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Autoimmune encephalitis (AE) is a rare immune-mediated disorder comprised of non-infectious neuroinflammatory disease processes. Clinical presentation overlaps with a broad range of neurodegenerative disorders and infectious encephalitis; therefore, AE remains a diagnosis of exclusion. Patients may present with nonspecific symptoms such as psychiatric disturbances, cognitive deficits, seizures, movement disorders, and confusion. Prompt diagnosis and management are necessary for patients with AE to decrease mortality and improve quality of life. First-line therapy includes immunosuppression with corticosteroids, intravenous immunoglobulin, and plasmapheresis. We report the case of an 86-year-old female with a medical history of Parkinson's disease who presented with nonspecific seizure-like activity and was diagnosed with AE.

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The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations.

Asunto(s)

Modelos Animales de Enfermedad , Electroencefalografía , Lacosamida , Fármacos Neuroprotectores , Pregabalina , Topiramato , Animales , Lacosamida/farmacología , Lacosamida/uso terapéutico , Topiramato/farmacología , Topiramato/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Masculino , Pregabalina/farmacología , Pregabalina/uso terapéutico , Ratas , Conducta Animal/efectos de los fármacos , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Hipocampo/patología , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/inducido químicamente , Estado Epiléptico/fisiopatología , Ratas Wistar , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/inducido químicamente

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Trilostane is a 3ß-hydroxysteroid dehydrogenase/Δ5-4 isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography-electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats.

Asunto(s)

Epilepsia , Neuroesteroides , Ratas , Animales , Neuroesteroides/farmacología , Pregnanolona/farmacología , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Encéfalo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico

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Epilepsy is a chronic brain disease with a global prevalence of 70 million people. According to the World Health Organization, roughly 5 million new cases are diagnosed every year. Anti-seizure drugs are the treatment of choice. However, in roughly one third of the patients, these drugs fail to produce the desired effect. As a result, finding novel treatments for epilepsy becomes inevitable. Recently, angiotensin receptor blockers have been proposed as a treatment to reduce the over-excitation of neurons in epilepsy. For this purpose, we conducted a review using Medline/PubMed and Google Scholar using the relevant search terms and extracted the relevant data in a table. Our review suggests that this novel approach has a very high potential to treat epilepsy, especially in those patients who fail to respond to conventional treatment options. However, more extensive and human-based trials should be conducted to reach a decisive conclusion. Nevertheless, the use of ARBs in patients with epilepsy should be carefully monitored keeping the adverse effects in mind.

Asunto(s)

Epilepsias Parciales , Epilepsia Generalizada , Epilepsia Tónico-Clónica , Epilepsia , Humanos , Anticonvulsivantes/uso terapéutico , Epilepsia Tónico-Clónica/inducido químicamente , Epilepsia Tónico-Clónica/tratamiento farmacológico , Carbamazepina/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Epilepsia Generalizada/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Epilepsia/tratamiento farmacológico

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Although intracranial foreign bodies are typically associated with penetrating injuries or surgical interventions, they can also occur as a result of rare instances of child abuse. Enduring such abuse and neglect as an infant can lead to life-long neurological problems, developmental delays, and impairments. The present case involved a 14-year-old male adolescent who was brought to the emergency room due to recurrent generalized tonic seizures. A computed tomography (CT) scan revealed a ring-like metallic object within the right temporal lobe. The neurosurgeon declined the surgical removal of the object due to its position and orientation, as well as the patient's guardian's refusal to consent to surgery. Instead, drug treatment and care are advised. In infants, foreign objects are typically inserted through cranial sutures, fontanelles and less frequently into the orbits, often with the intention of harming unwanted children. However, no history of such an attempt is present in this case. The incidental discovery of intracranial foreign bodies typically occurs during investigations when patients present with neurological symptoms such as epileptic seizures (foreign body-induced epilepsy). The selection of an ideal treatment regimen is often challenging in such cases. If a patient can be effectively treated with drugs, surgical removal is usually avoided.

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Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.

Asunto(s)

Epilepsia del Lóbulo Temporal , Ratas , Animales , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/patología , Pilocarpina/efectos adversos , Lamotrigina/efectos adversos , Litio/efectos adversos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Anticonvulsivantes/efectos adversos , Convulsiones/tratamiento farmacológico , Hipocampo , Modelos Animales de Enfermedad

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Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.

Asunto(s)

Barrera Hematoencefálica , Estado Epiléptico , Ratas , Animales , Barrera Hematoencefálica/patología , Ratas Sprague-Dawley , Organofosfatos/efectos adversos , Organofosfatos/metabolismo , Estado Epiléptico/metabolismo , Convulsiones/metabolismo , Encéfalo/metabolismo

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus that belongs to the species severe acute respiratory syndrome-related coronavirus (SARSr-CoV), which is related to the SARS-CoV-1 virus that caused the 2002-2004 SARS outbreak. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). It has been associated with electrolyte abnormalities. In this report, we discuss the case of a SARS-CoV-2-infected person presenting with recurrent seizure episodes resulting from hypophosphatemia. A 52-year-old male patient with questionable prior seizure history presented to the emergency department (ED) twice within eight days with recurring seizure episodes. While the physical examination at the first presentation was significant for a head laceration with post-ictal confusion, that at the second presentation was only significant for post-ictal confusion. Laboratory examination at the first visit revealed SARS-CoV-2 positivity, hypokalemia, hypophosphatemia, and low vitamin D levels. On the second visit, the patient was again found to have hypophosphatemia. CT of the head and the cervical spine, as well as radiographs of the chest done on the first visit, were all normal. On his first visit, the patient's electrolyte abnormalities were corrected, and he was discharged with antiepileptic medications after 24 hours of observation and consultation with neurology. However, his vitamin D levels, the results of which came back only after his first discharge, were corrected only during his second visit. This time, he was discharged from the ED and had an effective resolution of symptoms. SARS-CoV-2 infections can result in vitamin D deficiency and hypophosphatemia, resulting in seizures, and hence should be treated with both replacement therapies and antiepileptic medications. This case also highlights the importance of obtaining phosphorus and vitamin D levels in SARS-CoV-2-infected patients with seizures.

RESUMEN

This case reports a 53-year-old Caucasian female previously diagnosed with viral encephalitis and Fahr's Syndrome who presented with altered mental status. Shortly after arrival, she displayed severe lactic acidosis and was transferred to the intensive care unit (ICU), where she had a brief seizure. Neurological workup was performed including carotid ultrasound, magnetic resonance angiography (MRA) brain, and computed tomography (CT) angiogram of the neck, all of which were unremarkable. Initial magnetic resonance imaging (MRI) performed showed small, acute ischemic foci in the bilateral occipital lobes and medial left thalamus. Subsequent diffusion-weighted imaging (DWI) MRI of the bilateral occipital lobes showed vasogenic edema, a common finding in Mitochondrial Encephalopathy, Lactic Acid, and Stroke-like episodes (MELAS). The patient was given Levetiracetam and managed supportively. She was progressively extubated and her seizure symptoms and lactic acidosis resolved. Our case represents a unique case in which a patient with non-contributory family history is first diagnosed with MELAS after age 40 after her symptoms were initially attributed to other pathologies.

RESUMEN

Growing studies indicate that vigilance states and circadian rhythms can influence seizure occurrence in patients with epilepsy and rodent models of epilepsy. Electrical kindling, referred to brief, repeated stimulations of a limbic structure, is a commonly used model of temporal lobe epilepsy. Kindling via the classic protocol lasting a few weeks does not generally induce spontaneous recurrent seizures (SRS), but extended kindling that applies over the course of a few months has shown to induce SRS in several animal species. Kindling-induced SRS in monkeys and cats were observed mainly during resting wakefulness or sleep, but the behavioral activities associated with SRS in rodent models of extended kindling remain unknown. We aimed to add information in this area using a mouse model of extended hippocampal kindling. Middle-aged C57 black mice experienced ≥80 hippocampal stimulations (delivered twice daily) and then underwent continuous 24 h electroencephalography (EEG)-video monitoring for SRS detection. SRS were recognized by EEG discharges and associated motor seizures. The five stages of the modified Racine scale for mice were used to score motor seizure severities. Seizure-preceding behaviors were assessed in a 3 min period prior to seizure onset and categorized as active and inactive. Three main observations emerged from the present analysis. (1) SRS were found to predominantly manifest as generalized (stage 3-5) motor seizures in association with tail erection or Straub tail. (2) SRS occurrences were not significantly altered by the light on/off cycle. (3) Generalized (stage 3-5) motor seizures were mainly preceded by inactive behaviors such as immobility, standing still, or apparent sleep without evident volitional movement. Considering deeper subcortical structures implicated in genesis of tail erection in other seizure models, we postulate that genesis of generalized motor seizures in extended kindled mice may involve deeper subcortical structures. Our present data together with previous findings from post-status epilepticus models support the notion that ambient cage behaviors are strong influencing factors of SRS occurrence in rodent models of temporal lobe epilepsy.

RESUMEN

Acute repetitive seizures or seizure clusters are common in epileptic patients. Seizure clusters are associated with a high risk of developing status epilepticus and increased morbidity and mortality. Seizure clusters are also recognizable in spontaneous recurrent seizures (SRS) that occur in animal models of epilepsy. The electrical kindling of a limbic structure is a commonly used model of temporal lobe epilepsy. Although classic kindling over the course of a few weeks does not generally induce SRS, extended kindling over the course of a few months can induce SRS in several animal species. SRS in kindled cats often occur in clusters, but the existence of seizure clusters in rodent models of extended kindling remains to be demonstrated. We explored the existence of seizure clusters in mice following extended hippocampal kindling. Adult male mice (C57BL/6) experienced twice daily hippocampal stimulations and underwent continuous 24-hour electroencephalogram (EEG)-video monitoring after ≥80 stimulations. SRS events were recognized by EEG discharges and associated motor seizures. Seizure clusters, defined as ≥4 seizures per cluster and intra-cluster inter-seizure intervals ≤ 120 min, were observed in 19 of the 20 kindled mice. Individual mice showed variable seizure clusters in terms of cluster incidence and circadian-like expression patterns. For clusters consisting of 4-7 seizures and intra-seizure intervals ≤ 20 min, no consistent changes in inter-seizure intervals, EEG discharge duration, or motor seizure severity scores were observed approaching cluster termination. These results suggested that seizure clustering represents a prominent feature of SRS in hippocampal kindled mice. We speculate that, despite experimental limitations and confounding factors, systemic homeostatic mechanisms that have yet to be explored may play an important role in governing the occurrence and termination of seizure clusters.

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Introduction This study aimed to determine the factors that trigger seizures in patients reporting to our emergency department (ED) with seizures and the factors that affect recurrent seizures during the emergency department stay. Materials and methods This study was designed prospectively and was conducted among patients over the age of 18 years who reported to the ED of the Education and Research Hospital with complaints of epileptic seizure between July 01, 2020 and July 01, 2021. In addition to the sociodemographic information of the patients, the time of admission after the seizure, the medications used, comorbidities, the treatment given in the ED, history of trauma, previous epilepsy diagnosis, time of last seizure, alcohol use in the last 24 hours, insomnia, presence of infective symptoms in the past week, vital parameters, blood tests, and presence of recurrent seizure during hospital follow-up were recorded. Results The median age of the 102 patients included in the statistical analysis was 37 (25%-57%), and 61 (59.8%) were men. Patients who came to the ED with the complaint of seizures were divided into two groups, namely, those who had recurrent seizures and those who did not. When the differences between the groups in terms of various variables were examined, no statistically significant difference was found in the univariate analysis, except for WBC, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) values. The diagnostic value of WBC, AST, and ALT levels in predicting recurrent seizures in emergency follow-up was analyzed using a receiver operating characteristic curve. Conclusion In this study, we could not find a parameter that can predict the probability of recurrent seizures in the ED in patients presenting with epileptic seizures.

RESUMEN

CNTNAP2 (coding for protein Caspr2), a member of the neurexin family, plays an important role in the balance of excitatory and inhibitory post-synaptic currents (E/I balance). Here, we describe a novel pathogenic missense mutation in an infant with spontaneous recurrent seizures (SRSs) and intellectual disability. Genetic testing revealed a missense mutation, c.2329 C>G (p. R777G), in the CNTNAP2 gene. To explore the effect of this novel mutation, primary cultured neurons were transfected with wild type homo CNTNAP2 or R777G mutation and the morphology and function of neurons were evaluated. When compared with the vehicle control group or wild type group, the neurites and the membrane currents, including spontaneous excitatory post-synaptic currents (sEPSCs) and inhibitory post-synaptic currents (sIPSCs), in CNTNAP2 R777G mutation group were all decreased or weakened. Moreover, the action potentials (APs) were also impaired in CNTNAP2 R777G group. Therefore, CNTNAP2 R777G may lead to the imbalance of excitatory and inhibitory post-synaptic currents in neural network contributing to SRSs.

RESUMEN

BACKGROUND: The incidence of recurrent febrile seizures during the same febrile illness (RFS) is 14-24%. A pilot study found that body temperature and male sex were predictors of RFS. This study sought to validate body temperature as a predictor of RFS, calculate the optimal cut-off body temperature for predicting RFS, and identify the other predictors of RFS. METHODS: This prospective cohort study enrolled children with febrile seizures aged 6-60 months who visited the emergency department at Atsugi City Hospital, Japan, between March 1, 2019, and February 29, 2020. Children who had multiple seizures, diazepam administration before the emergency department visit, seizures lasting >15 min, underlying diseases, or who could not be followed up were excluded. The optimal cut-off body temperature was determined using a receiver-operating characteristic curve. RESULTS: A total of 109 children were enrolled, of whom 13 (11.9%) had RFS. A lower body temperature was significantly associated with RFS (P = 0.02). The optimal cut-off body temperature for predicting RFS was 39.2 °C. Children with RFS also had significantly lower C-reactive protein and blood glucose levels (P = 0.01 and 0.047, respectively), but none of the other factors considered were significantly associated with RFS. CONCLUSIONS: This large prospective study confirmed that body temperature is a predictor of RFS. The optimal cut-off body temperature for predicting RFS was 39.2 °C. Low C-reactive protein level and blood glucose level might be predictors of RFS, but this needs to be confirmed in prospective multicenter studies.

Asunto(s)

Temperatura Corporal/fisiología , Convulsiones Febriles/diagnóstico , Convulsiones Febriles/fisiopatología , Biomarcadores , Preescolar , Femenino , Humanos , Lactante , Masculino , Pronóstico , Estudios Prospectivos , Recurrencia

RESUMEN

Stereo electroencephalogram (SEEG) electrode placement with cranially fixed guide bolts is recognized as one of the most accurate and safest implantation strategies to sample deep and buried cortex during certain clinical scenarios involving epilepsy surgery. Bone thickness of less than 2 mm is a relative contraindication to SEEG. Here, we describe a case drug-resistant focal epilepsy where prior craniotomies, infections and radiation therapy yielded limited skull bone requiring invasive EEG monitoring. Due to the inability to use bolts over areas with limited skull bone, we successfully utilized a combination of the standard and a modified SEEG techniques for implantation and stabilization of intracranial electrodes without complications. This strategy enabled optimal intracranial EEG monitoring and surgical management of the patient's drug-resistant focal seizures.

RESUMEN

Mesial temporal lobe epilepsy (mTLE) is the most common epilepsy induced by previous cerebral injury, and one out of three mTLE patients develops drug resistance (DR). AIM: To assess the expression of Bcl-2, Caspase-3, Caspase-9, IL1-ß, SEMA-3a, NT-3 and P-glycoprotein in the temporal cortex and their relationship with the progression of mTLE-DR clinical features in patients with mTLE-DR. METHOD: Tissue samples from 17 patients were evaluated for protein expression by Western blot and the relationships of the evaluated proteins with the clinical features of the mTLE were assessed through hierarchical cluster analysis. RESULTS: The mTLE-DR group showed significantly higher P-glycoprotein, Bcl-2 and Caspase-9 levels ***p < 0.0001, ****p < 0.0001 and ***p < 0.0002, respectively, than the autopsy control group. Four patient clusters were identified: Clusters 1 and 3 showed relationships among the age of mTLE onset, duration of mTLE-DR, average number of epileptic seizures per week, number of previous antiepileptic drugs (AEDs) and increased expression of Caspase-3, Caspase-9, Neurotrophin-3 and Semaphorin-3a. Clusters 2 and 4 showed relationships among the mTLE onset age, current age, average number of epileptic seizures per week, number of previous AEDs and increased expression of IL1-ß, Bcl-2, P-glycoprotein, Caspase-3 and NT-3. CONCLUSION: The relationships among the clinical data the age of mTLE onset, DR duration, number of previous AEDs, and average number of seizures per week and the expression of proteins involved in neuronal death, neuroinflammation and aberrant connection formation, as which are biological markers in the cerebral temporal cortex, are important factors in the progression and severity of mTLE-DR and support the intrinsic severity hypothesis.

Asunto(s)

Biomarcadores/análisis , Biomarcadores/metabolismo , Epilepsia Refractaria/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adulto , Anciano , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Femenino , Humanos , Interleucina-1beta/metabolismo , Masculino , Persona de Mediana Edad , Neurotrofina 3/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Semaforina-3A/metabolismo , Adulto Joven

RESUMEN

Introduction: Status epilepticus (SE) is a neurologic and medical emergency with significant related morbidity and mortality. Hepatic or renal dysfunction can considerably affect the pharmacokinetics of drugs used for SE through a variety of direct or indirect mechanisms.Areas Covered: This review aims to focus on the therapeutic management of SE in patients with hepatic or renal impairment, highlighting drugs' selection and dose changes that may be necessary due to altered drug metabolism and excretion. The references for this review were identified by searches of PubMed and Google Scholar until May 2020.Expert opinion: According to literature evidence and clinical experience, in patients with renal disease, the authors suggest considering lorazepam as the drug of choice in pre-hospital and intra-hospital early-stage SE, phenytoin in definite SE, propofol in refractory or super-refractory SE. In patients with liver disease, the authors suggest the use of lorazepam as drug of choice in pre-hospital and intra-hospital early-stage SE, lacosamide in definite SE, propofol in refractory or super-refractory SE. A list of preferred drugs for all SE stages is provided.

Asunto(s)

Enfermedades Renales , Estado Epiléptico , Anticonvulsivantes/uso terapéutico , Humanos , Enfermedades Renales/complicaciones , Enfermedades Renales/tratamiento farmacológico , Hígado , Fenitoína/uso terapéutico , Estado Epiléptico/tratamiento farmacológico

RESUMEN

Objective:To investigate the effects of hippocampal injection of tyrosine kinase receptor binding protein B3(Ephrin-B3) agonist on spontaneous seizures and the expression of hippocampal secretory glycoprotein (Reelin) and phosphorylated adaptor protein (p-Dab1) in epileptic model rats.Methods:Seventy-eight rats were randomly divided into control group and model group according to body mass matching with 39 rats in each group.The rats in control group were fed normaly, and the rats in model group were established epilepsy model by intraperitoneal injection of lithium chloride pilocarpine. The hippocampal tissues were taken in the acute phase (7 days), quiescent phase (14 days) and chronic phase (60 days) after the successful induction of status epilepticus. The levels of Reelin protein and p-Dab1 protein in the hippocampal tissues of epileptic model rats and normal rats were detected by immunohistochemistry and Western blot.And thirteen rats were randomly selected at each time point. Another 48 rats were randomly divided into normal Fc-control group, normal EphB3-Fc group, epilepsy Fc-control group and epilepsy EphB3-Fc group, with 12 rats in each group. Rats in the first two groups were fed normally, and those in the latter two groups were established epileptic model. Seven days after modeling, all rats were injected into bilateral hippocampus with EphB3-Fc (Ephrin-B3 agonist) and FC control (control agent of Ephrin-B3 agonist) according to the grouping, once a day for 7 days. After administration, the changes of behavior and EEG were observed within two weeks. At the same time, the expression of Reelin protein and p-Dab1 protein were detected by immunohistochemistry and Western blot. SPSS 21.0 was used for statistical analysis, One-way ANOVA was used for multi group comparison, and Tukey's test was used for pairwise comparison.Results:The results of immunohistochemistry and Western blot showed that compared with the control group, the levels of Reelin and p-Dab1 protein in hippocampus of model group decreased significantly at 7, 14 and 60 days after epilepsy (all P<0.01). The results of immunohistochemistry showed that compared with epilepsy Fc-control group, the levels of p-Dab1 ((0.41±0.04), (0.58±0.06), P<0.05) in epilepsy EphB3-Fc group increased significantly.Western blot result showed that the level of p-Dab1 in epilepsy EphB3-Fc group increased compared with that of epilepsy Fc-control group (1.34±0.04), (2.26±0.10), P<0.01). Compared with epilepsy Fc-control group, epilepsy EphB3-Fc group showed less average seizure duration ((39.00±1.79)s, (26.50±1.87)s; t=23.21, P<0.01), less frequencies ((2.00±0.89), (0.50±0.55); t=2.32, P<0.01) and less latent period ((6.33±1.37)day, (12.50±1.87)day; t=2.52, P<0.01) in spontaneous recurrent seizures. Compared with epilepsy Fc-control group, epilepsy EphB3-Fc group showed lower average amplitude ((37.30±1.21)μV, (29.00±1.41)μV; t=25.14, P<0.01), less average seizure duration ((5.35±0.19)s, (2.35±0.19)s; t=3.13, P<0.01). Conclusion:Ephrin-B3 alleviated spontaneous recurrent seizures by upregulating Reelin and p-Dab1 in temporal lobe epilepsy rat.

RESUMEN

@#Objective　To explore dynamic expression of Ephrin-B3 in hippocampus of pilocarpine induced epileptic rats and the role of Ephrin-B3 in the process of epileptogenesis.Methods　We first established pilocarpine induced epileptic rat model and then detected Ephrin-B3 expression at 7,14 and 60 days post status epilepticus (SE) by real time qPCR,immunohistochemistry and Western blot.Results　After pilocarpine injection,rats showed facial muscles,forelimb and tail clonus and ataxic lurching,head bobbing and wet dog shakes.Real time qPCR revealed that Ephrin-B3 mRNA expression in hippocampus decreased during spontaneous seizure period.Compared with controls,epileptic rats showed decreased Ephrin-B3 expression at 7 days,reached the lowest level at 14 days and then increased slightly at 60 days post-SE (P<0.001).Ephrin-B3 protein in hippocampus also decreased at 7,14 and 60 days detected by Western blot (P<0.001).Immunohistochemistry results showed that Ephrin-B3 mainly expressed in granule cells in dentate gyrus.Analysis of immunohistochemistry revealed decreased Ephrin-B3 expression in epileptic rats compared with controls (P<0.001).Conclusion　The dynamic changes of Ephrin-B3 expression in hippocampus of epileptic rats indicated that Ephrin-B3 may participate in the process of spontaneous recurrent seizures.

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Temporal lobe epilepsy is a widespread chronic disorder that manifests as spontaneous seizures and is often characterized by refractoriness to drug treatment. Temporal lobe epilepsy can be caused by a primary brain injury; therefore, the prevention of epileptogenesis after a primary event is considered one of the best treatment options. However, a preventive treatment for epilepsy still does not exist. Neuroinflammation is directly involved in epileptogenesis and neurodegeneration, leading to the epileptic condition and cognitive decline. In the present study, we aimed to clarify the effect of treatment with a recombinant form of the Interleukin-1 receptor antagonist (anakinra) on epileptogenesis and behavioral impairments in rats using the lithium-pilocarpine model. We found that anakinra administration during the latent phase of the model significantly suppressed the duration and frequency of spontaneous recurrent seizures in the chronic phase. Moreover, anakinra administration prevented some behavioral impairments, including motor hyperactivity and disturbances in social interactions, during both the latent and chronic periods. Histological analysis revealed that anakinra administration decreased neuronal loss in the CA1 and CA3 areas of the hippocampus but did not prevent astro- and microgliosis. The treatment increased the expression level of the solute carrier family 1 member 2 gene (Slc1a2, encoding excitatory amino acid transporter 2 (EAAT2)) in the hippocampus, potentially leading to a neuroprotective effect. However, the increased gene expression of proinflammatory cytokine genes (Interleukin-1ß (Il1b) and tumor necrosis factor α (Tnfa)) and astroglial marker genes (glial fibrillary acidic protein (Gfap) and inositol 1,4,5-trisphosphate receptor type 2 (Itpr2)) in experimental rats was not affected by anakinra treatment. Thus, our data demonstrate that the administration of anakinra during epileptogenesis has some beneficial disease-modifying effects.