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2.
Epilepsy Behav ; : 106578, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31680025

RESUMO

OBJECTIVE: The objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH). METHODS: We reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up. RESULTS: A total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS. CONCLUSIONS: Patients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.

3.
Headache ; 59(10): 1832-1833, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31710106
4.
Neurosci Biobehav Rev ; 107: 750-764, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31626816

RESUMO

The gut-microbiota, the complex intestinal microbial ecosystem essential to health, is an emerging concept in medicine. Several studies demonstrate a microbiota-gut-brain bidirectional connection via neural, endocrine, metabolic and immune pathways. Accordingly, the gut microbiota has a crucial role in modulating intestinal permeability, to alter local/peripheral immune responses and in production of essential metabolites and neurotransmitters. Its alterations may consequently influence all these pathways that contribute to neuronal hyper-excitability and mirrored neuroinflammation in epilepsy and similarly other neurological conditions. Indeed, pre- and clinical studies support the role of the microbiome in pathogenesis, seizure modulation and responses to treatment in epilepsy. Up to now, researchers have focussed attention above all on the brain to develop antiepileptic treatments, but considering the microbiome, could extend our possibilities for developing novel therapies in the future. We provide here a comprehensive overview of the available data on the potential role of gut microbiota in the physiopathology and therapy of epilepsy and the supposed underlying mechanisms.

6.
Am J Hum Genet ; 105(4): 689-705, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31495489

RESUMO

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

7.
Seizure ; 71: 247-257, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31476531

RESUMO

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.

8.
Sci Rep ; 9(1): 13983, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562378

RESUMO

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy.

9.
Epilepsy Res ; 156: 106181, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31394400

RESUMO

Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.

10.
Expert Opin Pharmacother ; 20(17): 2115-2120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446808

RESUMO

Introduction: Atypical absences are generalized epileptic seizures typically affecting children with severe epilepsies and learning difficulties along with other seizure types. Video-EEG is essential for their diagnosis. Recently, atypical absence seizures have been reported as a hallmark of some developmental and epileptic encephalopathies.Areas covered: This is a narrative review of the literature which describes the electroclinical features of atypical seizures, the characteristics of developmental epileptic encephalopathies in which this seizure type can occur, and the evidence supporting the use of individual antiseizure drugs for the treatment of atypical absences.Expert opinion: Treatment of absence seizures typically relies on ethosuximide (ineffective against tonic-clonic seizures), valproate (associated with larger proportion of adverse events), or lamotrigine (less effective than the other two). However, unlike typical absences, atypical absences are usually intractable, persist lifetime, and their prognosis depends on the underlying etiology or associated epilepsy syndrome. Besides efficacy, other relevant factors, such as drug formulation, ease of titration and dosing, and drug interactions, should be considered. Drugs that may worsen epilepsy, cognition and behavior should be avoided. In the vast majority of patients, a polytherapy is required, although usually with limited efficacy. Finally, epilepsy syndromes featuring atypical absences require a multidisciplinary approach.

11.
Epilepsy Res ; 156: 106191, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446282

RESUMO

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ±â€¯15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2-12 mg (5.3 ±â€¯2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4-6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the 'Action myoclonus' section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

12.
Nat Commun ; 10(1): 3094, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300657

RESUMO

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de AMPA/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Lactente , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Adulto Jovem
13.
Expert Rev Neurother ; 19(10): 1037-1050, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31260640

RESUMO

Introduction: The microbiota-gut brain (MGB) axis is the bidirectional communication between the intestinal microbiota and the brain. An increasing body of preclinical and clinical evidence has revealed that the gut microbial ecosystem can affect neuropsychiatric health. However, there is still a need of further studies to elucidate the complex gene-environment interactions and the role of the MGB axis in neuropsychiatric diseases, with the aim of identifying biomarkers and new therapeutic targets, to allow early diagnosis and improving treatments. Areas covered: To review the role of MGB axis in neuropsychiatric disorders, prediction and prevention of disease through exploitation, integration, and combination of data from existing gut microbiome/microbiota projects and appropriate other International '-Omics' studies. The authors also evaluated the new technological advances to investigate and modulate, through nutritional and other interventions, the gut microbiota. Expert opinion: The clinical studies have documented an association between alterations in gut microbiota composition and/or function, whereas the preclinical studies support a role for the gut microbiota in impacting behaviors which are of relevance to psychiatry and other central nervous system (CNS) disorders. Targeting MGB axis could be an additional approach for treating CNS disorders and all conditions in which alterations of the gut microbiota are involved.

14.
Epileptic Disord ; 21(3): 271-277, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225800

RESUMO

To further characterise CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy. We describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of "honeymoon periods", as well as EEG features. The "honeymoon period", defined as a seizure-free period longer than two months, represented, in our case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the "honeymoon period", the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared between the three girls, focusing on the relationship between electroclinical features and neurological development. Our findings suggest that CDKL5 mutations likely play a direct role in psychomotor development, whereas epilepsy is one of the clinical features associated with this complex disorder.

15.
Eur J Paediatr Neurol ; 23(4): 657-661, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31176596

RESUMO

GRIN1 encodes the obligate subunit (GluN1) of glutamate N-methyl-d-aspartate receptor (NMDAr). Pathogenic variants in GRIN1 are a well-known cause of infantile encephalopathy characterized by profound developmental delay (DD), variable epileptic phenotypes, and distinctive behavioral abnormalities. Recently, GRIN1 has also been implicated in the pathogenesis of polymicrogyria (PMG). We investigated two patients presenting with severe intellectual disability (ID), epilepsy, stereotyped movements, and abnormal ocular movements. They showed distinctive circadian rhythm alterations and sleep-wake patterns anomalies characterized by recurrent cyclic crying or laughing spells. Genetic analysis led to the identification of two distinct de novo variants in GRIN1 affecting the same amino acid residue of an important functional protein domain. Recent advances in circadian rhythm and sleep regulation suggest that abnormal GluN1 function might play a relevant pathogenetic role for the peculiar behavioral abnormalities observed in GRIN1 patients. Our cases highlight the relevance of circadian rhythm abnormalities in epileptic children as a clue toward GRIN1 encephalopathy and expand the complex phenotypic spectrum of this severe genetic disorder.


Assuntos
Encefalopatias/genética , Ritmo Circadiano/genética , Epilepsia/genética , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Transtornos do Sono-Vigília/genética , Adolescente , Encefalopatias/fisiopatologia , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino
16.
Neurol Sci ; 40(9): 1775-1783, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31055731

RESUMO

BACKGROUND: Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy. METHODS: We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018. RESULTS: Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives. CONCLUSIONS: Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.

17.
Expert Opin Pharmacother ; 20(12): 1449-1456, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31099271

RESUMO

Introduction: Sodium valproate is a widely used anti-epileptic drug with a broad spectrum of activity and mechanism of action. It has consequently been the first-line drug for most seizure types in children for the past fifty years. A wide range of side effects come along with these exceptional properties, including teratogenicity and neuro-cognitive impairments in offspring. Therefore, epilepsy treatment in children and adolescents should be reassessed in light of newer antiepileptic drugs as well as a more targeted-approach with older drugs. Areas covered: The authors review the main concerns of valproate use in terms of adverse effects on different systems and drug interactions. The current alternatives to valproate in absence, myoclonic, tonic-clonic and focal onset seizures in children/adolescents are also reviewed. Expert opinion: There are several issues that research should address in antiepileptic therapy and in clinical studies with children, given the peculiarity of this population. Future perspectives in epilepsy therapy should now lead towards an individualized treatment.


Assuntos
Anticonvulsivantes/uso terapêutico , Comportamento de Escolha , Epilepsia/tratamento farmacológico , Ácido Valproico/uso terapêutico , Adolescente , Criança , Epilepsia/epidemiologia , Epilepsia Generalizada/tratamento farmacológico , Humanos , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Convulsões/tratamento farmacológico , Convulsões/epidemiologia , Ácido Valproico/efeitos adversos
19.
Epilepsy Res ; 154: 86-89, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31112901

RESUMO

BACKGROUND: Geographic isolates are the ideal setting to study the genetic background and the epidemiology of epilepsy. There are only few published reports on the epidemiology of pediatric epilepsy in geographic isolates. METHODS: This study was performed in the Ischia island, district of Napoli (Southern Italy). The local population includes 61,086 individuals, 8381 of them aged from 0 to 14 years. We included children with two or more unprovoked seizures or one unprovoked seizure associated to a high risk of relapse, observed from 2004 to 2017. Neonatal, febrile and acute symptomatic seizures were excluded. Eligible patients were identified through the local pediatricians' medical records. All probands and their parents underwent a face-to-face interview. Clinical charts were reviewed and electroclinical diagnoses were confirmed by two authors (AC, VB). RESULTS: Thirty-six children and adolescents were included. Overall, the prevalence of epilepsy in the Ischia island was 4.3 per 1,000 (95% CI 3.0-5.9). Incidence was 51.7 per 100,000 person-years (95% CI 36.2-71.6). Sixteen (44.4%) patients had a genetic (idiopathic) origin and 20 (55.6%) a symptomatic (structural/metabolic) etiology. Nine probands (25%) had at least one family member with epilepsy (including third-degree relatives). Their pedigrees were suggestive of dominant inheritance in six and of recessive inheritance in three families. CONCLUSIONS: The epidemiological features of pediatric epilepsy in this geographic isolate are similar to the general population. A family history was reported in one fourth of the patients with a wide clinical heterogeneity, likely reflecting genetic heterogeneity in this population.

20.
Epilepsia ; 60(5): 830-844, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30968951

RESUMO

OBJECTIVE: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. METHODS: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. RESULTS: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. SIGNIFICANCE: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

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