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1.
Epilepsy Behav ; 152: 109607, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38277852

RESUMEN

AIM: The current study aims to investigate the effect of Executive Functions (EFs) on Health Related Quality of Life (HRQoL) in a cohort of children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and to identify possible factors that impact HRQoL specifically related to epilepsy-related variables and EFs skills. MATERIAL AND METHOD: The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) and The Behavior Rating Inventory of Executive Function (BRIEF-2 and BRIEF-P) were completed by the parents of 129 patients with SeLECTS. Demographic variables and epilepsy-related variables were collected. RESULTS: Our sample performed in the average range across all the subscales and summary scores of the PedsQL and performed in the normal range of the BRIEF questionnaire. We observed that a lower functioning in EFs was associated with lower overall HRQoL scores. We explored the relationship between epilepsy characteristics and scores on the PedsQL. We found that the use of antiseizure medications (ASMs), longer duration of the treatment, and a higher seizure frequency were associated with a lower HRQoL. Moreover, we observed that executive dysfunction was a significant predictor of reduced HRQoL. CONCLUSION: Our results suggest the importance of the identification of patients with SeLECTS with a high level of risk for a poor HRQoL. We may now add executive dysfunction to the list of known risk factors for poor HRQoL in children with SeLECTS, along with such factors as seizure frequency, recent seizures, use of ASMs and longer duration of therapy. The early identification of children with SeLECTS at risk of a poor HRQoL could allow the activation of adequate interventions.


Asunto(s)
Disfunción Cognitiva , Epilepsia , Niño , Humanos , Función Ejecutiva/fisiología , Calidad de Vida , Epilepsia/tratamiento farmacológico , Convulsiones , Encuestas y Cuestionarios
2.
Cereb Cortex ; 33(17): 9709-9717, 2023 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-37429835

RESUMEN

The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (ρ = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed.


Asunto(s)
Espasmos Infantiles , Humanos , Espasmos Infantiles/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Convulsiones/patología , Atrofia/patología , Proteínas Serina-Treonina Quinasas/genética
3.
Epilepsia ; 64(7): e148-e155, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37203213

RESUMEN

Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between -40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.


Asunto(s)
Epilepsias Mioclónicas , Convulsiones Febriles , Cricetinae , Animales , Fluoxetina/uso terapéutico , Cricetulus , Medicina de Precisión , Mutación con Ganancia de Función , Convulsiones/genética , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/genética
4.
Epilepsia ; 64(12): e222-e228, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37746765

RESUMEN

Missense variants of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). Although variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared to wild-type, consistent with a dominant negative loss-of-function effect. Immunofluorescence staining showed that mutant channels are retained within the cell and do not reach the membrane. Moreover, mutant HCN2 also affect HCN1 channels, by reducing the Ih current expressed by the HCN1-HCN2 heteromers. Due to the persistence of frequent seizures despite pharmacological polytherapy, the patient was treated with a ketogenic diet, with a significant and long-lasting reduction of episodes. In vitro experiments conducted in a ketogenic environment demonstrated that the clinical improvement observed with this dietary regimen was not mediated by a direct action on HCN2 activity. These results expand the clinical spectrum related to HCN2 channelopathies, further broadening our understanding of the pathogenesis of DEE.


Asunto(s)
Dieta Cetogénica , Epilepsia Generalizada , Humanos , Ratas , Animales , Canales de Potasio/genética , Canales de Potasio/metabolismo , Células HEK293 , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Epilepsia Generalizada/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos
5.
Epilepsia ; 64(6): e98-e104, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37000415

RESUMEN

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.


Asunto(s)
Síndrome de Lennox-Gastaut , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Estudios Retrospectivos , Anticonvulsivantes/uso terapéutico , Resultado del Tratamiento , Convulsiones/tratamiento farmacológico
6.
Brain ; 145(9): 3274-3287, 2022 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-35769015

RESUMEN

Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.


Asunto(s)
Lisencefalia , Proteína Reelina , Adulto , Cerebelo/anomalías , Niño , Discapacidades del Desarrollo/genética , Humanos , Lisencefalia/complicaciones , Mutación , Malformaciones del Sistema Nervioso , Proteína Reelina/genética
7.
J Med Genet ; 59(4): 399-409, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34085948

RESUMEN

BACKGROUND: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes. METHODS: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters. RESULTS: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in TSEN54 and pathogenic variants in EXOSC3 accounted for 18% and 9% of cases, respectively. VLDLR, TOE1 and RARS2 were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with TSEN54 and lower motor neuron signs with EXOSC3. When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for EXOSC3. CONCLUSION: CASK represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between CASK and TSEN54-associated disorders.


Asunto(s)
Enfermedades Cerebelosas , Atrofias Olivopontocerebelosas , Enfermedades Cerebelosas/genética , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Femenino , Humanos , Masculino , Mutación/genética , Proteínas Nucleares/genética , Atrofias Olivopontocerebelosas/diagnóstico , Atrofias Olivopontocerebelosas/genética , Atrofias Olivopontocerebelosas/patología , Fenotipo
8.
Neurogenetics ; 23(1): 27-35, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34731330

RESUMEN

AMPA-type glutamate receptors (AMPARs) are postsynaptic ionotropic receptors which mediate fast excitatory currents. AMPARs have a heterotetrameric structure, variably composed by the four subunits GluA1-4 which are encoded by genes GRIA1-4. Increasing evidence support the role of pathogenic variants in GRIA1-4 genes as causative for syndromic intellectual disability (ID). We report an Italian pedigree where some male individuals share ID, seizures and facial dysmorphisms. The index subject was referred for severe ID, myoclonic seizures, cerebellar signs and short stature. Whole exome sequencing identified a novel variant in GRIA3, c.2360A > G, p.(Glu787Gly). The GRIA3 gene maps to chromosome Xq25 and the c.2360A > G variant was transmitted by his healthy mother. Subsequent analysis in the family showed a segregation pattern compatible with the causative role of this variant, further supported by preliminary functional insights. We provide a detailed description of the clinical evolution of the index subjects and stress the relevance of myoclonic seizures and cerebellar syndrome as cardinal features of his presentation.


Asunto(s)
Discapacidad Intelectual , Malformaciones del Sistema Nervioso , Estado Epiléptico , Cerebelo/anomalías , Niño , Discapacidades del Desarrollo , Humanos , Discapacidad Intelectual/genética , Masculino , Linaje
9.
Artículo en Inglés | MEDLINE | ID: mdl-35879055

RESUMEN

OBJECTIVE: To describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy. METHODS: In this retrospective observational cohort study, we enrolled patients with new-onset seizures in the context of AE. We compared clinical and paraclinical findings in patients with and without evidence of antibodies. RESULTS: Overall, 263 patients (138 females; median age 55 years, range 4-86) were followed up for a median time of 30 months (range 12-120). Antineuronal antibodies were detected in 63.50%.Antibody-positive patients had multiple seizure types (p=0.01) and prevalent involvement of temporal regions (p=0.02). A higher prevalence of episodes of SE was found in the antibody-negative group (p<0.001).Immunotherapy was prescribed in 88.60%, and effective in 61.80%. Independent predictors of favourable outcome of the AE were early immunotherapy (p<0.001) and the detection of antineuronal surface antibodies (p=0.01).Autoimmune-associated epilepsy was the long-term sequela in 43.73%, associated with cognitive and psychiatric disturbances in 81.73%. Independent predictors of developing epilepsy were difficult to treat seizures at onset (p=0.04), a high number of antiseizure medications (p<0.001), persisting interictal epileptiform discharges at follow-up (p<0.001) and poor response to immunotherapy during the acute phase (p<0.001). CONCLUSIONS: The recognition of seizures secondary to AE represents a rare chance for aetiology-driven seizures management. Early recognition and treatment at the pathogenic level may reduce the risk of long-term irreversible sequelae. However, the severity of seizures at onset is the major risk factor for the development of chronic epilepsy.This study provides class IV evidence for management recommendations.

10.
Neurol Sci ; 42(7): 2637-2644, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33929645

RESUMEN

BACKGROUND: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. METHODS: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. RESULTS: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. CONCLUSIONS: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.


Asunto(s)
COVID-19 , Telemedicina , Adulto , Niño , Humanos , Italia/epidemiología , Pandemias , Derivación y Consulta , SARS-CoV-2
11.
Eur J Nucl Med Mol Imaging ; 47(6): 1576-1584, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31858178

RESUMEN

PURPOSE: To describe cerebral glucose metabolism pattern as assessed by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of progressive myoclonus epilepsy caused by biallelic mutations in EPM2A or NHLRC1. METHODS: We retrospectively included patients with genetically confirmed LD who underwent FDG-PET scan referred to three Italian epilepsy centers. FDG-PET images were evaluated both visually and using SPM12 software. Subgroup analysis was performed on the basis of genetic and clinical features employing SPM. Moreover, we performed a systematic literature review of LD cases that underwent FDG-PET assessment. RESULTS: Eight Italian patients (3M/5F, 3 EPM2A/5 NHLRC1) underwent FDG-PET examination after a mean of 6 years from disease onset (range 1-12 years). All patients showed bilateral hypometabolic areas, more diffuse and pronounced in advanced disease stages. Most frequently, the hypometabolic regions were the temporal (8/8), parietal (7/8), and frontal lobes (7/8), as well as the thalamus (6/8). In three cases, the FDG-PET repeated after a mean of 17 months (range 7-36 months) showed a metabolic worsening compared with the baseline examination. The SPM subgroup analysis found no significant differences based on genetics, whereas it showed a more significant temporoparietal hypometabolism in patients with visual symptoms compared with those without. In nine additional cases identified from eight publications, FDG-PET showed heterogeneous findings, ranging from diffusely decreased cerebral glucose metabolism to unremarkable examinations in two cases. CONCLUSIONS: FDG-PET seems highly sensitive to evaluate LD at any stage and may correlate with disease progression. Areas of decreased glucose metabolism in LD are extensive, often involving multiple cortical and subcortical regions, with thalamus, temporal, frontal, and parietal lobes being the most severely affected. Prospective longitudinal collaborative studies are needed to validate our findings.


Asunto(s)
Fluorodesoxiglucosa F18 , Enfermedad de Lafora , Encéfalo/diagnóstico por imagen , Humanos , Enfermedad de Lafora/diagnóstico por imagen , Enfermedad de Lafora/genética , Tomografía de Emisión de Positrones , Estudios Prospectivos , Estudios Retrospectivos , Ubiquitina-Proteína Ligasas
12.
Epilepsia ; 61(11): 2474-2485, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33063863

RESUMEN

OBJECTIVE: Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder. METHODS: We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients. RESULTS: All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3 years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12 years, 60% become seizure-free; in the following years, up to age 18 years, 57% were seizure-free. After the age of 18 years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients. SIGNIFICANCE: Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.


Asunto(s)
Encefalopatías/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Simportadores/genética , Adolescente , Encefalopatías/diagnóstico , Encefalopatías/fisiopatología , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/fisiopatología , Electroencefalografía/tendencias , Epilepsia/diagnóstico , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Adulto Joven
13.
Epilepsia ; 61(2): 216-227, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31876960

RESUMEN

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.


Asunto(s)
Epilepsia/cirugía , Neurocirugia/tendencias , Procedimientos Neuroquirúrgicos/tendencias , Adolescente , Factores de Edad , Niño , Preescolar , Electroencefalografía , Epilepsia/epidemiología , Epilepsia/patología , Europa (Continente)/epidemiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neurocirugia/estadística & datos numéricos , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Estudios Retrospectivos , Convulsiones/epidemiología , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/cirugía , Resultado del Tratamiento
14.
Pharmacol Res ; 160: 105200, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32942014

RESUMEN

De novo variants in KCNQ2 encoding for Kv7.2 voltage-dependent neuronal potassium (K+) channel subunits are associated with developmental epileptic encephalopathy (DEE). We herein describe the clinical and electroencephalographic (EEG) features of a child with early-onset DEE caused by the novel KCNQ2 p.G310S variant. In vitro experiments demonstrated that the mutation induces loss-of-function effects on the currents produced by channels incorporating mutant subunits; these effects were counteracted by the selective Kv7 opener retigabine and by gabapentin, a recently described Kv7 activator. Given these data, the patient started treatment with gabapentin, showing a rapid and sustained clinical and EEG improvement over the following months. Overall, these results suggest that gabapentin can be regarded as a precision therapy for DEEs due to KCNQ2 loss-of-function mutations.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Gabapentina/uso terapéutico , Canal de Potasio KCNQ2/genética , Edad de Inicio , Animales , Células CHO , Carbamatos/uso terapéutico , Células Cultivadas , Niño , Cricetinae , Cricetulus , Electroencefalografía , Femenino , Humanos , Mutación , Fenilendiaminas/uso terapéutico , Medicina de Precisión , Ratas , Resultado del Tratamiento
16.
Brain ; 141(11): 3160-3178, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30351409

RESUMEN

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.


Asunto(s)
Epilepsia Generalizada/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Mutación/genética , Canales de Potasio/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Anciano , Animales , Células CHO , Niño , Preescolar , Cricetulus , Estimulación Eléctrica , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Potenciales de la Membrana/genética , Persona de Mediana Edad , Modelos Moleculares , Mutagénesis Sitio-Dirigida/métodos , Adulto Joven
17.
Epilepsy Behav ; 98(Pt A): 273-278, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31419648

RESUMEN

OBJECTIVES: The objective of this study was to investigate several clinical electroencephalogram (EEG) findings possibly predicting the early response to antiepileptic drugs (AEDs) and the late outcome in children with clinical EEG features fitting the syndromic diagnosis of childhood absence epilepsy (CAE). METHODS: In 117 untreated patients with typical absences, we analyzed clinical EEG features, and resting EEG activity using partial directed coherence to calculate out- and inflow of cortical oscillations in different regions of interest. RESULTS: Absences began before 4 years in 12.0%, at 4-9.5 years in 71.8%, and at 10-13 years in 16.2% of the cases. Valproate was started in 91 patients and ethosuximide in 27. With one of AEDs, 77.8% reached seizure control, while the remaining patients needed to switch to the alternative AED. Only 5.9% patients remained drug-resistant. Absences with simple automatisms were the only feature associated with a lack of response to the first AED. Connectivity analysis of resting EEGs showed increased frontal outflow in patients compared with controls, which was significantly greater in the nonresponders to the first AED than in responders. Among the 91 patients followed for 61.2 ±â€¯31.7 months, 14.2% relapsed after a seizure-free period, without differences between the responders to the first or second AED. CONCLUSIONS: The assessment of electroclinical features provided only minimal prognostic indices. The enhanced outflow of frontal oscillations suggests a circuitry dysfunction significantly greater in the nonresponder to the early treatment. Seizure relapses were rare and comparable in patients who reached seizure freedom with first or second AED, indicating that the resistance to one AED does not influence the outcome.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Electroencefalografía/tendencias , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/fisiopatología , Adolescente , Niño , Preescolar , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/diagnóstico , Etosuximida/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Recurrencia , Resultado del Tratamiento , Ácido Valproico/uso terapéutico
18.
Dev Med Child Neurol ; 61(9): 1101-1107, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31175679

RESUMEN

AIM: To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD: This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. RESULTS: Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo-18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2-4). Time to first relapse was median 31.5 months (range 7-89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2-4, vs median mRS 5, range 3-5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046-0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0-1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14-137mo) than in monophasic patients (median 32mo, range 4-108mo; p=0.002). INTERPRETATION: Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. WHAT THIS PAPER ADDS: Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.


Asunto(s)
Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Italia , Masculino , Recurrencia , Estudios Retrospectivos , Factores de Riesgo
19.
Neurobiol Dis ; 118: 55-63, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29936235

RESUMEN

The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C > G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.


Asunto(s)
Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Mutación/genética , Neuronas/fisiología , Canales de Potasio/genética , Potenciales de Acción/fisiología , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Epilepsia Generalizada/fisiopatología , Femenino , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/química , Masculino , Linaje , Canales de Potasio/química , Estructura Secundaria de Proteína , Ratas , Adulto Joven
20.
Epilepsia ; 59(12): 2260-2271, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30451291

RESUMEN

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.


Asunto(s)
Cadherinas/genética , Síndromes Epilépticos/genética , Síndromes Epilépticos/terapia , Adolescente , Adulto , Edad de Inicio , Trastorno Autístico/complicaciones , Trastorno Autístico/psicología , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/psicología , Masculino , Fenotipo , Protocadherinas , Estudios Retrospectivos , Convulsiones , Resultado del Tratamiento , Adulto Joven
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