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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.

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.

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.)

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.)

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.

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.

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.

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.

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.

This work set out to test the hypothesis that thalamotomy in the area of the thalamus which receives the input from the medial segment of the globus pallidus would decrease or prevent levodopa-induced dyskinesia. Peak dose dyskinesia is a major problem in the treatment of parkinsonian patients with levodopa therapy but this remains the best pharmacological agent for treating the condition. The hypothesis was derived from previous work which has suggested that reduced pallidal inhibition of the thalamus results in dyskinesia [Crossman (1990) Movement Dis. 5, 100-108]. A neuroanatomical tracing study was carried out prior to the thalamotomy work, using the anterograde tracer wheatgerm-agglutinin conjugated to horseradish peroxidase. This delineated the anterior part of the ventrolateral thalamus in the primate in terms of its afferent inputs. Wheatgerm agglutinin-horseradish peroxidase was injected into the medial segment of the globus pallidus bilaterally in three Macaca fascicularis and traced to terminals in the ventral thalamus and other brain areas. The appropriate thalamic area involved was plotted on atlas sections in preparation for stereotactic thalamotomy. Previous studies of neuronal input to the ventral thalamus are confusing due to the different nomenclatures used by different workers. Early workers used cytoarchitectonic boundaries which do not correspond with function. There are also differences in nomenclature between man, monkey and other animals. The current study maps the pallidal terminal territory within the thalamus in terms of stereotactic co-ordinates related to a published macaque atlas [Shantha et al. (1968) A Stereotaxic Atlas of the Java Monkey Brain. S. Karger, Basel] and can thus be used by other workers in the field. A well-established primate model of Parkinsonism was used for the thalamotomy study. Eight monkeys (Macaca fascicularis) were rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Regular dosing with levodopa or apomorphine reliably resulted in peak-dose dyskinesia which was scored in terms of its choreic and dystonic components. A radiofrequency electrode was used to create the ablative lesions. Chorea was always reduced and frequently abolished by a thalamotomy located in the pallidal terminal territory. This result was obtained after 10 thalamotomies in a total of six animals. Four animals received bilateral lesions, with an interval between operations and two animals underwent unilateral surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

Peak dose dyskinesia is a major problem in the treatment of parkinsonian patients with levodopa and yet this remains the best pharmacological agent for treating the condition. The hypothesis which this research set out to test was that thalamotomy in the area of the thalamus which receives the input from the medial segment of the globus pallidus would decrease or prevent the dyskinesia. A well established primate model of parkinsonism was used. Eight monkeys (Macaca fascicularis) were rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Regular dosing with levodopa or apomorphine reliably resulted in peak dose dyskinesia. Thalamotomy was carried out using a radiofrequency electrode. To ensure that the appropriate area of the thalamus was targeted, that is the area receiving the pallidal input, an anatomical tracing study was carried out. The anterograde anatomical tracer horseradish peroxidase, covalently bound to wheatgerm agglutinin, was injected into the medial segment of the globus pallidus bilaterally in three monkeys. The target site for thalamotomy was accurately worked out from the tracings obtained. Chorea was usually abolished and always reduced by a thalamotomy in the pallidal terminal territory. This result was obtained after 10 thalamotomies: 4 animals receiving bilateral lesions, with an interval between operations, and 2 animals undergoing unilateral surgery. Lesions in three control sites were carried out and had no permanent effect on chorea. The effect of lesions in other areas was also assessed. Dystonia was not relieved by any thalamic lesion. Thalamotomy is a long established procedure used to help parkinsonian tremor. Appropriately placed thalamotomy should be considered for the relief of disabling peak dose dyskinesia, which is predominantly choreic, in parkinsonian patients on otherwise successful levodopa therapy.

Levodopa-induced dyskinesia of the limbs in thirteen cases of Parkinsonism, which was choreic, ballistic or dystonic in type, was alleviated almost completely by stereotaxic surgery using a microelectrode technique for the ventralis oralis anterior and posterior nuclei of the thalamus, but much less by the ventralis intermedius nucleus. Control of levodopa-induced dyskinesias by thalamic lesions in the course of routine treatment of Parkinsonism is discussed.