Drug-resistant generalized epilepsies: Revisiting the frontiers of idiopathic generalized epilepsies.

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term "genetic generalized epilepsies" (GGEs) should be used for the broad group of epilepsies with so-called "generalized" seizure types and "generalized" spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term "frontiers of IGEs" refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities.

Pathways to epilepsy surgery in children with tuberous sclerosis complex-associated epilepsy.

BACKGROUND: Previous studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex. METHODS: We identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected. RESULTS: Forty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery. CONCLUSION: Despite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.

Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions.

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

Outcome of childhood-onset epilepsy from adolescence to adulthood: Transition issues.

This is the second of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper addresses the outcome for some particularly challenging childhood-onset epileptic disorders with the goal of recommending the best approach to transition. We have grouped these disorders in five categories with a few examples for each. The first group includes disorders presenting in childhood that may have late- or adult-onset epilepsy (metabolic and mitochondrial disorders). The second group includes disorders with changing problems in adulthood (tuberous sclerosis complex, Rett syndrome, Dravet syndrome, and autism). A third group includes epilepsies that change with age (Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, West Syndrome, and Lennox-Gastaut syndrome). A fourth group consists of epilepsies that vary in symptoms and severity depending on the age of onset (autoimmune encephalitis, Rasmussen's syndrome). A fifth group has epilepsy from structural causes that are less likely to evolve in adulthood. Finally we have included a discussion about the risk of later adulthood cerebrovascular disease and dementia following childhood-onset epilepsy. A detailed knowledge of each of these disorders should assist the process of transition to be certain that attention is paid to the most important age-related symptoms and concerns.

Pure endoscopic management of epileptogenic hypothalamic hamartomas.

Hypothalamic hamartomas (HH) are rare congenital malformations located in the region of the tuber cinereum and third ventricle. Their usual clinical presentation is characterized by gelastic/dacrystic seizures which often become pharmaco-resistant and progress to secondary focal/generalized intractable epilepsy causing mostly in children cognitive and behavioral problems (particularly in cases of progressive epileptic encephalopathy) and precocious puberty. Whereas gelastic seizures can be surgically controlled either by resection of the lesion or disconnection (tissue-destructive) procedures, aimed at functionally prevent the spreading of the epileptic burst; generalized seizures tend to respond better to HH excision rather than isolated neocortical resections, which generally fail to control them. Prospective analysis of 14 consecutive patients harboring HH treated in an 8-year period; 12 patients had unilateral and two bilateral HH. All patients were managed by pure endoscopic excision of the HH. The mean operative time was 48 min and mean hospital stay was 2 days; perioperative blood loss was negligible in all cases. Two patients showed a transient diabetes insipidus (DI); no transient or permanent postoperative neurological deficit or memory impairment was recorded. Complete HH excision was achieved in 10/14 patients. At a mean follow-up of 48 months, no wound infection, meningitis, postoperative hydrocephalus, and/or mortality were recorded in this series of patients. Eight patients became seizure free (Engel class I), 2 other experienced worthwhile improvement of disabling seizures (Engel class II); 2 patients were cured from gelastic attacks while still experiencing focal dyscognitive seizures; and 2, having bilateral HH (both undergoing unilateral HH excision), did not experience significant improvement and required later on a temporal lobectomy coupled to amygdalohyppocampectomy. Overall, the followings resulted to be predictive factors for better outcomes in terms of seizure control: (1) cases of unilateral, Delalande class B, HH, (2) shorter history of epilepsy. Endoscopic resection of HH proved, in our series, to be effective in achieving complete control or in reducing the frequency of seizures. Furthermore, this approach has confirmed its minimally invasive nature with a very low morbidity rate: of note, it allowed to better preserve short-term memory and hypothalamic function.

Better Understanding of Phosphoinositide 3-Kinase (PI3K) Pathways in Vasculature: Towards Precision Therapy Targeting Angiogenesis and Tumor Blood Supply.

The intracellular PI3K-AKT-mTOR pathway is involved in regulation of numerous important cell processes including cell growth, differentiation, and metabolism. The PI3Kα isoform has received particular attention as a novel molecular target in gene therapy, since this isoform plays critical roles in tumor progression and tumor blood flow and angiogenesis. However, the role of PI3Kα and other class I isoforms, i.e. PI3Kß, γ, δ, in the regulation of vascular tone and regional blood flow are largely unknown. We used novel isoform-specific PI3K inhibitors and mice deficient in both PI3Kγ and PI3Kδ (Pik3cg(-/-)/Pik3cd(-/-)) to define the putative contribution of PI3K isoform(s) to arterial vasoconstriction. Wire myography was used to measure isometric contractions of isolated murine mesenteric arterial rings. Phenylephrine-dependent contractions were inhibited by the pan PI3K inhibitors wortmannin (100 nM) and LY294002 (10 µM). These vasoconstrictions were also inhibited by the PI3Kα isoform inhibitors A66 (10 µM) and PI-103 (1 µM), but not by the PI3Kß isoform inhibitor TGX 221 (100 nM). Pik3cg(-/-)/Pik3cd(-/-)-arteries showed normal vasoconstriction. We conclude that PI3Kα is an important downstream element in vasoconstrictor GPCR signaling, which contributes to arterial vasocontraction via α1-adrenergic receptors. Our results highlight a regulatory role of PI3Kα in the cardiovascular system, which widens the spectrum of gene therapy approaches targeting PI3Kα in cancer cells and tumor angiogenesis and regional blood flow.

Epidemiology of epilepsy.

Epilepsy is a burden affecting no fewer than 50 million patients worldwide. It is a heterogeneous group of disorders comprising both common and very rare forms, thus rendering its epidemiological investigations rather difficult. Moreover, making an epilepsy diagnosis per se can be challenging due to an evolving system of classification, and its dependency on local habits and culture. Any attempt at meta-analyses must consider such biases when pooling data from different centers and countries. Differentiating a contextual seizure from chronic epilepsy is every epileptologist's daily mission, yet it is also crucial for achieving a proper estimation of the epidemiology of epilepsy. Our present objective was to provide an overview of the epidemiology of both syndromic and non-syndromic epilepsy. Most epileptic syndromes tend to be rare and, thus, the feasibility of epidemiological quantification in populations is also addressed. Regarding its prevalence and cost, epilepsy deserves greater attention than it generally receives, as it appears to continue to be a condition under persistent taboos.

Piperazine derivatives as iron chelators: a potential application in neurobiology.

Polysubstituted piperazine derivatives, designed as new iron chelators, were synthesized and fully characterized by nuclear magnetic resonance and mass spectroscopy. Their potential to prevent iron-induced neurotoxicity was assessed using a cellular model of Parkinson disease. We demonstrated their ability to provide sustained neuroprotection to dopaminergic neurons that are vulnerable in this pathology. The iron chelating properties of the new compounds were determined by spectrophotometric titration illustrating that high affinity for iron is not associated with important neuroprotective effects.

In search of innovative therapeutics for neuropsychiatric disorders: the case of neurodegenerative diseases.

The recent medical literature highlights the lack of new drugs able to prevent or treat neurodegenerative diseases such as Alzheimer disease or Parkinson disease. Yet, the prevalence of these diseases is growing, related to increasing life expectancy, and is leading to a rise in their economic and social cost. At the same time, pharmaceutical companies are reducing or halting their investment in neuropharmacological research. Why have advances in basic neuroscience and our understanding of these diseases not allowed innovative discoveries in drug research? This review will try to explain this failure and suggest possible solutions: develop basic and clinical research but with the emphasis on translational and truly collaborative research; improve preclinical studies by developing more appropriate animal models, using new biomarkers and methodologies such as imaging suitable for clinical trials, providing worthwhile information on the ability of the drug to reach its intended target and induce significant pharmacological changes; build a new system of research management, based on stronger interdisciplinary relations between preclinical and clinical research and including the introduction of international precompetitive research between academic teams, start-up companies and pharmaceutical laboratories; hold early discussions with the regulatory authorities during preclinical studies and at the beginning of clinical trials in order to validate the methodological approaches; involve patients' associations in this new organization of research. These changes should help to ensure the discovery of effective treatments for these pathologies.

Transforming growth factor beta1 gene expression during vaginal wound healing in a rabbit menopause model.

OBJECTIVE: Surgical outcome following reconstructive pelvic surgery is largely dependent on the vaginal wound healing process. As peri- and post-menopausal women are the most likely candidates to undergo these surgeries, it is important to understand the effect of estrogen deficiency on this process. Transforming growth factor beta (TGFß) is an important mediator of wound healing. We sought to assess TGFß1 gene expression during the vaginal incisional wound healing process in a rabbit menopause model. DESIGN: Animal study. SETTING: Animal laboratory. SAMPLE: Sixty-three rabbits were used for this study. METHODS: Twenty-one underwent bilateral oophorectomy, 21 underwent a sham surgery, and 21 served as controls. Eight weeks later, standardised full-thickness 6-mm diameter circular segments were excised from the vagina of all rabbits. Animals were killed sequentially, before wounding, and at 0, 4, 7, 14, 21 and 35 days after wounding, and the wounds were harvested. MAIN OUTCOME MEASURES: Wound closure and TGFß1 gene transcription, as measured by real-time polymerase chain reaction (PCR). RESULTS: Wound closure was significantly protracted (P < 0.02), whereas TGFß1 gene expression was significantly increased (P < 0.0001) during the wound healing process in oophorectomised rabbits, as compared with both control and sham groups. CONCLUSION: Oophorectomised rabbits show protracted incisional vaginal wound healing associated with increased TGFß1 gene transcription.

Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form.

Huntington's disease (HD) results from the expansion of a polyglutamine encoding CAG repeat in a gene of unknown function. The wide expression of this transcript does not correlate with the pattern of neuropathology in HD. To study the HD gene product (huntingtin), we have developed monoclonal antibodies raised against four different regions of the protein. On western blots, these monoclonals detect the approximately 350 kD huntingtin protein in various human cell lines and in neural and non-neural rodent tissues. In cell lines from HD patients, a doublet protein is detected corresponding to the mutated and normal huntingtin. Immunohistochemical studies in the human brain using two of these antibodies detects the huntingtin in perikarya of some neurons, neuropiles, varicosities and as punctate staining likely to be nerve endings.

[Autoimmune encephalitis, clinical, radiological and immunological data]. / Encéphalites dysimmunitaires, données cliniques, radiologiques et immunologiques.

INTRODUCTION: Encephalitis is an inflammatory or infectious disease with an acute or subacute presentation. Immunological abnormalities in serum can be found but may be underdiagnosed. In several cases, a paraneoplastic origin with anti-neuron antibodies is noted. In all cases, other auto-antibodies can be found with or without any neoplastic mechanism. OBJECTIVES: The aim of our study was to describe a clinical, radiological and immunological cohort of patients with autoimmune encephalitis and suggest a diagnostic and therapeutic algorithm. PATIENTS AND METHOD: We performed a retrospective study in an immunological unit of neurology. All patients with autoimmune encephalitis between March 2000 and October 2009 were included. The clinical, imaging and immunological evaluations were recorded for each patient. RESULTS: Our cohort included 16 patients (eight men and eight women), mean age 45.3±10years. All patients had acute or subacute neuropsychological or neuropsychiatric impairment and all patients but one had temporal lobe dysfunction confirmed by cerebral MRI, PET or SPECT. Epilepsy was observed in 56% of cases, extra-temporal lobe impairment in 50%, including sleep disturbances. A cancer was found in only 25% (two small-cell lung cancers, one testis seminoma, one non-small-cell lung cancer with Merckel cells cancer). Anti-neuron antibodies were noted in 56% of cases (two with anti-voltage gate potassium channel complex antibodies (ab), two with anti-NMDA-R ab, two with anti-glutamate acid decarboxylase ab, one with anti-Ma2, two with anti-Hu ab and two remained uncharacterized). Systemic antibodies were found in 50% (one anti-gangliosides, one anti-SSA and one anti-DNA and four antinuclear ab uncharacterized, two anti-TPO and two anti-phospholipids). All patients received immunomodulatory treatments, including intravenous immunoglobulins (IgIV) and cancer was treated. Five patients achieved complete recovery, partial improvement was observed in 10 patients and two patients died. DISCUSSION: Despite clinical homogeneity at presentation, clinical outcome seems to be different between patients with antibodies against neuronal surface antigens and those with antibodies against intracellular antigens, which are more likely refractory to immunotherapy and paraneoplastic. The frequency of extra-temporal lobe impairment suggests that the term of limbic encephalitis should be changed to autoimmune encephalitis.

Genetic analyses of integrin function in mice.

Recent mutations of most integrin genes in the mouse have provided new exciting insights into the role of these integrins in cell-extracellular matrix interactions during development. The embryonic lethal phenotypes obtained by ablating integrins which are predominantly expressed in the mesenchyme confirmed the essential function of those integrins in morphogenesis. In contrast, null alleles for several epithelial integrins which bind components of basement membranes showed milder phenotypes, suggesting the presence of novel and unexpected redundant and compensatory mechanisms.

[Memory improvement in patients with temporal lobe epilepsy at one-year postoperative]. / Amélioration mnésique postopératoire un an après traitement chirurgical de l'épilepsie du lobe temporal.

INTRODUCTION: Several studies have assessed the impact of surgery on both anterograde and remote memory in patients with temporal lobe epilepsy (TLE). The majority of results have shown an extensive memory deficit in patients after temporal resection (TL). However, few protocols have used a prospective longitudinal design. Moreover, the postoperative delays were variable from one study to the next, instead of regular monitoring to identify the potential effect of time elapsed after surgery on memory performance. In addition, some studies have not used strict inclusion criteria to establish homogeneous patient groups. Finally, the impact of surgery on memory has been often assessed by comparing memory skills between epileptic patients and healthy controls. Our aim was to examine the impact of TL on memory in patients with TLE, recruited according to clear-cut clinical criteria. Moreover, we focused on memory performance progression per se in epileptic patients pre- and postoperatively, rather than on memory performance analysis expressed as "deficient" or "normal". METHODS: We assessed 30 patients with unilateral TLE (17 right TLE and 13 left TLE) on four anterograde memory tests and six remote memory tasks. Patients completed all tests preoperatively, and 5 and 12 months after TL. RESULTS: Five months after surgery, performance was equivalent to the preoperative scores for both groups in anterograde memory tasks and remote memory tests. One year after TL, patients with right TLE showed enhanced performance in the verbal anterograde memory tests and in retrieving recent autobiographical memories. Results for left TL showed improved scores only in a recognition memory test of faces. CONCLUSIONS: In the present study, surgical patients were "double winners" gaining seizure freedom and potential of memory stability or recovery. The gain was observed only 12 months after surgery and following temporal resection lateralisation. Our data showed postoperative memory improvement in patients with temporal lobe epilepsy presenting with specific clinical characteristics.

Predictive factors of epilepsy in arteriovenous malformation.

OBJECTIVE: Structural epilepsy related to cerebral arteriovenous malformation (AVM) suggests different epileptogenic mechanisms. The aim of our study was to determine factors associated with epilepsy into a retrospective cohort of AVM patients. PATIENTS AND METHODS: Ruptured and unruptured AVM data retrieved from a prospective single center registry (2009-2016) were retrospectively assessed. Demographic, clinical and radiological features were identified in AVM patients with or without epilepsy according to the International League Against Epilepsy classification. RESULTS: Epilepsy concerned 22 out of 80 consecutive patients with AVM (27.5%). Univariate analysis comparing both groups revealed a significant association of different variables with the structural epilepsy: young age (P=0.02), large nidus size (P=0.02), venous dilation (P=0.02), posterior cerebral artery (PCA) feeder (P<0.001) and Spetzler-Martin grade (P=0.02). Based on multivariate analysis, only the PCA feeder was identified (OR=5.2 [95% CI 1.1-24,5], P=0.04). CONCLUSION: PCA feeder for cerebral AVM was significantly associated with structural epilepsy. The hypothesis of a vascular steal phenomenon to the detriment of internal temporal lobe vascularization could be related to the development of epilepsy.

Vagus nerve stimulation in epilepsy: Efficiency and safety of outpatient practice.

INTRODUCTION: Over the past 20 years, Vagus Nerve Stimulation (VNS) has become one of the tools for surgical treatment of patients with refractory cryptogenic epilepsy. The objective of this study was to determine the feasibility of implanting a Vagus Nerve Stimulation in ambulatory patients with chronic epilepsy. PATIENTS AND METHODS: VNS procedure was consecutively performed in outpatient surgery between November 2016 and November 2018 in patients with refractory epilepsy. The main endpoints were complications, prolonged hospitalization and readmission during the first postoperative month. This information was collected by retrospective analysis of clinical files. RESULTS: Of the 22 patients included, the majority were autonomous (77%) with only 5 institutionalized patients. Retrospective analysis revealed a single complication of temporary dysphonia (4.5%) and an unplanned hospitalisation for immediate post-operative vomiting (4.5%). No readmissions were observed during the postoperative month but an emergency room visit for generalized seizure disorder was reported for one patient. CONCLUSION: The outpatient implantation of VNS in patients with epilepsy is a valid strategy for 95% of patients.

A new irradiation effect and its implications for the disposal of high-level radioactive waste.

Materials containing alkali metals or alkaline earths are sensitized by bombardment with either ions, electrons, or photons to chemical attack by atmospheric moisture. The implications of this effect on the proposed immobilization and long-term storage of high-level nuclear waste in glass or similar materials is discussed.

Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation.

Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)-coupled PI3Kgamma were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kgamma-/- neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kgamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation.

[Is there a bridge between migraine and familial mesial temporal lobe epilepsy?]. / Migraines et épilepsies temporales mésiales familiales : quel est le lien ?

Numerous reviews have emphasized the links between certain types of epilepsy and migraine. Historically, Gowers was one of the first, in 1907, to have drawn attention to a possible relationship between migraine headache and epilepsy in a period when no additional examination was available. In the last two decades, progress in molecular biology, electrophysiology, and neuro-imaging has enabled a better approach to the fundamental elements underlying the interrelationship between these two nosological domains. During this same time, a new term "channelopathy" has appeared in the literature. This term groups together affections involving a dysfunction of ion channels. In this article, the links between the different types of migraine and familial mesial temporal lobe epilepsy are illustrated by two case reports. This association does not appear to occur at random but would undoubtedly depend on a common genetic substratum, leading to a direct comorbidity. These occasional recurring symptoms would lie within the framework of a more general concept of "Primary Brain Channelopathies".