Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies

Background and purpose: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. Methods: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. Results: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case–control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called ‘cryptogenic NORSE’. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. Conclusions: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE

Cortical and Subcortical Network Dysfunction in a Female Patient With NEXMIF Encephalopathy

The developmental and epileptic encephalopathies (DEE) are the most severe group of epilepsies. Recently, NEXMIF mutations have been shown to cause a DEE in females, characterized by myoclonic–atonic epilepsy and recurrent nonconvulsive status. Here we used advanced neuroimaging techniques in a patient with a novel NEXMIF de novo mutation presenting with recurrent absence status with eyelid myoclonia, to reveal brain structural and functional changes that can bring the clinical phenotype to alteration within specific brain networks. Indeed, the alterations found in the patient involved the visual pericalcarine cortex and the middle frontal gyrus, regions that have been demonstrated to be a core feature in epilepsy phenotypes with visual sensitivity and eyelid myoclonia with absences

Modulation of tregs and inkt by fingolimod in multiple sclerosis patients

The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127 12 cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14 12CD19 12 V\u3b124-J\u3b118 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4 12CD8 12 double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY

Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles

The broad-spectrum activity of perampanel: state of the art and future perspective of AMPA antagonism beyond epilepsy

Glutamate is the brain’s main excitatory neurotransmitter. Glutamatergic neurons primarily compose basic neuronal networks, especially in the cortex. An imbalance of excitatory and inhibitory activities may result in epilepsy or other neurological and psychiatric conditions. Among glutamate receptors, AMPA receptors are the predominant mediator of glutamate-induced excitatory neurotransmission and dictate synaptic efficiency and plasticity by their numbers and/or properties. Therefore, they appear to be a major drug target for modulating several brain functions. Perampanel (PER) is a highly selective, noncompetitive AMPA antagonist approved in several countries worldwide for treating different types of seizures in various epileptic conditions. However, recent data show that PER can potentially address many other conditions within epilepsy and beyond. From this perspective, this review aims to examine the new preclinical and clinical studies—especially those produced from 2017 onwards—on AMPA antagonism and PER in conditions such as mesial temporal lobe epilepsy, idiopathic and genetic generalized epilepsy, brain tumor-related epilepsy, status epilepticus, rare epileptic syndromes, stroke, sleep, epilepsy-related migraine, cognitive impairment, autism, dementia, and other neurodegenerative diseases, as well as provide suggestions on future research agenda aimed at probing the possibility of treating these conditions with PER and/or other AMPA receptor antagonists

Individualized Prediction of Drug Resistance in People with Post-Stroke Epilepsy: A Retrospective Study

Background: The study aimed to develop a model and build a nomogram to predict the probability of drug resistance in people with post-stroke epilepsy (PSE). Methods: Subjects with epilepsy secondary to ischemic stroke or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of drug-resistant epilepsy defined according to International League Against Epilepsy criteria. Results: One hundred and sixty-four subjects with PSE were included and 32 (19.5%) were found to be drug-resistant. Five variables were identified as independent predictors of drug resistance and were included in the nomogram: age at stroke onset (odds ratio (OR): 0.941, 95% confidence interval (CI) 0.907–0.977), intracerebral hemorrhage (OR: 6.292, 95% CI 1.957–20.233), severe stroke (OR: 4.727, 95% CI 1.573–14.203), latency of PSE (>12 months, reference; 7–12 months, OR: 4.509, 95% CI 1.335–15.228; 0–6 months, OR: 99.099, 95% CI 14.873–660.272), and status epilepticus at epilepsy onset (OR: 14.127, 95% CI 2.540–78.564). The area under the receiver operating characteristic curve of the nomogram was 0.893 (95% CI: 0.832–0.956). Conclusions: Great variability exists in the risk of drug resistance in people with PSE. A nomogram based on a set of readily available clinical variables may represent a practical tool for an individualized prediction of drug-resistant PSE

An ultra-long new onset refractory status epilepticus: Winning the battle but losing the war?

New onset refractory status epilepticus (NORSE), is a rare and challenging condition occurring in previously healthy people. The etiology often remains undiscovered and is frequently associated with an unfavorable outcome. We report the electroclinical and neuroradiological evolution of an ultra-long case of NORSE of unknown etiology. A 38-year-old woman with a prodrome of fever, vomiting and diarrhea was admitted to our Intensive Care Unit for refractory convulsive status epilepticus (SE). Her past medical history was unremarkable. Extensive examinations were negative for potential viral, autoimmune and metabolic etiologies. Despite multiple therapeutical attempts with antiseizures medications, anesthetics and immunotherapy, seizures persisted. After nearly 6 months of enduring seizures, SE finally ceased and the patient gradually recovered to a minimum state of awareness. She was then able to communicate through one-word utterances and to understand simple tasks. At a three-years follow-up, she developed multifocal drug-resistant epilepsy, subcortical myoclonus and severe spastic quadraparesis, becoming completely dependent for activities of daily living. To our knowledge, this represents one of the longest cases of NORSE with final status resolution at this time. However, ultra-long SE in this case led to severe and disabling neurological sequelae. Future studies focused on disease modifying treatments for refractory SE are needed

MICROZONATION STUDY FOR AN INDUSTRIAL SITE IN SOUTHERN ITALY

A microzonation study for an industrial area located in Sicily (southern Italy) has been carried out through anintegrated approach using GIS and modelling tools for subsurface geology, together with procedures for soilresponse estimation. The seismic input was provided by an updated seismic hazard analysis aimed at betterdefining and characterizing the seismogenic sources active in the region. The approach involved thedevelopment of a model of the subsurface geology through the interpretation of several borehole data comingfrom industrial or private wells records. The lithologies described in the borehole logs were reclassified according to main litotechnical units for which seismological properties were available from previous studies.The reclassified logs were then interpreted using the GSI3D software (Geological Surveying and Investigation in3 Dimensions), which allows to draw and cross-correlate geological sections over the whole study area, toproduce 3D surfaces which model the topography of each litotechnical unit at depth. The model was thenimported into a GIS and linked to a customised version of SHAKE91 for the estimation of 1D soil response at a grid of points. Maps of amplification factors for different periods of engineering interest have been produced.The methodology used in this work has produced a dynamic tool which allows an easy update of themicrozonation maps as new data become available, since both the subsurface model and the litotechnical unitsparameters can be quickly updated and new analyses run

Ictal apnea: A prospective monocentric study in patients with epilepsy

Background and purpose: Ictal respiratory disturbances have increasingly been reported, in both generalized and focal seizures, especially involving the temporal lobe. Recognition of ictal breathing impairment has gained importance for the risk of sudden unexpected death in epilepsy (SUDEP). The aim of this study was to evaluate the incidence of ictal apnea (IA) and related hypoxemia during seizures. Methods: We collected and analyzed electroclinical data from consecutive patients undergoing long-term video-electroencephalographic (video-EEG) monitoring with cardiorespiratory polygraphy. Patients were recruited at the epilepsy monitoring unit of the Civil Hospital of Baggiovara, Modena Academic Hospital, from April 2020 to February 2022. Results: A total of 552 seizures were recorded in 63 patients. IA was observed in 57 of 552 (10.3%) seizures in 16 of 63 (25.4%) patients. Thirteen (81.2%) patients had focal seizures, and 11 of 16 patients showing IA had a diagnosis of temporal lobe epilepsy; two had a diagnosis of frontal lobe epilepsy and three of epileptic encephalopathy. Apnea agnosia was reported in all seizure types. Hypoxemia was observed in 25 of 57 (43.9%) seizures with IA, and the severity of hypoxemia was related to apnea duration. Apnea duration was significantly associated with epilepsy of unknown etiology (magnetic resonance imaging negative) and with older age at epilepsy onset (p < 0.001). Conclusions: Ictal respiratory changes are a frequent clinical phenomenon, more likely to occur in focal epilepsies, although detected even in patients with epileptic encephalopathy. Our findings emphasize the need for respiratory polygraphy during long-term video-EEG monitoring for diagnostic and prognostic purposes, as well as in relation to the potential link of ictal apnea with the SUDEP risk

Middle cerebral artery ischemic stroke and COVID-19: a case report

We present a clinical case of a patient with SARS-CoV-2 infection and respiratory symptoms, complicated with a pro-thrombotic state involving multiple vascular territories and concomitant interleukin-6 increase. This case underlines the possibility to develop a COVID-19-related coagulopathy