with baseline by more than 40% (mean improvement, 61%; range, 44%-75%) in the first 10 patients included. In accord with the 2-step open Fleming procedure, we ended the trial at the first step and concluded that pallidal stimulation is an effective treatment for TD. The efficacy of the treatment was confirmed by a double-blind evaluation, with a mean decrease of 50% (range, 30%-66%) (P = .002) in the Extrapyramidal Symptoms Rating Scale score when stimulation was applied compared with the absence of stimulation. There were no marked changes in the patients' psychiatric status., Conclusion: Although these results need to be confirmed in a larger group of patients with a longer follow-up, bilateral globus pallidus deep brain stimulation seems to offer a much-needed new treatment option for disabling TD.

Background: Unilateral subthalamotomy has been reported to be effective in the treatment of rigidity, bradykinesia, and tremor of the contralateral limb. However, gait, clinical fluctuation, and postural stability are not significantly improved by unilateral lesioning of the STN in the long term. We sought to determine if bilateral surgery of the STN offers more benefits in the treatment of advanced PD., Methods: Radiofrequency thermal coagulation was performed bilaterally in the STN in 10 patients. Under microelectrode and stereotactic guidance, surgery was directed at the dorsolateral portion of the STN in stages and followed by MRI in each patient to confirm lesion location. Patients have been followed for a median duration of 26 months as measured from the date of first surgery (range, 6-48 months) with UPDRS before and after surgery., Results: Bilateral subthalamotomy demonstrated persistent benefits in bradykinesia, rigidity of the limbs, and consequently the improvement in activities of daily living, motor function, Schwab and England scales. In addition, significant improvement in axial motor features, gait, postural stability, and clinical fluctuation were present with bilateral STN surgeries. The benefits were sustained at the last evaluation period of 36 months. Tremor and drug-induced dyskinesia improved in early postoperative period, but the benefits declined over time. The reduction of daily l-dopa equivalent was 34%. No speech impairment was observed. Mild choreic movement occurred in 2 of 20 procedures that resolved spontaneously in 4 to 8 weeks., Conclusion: For advanced PD present with bilateral symptoms, axial motor impairment, or clinical fluctuation, staged bilateral subthalamotomy appears as a safe and effective treatment in the long term.

When medications no longer provide patients with Parkinson's disease a reasonable quality of life due to the presence of levodopa-associated motor fluctuations and dyskinesias, surgical treatment is often pursued. Numerous studies have examined the antiparkinsonian efficacy of procedures currently available, but surprisingly few studies have evaluated their effect on motor response complications in a systematic, controlled manner, using appropriate instruments. Nonetheless, the combined evidence from uncontrolled case series and more recent randomized controlled trials reviewed here indicates that unilateral pallidotomy, bilateral pallidal deep brain stimulation, and bilateral subthalamic deep brain stimulation all substantially alleviate levodopa-induced dyskinesias and, to a lesser extent, motor fluctuations. Incorporation of standardized, validated instruments for the quantification of motor response complications in future surgical study protocols will not only allow more accurate comparison of different interventions but also will help physicians select the most appropriate procedure for their patients., ((c) 2005 Movement Disorder Society.)

Levodopa is the most effective symptomatic treatment of Parkinson's disease. However, after an initial period of dramatic benefit, several limitations become apparent including, "dopa resistant" motor symptoms (postural abnormalities, freezing episodes, speech impairment), "dopa resistant" non-motor signs (autonomic dysfunction, mood and cognitive impairment, etc), and/or drug related side effects (especially psychosis, motor fluctuations, and dyskinesias). Motor complications include fluctuations, dyskinesias, and dystonias. They can be very disabling and difficult to treat. Therefore, strategies should ideally be developed to prevent them. Though mechanisms underlying motor complications are only partially understood, recent work has revealed the importance of pulsatile stimulation of postsynaptic dopamine receptors and the disease severity. As a result of intermittent stimulation there occurs a cascade of changes in cell signalling leading to upregulation of the N-methyl-D-aspartate subtype of gamma-aminobutryric acid-ergic neurones. Modified preparations of levodopa (controlled release preparations, liquid levodopa), catecholamine-o-methyltransferase inhibitors, dopamine agonists, amantidine, and various neurosurgical approaches have been used in the prevention and/or treatment of motor complications. Current management of motor complications is less than satisfactory. With better understanding of the pathogenetic mechanisms, it is hoped that future therapeutic strategies will provide a safer and targeted treatment.

We describe a patient with fluspirilene-induced tardive dyskinesia of the choreiform oro-facial-laryngeal type resistant to various conservative approaches for 7 years who underwent deep brain stimulation of the internal pallidal globe. We found immediate and marked suppression of her perioral involuntary movements with unilateral stimulation at 60 Hz., (Copyright 2003 Movement Disorder Society)

Thalamotomy and pallidotomy have been shown to have some efficacy for treating some movement disorders such as disabling tremor or parkinsonian levodopa-induced dyskinesias (LID). Compared to continuous deep brain stimulation (DBS), this surgical procedure has the disadvantage of irreversibility and a lack of adaptability. Making a lesion involves a risk of inducing permanent side effects, especially if the lesion is large, or of observing a resurgence of the symptoms if the lesion is too small. We performed unilateral pallidotomy in one patient suffering from LID and unilateral thalamotomy in two patients suffering from tremor through the lead classically used for DBS. The technique of lead implantation was similar to that used for DBS treatment but, instead of connecting the lead to a pulse generator, it was left in place and used to make a radiofrequency lesion. This technique allowed the lesion to be kept as small as possible, thereby minimizing the risk of permanent side effects and made possible to extend the lesion if the symptoms reappeared. One lesioning session was enough to relieve tremor in the two patients treated by thalamotomy; three lesioning sessions over a 7-month period were required to relieve drug-induced dyskinesias in the patient treated by pallidotomy. In all 3 patients, disabling symptoms were still relieved without any permanent side effects 6 months after the last lesion was performed., (Copyright 2003 Movement Disorder Society)

We describe a case of a quadriplegic brain-damaged man with severe upper airway obstruction. A diagnosis of tardive dystonia affecting the vocal folds was made and confirmed by flexible nasopharyngoscopy. Emergency tracheotomy was required. The tardive movement disorder resolved with discontinuation of thioridazine. This case serves to heighten awareness of potentially serious airway complications associated with the use of anti-psychotics and anti-emetics particularly in those with organic brain disease.

Pallidotomy is a neurosurgical procedure designed to ameliorate the akinesia and bradykinesia associated with Parkinson's disease. In the present study, the effects of pallidal-like lesions on motor behavior in the hemiparkinsonian rat were compared to the effects of lesions in the ventrolateral thalamus, a target of entopeduncular projections feeding motor-related information to motor cortex. Six aspects of spontaneous and evoked behavior induced by amphetamine and apomorphine in the hemiparkinsonian rat with either bilateral electrolytic entopeduncular lesions or bilateral electrolytic ventrolateral thalamic lesions were measured for 60 min. Saline or amphetamine, 5 mg/kg, or apomorphine, 0.3 mg/kg, were administered IP 5 min before the tests. The results show that on all measures except time spent resting the hemiparkinsonian rats with the entopeduncular lesions were more active than the hemiparkinsonian rats with the thalamic lesions. The asymmetrical rotation responses to dopamine receptor stimulation evoked by amphetamine and apomorphine were influenced by the general effect on gross motor behavior, as shown by the response being very large in the entopeduncular group and very small in the thalamic group. These results are consistent with current thinking about the functional organization of the basal ganglia according to which damage of the entopeduncular nucleus reduces its inhibitory control of the thalamic motor regions, thereby promoting thalamic facilitation of motor cortex, and damage to the thalamic motor regions has the opposite effect. These effects of the lesions translate, respectively, into hyperactivity and hypoactivity without blocking the asymmetrical rotation response of the hemiparkinsonian rat., (Copyright 2001 Wiley-Liss, Inc.)

Recent advances on understanding the pallidothalamic relation lead us to perform Vim-Vo thalamotomy (combined thalamic lesion in ventralis intermedius nucleus and ventralis oralis nucleus) for cases with dyskinesia. In our recent series of thalamotomies, there are 12 cases of dyskinesia caused by various etiologies. Therefore the clinical manifestation of the involuntary movement was different in each case, including, more or less, some elements of irregular involuntary hyperkinetic movement. Stereotactic operation was performed using Leksell's apparatus aided by Surgiplan and MRI. The Vim nucleus was identified by physiological study using microelectrodes. High background activity and kinesthetic neurons are reliable indicators of Vim nucleus (but only for the lateral part). Then, selective coagulation was made by dual coagulation needles. Since the Vo nucleus is located just rostral to the Vim nucleus, the coagulation needle was turned toward the anterior part to partly cover the Vo nucleus. Thus, selective Vim-Vo thalamotomy was shown to be quite successful for the treatment of dyskinesia., (Copyright 2002 S. Karger AG, Basel)

Current models about the organization of the basal ganglia have provided a resurgence of the surgical treatment of Parkinson's disease (PD). Surgical experience has served to corroborate many of the predictions supported by the model. For instance, hyperactivity of the subthalamopallidal pathway is the key feature in PD and its suppression is associated with an improvement of the cardinal signs and symptoms of the disease. Parkinsonian rest tremor may be related to the oscillatory activity of the subthalamic and pallidal neurons. However, some clinical observations can not be entirely explained by the model. The most important paradox is the disappearance of levodopa-induced dyskinesias after pallidal surgery. This review critically analyzes the validity of the current model based on the surgical observations.

The objective of this study was to explore the functional anatomy of the globus pallidus internus (GPi) by studying the effects of unilateral pallidotomy on parkinsonian 'off' signs and levodopa-induced dyskinesias (LID). We found significant positive correlations between the preoperative levodopa responsiveness of motor signs and the levodopa responsiveness of scores in timed tests (Core Assessment Program for Intracerebral Transplantations) in the contralateral limbs and the improvement in these scores after surgery, whereas there was no correlation with the improvement in LID. We also found a highly significant correlation (P: < 0.0001, r = 0.8) between the volume of the ventral lesion in the GPi and the improvement in LID in the contralateral limbs, whereas there was no correlation between the ventral volume and the improvement in parkinsonian 'off' signs. The volumes of the total lesion cylinder and the dorsal lesion did not correlate with the outcome of either dyskinesias or parkinsonian 'off' signs. The differential predictive value of levodopa responsiveness for the outcome of parkinsonian 'off' signs and LID and the different correlations of ventral lesion volume with dyskinesias and parkinsonian 'off' signs indicate that different anatomical or pathophysiological substrates may be responsible for the generation of parkinsonian 'off' signs and dyskinesias. Whereas cells in a wider area of the GPi may be implicated in parkinsonism, the ventral GPi seems to be crucial for the manifestation of LID. We suggest that our observations are additional proof of the functional somatotopy of the systems within the GPi that mediate parkinsonism and dyskinesias, especially along the dorsoventral trajectory used in pallidotomy. The outcome of pallidotomy in which the lesion involves the ventral and dorsal GPi could be the net effect of alteration in the activity of pathways which mediate different symptoms, and hence could be variable.

We found that Parkinson's disease(PD) patients receiving autotransplants of the cervical sympathetic ganglia show a significant improvement in the parkinsonian symptoms with a consequent reduction in the daily intake of levodopa. The grafting procedure have recently been modified to further enhance the efficacy of the transplantation. Thus, in order to increase the amount of donor tissue we opted for the endoscopically excised thoracic sympathetic ganglia as a donor. With the aid of CT-guided stereotaxic surgery, we unilaterally placed one transplant deposit in the caudate head and three deposits in the putamen. Four patients that had received the grafts were followed with antiparkinsonian medication being unchanged at least one year postgrafting. Although no patients exhibited a substantial improvement in motor performance rated in either "on" or "off" phase, the awake time spent in "off" phase was reduced by 30-40% in all the patients. In two patients, dyskinesia in "on" phase was also attenuated. Our new transplantation paradigm is encouraging and deserves further investigation.

Pallidotomy has recently regained acceptance as an effective treatment for Parkinson's disease. From our 50 cases of unilateral pallidotomy and 10 cases of staged bilateral pallidotomy, details and indications of the procedure is described. The unilateral pallidotomy is quite effective for L-dopa induced dyskinesia, which usually completely disappears soon after the operation. The effect is long-lasting. When on-off phenomenon exists, unilateral pallidotomy improves off-stage rigidity or akinesia. Symptoms during on-stage are not changed. Indications of pallidotomy is that(1) L-dopa induced dyskinesia, and(2) on-off phenomenon. Bilateral pallidotomy, even by staged one, causes severe drooling, or speech disturbance(the volume of the voice decreases and the articulation worsens), and is not recommended. Vim thalamotomy is, on the other hand, the established treatment for tremor of Parkinson's disease or of essential tremor. The effect is long-lasting. Rigidity or akinesia is not expected to be improved so much.

The effects of current neurosurgical interventions for levodopa-induced dyskiensias (DID) in Parkinson's disease are reviewed. Thalamotomy has been reported to be effective for DID when the lesions include Vo or CM-Pf nucleus, while thalamic deep brain stimulation(DBS) is less effective than thalamotomy. Both pallidotomy and pallidal DBS are probably the most effective neurosurgical treatment for DID, because they significantly improve all of the DID, including off-period dystonia, without reduction of levodopa dosage. Subthalamic DBS has no direct therapeutic effects on DID, but substantially can improve DID as a result of decreased levodopa dosage. The effects of cerebral transplantation on DID remain undefined. More researches are expected to clarify the pathophysiology of DID.

The effects of surgical interventions for levodopa-induced dyskinesias (LIDs) in Parkinson's disease are reviewed. Since the introduction of levodopa, thalamotomy has been reported to have variable effects on LIDs. Striking benefit has been demonstrated, and efficacy is probably dependent on the size and location of the lesion. However, it remains unclear whether it is an effective treatment for all types of LIDs. Currently, pallidotomy is probably the most reliable and effective surgical treatment for LIDs, and will continue to play an important role in its management until other treatments become more widely available. Deep brain stimulation is an extremely exciting mode of therapy, particularly in the subthalamic nucleus and the globus pallidus, and early results of its use in the treatment of LIDs are promising. The effects of cerebral transplantation, still an experimental technique, on LIDs are inconsistent and controversial, and there is little reliable evidence that gamma knife radiosurgery can be safely applied to parkinsonian patients for the treatment of LIDs.

Objectives: To analyze the results, efficacy and safety of unilateral microelectrode guided pallidotomy for the treatment of advanced Parkinson's disease, three months and one year after surgery., Patients and Methods: 23 patients with advanced Parkinson's disease (mean age 58.9 years and mean disease duration 14.4 years) were submitted to pallidotomy. Neurological evaluation, three months (n = 23) and one year (n = 16) after surgery, was performed during the morning in overnight "off" condition and after receiving 100-150% of their usual l-dopa dose. Parkinsonian symptoms were evaluated in each follow up visit through motor scales, activities of daily living scales, a dyskinesia rating scale and motor timed tests., Results: Contralateral dyskinesias improved 92% three months after surgery and 89% at one year. Parkinsonian motor scores were reduced by 36.5% after three months and by 26.7% one year after surgery. In the one year follow up visit, contralateral tremor improved 48%, rigidity 36.2% and bradykinesia 37.4%. All these changes were statistically significant (p < 0.01). Adverse effects were minor or transient. Antiparkinsonian medication dosage did not significantly change during the study period., Conclusion: Microelectrode guided unilateral pallidotomy is an effective and safe procedure to improve contralateral motor symptoms in Parkinson's disease, being specially useful for the treatment of l-dopa induced dyskinesias.

Methods of selective thalamotomy with microrecording for several kinds of movement disorder are described. Precise thalamotomy (Vim, VO or Vim+VO) depends on the understanding of the functional organization of the human thalamus on the one hand, and the patient's specific feature of movement disorders on the other. To realize selective thalamotomy, microrecording and a computerized planning system are essential. Thus, a properly selected thalamotomy for movement disorders is quite useful., (Copyright 2001 S. Karger AG, Basel)

Pallidotomy has been reported to improve parkinsonian symptoms, but its effects on levodopa-induced dyskinesia (LID) have not been thoroughly examined. We describe here the results of stereotactic, unilateral, posteroventral pallidotomy on LID in 42 patients (22 women), who were followed for up to 9 months. Their mean age was 60. 6+/-9.3 (range: 40-74), age at onset was 46.1+/-9.1 (range: 24-46), and duration of symptoms was 14.5+/-5.3 (range: 4-25) years. Three months following pallidotomy, the percent time with dyskinesia decreased from 37.0 to 17.3 (P<0.0001) and the percent time the patients were 'on' with dyskinesias decreased even more, from 71.0 to 22.9 (P<0.0001). Furthermore, the number of patients with troublesome (moderate to violent) dyskinesia had decreased from 36 (86%) prior to surgery to only 5 (12%) after surgery. The mean unified Parkinson disease rating scale (UPDRS) scores for LID-related disability and pain decreased from 1.95 to 0.74 (P<0. 0001) and from 1.02 to 0.17 (P<0.0001), respectively. Since the pre- and post-pallidotomy daily levodopa dosage remained essentially the same, the improvement in LID could not be attributed to a reduction in levodopa. Surgery-related complications occurred in eight (19%) patients, but none of them had persistent disability as a result of these complications. We conclude that pallidotomy is an effective and safe procedure in the treatment of medically intractable LID.

Objective: To evaluate the outcome of microelectrode-guided posteroventral pallidotomy (PVP) for L-dopa induced dyskinesia in patients with Parkinson's disease., Methods: Thirty-six patients with dyskinesia were evaluated with unified Parkinson's disease rating scale (UPDRS) before and after operation. Duration and disability of dyskinesia were analyzed respectively., Results: The total surgical improvement for dyskinesia was 76.2%. Duration improvement was 88.8% and disability 79.7%. Significant change (P < 0.05) happened postoperatively. Seventeen patients were followed up for 3 months. The result showed a stable improvement for dyskinesia., Conclusions: L-dopa induced dyskinesia may disappear or be improved after PVP. Surgical treatment promises a maximum L-dopa therapy without any severe pharmaceutical complications. Synergic treatment of drug and surgery are a new strategy for Parkinson's disease.

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.

Objective: The progression of Parkinson's disease (PD) and levodopa therapy leads to development of motor and psychic complications that cause serious limitations to the management of the advanced disease., Development: This article reviews the current literature regarding epidemiological, clinical, pathophysiological and therapeutics of levodopa-induced dyskinesias (LID)., Conclusions: 1) The most important risk factors for LID are the cumulated doses of levodopa, young age at onset and severity of PD. 2) Pathophysiological data include the nigrostriatal system denervation, the prolonged exposure to levodopa and the integrity of striatal eferences; in addition there are some alterations of dopamine receptors and other neurotransmitter systems. 3) Some pharmacological measures, different for each type of LID, and surgery (pallidotomy, pallidal stimulation, subthalamic stimulation) can be useful for the therapy of LID.

Parkinson's disease (PD) is a progressive neurologic condition characterized by tremor, slowness, stiffness, and unstable posture. Degeneration of dopamine-producing neurons in the substantia nigra causes PD. Treatment with levodopa, a precursor of dopamine, initially ameliorates the clinical manifestations of PD. However, chronic levodopa treatment can produce severe involuntary movements (so-called dopa-induced dyskinesias or DID), limiting treatment. Pallidotomy, placement of a surgical lesion in the internal segment of the globus pallidus, reduces DID. Because this result is inconsistent with current theories of both basal ganglia function and DID, it prompted us to investigate the brain's response to levodopa. We measured regional cerebral blood flow response to levodopa with positron-emission tomography in 6 PD patients with DID, 10 chronically treated PD patients without DID, 17 dopa-naïve PD patients, and 11 normals. The dose of levodopa was chosen to produce clinical benefit without inducing DID. This strategy allowed us to examine the brain response to levodopa across groups without the confounding effect of differences in motor behavior. We found that the DID group had a significantly greater response in ventrolateral thalamus than the other groups. This was associated with decreased activity in primary motor cortex. These findings are consistent with increased inhibitory output from the internal segment of the globus pallidus to thalamus after levodopa administration. They provide a physiological explanation for the clinical efficacy of pallidotomy and new insights into the physiology of the basal ganglia.

Object: To increase knowledge of the safety and efficacy of the use of gamma knife radiosurgery in patients with movement disorders, the authors describe their own experience in this field and include blinded independent assessments of their results., Methods: Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. The observers were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with maximum doses from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Of patients undergoing pallidotomy who had exhibited levodopainduced dyskinesias, 85.7% had total or near-total relief of that symptom. Clinical assessment indicated improvements in bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Total ipsilateral score and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Neuropsychological test scores that were obtained for the combined pallidotomy and thalamotomy treatment groups preoperatively and at 6 months postoperatively demonstrated an absence of cognitive morbidity. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular intervals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures., Conclusions: Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and in those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

In this report, we describe the effect of staged bilateral posteroventral pallidotomy in three patients with advanced Parkinson's disease who were all of the young-onset type. Two patients had developed response fluctuations after the use of levodopa, with severe hypokinesia, painful dystonia, and rigidity in the "off" phase and violent dyskinesias in the "on" phase. One patient, in a continuous hypokinetic rigid state, was totally unresponsive to dopaminergic medication. All were at Hoehn and Yahr stage 5 in the "off" phase before surgery. After surgery, the hypokinetic state was reversed and dyskinesias were abolished in all patients. Hoehn and Yahr stages were 3 in the "off" phase postoperatively. Overall functional improvement was marked and lasting after follow-up for 7, 12, and 13 months, respectively. Complications were visual field deficit and transient central facial paresis, both in the same patient. Bilateral posteroventral pallidotomy can ameliorate response fluctuations, hypokinesia, rigidity, and painful dystonia in advanced Parkinson's disease.