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Objectives: To explore the clinical significance of interleukin-1 and interleukin-6 in the development of lateralized temporal epilepsy. METHODS: The prospective study was conducted from January to April of 2022 at the Neurology Department of Training and Research Hospital, Istanbul Medeniyet University, Turkey, and comprised patients with lateralized temporal epilepsy aged 18-86 years who were in the interictal period in group A and healthy controls in group B. The levels of interleukin-1 and interleukin-6 of patients in both groups were compared. Data was analysed using SPSS 25. RESULTS: Of the 92 subjects, 60(65.2%) were in group A; 35(58.3%) were males and 25(41.7%) were females with a median age of 37.5 years (interquartile range: 2.2-42.7 years). There were 32(34.8%) subjects in group B; 19(40.6%) females and 13(40.6%) males with a median age of 40.5 years (interquartile range: 25-50 years) (p>0.05). Within group A, 41(68.3%) patients had left-sided epilepsy and 19(31.7%) had right-sided epilepsy (p<0.001). Both interleukin-1 and interleukin-6 levels were lower in group A than in group B (p<0.001). Both interleukin levels did not significantly differ between right and leftlateralised temporal seizures (p=0.44). In the left-lateralized temporal seizures, interleukin-1 levels correlated with epilepsy duration (p<0.006), lower onset age (p<0.050), and presence of prenatal risk (p<0.028). Interleukin-1 and interleukin-6 levels were positively correlated with each other for lateralized temporal epileptic hemispheres (p<0.001). CONCLUSIONS: Interleukin-1 level was correlated with epilepsy duration, lower onset age, and presence of prenatal risk in the left-lateralized temporal epilepsy.
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Epilepsia do Lobo Temporal , Interleucina-1 , Interleucina-6 , Humanos , Feminino , Masculino , Adulto , Interleucina-6/sangue , Pessoa de Meia-Idade , Epilepsia do Lobo Temporal/sangue , Adulto Jovem , Idoso , Interleucina-1/sangue , Adolescente , Estudos Prospectivos , Idoso de 80 Anos ou mais , Estudos de Casos e ControlesRESUMO
Myasthenia gravis (MG) is an autoimmune disease characterized by weakness and rapid fatigue of the voluntary muscles. Epilepsy is a neurological disorder marked by recurrent, unprovoked seizures. We present a case of a 34-year-old woman with idiopathic generalized epilepsy who developed MG at 33. While the relationship between MG and epilepsy remains unclear, it is known that antiepileptic drugs can exacerbate MG. The rarity of this association suggests a need for cautious selection of antiepileptic treatments to avoid worsening either condition.
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Stroke mimics are difficult to differentiate from each other. Symptomatic epilepsy can also occur, but it is necessary to perform a magnetic resonance imaging (MRI) scan to distinguish it from a stroke. Although respiratory acidosis has been reported to occur with partial-onset seizures due to prolonged apnea, respiratory acidosis is rarely suspected to be a sign of epilepsy. We report a case in which respiratory acidosis helped to diagnose symptomatic epilepsy with stroke mimics. The patient was a 52-year-old female who was brought to the emergency room with the chief complaint of difficulty in talking. When she visited the hospital, sensory aphasia was observed, and a computed tomography (CT) scan was performed. She vomited after the CT scan, and an arterial blood gas analysis showed a pH of 7.26 with a PaCO2 level of 71 mmHg, indicating respiratory acidosis. After the administration of diazepam, the seizures abated and her sensory aphasia improved. Later, an investigation of the patient's history revealed symptomatic epilepsy and discontinuation of antiepileptic drugs. If unexplained respiratory acidosis is noted in a patient with stroke mimics, a further investigation of the patient's history and physical examination may help to diagnose symptomatic epilepsy.
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Objectives: The objective were to evaluate structural alterations in the retina and choroid tissue of epilepsy patients and subtypes using enhanced depth imaging optic coherence tomography (EDI-OCT). Methods: 46 epilepsy patients and 50 sex- and age-matched control patients were analyzed in the study. Patients' epilepsy types were recorded. The central macular thickness (CMT), retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and choroidal thickness (CT) were investigated through the Spectralis-OCT device (SD-OCT). Image-J program was used to calculate the total choroidal area (TCA), the luminal area (LA), stromal area (SA), and the choroidal vascularity index (CVI). Results: CMT, TCA, LA, and SA outcomes were substantially reduced in epilepsy patients than in healthy controls. There was no significant difference between CT, RNFL, GCL, CVI results. There were no statistically significant differences between patients with partial and generalized epilepsy (p>0.05 for each). Conclusion: According to the results of our study, epilepsy disease has effects on the posterior segment of the eye. To the best of our knowledge, our study is the first to evaluate CVI in patients with epilepsy and the epilepsy subgroups.
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A man in his 70s with alcoholic dementia was admitted for acute, prolonged impaired consciousness. Blood and cerebrospinal fluid findings were unremarkable. Brain MRI revealed multiple high-signal cortical regions. Following diazepam and levetiracetam administration, electroencephalography (EEG) revealed <1 Hz lateralized periodic discharges, indicating that the seizures were ceasing. The periodic discharges had disappeared during the gradual recovery process by day 10; however, cortical arterial spin labeling findings persisted only in regions exhibiting cytotoxic edema. Without additional anti-seizure medication, no seizure recurred, but cognitive dysfunction remained. He was transferred to a rehabilitation hospital with the continued oral administration of levetiracetam at 1,000 mg/day. DWI-ADC (diffusion-weighted imaging-apparent diffusion coefficient) match may suggest an indication of a missed suitable treatment window for seizures.
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OBJECTIVE: Many patients with epilepsy require polytherapy, which increases their antiseizure medication (ASM) drug load, a measure that considers the doses of all ASMs a patient is taking. Changes in concomitant ASM drug load after adding cenobamate were evaluated post-hoc in a subset of the open-label, phase 3 study. METHODS: Patients 18-70 years old with uncontrolled focal seizures taking 1-3 ASMs were enrolled. Total concomitant ASM drug load (not including cenobamate) was calculated by dividing the patient's prescribed dose for each ASM by its defined daily dose, per the World Health Organization, then summing the ratios. Changes in concomitant ASM drug load were measured from baseline in 3-month intervals up to 24 months by both total and class-specific ASM drug load. Subgroups of interest included: older adults (65-70 years), prior epilepsy-related surgery vs none, and baseline seizure frequency < 3 vs ≥ 3 seizures/28 days. RESULTS: Data from 240 patients were available (mean age 41.8 years, mean baseline drug load 3.57). Following cenobamate initiation, the mean concomitant ASM drug load was reduced by 29.4 % at Month 12 % and 31.8 % at Month 24. Reductions occurred in all assessed ASM drug classes, with the largest reduction in benzodiazepines (55.2 % at Month 24). Each assessed subgroup exceeded a 30 % reduction in concomitant ASM drug load at Month 24. Over 24 months, maintenance of ≥ 50 % response occurred in 89.3 %, 86.4 %, and 90.6 % of patients with low (-0.25 to <0), moderate (-0.59 to -0.25), or high (-3.3 to -0.59) numerical reductions in concomitant ASM drug load from baseline, respectively, compared with 86.0 % in patients with no change in drug load; maintenance of 100 % response occurred in 80.7 %, 84.3 %, and 70.0 % of patients with low, moderate, or high numerical reductions in concomitant ASM drug load, compared with 82.0 % in patients with no change. CONCLUSIONS: Adding cenobamate led to reduced mean concomitant ASM drug loads during 1 and 2 years of treatment. Reductions occurred regardless of ASM drug class, patient age, or epilepsy disease characteristics and did not impact maintenance of response rates.
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Clorofenóis , Epilepsia , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Tetrazóis , Resultado do Tratamento , Ensaios Clínicos Fase III como Assunto , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Autonomic manifestations have been frequently studied in adults with epilepsy. Here, we evaluated cardiac autonomic (ANS) functions in children with epilepsy in the interictal period and determined the risks for their dysfunctions. RESEARCH DESIGN AND METHODS: This study included 60 patients (boys = 25; girls = 35 age: 14.53 ± 2.54 yrs) and 25 controls. Patients were well-controlled on antiseizure medications (ASMs). The battery of testing included measuring resting heart rate (HR) and blood pressure (BP), 30:15 ratio, HR variability (HRV) response to deep breathing, Valsalva ratio and BP changes in response to standing, isometric exercise and cold. RESULTS: Dizziness was reported in 25%. Autonomic dysfunctions were found in 45% (n = 27). Manifestations included high frequencies of abnormal 30:15 ratio (22%), HRV responses to deep breathing (45%), Valsalava ratio (45%), and BP responses to standing (35%), isometric exercise (27%) and cold (27%), indicating parasympathetic and sympathetic hypofunctions. There were positive correlations between parasympathetic and sympathetic dysfunctions. Logistic analysis showed that the durations of epilepsy and ASMs therapy were associated with ANS dysfunctions [95% CI: 0.895-4.719, p = 0.004]. CONCLUSIONS: Parasympathetic and sympathetic autonomic hypofunctions are common in children with epilepsy. This could be due to the depressant effect of sodium channel blocker ASMs on central and/or cardiac autonomic systems.
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Epilepsia , Adulto , Masculino , Criança , Feminino , Humanos , Adolescente , Epilepsia/tratamento farmacológico , Sistema Nervoso Autônomo , Pressão SanguíneaRESUMO
CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.
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Epilepsias Parciais , Epilepsia , Hidrocefalia , Lactente , Adulto , Humanos , Epilepsias Parciais/genética , Epilepsia/genética , Hidrocefalia/genética , Genótipo , Estudos de Associação Genética , Proteínas dos Microfilamentos/genética , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
OBJECTIVES: The MED12 gene encodes mediator complex subunit 12, which is a component of the mediator complex involved in the transcriptional regulation of nearly all RNA polymerase II-dependent genes. MED12 variants have previously been associated with developmental disorders with or without nonspecific intellectual disability. This study aims to explore the association between MED12 variants and epilepsy. MATERIALS AND METHODS: Trios-based whole-exome sequencing was performed in a cohort of 349 unrelated cases with partial (focal) epilepsy without acquired causes. The genotype-phenotype correlations of MED12 variants were analyzed. RESULTS: Five hemizygous missense MED12 variants, including c.958A>G/p.Ile320Val, c.1757G>A/p.Ser586Asn, c.2138C>T/p.Pro713Leu, c.3379T>C/p.Ser1127Pro, and c.4219A>C/p.Met1407Leu were identified in five unrelated males with partial epilepsy. All patients showed infrequent focal seizures and achieved seizure free without developmental abnormalities or intellectual disability. All the hemizygous variants were inherited from asymptomatic mothers (consistent with the X-linked recessive inheritance pattern) and were absent in the general population. The two variants with damaging hydrogen bonds were associated with early-onset seizures. Further genotype-phenotype analysis revealed that congenital anomaly disorder (Hardikar syndrome) was associated with (de novo) destructive variants in an X-linked dominant inheritance pattern, whereas epilepsy was associated with missense variants in an X-linked recessive inheritance pattern. Phenotypic features of intellectual disability appeared as the intermediate phenotype in terms of both genotype and inheritance. Epilepsy-related variants were located at the MED12-LCEWAV domain and the regions between MED12-LCEWAV and MED12-POL. CONCLUSION: MED12 is a potentially causative gene for X-linked recessive partial epilepsy without developmental or intellectual abnormalities. The genotype-phenotype correlation of MED12 variants explains the phenotypic variations and can help the genetic diagnosis.
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Epilepsias Parciais , Epilepsia , Deficiência Intelectual , Masculino , Humanos , Deficiência Intelectual/genética , Genes Ligados ao Cromossomo X/genética , Fenótipo , Complexo Mediador/genética , Complexo Mediador/química , Complexo Mediador/metabolismo , Epilepsias Parciais/genética , Epilepsia/genética , Fatores de Transcrição/genéticaRESUMO
Objective: Psychoses of epilepsy usually have an acute onset, accompanied by brief symptom duration and a risk of recurrence. Managing these conditions can be challenging due to the potential for seizures associated with certain antipsychotic medications, as well as exacerbating psychosis resulting from some antiepileptic medications. Our objective in this study was to assess the occurrence of psychosis among patients with epilepsy, as well as identify the factors linked to the presence and severity of psychosis in this population. Method : In this study, we included a total of 514 subjects diagnosed with epilepsy referring to our neuropsychiatry clinic affiliated with Tehran University of Medical Sciences from April 2011 to December 2021, among whom 57 patients showed psychotic presentations. We compared baseline and clinical characteristics between patients with psychosis of epilepsy and non-psychosis patients who also had epilepsy. Results: Marital status was the sole demographic factor that displayed a statistically significant difference between the psychosis and non-psychosis groups (P = 0.019). There was no significant difference observed between the two groups regarding family history of epilepsy and age at the onset of the epilepsy. Patients with psychosis experienced significantly more frequent seizures and generalized type (P < 0.001). Participants were matched for demographics and other clinical factors between the refractory and controlled psychosis groups, except for the psychosis frequency (P = 0.007). The type of epilepsy was significantly associated with psychosis when adjusted for the covariates (P < 0.001). Conclusion: Patients with psychosis of epilepsy experienced more episodes of epilepsy than non-psychotics. We identified generalized epilepsy as an independent risk factor for the development of psychosis. Additional cohorts are warranted to explore the factors associated with epilepsy-related psychosis across diverse populations.
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Canine idiopathic head tremor syndrome (CIHTS) represents a benign condition characterized by episodic, uncontrolled movement of the head. Even though the condition might be an expression of a partial motor epilepsy, to date, there is a limited number of studies describing the electroencephalographic features. In this report, we describe the case of a dog diagnosed with partial motor epilepsy resembling CIHTS symptomatology, a new slow spike-wave complex pattern similar to that of Lennox-Gastaut syndrome in humans identified on electroencephalographic examination. We also studied the efficacy of phenobarbitone therapy over a period of two years.
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OBJECTIVE: Cenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy. METHODS: A population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8-1.25. RESULTS: In the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816-0.925) for adjunctive carbamazepine and 1.24 (1.147-1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8-1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam. CONCLUSIONS: Based on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients.
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Anticonvulsivantes , Convulsões , Humanos , Clobazam/uso terapêutico , Anticonvulsivantes/efeitos adversos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Carbamazepina/uso terapêutico , Benzodiazepinas/uso terapêuticoRESUMO
BACKGROUND: HCFC1 encodes transcriptional co-regulator HCF-1, which undergoes an unusual proteolytic maturation at a centrally located proteolysis domain. HCFC1 variants were associated with X-linked cobalamin metabolism disorders and mental retardation-3. This study aimed to explore the role of HCFC1 variants in common epilepsy and the mechanism underlying phenotype heterogeneity. METHODS: Whole-exome sequencing was performed in a cohort of 313 patients with idiopathic partial (focal) epilepsy. Functional studies determined the effects of the variants on the proteolytic maturation of HCF-1, cell proliferation and MMACHC expression. The role of HCFC1 variants in partial epilepsy was validated in another cohort from multiple centers. RESULTS: We identified seven hemizygous HCFC1 variants in 11 cases and confirmed the finding in the validation cohort with additional 13 cases and six more hemizygous variants. All patients showed partial epilepsies with favorable outcome. None of them had cobalamin disorders. Functional studies demonstrated that the variants in the proteolysis domain impaired the maturation by disrupting the cleavage process with loss of inhibition of cell growth but did not affect MMACHC expression that was associated with cobalamin disorder. The degree of functional impairment was correlated with the severity of phenotype. Further analysis demonstrated that variants within the proteolysis domain were associated with common and mild partial epilepsy, whereas those in the kelch domain were associated with cobalamin disorder featured by severe and even fatal epileptic encephalopathy, and those in the basic and acidic domains were associated with mainly intellectual disability. CONCLUSION: HCFC1 is potentially a candidate gene for common partial epilepsy with distinct underlying mechanism of proteolysis dysfunction. The HCF-1 domains played distinct functional roles and were associated with different clinical phenotypes, suggesting a sub-molecular effect. The distinct difference between cobalamin disorders and idiopathic partial epilepsy in phenotype and pathogenic mechanism, implied a clinical significance in early diagnosis and management.
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Epilepsias Parciais , Epilepsia , Humanos , Proteólise , Epilepsia/genética , Vitamina B 12/genética , Vitamina B 12/metabolismo , Regulação da Expressão Gênica , Epilepsias Parciais/genética , Oxirredutases/genética , Oxirredutases/metabolismoRESUMO
Background: Recessive SZT2 variants are reported to be associated with developmental and epileptic encephalopathy 18 (DEE-18) and occasionally neurodevelopment abnormalities (NDD) without seizures. This study aims to explore the phenotypic spectrum of SZT2 and the genotype-phenotype correlation. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported SZT2 mutations were systematically reviewed to analyze the genotype-phenotype correlations. Results: SZT2 variants were identified in six unrelated cases with heterogeneous epilepsy, including one de novo null variant and five pairs of biallelic variants. These variants had no or low frequencies in controls. All missense variants were predicted to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients with null variants exhibited DEE. The patients with biallelic null mutations presented severe DEE featured by frequent spasms/tonic seizures and diffuse cortical dysplasia/periventricular nodular heterotopia. The three patients with biallelic missense variants presented mild partial epilepsy with favorable outcomes. Analysis of previously reported cases revealed that patients with biallelic null mutations presented significantly higher frequency of refractory seizures and earlier onset age of seizure than those with biallelic non-null mutations or with biallelic mutations containing one null variant. Significance: This study suggested that SZT2 variants were potentially associated with partial epilepsy with favorable outcomes without NDD, expanding the phenotypic spectrum of SZT2. The genotype-phenotype correlation helps in understanding the underlying mechanism of phenotypic variation.
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OBJECTIVE: Self-limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2-positive SeLIE only, and anti-seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2-positive SeLIE and to propose effective anti-seizure medications for seizure control. METHODS: We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal-onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2-related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti-seizure medications. RESULTS: Patients with PRRT2-related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short-duration (n = 33, 91.7%), and bilateral tonic-clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One-third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti-seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. SIGNIFICANCE: Our results delineated the clinical characteristics of PRRT2-positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti-seizure medications for initial clustered seizure control. If afebrile bilateral tonic-clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2-positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.
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Epilepsia Neonatal Benigna , Epilepsia , Lactente , Recém-Nascido , Humanos , Epilepsia Neonatal Benigna/tratamento farmacológico , Epilepsia Neonatal Benigna/genética , Epilepsia Neonatal Benigna/diagnóstico , Mutação , Estudos Retrospectivos , Bloqueadores dos Canais de Sódio , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Convulsões/tratamento farmacológico , Convulsões/genéticaRESUMO
Pure amnestic seizures are defined as self-limited episodes with isolated, anterograde memory loss and have been attributed to bilateral dysfunction of mesial temporal structures. This type of seizure can occur in patients with different forms of temporal lobe epilepsy and has been more recently associated with a late-onset epileptic syndrome, called transient epileptic amnesia (TEA). The mechanisms of such prolonged manifestations are not well known and notably its ictal or post-ictal origin remains poorly understood. We report a case of prolonged anterograde amnesia (lasting several hours) following a brief seizure induced by stimulation of the left entorhinal cortex, recorded during stereo-EEG (SEEG). This episode was associated with prolonged changes in the intracerebral EEG signal complexity (entropy) within bilateral mesial temporal structures, particularly the entorhinal cortices, with a progressive normalization paralleling the clinical recovery. Our case shows that long-lasting (hours) memory impairment may follow brief seizure that led to prolonged electrophysiological signals alterations in bilateral mesial temporal structures.
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Epilepsia do Lobo Temporal , Epilepsia , Humanos , Convulsões , Epilepsia do Lobo Temporal/diagnóstico por imagem , Amnésia/diagnóstico por imagem , Amnésia/complicações , EletroencefalografiaRESUMO
CELSR1 gene, encoding cadherin EGF LAG seven-pass G-type receptor 1, is mainly expressed in neural stem cells during the embryonic period. It plays an important role in neurodevelopment. However, the relationship between CELSR1 and disease of the central nervous system has not been defined. In this study, we performed trios-based whole-exome sequencing in a cohort of 356 unrelated cases with partial epilepsy without acquired causes and identified CELSR1 variants in six unrelated cases. The variants included one de novo heterozygous nonsense variant, one de novo heterozygous missense variant, and four compound heterozygous missense variants that had one variant was located in the extracellular region and the other in the cytoplasm. The patients with biallelic variants presented severe epileptic phenotypes, whereas those with heterozygous variants were associated with a mild epileptic phenotype of benign epilepsy with centrotemporal spikes (BECTS). These variants had no or low allele frequency in the gnomAD database. The frequencies of the CELSR1 variants in this cohort were significantly higher than those in the control populations. The evidence from ClinGen Clinical-Validity Framework suggested a strong association between CELSR1 variants and epilepsy. These findings provide evidence that CELSR1 is potentially a candidate pathogenic gene of partial epilepsy of childhood.
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Epilepsias Parciais , Humanos , Epilepsias Parciais/genética , Caderinas/genética , Alelos , Heterozigoto , Mutação de Sentido Incorreto/genéticaRESUMO
This post hoc analysis (n = 240) of a subset of study sites (10 eligible US sites) from an open-label phase 3 study assessed whether baseline seizure frequency (<3 seizures/28 days vs ≥3 seizures/28 days) impacted mean cenobamate dose required to achieve 100% seizure reduction, duration of this response, and responder rates. Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals. Further increases to 400 mg/day by 50-mg/day biweekly increments were allowed during the maintenance phase. Eligible patients were required to have consistent raw seizure data and good-quality data for ≥ 85% of the time spent in the study. Data were assessed until last visit and at data cut-off, on or after September 1, 2019. Among all 240 patients, 127 (52.9%) had < 3 seizures/28 days, and 113 (47.1%) had ≥ 3 seizures/28 days at baseline. Among patients continuing cenobamate at data cut-off (n = 177), 51% (90/177) and 49% (87/177) had < 3 and ≥ 3 seizures/28 days at baseline, respectively. Retention rate at data cut-off was 73.8% (177/240 patients), and these patients had a median time on study of 32.9 months (range: 22.1-43.0 months). 33.9% of patients continuing cenobamate (60/177) achieved 100% seizure reduction for ≥ 12 months at data cut-off, with 44.4% and 23.0% in patients with < 3 and ≥ 3 seizures/28 days at baseline, respectively. Regardless of baseline seizure frequency, responder rates at ≥ 50%, ≥ 75%, and ≥ 90% during the maintenance phase were similar (â¼81%, â¼62%, and â¼43%, respectively). Mean±SD cenobamate dose for patients continuing cenobamate was 254.0 ± 82.1 mg/day, with means of 237.9 ± 78.1 mg/day and 270.7 ± 83.1 mg/day in patients with < 3 and ≥ 3 seizures/28 days at baseline, respectively. Among patients who had 100% seizure reduction for ≥ 12 months at data cut-off (n = 60), the mean cenobamate dose was 226.4 ± 75.4 mg/day and 255.1 ± 93.7 mg/day in patients with < 3 and ≥ 3 seizures/28 days at baseline, respectively. The current data suggest that cenobamate was effective regardless of baseline seizure frequency, with both groups having a high number of patients reaching 100% seizure reduction. A higher percentage of patients with less vs more frequent seizures at baseline reached zero seizures, suggesting these patients may reach 100% seizure reduction at lower cenobamate doses than those with more frequent seizures. Cenobamate dose varied slightly (â¼30 mg/day) across patients who were stratified by baseline seizure frequency, but future analyses are necessary to determine whether patients with more frequent seizures require higher doses of cenobamate to achieve zero seizures.
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Anticonvulsivantes , Convulsões , Anticonvulsivantes/uso terapêutico , Carbamatos , Clorofenóis , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Tetrazóis , Resultado do TratamentoRESUMO
Objective.In partial epilepsies, interictal epileptiform discharges (IEDs) are paroxysmal events observed in epileptogenic zone (EZ) and non-epileptogenic zone (NEZ). IEDs' generation and recurrence are subject to different hypotheses: they appear through glutamatergic and gamma-aminobutyric acidergic (GABAergic) processes; they may trigger seizures or prevent seizure propagation. This paper focuses on a specific class of IEDs, spike-waves (SWs), characterized by a short-duration spike followed by a longer duration wave, both of the same polarity. Signal analysis and neurophysiological mathematical models are used to interpret puzzling IED generation.Approach.Interictal activity was recorded by intracranial stereo-electroencephalography (SEEG) electrodes in five different patients. SEEG experts identified the epileptic and non-epileptic zones in which IEDs were detected. After quantifying spatial and temporal features of the detected IEDs, the most significant features for classifying epileptic and non-epileptic zones were determined. A neurophysiologically-plausible mathematical model was then introduced to simulate the IEDs and understand the underlying differences observed in epileptic and non-epileptic zone IEDs.Main results.Two classes of SWs were identified according to subtle differences in morphology and timing of the spike and wave component. Results showed that type-1 SWs were generated in epileptogenic regions also involved at seizure onset, while type-2 SWs were produced in the propagation or non-involved areas. The modeling study indicated that synaptic kinetics, cortical organization, and network interactions determined the morphology of the simulated SEEG signals. Modeling results suggested that the IED morphologies were linked to the degree of preserved inhibition.Significance.This work contributes to the understanding of different mechanisms generating IEDs in epileptic networks. The combination of signal analysis and computational models provides an efficient framework for exploring IEDs in partial epilepsies and classifying EZ and NEZ.
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Epilepsias Parciais , Epilepsia , Simulação por Computador , Eletroencefalografia/métodos , Epilepsia/diagnóstico , Humanos , Convulsões/diagnóstico , Processamento de Sinais Assistido por ComputadorRESUMO
Introduction: Focal epilepsies are diseases of neuronal excitability affecting macroscopic networks of cortical and subcortical neural structures. These networks ("epileptogenic networks") can generate pathological electrophysiological activities during seizures, and also between seizures (interictal period). Many works attempt to describe these networks by using quantification methods, particularly based on the estimation of statistical relationships between signals produced by brain regions, namely functional connectivity (FC). Results: FC has been shown to be greatly altered during seizures and in the immediate peri-ictal period. An increasing number of studies have shown that FC is also altered during the interictal period depending on the degree of epileptogenicity of the structures. Furthermore, connectivity values could be correlated with other clinical variables including surgical outcome. Significance: This leads to a conceptual change and to consider epileptic areas as both hyperexcitable and abnormally connected. These data open the door to the use of interictal FC as a marker of epileptogenicity and as a complementary tool for predicting the effect of surgery. Aim: In this article, we review the available data concerning interictal FC estimated from intracranial electroencephalograhy (EEG) in focal epilepsies and discuss it in the light of data obtained from other modalities (EEG imaging) and modeling studies.