Paroxysmal Discharges Research Articles

Seizure Outcome and Predicting Factors in Adult Patients with Phenylketonuria: Single-center Experience

ABSTRACT Objective: Phenylketonuria (PKU) is one of the most common metabolic disorders worldwide. If left untreated, it causes neuropsychiatric sequelae, with seizures being a common occurrence. There is little information about the clinical features of epilepsy, electroencephalography (EEG) findings, and factors related to seizure outcomes in adult patients. We aimed to investigate these variables in adult PKU patients. Methods: We conducted a retrospective search in our database using the keywords “PKU and epilepsy” for the period between 2008 and 2022. Demographic, clinical, EEG, and cranial magnetic resonance imaging (MRI) findings of the patients were extracted from the electronic health records. Scalp EEG and MRI findings were reassessed. Phenylalanine (Phe) levels of the cases were retrieved. The potential correlation between seizure outcome and laboratory findings was analyzed. Results: Ten patients (4 females; aged: 19–55 years) were included. Seizure onset was various. The most common seizure type was bilateral tonic-clonic. Nine patients were on antiseizure medications (ASMs); seven were seizure-free. EEG background activity was slow in four patients, with paroxysmal discharges in eight individuals. The most frequent MRI finding was periventricular white matter hyperintensity. No correlation existed between seizure outcome and clinical, EEG, MRI results, or Phe levels. Seizure freedom was more common in patients with good dietary compliance. Conclusion: Bilateral tonic–clonic seizures were the most common type of seizure, accompanied by frequent paroxysmal activity in EEG. MRI scans revealed periventricular white matter hyperintensity. Seizure freedom was commonly achieved with ASMs, irrespective of blood Phe levels. Nevertheless, dietary compliance may play a role in seizure control.

Chronic stress intensify PTZ-induced seizures by triggering neuroinflammation and oxidative stress

BackgroundEpilepsy is a paroxysmal abnormal hypersynchronous electrical discharge characterized by recurrent seizures. It affects more than 50 million people worldwide. Stress is the leading cause of neurodegeneration and can produce seizures that may lead to or aggravate epilepsy. Inflammation plays a vital role in epilepsy by modulating oxidative stress, and levels of neuroinflammatory cytokines including NF-κB, TNF-α, and IL-1β. MethodsStress-induced changes in behavior were evaluated in mice by employing behavioral assessment tests such as an elevated plus maze, light-dark box, open field test, tail suspension test, Y-maze, novel object recognition test, and Morris water maze in pentylenetetrazole (PTZ) kindled mice. Behavioral changes in all these paradigms including seizure score, latency, and frequency showed an increase in symptoms in PTZ (35 mg/kg) induced seizures in stressed mice (RS-PTZ) as compared to PTZ, Stress, and normal animals. ResultsThe Enzyme-linked immunosorbent assay (ELISA) results confirmed increased in serum cortisol levels. Histological examinations showed neurodegenerative changes in the hippocampus and cortex regions. The spectrophotometric evaluation showed an increase in oxidative stress by decreasing antioxidant production i.e. reduced glutathione, glutathione -s- transferase, and catalase (CAT), and increasing oxidant levels such as maloaldehyde and nitric oxide. Immunohistochemistry results showed increased expression of NF-κB, TNF-α, and IL-1β in the cortex and hippocampus of mice brains. ConclusionsResults from the study conclude that stress increases the likelihood of eliciting an epileptic attack by increasing the level of reactive oxygen species and neuroinflammation.

Characterization of the intrahippocampal kainic acid model in female mice with a special focus on seizure suppression by antiseizure medications

Despite special challenges in the medical treatment of women with epilepsy, in particular preclinical animal studies were focused on males for decades and females have only recently moved into the focus of scientific interest. The intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy (TLE) is one of the most studied models in males reproducing electroencephalographic (EEG) and histopathological features of human TLE. Hippocampal paroxysmal discharges (HPDs) were described as drug resistant focal seizures in males. Here, we investigated the IHKA model in female mice, in particular drug-resistance of HPDs and the influence of antiseizure medications (ASMs) on the power spectrum.After injecting kainic acid (KA) unilaterally into the hippocampus of female mice, we monitored the development of epileptiform activity by local field potential (LFP) recordings. Subsequently, we evaluated the effect of the commonly prescribed ASMs lamotrigine (LTG), oxcarbazepine (OXC) and levetiracetam (LEV), as well as the benzodiazepine diazepam (DZP) with a focus on HPDs and power spectral analysis and assessed neuropathological alterations of the hippocampus.In the IHKA model, female mice replicated key features of human TLE as previously described in males. Importantly, HPDs in female mice did not respond to commonly prescribed ASMs in line with the drug-resistance in males, thus representing a suitable model of drug-resistant seizures. Intriguingly, we observed an increased occurrence of generalized seizures after LTG. Power spectral analysis revealed a pronounced increase in the delta frequency range after the higher dose of 30 mg/kg LTG. DZP abolished HPDs and caused a marked reduction over a wide frequency range (delta, theta, and alpha) of the power spectrum.By characterizing the IHKA model of TLE in female mice we address an important gap in basic research. Considering the special challenges complicating the therapeutic management of epilepsy in women, inclusion of females in preclinical studies is imperative. A well-characterized female model is a prerequisite for the development of novel therapeutic strategies tailored to sex-specific needs and for studies on the effect of epilepsy and ASMs during pregnancy.

Efficacy of Phenobarbital, Italept, and Topamax in the Treatment of Neonatal Seizures:A Double-Blinded Cross-Sectional Study of the Iranian Population.

Seizures are changes in the electrical activity of the brain. These changes can cause significant or otherwise asymptomatic symptoms. Phenobarbital and phenytoin are known drugs for treating neonatal seizures, but little clinical experience exists using other drugs. The present study aims to evaluate the efficacy of other drugs, such as Levetiracetam and Topiramate, compared to Phenobarbital in treating neonatal seizures. In a double-blind clinical trial, all neonates admitted to a referral hospital for two years (2020-2022) due to seizures were included. All of the neonates were treated with a dosage of 10-40mg/kg/state IV Phenobarbital to control the acute seizure. After that, they were divided into three groups with specific treatment programs. Groups were ordered with oral Phenobarbital 5mg/kg/day maintenance (first group), oral Topiramate 3-8mg/kg/day (second group), and 10-40mg/kg/day Levetiracetam (third group). Seizures and potential side effects were investigated through interviews and medical EEG tests. The data was analyzed using the Chi-square test. Sixty infants (20 neonates in each group) were studied. Phenobarbital, Italept, and Topiramate did not significantly differ in controlling convulsions and changes related to brain paroxysmal discharges. Due to the long treatment duration and side effects, it is essential to choose the appropriate drug for treating treatment-resistant seizures of neonates. The present study found that Phenobarbital, Levetiracetam, and Topiramate are equally effective in controlling seizures. These medications can also help eliminate abnormalities in children's brain paroxysmal.

A possibility of machine learning as a learning tool to evaluate paroxysmal discharge in interictal EEG of childhood focal epilepsy

A possibility of machine learning as a learning tool to evaluate paroxysmal discharge in interictal EEG of childhood focal epilepsy

Trpm2 deficiency in microglia attenuates neuroinflammation during epileptogenesis by upregulating autophagy via the AMPK/mTOR pathway

Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.

Clinical & etiological profile of new onset unprovoked seizure in children aged 2 months to 18 years

Seizure is defined as abnormal paroxysmal neuronal discharge, which is clinically manifested by motor, sensory, autonomic or behavioral disturbances. Seizures are common in pediatrics age group and occur in 10% of children. Less than 1/3of seizures in children are caused by epilepsy. The objective of the study was to determine the clinical and etiological profile of new onset unprovoked seizure in children aged between 2 month to 18 years. A hospital based prospective single centre study at RNT Medical College, Udaipur. 111 patients admitted in Balchikitsalya with new onset unprovoked seizures during one year. Out of 111 patients with new onset unprovoked seizures, majority of patients were between 1-5 years of age with male predominance. In which most common diagnosis was seizure disorder in 78 pts (70.2%) [Generalised 76 pts (97.4%) > Focal 2 pts (2.6%)] followed by 13.5% hypocalcemic seizure, 8.1% hypoglycemic seizure. Other diagnosis was tuberous sclerosis (2.7%), white matter changes (1.8%), adrenoleukodystrophy (0.9%), arachnoid cyst (0.9%), tuberculoma (0.9%) and HIE changes (0.9%). EEG abnormality was seen in 46% of patients. Hyponatremia (36%) was significantly associated with abnormal EEG changes. MRI was done in 38.7% of the patients, out of which, abnormality was seen in only 8.6% of the children. Seizure is mainly diagnosed clinically and EEG can be normal in many patients. First episode of unprovoked seizure was common in age group of 1-5 years. EEG and Neuroimaging is useful for better diagnosis, treatment can be started on clinical diagnosis.

STUDY OF CLINICAL AND ETIOLOGICAL PROFILE OF NEONATAL SEIZURES IN TERTIARY CARE HOSPITAL

Introduction: Neonatal seizure is defined as paroxysmal electrical discharge from the brain. The immature brain seems more prone to seizures. The in-cidence was found to increase with decreasing gestation and birth weight- preterm neonates (20.8 vs. 8.4 per 1000 live-births) while very low birth weight neonates had more than 4-fold higher incidence (36.1 per 1000 live-births). Objective: The study was conducted to estimate the incidence, etiological factor, time of onset, clinical types, and biochemical abnormalities among the different types of neonatal seizures. Methods: This is a hospital based prospective observational study con-ducted in NICU, Department of Pediatrics, SMIMER during the period of January 2020 to March 2021. Results: Total patients with neonatal seizures were 90 in our study. Inci-dence of neonatal seizures in our study was 1.1%. Incidence was higher in pre-term neonates (4.8%) and more in males (56.67%). Incidence of neona-tal seizures was higher in LBW babies (4.3%) and more common in SGA babies (51.11%). Incidence among vaginal delivered babies was 0.9%, LSCS was 1.7% and forceps was 1.1%. Birth asphyxia (41.1%) was the most common cause of all neonatal seizures followed by hypoglycemia (17.8%), neonatal meningitis/septicemia (14.5%), hypocalcemia (12.2%), ICH (7.8%). Subtle seizures (44.4%) were the commonest type of seizure followed by tonic (38.9%), focal clonic (11.1%), multifocal clonic (5.6%). 33.3% of neo-natal seizures occurred in < 24hrs & 40% in 24-72 hrs. The most common biochemical abnormality was hypoglycemia (17.8%) followed by hy-pocalcemia (12.2%). Conclusion: Incidence of neonatal seizures was 11.1/1000 live births (1.1%) & more common in preterm, LBW & LSCS deliveries. Birth asphyxia was the most common cause and subtle seizures were the most common type of seizure. Subtle seizures were more common in 24-72 hours of life. Most common biochemical abnormality was hypoglycemia followed by hy-pocalcemia.

Chemogenetic attenuation of cortical seizures in nonhuman primates

Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool—designer receptors exclusively activated by designer drugs (DREADDs)—for treating focal seizure in a nonhuman primate model. Acute infusion of the GABAA receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model.

Paroxysmal slow-wave discharges in a model of absence seizure are coupled to gamma oscillations in the thalamocortical and limbic systems

ObjectiveUsing the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if gamma (30–160 Hz) activity were cross-frequency modulated by the 2–6 Hz slow-wave discharges induced by GBL in the limbic system. We hypothesized that inactivation of the nucleus reuniens (RE), which projects to frontal cortex (FC) and hippocampus, would affect the cross-frequency coupling of gamma (γ) in different brain regions. MethodsLocal field potentials were recorded by electrodes implanted in the FC, ventrolateral thalamus (TH), basolateral amygdala (BLA), nucleus accumbens (NAC), and dorsal hippocampus (CA1) of behaving rats. At each electrode, the coupling between the γ amplitude envelope to the phase of the 2–6 Hz slow-waves (SW) was measured by modulation index (MI) or cross-frequency coherence (CFC) of γ amplitude with SW. In separate experiments, the RE was infused with saline or GABAA receptor agonist, muscimol, before the injection of GBL. ResultsFollowing GBL injection, an increase in MI and CFC of SW to γ1 (30–58 Hz), γ2 (62–100 Hz) and γ3 (100–160 Hz) bands was observed at the FC, hippocampus and BLA, with significant increase in SW-γ1 and SW-γ3 coupling at TH, and increase in peak SW-γ1 CFC at NAC. Strong SW-γ modulation was also found during baseline immobility high-voltage spindles. Muscimol inactivation of RE, as compared to saline infusion, significantly decreased SW-γ1 CFC in the FC, and peak frequency of the SW-γ1 CFC in the thalamus, but did not significantly alter SW-γ CFCs in the hippocampus, BLA or NAC. SignificanceThe paroxysmal 2–6 Hz SW discharges, a hallmark of absence seizure, significantly modulate γ activity in the hippocampus, BLA and NAC, suggesting a modulation of limbic functions. RE inactivation disrupted the SW modulation of FC and TH, partly supporting our hypothesis that RE participates in the modulation of SW discharges.

Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation.

To provide back-up compounds to support the development of the GABAA receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPP-III-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT: A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81.

Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges of absence seizures

Spike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge.

Long-term outcomes of classic and novel anti-seizure medication in a kainate-induced model of chronic epilepsy

ObjectiveIntrahippocampal injection of kainate (KA) is a reliable model of temporal lobe epilepsy (TLE) that replicates spontaneous recurrent seizures. Both electrographic seizures and electroclinical seizure (most generalized seizure) can be detected in KA model. Electrographic seizures such as high-voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs) are far more common and attracting much attention. A comprehensive study on the anticonvulsant effects of classic and novel antiseizure medications (ASMs) on spontaneous electroclinical seizures, especially during long-term treatment, is still lacking. Here, we evaluated the effects of six ASMs in this model on electroclinical seizures over eight weeks. MethodsUsing 24-hour continuous electroencephalographical (EEG) monitoring in free-moving mice, we tested the effectiveness of six ASMs (valproic acid, VPA; carbamazepine, CBZ; lamotrigine, LTG; perampanel, PER; brivaracetam, BRV; and everolimus, EVL) on the electroclinical seizures over eight weeks in the intrahippocampal kainate mouse model. ResultsVPA, CBZ, LTG, PER and BRV significantly suppressed electroclinical seizures in the early stages of treatment, but the mice gradually developed resistance to these drugs. Overall, the mean frequency of electroclinical seizures was not significantly lower during the 8-week treatment than that at baseline in any ASM-treated group. The individual responses to ASMs varied widely. ConclusionLong-term treatment with VPA, LTG, CBZ, PER, BRV and EVL did not relieve electroclinical seizures in this TLE model. Additionally, the window for screening new ASMs in this model should be set to at least 3 weeks to account for drug resistance.

Phase Lag Analysis Scalp Electroencephalography May Predict Seizure Frequencies in Patients with Childhood Epilepsy with Centrotemporal Spikes.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common epilepsy syndrome in school-aged children. However, predictors for seizure frequency are yet to be clarified using the phase lag index (PLI) analyses. We investigated PLI of scalp electroencephalography data at onset to identify potential predictive markers for seizure times. We compared the PLIs of 13 patients with CECTS and 13 age- and sex-matched healthy controls. For the PLI analysis, we used resting-state electroencephalography data (excluding paroxysmal discharges), and analyzed the mean PLIs among all electrodes and between interest electrodes (C3, C4, P3, P4, T3, and T4) and other electrodes. Furthermore, we compared PLIs between CECTS and control data and analyzed the associations between PLIs and total seizure times in CECTS patients. No differences were detected in clinical profiles or visual electroencephalography examinations between patients with CECTS and control participants. In patients with CECTS, the mean PLIs among all electrodes and toward interest electrodes were higher at the theta and alpha bands and lower at the delta and gamma bands than those in control participants. Additionally, the mean PLIs toward interest electrodes in the beta frequency band were negatively associated with seizure times (P = 0.02). The resting-state delta, theta, alpha, and gamma band PLIs might reflect an aberrant brain network in patients with CECTS. The resting-state PLI among the selected electrodes of interest in the beta frequency band may be a predictive marker of seizure times in patients with CECTS.

Chronic stress but not acute stress decreases the seizure threshold in PTZ-induced seizure in mice: role of inflammatory response and oxidative stress.

Seizure is paroxysmal abnormal electrical discharges in the cerebral cortex. Inflammatory pathways and oxidative stress are involved in the pathophysiology of seizures. Stress can induce an oxidative stress state and increase the production of inflammatory mediators in the brain. We investigated the effects of acute and chronic stresses on the seizure threshold in pentylenetetrazol (PTZ)-induced seizures in mice, considering oxidative stress and inflammatory mediators in the prefrontal cortex. In this study, 30 male Naval Medical Research Institute (NMRI) mice were divided into 3 groups, including acute stress, chronic stress, and control groups. PTZ was used for the induction of seizures. The gene expression of inflammatory markers (IL-1β, TNF-α, NLRP3, and iNOS), malondialdehyde (MDA) level, nitrite level, and total antioxidant capacity (TAC) were assessed in the prefrontal cortex and serum. Our results showed that stress could increase the expression of inflammatory cytokines genes and oxidative stress in the prefrontal cortex of the brain and serum following PTZ-induced seizures, which is associated with increased seizure sensitivity and decreased the seizure threshold. The effects of chronic stress were much more significant than acute stress. We concluded that the effects of chronic stress on seizure sensitivity and enhancement of neuroinflammation and oxidative stress are much greater than acute stress.

Pronounced antiseizure activity of the subtype-selective GABAA positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy.

AimDarigabat is an α2/3/5 subunit‐selective positive allosteric modulator of GABAA receptors that has demonstrated broad‐spectrum activity in several preclinical models of epilepsy as well as in a clinical photoepilepsy trial. The objective here was to assess the acute antiseizure effect of darigabat in the mesial temporal lobe epilepsy (MTLE) mouse model of drug‐resistant focal seizures.MethodsThe MTLE model is generated by single unilateral intrahippocampal injection of low dose (1 nmole) kainic acid in adult mice, and subsequent epileptiform activity is recorded following implantation of a bipolar electrode under general anesthesia. After a period of epileptogenesis (~4 weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) are recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3–10 mg kg−1, PO), and positive control diazepam (2 mg kg−1, IP).RESULTSDarigabat dose‐dependently reduced the expression of HPDs, demonstrating comparable efficacy profile to diazepam at doses of 3 and 10 mg kg−1.CONCLUSIONSDarigabat exhibited a robust efficacy profile in the MTLE model, a preclinical model of drug‐resistant focal epilepsy. A Phase II proof‐of‐concept placebo‐controlled, adjunctive‐therapy trial (NCT04244175) is ongoing to evaluate efficacy and safety of darigabat in patients with drug‐resistant focal seizures.

A short note in a long-standing discussion on the utility of EEG in patients with headache

Headache, especially migraine, has long been associated with epilepsy, based on the common clinical features, pathophysiological mechanisms and therapeutic options of these disorders. Epilepsy and headache can exist independently in the same patient or correlate in different ways. The utility of routine electroencephalogram (EEG) in patients with headache is to exclude a possible ictal origin when atypical symptoms exist. However, EEG abnormalities in migraine have been reported by a number of authors over the years. Herein, we report a case of a patient with migraine and paroxysmal epileptiform discharges (EDs) in the EEG, in an effort to contribute to the investigation of association between headache and abnormal EEG findings.

Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-κB pathway and iNOS production

Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-κB pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-κB activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.

Seizures and EEG characteristics in a cohort of pediatric patients with dystroglycanopathies

PurposeTo delineate the seizure type, phenotype and V-EEG patterns of dystroglycanopathy (DGP) and correlate them with the neuroradiological and genetic results. MethodsPatients with seizures were screened from our dystroglycanopathy database from January 2010 to March 2021. Detailed clinical information, including seizure type, brain magnetic resonance imaging (MRI), EEG and genetic analysis, was collected. ResultsThirteen patients (15.1%, 13/86) had seizures. Most patients had a severe phenotype. The mean age at first seizure onset was 2 years and 8 months. The most common seizure type was generalized tonic-clonic seizure (GTCS), with 92.3% (12/13) induced by fever. Three patients were diagnosed with epilepsy. Most patients did not take any medicine. A few patients had irregular use of antiseizure medications (ASMs). Of the 13 patients, seven patients were diagnosed with MEB, four patients with POMGNT1 mutations, two with ISPD mutations, and one with POMT1 mutation. Three patients were diagnosed with FCMD with FKTN mutations. Two patients were diagnosed with CMD-MR, one patient with ISPD mutation, and one with POMT1 mutation. One patient was diagnosed with LGMD with FKRP mutation. Nine patients underwent EEG examination, and eight patients had abnormal EEG results, including abnormal background activities in three patients, abnormal background activities combined with paroxysmal discharges in three patients, pure paroxysmal discharges in one patient and positive phase sharp waves in the occipital region in one patient. For radiology, brain MRI was available for 12 patients. The brain MRI of nine patients showed type II lissencephaly. Two patients showed cerebellar hypoplasia and brainstem hypoplasia. One patient had a normal brain MRI result. Patients with type II lissencephaly usually had abnormal background activities and paroxysmal discharges. ConclusionThe seizure phenotype of dystroglycanopathy (DGP) is characterized by GTCS, which was the most common seizure type, while focal seizures and epileptic spasms could also occur in DGP patients. Most seizures were induced by fever. Seizures were relatively more frequent in severe phenotypes of DGP, such as FCMD and MEB. Abnormal background activities were the most common EEG patterns, which were closely related to type II lissencephaly.

Calidad de vida en pacientes con epilepsia y crisis no epilépticas psicógenas: una revisión sistemática

Psychogenic non epileptic seizures (PNES) are disruptive changes in behaviour, thought, or emotion that resemble an epileptic seizure, but without paroxysmal neuronal discharge detectable by electroencephalography (EEG), and are not caused by another medical condition. On the other hand, epileptic seizures (ES) are defined as clinical events that reflect the presence of hypersynchronous discharges of neurons located in the cerebral cortex, which have the particularity of starting and ending abruptly. The diagnosis of epilepsy is made when an epileptic seizure was experienced and there is a risk of having another. The objective of this paper is to present the results of a systematic review of articles that have studied quality of life in people with PNES and ES. This review has been performed following the PRISMA guide (Preferred Reporting Items for Systematic reviews and Meta-Analyses). Prior to the beginning of the search, a protocol was carried out and it is published for consultation in the International prospective register of systematic reviews (PROSPERO). The review includes randomized and non-randomized, quantitative or mixed, cross-sectional or longitudinal studies, published in english or spanish until 2020. In addition, participants had to be over 16 years old. PNES diagnosis must have been confirmed by video-electroencephalography (VEEG) or a similar procedure-which is considered the gold standard for the diagnosis of PNES. In regards to research, PubMed, SciELO, Cochrane Library, Lilacs, Dialnet and Science Direct databases were reviewed. In addition, authors from epilepsy centers in Argentina were contacted in order to obtain local data and references of included studies were reviewed. The quality of the articles was evaluated using the guidelines of a tool created in a previous review by Brown and Reuber for PNES studies. It has been chosen to present the data in a narrative synthesis. As a result of the search, 678 references were obtained and after eliminating duplicates, 614 results were left. After filtering the results according to the selection criteria, 11 articles and a doctoral thesis were included. Their publication years date from 1998 to 2020. Most of them (10) were developed in the United States, one in Turkey and one in Argentina. English language was prevalent, being the doctoral thesis the only one written in spanish. Regarding the quality of the studies, most of them (9) were rated as medium quality; two of them as low quality and one as high quality. In regard to the scales employed to measure quality of life, the most widely used was Quality Of Life in Epilepsy (QOLIE), and QOLIE-31 was the most frequently used version of the instrument. It was found that people with PNES had a lower quality of life, mostly associated with the presence of psychopathology. Depression constitutes the most recurrent factor, followed by anxiety and personality traits. These results are consistent with previous research and gain importance when analysing the high rates of psychiatric comorbidity found in both groups of patients. To a lesser extent, other factors have shown a relationship with quality of life: taking anti-epileptic drugs, seizure-related factors (frequency, severity, duration of the disease), family functioning, demographic factors (sex), trauma and somatization. This study has potential limitations, including methodological problems of the articles included (non-randomized studies, dissimilar sample sizes between groups), quality of life scales dissimilarity among studies, and not having performed a meta-analysis, which would have provided more detailed information. Nevertheless, in conclusion, it could be stated that, in general, people with PNES have a lower quality of life than people with epileptic seizures. https://doi.org/10.1688/interd.2022.39.2.6