Tarek Sharshar

Université de Versailles Saint-Quentin, Versailles, Île-de-France, France

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Publications (180)729.67 Total impact


  • No preview · Article · Jan 2016 · The Lancet Respiratory Medicine
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    ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction of skeletal muscles. Triple-seronegative MG (tSN-MG, without detectable AChR, MuSK and LRP4 antibodies), which accounts for ~ 10% of MG patients, presents a serious gap in MG diagnosis and complicates differential diagnosis of similar disorders. Several AChR antibody positive patients (AChR-MG) also have antibodies against titin, usually detected by ELISA. We have developed a very sensitive radioimmunoprecipitation assay (RIPA) for titin antibodies, by which many previously negative samples were found positive, including several from tSN-MG patients. The validity of the RIPA results was confirmed by western blots. Using this RIPA we screened 667 MG sera from 13 countries; as expected, AChR-MG patients had the highest frequency of titin antibodies (40.9%), while MuSK-MG and LRP4-MG patients were positive in 14.6% and 16.4% respectively. Most importantly, 13.4% (50/372) of the tSN-MG patients were also titin antibody positive. None of the 121 healthy controls or the 90 myopathy patients, and only 3.6% (7/193) of other neurological disease patients were positive. We thus propose that the present titin antibody RIPA is a useful tool for serological MG diagnosis of tSN patients.
    Full-text · Article · Jan 2016
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    ABSTRACT: Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.
    Full-text · Article · Dec 2015 · Nature Communications

  • No preview · Article · Dec 2015
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    ABSTRACT: Experimental research has always been the cornerstone of pathophysiological and therapeutic advances in critical care medicine, where clinical observations and basic research mutually fed each other in a so-called translational approach. The objective of this review is to address the different aspects of translational research in the field of critical care medicine. We herein highlighted some demonstrative examples including the animal-to-human approach to study host-pathogen interactions, the human-to-animal approach for sepsis-induced immunosuppression, the still restrictive human approach to study critical illness-related neuromyopathy, and the technological developments to assess the microcirculatory changes in critically ill patients. These examples not only emphasize how translational research resulted in major improvements in the comprehension of the pathophysiology of severe clinical conditions and offered promising perspectives in critical care medicine but also point out the obstacles to translate such achievements into clinical practice.
    Preview · Article · Dec 2015 · Annals of Intensive Care
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    ABSTRACT: We prospectively studied early bedside standard EEG characteristics in 61 acute postanoxic coma patients. Five simple EEG features, namely, isoelectric, discontinuous, nonreactive to intense auditory and nociceptive stimuli, dominant delta frequency, and occurrence of paroxysms were classified yes or no. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) of each of these variables for predicting an unfavorable outcome, defined as death, persistent vegetative state, minimally conscious state, or severe neurological disability, as assessed 1 year after coma onset were computed as well as Synek's score. The outcome was unfavorable in 56 (91.8%) patients. Sensitivity, specificity, PPV, NPV, and AUC of nonreactive EEG for predicting an unfavorable outcome were 84%, 80%, 98%, 31%, and 0.82, respectively; and were all very close to the ones of Synek score >3, which were 82%, 80%, 98%, 29%, and 0.81, respectively. Specificities for predicting an unfavorable outcome were 100% for isoelectric, discontinuous, or dominant delta activity EEG. These 3 last features were constantly associated to unfavorable outcome. Absent EEG reactivity strongly predicted an unfavorable outcome in postanoxic coma, and performed as accurate as a Synek score >3. Analyzing characteristics of some simple EEG features may easily help nonneurophysiologist physicians to investigate prognostic issue of postanoxic coma patient. In this study (a) discontinuous, isoelectric, or delta-dominant EEG were constantly associated with unfavorable outcome and (b) nonreactive EEG performed prognostic as accurate as a Synek score >3.
    No preview · Article · Nov 2015 · Clinical EEG and neuroscience: official journal of the EEG and Clinical Neuroscience Society (ENCS)
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    ABSTRACT: Introduction Sepsis is associated with increased mortality, delirium and long-term cognitive impairment in intensive care unit (ICU) patients. Electroencephalogram (EEG) abnormalities occurring at the acute stage of sepsis may correlate with severity of brain dysfunction. Predictive value of early standard EEG abnormalities for mortality in ICU septic patients remains to be assessed. Methods In this prospective, single center, observational study, standard EEG was performed, analyzed and classified according to both Synek and Young EEG scales, in consecutive patients acutely admitted in ICU for sepsis. Delirium, coma and the level of sedation were assessed at the time of EEG recording; and duration of sedation, occurrence of in-ICU delirium or death were assessed during follow-up. Adjusted analyses were carried out using multiple logistic regression. Results One hundred ten patients were included, mean age 63.8 (±18.1) years, median SAPS-II score 38 (29–55). At the time of EEG recording, 46 patients (42%) were sedated and 22 (20%) suffered from delirium. Overall, 54 patients (49%) developed delirium, of which 32 (29%) in the days after EEG recording. 23 (21%) patients died in the ICU. Absence of EEG reactivity was observed in 27 patients (25%), periodic discharges (PDs) in 21 (19%) and electrographic seizures (ESZ) in 17 (15%). ICU mortality was independently associated with a delta-predominant background (OR: 3.36; 95% CI [1.08 to 10.4]), absence of EEG reactivity (OR: 4.44; 95% CI [1.37–14.3], PDs (OR: 3.24; 95% CI [1.03 to 10.2]), Synek grade ≥ 3 (OR: 5.35; 95% CI [1.66–17.2]) and Young grade > 1 (OR: 3.44; 95% CI [1.09–10.8]) after adjustment to Simplified Acute Physiology Score (SAPS-II) at admission and level of sedation. Delirium at the time of EEG was associated with ESZ in non-sedated patients (32% vs 10%, p = 0.037); with Synek grade ≥ 3 (36% vs 7%, p< 0.05) and Young grade > 1 (36% vs 17%, p< 0.001). Occurrence of delirium in the days after EEG was associated with a delta-predominant background (48% vs 15%, p = 0.001); absence of reactivity (39% vs 10%, p = 0.003), Synek grade ≥ 3 (42% vs 17%, p = 0.001) and Young grade >1 (58% vs 17%, p = 0.0001). Conclusions In this prospective cohort of 110 septic ICU patients, early standard EEG was significantly disturbed. Absence of EEG reactivity, a delta-predominant background, PDs, Synek grade ≥ 3 and Young grade > 1 at day 1 to 3 following admission were independent predictors of ICU mortality and were associated with occurence of delirium. ESZ and PDs, found in about 20% of our patients. Their prevalence could have been higher, with a still higher predictive value, if they had been diagnosed more thoroughly using continuous EEG.
    Full-text · Article · Oct 2015 · PLoS ONE
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    ABSTRACT: Objective: To determine the prevalence, type, and significance of brain damage in critically ill patients with a primary non-neurological diagnosis developing acute brain dysfunction. Methods: This retrospective cohort study was performed at the Johns Hopkins University School of Medicine, an academic tertiary care hospital. Medical records were reviewed of 479 consecutive ICU patients who underwent brain MRI over a 2-year period. Patients were selected for analysis if MRI was obtained to evaluate an acute onset of brain dysfunction (altered mental status, seizures, and/or focal neurological deficit). Subjects with a history of a central nervous system disorder were excluded. The principal clinical endpoint was Glasgow Outcome Scale (GOS) assessed at discharge. MRI-defined brain abnormalities were classified according to type and location. Factors associated with MRI-defined abnormalities were assessed in uni- and multivariable models. Results: 146 patients met inclusion criteria (mean age 54±7years). Brain damage was detected in 130 patients (89%). The most prevalent lesions were white matter hyperintensities (104/146, 71%) and acute cerebral infarcts (59/146, 40%). In a multivariable model, lesions on brain MRI were independently associated with unfavorable outcome (GOS1-3 in 71% of patients with lesions vs. 44% in those without, p=0.007). No adverse events occurred in relation to transport and MRI scanning. Conclusions: In critically ill patients without known neurological disease who have brain dysfunction, MRI reveals an unexpectedly high burden of underlying brain damage, which is associated with unfavorable outcome. The results indicate that brain damage could be an important and under-recognized factor contributing to critical illness brain dysfunction.
    Full-text · Article · Oct 2015 · Neurocritical Care
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    Dataset: CCM-OnLine

    Full-text · Dataset · Sep 2015
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    Full-text · Dataset · Sep 2015
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    ABSTRACT: Sepsis is a life-threatening condition caused by the systemic inflammatory response to a bacterial infection. Although much is known about the cellular and molecular changes that characterize the peripheral inflammatory response to sepsis, almost nothing is known of the neuronal changes that cause associated perturbations in the central control of homeostasis. Osmoregulation is one of the key homeostatic systems perturbed during sepsis. In healthy subjects, systemic hypertonicity normally excites osmoreceptor neurons in the organum vasculosum laminae terminalis (OVLT), which then activates downstream neurons that induce a parallel increase in water intake and arginine vasopressin (AVP) secretion to promote fluid expansion and maintain blood pressure. However, recent studies have shown that the early phase of sepsis is associated with increased AVP levels and suppressed thirst. Here we examined the electrophysiological properties of OVLT neurons and magnocellular neurosecretory cells (MNCs) in acute in vitro preparations obtained from rats subjected to sham surgery or cecal ligation and puncture (CLP).Wefound that the intrinsic excitability of OVLT neurons was not affected significantly 18-24 h after CLP. However, OVLT neurons in CLP rats were hyperpolarized significantly compared with shams. Moreover, a reduced proportion of these cells displayed spontaneous electrical activity and osmoresponsiveness in septic animals. In contrast, the osmoresponsiveness of MNCs was only attenuated by CLP, and a larger proportion of these neurons displayed spontaneous electrical activity in septic animals. These results suggest that acute sepsis disrupts centrally mediated osmoregulatory reflexes through differential effects on the properties of neurons in the OVLT and supraoptic nucleus.
    No preview · Article · Sep 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

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  • No preview · Article · Sep 2015
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    ABSTRACT: Seronegative myasthenia gravis (MG) presents a serious gap in MG diagnosis and understanding. We applied a cell based assay (CBA) for the detection of muscle specific kinase (MuSK) antibodies undetectable by radioimmunoassay. We tested 633 triple-seronegative MG patients' sera from 13 countries, detecting 13% as positive. MuSK antibodies were found, at significantly lower frequencies, in 1.9% of healthy controls and 5.1% of other neuroimmune disease patients, including multiple sclerosis and neuromyelitis optica. The clinical data of the newly diagnosed MuSK-MG patients are presented. 27% of ocular seronegative patients were MuSK antibody positive. Moreover, 23% had thymic hyperplasia suggesting that thymic abnormalities are more common than believed. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jul 2015 · Journal of neuroimmunology
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    ABSTRACT: Glucose toxicity may play a crucial role in evoking neurologic complications of critical illness. We studied whether the neuropathological alterations in fatal human critical illness observed under hyperglycemia are present and can be attenuated by maintaining normoglycemia in a mouse model of prolonged sepsis induced by cecal ligation and puncture. Mice were randomized to moderate hyperglycemia (>8.3 mmol/l, n=8) or normoglycemia (4.4-6.7 mmol/l, n=8). After 5 days, hippocampus and frontal cortex from septic mice were compared with healthy controls (n=8). Blood glucose was 7.8±1.3 mmol/l in hyperglycemic and 6.1±0.7 mmol/l in normoglycemic critically ill mice (p=0.007). The percentage of damaged neurons was two-fold higher in frontal cortex (p=0.01) and hippocampus (p=0.06) of hyperglycemic ill mice than that of healthy mice. In frontal cortex, neuronal damage was attenuated under normoglycemia (p=0.04). Critical illness reduced astrocyte density and activation status 4-fold in hippocampus (p≤0.02), but not in frontal cortex, irrespective of glycemic control. Microglia were 2-4-fold more abundant in both brain areas of hyperglycemic critically ill mice (p≤0.002), but only in frontal cortex reduced in number with normoglycemia (p=0.0008). The density of apoptotic cells and abundance of carbonylated proteins were significantly higher than normal in frontal cortex of hyperglycemic ill mice only (p=0.05). In a mouse model of prolonged polymicrobial sepsis, remarkable neuropathological changes develop with neuronal damage, impaired astrocyte activation, increased microglia, apoptosis and accumulation of carbonylated proteins. These changes were partially prevented or attenuated when hyperglycemia was prevented with insulin. Frontal cortex appeared more vulnerable to hyperglycemic insults than hippocampus.
    Full-text · Article · May 2015 · Shock (Augusta, Ga.)
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    ABSTRACT: To characterize etiology, clinical course and outcomes of patients in prolonged refractory status epilepticus (PRSE) and looking for prognostic factors. Retrospective study conducted in patients hospitalized from January 1, 2001 to December 31, 2011 in 19 polyvalent intensive care units in French university and general hospitals. Patients were adults with a generalized convulsive refractory status epilepticus that lasted more than seven days, despite treatment including an anesthetic drug and mechanical ventilation. Patients with anoxic encephalopathy were excluded. Follow-up phone call was used to determine functional outcome using modified Rankin Scale (mRS) with mRS 0-3 defining good and mRS 4-6 poor outcome. 78 patients (35 female) were included. Median age was 57 years. Causes of status epilepticus were various, mainly including prior epilepsy (14.1%), CNS infection (12.8%), and stroke (12.8%). No etiology was found in 27 (34.6%) patients. PRSE was considered controlled in only 53 (67.9%) patients after a median duration of 17 (IQR 12-26) days. The median length of ICU stay was 28 (19-48) days. Forty-one (52.5%) patients died in the ICU, 26 from multiple organ failure, 8 from care withdrawal, 2 from sudden cardiac arrest, 1 from brain death and 4 from unknown causes. PRSE was previously resolved in 20 patients who died in the ICU. At one-year follow-up, there were 12 patients with good outcome and 58 with poor outcome and 8 lost of follow-up. On multivariate analysis, only vasopressor use was a predictor of poor outcome (OR 6.54; 95%CI 1.09-39.29; p = 0.04). Poor outcome was observed in about 80% of this population of PRSE. Most patients died from systemic complications linked to their ICU stay. Some patients can recover satisfactorily over time though we did not identify any robust factor of good outcome.
    Full-text · Article · Apr 2015 · Critical care (London, England)
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    ABSTRACT: Purpose: Dysglycemia is a characteristic feature of critical illness associated with adverse outcome. Whether dysglycemia contributes to brain dysfunction during critical illness and long-term neurological complications is unclear. We give an overview of glucose metabolism in the brain and review the literature on critical illness-induced dysglycemia and the brain. Methods: Medline database search using relevant search terms on dysglycemia, critical illness, acute brain injury/dysfunction, and randomized controlled trial. Results: Hyperglycemia has been associated with deleterious effects on the nervous system. Underlying mechanisms in critical illness remain largely speculative and are often extrapolated from knowledge in diabetes mellitus. Increased hyperglycemia-induced blood-brain barrier permeability, oxidative stress, and microglia activation may play a role and compromise neuronal and glial cell integrity. Hypoglycemia is feared as critically ill patients cannot recognize or communicate hypoglycemic symptoms, which furthermore are masked by sedation and analgesia. However, observational data on the impact of brief hypoglycemia on the brain in critical illness are controversial. Secondary analysis of two large randomized studies suggested neuroprotection by strict glycemic control with insulin during intensive care, with lowered intracranial pressure, reduction of seizures, and better long-term rehabilitation in patients with isolated brain injury, and reduced incidence of critical illness polyneuromyopathy in the general critically ill patient population. Several subsequent studies failed to reproduce neurological benefit, likely explained by methodological issues, which include divergent achieved glucose levels and inaccurate glucose monitoring tools. Conclusions: Preventing hyperglycemia during critical illness holds promise as a neuroprotective strategy to preserve brain cell viability and prevent acute brain dysfunction and long-term cognitive impairment in survivors.
    Full-text · Article · Dec 2014 · Intensive Care Medicine
  • Djillali Annane · Tarek Sharshar
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    ABSTRACT: The modern era of sepsis management is characterised by a growing number of patients who survive in the short term and are discharged from hospital. Increasing evidence suggests that these survivors exhibit long-term neurological sequelae, particularly substantial declines in cognitive function. The exact prevalence and outcomes of these neuropsychological sequelae are unclear. The mechanisms by which sepsis induces cognitive dysfunction probably include vascular injuries and neuroinflammation that are mediated by systemic metabolism disorders and overwhelming inflammation, a disrupted blood-brain barrier, oxidative stress, and severe microglial activation, particularly within the limbic system. Interventions targeting the blood-brain barrier, glial activation, and oxidative stress have shown promise in prevention of cognitive dysfunction in various experimental models of sepsis. The next step should be to translate these favourable effects into positive clinical results. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Nov 2014 · The Lancet Respiratory Medicine
  • T. Ritzenthaler · T. Sharshar · D. Orlikowski
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    ABSTRACT: El síndrome de Guillain-Barré es la primera causa de parálisis aguda extensa en los países desarrollados desde la desaparición de la poliomielitis. Su diagnóstico se basa esencialmente en la clínica. Se trata de una patología evolutiva, por lo que una exploración neurológica minuciosa y repetida permite confirmar el diagnóstico y valorar su posible evolución y gravedad potencial. Las pruebas complementarias son útiles para descartar otras patologías, especialmente la meningorradiculitis, por punción lumbar, y la afectación medular, por resonancia magnética (RM). Un elemento esencial del tratamiento es la identificación del paciente con riesgo de desarrollar insuficiencia respiratoria aguda. Otro punto importante del tratamiento es la elección entre la plasmaféresis y la terapia con inmunoglobulinas intravenosas.
    No preview · Article · Nov 2014
  • T. Ritzenthaler · T. Sharshar · D. Orlikowski
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    ABSTRACT: La sindrome di Guillain-Barré è la prima causa di paralisi acuta estensiva nei paesi industrializzati dopo la scomparsa della poliomielite. La sua diagnosi resta essenzialmente clinica. Dal momento che la malattia è evolutiva, un esame neurologico preciso e ripetuto permette, il più delle volte, di confermare la diagnosi e di giudicare l’evolutività e la potenziale gravità. Gli esami complementari sono utili soprattutto per escludere un’altra patologia, in particolare una meningoradicolite attraverso la puntura lombare e una lesione midollare attraverso una risonanza magnetica (RM). Un elemento essenziale della gestione è l’identificazione dei pazienti a rischio di sviluppare un’insufficienza respiratoria acuta. L’altro risvolto terapeutico è la scelta terapeutica tra gli scambi plasmatici e le immunoglobuline endovenose.
    No preview · Article · Nov 2014

Publication Stats

4k Citations
729.67 Total Impact Points

Institutions

  • 2005-2015
    • Université de Versailles Saint-Quentin
      Versailles, Île-de-France, France
  • 1998-2015
    • Hôpital Raymond-Poincaré – Hôpitaux universitaires Paris Ile-de-France Ouest
      Garches, Île-de-France, France
    • Pierre and Marie Curie University - Paris 6
      • Centre de recherche des Cordeliers - UMR_S 872
      Lutetia Parisorum, Île-de-France, France
  • 2010-2014
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Imperial College London
      • Molecular Medicine
      Londinium, England, United Kingdom
  • 2004-2007
    • Royal Brompton and Harefield NHS Foundation Trust
      • Respiratory Medicine
      Harefield, England, United Kingdom
    • King's College London
      • Division of Asthma, Allergy and Lung Biology
      Londinium, England, United Kingdom
  • 1999-2001
    • Université Paris-Est Créteil Val de Marne - Université Paris 12
      • Faculty of medicine
      Créteil, Île-de-France, France