L’état de mal épileptique d’origine autoimmune : une étude clinique rétrospective multicentrique, suivie d’une revue des mécanismes et traitements et complétée d’un éditorial

Cette thèse de doctorat, composée de trois publications, s’intéresse à l’état de mal épileptique d’origine autoimmune. La première publication (2012) est une étude rétrospective multicentrique sur 13 cas, elle analyse les caractéristiques cliniques, biologiques, électrophysiologiques, de l’imagerie et du pronostic des patients qui en sont atteints. Elle montre que malgré un état de mal épileptique de longue durée, le pronostic reste favorable dans la moitié des cas et justifie des traitements et mesures de soins intensifs de longue durée. La deuxième publication (2014), résume les données de 111 cas publiés, revoit les mécanismes physiopathologiques ainsi que les traitements proposés et commente leurs preuves d’efficacité. La troisième publication (2018) est un éditorial au sujet d’une étude récente qui a confirmé les résultats de notre première étude et met en perspective nos connaissances actuelles de l’état de mal épileptique d’origine autoimmune

Autoimmunity and inflammation in status epilepticus: from concepts to therapies

The understanding of immunological mechanisms underlying some forms of epilepsy and encephalitis has rapidly increased for the last 10 years leading to the concept of status epilepticus of autoimmune origin. Actual treatment recommendations regarding autoimmune status epilepticus are based on retrospective case studies, pathophysiological considerations and experts' opinion. In addition, there are no clear indicators to predict outcome. In situations where autoimmune mechanisms are suspected in patients with status epilepticus, there is evidence that earlier treatment is related to better outcome. Increased awareness is mandatory to decrease the number of patients with major neurological problems or fatal outcome, which is overall about 50%. We here summarize findings of all pediatric and adult patients reported to date, and review the current state of knowledge in the field of immune therapeutic approaches of status epilepticus

Diagnostiquer et annoncer une démence : quels risques, quels bénéfices ?

While dementias represent an important problem of social health, they remained underdiagnosed. Data from the literature suggests that only 30% of cognitive impairment are detected and correctly evaluated, while most of the patient (up to 90%) and caregivers (up to 70-80%) ask for a precise diagnosis. Proper evaluation increase diagnostic accuracy from 30% to 80% but 20% of diagnoses remains inexact. Diagnostic disclosure seems to have a positive impact on patient's affective symptoms but is associated to an increase of suicide during the following 3 months, and thus must be a progressive and controlled process. Accompanying a patient in this process necessitates complexes competencies from the primary care physician. Difficulties related to this disclosure are counterbalanced by benefits for both patient and families

Causes inhabituelles de troubles de la marche

Gait disorder is a common complaint in general practice, in particular in the elderly, and more than one cause frequently interact to produce various abnormalities of gait, including neurological, orthopedic, rhumatologic or ophthalmologic conditions, among others. The most frequent etiologies of gait impairment include sensory deficits, cervical myelopathy, vascular encephalopathy, parkinsonism and normal pressure hydrocephalus. In a particular individual, several of them may contribute to alter gait and, as a general rule, the treatment of these well-established conditions is generally considered difficult. Besides them, a number of rare and underrecognized neurological conditions may also produce a gait disorder as their initial, main or exclusive feature, including dopa-responsive dystonia, stiff-person syndrome, orthostatic tremor, primary progressive freezing gait and cursive epilepsy. In this review article, the clinical, therapeutic and other characteristics of these conditions are revisited and a typical illustrative case is reported for each. Since most of these conditions are responsive to specific treatments, we believe that a better knowledge of these unusual forms of gait disorder may allow general practitioners to identify them more accurately, to assess them and to improve therapeutic strategies

Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors

Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9–34 (mean 22). The degree of common (0–94%) and private mutations per sample was strongly varying (6–100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted

Antibody-Mediated Status Epilepticus: A Retrospective Multicenter Survey

Background: In recent years, an increasing number of autoantibodies (AB) have been detected in the CSF and serum of patients with new onset epilepsy. Some of these patients develop convulsive or nonconvulsive status epilepticus (ABSE), necessitating intensive medical care and administration of multiple antiepileptic and immunomodulatory treatments of uncertain effectiveness. Objectives: In this retrospective multicenter survey we aimed to determine the spectrum of gravity, the duration and the prognosis of the disorder. In addition, we sought to identify the antibodies associated with this condition, as well as determine whether there is a most effective treatment regime. Methods: 12 European Neurology University Clinics, with extensive experience in the treatment of SE patients, were sent a detailed questionnaire regarding symptoms and treatment of AB-SE patients. Seven centers responded positively, providing a total of 13 patients above the age of 16. Results: AB-SE affects mainly women (12/13, 92%) with a variable age at onset (17– 69 years, median: 25 years). The duration of the disease is also variable (10 days to 12 years, median: 2 months). Only the 3 oldest patients died (55–69 years). Most patients were diagnosed with anti NMDAR encephalitis (8/13) and had oligoclonal bands in the CSF (9/13). No specific treatment regimen (antiepileptic, immunomodulatory) was found to be clearly superior. Most of the surviving 10 patients (77%) recovered completely or nearly so within 2 years of index poststatus. Conclusion: AB-SE is a severe but potentially reversible condition. Long duration does not seem to imply fatal outcome; however, age older than 50 years at time of onset appears to be a risk factor for death. There was no evidence for an optimal antiepileptic or immunomodulatory treatment. A prospective multicenter study is warranted in order to stratify the optimal treatment algorithm, determine clear risk factors of unfavorable outcome and long-term prognosis