Papers by Christian Denier
Neurological Complications Induced by Anti-PD-1 or Anti-PD-L1: Prevalence, Clinical Description and Treatment: 5-Years Experience of a National Network
SSRN Electronic Journal, 2019
Journal of Cerebrovascular and Endovascular Neurosurgery, 2021
Five trials published in 2015 showed the benefit of endovascular thrombectomy (ET) in patients wi... more Five trials published in 2015 showed the benefit of endovascular thrombectomy (ET) in patients with stroke and large vessel occlusion, extending the treatment window has become an obsession of all physicians. In 2018, the DAWN and DEFUSE-3 trials showed that, with careful selection of patients, the procedure could be carried out up to 24 hours after symptom onset with good outcomes. In addition, there have been cases where the DAWN criteria were met, and treatment occurred >24 hours after symptom onset. We present the case of a 68-year-old female whose groin puncture occurred 52 hours after the time last known well (TLKW), after neurological worsening of the initial situation, with a large mismatch ratio observed on magnetic resonance imaging, achieving TICI (the Thrombolysis in Cerebral Infarction scale) grade 3 recanalization. Five days after the procedure, the patient was discharged with NIHSS (National Institutes of Health Stroke Scale) score of 3. Some types of collateral ci...
Validation of a new test for early assessment of unilateral neglect in acute stroke: The Rapid Unilateral Neglect Screening (RUNS) test
Annals of Physical and Rehabilitation Medicine, 2021
Prognosis and risk factors associated with asymptomatic intracranial hemorrhage after endovascular treatment of large vessel occlusion stroke: a prospective multicenter cohort study
European Journal of Neurology, 2020
Asymptomatic intracranial hemorrhage (aICH) is a common occurrence after endovascular treatment (... more Asymptomatic intracranial hemorrhage (aICH) is a common occurrence after endovascular treatment (EVT) for acute ischemic stroke (AIS). The aims of this study were to address its impact on 3‐month functional outcome and to identify risk factors for aICH after EVT.
Novel CCM2 missense variants abrogating the CCM1–CCM2 interaction cause cerebral cavernous malformations
Journal of Medical Genetics, 2020
BackgroundCerebral cavernous malformations (CCMs) are vascular malformations mostly located withi... more BackgroundCerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three CCM genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few CCM2 missense variants have been shown to be deleterious by modifying the ternary CCM complex stability.ObjectivesTo investigate the causality of novel missense CCM2 variants detected in patients with CCM.MethodsThe three CCM genes were screened in 984 patients referred for CCM molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the CCM2 missense variants located in the phosphotyrosine binding (PTB) domain.Results11 distinct CCM2 rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a los...
Can developmental venous anomalies cause seizures?
Journal of Neurology, 2017
Developmental venous anomalies (DVAs) are congenital anatomical variants of normal venous drainag... more Developmental venous anomalies (DVAs) are congenital anatomical variants of normal venous drainage of normal brain. Although DVAs are often discovered on the occasion of a seizure, their involvement in epilepsy is poorly studied. Our objective was to determine whether DVA can cause seizures, in the cases where there is no associated lesion, including no cavernoma or dysplasia. Based on clinical history, cerebral MRI, EEG recording, and 18F-FDG PET, we report 4 patients with DVA revealed by seizures. The first patient had a convulsive seizure caused by a hemorrhagic infarction due to thrombosis of her DVA. The second patient had a left temporo-parietal DVA next to a nonspecific lesion, possibly a sequelae of a venous infarction. The last two patients disclosed an isolated and uncomplicated DVA with a concordant epileptic focus confirmed on ictal video EEG recording. We reviewed literature and identified 21 other published cases of seizures caused by complications of a DVA and 9 patients that may have a direct link between epilepsy and an isolated and uncomplicated DVA. Seizures are linked to a DVA in two main situations: presence of an associated epileptogenic lesion, such as cavernoma or dysplasia, and occurrence of a complication of the DVA. Before concluding that a seizure is caused by a DVA, it is essential to perform full MRI protocols to search them. It remains rare and uncertain that isolated and uncomplicated DVA can cause seizures. In this last situation, physiopathological processes are probably different in each patient.
Incidence, présentations et étiologies des infarctus cérébraux multifocaux : étude d’une série monocentrique à partir de cas consécutifs basée sur IRM systématique
Revue Neurologique, 2012
16 ncidence, présentations et étiologies des nfarctus cérébraux multifocaux : étude d’une érie mo... more 16 ncidence, présentations et étiologies des nfarctus cérébraux multifocaux : étude d’une érie monocentrique à partir de cas consécutifs asée sur IRM systématique ébastien Depuydt a, Thierry Guedj a, Elsa Melki a, laire-Joint Lambert a, Denis Ducreux b, David Adams a, hristian Denier a Neurologie, CHU de Bicêtre, 94270 le Kremlin-Bicêtre, France Neuroradiologie, CHU de Bicêtre, 94270 le Kremlin-Bicêtre, France
Myoclonies focales révélant une encéphalite limbique à anticorps anti-LGI1
Revue Neurologique, 2014
Diagnosis of Adult Onset Leukodystrophy in a Consecutive Study of 156 Patients (S60. 006)
OBJECTIVE: To determine relative frequencies of different leukodystrophies in a cohort of patient... more OBJECTIVE: To determine relative frequencies of different leukodystrophies in a cohort of patients with adult-onset and the rentability of a systematic diagnostic approach. BACKGROUND: Leukodystrophies are a rare and heterogeneous group of inherited disorders which usually occur during infancy. Patients with adult-onset are increasingly recognized. Systematic investigations of these patients are not clearly reported in the literature. DESIGN/METHODS: We have conducted a systematic study including all MS centers in France between January 2007 and July 2012. Inclusion criteria were: 1) symetrical involvement of white matter on the first available brain MRI, 2) age of onset above 16, 3) absence of acquired diseases. Classification was based on MRI patterns as vascular, metabolic, cavitary and unclassified. In each group, a systematic genetic and/or biochemical testing was realized. RESULTS: Among 400 files, 156 patients with adult-onset leukodystrophy were identified. The mean age of onset was 39.3 (range 16-75) and a sex ratio imbalance was noted (male/female = 60/96). Main initial clinical symptoms were paraparesis (n=33), ataxia (n=31), cognitive decline (n=27), psychiatric symptoms (n=24) and stroke (n=20). Based on MRI findings, 54/156 were vascular, 17/156 cavitary, 52/156 metabolic. 33 patients were unclassified. A final diagnosis was made in 39/54 vascular cases (72.2 %). Main causes were CADASIL (n=30) and COL4A1 mutation (n=7). 9/17 (52.9 %) patients with a cavitary MRI had a diagnosis of CACH syndrome, with a pathogenic eIF2B mutation. 30/52 (57.7 %) of patients with metabolic MRI had a diagnosis. Main causes were X-linked adrenoleukodystrophy (n=11/52), cerebrotendinous xanthomatosis (n=4/52), Krabbe disease (n= 2/52) and SPG 11 mutation (n=2/52). Among 33 patients with unclassified MRI pattern, a diagnosis was made in 39.4% (n=13 / 33). CONCLUSIONS: Adult-onset leukodystrophies are considered as rare. Utility of MRI classification is confirmed by our study with a final diagnosis rate of 58.3 % (91/156) cases. Disclosure: Dr. Labauge has nothing to disclose. Dr. Carra-Dalliere has nothing to disclose. Dr. Ayrignac has nothing to disclose. Dr. Menjot de Champfleur has nothing to disclose. Dr. Aubourg has nothing to disclose. Dr. Bellesme has nothing to disclose. Dr. Pelletier has received personal compensation for activities with Allergan, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi, Teva, and Genzyme. Dr Pelletier has received research support from Bayer Schering, Biogen Idec, BMS, GSK, Merck Serono, Novartis, Peptimmune, Roche, Sanofi, Teva and Wyeth. Dr. Audoin has nothing to disclose. Dr. De Seze has received personal compensation for activities with Allergan, Inc., Almirall, Bayer Schering, Biogen Idec, Genzyme Corporation, LFB, Merck Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Collongues has received personal compensation for activities with Biogen Idec, Bayer Schering, Teva Neuroscience, Merck Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Novartis. Dr. Magnin has nothing to disclose. Dr. Rumbach has nothing to disclose. Dr. Confavreux has received personal compensation for activities with Biogen Dompe, Biogen Idec, Gemacbio, Genzyme Corporation, Hertie Foundation, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, UCB Pharma, Bayer Schering, and Merck Serono. Dr. Confavreux has received research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Vukusic has nothing to disclose. Dr. Camdessanche has nothing to disclose. Dr. Cohen has received personal compensation for activities with Schering, Biogen Idec, Serono, Inc., Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., and Novartis. Dr. Lebrun has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Schering, Biogen Idec, Merck Serono, Genzyme, Almirall, Allergan, Inc., Novartis, and Sanofi as a speaker. Dr. Lebrun has received personal compensation in an editorial capacity from Elsevier. Dr. Brassat has received personal compensation from Schering, Biogen Idec, Serono and Sanofi for speaking in symposia. Dr. Clanet has received personal compensation for activities with Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, and Genzyme Corporation. Dr. Vermersch has received personal compensation for activities with Biogen Idec, Sanofi-Aventis Pharmaceuticals, Inc., Bayer, Novartis, Merck Serono, GlaxoSmithKline, Inc., and Almirall. Dr. Vermersch has received research support from Biogen Idec, Sanofi-Aventis Pharmaceuticals, Inc., Bayer, and Merck Serono. Dr. Zephir has nothing to disclose. Dr. Outteryck has received personal compensation for activities with Biogen Idec, Bayer, Teva Neuroscience, Merck & Co., Inc., and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Wiertlevski has nothing to disclose. Dr. Ouallet has…
Migraine hémiplégique familiale
EMC - Neurologie, 2004
Tools and Early Management of Language and Swallowing Disorders in Acute Stroke Patients
Current Neurology and Neuroscience Reports, 2011
The role of the stroke units in improving morbidity, mortality, and recovery from stroke is clear... more The role of the stroke units in improving morbidity, mortality, and recovery from stroke is clearly demonstrated. However, acute management of language disorders in these specialized units remains controversial, and management of swallowing disorders is usually nonstandardized. The recent validation of a scale for rapid screening of language disorders (LAST [Language Screening Test]) in acute stroke patients should allow optimization of their detection and early management. Swallowing disorders should be screened and managed using a standardized protocol. Following early initial evaluation repeated on a daily basis, they justify tailored rehabilitation sessions, adaptation of food textures, team formation, and families' information. The use of these protocols implies the cooperation and coordination of the medical and paramedical teams and the daily presence of speech therapists. These aspects are crucial for patients in the stroke units to achieve full benefits from the management proposed in this paper, leading to diminution of complications and better long-term functional prognosis.
Évolution À Court Terme Des Lesions Medullaires De La Sclérose en Plaques : Une Étude Prospective en Imagerie Par Tenseur De Diffusion
Revue Neurologique, 2012
Histoire naturelle des leucodystrophies avec mutation EIF2B : étude rétrospective multicentrique de 24 cas adultes
Revue Neurologique, 2011
The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome ... more The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome (CACH-VWM) was first characterized in children (2-5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation.
CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy
Neurology, 2000
Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, includin... more Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.
Spectrum and prognosis of neurologic complications after hematopoietic transplantation
Neurology, 2006
To describe the neurologic complications after hematopoietic progenitor cell transplantation (HPC... more To describe the neurologic complications after hematopoietic progenitor cell transplantation (HPCT) in order to design rules for their management. We reviewed 361 consecutive patients over 6 years, including 245 autologous and 116 allogeneic HPCT recipients for hematologic malignancies (87%) and solid cancers (13%). Fifty-seven patients developed 65 symptomatic neurologic complications (16%), with a higher incidence in allogeneic than in autologous HPCT recipients (p = 0.01) and in chronic myelogenous leukemia (42%) than in Hodgkin disease (2.5%) (p < 0.001). CNS infections (4.2%) were the main complications, marked by an early onset (within the first 4 months) after HPCT (87%), diagnostic difficulties, and a high mortality rate (47%). They mainly included cerebral toxoplasmosis, fungal infections, and viral encephalitis. Their incidence was markedly higher in allogeneic than in autologous HPCT recipients (p = 0.002). However, two CD34(+) selected autologous HPCT recipients developed cerebral toxoplasmosis. Other CNS complications included recurrent tumors (3.6%), metabolic encephalopathies (2.8%), and cerebrovascular events (1.7%). Seizures occurred in 5% of patients, most often associated with cerebral lesions. Peripheral nervous system manifestations occurred in 3.3%. Twenty-one patients (5.8%) died directly of neurologic complications. The 4-year probability of survival was markedly lower in the case of neurologic events than in the absence thereof (12% vs 58%, p < 0.0001). Severe neurologic complications after hematopoietic progenitor cell transplantations are common, vary according to the underlying disease and type of transplantation, and are associated with poor survival rates. Better prophylactic protocols and therapy for CNS infections are required in future studies.
The Lancet Neurology, 2007
Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or... more Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of patients with a genetic form of the disease are now available. In addition, three CCM genes have been identifi ed: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.
Journal of the Neurological Sciences, 2011
Hematological disorders (HD) have been estimated to implicate approximately 1% of patients with a... more Hematological disorders (HD) have been estimated to implicate approximately 1% of patients with arterial ischemic stroke. However, previously published studies are mostly retrospective or based on case reports or small series in selected young patients. We herein prospectively included consecutive patients with MRI-confirmed cerebral arterial infarctions among individuals admitted in our stroke unit during a 32 month period to determine the clinical and neuroradiological features of ischemic stroke due to HD. Patients with both HD and other identified sources of stroke were excluded. Among patients who were admitted for suspected stroke, 590 had diffusion-weighted MRI confirmed acute arterial infarcts. Cause of the cerebral infarction was HD in 13 patients (2.2%): myeloproliferative disorders (n= 4), multiple myeloma (1), lymphoma (1), chronic lymphocytic leukemia (1), disseminated intravascular coagulation (2), thrombotic thrombocytopenic purpura (1), antiphospholipid antibody syndrome (2) and homozygous Q506 factor V mutation associated with lupus anticoagulant (1). The HD were previously known in 6 patients. The only significant difference between the groups of patients with or without HD was the prevalence of multiple acute infarcts in different vascular territories, detected in 53.8% of patients with HD versus 7.8% of patients without HD (mostly due to atherosclerosis, small vessel disease or cardioembolism) (pb 0.0001; Fisher exact test). Initial treatment in stroke unit included anticoagulation, steroids, chemotherapy, phlebotomy or plasmatic exchanges, according to etiology. Rankin score at six months was ≤2 in 8 patients. A large spectrum of hematological diseases can be associated with cerebral infarction. In the etiologic work up, HD should be particularly looked for in patients with multifocal acute infarcts to adapt specific therapeutic management.
A case of homocystinuria due to CBS gene mutations revealed by cerebral venous thrombosis
Journal of the Neurological Sciences, 2014
Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in ... more Homocystinuria caused by cystathionine beta synthase (CBS) deficiency is most often diagnosed in childhood and has a variable expressivity. The most frequent abnormalities include intellectual disability, ectopia lentis, myopia, skeletal abnormalities or thromboembolism. To report a case of homocystinuria unraveled by cerebral venous thrombosis (CVT). A 17 year old female was admitted in our department of neurology for subacute headache and presented seizures in the emergency room. Cerebral imaging revealed CVT. Severe hyperhomocysteinemia was found and led to the diagnosis of homocystinuria due to composite heterozygous mutations in the CBS gene. Further investigations disclosed lens subluxation in association with myopia, mild scoliosis and osteopenia. The patient was treated by heparin followed by warfarin, vitamin therapy and dietary methionine restriction. Total homocysteine and methionine levels became normal in a few weeks and the patient had a complete recovery. In patients with CVT, plasma total homocysteine measurement as part of the etiologic work up may reveal severe hyperhomocysteinemia due to CBS or remethylation defects that require specific treatment and management including perhaps protein-restricted diet and/or vitamin therapy for life.
Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease?
Journal of Neurology, 2001
We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical feature... more We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examination was performed in one patient and molecular analysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1-2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This late-onset paroxysmal cerebellar ataxia with neuropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process.
European Journal of Human Genetics, 2002
Cerebral Cavernous Malformations (CCM/MIM 604214) are vascular malformations characterised by abn... more Cerebral Cavernous Malformations (CCM/MIM 604214) are vascular malformations characterised by abnormally enlarged capillary cavities without intervening brain parenchyma. Clinical manifestations include seizures, cerebral haemorrhages and focal neurological deficits. They occur as a sporadic or autosomal dominant condition. Most often, sporadic cases have only one lesion and familial cases are characterised by a high frequency of multiple lesions. Three CCM loci were previously mapped on 7q (CCM1), 7p (CCM2) and 3q (CCM3) and CCM1 gene was identified as coding Krit1, a protein of unknown function, which was shown initially to interact in yeast two hybrid assays with Rap1A, a small ras GTPase and more recently to Icap1a, a modulator of b1 integrin signal transduction. Herein, we screened KRIT1 gene in 121 unrelated, consecutively recruited, CCM probands having at least one affected relative and/ or showing multiple lesions on cerebral MRI. Fifty-two of these probands (43%) were shown to carry a KRIT1 mutation. Forty-two distinct mutations were identified including six recurrent ones. Three-quarters of these mutations were located in the C-terminal half of the gene, mostly within exons 13, 15 and 17. All of them are predicted to lead to a premature stop codon. No missense mutation was identified. The only two nucleotide substitutions predicted to be missense mutations led in fact to an abnormal splicing and a premature stop codon. Altogether these data suggest that KRIT1 mRNA decay due to the presence of premature stop codons and Krit1 haploinsufficiency may be the underlying mechanism of CCM.
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Papers by Christian Denier