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OBJECTIVE: We explored the efficacy and safety of lacosamide combined with inhibitors of fast-inactivated sodium channels or with other antiepileptic drugs, in patients with drug refractory focal epilepsy associated with intellectual or psychiatric disability. METHODS: Observational study of lacosamide including the monitoring of lacosamide trough plasma levels and of electroencephalograms. RESULTS: We followed up 44 patients from the start of lacosamide therapy for up to 3â¯years, with a clinical, electroencephalogram (EEG), and pharmacological follow-up. Median patients' age was 32.7â¯years, median age at epilepsy onset was 3.5â¯years. Intellectual disability was severe in 55.4% of the cohort and drug refractoriness was diagnosed in 88.6% of patients, who had predominantly focal seizures (80%). The severity of their epilepsy was suggested by the use of combined therapies with non-sodium blockers and sodium blockers in 75% of patients. Lacosamide was added to previous therapies and up-titrated to a median of 300â¯mg/d. Lacosamide add-on led to simplification of the previous drug regimen with a dose reduction in 87.9% of users of sodium blockers and in 66.7% of users of non-sodium blockers, and to withdrawal of previously administered sodium blockers in 48.5% users and non-sodium blockers in 47.6% users. Lacosamide was prescribed at lower doses in the presence of oxcarbazepine (pâ¯=â¯0.029), lamotrigine (pâ¯=â¯0.015), and topiramate (pâ¯<â¯0.001). Mean lacosamide plasma levels were 6.0⯱â¯2.4â¯mg/L; they were in linear correlation with the administered dose (R2â¯=â¯0.38, pâ¯<â¯0.001) and were influenced by the association with lamotrigine (pâ¯=â¯0.008), zonisamide (pâ¯=â¯0.012), and clobazam (pâ¯=â¯0.028). Lacosamide combination regimens led to an average reduction of 42% in baseline seizure frequency, with 50% patients reporting ≥50% seizure frequency reduction. Efficacy was directly correlated with lacosamide dose (R2â¯=â¯0.47, pâ¯<â¯0.001, Bâ¯=â¯0.53) and trough plasma levels (R2â¯=â¯0.31, pâ¯<â¯0.001, Bâ¯=â¯0.16). Electroencephalogram profiles were improved in 40.9% of patients and EEG improvement was not significantly correlated with seizure frequency reduction. Lacosamide safety was good, with 37 adverse reactions in 30 patients, of which 50% were attributed to lacosamide and led to lacosamide withdrawal in 18% of cases. The retention rate of lacosamide was of 88.6% at 1â¯year, 86.4% at 2â¯years, and 72.7% after three years. The severity of intellectual disability was directly correlated with increased possibility of lacosamide retention (ORâ¯=â¯0.46 per severity tier, pâ¯=â¯0.016). CONCLUSION: Lacosamide add-on allowed dose reduction of previous therapies and reduced the frequency of seizures, showing good tolerability even at high doses, without exceeding reference plasma levels.
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Epilepsia Resistente a Medicamentos , Epilepsia , Adulto , Anticonvulsivantes/efeitos adversos , Epilepsia Resistente a Medicamentos/induzido quimicamente , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Humanos , Lacosamida/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population. METHODS: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1â¯=â¯0-4; t2â¯=â¯5-12; t3â¯=â¯>13â¯years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed. RESULTS: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5â¯years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4⯱â¯2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2⯱â¯0.9 SD); no one had absences before 6 and over 16â¯years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (pâ¯=â¯0.002) and a reduction during adolescence (pâ¯=â¯0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13â¯years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam. CONCLUSIONS: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.
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PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fácies , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
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Encéfalo/diagnóstico por imagem , Doença de Hirschsprung/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Imageamento por Ressonância Magnética , Microcefalia/diagnóstico por imagem , Neuroimagem , Encéfalo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/patologia , Fácies , Feminino , Genótipo , Haploinsuficiência , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Estudos Longitudinais , Masculino , Microcefalia/genética , Microcefalia/patologia , Fenótipo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.
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Doença de Hirschsprung/fisiopatologia , Deficiência Intelectual/fisiopatologia , Microcefalia/fisiopatologia , Convulsões/fisiopatologia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Fácies , Feminino , Doença de Hirschsprung/tratamento farmacológico , Doença de Hirschsprung/genética , Proteínas de Homeodomínio/genética , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Masculino , Microcefalia/tratamento farmacológico , Microcefalia/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Convulsões/genética , Ácido Valproico/uso terapêutico , Adulto Jovem , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
PURPOSE: Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern. METHODS: Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed. KEY FINDINGS: We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic-clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature. SIGNIFICANCE: Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients.
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Ondas Encefálicas/fisiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Genes Duplicados/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) is a rare disease linked to mutations of the CSNK2B gene, which encodes for a subunit of caseinkinase CK2 involved in neuronal growth and synaptic transmission. Its main features include early-onset epilepsy and intellectual disability. Despite the lack of cases described, it appears that POBINDS could manifest with a wide range of phenotypes, possibly related to the different mutations of CSNK2B. METHODS: Our multicentric, retrospective study recruited nine patients with POBINDS, detected using next-generation sequencing panels and whole-exome sequencing. Clinical, laboratory, and neuroimaging data were reported for each patient in order to assess the severity of phenotype, and eventually, a correlation with the type of CSNK2B mutation. RESULTS: We reported nine unrelated patients with heterozygous de novo mutations of the CSNK2B gene. All cases presented epilepsy, and eight patients were associated with a different degree of intellectual disability. Other features detected included endocrinological and vascular abnormalities and dysmorphisms. Genetic analysis revealed six new variants of CSNK2B that have not been reported previously. CONCLUSION: Although it was not possible to assess a genotype-phenotype correlation in our patients, our research further expands the phenotype spectrum of POBINDS patients, identifying new mutations occurring in the CSNK2B gene.
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Epilepsia , Deficiência Intelectual , Criança , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Humanos , Deficiência Intelectual/genética , Fenótipo , Estudos Retrospectivos , SíndromeRESUMO
Pathogenic variants of the SCN2A gene (MIM 182390) are associated with several epileptic syndromes ranging from benign familial neonatal-infantile seizures (BFNIS) to early infantile epileptic encephalopathy. The aim of this work was to describe clinical features among five patients with concomitant SCN2A gene variants and cryptogenic epileptic syndromes, thus expanding the SCN2A spectrum of phenotypic heterogeneity. De novo variants were identified in four patients, while one inherited variant was identified in a patient with an unaffected carrier biological father with somatic mosaicism. Two of five patients were diagnosed with a neonatal epileptic encephalopathy. The remaining three patients manifested a focal epileptic syndrome associated with autistic spectrum disorders (ASD) or with a variable degree of intellectual disability (ID), one of them displaying a hitherto unreported atypical late onset epilepsy. Overall, the pattern of clinical manifestations among these patients suggest that any observed neurological impairment may not be directly related to the severity of the electroclinical pattern, but instead likely associated with the mutation itself. Moreover, our results highlight the importance of SCN2A mutational screening in cases of ID/ASD with or without epilepsy.
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PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency. METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy". RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms. CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.
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Epilepsias Mioclônicas , Epilepsia , Deficiência Intelectual , Fatores de Transcrição MEF2 , Eletroencefalografia , Epilepsia/genética , Haploinsuficiência , Humanos , Deficiência Intelectual/genética , Fatores de Transcrição MEF2/genética , ConvulsõesRESUMO
BACKGROUND: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6). OBJECTIVE: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation. PATIENTS AND METHODS: A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects. RESULTS: A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed. CONCLUSIONS: This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.
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Canais de Cálcio/genética , Mutação/fisiologia , Doenças do Sistema Nervoso/genética , Idade de Início , Sequência de Aminoácidos , Encéfalo/patologia , Córtex Cerebral/patologia , Criança , Análise Mutacional de DNA , Eletrodiagnóstico , Eletroencefalografia , Potenciais Evocados/fisiologia , Éxons/genética , Feminino , Quarto Ventrículo/patologia , Humanos , Enxaqueca com Aura/etiologia , Enxaqueca com Aura/genética , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Linhagem , Ataxias Espinocerebelares/etiologia , Ataxias Espinocerebelares/genéticaRESUMO
OBJECTIVE: The aim of this study was to evaluate the epileptic and developmental evolution in infants with West syndrome. METHODS: A prospective study of 21 infants was performed, with a follow-up at 2 years. Serial assessment included long-term EEG monitoring, visual and auditory evaluation and assessment of neurodevelopment. RESULTS: Neurosensory and developmental impairments at the spasm onset were transitory in seven cases, including four cryptogenic forms. In all other cases, there was a progressive worsening in neurosensory and developmental impairments. The epileptic evolution was generally better: in 11 of the 16 infants without seizures at outcome, spasms had already disappeared by 2 months after disease onset. Statistic analysis of results showed a correlation between neurosensory impairment and development throughout the whole follow-up. In addition, visual function at T1 resulted significant predictor of developmental outcome. Among the epileptic features, disorganization of slow sleep was an unfavorable prognostic factor. CONCLUSION: Some forms of West syndrome are confirmed to have a benign evolution: among them there are not only cryptogenic cases but also symptomatic ones without significant neurodevelopmental impairment. Abnormalities of sleep organization, expression of the pervasive epileptic disorder, seem to play a role in determining a developmental deterioration. Neurosensory impairment since the onset of the disease could be a relevant cause of the developmental disorder.
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Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/fisiopatologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/fisiopatologia , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/etiologia , Avaliação da Deficiência , Progressão da Doença , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Exame Neurológico , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia , Espasmos Infantis/complicações , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologiaRESUMO
AIM: Mowat-Wilson Syndrome (MWS) is a genetic rare disease. Epilepsy is present in 70-75% of Patients and an age-dependent electroclinical pattern has been described. Up to date, there are studies with overnight sleep EEGs, probably because of the severe intellectual disability (ID) and hyperactivity of these Patients. Our purpose was to verify the hypothesis that MWS Patients might have electrical status epilepticus in slow wave sleep (ESES pattern). METHODS: A retrospective analysis of anamnestic and electrographic data was performed on 7 consecutive MWS Patients followed between 2007 and 2016. Only Patients with at least one overnight sleep EEG were included in the study. RESULTS: Five out of 7 Patients had overnight sleep EEG studies and were included in this study. All of them had an anterior ESES pattern with spike-and-wave index>85%. The architecture of sleep was abnormal. An ESES related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) Patients. In two Patients marked improvement of cognitive and motor performances was observed when the epileptiform activity during sleep was successfully controlled or it was spontaneously reduced. CONCLUSIONS: The clinical significance of the ESES pattern is hard to assess in MWS Patients due to severe ID, but changing in behaviour or in motor and cognitive functions should mandate sleep EEG investigation and, if ESES is present, an appropriate treatment should be tried. Furthermore, overnight sleep EEG recordings, if regularly performed in the follow up, might help to understand if ESES pattern hampers the cognitive and communicative profile in MWS.
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Doença de Hirschsprung/complicações , Deficiência Intelectual/complicações , Microcefalia/complicações , Sono/fisiologia , Estado Epiléptico/etiologia , Adolescente , Adulto , Criança , Eletroencefalografia , Fácies , Feminino , Doença de Hirschsprung/diagnóstico por imagem , Humanos , Deficiência Intelectual/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Testes Neuropsicológicos , Estudos Retrospectivos , Estado Epiléptico/diagnóstico por imagem , Vigília/fisiologiaRESUMO
We report on a child, aged 47/12 years, with borderline intelligence quotient, normal brain magnetic resonance imaging, and focal epilepsy. The polysomnographic electroencephalogram recording revealed asynchronous central spikes at both brain hemispheres resembling the features observed in focal idiopathic epileptic syndromes. Array comparative genomic hybridization analysis revealed a 32-kb partial deletion of the DEP domain-containing protein 5 (DEPDC5) gene, involved in a wide spectrum of inherited focal epileptic syndromes. The parental origin of the deletion could not be fully ascertained because the pregnancy had been achieved through anonymous egg donation and insemination by intracytoplasmic sperm injection. However, we demonstrate that the deletion, shared by all alternatively spliced isoforms of DEPDC5, produces a transcript presumably generating a DEPDC5 protein missing the entire DEP domain. Our findings suggest that partial deletion of DEPDC5 may be sufficient to cause the focal epilepsy in our patient, highlighting the importance of the DEP domain in DEPDC5 function. This study expands the phenotypic spectrum of DEPDC5 to sporadic forms of focal idiopathic epilepsy and underscores the fact that partial deletions, albeit probably very rare, are part of the genetic spectrum of DEPDC5 mutations.
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BACKGROUND: After traumatic brain injury, epilepsy affects up to 20 % of children. It is a risk factor, for both clinical recovery and cognitive performance; therefore pharmacological therapy is advisable. Current guidelines recommend prophylaxis to be initiated as soon as possible and tapered 1 week after trauma. However, no guideline exists for paediatric patients and the clinical practice is heterogeneous. OBJECTIVE: In our institute, prophylaxis was routinely tapered 6 months after trauma. Therefore we investigated whether this prophylaxis or its tapering influenced the development of post-traumatic epilepsy, together with several clinical-demographic factors. METHODS: The study population comprised all patients with post-traumatic brain injury referred to this institute between 2002 and 2009 who consented to participate. Clinical, epileptological and pharmacological data were collected. The role of prophylaxis and several other predictors on occurrence of post-traumatic epilepsy was analysed through logistic regressions. RESULTS: Two hundred and three patients (145 paediatric) were followed for 57 months on average. Risk factors for epilepsy were past neurosurgery [odds ratio (OR) = 2.61, 95 % confidence interval (CI) 1.15-5.96], presence of epileptiform anomalies (OR = 6.92, 95 % CI 3.02-15.86) and the presence of prophylaxis (OR = 2.49, 95 % CI 1.12-5.52), while higher intelligence quotient (IQ) was protective (OR = 0.96, 95 % CI 0.95-0.98). While evaluating possible different effects within and after 6 months (tapering, for those under prophylaxis), we found that epileptiform anomalies (OR = 7.61, 95 % CI 2.33-24.93, and OR = 8.21, 95 % CI 3.00-22.44) and IQ (OR = 0.96, 95 % CI 0.94-0.98, and OR = 0.97, 95 % CI 0.95-0.98) were always significant predictors of epilepsy, while neurosurgery (OR = 4.38, 95 % CI 1.10-17.45) was significant only within 6 months from trauma, and prophylaxis (OR = 3.98, 95 % CI 1.62-9.75) only afterwards. CONCLUSIONS: These results suggest that prophylaxis was irrelevant when present; furthermore its tapering increased the risk of epilepsy. Since the presence of epileptiform anomalies was the main predictor of post-traumatic epilepsy, such anomalies may be useful to better direct the choice of prophylaxis.
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Anticonvulsivantes/uso terapêutico , Epilepsia Pós-Traumática/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
To provide an estimate of the occurrence of misdiagnosis in paroxysmal events in institutionalized children with severe disabilities and refractory epilepsy. A multi-step diagnostic survey, from observational to long-term video-EEG monitoring was performed in 46 severe disabled children. Multirater Kappa statistic was used to assess agreement between investigators and to individualize children who remained with dubious events. Subsequently, prolonged EEG-video monitoring analysis was performed in selected children to define phenomena due to seizures. A total of 128 video records were performed, 64 routine video-EEG and 27 long-monitoring video-EEG data were screened for detailed analysis. Thirty (21 female, 9 male) children (65%) with dubious seizures were identified by video records (concordance K=0.63). Of these, in 18 children (39%) seizures were excluded by routine video-EEG monitoring (K=0.86). Twelve children (26%) required accurate investigations with long-term video-EEG. In 5 children (11%), 3 symptomatic and 2 cryptogenic, very short and subtle seizures were confirmed by investigators concordance (K=0.83). Distinguishing paroxysmal phenomena is a challenge in children with severe disabilities; its most remarkable consequence is inappropriate pharmacological treatment and social costs. Our data suggest that the frequency of misdiagnosis could have been underestimated. The clinicians who manage children with severe disabilities and refractory epilepsy must remain alert to risk of an incorrect treatment.
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BACKGROUND: Sodium channel alpha 1 subunit gene, SCN1A, is the gene encoding the neuronal voltage-gated sodium channel alpha 1 subunit (Na(v)1.1) and is mutated in different forms of epilepsy. Mutations in this gene were observed in more than 70% of patients with severe myoclonic epilepsy of infancy (SMEI) and were also found in different types of infantile epileptic encephalopathy. OBJECTIVE: To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause). DESIGN: Clinical characterization and molecular genetic analysis of a cohort of patients. SETTING: University hospitals, rehabilitation centers, and molecular biology laboratories. PATIENTS: Sixty unrelated patients with cryptogenic epileptic syndromes. MAIN OUTCOME MEASURES: Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening. RESULTS: No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative. CONCLUSIONS: These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.
Assuntos
Análise Mutacional de DNA , Epilepsia/genética , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Deleção Cromossômica , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/genética , Epilepsia/diagnóstico , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Feminino , Seguimentos , Triagem de Portadores Genéticos , Genótipo , Humanos , Lactente , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1 , Fenótipo , Mutação Puntual , Convulsões Febris/diagnóstico , Convulsões Febris/genéticaRESUMO
The aim of this study was to evaluate cognitive development at the onset of West syndrome (WS) with regard to electroencephalogram (EEG) patterns and visual function. Twenty-five patients (14 males, 11 females) at the onset of spasms (T0) in WS and 2 months later (T1) underwent a full clinical evaluation, including neuroimaging, cognitive assessment, video-EEG, and visual function. Mean age of the patients at spasm onset was 5.9 months (SD 2.5; range 2 to 13mo). Cognitive development, assessed with Griffiths Mental Development Scales (GMDS), was generally impaired at T0 and was significantly related to visual function (p<0.001) at both T0 and T1. In general, there was a specific major impairment in the eye-hand coordination scale of the GMDS which tended to disappear after 2 months in less severe cases. At the onset of spasms, sleep EEG organization seemed to be better related to cognitive abilities than awake hypsarrhythmia. These results support a close link between visual function and cognitive competence in WS and provide additional information to improve the understanding of possible mechanisms underlying cognitive impairment.
Assuntos
Transtornos Cognitivos/etiologia , Espasmos Infantis/complicações , Transtornos da Visão/etiologia , Desenvolvimento Infantil , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Transtornos das Habilidades Motoras , Psicometria , Índice de Gravidade de Doença , Espasmos Infantis/fisiopatologia , Espasmos Infantis/psicologiaRESUMO
PURPOSE: Several studies have reported behavioral and electrophysiological evidence of visual impairment during the active stage of West syndrome. The underlying mechanisms are, however, poorly understood, and little has been reported about the correlation between visual impairment, EEG patterns, and brain lesions. The aim of the study was to assess visual function at the onset of spasm and 2 months thereafter and relate visual findings to brain lesions and EEG features. METHODS: Twenty-five infants with West syndrome were enrolled and studied with (a) a full clinical assessment including a battery of tests specifically designed to assess visual function, (b) a video-polygraphic study, and (c) brain magnetic resonance imaging (MRI). Besides brain neuroimaging and EEG comparison with visual function, an intra-EEG analysis was performed to investigate the possible relation of EEG patterns to fluctuating visual behavior (fixation and following). RESULTS: Twenty-two children had at least one abnormal result on one or more of the tests assessing visual function at T0. Visual impairment at the spasm onset was related to the sleep disorganization rather than to the hypsarrhythmic pattern in awake EEG. After 2 months, both EEG features become significantly linked to visual function. Visual function improved in several cases after 2 months, in parallel with the seizure regression. No relation was found between EEG patterns and fluctuating visual behavior. CONCLUSIONS: The study supplies new evidence of the involvement of visual function in West syndrome. The presence of abnormal visual findings in infants without lesions on brain MRI suggests that visual abnormalities are due not only to brain injury but also to epileptic disorder per se. New insight is also provided into the possible mechanisms underlying clinical and EEG abnormalities.