Alexandre Eusebio

Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial

BACKGROUNDnDespite optimum medical management, many patients with Parkinsons disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate--through its combined action on dopamine and noradrenaline reuptake--would improve gait disorders and freezing of gate in patients with advanced Parkinsons disease without dementia who also received subthalamic nucleus stimulation.nnnMETHODSnThis multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinsons disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov, number NCT00914095.nnnFINDINGSnWe screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26-45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26-42], F((1, 62))=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group.nnnINTERPRETATIONnMethylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinsons disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinsons disease. The long term risk-benefit balance should be further studied.nnnFUNDINGnFrench Ministry of Health and Novartis Pharma.

Chronic high‐frequency stimulation of the subthalamic nucleus and L‐DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission

Hyperactivity of striatal glutamatergic synaptic transmission in response to dopamine depletion plays a major role in the pathogenesis of parkinsonian motor symptoms. In the present study we investigated the impact, on this hyperactivity, of chronic dyskinesiogenic L‐DOPA treatment, combined or not with high‐frequency stimulation (HFS) of the subthalamic nucleus (STN). In vitro patch‐clamp recordings were performed from striatal spiny neurons of hemiparkinsonian rats (intranigral 6‐OHDA injection). Here we show that dyskinesiogenic L‐DOPA treatment exacerbated striatal glutamatergic hyperactivity induced by 6‐OHDA lesion. Chronic 5‐day STN HFS had the opposite effect, reducing striatal glutamatergic transmission in both parkinsonian and dyskinetic animals. Consistently, chronic HFS stimulation could progressively ameliorate motor parkinsonian signs (akinesia) but, conversely, did not improve L‐DOPA‐induced dyskinesia (LID). Thus, the effects of L‐DOPA and HFS on corticostriatal transmission seem to be dissociated. These data show for the first time that dyskinesiogenic L‐DOPA treatment and chronic STN HFS with antiakinetic effects induce opposite plastic rearrangements in the striatum. The interaction between these two treatments provides further evidence that striatal glutamatergic hyperactivity is a pathophysiological correlate of akinesia rather than LID.

Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson's disease

Background Behavioural disorders associated with compulsive use of dopaminergic drugs for Parkinsons disease (PD) such as dopamine dysregulation syndrome (DDS) and impulse control disorders (ICDs) may have devastating consequences and are challenging to manage. Whether or not such patients should undergo subthalamic nucleus (STN) deep brain stimulation (DBS) is controversial. A few case reports and small series have reported contrasting effects of STN DBS on dopamine misuse and ICDs, while a recent prospective study found clear beneficial effects of STN DBS on these disorders. Methods We conducted an observational study on 110 consecutive parkinsonian patients scheduled for STN DBS surgery. Patients were assessed preoperatively through extensive behavioural and psychiatric evaluations and divided into two groups: with or without compulsive dopaminergic medication use. Evaluations were repeated 1u2005year after surgery in both groups. Results Before surgery 18 patients (16.3%) were compulsive dopamine users of whom 12 (10.9%) fulfilled all criteria for DDS. 90% of these patients also had at least one ICD compared to 20% in the group without compulsive dopamine use. One year after surgery, one patient had persistent compulsive dopamine use, while no new occurrences were reported in the group without the condition before surgery. STN DBS did not provoke any major psychiatric complications and ICDs were reduced in all patients. Conclusions Our results suggest that STN DBS may reduce compulsive use of dopaminergic medication and its behavioural consequences. Whether this improvement is the result of STN DBS or the consequence of better treatment management remains to be established.

Dopamine-Deprived Striatal GABAergic Interneurons Burst and Generate Repetitive Gigantic IPSCs in Medium Spiny Neurons

Striatal GABAergic microcircuits modulate cortical responses and movement execution in part by controlling the activity of medium spiny neurons (MSNs). How this is altered by chronic dopamine depletion, such as in Parkinsons disease, is not presently understood. We now report that, in dopamine-depleted slices of the striatum, MSNs generate giant spontaneous postsynaptic GABAergic currents (single or in bursts at 60 Hz) interspersed with silent episodes, rather than the continuous, low-frequency GABAergic drive (5 Hz) observed in control MSNs. This shift was observed in one-half of the MSN population, including both “D1-negative” and “D1-positive” MSNs. Single GABA and NMDA channel recordings revealed that the resting membrane potential and reversal potential of GABA were similar in control and dopamine-depleted MSNs, and depolarizing, but not excitatory, actions of GABA were observed. Glutamatergic and cholinergic antagonists did not block the GABAergic oscillations, suggesting that they were generated by GABAergic neurons. In support of this, cell-attached recordings revealed that a subpopulation of intrastriatal GABAergic interneurons generated bursts of spikes in dopamine-deprived conditions. This subpopulation included low-threshold spike interneurons but not fast-spiking interneurons, cholinergic interneurons, or MSNs. Therefore, a population of local GABAergic interneurons shifts from tonic to oscillatory mode when dopamine deprived and gives rise to spontaneous repetitive giant GABAergic currents in one-half the MSNs. We suggest that this may in turn alter integration of cortical signals by MSNs.

Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects

AIMSnTo assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinsons disease and restless legs syndrome, without the problem of the confounding factors related to the disease.nnnMETHODSnPlacebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 +/- 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled.nnnRESULTSnPramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [-6.1 min (-9.8, -2.4), P = 0.002] and 5 h 30 min [-5.6 min (-7.7, -3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning.nnnCONCLUSIONSnThese results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.

Evaluation of a visual biofeedback on the postural control in Parkinson's disease

OBJECTIVESnBoth stabilization and orientation components of postural control are affected in Parkinsons disease (PD). These deficits are partly due to proprioceptive impairments, which frequently coexist with a visual dependence. This study aimed to evaluate if a visual biofeedback -xa0i.e. real time anteroposterior trunk and head orientations indicated with a simplified avatar and represented in a head-mounted displayxa0- could improve the postural control of PD patients in response to a postural disturbance. The influence of focusing on one specific component of the postural control (stabilization or orientation) was also examined.nnnMETHODSnSeventeen medicated PD patients performed sequences of pull-tests, either with eyes open, eyes closed or visual biofeedback, crossed with the verbal instruction to focus either on the stabilization or on the vertical body orientation. Kinematics data were collected.nnnRESULTSnBackward trunk tilts consequent to the pulls were unchanged across the different conditions. With eyes open and eyes closed, patients did not recover their initial vertical orientation by adopting a slightly tilted backward position. This bias disappeared with the visual biofeedback. Moreover, falls consecutive to the test were significantly less frequent with the visual biofeedback than in the two other visual conditions. These different orientation and stabilization parameters were not affected by the instruction.nnnCONCLUSIONnUnlike a verbal instruction, visualizing in real time their own bodys geometry improved both components of postural control of PD patients. This provides evidences in PD about links between impaired vertical orientation, deficits in balance control, and contribution of supplementary sensory cues.

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson’s disease

After more than 50 years of treating Parkinsons disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinsons disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinsons disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinsons Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinsons Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinsons disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Quality of life in Parkinson’s disease improved by apomorphine pump: the OPTIPUMP cohort study

To report on OPTIPUMP, a cohort study, investigating the impact in real-life clinical settings of continuous subcutaneous apomorphine infusion (CSAI) on the quality of life (HRQoL) of patients with Parkinson’s disease. OPTIPUMP was a prospective, open-label, observational cohort study involving 30 investigational sites in France. CSAI was proposed as part of routine clinical care to patients aged ≥18xa0years, in absence of dementia, with a PD diagnosis and based on the presence of motor fluctuations not controlled by oral treatments. The impact of APO-pump on quality of life was evaluated as the difference in PDQ-39 scores between the initiation treatment and the follow-up visit after 6xa0months’ treatment. All adverse events were recorded. Hyper- and hypodopaminergic behavioral tolerance was assessed on the Ardouin Scale of Behavior in Parkinson’s Disease. Between September 2011 and January 2013, we enrolled 142 patients: 42 patients were withdrawn due to pump removal (33), death (4), lost of follow-up (4), no available data (1). 100 completed the study. At 6xa0months, their HRQoL had significantly improved (pxa0=xa00.011), as had their total UPDRS score (pxa0<xa00.001). Regarding the safety profile, Ardouin scale scores indicated that their hyperdopaminergic behaviors had not increased. CSAI had a favorable impact on HRQoL, with benefits outweighing risks. The analysis of the withdrawn patients highlights the heterogeneity of the use of the pump having an impact on its efficacy and tolerability.

News and controversies regarding essential tremor

Essential tremor is the most common movement disorder in adults. It is characterized by a postural and kinetic tremor affecting the arms, but it can also affect other body parts. It evolves gradually and can be responsible for a functional impairment in activities of daily living. Its pathophysiology remains poorly understood and effective therapeutic options are limited. There are significant semiological variations between patients, and the term essential tremor seems to encompass a wide range of heterogeneous clinical phenotypes. The diagnostic criteria presented in 1998 are now challenged. Furthermore, there is a current debate concerning the etiology of this affection, as to whether essential tremor is a complex degenerative disorder or a functional reversible disorder of neuronal oscillation. In this review, we summarize some aspects of clinical, etiologic and therapeutic news, to better address the questioning on unravelling the clinical presentation and examine the current pathophysiological controversy in this disorder.

Limited Contribution of Primary Motor Cortex in Eye-Hand Coordination: A TMS Study.

The ability to track a moving target with the eye is substantially improved when the target is self-moved compared with when it is moved by an external agent. To account for this observation, it has been postulated that the oculomotor system has access to hand efference copy, thereby allowing to predict the motion of the visual target. Along this scheme, we tested the effect of transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex (M1) when human participants (50% females) are asked to track with their eyes a visual target whose horizontal motion is driven by their grip force. We reasoned that, if the output of M1 is used by the oculomotor system to keep track of the target, on top of inducing short latency disturbance of grip force, single-pulse TMS should also quickly disrupt ongoing eye motion. For comparison purposes, the effect of TMS over M1 was monitored when subjects tracked an externally moved target (while keeping their hand at rest or not). In both cases, results showed no alterations in smooth pursuit, meaning that its velocity was unaffected within the 25–125 ms epoch that followed TMS. Overall, our results imply that the output of M1 has limited contribution in driving the eye motion during our eye-hand coordination task. This study suggests that, if hand motor signals are accessed by the oculomotor system, this is upstream of M1. SIGNIFICANCE STATEMENT The ability to coordinate eye and hand actions is central in everyday activity. However, the neural mechanisms underlying this coordination remain to be clarified. A leading hypothesis is that the oculomotor system has access to hand motor signals. Here we explored this possibility by means of transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex (M1) when humans tracked with the eyes a visual target that was moved by the hand. As expected, ongoing hand action was perturbed 25–30 ms after TMS, but our results fail to show any disruption of eye motion, smooth pursuit velocity being unaffected. This work suggests that, if hand motor signals are accessed by the oculomotor system, this is upstream of M1.