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.

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.

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.

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.

Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole.

Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.

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.

Efficacy and safety in frameless robot-assisted stereo-electroencephalography (SEEG) for drug-resistant epilepsy.

INTRODUCTION: Stereo-electroencephalography (SEEG) is an invasive procedure, used to identify the epileptogenic zone that can be surgically removed in order to treat drug-resistant epilepsy. Frameless robot-assisted positioning of depth electrodes permits a 3D approach with different obliquities and trajectories. The objective of the present study was to evaluate the morbidity and the accuracy related to this frameless procedure. PATIENTS AND METHODS: Sixty-six patients were managed wherein 901 electrodes were implanted during a 6-year-period. All patients had a postoperative CT-scan that was fused with preoperative MRI planning. In order to assess the accuracy of the procedure, the Euclidian distance was calculated between the coordinates of the planned trajectory and the actual position of the electrode at the entry point and at the target point for 857 electrodes. RESULTS: Among the 66 patients, one (1.5%) experienced a symptomatic brain haematoma and one (1.5%) a stroke-like migraine after radiation therapy (SMART) syndrome. There was no permanent morbidity or mortality. Compared to the classical SEEG approach, a higher rate of asymptomatic postoperative bleeding was found on the CT-scan in 8 patients (12.1%). Any infectious events were recorded. The median accuracy of frameless robotic SEEG procedure was equivalent to a 1.1mm error deviation (0.15-2.48) at the entry point and 2.09mm (1.06-3.72) at the target point respectively, with no differences for double obliquity trajectories. CONCLUSION: Frameless robot-assisted SEEG appears to be a safe procedure, providing sufficient accuracy in order to delineate the epileptogenic zone and represents a helpful tool in the pre-surgical management of refractory epilepsy.

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.

Xenon-mediated neuroprotection in response to sustained, low-level excitotoxic stress.

Noble gases such as xenon and argon have been reported to provide neuroprotection against acute brain ischemic/anoxic injuries. Herein, we wished to evaluate the protective potential of these two gases under conditions relevant to the pathogenesis of chronic neurodegenerative disorders. For that, we established cultures of neurons typically affected in Alzheimer's disease (AD) pathology, that is, cortical neurons and basal forebrain cholinergic neurons and exposed them to L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) to generate sustained, low-level excitotoxic stress. Over a period of 4 days, PDC caused a progressive loss of cortical neurons which was prevented substantially when xenon replaced nitrogen in the cell culture atmosphere. Unlike xenon, argon remained inactive. Xenon acted downstream of the inhibitory and stimulatory effects elicited by PDC on glutamate uptake and efflux, respectively. Neuroprotection by xenon was mimicked by two noncompetitive antagonists of NMDA glutamate receptors, memantine and ketamine. Each of them potentiated xenon-mediated neuroprotection when used at concentrations providing suboptimal rescue to cortical neurons but most surprisingly, no rescue at all. The survival-promoting effects of xenon persisted when NMDA was used instead of PDC to trigger neuronal death, indicating that NMDA receptor antagonism was probably accountable for xenon's effects. An excess of glycine failed to reverse xenon neuroprotection, thus excluding a competitive interaction of xenon with the glycine-binding site of NMDA receptors. Noticeably, antioxidants such as Trolox and N-acetylcysteine reduced PDC-induced neuronal death but xenon itself lacked free radical-scavenging activity. Cholinergic neurons were also rescued efficaciously by xenon in basal forebrain cultures. Unexpectedly, however, xenon stimulated cholinergic traits and promoted the morphological differentiation of cholinergic neurons in these cultures. Memantine reproduced some of these neurotrophic effects, albeit with less efficacy than xenon. In conclusion, we demonstrate for the first time that xenon may have a therapeutic potential in AD.

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.

Recurrence of group B streptococcus colonization in successive pregnancies.

OBJECTIVE: To identify risk factors for group B streptococcus (GBS) colonization in a subsequent pregnancy using microbiological and clinical data from a prior pregnancy. STUDY DESIGN: A retrospective cohort study of women over a 10-year period, using laboratory records to identify women with GBS culture results available in two successive pregnancies. RESULT: One thousand eight hundred and ninety-four women met eligibility criteria. Of these, 1293 were not GBS-colonized in either pregnancy, 198 were colonized in both pregnancies and 403 had discordant colonization status. GBS colonization in the index pregnancy was positively associated with multiparity, premature delivery and lower maternal age and negatively associated with chorioamnionitis. The strongest predictor of colonization in a subsequent pregnancy was colonization in the index pregnancy (50% likelihood if colonized compared with 14% if not in the index pregnancy, relative risk 3.6, confidence interval (CI)=3.1 to 4.3). GBS colonization in the subsequent pregnancy was independently associated with: GBS colonization in the index pregnancy (odds ratio (OR)=6.28; CI=4.91 to 8.05), preterm delivery in the index pregnancy (OR=1.80; CI=1.05 to 3.09) and prior early pregnancy loss (OR=1.15; CI=1.04 to 1.27). CONCLUSION: GBS colonization in a prior pregnancy is informative of colonization in a subsequent pregnancy. These data support providing antimicrobial prophylaxis in unscreened parous women with known prior GBS colonization.

Severe perineal laceration during operative vaginal delivery: the impact of occiput posterior position.

OBJECTIVE: To identify risk factors for severe (third/fourth degree) perineal laceration with operative vaginal delivery (OVD, forceps or vacuum). STUDY DESIGN: Case-control study comparing singleton OVDs with or without severe laceration (n=138). RESULT: In multivariable analyses, severe perineal laceration was associated with occiput posterior (OP) position at delivery, vaginal nulliparity, use of forceps, longer period pushing in the second stage and lower gestational age, but not birth weight, labor induction or episiotomy. Among 29 OP patients at full dilation, 9/13 (69%) attempted rotations to occiput anterior (OA) were successful, and 14/16 (88%) patients in whom rotation was not attempted remained OP at delivery. Successful rotation from OP to OA was associated with fewer severe lacerations than no attempt or unsuccessful rotation (22 vs 75%, P=0.01). CONCLUSION: Severe perineal laceration during OVD is associated with OP position at delivery and is reduced threefold in patients successfully rotated from OP to OA.

PI3K in cancer-stroma interactions: bad in seed and ugly in soil.

Over the past decade the phosphoinositide-3 kinase (PI3K) signaling pathway emerged as an important player for tumor initiation and growth and, currently, PI3K inhibition constitutes a promising therapeutic approach for solid and hematological tumors. Beside its role in tumor cell evolution, PI3K signaling also provides integral functions for noncancerous cells that reside in healthy tissues surrounding the tumor, also referred as tumor microenvironment (TME). This review will address how PI3K signaling participates to the tumorigenic process and discuss the interaction between tumor cells and the surrounding TME, with particular focus on the role of PI3Ks in tumor-associated immune responses, tumor angiogenesis and metastasis formation.

[An atypical form of neurosarcoidosis]. / Neurosarcoïdose de présentation atypique.

INTRODUCTION: Nervous system involvement occurs in 5 to 15% of the patients with sarcoidosis. Neurosarcoidosis remains very difficult to diagnose because clinical presentation and imaging characteristics lack specificity. OBSERVATION: We report a 26-year-old man who gradually developed headaches, memory disturbance and epilepsy. CT-scan and MRI showed a temporal-parietal cystic mass, secondary to a rare and focal form of hydrocephalus, called "trapped temporal horn" revealing neurosarcoidosis. CONCLUSION: The "entrapped temporal horn" is due to an obstacle on the cerebrospinal fluid pathway at the trigone of the lateral ventricle that seals off the temporal horn and the choroid plexus from the rest of the ventricular system. The obstacle is related to the granulomatous tissue of sarcoidosis. Therefore, the "trapped temporal horn" acts as a space occupying process, causing headaches, memory pain, hemiparesis, homonymous hemianopsia, and requires medico-surgical management.