Publications by authors named "Cécile Delorme"

41 Publications

Multiparametric characterization of white matter alterations in early stage Huntington disease.

Sci Rep 2021 Jun 23;11(1):13101. Epub 2021 Jun 23.

INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau Et de La Moelle Épinière, ICM, 75013, Paris, France.

Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite N-acetylaspartate, co-measured with N-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD.
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http://dx.doi.org/10.1038/s41598-021-92532-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222368PMC
June 2021

Long-term effect of apomorphine infusion in advanced Parkinson's disease: a real-life study.

NPJ Parkinsons Dis 2021 Jun 11;7(1):50. Epub 2021 Jun 11.

Neurology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson's disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson's disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
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http://dx.doi.org/10.1038/s41531-021-00194-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196159PMC
June 2021

Delayed Benefit From Aggressive Immunotherapy in Waxing and Waning Anti-IgLON5 Disease.

Neurol Neuroimmunol Neuroinflamm 2021 07 13;8(4). Epub 2021 May 13.

From the Department of Neurology (P.S., A.H., C.M., C.D., C.L., A.M.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Neurology (D.Z., J.S., F.P.), Versailles Hospital, Le Chesnay, France; Department of Neurology (D.Z.), CHU Yalgado Ouédraogo, Ouagadougou, Burkina Faso; Department of Neurophysiology (B.G.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Sorbonne University (C.L., I.A., A.M.), Paris, France; Sleep Disorder Unit (I.A., A.G.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Service de Neurologie 2-Mazarin (D.P.), Groupe Hospitalier Pitié-Salpêtrière et Université Pierre et Marie Curie-Paris 6, AP-HP, Centre de Compétence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes, Paris, France; French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (J.H.), Hospices Civils de Lyon, Institut NeuroMyoGene, INSERM U1217/CNRS UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, France.

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http://dx.doi.org/10.1212/NXI.0000000000001009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192057PMC
July 2021

Association of Clinical, Biological, and Brain Magnetic Resonance Imaging Findings With Electroencephalographic Findings for Patients With COVID-19.

JAMA Netw Open 2021 03 1;4(3):e211489. Epub 2021 Mar 1.

Sorbonne Université, Paris Brain Institute, Institut du Cerveau, Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, Paris, France.

Importance: There is evidence of central nervous system impairments associated with coronavirus disease 2019 (COVID-19) infection, including encephalopathy. Multimodal monitoring of patients with COVID-19 may delineate the specific features of COVID-19-related encephalopathy and guide clinical management.

Objectives: To investigate clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with COVID-19, and to better refine the features of COVID-19-related encephalopathy.

Design, Setting, And Participants: This retrospective cohort study conducted in Pitié-Salpêtrière Hospital, Paris, France, enrolled 78 hospitalized adults who received a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and underwent EEG between March 30 and June 11, 2020.

Exposures: Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription-polymerase chain reaction assay or, in the case of associated pneumonia, on a computed tomography scan of the chest.

Main Outcomes And Measures: Data on the clinical and paraclinical features of the 78 patients with COVID-19 were retrieved from electronic patient records.

Results: Of 644 patients who were hospitalized for COVID-19, 78 (57 men [73%]; mean [SD] age, 61 [12] years) underwent EEG. The main indications for EEG were delirium, seizure-like events, and delayed awakening in the intensive care unit after stopping treatment with sedatives. Sixty-nine patients showed pathologic EEG findings, including metabolic-toxic encephalopathy features, frontal abnormalities, periodic discharges, and epileptic activities. Of 57 patients who underwent brain MRI, 41 showed abnormalities, including perfusion abnormalities, acute ischemic lesions, multiple microhemorrhages, and white matter-enhancing lesions. Fifty-five patients showed biological abnormalities, including dysnatremia, kidney failure, and liver dysfunction, the same day as the EEG. The results of cerebrospinal fluid analysis were negative for SARS-Cov-2 for all tested patients. Nine patients who had no identifiable cause of brain injury outside COVID-19 were further isolated; their brain injury was defined as COVID-19-related encephalopathy. They represented 1% (9 of 644) of patients with COVID-19 requiring hospitalization. Six of these 9 patients had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter-enhancing lesions.

Conclusions And Relevance: The results from this cohort of patients hospitalized with COVID-19 suggest there are clinical, EEG, and MRI patterns that could delineate specific COVID-19-related encephalopathy and guide treatment strategy.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961310PMC
March 2021

[SARS-CoV-2 and neurological disorders: the revelance of biomarkers?]

Ann Biol Clin (Paris) 2021 02;79(1):7-16

DMU BioGeM, Service de biochimie métabolique, APHP, Sorbonne Université, Hôpitaux universitaires Pitié-Salpêtrière, Paris, France.

Soon after the pandemic, numerous publications described cases of neurological disorders associated with the SARS-CoV-2 infection. The range of neurological symptoms is becoming increasingly more extensive as the pandemic progresses. However, it is not yet well established whether the manifestations are due to direct viral damage to the nervous system or indirect consequences of the infection. This review presents an inventory of the biochemical markers studied in the context of neurological disorders related to SARS-CoV-2. By reflecting various physiopathological mechanisms, these biomarkers allow both a better understanding of the pathophysiology of Covid-19 and a contribution to the diagnosis of neurologic troubles; they could participate in the prognostic evaluation of patients.
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http://dx.doi.org/10.1684/abc.2021.1622DOI Listing
February 2021

The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study.

Eur J Nucl Med Mol Imaging 2021 07 15;48(8):2543-2557. Epub 2021 Jan 15.

Département de Neurologie, Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, 75013, Paris, France.

Purpose: Little is known about the neuronal substrates of neuropsychiatric symptoms associated with COVID-19 and their evolution during the course of the disease. We aimed at describing the longitudinal brain metabolic pattern in COVID-19-related encephalopathy using 18F-FDG-PET/CT.

Methods: Seven patients with variable clinical presentations of COVID-19-related encephalopathy were explored thrice with brain 18F-FDG-PET/CT, once in the acute phase, 1 month later and 6 months after COVID-19 onset. PET images were analysed with voxel-wise and regions-of-interest approaches in comparison with 32 healthy controls.

Results: Patients' neurological manifestations during acute encephalopathy were heterogeneous. However, all of them presented with predominant cognitive and behavioural frontal disorders. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. MRI revealed no specific abnormalities for most of the subjects. All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities.

Conclusion: The implication of this widespread network could be the neural substrate of clinical features observed in patients with COVID-19, such as frontal lobe syndrome, emotional disturbances and deregulation of respiratory failure perception. This study suggests that this network remains mildly to severely impaired 6 months after disease onset.
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http://dx.doi.org/10.1007/s00259-020-05178-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810428PMC
July 2021

Neurologic manifestations associated with COVID-19: a multicentre registry.

Clin Microbiol Infect 2021 Mar 13;27(3):458-466. Epub 2020 Nov 13.

Department of Neurology, Centre Hospitalier de Saint-Denis, Hôpital Delafontaine, Saint-Denis, France.

Objectives: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible.

Results: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%).

Conclusions: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.
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http://dx.doi.org/10.1016/j.cmi.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661948PMC
March 2021

Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders.

Expert Rev Neurother 2021 Jan 8;21(1):81-97. Epub 2020 Nov 8.

Département de Neurologie, AP-HP, Hôpital Pitié-Salpêtrière , Paris, France.

Introduction: Paroxysmal movement disorders mostly comprise paroxysmal dyskinesia and episodic ataxia, and can be the consequence of a genetic disorder or symptomatic of an acquired disease.

Areas Covered: In this review, the authors focused on certain hot-topic issues in the field: the respective contribution of the cerebellum and striatum to the generation of paroxysmal dyskinesia, the importance of striatal cAMP turnover in the pathogenesis of paroxysmal dyskinesia, the treatable causes of paroxysmal movement disorders not to be missed, with a special emphasis on the treatment strategy to bypass the glucose transport defect in paroxysmal movement disorders due to GLUT1 deficiency, and functional paroxysmal movement disorders.

Expert Opinion: Treatment of genetic causes of paroxysmal movement disorders is evolving towards precision medicine with targeted gene-specific therapy. Alteration of the cerebellar output and modulation of the striatal cAMP turnover offer new perspectives for experimental therapeutics, at least for paroxysmal movement disorders due to selected causes. Further characterization of cell-specific molecular pathways or network dysfunctions that are critically involved in the pathogenesis of paroxysmal movement disorders will likely result in the identification of new biomarkers and testing of innovative-targeted therapeutics.
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http://dx.doi.org/10.1080/14737175.2021.1840978DOI Listing
January 2021

Whispering dysphonia in TUBB4A-related disorders responsive to bipallidal deep brain stimulation.

Eur J Neurol 2021 Mar;28(3):1082-1083

Département de Neurologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.

Background: Mutations in TUBB4A are associated with a wide phenotypic spectrum including generalized dystonia with whispering dysphonia (DYT-TUBB4A).

Methods: We report the case of a 44-year-old patient with DYT-TUBB4A with a clinical presentation of disabling progressive dystonia, with a prominent laryngeal, cervical and facial involvement.

Results: Bipallidal deep brain stimulation (DBS) resulted in a 55% reduction of dystonia severity assessed by the Burke-Fahn-Marsden scale score 6 months after surgery. The effect was obvious on the cervical and facial components of dystonia.

Conclusion: We suggest that bipallidal DBS should be considered in patients with disabling dystonia related to TUBB4A variants.
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http://dx.doi.org/10.1111/ene.14602DOI Listing
March 2021

Impulsive prepotent actions and tics in Tourette disorder underpinned by a common neural network.

Mol Psychiatry 2020 Sep 29. Epub 2020 Sep 29.

Sorbonne University, 75005 Paris; Inserm U1127, CNRS UMR7225, UM75, ICM, F-75013, Paris, France.

Tourette disorder (TD), which is characterized by motor and vocal tics, is not in general considered as a product of impulsivity, despite a frequent association with attention deficit hyperactivity disorder and impulse control disorders. It is unclear which type of impulsivity, if any, is intrinsically related to TD and specifically to the severity of tics. The waiting type of motor impulsivity, defined as the difficulty to withhold a specific action, shares some common features with tics. In a large group of adult TD patients compared to healthy controls, we assessed waiting motor impulsivity using a behavioral task, as well as structural and functional underpinnings of waiting impulsivity and tics using multi-modal neuroimaging protocol. We found that unmedicated TD patients showed increased waiting impulsivity compared to controls, which was independent of comorbid conditions, but correlated with the severity of tics. Tic severity did not account directly for waiting impulsivity, but this effect was mediated by connectivity between the right orbito-frontal cortex with caudate nucleus bilaterally. Waiting impulsivity in unmedicated patients with TD also correlated with a higher gray matter signal in deep limbic structures, as well as connectivity with cortical and with cerebellar regions on a functional level. Neither behavioral performance nor structural or functional correlates were related to a psychometric measure of impulsivity or impulsive behaviors in general. Overall, the results suggest that waiting impulsivity in TD was related to tic severity, to functional connectivity of orbito-frontal cortex with caudate nucleus and to structural changes within limbic areas.
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http://dx.doi.org/10.1038/s41380-020-00890-5DOI Listing
September 2020

Isolated parkinsonism is an atypical presentation of GRN and C9orf72 gene mutations.

Parkinsonism Relat Disord 2020 11 15;80:73-81. Epub 2020 Sep 15.

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Centre de Référence des Démences Rares ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Paris Brain Institute - Institut du Cerveau - ICM, FrontLab, Paris, France. Electronic address:

Introduction: A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their "red flags" according to current IPD criteria.

Methods: Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and "red flag" features from MDS criteria were analyzed for each case.

Results: Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype.

Conclusion: We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.019DOI Listing
November 2020

Dissociation in reactive and proactive inhibitory control in Myoclonus dystonia.

Sci Rep 2020 08 18;10(1):13933. Epub 2020 Aug 18.

Sorbonne University, 75005, Paris, France.

Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive-compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.
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http://dx.doi.org/10.1038/s41598-020-70926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434767PMC
August 2020

Retrospective Observational Study of Brain MRI Findings in Patients with Acute SARS-CoV-2 Infection and Neurologic Manifestations.

Radiology 2020 12 17;297(3):E313-E323. Epub 2020 Jul 17.

From the Sorbonne Université, Inserm, CNRS, Institut du Cerveau-Paris Brain Institute (ICM), F-75013 Paris, France (L.C., D.G., B.M., C.R., D.D., J.C.C., S.L., N.P.); Sorbonne Université, INSERM 75013 Paris, France (L.C., N.S., N.W., D.G., B.M., S. Burrel, D.B., A.D., C.R., D.S., D.D., E.M., M.R., T.S., V.D., J.C.C., S.L., N.P.); Paris Brain Institute - ICM, Movement Investigations and Therapeutics Team (MOV'IT), Paris, France (L.C., S.L., N.P.); ICM, Centre de NeuroImagerie de Recherche-CENIR, Paris, France (L.C., D.G., S.L., N.P.); Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Service de Neuroradiologie (L.C., N.S., D.G., D.L., S. Belkacem, S.S., D.D., S.G., S.T., S.L., N.P.), Médecine Intensive Réanimation Neurologique (N.W.), Service de Neurochirurgie (B.M.), Service de Virologie, Centre d'Investigation Clinique Neurosciences (S. Burrel, D.B.), Service de Pneumologie, Médecine Intensive et Réanimation (A.D., E.M., T.S.), Urgences Cérébro-Vasculaires (C.R.), Département de Neurologie, Centre d'Investigation Clinique Neurosciences (C.D., J.C.C.), Département de Neuropathologie (D.S.), Department of Anesthesia, Critical Care and Peri-Operative Medicine (M.R., V.D.), Paris, France; Brain Liver Pitié-Salpêtrière Study Group, INSERM UMR S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, biliaires et fibro-inflammatoire du foie, Institute of Cardiometabolism and Nutrition (N.W., S.D.); CNR Herpèsvirus (laboratoire associé HSV), SU-INSERM UMR_S 1136 Team 3 THERAVIR IPLESP (S. Burrel, D.B.); ICM, Stroke Network, STAR Team, Paris, France (C.R.); Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière,; ICM, INRIA, ARAMIS project-team, Paris, France (D.D., M.R.); Clinical Research Group ARPE, Sorbonne University, Paris, France (V.D.); INSERM UMR 1141, Paris France (V.D.); and Assistance Publique Hôpitaux de Paris, DMU ESPRIT, Paris, France (P.R.).

Background This study provides a detailed imaging assessment in a large series of patients infected with coronavirus disease 2019 (COVID-19) and presenting with neurologic manifestations. Purpose To review the MRI findings associated with acute neurologic manifestations in patients with COVID-19. Materials and Methods This was a cross-sectional study conducted between March 23 and May 7, 2020, at the Pitié-Salpêtrière Hospital, a reference center for COVID-19 in the Paris area. Adult patients were included if they had a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with acute neurologic manifestations and referral for brain MRI. Patients with a prior history of neurologic disease were excluded. The characteristics and frequency of different MRI features were investigated. The findings were analyzed separately in patients in intensive care units (ICUs) and other departments (non-ICU). Results During the inclusion period, 1176 patients suspected of having COVID-19 were hospitalized. Of 308 patients with acute neurologic symptoms, 73 met the inclusion criteria and were included (23.7%): thirty-five patients were in the ICU (47.9%) and 38 were not (52.1%). The mean age was 58.5 years ± 15.6 [standard deviation], with a male predominance (65.8% vs 34.2%). Forty-three patients had abnormal MRI findings 2-4 weeks after symptom onset (58.9%), including 17 with acute ischemic infarct (23.3%), one with a deep venous thrombosis (1.4%), eight with multiple microhemorrhages (11.3%), 22 with perfusion abnormalities (47.7%), and three with restricted diffusion foci within the corpus callosum consistent with cytotoxic lesions of the corpus callosum (4.1%). Multifocal white matter-enhancing lesions were seen in four patients in the ICU (5%). Basal ganglia abnormalities were seen in four other patients (5%). Cerebrospinal fluid analyses were negative for SARS-CoV-2 in all patients tested ( = 39). Conclusion In addition to cerebrovascular lesions, perfusion abnormalities, cytotoxic lesions of the corpus callosum, and intensive care unit-related complications, we identified two patterns including white matter-enhancing lesions and basal ganglia abnormalities that could be related to severe acute respiratory syndrome coronavirus 2 infection. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020202422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370354PMC
December 2020

Visual sensory processing is altered in myoclonus dystonia.

Mov Disord 2020 01 30;35(1):151-160. Epub 2019 Sep 30.

Sorbonne Université, Paris, France; Inserm U1127, CNRS UMR 7225, UM 75, ICM, Paris, France.

Background: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes.

Objective: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates.

Methods: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with μ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold.

Results: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (μ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower μ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower μ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022).

Conclusion: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27857DOI Listing
January 2020

Motor Timing in Tourette Syndrome: The Effect of Movement Lateralization and Bimanual Coordination.

Front Neurol 2019 26;10:385. Epub 2019 Apr 26.

Ospedale Policlinico San Martino-IRCCS, Genoa, Italy.

The study of motor timing informs on how temporal information integrates with motor acts. Cortico-basal ganglia and cortico-cerebellar circuits control this integration, whereas transcallosal interhemispheric connectivity modulates finely timed lateralized or bimanual actions. Motor timing abilities are under-explored in Tourette syndrome (TS). We adopted a synchronization-continuation task to investigate motor timing in sequential movements in TS patients. We studied 14 adult TS patients and 19 age-matched healthy volunteers. They were asked to tap in synchrony with a metronome cue (SYNC) and then, when the tone stopped, to keep tapping, maintaining the same rhythm (CONT). We tested both a sub-second and a supra-second inter-stimulus interval between the cues. Subjects randomly performed a single-hand task with the right hand and a bimanual task using both hands simultaneously wearing sensor-engineered gloves. We measured the temporal error and the interval reproduction accuracy index. We also performed MRI-based diffusion tensor imaging and probabilistic tractography of inter-hemispheric corpus callosum (CC) connections between supplementary motor areas (SMA) and the left SMA-putamen fiber tract. TS patients were less accurate than healthy individuals only on the single-hand version of the CONT task when asked to reproduce supra-second time interval. Supra-second time processing improved in TS patients in the bimanual task, with the performance of the right hand on the bimanual version of the CONT task being more accurate than that of the right hand on the single-hand version of the task. We detected a significantly higher fractional anisotropy (FA) in both SMA-SMA callosal and left-sided SMA-putamen fiber tracts in TS patients. In TS patients only, the structural organization of transcallosal connections between the SMAs and of the left SMA-putamen tract was higher when the motor timing accuracy of the right hand on the bimanual version of the task was lower. Abnormal timing performance for supra-second time processing is suggestive of a defective network inter-connecting the striatum, the dorsolateral prefrontal cortex and the SMA. An increase in accuracy on the bimanual version of the CONT task may be the result of compensatory processes linked to self-regulation of motor control, as witnessed by plastic rearrangement of inter-hemispheric and cortical-subcortical fiber tracts.
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http://dx.doi.org/10.3389/fneur.2019.00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497760PMC
April 2019

Tremor Associated with Chronic Inflammatory Demyelinating Polyneuropathy and Anti-Neurofascin-155 Antibodies.

Tremor Other Hyperkinet Mov (N Y) 2018 4;8:606. Epub 2018 Dec 4.

Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, FR.

Background: Tremor is an underrecognized feature in certain neuropathy subtypes.

Phenomenology Shown: We show a patient with a disabling neuropathic tremor and mild cerebellar syndrome associated with chronic inflammatory demyelinating polyneuropathy (CIDP) and anti-neurofascin-155 (NF155) antibodies.

Educational Value: Anti-NF155 testing should be considered in patients with CIDP and disabling tremor because of therapeutic implications.
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http://dx.doi.org/10.7916/D81560ZWDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312907PMC
March 2019

Rituximab in chronic inflammatory demyelinating polyradiculoneuropathy with associated diseases.

J Peripher Nerv Syst 2018 12 7;23(4):235-240. Epub 2018 Oct 7.

Department of Clinical Neurophysiology, APHP, Pitié-Salpêtrière Hospital, Paris, France.

We aimed to analyse the response to rituximab in a cohort of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients with associated disorders. We conducted a clinical and electrophysiological retrospective monocentric study in 28 CIDP patients. Response to rituximab was defined as (a) a five-point increase in the Medical Research Council sum score or a one-point decrease in the Overall Neuropathy Limitations Scale score, compared to the score at the first rituximab infusion, or (b) the discontinuation of, or reduced need for, the last treatments before rituximab initiation. Twenty-one patients (75%) were responders to rituximab. The median time before response was 6 months (1-10 months). Only two patients needed to be treated again during a median follow-up of 2.0 years (0.75-9 years). Interestingly, the response rate was good in patients with associated autoimmune disease (5/8) and similar to the response rate observed in patients with a haematological disease (16/20) (P = 0.63). A shorter disease duration was associated with a better clinical response to rituximab (odds ratio 0.81, P = 0.025) and the response rate was better (P = 0.05) in common forms (83.3%) than in sensory forms (42.9%). No major adverse events were recorded. Rituximab is efficacious in CIDP patients with haematological or autoimmune disease. It improves clinical response and decreases dependence on first-line treatments.
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http://dx.doi.org/10.1111/jns.12287DOI Listing
December 2018

Miming neurological syndromes improves medical student's long-term retention and delayed recall of neurology.

J Neurol Sci 2018 08 7;391:143-148. Epub 2018 Jun 7.

Faculty of Medicine of Sorbonne University, University Pierre-et-Marie-Curie (UPMC), 91, boulevard de l'Hôpital, 75013 Paris, France; Department of Internal Medicine, Hôpital Tenon, AP-HP, 4, rue de la Chine, 75020 Paris, France.

Basic examination and diagnostic skills in neurology are important for every graduating medical student. However, a majority of medical students consider neurology as complex and difficult to master. We evaluate the impact a learner-friendly, innovative simulation-based training programme has on long-term retention and delayed recall of neurological semiology amongst third-year medical students from the University Pierre et Marie Curie in Paris, France. The 2013 class received standard teaching in neurological semiology. The 2015 class who received the same standard teaching in neurological semiology were also invited to voluntarily participate in The Move, a mime-based role-play training programme of neurological semiology. During the Move, students were trained to simulate a patient with a neurological syndrome or the physician examining the patient. Students were evaluated with an assessment thirty months after their neurological rotation, including 15 questions to evaluate long-term retention of neurological semiology, and 10 to test background knowledge in general semiology. The semiology test was performed by 366/377 students from the 2013 class (standard education group) and by 272/391 students from the 2015 class, among which 186 participated in The Move (The Move group) and 86 did not (standard education group). The mean neurological semiology score was higher in the 2015 class compared to the 2013 class (p = 0.007) and remained so after adjustment for the general semiology performance (p = 0.003). The adjusted mean neurological semiology score was 1.21/15 points higher [95% CI 0.66, 1.75] in The Move group compared to the standard education group, corresponding to a 14% better ranking. The Move programme improves medical student's long-term retention and delayed recall of neurological semiology. This learner-friendly interactive teaching may in turn enhance clinical proficiency of future physicians in neurological semiology.
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http://dx.doi.org/10.1016/j.jns.2018.06.003DOI Listing
August 2018

Specific effect of a dopamine partial agonist on counterfactual learning: evidence from Gilles de la Tourette syndrome.

Sci Rep 2017 07 24;7(1):6292. Epub 2017 Jul 24.

Laboratoire de Neurosciences Cognitives, Institut National de la Santé et de la Recherche Médicale, Paris, France.

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication.
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http://dx.doi.org/10.1038/s41598-017-06547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524760PMC
July 2017

Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death.

Acta Neuropathol Commun 2017 07 14;5(1):55. Epub 2017 Jul 14.

Unité fonctionnelle de neurogénétique moléculaire, CHU de Lyon - HCL groupement Est, Bron, France.

Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.
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http://dx.doi.org/10.1186/s40478-017-0457-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513089PMC
July 2017

A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions.

Hum Mol Genet 2017 05;26(9):1599-1611

Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France.

Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient-derived fibroblasts. This Ca2+ dysregulation was associated with increased ER-mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease.
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http://dx.doi.org/10.1093/hmg/ddx060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411739PMC
May 2017

Alternating Upper Limb Monoplegia due to ATP1A3 Mutation.

Pediatr Neurol 2017 Mar 5;68:79-80. Epub 2017 Jan 5.

Sorbonne Universités, UPMC Univ Paris 06, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Département de Neurologie, APHP, Hôpital Pitié Salpêtrière, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2016.12.001DOI Listing
March 2017

Explicit Agency in Patients with Cervical Dystonia: Altered Recognition of Temporal Discrepancies between Motor Actions and Their Feedback.

PLoS One 2016 30;11(8):e0162191. Epub 2016 Aug 30.

UMR S 975, CNRS UMR 7225, ICM, Sorbonne Universités, UPMC University Paris 06, Paris, France.

Background: Abnormalities in the cognitive processing of movement have been demonstrated in patients with dystonia. The sense of agency, which is the experience of initiating and controlling one's own actions, has never before been studied in these patients.

Objectives: We investigated whether the sense of agency is altered in patients with cervical dystonia.

Methods: We used an explicit metacognitive agency task in which participants had to catch targets with a cursor by moving a computer's mouse. The task included several conditions in which the control over the cursor could be disrupted by adding a spatial or a temporal discrepancy between the mouse and the cursor's movements. Participants had to acknowledge these discrepancies and reflect them in metacognitive judgements of agency.

Results: Twenty cervical dystonia patients and 20 matched controls were included in the study. Despite performing equally well as the matched controls, cervical dystonia patients did not fully recognize alterations of agency when a temporal lag was added between their movement and the visual feedback. Moreover, they relied predominantly on their perceived performance to provide judgements of agency and less on their objective degree of controls. There was no correlation between agency scores and clinical severity of dystonia measured by the Toronto Western Spasmodic Torticollis Rating Scale.

Conclusion: We demonstrated an abnormal processing of agency in cervical dystonia patients, even for motor actions not affected by dystonia. The exact contribution of abnormal agency to dystonia pathophysiology remains to be clarified.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004868PMC
August 2017

Progressive Ataxia and Palatal Tremor: Think about POLG Mutations.

Tremor Other Hyperkinet Mov (N Y) 2016 2;6:382. Epub 2016 May 2.

Département de Neurologie, Assistance Publique - Hôpitaux de Paris, Hôpital de la Pitié Salpêtrière, Paris, France; Inserm U 1127, Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

Background: Progressive ataxia and palatal tremor (PAPT) can be observed in both acquired brainstem or cerebellar lesions and genetic disorders.

Phenomenology Shown: PAPT due to mutation in POLG, the gene encoding the mitochondrial DNA polymerase.

Educational Value: POLG mutation should be considered in patients with PAPT, particularly when additional clues such as a sensory neuronopathy or an ophthalmoplegia are present.
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http://dx.doi.org/10.7916/D86M36RKDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862008PMC
June 2016

Forceful Backbending Stereotypies Revealing MEF2C Haploinsufficiency.

Pediatr Neurol 2016 07 23;60:90-1. Epub 2016 Mar 23.

Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital de la Pitié Salpêtrière, Département de Neurologie, Paris, France; Sorbonne Universités, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2016.03.004DOI Listing
July 2016

Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor.

Mol Cancer Ther 2016 07 12;15(7):1460-71. Epub 2016 May 12.

Sanofi Oncology Drug Discovery, Sanofi Research and Development, Vitry-sur-Seine, France.

Class IA PI3K pathway activation resulting from PTEN deficiency has been associated with lack of sensitivity of melanoma to BRAF kinase inhibitors. Although previous studies have shown synergistic activity when pan-PI3K inhibitors were combined with MAPK inhibitors in the treatment of melanoma exhibiting concurrent genetic abnormalities, overlapping adverse events in patients limit optimal dosing and clinical application. With the aim of specifically targeting PTEN-deficient cancers and minimizing the potential for on-target toxicity when inhibiting multiple PI3K isoforms, we developed a program to discover PI3Kβ-selective kinase inhibitors and identified SAR260301 as a potent PI3Kβ-selective, orally available compound, which is now in clinical development. Herein, we provide a detailed biological characterization of SAR260301, and show that this compound has outstanding biochemical and cellular selectivity for the PI3Kβ isoform versus the α, δ, and γ isoforms and a large panel of protein and lipid kinases. We demonstrate that SAR260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models, and has synergistic antitumor activity when combined with vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models. Combination treatments were very well tolerated, suggesting the potential for a superior safety profile at optimal dosing using selective compounds to inhibit multiple signaling pathways. Together, these experiments provide a preclinical proof-of-concept for safely combining inhibitors of PI3Kβ and BRAF or MEK kinase modulators to improve antitumor activity in PTEN-deficient/BRAF-mutant melanoma, and support the evaluation of SAR260301-based combinations in clinical studies. Mol Cancer Ther; 15(7); 1460-71. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0496DOI Listing
July 2016