Publications by authors named "Chloe Laurencin"

27 Publications

  • Page 1 of 1

Comparison of clinical outcomes and accuracy of electrode placement between robot-assisted and conventional deep brain stimulation of the subthalamic nucleus: a single-center study.

Acta Neurochir (Wien) 2021 May 2;163(5):1327-1333. Epub 2021 Mar 2.

Service de Neurologie C, Centre Expert Parkinson, Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, Hospices Civils de Lyon, 69003, Lyon, France.

Background: Several surgical methods are used for deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD). This study aimed to compare clinical outcomes and electrode placement accuracy after robot-assisted (RAS) versus frame-based stereotactic (FSS) STN DBS in Parkinson's disease.

Methods: In this single-center open-label study, we prospectively collected data from 48 consecutive PD patients who underwent RAS (Neuromate®; n = 20) or FSS (n = 28) STN DBS with the same MRI-based STN targeting between October 2016 and December 2018 in the university neurological hospital of Lyon, France. Clinical variables were assessed before and 1 year after surgery. The number of electrode contacts within the STN was determined by merging post-operative CT and pre-operative MRI using Brainlab® GUIDE™XT software.

Results: One year after surgery, the improvement of motor manifestations (p = 0.18), motor complications (p = 0.80), and quality of life (p= 0.30) and the reduction of dopaminergic treatment (p = 0.94) and the rate of complications (p = 0.99) were similar in the two groups. Surgery duration was longer in the RAS group (p = 0.0001). There was no difference in the number of electrode contacts within the STN.

Conclusion: This study demonstrates that RAS and FSS STN DBS for PD provide similar clinical outcomes and accuracy of electrode placement.
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http://dx.doi.org/10.1007/s00701-021-04790-7DOI Listing
May 2021

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Brain 2020 12;143(11):3242-3261

Département de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
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http://dx.doi.org/10.1093/brain/awaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719027PMC
December 2020

The blood copper isotopic composition is a prognostic indicator of the hepatic injury in Wilson disease.

Metallomics 2020 11 15;12(11):1781-1790. Epub 2020 Oct 15.

Univ Lyon, ENSL, Univ Lyon 1, CNRS UMR 5276, LGL-TPE, F-69007, Lyon, France.

Wilson disease (WD) is an autosomal recessive disorder of copper (Cu) metabolism. The gene responsible for WD, ATP7B, is involved in the cellular transport of Cu, and mutations in the ATP7B gene induce accumulation of Cu in the liver and ultimately in the brain. In a pilot study, the natural variations of copper stable isotope ratios (Cu/Cu) in the serum of WD patients have been shown to differ from that of healthy controls. In the present study, we challenged these first results by measuring the Cu/Cu ratios in the blood of treated (n = 25), naïve patients (n = 11) and age matched healthy controls (n = 75). The results show that naïve patients and healthy controls exhibit undistinguishable Cu/Cu ratios, implying that the Cu isotopic ratio cannot serve as a reliable diagnostic biomarker. The type of treatment (d-penicillamine vs. triethylenetetramine) does not affect the Cu/Cu ratios in WD patients, which remain constant regardless of the type and duration of the treatment. In addition, the Cu/Cu ratios do not vary in naïve patients after the onset of the treatment. However, the Cu/Cu ratios decrease with the degree of liver fibrosis and the gradient of the phenotypic presentation, i.e. presymptomatic, hepatic and neurologic. To get insights into the mechanisms at work, we study the effects of the progress of the WD on the organism by measuring the Cu concentrations and the Cu/Cu ratios in the liver, feces and plasma of 12 and 45 week old Atp7b mice. The evolution of the Cu/Cu ratios is marked by a decrease in all tissues. The results show that Cu accumulates in the liver preferentially to Cu due to the preferential cellular entry of Cu and the impairment of the Cu exit by ceruloplasmin. The hepatic accumulation of monovalent Cu is likely to fuel the production of free radicals, which is potentially an explanation of the pathogenicity of WD. Altogether, the results suggest that the blood Cu/Cu ratio recapitulates WD progression and is a potential prognostic biomarker of WD.
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http://dx.doi.org/10.1039/d0mt00167hDOI Listing
November 2020

Impact of Subthalamic Deep Brain Stimulation on Impulse Control Disorders in Parkinson's Disease: A Prospective Study.

Mov Disord 2021 03 6;36(3):750-757. Epub 2020 Oct 6.

Department of Neurology, NS-PARK/F-CRIN, Assistance Publique - Hôpitaux de Paris (APHP), Pitié-Salpêtrière Hospital, Paris, France.

Background: Impact of subthalamic deep brain stimulation (DBS) on impulse control disorders (ICD) in Parkinson's disease (PD) remains controversial.

Objectives: The objectives of this study were to analyze the natural history of ICD between baseline and 1 year after subthalamic DBS in patients with PD and to identify predictive factors, taking into account the positions of the active contact and stimulation parameters.

Methods: We analyzed postoperative modifications of ICD based on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. ICD status and Ardouin Scale of Behaviour in PD were assessed at baseline and 1 year following subthalamic DBS. Location of active contacts within the 3 subthalamic nucleus functional territories was investigated.

Results: A total of 217 were patients included. Of the patients, 10.6% had ICD at baseline of which 95.6% improved at 1 year following subthalamic DBS; 3.6% of the patients experienced de novo ICD at 1 year following subthalamic DBS. Dopamine agonist dose reduction (from 309.8 to 109.3 mg) was the main driver of ICD regression (P = 0.05). Higher preoperative dyskinesias were associated with poorer ICD evolution (P = 0.04). Whereas baseline apathy was a risk factor of de novo ICD (P = 0.02), ICD improvement correlated with postoperative apathy (P = 0.004). Stimulation power and position of active contacts-mainly located within the sensorimotor part of the subthalamic nucleus-did not influence ICD.

Conclusions: This 1-year, postoperative follow-up study showed ICD regression and dopaminergic drug reduction with optimal position of the active contacts within the subthalamic nucleus. Whereas patients with PD with preoperative ICD were prone to postoperative apathy, we also showed that those with preoperative apathy had a higher risk to experience postoperative de novo ICD, further highlighting the meaningful influence of postoperative management of dopaminergic medication on outcome and the continuum between apathy and ICD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28320DOI Listing
March 2021

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

Neurology 2020 05 12;94(21):e2189-e2202. Epub 2020 May 12.

From the Neurology Department (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital; National Reference Centre for Wilson's Disease (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital, Paris; Hepatobiliary Centre (R.S., D.C., D.S., J.-C.D.-V.), DHU Hepatinov, UMR-1193, AP-HP, Paul Brousse Hospital, Villejuif; Service de Neurologie (W.G.M.), CHU Bordeaux; Université de Bordeaux (W.G.M.), Institut des Maladies Neurodégénératives, CNRS UMR 5393, France; Department of Medicine (W.G.M.), University of Otago and New Zealand Brain Research Institute (W.G.M.), Christchurch; Hepatology, Gastroenterology and Nutrition Department (A.-S.B., A.L.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon; National Reference Centre for Wilson's Disease (A.-S.B., E.B., C.L., L.L.-F., O.G., A.L.), Hospices Civils de Lyon; Neurology Department (E.B., C.L.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon; CNRS (E.B., C.L.), UMR 5229, Institut des Sciences Cognitives Marc-Jeannerod, Bron; Faculté de Médecine Lyon Sud Charles-Mérieux (E.B., C.L., A.L.), Université Claude-Bernard Lyon 1; Neurology and Paediatrics Department (L.L.-F.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron; Hepatogastroenterology Department (O.G.), Edouard Herriot Hospital, Hospices Civils de Lyon; Internal Medicine Department (F.M.), National Reference Centre for Inborn Errors of Metabolism, Université François Rabelais; Neurology Department (J.B.), CHRU Bretonneau, Tours; Surgery, Oncology and Liver Transplantation Department (E.S.), CHRU Tours; Hepatology and Gastroenterology Department (C.V.) and Surgery and Liver Transplantation Department (B.H.), CHU Besançon; Neurology and Paediatrics Department (C. Bellesme), AP-HP, Bicêtre University Hospital, Kremlin-Bicetre; Pediatric Hepatology and Pediatric Liver Transplantation Unit (U.H) and National Reference Centre for Rare Pediatric Liver Diseases (U.H), Bicêtre University Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, DHU Hepatinov, AP-HP, Le Kremlin Bicêtre; INSERM (D.H.), UMR-S1174, Hepatinov, University of Paris Sud 11, Orsay; Hepatology and Gastroenterology Department (C. Bureau) and Neurology Department (F.O.-M.), CHU Toulouse; Centre D'investigation de la Fibrose Hépatique (V.L.), Hôpital Haut-Lévêque, CHU Bordeaux; and INSERM U1053 (V.d.L.), Université de Bordeaux, France. A. Poujois is currently at Neurology Department, Rothschild Foundation Hospital, and National Reference Centre for Wilson's Disease, Rothschild Foundation Hospital, Paris.

Objective: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved ( < 0.0001 and = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved ( = 0.0007). Severe sepsis ( = 0.011) and intensive care unit admission ( = 0.001) before LT were significantly associated with death.

Conclusions: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

Classification Of Evidence: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.
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http://dx.doi.org/10.1212/WNL.0000000000009474DOI Listing
May 2020

Phenotypic and Imaging Spectrum Associated With WDR45.

Pediatr Neurol 2020 08 11;109:56-62. Epub 2020 Mar 11.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.

Methods: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected.

Results: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age.

Conclusions: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387198PMC
August 2020

Semiquantitative Scale for Assessing Brain MRI Abnormalities in Wilson Disease: A Validation Study.

Mov Disord 2020 06 17;35(6):994-1001. Epub 2020 Mar 17.

2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.

Background: MRI is a sensitive method for the assessment of brain abnormalities in Wilson disease, that is, T hyperintensities, T hypointensities, and atrophy, but a validated scoring system for the classification of radiological severity is lacking. The objective of this study was to develop and validate a brain MRI visual rating scale for Wilson disease.

Methods: The proposed Wilson disease brain MRI severity scale consists of acute toxicity and chronic damage subscores from predefined structures. The former, calculated by summing scores of T hyperintensities (excluding cavitation), is likely to be partially reversible with treatment. The latter, representing the sum of scores of T hypointensities and brain atrophy, reflects pathology that is not readily reversible. Validation was performed on MRI scans acquired using 1.5T system from 39 Wilson disease patients examined at baseline and after 24 months on anticopper treatment. Intraclass correlation coefficients of 5 ratings from 3 raters were calculated. Temporal evolution of the MRI severity score and its association with clinical severity, assessed using the Unified Wilson Disease Rating Scale part III, was calculated.

Results: Intrarater and interrater agreement were good (r > 0.93; P < 0.001; and r > 0.74; P < 0.001, respectively). In neurologic Wilson disease patients, the total MRI severity score improved over 2 years (P = 0.032), mainly because of reduced acute toxicity (P = 0.0015), whereas the chronic damage score deteriorated (P = 0.035). Unified Wilson Disease Rating Scale part III score was positively associated with chronic damage and total score at baseline (P = 0.005 and P = 0.003, respectively) and in month 24 (P < 0.001 and P = 0.001, respectively).

Conclusions: The Wilson disease brain MRI severity scale is a simple, reliable, and valid instrument that allows semiquantitative assessment of radiological Wilson disease severity. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28018DOI Listing
June 2020

A novel heterozygous ANO3 mutation responsible for myoclonic dystonia.

J Neurol Sci 2019 Aug 13;403:65-66. Epub 2019 Jun 13.

Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, 69000 Lyon, France; Université de Lyon, Lyon 1 University, Lyon, F-69373; Centre de Neurosciences Cognitives de Lyon, CNRS UMR 5229, Bron F-69500, France.

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http://dx.doi.org/10.1016/j.jns.2019.06.014DOI Listing
August 2019

[Parkinson's disease: from the description of the disease to its surgical treatment].

Rev Prat 2018 May;68(5):574-578

Université de Lyon, institut des sciences cognitives Marc-Jeannerod, CNRS, UMR 5229, Bron, France.

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May 2018

[Parkinson's disease treatment: from honey moon to motor fluctuations].

Rev Prat 2018 May;68(5):502-507

Faculté de médecine Lyon-Sud-Charles- Mérieux, université Lyon-1, université de Lyon, Lyon, France.

Parkinson's disease treatment: from honey moon to motor fluctuations. The treatment of Parkinson's disease remains symptomatic but allows, for many years, a good control of motor and non-motor signs. This treatment is complex and has to deal with very heterogeneous motor and non-motor presentation. Initial treatment is started once disability occurs and is mainly based either on levodopa or dopamine agonists. When motor fluctuations start, the principle of treatment is to optimize levodopa intake and combine various drugs depending on the clinical presentation. Third line strategies of treatment such as pumps or deep brain stimulation may be proposed at this stage. Later on, when doparesistant signs appear, treatment has often to be simplified, cognitive decline to be taken in charge and physiotherapy is crucial even if physical exercise is of great importance whatever the stage of the disease. Finally, non-motor manifestations have to be carefully addressed throughout the course of the disease because their impact on quality of life is sometimes greater than the one of motor signs.
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May 2018

Functional imaging studies of Impulse Control Disorders in Parkinson's disease need a stronger neurocognitive footing.

Neurosci Biobehav Rev 2019 03 9;98:164-176. Epub 2019 Jan 9.

Université de Lyon, Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, INSERM, U 1028, CNRS, UMR 5292, Action Control and Related Disorders team, F-69000, Lyon, France. Electronic address:

Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated with dopaminergic dysfunction and treatment, but have no satisfactory therapeutic solution. While studies assessing the neurofunctional bases of ICDs are important for advancing our understanding and management of ICDs, they remain sparse and inconsistent. Based on a systematic analysis of the neuroimaging literature, the present review pinpoints various abnormalities beyond the mesocorticolimbic circuit that supports reward processing, suggesting possible dysfunction at the sensorimotor, executive and affective levels. We advocate that: 1) Future studies should use more sophisticated psychological models and behavioral designs that take into account the potentially multifaceted aspect of ICDs; this would allow a more accurate assessment of the underlying neurocognitive processes, which are not all dependent on the dopaminergic system. 2) Future neuroimaging studies should rely more strongly on task-based, event-related analyses to disentangle the various mechanisms that can be dysfunctional in ICDs. We believe these guidelines constitute a prerequisite towards distinguishing causes, correlates and individual susceptibility factors of PD patients with ICDs.
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http://dx.doi.org/10.1016/j.neubiorev.2019.01.008DOI Listing
March 2019

Age and time course of long-term motor and nonmotor complications in Parkinson disease.

Neurology 2019 01 12;92(2):e148-e160. Epub 2018 Dec 12.

From Université Lyon (S.P., T.D., C.L., E.M., E.B., S.T.), Institut des Sciences Cognitives-Marc Jeannerod, CNRS, UMR 5229, Bron; Hospices Civils de Lyon (S.P., T.D., C.C., C.L., E.M., H.M., E.B., S.T.), Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Centre Expert Parkinson, Bron; Université Lyon (C.L., E.B., D.M.-B., S.T.), Faculté de Médecine Lyon Sud Charles Mérieux, Oullins; Hospices Civils de Lyon (D.M.-B.), Service de Biostatistique, Lyon; and Université Lyon (D.M.-B.), Laboratoire de Biométrie et Biologie Évolutive, CNRS, UMR 5558, Pierre Benite, France.

Objective: To determine the time course of hazard for motor and nonmotor milestones of Parkinson disease (PD) in the long term and to investigate whether risk scales nonlinearly with time is instrumental in identifying changes in pathological processes and evaluating disease-modifying therapies in PD.

Methods: Outpatients with PD at the Lyon University Movement Disorders Center were evaluated for 7 clinical milestones in this retrospective cohort study, encompassing 4 domains of PD progression: (1) motor (motor fluctuations, dyskinesias); (2) axial (postural instability and falls, freezing of gait); (3) neuropsychiatric (impulse control disorders, hallucinations); and (4) cognitive (dementia) complications. For each complication, we estimated the outcome-specific hazard using parsimonious smooth parametric Poisson regression models allowing for nonlinear scaling over disease duration, age at diagnosis, current age, and their interaction.

Results: A total of 1,232 patients with PD experienced 1,527 disease-related complications in up to 12 years of follow-up. Specific to each complication, hazard rates increased dramatically starting from diagnosis and were highest for motor fluctuations and lowest for dementia up to 6 years after diagnosis in patients aged 65 years at diagnosis. Nonlinear patterns indicated dramatic changes in the course of PD after 5 years and predicted more severe axial prognosis after 70 years and for motor fluctuations, dyskinesias, and impulse control disorders before 60 years at diagnosis.

Conclusion: Time course of motor and nonmotor milestones in PD is determined by disease duration and age at diagnosis in nonlinear patterns and their interaction. This indicates disease- and age-specific thresholds across the multiple neurodegenerative processes accumulating in PD at different paces.
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http://dx.doi.org/10.1212/WNL.0000000000006737DOI Listing
January 2019

Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect.

Orphanet J Rare Dis 2018 10 1;13(1):175. Epub 2018 Oct 1.

Reference Centre for Lysosomal Diseases (CRML), Department of Pediatric Neurology, and Sorbonne Université, GRC n°19, Pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Hôpital Armand Trousseau, F-75012, Paris, France.

Background: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date.

Methods: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed.

Results: In France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8-56) years and 34 ± 13.5 (15-65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02).

Conclusion: The proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000-2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.
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http://dx.doi.org/10.1186/s13023-018-0913-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167825PMC
October 2018

Toe dystonia in Parkinson's disease: Impact of subthalamic nucleus deep brain stimulation.

J Neurol Sci 2018 09 12;392:65-68. Epub 2018 Jul 12.

Institut des Sciences Cognitives Marc Jeannerod, UMR 5229, CNRS, Bron, France; Service de Neurologie C, Centre Expert Parkinson, Hôpital Neurologique Pierre, Wertheimer, Hospices Civils de Lyon, Lyon, France; Faculté de médecine Lyon Sud Charles Mérieux, Université Lyon 1, Univ Lyon, Lyon, France.

Background: Off state toe dystonia (TD) is a symptom frequently encountered in Parkinson's disease (PD), but little is known about its evolution after subthalamic nucleus deep brain stimulation (STN-DBS).

Objective: To analyze the prevalence and the evolution of TD in PD patients candidate to STN-DBS.

Methods: Individual data of consecutive 130 PD patients who underwent STN-DBS between 2010 and 2015 were collected.

Results: Data were successfully collected in 95 patients. TD affect 45.3% of the patients in our cohort. TD was present in 32.7% of patients before surgery and was alleviated by STN-DBS in 48% of the cases. Motor improvement provided by STN-DBS, levodopa-equivalent treatment diminution after surgery, disease duration or age at the time of surgery were not predictive of TD evolution. A younger age at PD diagnosis was significantly associated with TD resolution.

Conclusion: STN-DBS is partially efficient for TD but its evolution seems independent of significant predictive factors.
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http://dx.doi.org/10.1016/j.jns.2018.07.004DOI Listing
September 2018

Novel XK mutation in a McLeod patient diagnosed after heart transplant.

Clin Neurol Neurosurg 2018 05 1;168:64-66. Epub 2018 Mar 1.

Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, 69000 Lyon, France; Université de Lyon, CNRS, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229, 69500 Bron, France; Université de Lyon, Université Claude Bernard Lyon 1, Faculté de médecine Lyon Sud Charles Mérieux, 69000 Lyon, France.

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http://dx.doi.org/10.1016/j.clineuro.2018.02.039DOI Listing
May 2018

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

JAMA Neurol 2018 04;75(4):495-502

Pediatric Neurology, Emma Children's Hospital, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels.

Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations.

Design, Setting, And Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016.

Main Outcomes And Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations.

Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).

Conclusions And Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
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http://dx.doi.org/10.1001/jamaneurol.2017.4373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933354PMC
April 2018

Imagerie cérébrale dans les syndromes parkinsoniens.

Presse Med 2017 Mar 28;46(2 Pt 1):202-209. Epub 2016 Dec 28.

Université de Lyon, université Claude-Bernard Lyon I, faculté de médecine Lyon Sud Charles-Mérieux, Lyon, France; Hospices civils de Lyon, hôpital neurologique Pierre-Wertheimer, service de neurologie C, centre expert parkinson, Lyon, France; CNRS, centre de neurosciences cognitives, UMR 5229, Bron, France. Electronic address:

Role of brain imaging for Parkinsonism T brain MRI is normal in Pakinson's disease. Brain MRI is useless when clinical presentation is typical of idiopathic Parkinson's disease. Brain MRI is the exam of choice for differentiating idiopathic Parkinson's disease and atypical parkinsonism. DATscan* confirms or rules out dopaminergic degeneration but does not separate idiopathic Parkinson's disease from Parkinson "plus" syndromes. FDG PET is helpful to separate idiopathic Parkinson's disease from Parkinson "plus" syndromes.
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http://dx.doi.org/10.1016/j.lpm.2016.09.025DOI Listing
March 2017

Liver Transplantation in Wilson's Disease with Neurological Impairment: Evaluation in 4 Patients.

Eur Neurol 2017 19;77(1-2):5-15. Epub 2016 Nov 19.

Service de Neurologie C, Hôpital Neurologique, Bron, France.

Background: The aim of this work is to report our early experiences about the benefits of liver transplantation (LT) in the treatment of persistent neurological symptoms in Wilson's disease (WD) patients.

Methods: We describe our findings in 4 WD patients with neurological impairment or symptoms treated by LT: 2 patients had transplants due to worsening of neurological symptoms despite long-term appropriate medical treatment. The other 2 required LT because of symptoms associated with liver failure. Patients were evaluated using the modified Rankin scale and the Unified Wilson's Disease Rating Scale (UWDRS).

Results: The 4 patients experienced neurological improvement after LT. The pre-LT Rankin score of the 2 patients transplanted due to neurological impairment was 4 compared to 3 and 2, respectively, post LT. The pre-LT Rankin scores of the 2 WD cases transplanted because of hepatic failure were 1 and 2, respectively, compared to 0 in both cases post LT. UWDRS score improved in 2 cases and remained stable in 1 less severely impaired case. Brain MRI abnormalities proved partially reversible in 3 patients and remained stable for 1 patient.

Conclusions: These results suggest that LT could be envisaged for neurologically impaired WD patients.
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http://dx.doi.org/10.1159/000452658DOI Listing
September 2017

Not everything that shakes is a seizure… Role of continuous EEG in the intensive care unit.

Neurophysiol Clin 2017 Feb 14;47(1):13-18. Epub 2016 Nov 14.

Service de réanimation neurologique, hôpital neurologique, hospices civils de Lyon, 59, boulevard Pinel, 69677 Bron cedex, France.

Treatment of status epilepticus often requires highly sedative drugs with risk of side effects. Correct diagnosis is mandatory in order to prevent introduction of usefulness treatments. We report a case of suspected myoclonic status epilepticus. A thalamic lesion secondary to an osmotic demyelination syndrome was found to be the likely etiology of the myoclonus. Electrophysiological data (electroencephalography and electromyography) provided evidence for a subcortical origin of myoclonus and use of continuous EEG allowed monitoring of drug withdrawal.
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http://dx.doi.org/10.1016/j.neucli.2016.10.001DOI Listing
February 2017

High incidence of carpal tunnel syndrome after deep brain stimulation in Parkinson's disease.

J Neurol 2016 Dec 13;263(12):2416-2418. Epub 2016 Sep 13.

Service de Neurologie C, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69000, Lyon, France.

We observed several cases of carpal tunnel syndrome (CTS) revealed after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). 115 consecutive PD patients who underwent STN-DBS between 2010 and 2014 at the Neurological Hospital in Lyon were retrospectively included. CTS was accepted as the diagnosis only if clinical examination and ENMG both confirmed it. Nine patients (7.8 %) developed CTS in the 2 years following surgery, which is far beyond the 2.7/1000 incidence in the general population. The present study shows an overrepresentation of CTS occurrence after STN-DBS in PD.
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http://dx.doi.org/10.1007/s00415-016-8279-9DOI Listing
December 2016

Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia.

Neurology 2016 Feb 20;86(7):651-9. Epub 2016 Jan 20.

From the Centre d'Investigation Clinique, Department of Neurology (H.P.-C., T.R., P. Damier), Department of Medical Evaluation and Epidemiology (J.-M.N.), and Department of Neurosurgery (S.R.), CHU Nantes, INSERM; Hôpital Neurologique (S.T., C.L., P.M.), Hospices Civils de Lyon, Université de Lyon 1; Centre d'Investigation Clinique, Department of Neurology (C.B.-C., F.O.-M., O.R.), CHU Toulouse, INSERM; Departments of Psychiatry (I.C.) and Neurology (P. Derost, M.U.), CHU Clermont-Ferrand; Departments of Neurosurgery (E.C.) and Neurology (D.G., P.B.), Bordeaux CHU; and the Departments of Neurology (A.E., T.W.) and Neurosurgery (J.R.), Assistance Publique Hôpitaux de Marseille, France.

Objective: To confirm the efficacy and safety of deep brain stimulation (DBS) of the internal part of the globus pallidus in improving severe tardive dyskinesia (TD).

Methods: Nineteen patients with severe pharmacoresistant TD were included. All were assessed at baseline and at 3, 6 (main outcome measure), and 12 months, and in the long term (6-11 years) for 14 patients, after bilateral pallidal DBS, using motor scales (Extrapyramidal Symptoms Rating Scale [ESRS], Abnormal Involuntary Movement Scale [AIMS]), cognitive scales, and a psychiatric assessment. At 6 months, a double-blind ESRS evaluation was performed in the stimulation "on" and stimulation "off" conditions.

Results: At 6 months, all patients had a decrease of more than 40% on the ESRS. The efficacy of the procedure was confirmed by a double-blind evaluation. This improvement was maintained at 12 months (ESRS: decrease of 58% [21%-81%];

Aims: decrease of 50% [7%-77%]) and in the long term (ESRS: decrease of 60% [22%-90%];

Aims: decrease of 63% [14%-94%], n = 14). All the subscores of the ESRS (parkinsonism, dystonia, and chorea) and of the AIMS (facial, oral, extremities, and trunk movements) improved. Despite psychiatric comorbidities at baseline, cognitive and psychiatric tolerability of the procedure was excellent. No cognitive decline was observed and mood was improved in most of the patients.

Conclusions: Pallidal DBS procedure should be considered as a therapeutic option in disabling TD refractory to medical treatment.

Classification Of Evidence: This study provides Class II evidence that in patients with severe pharmacoresistant TD with implanted pallidal leads, the stimulation "on" condition significantly improved ESRS scores compared to the stimulation "off" condition.
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http://dx.doi.org/10.1212/WNL.0000000000002370DOI Listing
February 2016

Outcome of deep brain stimulation in slowly progressive multiple system atrophy: A clinico-pathological series and review of the literature.

Parkinsonism Relat Disord 2016 Mar 7;24:69-75. Epub 2016 Jan 7.

Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Expert Parkinson's Disease Center, 69000 Lyon, France; Université Lyon 1, Faculté de Médecine Lyon Sud Charles Mérieux, 69000 Lyon, France; CNRS, Centre de Neurosciences Cognitives, UMR5229, Bron, France. Electronic address:

Objectives: To highlight the risk of clinical worsening after deep brain stimulation in histologically proven multiple system atrophy (MSA) patients presenting slow and relatively benign disease progression mimicking Parkinson's disease (PD). In such cases but also in more typical MSA patients, the results of deep brain stimulation have been mostly reported as case reports and small patient series.

Methods: The present study describes the outcome of the largest series of histologically proven MSA patients who underwent deep brain stimulation (DBS) of the subthalamic nucleus because they were considered as having PD at the time of surgery.

Results: Three patients showed significant improvement of motor signs after surgery while two did not. Clinical improvement was short-lasting and rapidly followed by the occurrence of disabling manifestations of MSA that counteracted DBS benefits.

Conclusions: Together with previous reports, our study demonstrates that DBS should not be recommended for MSA patients. It also underlines that detecting subtle red flags is crucial to avoid DBS surgery in this population.
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http://dx.doi.org/10.1016/j.parkreldis.2016.01.005DOI Listing
March 2016

Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia.

Tremor Other Hyperkinet Mov (N Y) 2015 21;5:332. Epub 2015 Sep 21.

Département de Psychiatrie et de Neurologie, Unité des Mouvements Anormaux, Centre Hospitalier Universitaire de Grenoble, Grenoble, France ; INSERM Unité 836, Grenoble Institut des Neurosciences, Grenoble, France ; Université Joseph Fourier, Grenoble, France.

Background: Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste.

Results: In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called "simple mannerisms, childish behaviour or fake pathological movements" was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud's pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim's 1911 seminal description of dystonia musculorum deformans in Berlin.

Discussion: Brissaud-Meige's misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970-1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society's classification of dystonia.
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http://dx.doi.org/10.7916/D8KD1X74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582593PMC
September 2015

Peripheral small fiber dysfunction and neuropathic pain in patients with Morvan syndrome.

Neurology 2015 Dec 23;85(23):2076-8. Epub 2015 Sep 23.

From Explorations Fonctionnelles Neurologiques (C.L., E.O., P.P.), Hôpital de la Croix Rousse, Hospices Civils de Lyon; Service de Neurologie Fonctionnelle et d'Epileptologie (N.A.-O., F.M., L.P.-D.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon; French Reference Center for Paraneoplastic Neurological Syndrome (J.-P.C., F.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron; Service de Neurologie (J.-P.C.), Hôpital Nord, CHU de Saint Etienne; Lyon Neuroscience Research Center (J.-P.C., F.D., J.H.), INSERM U1028/CNRS UMR 5292, Lyon; Université de Lyon-Université Claude Bernard Lyon 1 (F.M., S.V., F.D., J.H.), Lyon; Service de Neurologie A (S.V.) and Service d'Electroneuromyographie et Pathologies Neuromusculaires (F.B., C.V.), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon; and Service d'Anatomopathologie (D.M.), Groupement Hospitalier Est, Hospices Civils de Lyon, France.

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http://dx.doi.org/10.1212/WNL.0000000000002037DOI Listing
December 2015

Parkinson's Disease Revealed by a Resting Tongue Tremor.

Mov Disord Clin Pract 2015 Dec 24;2(4):432-433. Epub 2015 Aug 24.

Hospices Civils de Lyon Hôpital Neurologique Pierre Wertheimer, Neurologie C Lyon France.

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http://dx.doi.org/10.1002/mdc3.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178599PMC
December 2015

Thrombolysis for Acute Minor Stroke: Outcome and Barriers to Management. Results from the RESUVAL Stroke Network.

Cerebrovasc Dis 2015 14;40(1-2):3-9. Epub 2015 May 14.

Department of Neurology, Stroke Unit, Neurological Hospital, University of Lyon, Lyon, France.

Background: We evaluated the management, outcome and haemorrhagic risk in a cohort of ischaemic stroke patients with mild symptoms treated with intravenous tissue plasminogen activator (tPA) within the first 4.5 h.

Methods: We analysed data from a prospective stroke thrombolysis registry. A total of 1,043 patients received tPA between 2010 and 2014 in the 5 stroke units of the RESUVAL stroke network (Rhône Valley, France). Among them, 170 patients had a National Institute of Health Stroke Scale (NIHSS) score ≤4 (minor group: MG) before tPA and 873 patients had a NIHSS score >4.

Results: A high rate (77%) of excellent outcome (3-month-modified Rankin Scale score ≤1) was observed in the MG. No symptomatic intracerebral haemorrhage occurred and the rate of any haemorrhagic transformation was 5%. Fifty-four percent of the MG patients had visible arterial occlusion before tPA. Patients of the MG were less likely to be transported by Emergency Medical Services and to be directly admitted to the stroke unit or to imaging. Median delays from onset to admission, from admission to imaging and from onset to tPA were longer in the MG.

Conclusion: Our data provided evidence of safety and suggested potential benefit of thrombolysis in patients with NIHSS score ≤4. A majority of these patients exhibited arterial occlusion before thrombolysis. Most often, patients with mild stroke are not given priority in terms of the mode of transport, direct admission to stroke unit and rapid imaging, resulting in an increased delay from onset to thrombolysis. Health system improvements are needed to provide all suspected stroke victims equal access to imaging and treatment on an emergency basis.
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http://dx.doi.org/10.1159/000381866DOI Listing
May 2016

Pitfalls in ataxia with ocular motor apraxia type 1: pseudodominant inheritance and very late onset.

J Neurol 2015 May 7;262(5):1366-8. Epub 2015 Apr 7.

Neurologie C, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Lyon, France,

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http://dx.doi.org/10.1007/s00415-015-7717-4DOI Listing
May 2015