Seizure Threshold Research Articles

Should We Re-estimate the Seizure Threshold during Maintenance ECT?

Should We Re-estimate the Seizure Threshold during Maintenance ECT?

Supplementation of n-3 PUFAs in Adulthood Attenuated Susceptibility to Pentylenetetrazol Induced Epilepsy in Mice Fed with n-3 PUFAs Deficient Diet in Early Life.

The growth and development of the fetus and newborn throughout pregnancy and lactation are directly related to the nutritional status of the mother, which has a significant impact on the health of the offspring. The purpose of this experiment was to investigate the susceptibility of n-3 polyunsaturated fatty acid deficiency in early life to seizures in adulthood. The n-3 PUFAs-deficient mice's offspring were established and then fed with α-LNA diet, DHA-enriched ethyl ester, and DHA-enriched phospholipid-containing diets for 17 days at the age of eight weeks. During this period, animals received intraperitoneal injections of 35 mg/kg of pentylenetetrazol (PTZ) every other day for eight days. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate PTZ-induced epileptic seizures and brain disorders. Notably, nutritional supplementation with n-3 PUFAs in adulthood for 17 days could significantly recover the brain n-3 fatty acid and alleviate the epilepsy susceptibility as well as raise seizure threshold to different levels by mediating the neurotransmitter disturbance and mitochondria-dependent apoptosis, demyelination, and neuroinflammation status of the hippocampus. DHA-enriched phospholipid possessed a superior effect on alleviating the seizure compared to α-LNA and DHA-enriched ethyl ester. Dietary n-3 PUFA deficiency in early life increases the susceptibility to PTZ-induced epilepsy in adult offspring, and nutritional supplementation with n-3 PUFAs enhances the tolerance to the epileptic seizure.

The sub-chronic Administration of Echium Oil Attenuates the Seizure Threshold and Improves Antioxidant Activity in Pentylenetetrazol-induced Seizure Model of Mice.

Recently polyunsaturated fatty acids (PUFAs) have been considered as the supplementation with no side effects for epilepsy treatment. Echium oil (EO) has been recommended as a novel plant-based source with a significant amount of omega-3 and omega-6. This study evaluates the effects of the sub-chronic consumption of Iranian EO on seizure threshold, antioxidant status, and biochemical parameters in mice with pentylenetetrazol (PTZ)-induced seizures. The study was performed on 5 groups of mice (10 in each group). Group1 and control, had no treatment. Group 2 received sesame oil as a vehicle and groups 3-5 received EO doses of 1gr/kg, 3gr/kg and 5gr/kg, respectively. Administration was performed daily by gavage for 4 weeks. Then, the mice received intravenous PTZ for induction seizure and the threshold of seizure was evaluated. Finally, the animals were sacrificed and the concentration of lipid, Alkaline Phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate Transaminase (AST), Creatinine, and the SOD activity of the serum were determined. Compared to vehicle groups, the sub-chronic administration of EO could increase the seizure threshold dose-dependently. The level of ALT, AST, ALP, Creatinine, HDL, and LDL in EO treatment groups did not change significantly. The level of cholesterol, VLDL (P<0.05), and TG (P<0.01) decreased in the 3gr/kg and 5gr/kg of EO groups. Moreover, the level of SOD activity increased in groups with EO of 1gr/kg and 3gr/kg (P<0.01) but had no change in the group with 5gr/kg EO. We found that the supplementation of Echium Oil attenuated the seizure induced by iv PTZ and had beneficial effects on the blood lipids and antioxidant system with no side effects on effects on the liver and kidney.

Acute and Sub-chronic Anticonvulsant Effects of Edaravone on Seizure Induced by Pentylenetetrazole or Electroshock in Mice, Nitric Oxide Involvement.

Edaravone is an anti-stroke medication that may have nitric oxide (NO) modulating properties. This study evaluated the role of NO in the acute and sub-chronic anticonvulsant effects of edaravone in murine models of seizures induced by intraperitoneal (IP) or intravenous (IV) injections of pentylenetetrazole (PTZ) or electroshock (maximal electroshock seizure [MES]). 132 male albino mice were randomly divided into 22 groups (n=6) and given IP injections of vehicle or edaravone either acutely or for eight days (sub-chronically). The seizure was induced by electroshock or PTZ (IP or IV). The following edaravone doses were used: 7.5, 10, 12.5 (acute); 5, 7.5, 10 (sub-chronic) in IP PTZ model; 5, 7.5, 10 in IV PTZ model; and 5, 10 mg/Kg in the MES. To evaluate NO involvement, 216 mice were randomly divided into 36 groups (n=6) and pretreated with vehicle, edaravone, a non-specific nitric oxide synthase (NOS) inhibitor: N(ω)-nitro-L-arginine methyl ester (L-NAME) (5 mg/Kg), a specific nNOS inhibitor: 7-nitroindazole (7-NI) (60 mg/Kg), or a combination of edaravone plus L-NAME or 7-NI, either acutely or for eight days before seizure induction. Doses of edaravone were as follows: in IP PTZ model: 12.5 (acute) and 10 (sub-chronic); in IV PTZ model: 10; and in the MES: 5 mg/Kg. Data were analyzed using the one-way analysis of variance (ANOVA) followed by Tukey's test (SPSS 18). P≤0.05 was considered statistically significant. In the IP PTZ model, edaravone increased time latencies to seizures (P<0.001), prevented tonic seizures, and death. Edaravone increased the seizure threshold (P<0.001) in the IV PTZ model and shortened the duration of tonic hind-limb extension (THE) in the MES model (P<0.001). In comparison to mice treated with edaravone alone, adding L-NAME or 7-NI reduced seizure time latencies (P<0.001), reduced seizure threshold (P<0.001), and increased THE duration (P<0.001). Edaravone (acute or sub-chronic) could prevent seizures by modulating NO signaling pathways.

GABAA receptor-mediated seizure liabilities: a mixed-methods screening approach

GABAA receptors, members of the pentameric ligand-gated ion channel superfamily, are widely expressed in the central nervous system and mediate a broad range of pharmaco-toxicological effects including bidirectional changes to seizure threshold. Thus, detection of GABAA receptor-mediated seizure liabilities is a big, partly unmet need in early preclinical drug development. This is in part due to the plethora of allosteric binding sites that are present on different subtypes of GABAA receptors and the critical lack of screening methods that detect interactions with any of these sites. To improve in silico screening methods, we assembled an inventory of allosteric binding sites based on structural data. Pharmacophore models representing several of the binding sites were constructed. These models from the NeuroDeRisk IL Profiler were used for in silico screening of a compiled collection of drugs with known GABAA receptor interactions to generate testable hypotheses. Amoxapine was one of the hits identified and subjected to an array of in vitro assays to examine molecular and cellular effects on neuronal excitability and in vivo locomotor pattern changes in zebrafish larvae. An additional level of analysis for our compound collection is provided by pharmacovigilance alerts using FAERS data. Inspired by the Adverse Outcome Pathway framework, we postulate several candidate pathways leading from specific binding sites to acute seizure induction. The whole workflow can be utilized for any compound collection and should inform about GABAA receptor-mediated seizure risks more comprehensively compared to standard displacement screens, as it rests chiefly on functional data.

Differential role of oxidative stress in synaptic and nonsynaptic in vitro ictogenesis.

It is well established that dysfunctional glucose metabolism and in particular hypoglycemia can lead to hyperexcitability and exacerbate epileptic seizures. The precise mechanisms behind this form of hyperexcitability are still unresolved. The present study investigates to what extent oxidative stress can account for the acute proconvulsant effect of hypoglycemia. We used the glucose derivative 2-deoxy-d-glucose (2-DG) to mimic glucose deprivation in hippocampal slices during the extracellular recording of interictal-like (IED) and seizure-like (SLE) epileptic discharge in areas CA3 and CA1. After induction of IED in area CA3 by perfusion of Cs+ (3 mM), MK801 (10 µM), and bicuculline (10 µM), subsequent application of 2-DG (10 mM) resulted in the appearance of SLE in 78.3% of experiments. This effect was only observed in area CA3 and was reversibly blocked by tempol (2 mM), a scavenger of reactive oxygen species, in 60% of experiments. Preincubation with tempol reduced the incidence of 2-DG-induced SLE to 40%. Low-Mg2+-induced SLE in area CA3 and in the entorhinal cortex (EC) was also reduced by tempol. In contrast, to the above models, which depend on synaptic transmission, nonsynaptic epileptiform field bursts induced in area CA3 by a combination of Cs+ (5 mM) and Cd2+ (200 µM), or in area CA1 using the "low-Ca2+ model," was unaffected or even enhanced by tempol. These results indicate that oxidative stress significantly contributes to 2-DG-induced seizures in area CA3 and that the impact of oxidative stress differs between synaptic and nonsynaptic ictogenesis.NEW & NOTEWORTHY The main findings of the current study are that area CA3 but not area CA1 can support 2-DG-induced seizure activity, that oxidative stress significantly contributes to 2-DG-induced seizure activity in area CA3, and that the impact of oxidative stress differs between synaptic and nonsynaptic epileptiform activity. In in vitro models where ictogenesis depends on synaptic interactions, oxidative stress lowers the seizure threshold, whereas in nonsynaptic models seizure threshold is unchanged or even increased.

Antipsychotic Treatment of Alcohol Withdrawal Syndrome with Focus on Delirium Tremens: a Systematic Review

Delirium tremens (DT) is a common complication of alcohol withdrawal. Pharmacological treatment of hospitalized patients with DT is important in addiction medicine but also in other medical disciplines where DT can occur as a complication of hospitalization. Patients suffering from DT require treatment with benzodiazepines (short-acting benzodiazepines for elderly patients to reduce accumulation), and in cases of psychotic symptoms, treatment with antipsychotics. Benzodiazepines are a first-line treatment for DT. A specific guideline for the use of antipsychotics has yet to be developed. This review discusses the current guidelines and literature on the antipsychotic treatment options in DT. Systematic presentation of relevant antipsychotics for the treatment of DT. A systematic literature search was conducted using Scopus and PubMed. The last search was conducted on May 22nd 2022. Original articles and reviews on antipsychotic treatment in alcohol withdrawal and DT were included in this review. Further, international guidelines were also considered. The review was registered using the PROSPERO database (https://www.crd.york.ac.uk/prospero/); CRD42021264611. Haloperidol is mainly recommended for use in the intensive care unit. There is little literature on the use of atypical antipsychotics to treat DT. Treatment with antipsychotics always should be combined with benzodiazepines, and physicians should watch out for complications like neuroleptic malignant syndrome, QTc interval prolongation, extrapyramidal symptoms and withdrawal seizures resulting from lowering the threshold for seizures. Antipsychotic treatment should depend on the experience of the physician. Beside haloperidol, no other clear recommendations are available.

Current and emerging medications for the management of obesity in adults.

Current and emerging medications for the management of obesity in adults.

Developmental changes in brain activity of heterozygous Scn1a knockout rats.

Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy characterized by an age-dependent evolution of drug-resistant seizures and poor developmental outcomes. Functional impairment of gamma-aminobutyric acid (GABA)ergic interneurons due to loss-of-function mutation of SCN1A is currently considered the main pathogenesis. In this study, to better understand the age-dependent changes in the pathogenesis of DS, we characterized the activity of different brain regions in Scn1a knockout rats at each developmental stage. We established an Scn1a knockout rat model and examined brain activity from postnatal day (P) 15 to 38 using a manganese-enhanced magnetic resonance imaging technique (MEMRI). Scn1a heterozygous knockout (Scn1a +/-) rats showed a reduced expression of voltage-gated sodium channel alpha subunit 1 protein in the brain and heat-induced seizures. Neural activity was significantly higher in widespread brain regions of Scn1a +/- rats than in wild-type rats from P19 to P22, but this difference did not persist thereafter. Bumetanide, a Na+-K+-2Cl- cotransporter 1 inhibitor, mitigated hyperactivity to the wild-type level, although no change was observed in the fourth postnatal week. Bumetanide also increased heat-induced seizure thresholds of Scn1a +/- rats at P21. In Scn1a +/- rats, neural activity in widespread brain regions increased during the third postnatal week, corresponding to approximately 6 months of age in humans, when seizures most commonly develop in DS. In addition to impairment of GABAergic interneurons, the effects of bumetanide suggest a possible contribution of immature type A gamma-aminobutyric acid receptor signaling to transient hyperactivity and seizure susceptibility during the early stage of DS. This hypothesis should be addressed in the future. MEMRI is a potential technique for visualizing changes in basal brain activity in developmental and epileptic encephalopathies.

THE COMPLEXITY OF DUAL PATHOLOGY: REGARDING A CASE REPORT OF SEIZURES

IntroductionWernicke’s encephalopathy (WE) is a potentially reversible neuropsychiatric emergency caused by thiamine deficiency, whose classical triad consists of acute onset of confusion, gait ataxia, and oculomotor dysfunction. The diagnosis is missed in 75-80% of cases and approximately 80% of untreated patients develop Korsakoff Syndrome, which is characterized by memory impairment associated with confabulation. Early recognition of nutritional deficiency or any portion of the triad is critical and should prompt treatment, since WE is readily reversible if treated with adequate doses of parenteral thiamine.ObjectivesStarting from a case report of suspected WE, we pretend to discuss the differential diagnosis of seizures in dual pathology.MethodsNon-systematic review of the literature was performed in PubMed database using the keywords “Wernicke’s Encephalopathy”, “Seizures”, “Alcohol” and “Benzodiazepines”. The articles were selected according to their relevance. A patient´s clinical record was reviewed and presented.ResultsWe present a case of a 44-year-old Ukrainian man with suspected background of chronic alcohol abuse and psychiatric history of schizoaffective disorder, who presented with acute onset of confusion, psychomotor agitation, gait ataxia and nystagmus. Anamnesis was hampered by the language barrier and absence of past medical history and patient’s alcoholic habits remained unclear. After suspicion of WE it was introduced thiamine and diazepam, with significant improvement. After discontinuation of diazepam, the patient presented with several episodes of tonic-clonic seizures. He was medicated for seizures with clinical stabilization. At time of discharge the diagnostic discussion prevailed.Seizures are a common presentation of various conditions associated with alcohol use, whose differential diagnosis is difficult, especially in patients with dubious alcohol consumption. Alcohol abuse is a major precipitant of status epilepticus as seizure threshold is raised by alcohol drinking. Seizures may also occur during alcohol withdrawal, for which treatment with benzodiazepines is recommended, however carefully, since both abrupt cessation and high-dose use are critical for the appearance of seizures. Although very rare, WE may also present with seizures, whereby overdiagnosis and overtreatment are preferred to prevent persistent neurocognitive impairments.ConclusionsThis case illustrates the complexity of neuropsychiatric diagnoses in dual pathology. It requires a longitudinal assessment for a better understanding of clinical conditions and establishment of the best therapeutic approach.Disclosure of InterestNone Declared

Comment on the Need to Fill a Gap in the Assessment of Neurological Status Before Elective Surgery.

Comment on the Need to Fill a Gap in the Assessment of Neurological Status Before Elective Surgery.

ELECTROCONVULSIVE THERAPY FOR AGITATION IN LEWY BODIES DEMENTIA

IntroductionDementia with Lewy Bodies (DLB) is a primary degenerative dementing syndrome characterized by visual hallucinations, fluctuation in cognition, depressive symptoms and parkinsonism. Literature has shown the utility of electroconvulsive therapy (ECT) in demented patients regarding depressive symptoms and agitation. Nevertheless, the majority of cases described include patients with vascular dementia and Alzheimer’s disease. There are no cases informed concerning ECT in DLB patients with agitation and aggressive behaviors.ObjectivesEvaluate the impact of electroconvulsive therapy (ECT) for agitation in a patient with diagnosis of Lewy Bodies Dementia (DLB).MethodsCase report. 68-year-old male, with no prior neuropsychiatric history, was present for psychiatric evaluation for 5 year history of progressive dementia with fluctuations in cognition, complex visual hallucinations, delusional beliefs, depressive mood, anhedonia, irritability, associated to parkinsonism and increasing autoaggressive behaviors and agitation.An extensive neurologic workup including neuroimaging, EEG and laboratory studies failed to reveal a specific etiology. Neuropsychological testing reveals frontal, attentional, and visuospatial dysfunction. A presumptive diagnosis of DLB was made.Medication trials including donepezil, memantine, lamotrigine, sertraline, quetiapine, risperidone and melatonin failed to manage his depressive, psychotic and behavioral disturbances.ResultsConsidering past medication failures and prominent behavioral disturbances family consented for an acute course of ECT.Initial acute phase consisted of 6 sessions of right unilateral, brief pulse width (0.3 ms) ECT tri-weekly utilizing Mecta Spectrum. Anesthesia was induced with propofol, and received succinylcholine for muscle relaxation. Initial charge was 115 mC (6x seizure threshold), then raised to 192 mC. Seizure duration averaged in 22 seconds. No adverse reactions reported.Clinical outcomes were measured with the CGI-Efficacy Index. Pre-ECT CGI-SI score was 6 (severely ill) and post-ECT CGI-I was 3 (minimally improved).ConclusionsMood and behavioral disturbances are a frequent primary motive consultations in DLB patients. The treatment is challenging due to the sensitivity to antidopaminergic medications evidenced in this type of patients. This case suggests that ECT has an impact in the treatment of agitation and aggression in DLB patients, although further investigation is needed.Disclosure of InterestNone Declared

Alterations in the Properties of the Rat Hippocampus Glutamatergic System in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.

Exploring the concept and management of post ictal psychosis through a clinical case and review

IntroductionPostictal Psychosis of Epilepsy (PIPE), part of the group collectively known as Psychosis of Epilepsy, is characterized by an onset of confusion or psychotic symptoms within one week of apparent normal mental function. PIPE has been argued to be underdiagnosed in the clinical population, perhaps due to a failure to recognize the temporal relation between the seizure and the psychotic episode.ObjectivesTo explore the concept and management of post ictal psychosis.MethodsWe present a clinical case and a review of the literature concerning post ictal psychosis.Results We report the case of a 36 year old woman with focal refractory epilepsy after a likely episode of limbic encephalitis in 2015. Cognitive and psychiatric sequelae in the form of depressive symptoms, in treatment with neurology and psychiatry since 2021. One previous episode of psychotic symptoms during seizures. Worsening of seizure frequency since march of 2022 with apparent normalization (absence of seizures after dose reduction of eslicarbamazepine and introduction oflamotrigine) for about four days before being hospitalized in the neurology unit due tobehavioral abnormalities. During psychiatric exploration, the patient showed signs of partial clouding of consciousness with manierisms, ecopraxias and ecolalias; verbigerance in the form of the neurologist’s name and bizarre movements like looking behind suggestive of sensoroperceptive disturbances. The symptomatology resolved itself during the following week after treatment with diazepam.Finally, a narrative review concerning the case was also performed; with particular emphasis on antipsychotic drugs with low risk of lowering seizure threshold (such as risperidone or aripiprazole) as the recommended treatment.ConclusionsOur findings point to the relevance of Postictal Psychosis of Epilepsy as a clinical entity. Further studies on pathogenic mechanisms and therapeutic management are required.Disclosure of InterestNone Declared

Non-Convulsive Status Epilepticus as A Complication of Electroconvulsive Therapy: A Case Report

IntroductionStatus Epilepticus is defined as a condition that can have long-term outcomes involving neuronal death and injury due to the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures. Electroconvulsive therapy (ECT) is a highly effective treatment option for psychiatric disorders. Although it rarely occurs in the treatment, non-convulsive status epilepticus can be seen as a complication after ECT. Due to its rarity, this complication is not yet well understood, is challenging to diagnose, and information about treatment options is limited.ObjectivesBy sharing this case report, we aim to emphasize the importance of being careful in terms of the risk of status epilepticus in patients receiving electroconvulsive therapy.MethodsHere in we present a 29-year-old patient with no previous neurological disease and who had a history of schizophrenia. Electroconvulsive therapy was planned because the patient was resistant to antipsychotic treatment. EEG was planned for the patient who had urinary incontinence during the ninth session of ECT. Generalized slow wave activity and intermittent rhythmic delta activity were observed in the EEG, therefore it was found suspicious for NCSE, and the patient was planned to perform an EEG again by administering diazepam to confirm the diagnosis. After diazepam, the patient whose EEG tracing was clearly improved was admitted to the neurology intensive care unit. He was followed up for 48 hours with continuous 4 mg/hour/day midazolam and continuous bedside EEG in the neurology intensive care unit. Concomitant lamotrigine was started at 100 mg/day. Significant improvement in EEG, sinusoidal alpha, and beta waves with the eye open was observed at the 48th hour, and the patient was transferred back to the psychiatry service. Lamotrigine treatment was increased up to 200 mg/day and clozapine treatment was adjusted to 350 mg/day in the psychiatry service. In the patient whose EEG was requested again before discharge.ResultsThe diagnosis of NCSE post-ECT can be laborious; the symptoms may not be characteristic and clear, and usually not distinguish from symptoms of confusion, delirium, or psychiatric illness, hence the follow-up psychiatrist should be careful. In suspicious cases, EEG should be taken, especially in patients at risk for seizures. These risky conditions include previous seizure history, and lithium or clozapine use.ConclusionsThe diagnosis of NCSE after ECT is a demanding condition. Particular attention should be paid to factors that will lower the seizure threshold. In cases with ECT treatment with clozapine, intermittent clozapine blood levels can be quantified and medication interactions and smoking can be considered. When the cases are examined, the common aspect of most of them is that the treatments have good results.Disclosure of InterestNone Declared

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview.

Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo. In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of "bang-sensitive" mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila. Furthermore, we discuss newly established analysis techniques that might be used to further unravel the pathophysiological aspects of genetic epilepsies.

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

KIF4 regulates neuronal morphology and seizure susceptibility via the PARP1 signaling pathway.

Epilepsy is a common neurological disease worldwide, and one of its causes is genetic abnormalities. Here, we identified a point mutation in KIF4A, a member of kinesin superfamily molecular motors, in patients with neurological disorders such as epilepsy, developmental delay, and intellectual disability. KIF4 is involved in the poly (ADP-ribose) polymerase (PARP) signaling pathway, and the mutation (R728Q) strengthened its affinity with PARP1 through elongation of the KIF4 coiled-coil domain. Behavioral tests showed that KIF4-mutant mice exhibited mild developmental delay with lower seizure threshold. Further experiments revealed that the KIF4 mutation caused aberrant morphology in dendrites and spines of hippocampal pyramidal neurons through PARP1-TrkB-KCC2 pathway. Furthermore, supplementing NAD, which activates PARP1, could modulate the TrkB-KCC2 pathway and rescue the seizure susceptibility phenotype of the mutant mice. Therefore, these findings indicate that KIF4 is engaged in a fundamental mechanism regulating seizure susceptibility and could be a potential target for epilepsy treatment.

Sildenafil induced seizures in a patient treated for pulmonary hypertension: A case report

Sildenafil is one of the common drugs used to treat pulmonary hypertension. We report a rare case of a life-threatening adverse effect of Sildenafil. The patient was admitted to our intensive care unit for the management of urosepsis with obesity hypoventilation syndrome with pulmonary hypertension. After administration of the first dosage of Sildenafil, the patient developed generalized tonic-clonic seizure. She had no previous history of seizure disorder. She was investigated for the possible cause of seizure, but none were conclusive. Sildenafil was discontinued and she remained seizure free after discontinuation of it. Sildenafil can increase the effects mediated by nitric oxide and can thus affect the seizure threshold. Though rare, seizure as an adverse effect of Sildenafil should be considered before initiating this drug.

Anticonvulsant effect of quercetin in pentylenetetrazole (PTZ)-induced seizures in male mice: The role of anti-neuroinflammatory and anti-oxidative stress

BackgroundEpilepsy is one of the major neurological disorders. The inflammatory process and oxidative stress are closely related to seizure progression. Quercetin is a flavonoid with anti-inflammatory and antioxidant properties as well as neuroprotective effects. We aimed to evaluate the effect of quercetin on pentylenetetrazole- (PTZ-) induced seizures in male mice focusing on its possible anti-neuroinflammatory and anti-oxidative stress. MethodsIn this study, 50 male NMRI mice were divided into five groups (n = 10) and given the following treatments: normal saline, quercetin at doses of 10, 20, and 40 mg/kg, and diazepam at a dose of 10 mg/kg. In order to induce seizures, PTZ was administered intravenously. Drugs were administered intravenously 60 min before the seizure induction. The seizure threshold was measured, and finally, malondialdehyde (MDA), total antioxidant capacity (TAC), and the gene expression of IL-1β, TNF-α, NLRP3, and iNOS were determined in the prefrontal cortex. ResultsIt was confirmed that quercetin increased the seizure threshold. And quercetin increased TAC, and decreased levels of MDA as well as gene expression of TNF- α, NLRP3, IL-1β, and iNOS in the prefrontal cortex at the time of seizure induction. ConclusionIt was suggested that the anticonvulsant effect of quercetin in PTZ-induced seizures in mice may be due to the reduction of inflammatory responses and oxidative stress in the prefrontal cortex.