Alexandre Kreisler

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

<h3>Background</h3> Even with optimal dopaminergic treatments, many patients with Parkinson9s disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine9s ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. <h3>Methods</h3> We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. <h3>Finding</h3> 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from −11.5 (−15/−7) at baseline to −20 (−25/−12) after treatment; F_{(1, 25)}=5.2; p=0.031; adjusted size effect: −0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. <h3>Interpretation</h3> Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. <h3>Registration</h3> Clinicaltrials.gov reference: NCT00767091.

To gain insight into systemic molecular events associated with an age-related neurodegenerative disorder, we compared gene expression patterns in peripheral blood mononuclear cells (PBMCs) sampled from elderly, healthy controls and from Parkinson's disease (PD) patients carrying the most frequently found mutation of the LRRK2 gene (G2019S). A transcriptomic approach enabled us to detect differentially expressed genes and revealed perturbations of pathways known to be involved in PD-related neurodegeneration: the ubiquitin–proteasome system, the mitochondrial oxidation system, inflammation, axonal guidance, calcium signalling and apoptosis. Moreover, alterations of the MAP kinase pathway, the actin cytoskeleton, the ephrin receptor system and vesicular transport – all recently associated with the LRRK2 G2019S mutation pathogenesis – were noted. Furthermore, we acquired new evidences of dysregulation in leukocyte extravasation signalling and immune system pathways in PD. These data show that the G2019S mutation affects the entire body and highlight some of the molecular events observed in the brain. This PBMC transcriptomic approach could be used to better understand neurodegeneration in PD and decipher new pathogenetic mechanisms, even at early stages of the disease.

Most available pattern recognition methods in neuroimaging address binary classification problems. Here, we used relevance vector machine (RVM) in combination with booststrap resampling (‘bagging’) for non-hierarchical multiclass classification. The method was tested on 120 cerebral 18fluorodeoxyglucose (FDG) positron emission tomography (PET) scans performed in patients who exhibited parkinsonian clinical features for 3.5 years on average but that were outside the prevailing perception for Parkinson's disease (PD). A radiological diagnosis of PD was suggested for 30 patients at the time of PET imaging. However, at follow-up several years after PET imaging, 42 of them finally received a clinical diagnosis of PD. The remaining 78 APS patients were diagnosed with multiple system atrophy (MSA, N = 31), progressive supranuclear palsy (PSP, N = 26) and corticobasal syndrome (CBS, N = 21), respectively. With respect to this standard of truth, classification sensitivity, specificity, positive and negative predictive values for PD were 93% 83% 75% and 96%, respectively using binary RVM (PD vs. APS) and 90%, 87%, 79% and 94%, respectively, using multiclass RVM (PD vs. MSA vs. PSP vs. CBS). Multiclass RVM achieved 45%, 55% and 62% classification accuracy for, MSA, PSP and CBS, respectively. Finally, a majority confidence ratio was computed for each scan on the basis of class pairs that were the most frequently assigned by RVM. Altogether, the results suggest that automatic multiclass RVM classification of FDG PET scans achieves adequate performance for the early differentiation between PD and APS on the basis of cerebral FDG uptake patterns when the clinical diagnosis is felt uncertain. This approach cannot be recommended yet as an aid for distinction between the three APS classes under consideration.

Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred treatment for parkinsonian patients with severe motor fluctuations. Proper targeting of the STN sensorimotor segment appears to be a crucial factor for success of the procedure. The recent introduction of directional leads theoretically increases stimulation specificity in this challenging area but also requires more precise stimulation parameters.We investigated whether commercially available software for image guided programming (IGP) could maximize the benefits of DBS by informing the clinical standard care (CSC) and improving programming workflows.We prospectively analyzed 32 consecutive parkinsonian patients implanted with bilateral directional leads in the STN. Double blind stimulation parameters determined by CSC and IGP were assessed and compared at three months post-surgery. IGP was used to adjust stimulation parameters if further clinical refinement was required. Overall clinical efficacy was evaluated one-year post-surgery.We observed 78% concordance between the two electrode levels selected by the blinded IGP prediction and CSC assessments. In 64% of cases requiring refinement, IGP improved clinical efficacy or reduced mild side effects, predominantly by facilitating the use of directional stimulation (93% of refinements).The use of image guided programming saves time and assists clinical refinement, which may be beneficial to the clinical standard care for STN-DBS and further improve the outcomes of DBS for PD patients.

We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and attenuated the loss of tyrosine hydroxylase immunoreactivity in the striatum. The dosage of 1-methyl-4-phenyl pyridinium (MPP+) in the striatum by high-performance liquid chromatography indicated that fenofibrate did not affect MPTP metabolism. Bezafibrate had no effect and, strikingly, simvastatin and atorvastatin had a negative effect. We also demonstrated the presence of PPAR-alpha in the dopaminergic neurons of the murine substantia nigra. Our data suggest that PPAR-alpha activation by fenofibrate could have a neuroprotective effect in PD through inhibition of inflammation, oxidative stress and/or apoptosis.

The neuron-restrictive silencer factor/RE1-silencing transcription factor (NRSF/REST) is a negative regulator of gene expression restricting the expression of neuronal genes to the nervous system. NRSF/REST is highly expressed in non-neuronal tissues like the lung. In previous work, we identified small-cell lung cancer (SCLC) cell lines with no detectable NRSF/REST expression that, as a consequence, expressed neuronal markers like L1-cell adhesion molecule (L1-CAM) and neural cell adhesion molecule (NCAM). The loss of NRSF/REST expression was linked to malignant progression; however, its mechanistic role remained elusive. Here, we show that NRSF/REST itself, rather than one of its regulated genes, acts like a classic tumour suppressor, being in part regulated by methylation. In SCLCs, NRSF/REST is positively regulated by CREB, with an NRSF/REST promoter fragment showing cell type specificity. Downstream, NRSF/REST directly regulates AKT2, in which NRSF/REST loss leads to an epidermal growth factor-mediated de-regulation of AKT-Serine473 phosphorylation, important for cellular proliferation and survival. Assaying anchorage-independent growth, we observed that with reduced NRSF/REST expression, proliferation was significantly enhanced, whereas NRSF/REST rescue decreased the potential of cells to grow anchorage independently. Our observations support the fact that NRSF/REST may act as an important modulator of malignant progression in SCLC.

Results from preclinical studies suggest that inhibition of glycogen synthase kinase (GSK-3) is a therapeutic option for tauopathies. The aim of the present study was therefore to determine the effects of sodium valproate (VPA), a GSK-3 inhibitor, on disease progression in progressive supranuclear palsy (PSP). We performed a double-blind, randomized, placebo-controlled trial, in 28 PSP patients who received VPA (1500 mg/day) or matching placebo for 24 months. The primary endpoint was the change from baseline in Progressive Supranuclear Palsy Rating Scale (PSPRS) at 12 and 24 months. Secondary endpoints evaluated the effects of VPA on cognitive and behavioral status (MMSE, Mattis Dementia Rating Scale, Wisconsin Card Sorting, Gröber and Buschke and Oral Denomination 80 tests), tolerability of treatment, and patient compliance. There were no baseline differences between active treatment and placebo groups in age and clinical rating scores. PSPRS score at 12 months was significantly higher in the VPA than in the placebo group (60.8 ± 20 versus 46.9 ± 18.6 respectively, p = 0.01), but was similar between the two groups at 24 months. No significant differences were observed between VPA and placebo groups for the secondary endpoints. Our results suggest that VPA is not effective as a disease-modifying agent in PSP.

<h2>Abstract</h2><h3>Background</h3> Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles. <h3>Objective</h3> To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS. <h3>Methods</h3> Patients with STN-DBS were screened for <i>LRRK2</i>, <i>GBA</i>, and <i>PRKN</i> mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes. <h3>Results</h3> We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 <i>LRRK2</i>, 22 <i>PRKN</i>, and 143 PD patients without mutations. <i>PRKN</i> patients were younger and had a longer disease duration at baseline. A <i>GBA</i> mutation was the only significant genetic factor associated with MDRS change (β = −2.51, p = 0.009). <i>GBA</i> mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with <i>LRRK2</i> (0.9 ± 4.8), <i>PRKN</i> (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups. <h3>Conclusion</h3> <i>GBA</i> mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population.

Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials.In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24.A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia.Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

ABSTRACT Background Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. Methods We performed a multicenter case‐control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of &gt;300 mg levodopa‐equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. Results The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P &lt; 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant ( OPRM1 rs179991, OR, 0.49; 95%CI, 0.32‐0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40‐base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24‐2.68; P = 0.0021; Bonferroni adjusted P = 0.105). Conclusions Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1 . Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cell-derived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients.

Fibrates and statins activate the Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha). This nuclear receptor regulates genes governing inflammation, apoptosis and oxidative stress, three important mechanisms of neuronal death in Parkinson's disease (PD). We retrospectively studied the effect of statins and fibrates in a cohort of 419 patients with PD. In PD patients receiving either a statin or a fibrate, the mean age of disease onset was delayed by nearly 9 years, when compared with (control) PD patients not taking a lipid-lowering treatment. According to a mixed linear model, the increase in the levodopa-equivalent daily dose over 2 years was significantly smaller in the group taking a statin (+24 mg) than in the matched control group (+212 mg) (p=0.004), whereas the Unified Parkinson's Disease Rating Scale motor score progression was similar. The course of the disease in patients taking a fibrate did not differ from the controls. These data suggest that lipid-lowering drugs may have a disease modifier effect, with a stronger action for statins than for fibrates.

Abstract The concept of peripheral myoclonus is not yet fully accepted by the medical community because of the difficulty in establishing a cause‐and‐effect relationship between trauma and subsequent movement disorders. Here, we report two cases of patients suffering from peripheral myoclonus after nerve injury. The first patient experienced myoclonus of the 4th dorsal interosseous muscle several days after trauma to the elbow. The second patient presented myoclonus of the arm stump (combined with phantom‐limb pain) 1 year after amputation. In both cases, central nervous system function (spine and brain imaging, somesthetic evoked potentials, EEG back‐averaging) was normal. For the second patient, local infiltration of xylocaine and botulinum toxin into the stump scar rapidly stopped myoclonus and pain. Nerve injury induces ephaptic transmission and ectopic excitation. The physiopathological mechanisms of this type of myoclonus involve a peripheral generator that induces central (spinal) generator activity. © 2008 Movement Disorder Society

Movement DisordersVolume 31, Issue 8 p. 1251-1252 Letters: New Observations Novel heterozygous mutation in ANO3 responsible for craniocervical dystonia Morgane Miltgen MS, Morgane Miltgen MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorArnaud Blanchard PhD, Arnaud Blanchard PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorHélène Mathieu MS, Hélène Mathieu MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAlexandre Kreisler MD, PhD, Alexandre Kreisler MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this author Jean-Pierre-Desvignes MS, Jean-Pierre-Desvignes MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorDavid Salgado PhD, David Salgado PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAgathe Roubertie MD, PhD, Agathe Roubertie MD, PhD CHRU Montpellier, Service de Neuro-pédiatrie, Hôpital Gui de Chauliac, Montpellier, France; Institut des Neurosciences de Montpellier, U1051 de l'INSERM, Université de Montpellier, BP 74103 Montpellier, FranceSearch for more papers by this authorLaura Barre MS, Laura Barre MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorGhadi Rai MS, Ghadi Rai MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorVeronique Blanck MS, Veronique Blanck MS Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorMelissa Frederic PhD, Melissa Frederic PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorXavier Douay MD, PhD, Xavier Douay MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorRonald Mazzolenni MD, PhD, Ronald Mazzolenni MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorPierre Charpentier MD, PhD, Pierre Charpentier MD, PhD Service de Neurologie, CH Béthune, FranceSearch for more papers by this authorVictoria Gonzalez MD, Victoria Gonzalez MD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorAlain Destée MD, PhD, Alain Destée MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this authorChristophe Béroud PharmD, PhD, Christophe Béroud PharmD, PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorGwenaelle Collod-Béroud PhD, Corresponding Author Gwenaelle Collod-Béroud PhD orcid.org/0000-0003-4098-6161 Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceCorrespondence to: Dr. Gwenaelle Collod-Béroud, INSERM UMR_S910, Medical Genetics and Functional Genomics, Faculté de Médecine la Timone, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France; E-mail: gwenaelle.collod-beroud@inserm.frSearch for more papers by this author Morgane Miltgen MS, Morgane Miltgen MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorArnaud Blanchard PhD, Arnaud Blanchard PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorHélène Mathieu MS, Hélène Mathieu MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAlexandre Kreisler MD, PhD, Alexandre Kreisler MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this author Jean-Pierre-Desvignes MS, Jean-Pierre-Desvignes MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorDavid Salgado PhD, David Salgado PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorAgathe Roubertie MD, PhD, Agathe Roubertie MD, PhD CHRU Montpellier, Service de Neuro-pédiatrie, Hôpital Gui de Chauliac, Montpellier, France; Institut des Neurosciences de Montpellier, U1051 de l'INSERM, Université de Montpellier, BP 74103 Montpellier, FranceSearch for more papers by this authorLaura Barre MS, Laura Barre MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorGhadi Rai MS, Ghadi Rai MS Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorVeronique Blanck MS, Veronique Blanck MS Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorMelissa Frederic PhD, Melissa Frederic PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceSearch for more papers by this authorXavier Douay MD, PhD, Xavier Douay MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorRonald Mazzolenni MD, PhD, Ronald Mazzolenni MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorPierre Charpentier MD, PhD, Pierre Charpentier MD, PhD Service de Neurologie, CH Béthune, FranceSearch for more papers by this authorVictoria Gonzalez MD, Victoria Gonzalez MD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorAlain Destée MD, PhD, Alain Destée MD, PhD Université de Lille, CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, France INSERM UMR-S1172, Lille, FranceSearch for more papers by this authorChristophe Béroud PharmD, PhD, Christophe Béroud PharmD, PhD Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France Département de Génétique Médicale, Hôpital La Timone, Marseille, FranceSearch for more papers by this authorGwenaelle Collod-Béroud PhD, Corresponding Author Gwenaelle Collod-Béroud PhD orcid.org/0000-0003-4098-6161 Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, FranceCorrespondence to: Dr. Gwenaelle Collod-Béroud, INSERM UMR_S910, Medical Genetics and Functional Genomics, Faculté de Médecine la Timone, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France; E-mail: gwenaelle.collod-beroud@inserm.frSearch for more papers by this author First published: 09 July 2016 https://doi.org/10.1002/mds.26717Citations: 20 Relevant conflicts of interest/financial disclosures: : Nothing to report. 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Filename Description mds26717-sup-0001-suppinfo.pdf112.1 KB Supporting Information mds26717-sup-0002-suppmovie1.mov54 MB Supporting Information Movie 1. mds26717-sup-0003-suppmovie2.mov54.3 MB Supporting Information Movie 2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume31, Issue8August 2016Pages 1251-1252 RelatedInformation

This report emphasizes the precise topographic distribution of cerebral metabolic impairment in corticobasal degeneration (CBD) and the pathophysiological differences between CBD and progressive supranuclear palsy (PSP). Statistical parametric mapping (SPM96) analysis of 18FDG positron emission tomography (PET) data was performed in 22 patients with CBD compared with 46 healthy subjects (HS) and 21 patients with PSP who were studied at rest. A statistical threshold of p <0.001 was fixed, further corrected for multiple or independent comparisons (p <0.05). In comparison with HS, the metabolic impairment in CBD was asymmetrically distributed in the putamen, thalamus, precentral (Brodmann's area, BA 4), lateral premotor (BA 6/44) and supplementary motor areas (SMA, BA 6), dorsolateral prefrontal (8/9/46) cortex, and the anterior part of the inferior parietal lobe (BA 40) including the intraparietal sulcus (BA 7/40). A similar hypometabolic pattern was observed for most individual analyses. When PSP was compared with CBD, metabolic impairment predominated in the midbrain, anterior cingulate (BA 24/32), and orbitofrontal regions (BA 10). The reverse contrast showed more posterior involvement in CBD (BA 6 and 5/7/40) including SMA. Our data suggest that multiple components of neural networks related to both movement execution and production of skilled movements are functionally disturbed in CBD compared with both HS and PSP.

Botulinum neurotoxin (BoNT) injections are the main medical treatment of writer's cramp. When the outcome is favourable, patients usually receive injections several times per year in the long-term. However, we know little about the course of BoNT doses and nothing about the impact of the guidance method on the clinical outcome or injection strategy. We studied, in the long-term, the doses of BoNT and the target muscles in a group of patients with writer's cramp, according to the guidance method (electrical stimulation or ultrasound). Patients received at least three injection cycles guided by electrical stimulation, followed by at least three injection cycles guided by ultrasound. Twenty-four patients were included. More target muscles were injected after switching to ultrasound guidance, especially the flexor carpi ulnaris and the flexor carpi radialis. The mean dose by muscle was lower when ultrasound guidance was used. When using electrical stimulation guidance, the dose in the flexors of the fingers decreased in the long-term, but increased in the flexors of the wrist. The course of the BoNT doses and of the number of target muscles per cycle were not the same during the first period (electrical stimulation) and the second period (ultrasound). Switching to ultrasound guidance, the BoNT dose decreased, mainly in the flexors of the wrist. Based on the results of our study, we suggest a starting dose in several muscles (flexor carpi ulnaris, flexor carpi radialis, flexor digitorum profundus and flexor pollicis longus).

Earlier study from our group indicated that the peroxisome proliferator-activated receptor-alpha agonist fenofibrate prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss in C57Bl/6 mice. Our objective was to determine whether or not fibratescan improve motor activity in two experimental models of Parkinson's disease: the MPTP C57Bl/6 mouse and the 6-hydroxydopamine (6-OHDA) Wistar rat. Six groups of mice were set up: sham, sham-fenofibrate, sham-bezafibrate, MPTP, MPTP-fenofibrate and MPTP-bezafibrate. Mice were fed a diet containing 0.2% fenofibrate, 0.2% bezafibrate or no hypolipidaemic agent for 2 weeks. Four groups of rats were set up: sham, sham-fenofibrate, 6-OHDA and 6-OHDA-fenofibrate. Rats were fed a diet containing 0.2% fenofibrate or no hypolipidaemic agent for 4 weeks. In mice, motor activity was quantified using actimetry. Nine parameters were recorded. The results were analyzed with a mixed linear model. In rats, behavioural sensitization was studied with repetitive injections of apomorphine. All the actimetry parameters indicated a decrease of locomotion the day after MPTP injections and eight parameters improved in MPTP mice treated with fenofibrate or bezafibrate. The apomorphine-induced rotation behaviour mildly decreased in 6-OHDA rats treated with fenofibrate, but behavioural sensitization was unchanged. The 6-OHDA and MPTP compounds have different toxicity mechanisms, which could explain why we did not observe the same effect in 6-OHDA rats as in MPTP mice. These data suggest that the protective effect of fibrates can be carried through inhibition of inflammation rather than oxidative stress.

Continuous subcutaneous infusion of apomorphine (CAI) has shown efficacy in the treatment of motor fluctuations but its place in the therapeutic arsenal remains poorly defined in terms of indication, acceptability and long-term tolerance. Indeed, few studies have been carried out with a follow-up greater than 12 months. The main objective was to assess the quality of life of Parkinson's disease (PD) patients treated with CAI. We also evaluate the effectiveness on the motor fluctuations, the long-term tolerance of this treatment with its causes of discontinuation and the treatment regimens used.We conducted a retrospective study of 81 PD patients treated with CAI between April 2003 and June 2012. Data were collected from medical records. A repeated measures analysis of variance by the linear mixed model was used (significance level: 5%).In August 2012, 27/81 patients were still treated with CAI with a mean duration of 28 months, 46/81 discontinued CAI (9 precociously), and 8 were lost to view. We didn't show improvement in the quality of life nor efficacy of CAI on the UPDRS IV score (P=0.54) and dyskinesia score (P=0.95). The CGI score patient also reflects this result with a majority response suggesting no significant change with CAI. We observed relative good cognitive and psychiatric tolerance. Adverse events were frequent but often benign. The average (±SD) rate of apomorphine was 3.15±1.71 mg/h and the oral dopaminergic treatment was decreased by 37.8%.The results are consistent with the literature except for the lack of efficiency on motor fluctuations which may be due to the use of too small doses of apomorphine. This seems to be a leading cause of discontinuation of CAI, especially when it is associated with side effects or important constraints. For better efficiency on motor fluctuations, we recommend the use of apomorphine at higher doses to obtain an optimal continuous dopaminergic stimulation.

Purpose To better define the clinical characteristics of idiopathic oromandibular dystonia, we studied voice, speech, and swallowing disorders and their impact on activities of daily living. Method Fourteen consecutive patients with idiopathic oromandibular dystonia and 14 matched, healthy control subjects were included in the study. Results Dysarthria was the most common disorder and its characteristics varied from one patient to another. However, we frequently observed a hyperkinetic, dysarthric profile characterized by imprecise consonants, a rough voice, changes in intensity, and hypernasality. Dysphagia appeared to be slightly less frequent and less disabling than dysarthria. Most patients had difficulty swallowing solids, and the oral phase was particularly problematic. Dysarthria and dysphagia affected activities of daily living in general and the psychological/emotional domain in particular. Conclusions The characteristics of dysarthria in oromandibular dystonia vary significantly from one patient to another due to differences in the set of affected muscles, so each patient should receive a personalized rehabilitation program. Dysarthria was the most prominent symptom, although spasmodic dysphonia was more frequent than expected. Further laboratory-based studies are needed to clarify the mechanisms and consequences of dysphagia in oromandibular dystonia.

<strong>Background:</strong> Tremor is an important phenotypic feature of dystonia. Using the new concept (Col-Cap) of classification we examined the frequency of tremor in cervical dystonia (CD) patients, their main subtypes and muscles injected. <strong>Methods:</strong> In this large study conducted at multiple movement disorder centres in Europe and India, between January and June 2019, we examined 293 patients with idiopathic CD who were all treated with botulinum toxin (BTX). <strong>Results:</strong> The dystonic head tremor (DHT+) was present in 57.6 % of CD patients and they had a significantly longer duration of symptoms than patients without head tremor (DHT–). In DHT+ patients torticaput was the most common subtype and the majority (63.3%) had one or two subtypes only. There was no significant difference between the number of unilateral injections for any of the muscles in the DHT+ and DHT– groups, while the number of patients receiving bilateral injections in splenius capitis (78 vs 25; p = 0.00001), sternocleidomastoid (31 vs 6; p = 0.0005), trapezius (28 vs 9; p = 0.01), and obliquus capitis inferior (15 vs 2; p = 0.008) were significantly more in the DHT+ group. The mean doses of all three types of BTX/A were not significantly different between the two groups. <strong>Conclusions:</strong> The frequency of head tremor was 57.6% in our CD patients and torticaput was the most common dystonic subtype associated with tremor. Simple forms of CD seemed more likely associated with head tremor, than complex forms of CD. Most of the DHT+ patients received bilateral injections. The use of ‘Col-Cap’ classification was helpful in the identification of muscles likely to be involved in tremor in CD patients.

Treatment with levodopa-carbidopa intestinal gel (LCIG) can effectively relieve motor and non-motor symptoms in advanced Parkinson's disease (PD). However, adverse events (AEs) are frequent. To describe AEs associated with LCIG treatment and the main reasons for treatment discontinuation. We also looked for factors that were potentially predictive of serious AEs and assessed the effectiveness of and satisfaction with LCIG. We retrospectively analyzed data on AEs in patients treated with LCIG at a French university medical center. For patients still receiving treatment at last follow-up, effectiveness was assessed according to the Clinical Global Impression (CGI) scale and the Movement Disorders Society – Unified Parkinson's Disease Rating Scale motor score. Of the 63 patients treated with LCIG for a mean (range) of 19 months (8–47), 57 (90%) experienced at least one AE (340 AEs in total). Most of the AEs (in 69.8% of the patients) were related to percutaneous endoscopic gastrostomy with a jejunal tube (PEG-J) or affected the gastrointestinal tract (granuloma, leakage, or a local infection). Device-related AEs (such as PEG-J removal and device occlusion) were frequent (in 63.5% of patients). Forty-three patients (68%) required at least one additional endoscopic procedure. Dopatherapy-related AEs occurred in 30 patients (48%). Most of the AEs occurred long after treatment initiations, and only a small proportion led to discontinuation. On the CGI scale, 53 patients (84.4%) considered that their condition had improved during LCIG treatment. Despite the high frequency of AEs, patients with advanced PD gain clinical benefit from treatment with LCIG. This treatment requires a competent, multidisciplinary team on site.

The folate receptor is a 38 to 39 kd glycoprotein attached to the cell membrane via a glycosylphosphatidylinositol anchor. It serves as the initiation point for receptor-coupled transport of folate in a process known as potocytosis. The receptor is overproduced by a number of malignant cell lines in vitro and in a large percentage of ovarian and uterine malignancies. Immunohistochemistry has shown the receptor to be expressed primarily in normal differentiated tissues such as choroid plexus, placenta, thyroid, and kidney. The receptor gene(s) has been mapped to the human chromosomal locus 11q13.In order to better understand regulation of the synthesis of the receptor, we studied the expression and accumulation of the folate receptor in UMSCC 38 cells, a human malignant squamous cell carcinoma line with a karyotype that is amplified at the folate receptor gene locus.Western blot analysis of octylglucoside-solubilized cell membranes was used to analyze expression of several proteins by UMSCC 38 cells grown in culture under varied conditions. Bands on autoradiographs, representing electrophoresed proteins detected by indirect antibody labeling and an enhanced chemiluminescence reaction, were quantitated by densitometry.The expression of the folate receptor was found to increase approximately fourfold as UMSCC 38 cells were grown to higher cell densities over increasing lengths of time, ranging from 3 to 9 days, in culture. The expression of K1 keratin protein, a known marker of differentiation in squamous cell carcinomas, was elevated to a similar degree (3.2-fold) between day 5 and day 9 in cultures of these cells. Expression of folate-receptor protein in UMSCC 38 cells was also found to be reduced approximately 10-fold when cells were exposed to 1 microM retinoic acid for 48 hours and increased approximately eightfold after a 5-day exposure to 3 microM hydrocortisone.We present evidence that synthesis of the folate receptor in UMSCC 38 cells is affected by the same pathway that changes the expression of some markers of differentiation in squamous cell carcinomas.The fact that folate receptor expression in these malignant cells can be manipulated using retinoids and steroids suggests that these hormones could modulate the efficiency of folate and antifolate uptake via the folate receptor and may enhance the usefulness of the receptor as a target for immunotherapy.

We report on five patients with a clinical presentation of corticobasal degeneration (CBD), including gradually progressive, asymmetric, L-DOPA-resistant parkinsonism associated variously with apraxia, focal action myoclonus, focal dystonia, cortical sensory loss and alien limb phenomenon. Some patients also presented an atypical CBD clinical history or signs - notably sudden onset. The disease was however not suggestive of another diagnosis. Magnetic resonance imaging of the brain revealed extensive vascular lesions. Only five similar cases have been published to our knowledge. Although we cannot exclude underlying CBD pathology, our cases illustrate the fact that multi-infarct pathology can masquerade as CBD or alter the clinical phenotype of the disease.

Background and purpose In cervical dystonia, the accuracy of botulinum neurotoxin (BoNT) injections may influence the response to the treatment. Methods We used ultrasound to evaluate the accuracy of anatomy‐guided injections of BoNT in the neck muscles. Results A total of 56 consecutive patients and 332 injections were evaluated. The overall accuracy was 76.6%. The lowest accuracy (67.9%) was observed for the splenius capitis muscle. Conclusions Anatomic guidance of BoNT injections in the neck muscles is often inaccurate. Imaging guidance may improve the accuracy of BoNT injections in cervical dystonia.

Ultrasound-guided injections of botulinum neurotoxin in cervical dystonia have a number of theoretical advantages. However, their action has never been compared to that of non-guided injections. The objectives of the study were to compare the outcome of botulinum neurotoxin type A treatment in patients with idiopathic, focal cervical dystonia, according to two methods: inspection and palpation of anatomical landmarks (non-guided group) or ultrasound guidance (ultrasound-guided group).We included consecutive patients in this single-center, prospective, real-life, non-randomized study. The outcomes were evaluated one month after the injections: Cervical Dystonia Impact Profile 58 (main outcome), Toronto Western Spasmodic Torticollis Rating Scale-2 (pain and disability subscores), Toronto Western Spasmodic Torticollis Rating Scale-PSYCH, patient-rated Clinical Global Impression - Improvement and adverse events. We used propensity score methods for statistical analysis; ten predefined confounding factors were used to build the propensity score.Sixty-three patients were included in the non-guided group, and 60 other patients in the ultrasound-guided group. We found no difference in main and secondary outcomes between the two study groups.This is the first direct comparison between ultrasound-guided and non-guided botulinum neurotoxin type A injections in patients with cervical dystonia. We hypothesize that ultrasound guidance made it possible to obtain the same results in the most severe (or the most demanding) patients as in the best responders. Further studies are still needed to assess the impact of botulinum neurotoxin injections into deep cervical muscles.

Two scales have been developed and validated in English to evaluate the impact of tremor on daily life, namely Quality of life in Essential Tremor Questionnaire (QUEST) and Essential Tremor Embarrassment Assessment (ETEA). The psychometric properties of the French version of these two scales were assessed for 117 patients with head tremor. Both scales showed excellent acceptability, very good internal consistency (Cronbach's alpha coefficient>0.8) and reproducibility (Lin concordance coefficient>0.8), satisfactory external validity and satisfactory sensitivity to change. In conclusion, the French versions of QUEST and ETEA are comprehensive, valid and reliable instruments for assessing patients with head tremor.

The diagnosis of corticobasal degeneration (CBD) is difficult despite the existence of some typical clinical features. Single photon emission computerized tomography (SPECT) in CBD presents an original pattern (with asymmetric hypoperfusion in pre- and retrorolandic regions) that could facilitate the differential diagnosis of CBD relative to the other degenerative parkinsonian syndromes. The objective of our study was to compare the regional cerebral blood flow measurements studied by SPECT in both CBD and Parkinson's disease (PD) using a multivariate procedure. Twenty-one patients with probable CBD and 20 patients with probable PD underwent brain (99m)Tc HmPaO SPECT. We used factorial discriminant analysis (FDA) to study the relative fixation of 26 regions of interest (ROIs) drawn on two transverse slices, together with the asymmetry indexes of 13 pairs of ROIs. FDA performed using the full set of parameters classified all the patients correctly. In order to classify the patients more easily, a predictive score using a selection of parameters was established. The most discriminating ROIs were the temporoinsular, temporoparietal, and frontal medial regions. We believe that this semiautomatic classification may be a precious tool for reinforcing the current clinical differential diagnosis of CBD and PD.

Movement DisordersVolume 26, Issue 9 p. 1775-1776 Letters: New Observation Singular DYT6 phenotypes in association with new THAP1 frameshift mutations† Arnaud Blanchard MS, Arnaud Blanchard MS INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, France Arnaud Blanchard and Agathe Roubertie contributed equally to this work.Search for more papers by this authorAgathe Roubertie MD, PhD, Agathe Roubertie MD, PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, France CHU Montpellier, Hôpital Gui de Chauliac, Service de Neuropédiatrie, Montpellier, France Arnaud Blanchard and Agathe Roubertie contributed equally to this work.Search for more papers by this authorMarion Simonetta-Moreau MD, PhD, Marion Simonetta-Moreau MD, PhD Hôpitaux de Toulouse, Pôle Neurosciences, Toulouse, FranceSearch for more papers by this authorVuthy Ea MS, Vuthy Ea MS INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceSearch for more papers by this authorColine Coquart, Coline Coquart CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, FranceSearch for more papers by this authorMelissa Y. Frederic PhD, Melissa Y. Frederic PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceSearch for more papers by this authorGael Gallouedec MD, Gael Gallouedec MD CHU Dupuytren, Service de Neurologie, Limoges, FranceSearch for more papers by this authorJean-Paul Adenis MD, Jean-Paul Adenis MD CHU Dupuytren, Service d'Ophtalmologie, Limoges, FranceSearch for more papers by this authorIsabelle Benatru MD, Isabelle Benatru MD CHU de Dijon, Hôpital Général, Service de Neurologie, Dijon, FranceSearch for more papers by this authorMichel Borg MD, Michel Borg MD CHU de Nice, Service de Neurologie, Nice, FranceSearch for more papers by this authorPierre Burbaud MD, PhD, Pierre Burbaud MD, PhD CHU Pellegrin, Service de Neurophysiologie Clinique, Bordeaux, FranceSearch for more papers by this authorPatrick Calvas MD, PhD, Patrick Calvas MD, PhD CHU Toulouse, Hôpital Purpan, Service de Génétique Médicale, Toulouse, FranceSearch for more papers by this authorLaura Cif MD, Laura Cif MD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorPhilippe Damier MD, PhD, Philippe Damier MD, PhD CHU Nantes, CIC0004, Service de Neurologie, Nantes, FranceSearch for more papers by this authorAlain Destee MD, PhD, Alain Destee MD, PhD CHU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorLaurence Faivre MD, PhD, Laurence Faivre MD, PhD CHU de Dijon, Hôpital d'Enfants, Centre de Génétique, Dijon, FranceSearch for more papers by this authorLucie Guyant-Marechal MD, Lucie Guyant-Marechal MD CHU de Rouen, Hôpital Charles Nicolle, Département de Neurologie, Rouen, FranceSearch for more papers by this authorPiotr Janik MD, PhD, Piotr Janik MD, PhD Department of Neurology, Medical University of Warsaw, PolandSearch for more papers by this authorSamer Janoura MD, Samer Janoura MD CHG Roanne, Service de Neurologie, Roanne, FranceSearch for more papers by this authorAlexandre Kreisler MD, PhD, Alexandre Kreisler MD, PhD CHU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorAnna Lusakowska MD, PhD, Anna Lusakowska MD, PhD Department of Neurology, Medical University of Warsaw, PolandSearch for more papers by this authorSylvie Odent MD, PhD, Sylvie Odent MD, PhD Service de Génétique Clinique, CHU de Rennes, Hôpital Sud, Rennes, FranceSearch for more papers by this authorAnna Potulska-Chromik MD, PhD, Anna Potulska-Chromik MD, PhD Department of Neurology, Medical University of Warsaw, PolandSearch for more papers by this authorMonika Rudzińska MD, PhD, Monika Rudzińska MD, PhD Department of Neurology, Jagiellonian University Medical College, PolandSearch for more papers by this authorStephane Thobois MD, PhD, Stephane Thobois MD, PhD Hospices Civils de Lyon, Hôpital Neurologique, Service de Neurologie C, Lyon, FranceSearch for more papers by this authorIsabelle Vuillaume MD, PhD, Isabelle Vuillaume MD, PhD CHRU de Lille, Département de Biochimie et de Biologie Moléculaire, Lille, FranceSearch for more papers by this authorChristine Tranchant MD, Christine Tranchant MD Hôpitaux Universitaires de Strasbourg, Service de Neurologie, Strasbourg, FranceSearch for more papers by this authorSylvie Tuffery-Giraud PhD, Sylvie Tuffery-Giraud PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceSearch for more papers by this authorPhilippe Coubes MD, PhD, Philippe Coubes MD, PhD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorBernard Sablonnière MD, PhD, Bernard Sablonnière MD, PhD CHRU de Lille, Département de Biochimie et de Biologie Moléculaire, Lille, FranceSearch for more papers by this authorMireille Claustres MD, PhD, Mireille Claustres MD, PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, France CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, FranceSearch for more papers by this authorGwenaelle Collod-Béroud PhD, Corresponding Author Gwenaelle Collod-Béroud PhD [email protected] INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceINSERM, U827, Montpellier, FranceSearch for more papers by this author Arnaud Blanchard MS, Arnaud Blanchard MS INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, France Arnaud Blanchard and Agathe Roubertie contributed equally to this work.Search for more papers by this authorAgathe Roubertie MD, PhD, Agathe Roubertie MD, PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, France CHU Montpellier, Hôpital Gui de Chauliac, Service de Neuropédiatrie, Montpellier, France Arnaud Blanchard and Agathe Roubertie contributed equally to this work.Search for more papers by this authorMarion Simonetta-Moreau MD, PhD, Marion Simonetta-Moreau MD, PhD Hôpitaux de Toulouse, Pôle Neurosciences, Toulouse, FranceSearch for more papers by this authorVuthy Ea MS, Vuthy Ea MS INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceSearch for more papers by this authorColine Coquart, Coline Coquart CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, FranceSearch for more papers by this authorMelissa Y. Frederic PhD, Melissa Y. Frederic PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceSearch for more papers by this authorGael Gallouedec MD, Gael Gallouedec MD CHU Dupuytren, Service de Neurologie, Limoges, FranceSearch for more papers by this authorJean-Paul Adenis MD, Jean-Paul Adenis MD CHU Dupuytren, Service d'Ophtalmologie, Limoges, FranceSearch for more papers by this authorIsabelle Benatru MD, Isabelle Benatru MD CHU de Dijon, Hôpital Général, Service de Neurologie, Dijon, FranceSearch for more papers by this authorMichel Borg MD, Michel Borg MD CHU de Nice, Service de Neurologie, Nice, FranceSearch for more papers by this authorPierre Burbaud MD, PhD, Pierre Burbaud MD, PhD CHU Pellegrin, Service de Neurophysiologie Clinique, Bordeaux, FranceSearch for more papers by this authorPatrick Calvas MD, PhD, Patrick Calvas MD, PhD CHU Toulouse, Hôpital Purpan, Service de Génétique Médicale, Toulouse, FranceSearch for more papers by this authorLaura Cif MD, Laura Cif MD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorPhilippe Damier MD, PhD, Philippe Damier MD, PhD CHU Nantes, CIC0004, Service de Neurologie, Nantes, FranceSearch for more papers by this authorAlain Destee MD, PhD, Alain Destee MD, PhD CHU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorLaurence Faivre MD, PhD, Laurence Faivre MD, PhD CHU de Dijon, Hôpital d'Enfants, Centre de Génétique, Dijon, FranceSearch for more papers by this authorLucie Guyant-Marechal MD, Lucie Guyant-Marechal MD CHU de Rouen, Hôpital Charles Nicolle, Département de Neurologie, Rouen, FranceSearch for more papers by this authorPiotr Janik MD, PhD, Piotr Janik MD, PhD Department of Neurology, Medical University of Warsaw, PolandSearch for more papers by this authorSamer Janoura MD, Samer Janoura MD CHG Roanne, Service de Neurologie, Roanne, FranceSearch for more papers by this authorAlexandre Kreisler MD, PhD, Alexandre Kreisler MD, PhD CHU de Lille, Service de Neurologie et Pathologie du Mouvement, Lille, FranceSearch for more papers by this authorAnna Lusakowska MD, PhD, Anna Lusakowska MD, PhD Department of Neurology, Medical University of Warsaw, PolandSearch for more papers by this authorSylvie Odent MD, PhD, Sylvie Odent MD, PhD Service de Génétique Clinique, CHU de Rennes, Hôpital Sud, Rennes, FranceSearch for more papers by this authorAnna Potulska-Chromik MD, PhD, Anna Potulska-Chromik MD, PhD Department of Neurology, Medical University of Warsaw, PolandSearch for more papers by this authorMonika Rudzińska MD, PhD, Monika Rudzińska MD, PhD Department of Neurology, Jagiellonian University Medical College, PolandSearch for more papers by this authorStephane Thobois MD, PhD, Stephane Thobois MD, PhD Hospices Civils de Lyon, Hôpital Neurologique, Service de Neurologie C, Lyon, FranceSearch for more papers by this authorIsabelle Vuillaume MD, PhD, Isabelle Vuillaume MD, PhD CHRU de Lille, Département de Biochimie et de Biologie Moléculaire, Lille, FranceSearch for more papers by this authorChristine Tranchant MD, Christine Tranchant MD Hôpitaux Universitaires de Strasbourg, Service de Neurologie, Strasbourg, FranceSearch for more papers by this authorSylvie Tuffery-Giraud PhD, Sylvie Tuffery-Giraud PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceSearch for more papers by this authorPhilippe Coubes MD, PhD, Philippe Coubes MD, PhD CHU Montpellier, Hôpital Gui de Chauliac, Service de Neurochirurgie, Montpellier, FranceSearch for more papers by this authorBernard Sablonnière MD, PhD, Bernard Sablonnière MD, PhD CHRU de Lille, Département de Biochimie et de Biologie Moléculaire, Lille, FranceSearch for more papers by this authorMireille Claustres MD, PhD, Mireille Claustres MD, PhD INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, France CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, FranceSearch for more papers by this authorGwenaelle Collod-Béroud PhD, Corresponding Author Gwenaelle Collod-Béroud PhD [email protected] INSERM, U827, Montpellier, France Université Montpellier 1, UFR Médecine, Montpellier, FranceINSERM, U827, Montpellier, FranceSearch for more papers by this author First published: 25 April 2011 https://doi.org/10.1002/mds.23641Citations: 8 † Relevant conflicts of interest/financial disclosures: This study was supported by grants from the French Ministry of Health (National PHRC 2007-A00614-49), AMADYS-LFCD, Alliance France Dystonie, Lions Club, French Dystonia Network, Université Montpellier 1 and INSERM. Arnaud Blanchard and Vuthy Ea are supported by a grant from the Ministère de l'Enseignement Supérieur et de la Recherche (MESR). Full financial disclosures and author roles may be found in the online version of this article. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 2009; 41: 286–288. 2 Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saunders-Pullman R. Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol 2009; 8: 441–446. 3 Koukouni V, Martino D, Arabia G, Quinn NP, Bhatia KP. The entity of young onset primary cervical dystonia. Mov Disord 2007; 22: 843–847. 4 Paisan-Ruiz C, Ruiz-Martinez J, Ruibal M, et al. Identification of a novel THAP1 mutation at R29 amino-acid residue in sporadic patients with early-onset dystonia. Mov Disord 2009; 24: 2428–2429. 5 Bonetti M, Barzaghi C, Brancati F, et al. Mutation screening of the DYT6/THAP1 gene in Italy. Mov Disord 2009; 24: 2424–2427. 6 Djarmati A, Schneider SA, Lohmann K, et al. Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol 2009; 8: 447–452. 7 Houlden H, Schneider SA, Paudel R, et al. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 2010; 74: 846–850. 8 Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence variants in primary dystonia. Neurology 2010; 74: 229–238. Citing Literature Volume26, Issue91 August 2011Pages 1775-1776 ReferencesRelatedInformation

The classification of abnormal posture and the assessment of the affected muscles in cervical dystonia (CD) have changed in recent years. To determine the frequency of injected muscles, we studied 306 patients with CD. The mean age was 55.5 ± 13.1 years (range 21–90), 67% were female. Splenius capitis was the most commonly injected muscle (83%), followed by sternocleidomastoid (79.1%), and trapezius muscles (58.5%). The three next most common were the levator scapulae, semispinalis capitis, and obliquus capitis inferior muscles. The study shows that the most commonly injected muscles have remained unchanged over the past few decades, although the concept has changed. However, several new muscles have been added that were previously never, or hardly ever, considered.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

<strong>Background:</strong> Botulinum neurotoxin’s degree of effectiveness on upper limb tremor is subject to debate; although this treatment reduces the tremor’s amplitude, a clear functional benefit has not been demonstrated. The objective of this study was to assess the effect of botulinum neurotoxin type A treatment on activities of daily living and quality of life in patients with upper limb tremor. <strong>Methods:</strong> We retrospectively examined the medical records of 50 consecutive patients treated with botulinum neurotoxin for upper limb tremor that was refractory to oral medication. One month after the injection, the patient was evaluated according to the Quality of Life in Essential Tremor Questionnaire, and the Essential Tremor Embarrassment Assessment. <strong>Results:</strong> Full data sets were available for 38 patients suffering variously from essential tremor (<em>n</em> = 21), Holmes tremor secondary to a focal brain lesion (n = 8), idiopathic dystonic tremor (n = 4), primary writing tremor (n = 4), and Parkinson's disease (n = 1). The Quality of Life Essential Tremor Questionnaire and the Essential Tremor Embarrassment Assessment scores improved significantly (p &lt; 0.001) in the study population as a whole, and in the essential tremor and Holmes tremor subgroups. <strong>Discussion:</strong> Botulinum neurotoxin treatment of patients with upper limb tremor is associated with improved quality of life and activities of daily living, irrespective of the tremor’s etiology. Long-term treatment enables the physician to adjust the injection strategy to the patient’s needs. Our study was limited by its retrospective design. The results must therefore be confirmed in a prospective, double-blind, placebo-controlled, randomized clinical trial.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated with dopamine agonist treatment. Although discontinuation of dopamine agonist is recommended, ICD management has not been precisely stated. The aims of the study were to describe demographic and clinical characteristics in a group of PD patients with ICDs and to evaluate the management of dopamine agonist treatment proposed to the same patients in order to treat the ICDs.Thirty-five PD patients with ICD and 607 PD patients without ICD were studied. In the ICD group, demographic and clinical data were collected prospectively (ICD characteristics, motor and cognitive evaluation); demographic and clinical data were obtained retrospectively in the group without ICD.In the ICD group, the sex ratio was 2.9 (versus 1.2 in the absence of ICD; p<0.05), the mean age was 57.5 years (versus 66.9 years; p<0.01) and the mean age at PD onset was 48.3 years (versus 55.5 years; p<0.01). All ICD patients were receiving a dopamine agonist when the ICD started (versus 50.9 % of patients receiving a dopamine agonist in the absence of ICD; p<10(-6)). In mean, ICDs started 2.8 years before they were diagnosed. No particular dopamine agonist was associated with ICDs more frequently than the others. Discontinuation of the dopamine agonist was the treatment the more frequently associated with the recovery of ICDs (93.3 %). Dose lowering and the change of dopamine agonist resulted in complete regression of ICDs respectively in 9.1% and 33.3% of patients.Young age, male gender and young age at PD onset are frequent in PD patients developing ICDs, as already described in American or Asian cohorts. We highlighted a long diagnosis delay and confirmed the strong efficacy of dopamine agonist withdrawal.

Botulinum neurotoxin's degree of effectiveness on upper limb tremor is subject to debate; although this treatment reduces the tremor's amplitude, a clear functional benefit has not been demonstrated. The objective of this study was to assess the effect of botulinum neurotoxin type A treatment on activities of daily living and quality of life in patients with upper limb tremor.We retrospectively examined the medical records of 50 consecutive patients treated with botulinum neurotoxin for upper limb tremor that was refractory to oral medication. One month after the injection, the patient was evaluated according to the Quality of Life in Essential Tremor Questionnaire, and the Essential Tremor Embarrassment Assessment.Full data sets were available for 38 patients suffering variously from essential tremor (n = 21), Holmes tremor secondary to a focal brain lesion (n = 8), idiopathic dystonic tremor (n = 4), primary writing tremor (n = 4), and Parkinson's disease (n = 1). The Quality of Life Essential Tremor Questionnaire and the Essential Tremor Embarrassment Assessment scores improved significantly (p < 0.001) in the study population as a whole, and in the essential tremor and Holmes tremor subgroups.Botulinum neurotoxin treatment of patients with upper limb tremor is associated with improved quality of life and activities of daily living, irrespective of the tremor's etiology. Long-term treatment enables the physician to adjust the injection strategy to the patient's needs. Our study was limited by its retrospective design. The results must therefore be confirmed in a prospective, double-blind, placebo-controlled, randomized clinical trial.

Early onset torsion dystonia are rare movement disorders. Molecular defect is known for only a subgroup, consisting of a unique and recurrent mutation in the TOR1A gene. We undertook a nationwide census of French TOR1A-mutation carriers and the assessment of clinical associated signs. Overall, 53 index cases and 104 relatives were studied and haplotypes linked to the mutation constructed. The previously reported Ashkenazi-Jewish haplotype was found in 11 families with the remainder carrying distinct haplotypes suggesting independent mutation events. This study demonstrates the scarcity of this disease in France with estimated disease frequency of 0.13:100,000 and mutation frequency of 0.17:100,000.

We report the case of a young woman who suffered from a seizure after use of almotriptan. There was a recurrence with ergotamine. We discuss possible link with susceptibility genes.

The monogenic forms of Parkinson's disease represent <10% of familial cases and a still lower frequency of sporadic cases. However, guidelines to orient genetic testing are lacking. The aim was to establish the interest of multiplex ligation-dependent probe amplification (MLPA) as a primary screening test and to propose clinical criteria to guide genetic diagnostic tests for patients with suspected Mendelian Parkinson's disease.In all, 567 patients with parkinsonism from 547 unrelated families were recruited and two MLPAs were performed for each. All pathogenic G2019S variants in the LRRK2 gene were confirmed by Sanger sequencing and the PRKN gene was screened for a second mutation in the cases of one heterozygous structural variant in the PRKN gene.The performance of MLPA was 51/567 (9%) for the entire cohort and included 27 (4.8%) LRRK2 G2019S mutations, 19 (3.4%) PRKN mutations and five (0.9%) SNCA locus duplications. The variables significantly associated with a positive test in the total cohort were North African ancestry (p < 0.0001), female sex (p = 0.004) and younger age at onset (p < 0.0008).Retrospective analysis allowed us to refine our indication criteria: (i) North African ancestry, (ii) an age at onset <40 years or (iii) a familial history of parkinsonism with at least one affected first-degree relative. Our study highlights the interest of MLPA testing for other parkinsonism cases with a family history, especially for patients with dementia with Lewy bodies or a multiple-system-atrophy-like phenotype.

La toxine botulique est utilisée dans le traitement de nombreuses affections neurologiques. Les possibilités de formation à ces injections sont nombreuses mais leur contenu est hétérogène. L’objectif du travail consistait à évaluer et identifier, au niveau national, les pratiques d’injection et les ressources dont disposent les injecteurs ainsi que leurs besoins. Un questionnaire informatique a été adressé à 221 neurologues. Cent réponses ont été obtenues. L’âge médian des répondants se situait entre 31 et 40 ans. La plupart d’entre eux ont travaillé en Centre Hospitalier Universitaire. L’expérience médiane était de 10 à 20 ans. La toxine botulique était principalement utilisée dans des indications disposant d’une autorisation de mise sur le marché, mais plus de 80 % des répondants injectaient dans au moins une indication hors autorisation de mise sur le marché. Un repérage électrophysiologique ou échographique était exploité par la majorité des injecteurs. Plus de 60 % des neurologues ont souhaité bénéficier de documents supplémentaires à destination des patients. Par conséquent, une lettre d’information pour les indications hors autorisation de mise sur le marché sera mise à disposition prochainement par la Société Francophone des Mouvements Anormaux. Botulinum toxin is used to treat many neurological conditions. Numerous training possibilities exist for injecting botulinum toxin but their content is heterogeneous. The objective of this study was to determine what the injection practices are in France and ascertain the resources and needs of the injectors. An internet questionnaire was sent to 221 neurologists, and 100 responses were obtained. The age of the responding neurologists ranged between 31 and 40 years. Most of them worked at a University Medical Center. Experience with botulinum toxin ranged from 10 to 20 years. Botulinum toxin was mainly used in indications with marketing authorization, but more than 80% of neurologists injected in at least one off-label indication. Electrophysiological or ultrasound guidance was used by the majority of the injectors. More than 60% of the neurologists expressed interest in additional documents intended for patients. Consequently, an information letter for off-label indications will be made available shortly by the French Society of Movement Disorders (Société Francophone des Mouvements Anormaux).

The objective was to assess the value of single photon emission computerized tomography (SPECT) and factorial discriminant analysis (FDA) in the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).Sixty-two patients with clinical diagnoses of either CBD, PSP or PD were studied using brain HmPaO-SPECT. Thirteen pairs of regions of interest (ROIs) were drawn on the slices located 50mm and 90mm above the canthomeatal plane. Twenty-six uptake indices and 13 asymmetry indices were determined. FDA was performed in order to determine whether or not the patients could be classified into the correct clinical group on the basis of SPECT data alone. The most discriminant parameters were used to generate two predictive scores, which were tested in a second group of 15 patients.FDA of all 39 variables correctly classified all the patients. A subset of 10 variables was used to build predictive scores, which correctly classified 90% of PD patients, 100% of PSP patients and 86% of CBD patients. When tested in the validation group of 15 patients, these predictive scores correctly classified 87% of the individuals. The frontal medial, temporoparietal and parietal regions were the most discriminant.Using SPECT data alone, this study enabled us to distinguish between PD, PSP and CBD in patients with clear clinical presentations of the diseases in question. This novel, statistical approach provides reliable information. However, a prospective study dealing with de novo parkinsonian syndromes will be necessary.

Botulinum neurotoxin type A (BoNT/A) injections are the established treatment in cervical dystonia (CD). But clinical practice regarding the choice of muscles into which injections are made varies between centres. Until now, there have been no dose-per-muscle recommendations based on 'searching the dose' clinical trial data.We therefore examined the dosages under real world conditions at seven international movement disorders centres, using an identical clinical approach.We examined 305 patients with CD (55.6 ± 13.2 years, 204 female). The most commonly injected muscles were the splenius capitis (84.9%), sternocleidomastoid (80.3%), trapezius (59.7%), levator scapulae (49.8%), semispinalis capitis (39%), and obliquus capitis inferior (36.7%). The mean total dose per treatment session with aboBoNT/A was 652.5 (SD = 285.5), with onaBoNT/A it was 159.5 (SD = 62.4), and with incoBoNT/A it was 173.4 (SD = 99.2) units. The doses injected into each muscle in the ona- or incoBoNT/A groups were between 19.7 and 48.2 units, with the highest dose for the splenius capitis with 49.2 ± 26.0 units. The doses in the aboBoNT/A group were between 69.6 and 146.4 units, and the highest dose being injected into the splenius capitis (139.6 ± 80.7 units).In clinical trials the doses per muscle are based on an arbitrary decision. In our study, the doses were lower than in other studies, which may be due to the number of muscles per session, the use of ultrasound guidance (and therefore more precise injections), as well as the use of the Col-Cap concept. Our results exemplify everyday practice, and may help as the basis for recommendations and further investigations.

Abstract In writer's cramp (WC), a form of focal hand dystonia, cortical GABAergic inhibitory mechanisms are altered and may cause involuntary tonic contractions while writing. The objective of this study was to explore the time course of long‐interval intracortical inhibition (LICI) that involves gamma‐amino butyric acid (GABA)‐B transmission and late cortical disinhibition (LCD) (that combines GABA‐A and GABA‐B mechanisms) in patients with WC and in control subjects. A double pulse transcranial magnetic stimulation protocol was used to evoke LICI and LCD while the subjects either gripped a cylinder between their thumb and index fingers or relaxed all their upper limb muscles. We measured the ratio between primed and unprimed motor evoked potential in the first dorsal interosseous at interstimulus intervals ranging between 60 and 300 ms. Though the cortical silent period was not different between the groups, LICI lasted longer in patients with WC, that is, LCD was delayed for more than 30 ms and reached a higher level. In addition to the alteration of inhibitory mechanism mediated by GABA‐B transmission, LCD which probably involves presynaptic inhibition is also modified in patients with WC with possible consequences on the activity of primary motor cortex inhibitory and excitatory circuits which control the hand muscles.caus

Les dyskinésies sont des complications bien connues du traitement dopaminergique dans la maladie de Parkinson. Dans l’atrophie multi-systématisée de type parkinsonien, ces manifestations sont moins étudiées de par la faible incidence de la maladie et de leur fréquence relativement faible au sein même de ce cadre pathologique. L’optimisation du traitement dopaminergique au cours de l’AMS se heurte à plusieurs écueils : d’une part, le bénéfice apporté est parfois difficile à vérifier, d’autre part, la sémiologie des dyskinésies dopa-induites est méconnue. Nous présentons le cas d’un patient de 65 ans présentant des accès dystoniques cervico-faciaux sériels dans le cadre d’une atrophie multi-systématisée de type parkinsonien répondant partiellement à la stimulation dopaminergique continue par une pompe à apomorphine. Dyskinesias are well-known side effects of the dopaminergic treatment in Parkinson's disease. In multiple system atrophy (MSA), these events are less well studied because of the low incidence of this disease and their relatively low frequency amongst patients suffering from this condition. Optimizing dopaminergic treatment in patients with MSA is difficult for two main reasons: the clinical benefit is sometimes hard to evaluate and the signs of the dopa-induced dyskinesia are not well-known. We report the case of a 65-year-old male patient with a parkinsonian variant of MSA who present repeated dystonic accesses involving the neck and face and partially responsive to continued dopaminergic stimulation with an apomorphine pump.

[123I]-Ioflupane single photon emission computed tomography (SPECT) is widely used to evaluate the impairment of the nigrostriatal pathway in patients with parkinsonism. We describe a patient with visually undetectable specific striatal [123I]-ioflupane binding in the striatum. Of the 950 [123I]-ioflupane SPECT scans of patients acquired in our department, only one did not show any visually detectable striatal binding. To investigate this issue, we described multimodality imaging in this patient, including a second [123I]-ioflupane SPECT with a higher dose of [123I]-ioflupane, a [18 F]-fluoro-l-dopa positron emission tomography (PET), a new MRI and an FDG-PET. Clinical and imaging data (FDG-PET and MRI) led to a diagnosis of progressive supranuclear palsy (PSP). Visual analysis of the second [123I]-ioflupane SPECT performed with a higher dose of [123I]-ioflupane confirmed nearly undetectable specific striatal binding of the tracer. The [18 F]-fluoro-l-dopa-PET striatal binding was decreased. After ruling out all technical issues, an undetectable specific [123I]-ioflupane striatal binding in a patient with parkinsonism can be a sign of severe DaT loss as we have observed in a case of probable PSP even with moderate motor signs.

•TOR1A mutation may present as an (almost) isolated writing tremor. •DYT1, DYT7 and DYT11 should primarily be considered in patients with dystonic writing tremor. •To reduce the risk of late diagnosis, it is mandatory to record the family medical history in patients with writing tremor.

L'expérimentation animale ne s'est pas intéressée spécifiquement au problème des fortes doses de toxine botulinique. Cependant, elle est riche d'enseignements à plusieurs titres. Tout d'abord, elle montre que l'efficacité est corrélée non linéairement à la dose, mais jusqu'à un certain point au-delà duquel l'utilisation de doses supérieures n'apporte plus de bénéfice supplémentaire. Il est d'autant moins intéressant de dépasser cette dose ≪ plafond ≫ que le risque de migration en dehors du muscle cible apparaît, non pas tant régional que surtout systémique. L'efficacité et le risque pourraient différer selon que l'on injecte un ou plusieurs muscles, et selon le type de toxine utilisé. Ce qui est constaté chez l'animal tend à se vérifier empiriquement en pathologie humaine. Ainsi, les données expérimentales apportent un modèle théorique à notre expérience clinique quotidienne et peuvent nous aider à la manipulation des fortes doses de toxine botulinique. Elles permettent notamment de prendre la mesure d'un risque systémique qui, le plus souvent ≪ abstrait ≫ voire quasi ≪ conceptuel ≫ dans notre pratique quotidienne, prend ici toute sa signification. Experimental studies in the animal have not been designed to specifically address the use of high doses of botulinum toxinum. However, it allows us to draw some very interesting findings. First, it has been showed that efficacy correlates to the dose, albeit up to a point beyond higher doses do not induce a greater benefit. Over this “ceiling” dose, the risk of migration outside the targeted muscle increases. The systemic risk is superior to the local risk. The efficacy could differ according to the number of injected muscles, and according to the type of toxin. What has been observed in the animals tend to be confirmed in human, despite precise studies are still lacking. Thus, experimental data support our daily clinical experience and provide us some very useful informations when high doses are injected. They especially help us to keep in mind the systemic risk which is, most of the time, unclear in our daily practice.

Le très grand bénéfice des deux traitements pivots dans la Maladie de Parkinson (MP) que sont la L-dopa et la stimulation subthalamique sont mis en péril à long terme par l’apparition de troubles axiaux avec des freezing de la marche (FOG). Ceux-ci pourraient être en partie liés à une déplétion dopaminergique et noradrénergique dans les boucles striato-frontales. Le méthylphenidate (MPD) pourrait augmenter le niveau dopaminergique et noradrénergique synaptique striatal par inhibition des transporteurs pré synaptique. Nous avons étudié si le MPD améliorait les FOG et les capacités attentionnelles chez les patients non déments au stade avancé de la MP. Dans cette étude randomisée en double aveugle versus placebo (ClinicalTrials.gov : NCT00914095), les patients, de 13 centres en France, qui avaient des troubles axiaux sévères avec des FOG, en dépit d’un contrôle optimal des fluctuations motrices par dopathérapie et stimulation subthalamique, étaient éligibles pour l’inclusion. Les patients étaient assignés au groupe MPD (1 mg/kg/j) ou placebo pendant 3 mois. Le critère primaire était le nombre de pas au Stand Walk Sit Test (SWS) dans des conditions standardisées sans L-dopa entre la première et la dernière visite. Quatre vingt patients ont été screenés et 69 patients éligibles ont terminé l’étude. Par rapport au groupe placebo, on notait sous MPD une diminution significative du nombre de pas et du temps (au SWS), du nombre de freezing (au FOG trajectory) et du score de handicap moteur (UPDRS III) sans L-dopa associée à une diminution du nombre de freezing après test au L-dopa. L’attention et la somnolence étaient également améliorées sous MPD. Il n’y avait pas d’aggravation significative des dyskinésies, ni de l’humeur ou de comportement addictif. Une inhibition des transporteurs pré synaptiques de dopamine était observée sur le DaTSCAN™. Le MPD améliore le freezing de la marche avec un impact positif sur la cognition et le comportement dans une population sélectionnée de patients parkinsoniens évolués sous stimulation subthalamique avec des doses modérées quotidiennes de L-dopa.

Le valproate de sodium injectable est présenté comme un produit pratique et dénué d'effets secondaires. Qu'en est-il de sa place, de ses indications et de sa posologie en situations d'urgence? Après l'avoir utilisé sur une période d'1 an dans notre service d'urgences Smur, quelques commentaires sont à faire, face aux résultats et à la revue de la littérature: un faible nombre d'inclus dans notre série (n = 16), avec une efficacité sur huit cas sans récidive à des doses de charge supérieures à 25 mg/kg, un surcroît de traitement non négligeable, peu d'études de référence en ce qui concerne les indications d'urgence et la posologie.The intravenous sodium valproate has been presented as a practical product devoid of side effects. What should its use, indications and dosage be in emergency situations? After having used the substance for one year in our Emergency Room Department and Emergency Mobile Medical Unit, some coments need to be made concerning our results and in light of the written reviews: a low number of cases in our series (n = 16), eight non-recurring cases at doses of amounts greater than 25 mg/kg were effective, a not unimportantly hight cost of treatment, and few studies for reference in regards to the indications of emergency and dosage.

L’implication de facteurs génétiques dans la maladie de Parkinson (MP) a été démontrée par la découverte de loci chromosomiques liés à la maladie puis des gènes responsables de formes de transmission mendélienne. Concernant les formes autosomiques dominantes, les gènes SNCA et LRRK2 sont formellement associés à la maladie. Le gène SNCA joue un rôle central dans la pathogénie de la maladie et la mutation G2019S du gène LRRK2 est la plus fréquente en population caucasienne. D’autres gènes ont été plus récemment associés à ces formes comme VPS35, EIF4G1 et les gènes des ataxies spinocérébelleuses 2 et 3. Concernant les formes autosomiques récessives, les gènes PRKN, PINK1 et DJ-1 sont identifiés et les mutations de la Parkin représentent près de 50 % des formes précoces de la maladie. À côté de ces formes monogéniques, les études d’association pangénomique ont identifié des facteurs de susceptibilité génétique à développer la MP. Les variants les plus robustes sont retrouvés au sein des gènes SNCA, MAPT et LRRK2. Des mutations hétérozygotes du gène de la glucocérébrosidase constituent également un facteur de risque pour la MP voire seraient des mutations causales à pénétrance réduite. L’étude de la pathogénie de ces différents gènes a permis de proposer des mécanismes associés à la neurodégénérescence comme le dysfonctionnement mitochondrial, le stress oxydant, l’altération des voies de dégradation des protéines et des organites cellulaires et la perturbation du transport des vésicules. Le développement actuel de puissantes techniques de séquençage permettra d’identifier de nouveaux variants pathologiques associés à la MP et ainsi de mieux comprendre les mécanismes associés à la mort neuronale dans le but de développer des traitements efficaces sur le cours évolutif de la maladie.The role of genetic factors in Parkinson's disease has been demonstrated by the discovery of chromosomal loci associated with the disease and genes responsible for Mendelian forms. Among autosomal-dominant forms, the genes SNCA and LRRK2 are formally associated with the disease. SNCA gene plays a central role in the pathogenesis of the disease and the G2019S mutation of LRRK2 is the most common in the Caucasian population. Other genes have recently been associated with such forms as VPS35, EIF4G1 and spinocerebellar ataxias 2 and 3 genes. Among autosomal recessive forms, PRKN, PINK1 and DJ-1 genes are identified and Parkin mutations account for 50 % of early forms of the disease. Besides these monogenic forms, genome-wide association studies have identified susceptibility factors to develop Parkinson's disease. Variants which are the most robust are found within SNCA, MAPT and LRRK2 genes. Heterozygous mutations of the glucocerebrosidase gene are also risk factors for Parkinson's disease or may be causal mutations with reduced penetrance. The study of the pathogenesis of these genes has led to propose mechanisms associated with neurodegeneration such as mitochondrial dysfunction, oxidative stress, altered proteins and cellular organelles degradation pathways and disruption of vesicular transport. The current development of powerful next-generation sequencing technologies will identify new variants associated with Parkinson's disease and will help better understand the mechanisms associated with neuronal death in order to develop treatments effective on disease progression.

Le caractère dystonique, essentiel ou primaire du tremblement de l’écriture(TE) est encore débattu. Le caractère asymétrique, l’association à une posture dystonique et la réponse aux anticholinergiques supportent l’hypothèse dystonique. Un patient de 51 ans consultait en 1999 pour un tremblement isolé de l’écriture apparue à l’âge de 41 ans. Son frère aîné étant déjà suivi pour une dystonie généralisée rattachée à une mutation DYT1, une recherche de cette mutation était effectuée chez le patient présentant un TE et se révélait également positive. Durant les 13 premières années du suivi, le mouvement anormal s’est limité à un tremblement à type de prono-supination spécifique de l’écriture, stable dans le temps. Le caractère essentiel du tremblement était écarté par l’enregistrement électrophysiologique. Les injections de toxine botulique et les traitements par voie orale n’apportèrent aucun bénéfice. Les caractéristiques du mouvement anormal évoluèrent avec l’apparition d’une composante posturale et de repos au tremblement, ainsi que d’une dystonie en flexion du poignet, constatées à l’âge de 68 ans, soit 27 ans après le début de la maladie. La famille présentée illustre bien la variabilité phénotypique des mutations DYT1. Une dystonie est exceptionnellement révélée par un tremblement isolé. Si le tremblement est premier, la dystonie apparaît en général peu de temps après. Notre observation montre qu’un délai beaucoup plus important est possible. Cette observation constitue par ailleurs le premier cas de tremblement isolé de l’écriture rattaché à une mutation DYT1. Un TE peut constituer le premier symptôme d’une dystonie et implique un suivi prolongé pour ne pas méconnaître une dystonie sous-jacente. La recherche de la mutation DYT1 doit être envisagée.

Abstract Levels of expression or of phosphorylation of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have the potential for use as disease or pharmacodynamic biomarkers. LRRK2 phosphorylation levels at the S910-S935-S955-S973 phosphosites are reduced for most disease mutant forms of LRRK2, while for phospho-S1292, phospho-T72-Rab8 and phospho-T73-Rab10 levels are increased for most mutants. In addition, all of these 5 phosphosites on LRRK2 are rapidly dephosphorylated upon LRRK2 inhibitor treatment, considered potential therapeutics. The main objective of this study is therefore to characterize leucine-rich repeat kinase 2 (LRRK2) and Rab8/10 in human, non-human primate and rat urine for use as potential disease or pharmacodynamic biomarkers. With urine collected from human subjects as well as animals, we have applied an ultracentrifugation based fractionation protocol to isolate small extracellular vesicles (EVs). We used western blot with antibodies directed against LRRK2, LRRK2 phosphorylation sites as well as Rab8 and Rab10 total and phosphorylated proteins in order to measure these LRRK2 and Rab epitopes in urinary EVs (uEVs). We confirm the presence of LRRK2 and Rab8/10 in human and non-human primate (NHP) uEVs, including total LRRK2 as well phosphorylated forms of LRRK2 pS910, pS935, pS955, pS973, pS1292 and phosphorylated Rab8 and Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, but did not differ significantly between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to an increase in Rab8 levels and a decrease in S910-LRRK2 and S935-LRRK2 phosphorylation rates. In animals, we found that acute treatment with LRRK2 kinase inhibitor led to decreases in Rab10 phosphorylation rates and to a decrease in pS935-LRRK2 rates in uEVs from NHPs. The identification of changes in LRRK2 phosphorylation at heterologous phosphorylation sites in uEVs of PD patients further reinforces the potential of the LRRK2-Rab pathway as a source of PD biomarkers in uEVs.

La maladie de Parkinson est une maladie neurodegenerative grave et frequente de l'adulte. Ses traitements restent purement symptomatiques et sont frequemment responsables d'effets indesirables a court ou a long terme. La mise a disposition d'un traitement permettant de ralentir le cours evolutif de cette maladie constitue donc un enjeu de sante majeur. Pour limiter l'evolution de la maladie de Parkinson, un traitement devra attenuer plusieurs des mecanismes de mort neuronale impliques dans cette affection. Les activateurs du Peroxysome Proliferator-Activated Receptor (PPAR) alpha constituent des candidats interessants par leurs proprietes anti-inflammatoires, anti-oxydantes et anti-apoptotiques. Nous avons teste plusieurs activateurs du PPAR alpha : des fibrates, qui en sont des activateurs directs, et des inhibiteurs de la 3-hydroxy 3-methyl glutaryl co-enzyme A reductase -ou statines- qui en sont des activateurs indirects (par augmentation de sa sensibilite a ses agonistes naturels). Les traitements ont d'abord ete testes dans des modeles murins de maladie de Parkinson. Le fenofibrate delivre par voie orale dans l'alimentation s'est avere efficace chez la souris C57Bl/6 intoxiquee par le 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), en supprimant la perte des neurones dopaminergiques dans la substance noire compacte (comptage des neurones marques par anticorps anti-tyrosine hydroxylase (TH)), et en reduisant la perte de l'immunoreactivite striatale (mesure de densite optique apres marquage par anticorps anti-TH) (Kreisler A. Et al. , Brain Research 2007). A egalement ete montree l'amelioration sensible de plusieurs parametres moteurs mesures par actimetrie, notamment la distance totale parcourue, la vitesse moyenne des deplacements, le temps passe au repos, le temps passe dans la zone peripherique de l'aire de mesure et le nombre de mouvements lents. Cet effet ne semble pas passer par une modification du metabolisme du MPTP : la quantite de 1-methyl-4-phenyl pyridinium (MPP+) (metabolite actif du MPTP dose par chromatographie liquide haute performance / spectroscopie de masse en mode tandem) etait inchangee que les animaux intoxiques par MPTP recoivent ou non le traitement par fenofibrate. Les experiences realisees n'ont pas montre d'effet anti-oxydant du fenofibrate au niveau striatal ou cortical (mesure de l'activite d'enzymes anti-oxydantes : Cu/Zn superoxyde dismutase et gluthation peroxydase). Le bezafibrate, l'atorvastatine et la simvastatine n'avaient pas d'effet favorable ; un effet deletere etait meme observe avec les statines en terme de survie des neurones dopaminergiques de la substance noire compacte. Chez le rat Wistar intoxique par 6-hydroxydopamine, le traitement par fenofibrate n'avait pas d'effet significatif, que ce soit en terme de survie neuronale ou d'amelioration comportementale (sensibilisation comportementale par injections repetees d'apomorphine), meme si une tendance favorable etait observee. La presence du PPAR alpha a ete confirmee par immunohistochimie dans les neurones dopaminergiques mesencephaliques des souris C57Bl/6. Nous avons etudie retrospectivement l'effet des fibrates et des statines dans une cohorte de 419 patients presentant une maladie de Parkinson, ces traitements etant prescrits pour un dyslipidemie. Les resultats indiquent que les fibrates et les statines, introduits avant le debut clinique de la maladie de Parkinson, permettent de retarder de neuf ans en moyenne l'âge auquel en apparaissent les premiers symptomes : 54,6+/-11,4 ans en l'absence d'hypolipemiant, 63,6+/-8,9 ans avec une statine, 63,3+/-8,9 ans avec un fibrate. Le suivi de certains patients indique que les statines semblent aussi ralentir l'evolution de la maladie (Mutez M. , Kreisler A. Et al. , soumis) : lors d'un suivi sur deux ans, la stabilite des parametres moteurs de l'Unified Parkinson's Disease Rating Scale (UPDRS III) etait obtenue avec une faible augmentation du traitement anti-parkinsonien en cas de traitement par statine (+24,4 mg d'equivalent de L-Dopa) mais necessitait une augmentation sensiblement plus importante de l'equivalent de L-Dopa en l'absence de traitement hypolipemiant (+212,2 mg). Les fibrates n'avaient pas d'influence significative. Nos resultats indiquent un effet favorable de certains des traitements evalues, aussi bien chez la souris intoxiquee par le MPTP, modele experimental de maladie de Parkinson, que chez le patient parkinsonien. La discordance des resultats obtenus chez l'animal remet en question l'hypothese selon laquelle l'effet est medie par une activation du recepteur PPAR alpha. Il est donc necessaire de determiner si le fenofibrate exerce le meme effet chez la souris dont le gene codant pour le PPAR alpha a ete invalide. Les mecanismes de la mort neuronale qui sont attenues par le fenofibrate doivent aussi etre precises : inflammation, stress oxydant, apoptose. Une etude prospective randomisee-controlee visant a evaluer l'effet des fibrates et des statines sur le cours evolutif de la maladie de Parkinson est egalement en projet.

La physiopathologie de maladie de Parkinson repose sur le stress oxydant et l’inflammation. L’activation du Peroxisme Proliferator-Activated Receptor-alpha limite ces mécanismes et pourrait exercer un effet neuroprotecteur. Étudier si un traitement par fibrate ou statine, respectivement activateurs directs et indirects du Peroxisme Proliferator-Activated Receptor-alpha, exerce un effet neuroprotecteur lors de la maladie de Parkinsnon (MP). Nous avons inclus 419 parkinsoniens consécutifs : 44 recevaient une statine, 29 un fibrate et 346 aucun traitement hypolipémiant. Nous avons comparé l’âge de début de la maladie selon le groupe (ANOVA). Une étude rétrospective sur des sous-groupes de 18 patients sous statines et 10 patients sous fibrates (appariés avec des témoins du groupe sans hypolipémiant) comparait la progression du score UPDRS moteur et de la posologie de L-dopa sur deux ans (modèle linéaire mixte). L’âge moyen du début de la MP était inférieur chez les patients sans hypolipémiant (54,6 ans) que chez les patients sous statines (63,6 ans) ou fibrates (63,3 ans). La progression de dose de L-dopa était moindre dans le groupe sous statines (+24 mg) que dans le groupe contrôle (+200 mg) ; l’évolution du score moteur était similaire. Il n’y avait pas de différence lors du suivi des patients sous fibrates par rapport aux contrôles. Nos résultats indiquent un recul de l’âge de début de la MP sous statines ou fibrates et une progression plus lente du traitement dopaminergique sous statines, alors même que la perte dopaminergique est avancée : 17 des 18 sujets avaient débuté leur statine après le début de la MP. Le faible effectif du groupe fibrates limite la puissance des analyses. Les statines semblent exercer un effet neuroprotecteur plus net que les fibrates lors de la MP. Ces données, issues d’un travail rétrospectif, nécessitent confirmation par une étude randomisée contre placebo.

La stimulation du noyau sous-thalamique (NST) semble réduire les fluctuations et les dyskinésies dopa-induites dans la maladie de Parkinson, mais cet effet a été beaucoup moins étudié que les autres symptômes de la maladie. Évaluer précisément l’efficacité à long terme de la stimulation du NST sur les complications motrices dopa-induites. 36 patients furent évalués avant la chirurgie et 1 et 5 ans après, avec les échelles du CAPSIT-PD pour la dystonie off drug et les dyskinésies on drug, stimulateur éteint ou allumé, avant et après l’administration de L-dopa dispersible. les échelles UPDRS II, IV et de Schwab et England (SE) furent aussi utilisées. L’UPDRS IV s’améliora de 62 % à 1 an et 68 % à 5 ans, l’UPDRS IVA de 72 % à 1 an et 71 % à 5 ans. Les dyskinésies on drug s’améliorèrent à 1 an de 61 % on stim et 60 % off stim, à 5 ans de 85 % on stim et 77 % off stim. Les dystonies off drug s’améliorèrent à 1 an de 45 % on stim et 12 % off stim, à 5 ans de 66 % on stim et 35 % off stim. Pour l’UPDRS II et la SE, il y eut une amélioration significative à 1 et 5 ans. À 5 ans, 1 patient/3 avait le même score on et off drug à l’UPDRS II (aucun à 1 an), et à la SE (16 % à 1 an). Il y a un effet positif de la stimulation du NST sur les complications liées à la L-dopa qui persiste et même augmente à long terme. Les scores de dyskinésie sont améliorés à la fois de manière chronique et lors d’un test d’administration aiguë de L-dopa. De plus cet effet persiste lorsque le stimulateur est éteint. La diminution des doses de L-dopa après stimulation peut expliquer en partie l’amélioration des complications motrices, mais nos résultats sont aussi en faveur du renversement des mécanismes entraînant ces complications.

Plusieurs études ont montré que les injections de toxine botulique réduisent l’amplitude du tremblement de membre supérieur. Leur bénéfice sur les activités de la vie quotidienne reste cependant incertain. Préciser les caractéristiques cliniques d’un groupe de patients présentant un tremblement de membre supérieur réfractaire aux médications per os, les modalités d’injections de toxine botulique et la réponse au traitement. L’étude fut menée sur 44 patients présentant un tremblement de membre supérieur traité par toxine botulique. Furent évalués : étiologie, complexité du tremblement ; posologies (unités onabotulinumtoxinA), effets indésirables des injections ; amélioration clinique un mois après les injections par les échelles The quality of life essential tremor (QUEST), Essential tremor embarrassment assessment (ETEA), Clinical Global Impression-Improvement (CGI-I). Variables quantitatives : test-t de Student. Âge moyen : 64,2 ± 16,7 ans. Étiologies principales : 21 tremblements essentiels (TE), 13 tremblements de Holmes (TH). Posologie moyenne : TE = 17,1 ± 6,5 ; TH = 30,5 ± 11,6. À un mois (chez 31 patients dont 16 TE et sept TH) : déficit moteur 22,6 %, douleurs 12,9 % ; aucune amélioration 9,7 %, amélioration légère 29,0 %, amélioration modérée 32,3 %, amélioration importante 29,0 % (CGI-I) ; activités de vie quotidienne améliorées dans la population globale et les sous-groupes TE et TH. Lors de cette étude, muscles et posologies étaient adaptés à la séméiologie du tremblement, et plusieurs cycles d’injection préalables avaient permis une révision progressive de la stratégie. Cela nous distingue des études pionnières (procédure d’injection uniforme), ainsi que de certains travaux récents (stratégie adaptable mais analyse basée sur un seul cycle) et peut expliquer les résultats favorables. La toxine botulique améliore les activités de la vie quotidienne dans le tremblement du membre supérieur. Un bon résultat n’est souvent obtenu qu’après plusieurs cycles d’injections.

Dans la crampe de l’écrivain, une forme de dystonie focale de fonction, certains mécanismes inhibiteurs GABAergiques corticaux comme l’inhibition corticale à courte latence (SICI) sont altérés et pourraient être à l’origine de contractions toniques involontaires au cours du mouvement. D’autres mécanismes GABAergiques ont été mis en évidence chez l’homme, l’un mettant en jeu des récepteurs GABA-B, l’inhibition intracorticale à longue latence (LICI), l’autre, la désinhibition corticale à longue latence (LCD) associant les deux mécanismes GABA-A et GABA-B. Seules deux études ont exploré la LICI chez des patients atteints de crampe de l’écrivain, avec des résultats contradictoires. La LCD n’a quant à elle jamais été explorée chez ces patients. L’objectif de cette étude était d’étudier le décours de la LICI et de la LCD chez des patients atteints de la crampe de l’écrivain et des sujets contrôles. Un protocole de doubles chocs TMS a été utilisé : un premier choc supraliminaire était délivré en regard de la zone du cortex moteur primaire contrôlant le muscle premier intersosseus dorsalis, suivi à des intervalles compris entre 50ms et 300ms d’un second choc supraliminaire alors que les sujets réalisaient une tâche de pince de précision entre le pouce et l’index. Nos résultats montrent que la LICI était prolongée chez les patients dystoniques et que la LCD intervenait à des intervalles interstimuli plus longs et de manière plus marquée. Ces résultats suggèrent que les mécanismes GABA-B sont également altérés dans la crampe de l’écrivain et pourraient contribuer aux déficits sensorimoteurs.