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OBJECTIVE: To identify predisposing factors for hyperkinetic seizure occurrence in a representative cohort of surgically treated patients with drug-resistant focal epilepsy. METHODS: We retrospectively recruited all seizure-free patients after epilepsy surgery with a postoperative follow-up ≥12â¯months. Patients were classified as presenting with hyperkinetic seizures if at least 2 episodes occurred during their disease history, based on clear-cut anamnestic description and/or video-EEG/stereo-EEG recordings. We performed univariable and multivariable logistic regression models to study the association between the occurrence of hyperkinetic seizures and some predictors. RESULTS: From a pool of 1758 consecutive patients who underwent surgery from 1996 to 2017, we identified 974 seizure-free cases. Considering at least 1-year follow-up, 937 cases were included (511 males, 91 patients with hyperkinetic seizures). Variables significantly associated with an increased risk of hyperkinetic seizure occurrence were (1) presence of epilepsy with sleep-related seizures (SRE) (Pâ¯<â¯0.001); (2) histological diagnosis of type II focal cortical dysplasia (FCD) (Pâ¯<â¯0.001); (3) resection including the frontal lobe (Pâ¯=â¯0.002) (4) duration of epilepsy at surgery (Pâ¯<â¯0.001) and (5) high seizure frequency at surgery (weekly: Pâ¯=â¯0.02 - daily: Pâ¯=â¯0.05). A resection including the occipital lobe reduced the risk of hyperkinetic seizures (Pâ¯=â¯0.05). About 63% of patients had hyperkinetic seizure onset before 12â¯years and it was rarely reported before 5â¯years of age. SIGNIFICANCE: Our findings underlie the role of SRE, type II FCD and frontal epileptogenic zone as predictors of hyperkinetic seizure occurrence and highlight an age-dependent effect in favoring hyperkinetic manifestations.
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Epilepsia Reflexa , Convulsões , Eletroencefalografia , Epilepsia Reflexa/complicações , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Convulsões/complicações , Convulsões/diagnóstico , Convulsões/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the long-term outcome of epilepsy with auditory features (EAF) and to identify the clinical predictors for prognosis. METHODS: The study involved consecutive EAF patients with a follow-up of ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimate to calculate the cumulative time-dependent probability of conversion to TR. Log-rank test and multivariate Cox regression analyses were performed to study the association between time to TR and prognostic determinants. RESULTS: We included 123 EAF patients (male/female = 58/65) with a median follow-up of 11 years (1626.9 person-years). Most were sporadic cases (68.3%), whereas 31.7% reported a family history of epilepsy. At last assessment, 42 patients had achieved TR (34.1%). Of the remaining 81 cases with no TR (65.9%), 37% had been in remission for 1-4 years and 62.9% still had seizures within the past year. The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion. On multivariate analysis, age at onset > 10 years (hazard ratio [HR] = 3.2, P = .028), auditory aura characterized by distortions only versus simple/complex hallucinations (HR = 2.9, P = .041), and unremarkable scalp electroencephalogram (EEG) versus EEG with focal epileptiform activity (HR = 3.5, P = .041) were associated with TR. SIGNIFICANCE: Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. These predictors, easy to collect even at the first visit, may inform both clinicians and patients about the long-term prognosis and aid patient management.
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Epilepsia/diagnóstico , Epilepsia/epidemiologia , Alucinações/diagnóstico , Alucinações/epidemiologia , Adulto , Estudos de Coortes , Eletroencefalografia/tendências , Epilepsia/fisiopatologia , Feminino , Seguimentos , Alucinações/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
The beneficial effect of nicotine has been reported in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) patients, but not tested in sporadic cases. Recently, a nicotine defect in the arousal pathway has been hypothesized even in sporadic NFLE patients and their relatives. This case-control family study was designed to test whether NFLE subjects were more likely to use tobacco than controls, as an indirect marker of cholinergic arousal system dysregulation. At least four relatives were included for each NFLE proband and control. Each subject was questioned about tobacco habits; 434 individuals were recruited. Moreover, we compared NFLE patients with age- and sex-matched controls to determine whether they are more likely to use tobacco. We found a slightly higher trend of tobacco use in NFLE probands compared to that in control subjects; we did not find any significant difference in the distribution of tobacco use among NFLE group compared to that in the control group.
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Epilepsia do Lobo Frontal/epidemiologia , Epilepsia do Lobo Frontal/psicologia , Hábitos , Tabagismo/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Eletroencefalografia , Epilepsia do Lobo Frontal/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polissonografia , Receptores Nicotínicos/genética , Estudos Retrospectivos , Tabagismo/psicologia , Gravação em Vídeo , Adulto JovemRESUMO
Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent complications, mainly focal neurological deficits. We report the case of a patient with drug-resistant epilepsy who complained of immediate seizure worsening and an unexpected event seven months following RF-TC. A 35-year-old male with drug-resistant epilepsy from the age of 18 years underwent stereoelectroencephalography (SEEG) implantation for a right peri-silvian polymicrogyria. He was excluded from surgery due to extent of the epileptogenic zone and the risk of visual field deficits. RF-TC was attempted to ablate the most epileptogenic zone identified by SEEG. After RF-TC, the patient reported an increase in seizure severity/frequency and experienced episodes of postictal psychosis. Off-label cannabidiol treatment led to improved seizure control and resolution of postictal psychosis. Patients with polymicrogyria (PwP) may present with a disruption of normal anatomy and the co-existence between epileptogenic zone and eloquent cortex within the malformation. RF-TC should be considered in PwP when they are excluded from surgery for prognostic and palliative purposes. However, given the complex interplay between pathological and electrophysiological networks in these patients, the remote possibility of clinical exacerbation after RF-TC should also be taken into account.
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BACKGROUND: Ictal piloerection (IP) is a rare manifestation of focal epilepsy. Autoimmune limbic encephalitis (LE) and malignant brain tumours are the most frequent recognized aetiologies. METHODS: We selected all patients diagnosed with LE in our Institute from 2004 to 2020 and manifesting with IP. We performed a literature review on LE patients presenting IP. RESULTS: Of 15 patients diagnosed with LE (13.3%), two manifested IP as prominent ictal feature. One of them also had stiff-limb syndrome. Video-EEG documented ictal discharges from the right temporal regions with concomitant sympathetic skin response (SSR) recording. Antibody testing showed elevated serum and CSF titres of GAD65 antibodies (Ab), in both cases. Despite a combination of several anti-seizure medications and first- and second-line immunotherapy, they showed a poor clinical outcome after 2 and 9 years of follow-up, respectively. The literature review yielded 13 papers reporting 26 LE cases with IP. LGI1 Ab were the most frequently associated (73.1%) followed by VGKC-complex (7.7%), GAD65 (7.7%), NMDAr (3.8%), Ma2 (3.8%) and Hu (3.8%) Ab. Cases with LGI1 Ab showed a good response to immunotherapy. DISCUSSION AND CONCLUSION: The prevalence of IP in our LE cohort was of 13.3%, higher than expected. According to the literature review, most cases were associated with LGI1 Ab and showed a good response to immunotherapy. With the contribution of our cases, GAD65 emerged as the second most frequently detected Ab, showing a poor outcome. Our findings widen the spectrum of IP-associated Ab, with the respective prognostic implications.
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Doenças Autoimunes , Encefalite Límbica , Autoanticorpos , Doenças Autoimunes/complicações , Eletroencefalografia , Humanos , Encefalite Límbica/complicaçõesRESUMO
OBJECTIVE: To evaluate the long-term outcomes of patients with epilepsy and malformations of cortical development (MCD). METHODS: We conducted a historical cohort study of patients with epilepsy and MCD due to impaired neuronal migration and postmigration organization with a follow-up period of ≥5 years. For each patient, MCD was classified after accurate neuroimaging reappraisal by an expert neuroradiologist. The primary outcome was remission, defined as a period of seizure freedom ≥5 years at any time from epilepsy onset. We used Kaplan-Meier estimates for survival analysis and univariate and multivariate Cox regression analyses to evaluate baseline variables as possible factors associated with remission. RESULTS: The cohort included 71 patients (M/F 31/40) with a 17-year median follow-up (1,506 person-years). About half (49.3%) had heterotopia, 35.2% polymicrogyria, 7% lissencephaly, and 8.5% the combination of 2 MCD. The mean age at seizure onset was 12.4 ± 7.2 years. Intellectual disability and neurologic deficits were observed in 30.4% and 40.9%, respectively. More than 60% of patients had refractory epilepsy. In 3 patients who underwent epilepsy surgery, MCD diagnosis was confirmed by histology. At the last visit, 44% of patients had been seizure-free during the previous year, but none of them had stopped antiseizure medication. Thirty patients achieved remission (42.2%) at some point in their disease history, whereas 41 individuals (57.8%) had never been in remission for ≥5 years. The cumulative remission rate was 38% by 20 years from inclusion. In the Cox model, unilateral distribution of MCD (hazard ratio [HR] 2.68, 95% CI 1.04-6.92) and a low seizure frequency at onset (HR 5.01, 95% CI 1.12-22.5) were significantly associated with remission. DISCUSSION: Patients with epilepsy and MCD showed a remission rate of 38% by 20 years from onset. Unilateral distribution of the MCD is associated with a 3-fold probability of achieving remission. About 40% of patients showed a drug-sensitive condition with risk of relapse during their epilepsy course. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with epilepsy and MCD, unilateral MCD and low seizure frequency at onset are associated with achieving epilepsy remission.
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Epilepsia Resistente a Medicamentos , Epilepsia , Malformações do Desenvolvimento Cortical , Anticonvulsivantes/uso terapêutico , Estudos de Coortes , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Humanos , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/cirurgia , Convulsões/tratamento farmacológicoRESUMO
Epilepsy with auditory features (EAF) is a focal epilepsy belonging to the focal epileptic syndromes with onset at variable age according to the new ILAE Classification. It is characterized by seizures with auditory aura or receptive aphasia suggesting a lateral temporal lobe involvement of the epileptic discharge. Etiological factors underlying EAF are largely unknown. In the familial cases with an autosomal dominant pattern of inheritance several genes have been involved, among which the first discovered, LGI1, was thought to be predominant. However, increasing evidence now points to a multifactorial etiology, as familial and sporadic EAF share a virtually identical electro-clinical characterization and only a few have a documented genetic etiology. Patients with EAF usually have an unremarkable neurological examination and a good response to antiseizure medications. However, it must be underscored that total remission might be lower than expected and that treatment withdrawal might lead to relapses. Thus, a proper understanding of this condition is in order for better patient treatment and counseling. Further studies are still required to further characterize the many facets of EAF.
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Objectives: We explored the impact of the coronavirus disease-19 (COVID-19) emergency on the health of people with epilepsy (PwE). We also investigated their attitude toward telemedicine. Methods: The PubMed database up to September 10, 2020 was searched for questionnaire-based studies conducted in PwE during the COVID-19 emergency, and the literature retrieved was reviewed. In addition, all patients who had a telephone consultation with our center between May 7 and July 31, 2020 were invited to fill in a 57-item online questionnaire focusing on epilepsy and comorbidities, any changes in lifestyle or clinical conditions and any emergency-related problems arising during the COVID-19 emergency, and their views on telemedicine. Associations between variables were detected through X 2 test and Fisher's exact test. Univariate and multivariate logistic regression models were used to evaluate the effects of different factors on clinical conditions. Results: Twelve studies met the literature search criteria. They showed that the rate of seizure worsening during the emergency ranged from 4 to 35% and was mainly correlated with epilepsy severity, sleep disturbances and COVID-19-related issues. Our questionnaire was filled in by 222 PwE or caregivers. One hundred (76.6%) reported unchanged clinical conditions, 25 (11.3%) an improvement, and 27 (12%) a deterioration. Reported clinical worsening was associated with a psychiatric condition and/or medication (OR = 12.59, p < 0.001), sleep disorders (OR = 8.41, p = 0.001), limited access to healthcare (OR = 4.71, p = 0.016), and experiencing seizures during the emergency (OR = 4.51, p = 0.007). Telemedicine was considered acceptable by 116 subjects (52.3%). Conclusions: Most PwE did not experience a significant change in their clinical conditions during the COVID-19 emergency. However, severity of epilepsy, concomitant disability, comorbid psychiatric conditions, sleep disorders and limited access to healthcare may affect their health.
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BACKGROUND: Formalin-fixed, paraffin-embedded brain specimens are a potentially rich resource to identify somatic variants, but their DNA is characterised by low yield and extensive degradation, and matched peripheral samples are usually unavailable for analysis. METHODS: We designed single-molecule molecular inversion probes to target 18 MTOR somatic mutational hot-spots in unmatched, histologically proven focal cortical dysplasias from formalin-fixed, paraffin-embedded tissues of 50 patients. RESULTS: We achieved adequate DNA and sequencing quality in 28 focal cortical dysplasias, mostly extracted within 2 years from fixation, showing a statistically significant effect of time from fixation as a major determinant for successful genetic analysis. We identified and validated seven encompassing hot-spot residues (found in 14% of all patients and in 25% of those sequenced and analysed). The allele fraction had a range of 2-5% and variants were absent in available neighbouring non-focal cortical dysplasia specimens. We computed an alternate allele threshold for calling true variants, based on an experiment-wise mismatch count distribution, well predicting call reliability. CONCLUSIONS: Single-molecule molecular inversion probes are experimentally simple, cost effective and scalable, accurately detecting clinically relevant somatic variants in challenging brain formalin-fixed, paraffin-embedded tissues.
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Alelos , Testes Genéticos , Malformações do Desenvolvimento Cortical/diagnóstico , Malformações do Desenvolvimento Cortical/genética , Mutação , Serina-Treonina Quinases TOR/genética , Análise Mutacional de DNA/métodos , Testes Genéticos/métodos , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Malformações do Desenvolvimento Cortical/cirurgia , Sondas Moleculares , Reprodutibilidade dos Testes , Imagem Individual de Molécula , Serina-Treonina Quinases TOR/metabolismoRESUMO
Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus (GEFS+). We aimed to investigate the role/impact of SCN1A mutations in EAF. We detailed the phenotype of this family and report on SCN1A screening in a cohort of 29 familial and 52 sporadic LGI1 variant-negative EAF patients. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. SCN1A mutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1A in EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.
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Transtornos da Percepção Auditiva , Epilepsias Parciais , Epilepsia Generalizada , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris , Adulto , Idoso , Transtornos da Percepção Auditiva/etiologia , Transtornos da Percepção Auditiva/genética , Transtornos da Percepção Auditiva/fisiopatologia , Epilepsias Parciais/complicações , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Proteína Reelina , Convulsões Febris/complicações , Convulsões Febris/genética , Convulsões Febris/fisiopatologiaRESUMO
OBJECTIVE: The differential diagnosis between sleep-related hypermotor epilepsy (SHE) and disorders of arousal (DOA) may be challenging. We analyzed the stage and the relative time of occurrence of parasomnic and epileptic events to test their potential diagnostic accuracy as criteria to discriminate SHE from DOA. METHODS: Video-polysomnography recordings of 89 patients with a definite diagnosis of DOA (59) or SHE (30) were reviewed to define major or minor events and to analyze their stage and relative time of occurrence. The "event distribution index" was defined on the basis of the occurrence of events during the first versus the second part of sleep period time. A group analysis was performed between DOA and SHE patients to identify candidate predictors and to quantify their discriminative performance. RESULTS: The total number of motor events (i.e. major and minor) was significantly lower in DOA (3.2 ± 2.4) than in SHE patients (6.9 ± 8.3; p = 0.03). Episodes occurred mostly during N3 and N2 in DOA and SHE patients, respectively. The occurrence of at least one major event outside N3 was highly suggestive for SHE (p = 2*e-13; accuracy = 0.898, sensitivity = 0.793, specificity = 0.949). The occurrence of at least one minor event during N3 was highly suggestive for DOA (p = 4*e-5; accuracy = 0.73, sensitivity = 0.733, specificity = 0.723). The "event distribution index" was statistically higher in DOA for total (p = 0.012) and major events (p = 0.0026). CONCLUSION: The stage and the relative time of occurrence of minor and major motor manifestations represent useful criteria to discriminate DOA from SHE episodes.
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Nível de Alerta/fisiologia , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Polissonografia/métodos , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/fisiopatologia , Adolescente , Adulto , Idoso , Diagnóstico Diferencial , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sono/fisiologia , Gravação em Vídeo/métodos , Adulto JovemRESUMO
Sleep-related hypermotor epilepsy (SHE), previously called nocturnal frontal lobe epilepsy (NFLE), is a focal epilepsy characterized by asymmetric tonic/dystonic posturing and/or complex hyperkinetic seizures occurring mostly during sleep. SHE fulfills the definition of rare disease with an estimated minimum prevalence of 1.8/100,000 individuals, and it represents about 10% of drug-resistant surgical cases. Although SHE and autosomal-dominant SHE (ADSHE) have been considered benign epileptic conditions for a long time, emerging data have shed light on the severity of this disorder and some peculiar features can impact negatively on the quality of life of SHE patients. In fact, seizure frequency can be very high, resulting in nocturnal sleep fragmentation with possible diurnal consequences such as excessive sleepiness and fatigue. Moreover, recent studies, adopting a systematic neuropsychological assessment, have shown deficits in memory, executive functions and visuo-spatial abilities in almost half of SHE patients. Intellectual disabilities and psychiatric disorders have also been reported in some genetic forms. SHE may also exert a negative effect on health-related quality of life, especially in domains pertaining to a patient's role in the family, social context and patient's illness experience. Despite a good response to pharmacological treatment, especially with carbamazepine, 30% of SHE patients suffer from drug-resistant seizures. Finally, recent studies suggest a poor prognosis in a high percentage of SHE patients with a 20.4% cumulative probability of achieving terminal remission at 10 years from onset. For selected drug-resistant SHE patients, epilepsy surgery is the only treatment offering high probability of recovery, both for seizures and for epilepsy-related sleep alterations.
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OBJECTIVE: The aim of this study was to characterize the neuropsychological features of a representative sample of Sleep-related Hypermotor Epilepsy (SHE) patients and to highlight clinical associations. METHODS: This cross-sectional study included 60 consecutive patients with video/video-electroencephalography-documented SHE. All were assessed by measures of intelligence. Individuals with normal scores underwent a standardized battery of tests. The Fisher exact test and Wilcoxon rank-sum test for statistical analysis. RESULTS: Mean total IQ was 96.96 ± 21.50, with significant differences between verbal and performance scores (p < 0.0001). Nine patients (15%) had intellectual disability (ID)/cognitive deterioration. Of the 49 assessed by the extensive battery, 23 (46.9%) showed deficits in at least one test evaluating phonemic fluency (24.5%), memory (24.5%), inhibitory control (22.4%), or working memory (10.2%). Patients with mutations in SHE genes had lower IQ than patients without mutations, irrespective of the specific gene (p = 0.0176). Similarly, pathological neurological examination (NE) and "any underlying brain disorder" (at least one among pathological NE, abnormal brain magnetic resonance imaging findings, perinatal insult) were associated with ID (p = 0.029, p = 0.036). A higher seizure frequency at last assessment and poor prognosis correlated with worse scores in visuo-spatial memory (p = 0.038, p = 0.040) and visuo-spatial abilities (p = 0.016). Status epilepticus (p = 0.035), poor response to antiepileptic drugs (p = 0.033), and poor prognosis (p = 0.020) correlated with lower shifting abilities, whereas bilateral convulsive seizures correlated with worse working memory (p = 0.049). CONCLUSION: In all, 53.3% of SHE patients had neuropsychological deficits. The profile of impairment showed worse verbal IQ, as well as deficits in extrafrontal and selective frontal functions. Our data support the contribution of genetics in ID by different biological mechanisms. Variables of clinical severity affect memory and executive functioning.
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Transtornos Cognitivos/diagnóstico , Epilepsia do Lobo Frontal , Testes Neuropsicológicos/estatística & dados numéricos , Sono/fisiologia , Adulto , Anticonvulsivantes/uso terapêutico , Transtornos Cognitivos/genética , Estudos Transversais , Eletroencefalografia , Epilepsia do Lobo Frontal/tratamento farmacológico , Epilepsia do Lobo Frontal/genética , Feminino , Humanos , Inteligência/genética , Inteligência/fisiologia , Masculino , ConvulsõesAssuntos
Bradicardia/complicações , Epilepsia Resistente a Medicamentos/complicações , Epilepsia do Lobo Temporal/complicações , Síncope Vasovagal/etiologia , Acidentes por Quedas , Anticonvulsivantes/uso terapêutico , Bradicardia/terapia , Epilepsia Resistente a Medicamentos/fisiopatologia , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/fisiopatologia , Parada Cardíaca/etiologia , Frequência Cardíaca/fisiologia , Humanos , Hipotensão/etiologia , Hipotensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Marca-Passo Artificial , Postura , Recidiva , Inconsciência/etiologiaRESUMO
OBJECTIVE: To identify novel genes implicated in epilepsy with auditory features (EAF) in phenotypically heterogeneous families with unknown molecular basis. METHODS: We identified 15 probands with EAF in whom an LGI1 mutation had been excluded. We performed electroclinical phenotyping on all probands and available affected relatives. We used whole-exome sequencing (WES) in 20 individuals with EAF (including all the probands and 5 relatives) to identify single nucleotide variants, small insertions/deletions, and copy number variants. RESULTS: WES revealed likely pathogenic variants in genes that had not been previously associated with EAF: a CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5, and a missense SCN1A change. CONCLUSIONS: EAF is a clinically and molecularly heterogeneous disease. The association of EAF with CNTNAP2, DEPDC5, and SCN1A mutations widens the phenotypic spectrum related to these genes. CNTNAP2 encodes CASPR2, a member of the voltage-gated potassium channel complex in which LGI1 plays a role. The finding of a CNTNAP2 deletion emphasizes the importance of this complex in EAF and shows biological convergence.