Health economics and surgical treatment for Parkinson's disease in a world perspective: results from an international survey.

BACKGROUND: Most studies in the field of neurosurgical treatment for movement disorders have been published by a small number of leading centers in developed countries. This study aimed to investigate the clinical practice of stereotactic neurosurgery for Parkinson's disease (PD) worldwide. METHODS: Neurosurgeons were contacted via e-mail to participate in a worldwide survey. The results obtained are presented in order of the countries' economic development according to the World Bank, as well as by the source of financial support. RESULTS: A total of 353 neurosurgeons from 51 countries who had operated on 13,200 patients in 2009 were surveyed. Surgical procedures performed in high-income countries were more commonly financed by a public health care system. In contrast, in lower-middle-income and upper-middle-income countries, patients frequently financed surgeries themselves, and ablative surgeries were most commonly performed. Unexpectedly, ablative surgery is still used by about 65% of neurosurgeons, regardless of their country's economic status. CONCLUSIONS: This study provides a previously unavailable picture of the surgical aspects of PD across the globe in relation to health economics and sociodemographic factors. Global educational and training programs are warranted to raise awareness of economically viable surgical options for PD that could be adopted by public health care systems in lower-income countries.

Levodopa-induced abnormal involuntary movements correlate with altered permeability of the blood-brain-barrier in the basal ganglia.

Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment. Animals were scanned with [15O]-labeled water and [18F]-fluorodeoxyglucose, to map regional cerebral blood flow and glucose metabolism, and with [11C]-isoaminobutyric acid (AIB), to assess blood-brain-barrier (BBB) permeability, following separate injections of levodopa or saline. Multitracer scan data were acquired in each animal before initiating levodopa treatment, and again following the period of daily drug administration. Significant dissociation of vasomotor and metabolic levodopa responses was seen in the striatum/globus pallidus (GP) of the lesioned hemisphere. These changes were accompanied by nearby increases in [11C]-AIB uptake in the ipsilateral GP, which correlated with AIMs scores. Histopathological analysis revealed high levels of microvascular nestin immunoreactivity in the same region. The findings demonstrate that regional flow-metabolism dissociation and increased BBB permeability are simultaneously induced by levodopa within areas of active microvascular remodeling, and that such changes correlate with the severity of dyskinesia.

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia.

In a rodent model of Parkinson's disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis - a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts. We used H215O PET to scan 24 unmedicated PD subjects (12 LID and 12 NLID) and 12 matched healthy subjects in the rest state under normocapnic and hypercapnic conditions. Hypercapnic CBF responses were compared to corresponding levodopa responses from the same subjects. Group differences in hypercapnic vasoreactivity were significant only in the posterior putamen, with greater CBF responses in LID subjects compared with the other subjects. Hypercapnic and levodopa-mediated CBF responses measured in this region exhibited distinct associations with disease severity: the former correlated with off-state motor disability ratings but not symptom duration, whereas the latter correlated with symptom duration but not motor disability. These are the first in vivo human findings linking LID to microvascular changes in the basal ganglia.

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy.

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.

Modeling dyskinesia in animal models of Parkinson disease.

The treatment of motor symptoms of Parkinson disease (PD) with the dopamine (DA) precursor, l-3,4-dihydroxyphenylalanine (l-DOPA) introduced 50years ago still remains a very effective medication. However, involuntary movements termed l-DOPA-induced dyskinesias (LID) appear in the vast majority of PD patients after chronic treatment and may become disabling. Once they appeared, the first dose after a several-weeks drug holiday will trigger them again, showing that l-DOPA has permanently or persistently modified the brain response to DA. LID are very difficult to manage and no drug is yet approved for dyskinesias, aside from a modest benefit with amantadine. New drugs are needed for PD to alleviate parkinsonian symptoms without inducing dyskinesias. Hence, animal models have been developed to seek the mechanisms involved in LID and new drug targets. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered as a contamination of a derivative of heroin taken by drug users and produced similar motor symptoms as idiopathic PD. Since then, MPTP is used extensively to model PD and LID in non-human primates and mice in addition to the classical PD model in rats with a 6-hydroxydopamine (6-OHDA) lesion. This article reviews rodent and non-human primate models of PD that reproduce motor complications induced by DA replacement therapy. Moreover, key biochemical changes in the brain of post-mortem PD patients with LID will be compared to those observed in animal models. Finally, the translational usefulness of drugs found to treat LID in animal models will be compared to their clinical activities.

Subthalamotomy in the treatment of Parkinson's disease: clinical aspects and mechanisms of action.

Parkinson's disease (PD) is a neurodegenerative condition that can be pharmacologically treated with levodopa. However, important motor and nonmotor symptoms appear with its long-term use. The subthalamic nucleus (STN) is known to be involved in the pathophysiology of PD and to contribute to levodopa-induced complications. Surgery is considered in patients who have advanced PD that is refractory to pharmacotherapy and who display disabling dyskinesia. Deep brain stimulation of the STN is currently the main surgical procedure for PD, but lesioning is still performed. This review covers the clinical aspects and complications of subthalamotomy as one of the lesion-based options for PD patients with levodopa-induced dyskinesias. Moreover, the authors discuss the possible effects of subthalamic lesioning.

Subthalamotomy-induced changes in dopamine receptors in parkinsonian monkeys.

Subthalamotomy allows a reduction of doses of l-DOPA in dyskinetic patients while its antiparkinsonian benefits are preserved. However, the mechanisms of the potentiation of this response to medication remain to be elucidated. Hence, dopamine D1 and D2 receptors as well as the dopamine transporter were investigated using receptor binding autoradiography. D1 and D2 receptors as well as preproenkephalin and preprodynorphin mRNA levels were measured by in situ hybridization. Four dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys that underwent unilateral subthalamotomy were compared to four controls, four saline-treated and four l-DOPA-treated MPTP monkeys. Dopamine, its metabolites and its transporter were extensively and similarly decreased in all parkinsonian monkeys. D1 receptor specific binding was decreased in the striatum of all MPTP monkeys. The l-DOPA-induced decrease in D1 receptor specific binding was reversed in the striatum ipsilateral to subthalamotomy. D1 receptor mRNA levels followed a similar pattern. D2 receptor specific binding and mRNA levels remained unchanged in all groups. Striatal preproenkephalin mRNA levels were overall increased in MPTP monkeys; the STN-lesioned parkinsonian group had significantly lower values than the saline-treated and l-DOPA-treated parkinsonian monkeys in the dorsolateral putamen. Striatal preprodynorphin mRNA levels remained unchanged in MPTP monkeys compared to controls whereas it increased in all monkeys treated with l-DOPA compared to controls; subthalamotomy induced a decrease in the dorsolateral putamen ipsilateral to surgery. The improved motor response to l-DOPA after subthalamotomy in the parkinsonian monkeys investigated may be associated with an increased synthesis and expression of D1 receptors ipsilateral to STN lesion of the direct pathway.

Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys.

Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs decrease L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID); the implication of dopamine neurotransmission is not documented in this anti-LID activity. Therefore, we evaluated changes of dopamine receptors, their associated signaling proteins and neuropeptides mRNA, in normal control monkeys, in saline-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in L-DOPA-treated MPTP monkeys, without or with an adjunct treatment to reduce the development of LID: 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist. All de novo treatments were administered for 1 month and the animals were sacrificed thereafter. MPTP monkeys treated with l-DOPA + MPEP developed significantly less LID than MPTP monkeys treated with l-DOPA alone. [(3)H]SCH-23390 specific binding to D1 receptors of all MPTP monkeys was decreased as compared to controls in the basal ganglia and no difference was observed between all MPTP groups, while striatal D1 receptor mRNA levels remained unchanged. [(3)H]raclopride specific binding to striatal D2 receptors and mRNA levels of D2 receptors were increased in MPTP monkeys compared to controls; l-DOPA treatment reduced this binding in MPTP monkeys while it remained elevated with the l-DOPA + MPEP treatment. Striatal [(3)H]raclopride specific binding correlated positively with D2 receptor mRNA levels of all MPTP-lesioned monkeys. Striatal preproenkephalin/preprodynorphin mRNA levels and phosphorylated ERK1/2 and Akt/GSK3ß levels increased only in L-DOPA-treated MPTP monkeys as compared to controls, saline treated-MPTP and l-DOPA + MPEP treated MPTP monkeys. Hence, reduction of development of LID with MPEP was associated with changes in D2 receptors, their associated signaling proteins and neuropeptides.

Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys.

INTRODUCTION: Safinamide is a compound under investigation for use in the treatment of Parkinson's disease for combination with pharmacological therapy currently available. The objective of this study was to test the effects of safinamide in an animal model of l-DOPA-induced dyskinesias (LID), the MPTP lesioned dyskinetic macaque monkey, in comparison to and in combination with amantadine. METHODS: LID and parkinsonian symptoms were measured in dyskinetic monkeys treated with l-DOPA with and without several dose levels of safinamide, amantadine, and the two in combination. Safinamide plasma levels were monitored during the experiments. RESULTS: Safinamide pre-treatment (3, 10, 20 and 30 mg/kg) dose-dependently reduced LID scores, in two acute and one semi-chronic experiment. Intensity and duration of LID were reduced and inversely correlated with safinamide blood levels. All doses of safinamide tested prolonged the duration of the beneficial antiparkinsonian effect of l-DOPA. Amantadine (5 and 20 mg/kg) reduced LID, but reduced duration of antiparkinsonian response to l-DOPA. When added to amantadine (5 mg/kg), safinamide showed no (3 mg/kg) or modest (20 mg/kg) additional beneficial effects on LID while the combined treatment prevented the reduction of the duration of the l-DOPA antiparkinsonian effect observed with amantadine only. CONCLUSIONS: Safinamide and amantadine reduced LID in this primate model while only safinamide increased the duration of the antiparkinsonian response of l-DOPA, suggesting that safinamide may have effects on LID that are pharmacologically distinct from amantadine, which is in current clinical use for control of LID.

Potentiation of response to low doses of levodopa in MPTP-injected monkeys by chemical unilateral subthalamotomy.

OBJECT: Subthalamotomy is a stereotactic surgery performed in patients with disabling dyskinesias due to Parkinson disease. The authors set out to model this human condition in MPTP monkeys and determine if subthalamotomy allowed a reduction of levodopa for similar benefit. METHODS: The authors performed unilateral subthalamotomy in 4 parkinsonian dyskinetic monkeys by stereotactic injection of ibotenic acid. An optimal dose, defined as the highest dose of levodopa improving parkinsonian motor symptoms while inducing low or no dyskinesias, was established in these animals. Each monkey was scored for the antiparkinsonian and dyskinetic effects of the optimal dose of levodopa, as well as suboptimal and dyskinesia-inducing doses (60% and 140% of the optimal dose, respectively), and these scores were compared with those obtained at baseline before and after subthalamotomy. Bradykinesia was assessed by a prehension task. RESULTS: Unilateral subthalamotomy had a positive effect on the antiparkinsonian response for all doses of levodopa as well as the baseline. There were no differences in the antiparkinsonian response between the suboptimal dose postsurgery and the optimal dose presurgery. Dyskinesias were increased at the suboptimal and the optimal doses. After surgery, the duration of response to levodopa increased between 20% and 25% in the suboptimal dose, whereas it remained unchanged with higher doses. Bradykinesia was significantly reduced after surgery only at the suboptimal dose. CONCLUSIONS: Subthalamotomy potentiated the response to suboptimal doses of levodopa. Thus, levodopa can be reduced by 40% after surgery for similar beneficial antiparkinsonian response and less dyskinesia than with an optimal dose before surgery.