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OBJECTIVE: Typically diagnosed in early childhood or adolescence, TSC is a chronic, multisystemic disorder with age-dependent manifestations posing a challenge for transition and for specific surveillance throughout the lifetime. Data on the clinical features and severity of TSC in adults and on the prognosis of epilepsy are scarce. We analyzed the clinical and genetic features of a cohort of adult patients with TSC, to identify the prognostic predictors of seizure remission after a long follow-up. METHOD: We conducted a retrospective analysis of patients diagnosed with TSC according to the updated international diagnostic criteria. Pearson's chi-square or Fisher's exact test and Mann Whitney U test were used to compare variables among the Remission (R) and Non-Remission (NR) group. Univariate and multivariate logistic regression analyses were performed. RESULTS: We selected 43 patients with TSC and neurological involvement in terms of epilepsy and/or brain lesions, attending the Epilepsy Center of our Institute: of them, 16 (37.2%) were transitioning from the pediatric care and 6 (13.9%) were referred by other specialists. Multiorgan involvement includes cutaneous (86.0%), nephrological (70.7%), hepatic (40.0%), ocular (34.3%), pneumological (28.6%) and cardiac (26.3%) manifestations. Thirty-nine patients (90.7 %) had epilepsy. The mean age at seizure onset was 4 ± 7.3 years: most patients (29, 76.3 %) presented with focal seizures or spasms by age 3 years; only 2 (5.3 %) had seizure onset in adulthood. Twenty-seven patients (69.2 %) experienced multiple seizure types overtime, 23 (59.0 %) had intellectual disability (ID). At last assessment, 14 (35.9 %) were seizure free (R group) and 25 (64.1 %) had drug-resistant seizures (NR group). At logistic regression univariate analysis, ID (OR 7.9, 95 % CI 1.8--34.7), multiple seizure types lifelong (OR 13.2, 95 % CI 2.6- 67.2), spasms/tonic seizures at presentation (OR 6.5, 95 % CI 1.2--35.2), a higher seizure frequency at onset (OR 5.4, 95 % CI 1.2--24.3), abnormal neurological examination (OR 9.8, 95 % CI 1.1--90.6) and pathogenic variants in TSC2 (OR 5.4, 95 % CI 1.2--24.5) were significantly associated with non-remission. In the multivariate analysis, both ID and multiple seizure types lifelong were confirmed as independent predictors of poor seizure outcome. CONCLUSIONS: In our cohort of adult patients with TSC, epilepsy remains one of the main neurological challenges with only 5.3% of cases manifesting in adulthood. Approximately 64% of these patients failed to achieve seizure remission. ID and multiple seizure types were the main predictors of poor outcome. Nephrological manifestations require continuous specific follow-up in adults.
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Epilepsia , Esclerosis Tuberosa , Niño , Adulto , Adolescente , Humanos , Preescolar , Anticonvulsivantes/uso terapéutico , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/tratamiento farmacológico , Estudios Retrospectivos , Epilepsia/etiología , Epilepsia/complicaciones , Convulsiones/tratamiento farmacológico , Pronóstico , EspasmoRESUMEN
Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them.
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Arginino-ARNt Ligasa/genética , Proteínas del Citoesqueleto/genética , Epilepsia/genética , Predisposición Genética a la Enfermedad , Trastornos del Neurodesarrollo/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Diagnóstico Tardío , Epilepsia/diagnóstico , Epilepsia/patología , Exoma/genética , Femenino , Pruebas Genéticas , Genómica , Humanos , Lactante , Masculino , Persona de Mediana Edad , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/patología , Secuenciación del Exoma/métodos , Adulto JovenRESUMEN
We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [µg/mL]/mg kg-1 d-1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12-66 years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Piridonas/farmacocinética , Piridonas/uso terapéutico , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Anciano , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/clasificación , Niño , Inductores de las Enzimas del Citocromo P-450/efectos adversos , Inductores de las Enzimas del Citocromo P-450/uso terapéutico , Inhibidores Enzimáticos del Citocromo P-450/efectos adversos , Inhibidores Enzimáticos del Citocromo P-450/uso terapéutico , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Estudios Prospectivos , Ácido Valproico/efectos adversos , Adulto JovenRESUMEN
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/epidemiología , Alucinaciones/diagnóstico , Alucinaciones/epidemiología , Adulto , Estudios de Cohortes , Electroencefalografía/tendencias , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Alucinaciones/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Lateral temporal lobe epilepsy (lTLE) is a rare condition characterized by auditory auras or receptive aphasia, negative MRI, and relatively benign evolution. With the low number of cases in the world, our objective was to analyze a cohort of sporadic cases with lTLE (slTLE), in order to investigate possible cerebral morphological alterations. Forty patients with lTLE (34.93±12.08years of age) and 38 healthy controls (CTRL, 34.55±9.08years of age) were enrolled from four tertiary Italian epilepsy centers, which provided brain MRI T1-weighted images following a standard protocol for patients with epilepsy. We performed group comparison by following different approaches: voxel-based morphometry (VBM, SPM8), cortical thickness (CT), and local gyrification index (lGI) (FreeSurfer 5.3). At a more conservative threshold (p<0.05, FWE correction), no significant differences between groups survived, neither in VBM nor CT/lGI. Multicenter studies have more power than smaller studies in conducting sophisticated evaluations of rare diseases, and further investigations are required to develop a full picture of this rare phenotype.
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Corteza Cerebral/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Imagen por Resonancia Magnética , Neuroimagen/métodos , Adulto , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: To clinically and genetically characterize a large Brazilian family with autosomal dominant partial epilepsy with auditory features (ADPEAF) not related to leucine-rich, glioma-inactivated 1 (LGI1) gene. METHODS: Seventy family members (four married-ins) participating in the study were assessed by a detailed clinical interview and a complete neurologic examination. Genetic mapping was conducted through autosome-wide single nucleotide polymorphism (SNP) genotyping and subsequent linkage analysis on 16 and haplotype analysis on 25 subjects, respectively. RESULTS: The pedigree comprised 15 affected members, of whom 11 were included in the study (male/female: 6/5; mean age 39.5 years). All but two (III:22 and IV:92) had focal seizures with auditory aura followed by secondary generalization in 44.4%. The mean age at onset of epilepsy seizures was 13.7 years. Initial autosome-wide SNP linkage analysis conducted on 12 subjects (8 affected) pointed to a single genomic region on chromosome 19 with a maximum multipoint logarithm of the odds (LOD) score of 2.60. Further refinement of this region through SNP and microsatellite genotyping on 16 subjects (11 affected) increased the LOD score to 3.41, thereby establishing 19q13.11-q13.31 as a novel ADPEAF locus. Haplotype analysis indicated that the underlying mutation is most likely located in a 9.74 Mb interval between markers D19S416 and D19S420. Sequence analysis of the most prominent candidate genes within this critical interval (SCN1B, LGI4, KCNK6, and LRFN1) did not reveal any mutation. SIGNIFICANCE: This study disclosed a novel ADPEAF locus on chromosome 19q13.11-q13.31, contributing to future identification of a second dominant gene for this epileptic syndrome. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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Cromosomas Humanos Par 19/genética , Epilepsia del Lóbulo Frontal/genética , Trastornos del Sueño-Vigilia/genética , Adolescente , Adulto , Mapeo Cromosómico , Femenino , Ligamiento Genético/genética , Sitios Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Haplotipos/genética , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
BACKGROUND: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. CASE PRESENTATION: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. CONCLUSION: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation.
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Encefalopatías/genética , Tronco Encefálico , ADN Mitocondrial/genética , Mutación/genética , Atrofia Óptica Hereditaria de Leber/genética , Adolescente , Encefalopatías/complicaciones , Humanos , Masculino , Atrofia Óptica Hereditaria de Leber/complicaciones , Linaje , Núcleos Vestibulares/patologíaRESUMEN
BACKGROUND: Biallelic pathogenic variants in the mitochondrial prolyl-tRNA synthetase 2 gene (PARS2, OMIM * 612036) have been associated with Developmental and Epileptic Encephalopathy-75 (DEE-75, MIM #618437). This condition is typically characterized by early-onset refractory infantile spasms with hypsarrhythmia, intellectual disability, microcephaly, cerebral atrophy with hypomyelination, lactic acidemia, and cardiomyopathy. Most affected individuals do not survive beyond the age of 10 years. METHODS: We describe a patient with early-onset DEE, consistently showing an EEG pattern of Spike-and-Wave Activation in Sleep (SWAS) since childhood. The patient underwent extensive clinical, metabolic and genetic investigations, including whole exome sequencing (WES). RESULTS: WES analysis identified compound heterozygous variants in PARS2 that have been already reported as pathogenic. A literature review of PARS2-associated DEE, focusing mainly on the electroclinical phenotype, did not reveal the association of SWAS with pathogenic variants in PARS2. Notably, unlike previously reported cases with the same genotype, this patient had longer survival without cardiac involvement or lactic acidosis, suggesting potential genetic modifiers contributing to disease variability. CONCLUSION: These findings widen the genetic heterogeneity of DEE-SWAS, including PARS2 as a causative gene in this syndromic entity, and highlight the importance of prolonged sleep EEG recording for the recognition of SWAS as a possible electroclinical evolution of PARS2-related DEE.
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Microcefalia , Espasmos Infantiles , Humanos , Niño , Espasmos Infantiles/genética , Sueño/fisiología , Electroencefalografía , FenotipoAsunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/genética , Epilepsia Generalizada/complicaciones , Epilepsia Generalizada/genética , Variación Genética/genética , Transportador de Glucosa de Tipo 1/genética , Proteínas de Transporte de Monosacáridos/deficiencia , Convulsiones/etiología , Adulto , Femenino , Humanos , Masculino , Proteínas de Transporte de Monosacáridos/genética , Mutación , FenotipoRESUMEN
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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PURPOSE: To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting. METHODS: In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety. RESULTS: Forty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were "responders" and 12 (29%) were "super-responders". Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively. CONCLUSIONS: In this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.
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Epilepsy and mental retardation limited to females (EFMR) is a genetic disorder that affects females but spares transmitting males. The condition is caused by protocadherin 19 mutations and is characterised by seizures beginning at around 1 year of age, frequently associated with cognitive regression at seizure onset or later. Seizures can be generalised or focal, exacerbated by febrile illnesses, and grouped in clusters. This report shows the first video-EEG recording of EFMR, in a 7-year-old female presenting peculiar ictal features. [Published with video sequences].
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Epilepsia , Discapacidad Intelectual , Electroencefalografía , Femenino , Humanos , Mutación , Convulsiones , Accidente CerebrovascularRESUMEN
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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A 36-year-old right-handed man, who had experienced partial seizures since the age of 24 every time he played or listened to music with a strong emotional charge, underwent videopolygraphic recording, including autonomic variables, and brain fMRI study during which he listened to both "neutral" and "emotionally charged" music. Three right temporal seizures recorded during videopolygraphic monitoring were elicited by listening to the triggering song. The fMRI study disclosed activation in right acoustic areas during "neutral music," whereas an "emotionally charged melody" provoked widespread activation over the right fronto-temporo-occipital area before seizure onset. The literature review disclosed 110 published cases of musicogenic epilepsy that seemed to suggest a right-sided predominance of the epileptogenic zone. Our results support the role of the right temporal lobe in musicogenic epilepsy and demonstrate that the cerebral areas activated during the period of strong emotion leading to the seizures encompass the auditory cortex activated by neutral music.
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Encéfalo , Epilepsia Refleja/patología , Imagen por Resonancia Magnética/métodos , Música , Grabación de Cinta de Video , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/patología , Encéfalo/fisiopatología , Mapeo Encefálico , Electroencefalografía/métodos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Oxígeno/sangreRESUMEN
We describe a 68-year-old woman who had typical absence seizures since 14 years of age. The absences were refractory to treatment and persisted into adulthood, with no seizure-free periods until seizure control at 59 years of age. After six years of being seizure-free, she presented with an episode characterized by mental confusion, abnormal behaviour, and amnesia, lasting for several hours. An EEG performed the day after, when the patient had already recovered, was unremarkable. The episode was interpreted as transient global amnesia. After two and three years, respectively, she presented with two analogous episodes lasting >24 hours. An EEG disclosed, on both occasions, subcontinuous generalized spike-and-wave discharges, consistent with absence status epilepticus (AS). The last episode occurred at 68 years of age and was successfully treated with intravenous lorazepam. After one month of follow-up, no further episodes occurred. AS is common in juvenile absence epilepsy, however, our patient showed a rather atypical course, characterized by refractory and persistent absences during adolescence and adulthood, and a tendency for AS to recur with no more absences in later life. Despite the known epilepsy history, AS episodes were initially misdiagnosed. Moreover, EEG recording and subsequent treatment were not performed until the second day of status.
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Amnesia Global Transitoria/diagnóstico , Epilepsia Tipo Ausencia/diagnóstico , Anciano , Amnesia Global Transitoria/fisiopatología , Encéfalo/fisiopatología , Diagnóstico Diferencial , Electroencefalografía , Epilepsia Tipo Ausencia/fisiopatología , Femenino , Humanos , RecurrenciaRESUMEN
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.
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OBJECTIVE: To describe the anatomo-electro-clinical findings of patients with nocturnal hypermotor seizures (NHS) preceded by auditory symptoms, to evaluate the localizing value of auditory aura. METHODS: Our database of 165 patients with nocturnal frontal lobe epilepsy (NFLE) diagnosis confirmed by videopolysomnography (VPSG) was reviewed, selecting those who reported an auditory aura as the initial ictal symptom in at least two NHS during their lifetime. RESULTS: Eleven patients were selected (seven males, four females). According to the anatomo-electro-clinical data, three groups were identified. Group 1 [defined epileptogenic zone (EZ)]: three subjects were studied with stereo-EEG. The EZ lay in the left superior temporal gyrus in two cases, whereas in the third case seizures arose from a dysplastic lesion located in the left temporal lobe. One of these three patients underwent left Heschl's gyrus resection, and is currently seizure-free. Group 2 (presumed EZ): three cases in which a presumed EZ was identified; in the left temporal lobe in two cases and in the left temporal lobe extending to the insula in one subject. Group 3 (uncertain EZ): five cases had anatomo-electro-clinical correlations discordant. CONCLUSIONS: This work suggests that auditory aura may be a helpful anamnestic feature suggesting an extra-frontal seizure origin. This finding could guide secondary investigations to improve diagnostic definition and selection of candidates for surgical treatment.
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Epilepsia del Lóbulo Frontal/complicaciones , Lóbulo Frontal/patología , Alucinaciones/etiología , Adulto , Anciano , Electroencefalografía , Epilepsia del Lóbulo Frontal/patología , Epilepsia del Lóbulo Frontal/fisiopatología , Femenino , Lóbulo Frontal/fisiopatología , Alucinaciones/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , PolisomnografíaRESUMEN
OBJECTIVES: To measure the accuracy of anamnestic features collected during clinical history for the diagnosis of nocturnal frontal lobe epilepsy (NFLE). METHODS: A case-control diagnostic study. Participants included a case group of people with ascertained target disease (NFLE group) and a control group of people with sleep disorders potentially confounding for NFLS (NOT-NFLE group), defined by means of a consensus procedure among experts (panel diagnosis as reference standard). Two major clinical patterns defining the semeiology of the epileptic event (i.e. dystonic, DP, and/or hyperkinetic pattern, HP), and 13 additional minor features were identified, formulated as questions, and telephonically administered to NFLE and NOT-NFLE groups by a trained doctor blinded to the final diagnosis. The diagnostic accuracy of each characteristic was tested against the reference standard. RESULTS: Out of 262 selected subjects, 101 were recruited; 42 were NFLE and 59 NOT-NFLE. A positive history of DP or HP had a sensitivity of 59.5% and a specificity of 91.5%, irrespective of the other minor anamnestic features. The anamnestic model improved, with a sensitivity of 59.5% and specificity of 96.6%, if at least one of the following four minor anamnestic features was added: (a) duration less than two minutes, (b) unstructured vocalization during the episode, (c) experience of an aura preceding the motor attack, and (d) a history of tonic-clonic seizures during sleep. CONCLUSIONS: The present study disclosed two major anamnestic patterns and four minor features that we called SINFLE, with unsatisfactory sensitivity but high specificity. These patterns could be the basis for developing future NFLE diagnostic criteria and to quantify the diagnostic accuracy of elements usually collected in the clinical history.