RESUMO
PURPOSE: This multicenter study aimed to evaluate the efficacy and tolerability of add-on cannabidiol (CBD) in treatment-resistant patients with epilepsy with myoclonic-atonic seizures (EMAtS) (n = 22) and Sturge Weber syndrome (SWS) with myoclonic-atonic seizures (n = 4). METHODS: Patients who met the diagnostic criteria of treatment-resistant EMAtS or SWS with myoclonic-atonic seizures were included. Cannabidiol was added in doses ranging from 8 to 40 mg/kg/day. Efficacy was assessed by comparing seizure frequency before and after initiating CBD therapy. Neurologic examinations, brain magnetic resonance imaging, repeated prolonged electroencephalography (EEG) and/or video-EEG recordings, and neurometabolic studies were performed in all patients, and genetic investigations in 15. RESULTS: After a mean follow-up of 19 months, 15/26 patients (57.7%) who received add-on CBD had a >50% seizure decrease; three (11.5%) became seizure-free. The remaining 11 patients (42.3%) had a 25-50% seizure reduction. Drop attacks, including myoclonic-atonic seizures and generalized tonic-clonic seizures, as well as atypical absences and nonconvulsive status epilepticus responded well to CBD. In SWS patients, focal motor seizures without consciousness impairment and focal non-motor seizures with consciousness impairment were recognized in two each; in three a 30% reduction of focal seizures was observed. Side effects were mild and did not lead to CBD discontinuation. CONCLUSION: This study evaluating the use of add-on CBD in children with EMAtS or SWS with myoclonic-atonic seizures found that 15/26 (57.7%) had a >50% seizure reduction with good tolerability; three (11.5%) became seizure-free.
Assuntos
Canabidiol , Epilepsias Mioclônicas , Epilepsia Generalizada , Humanos , Criança , Canabidiol/uso terapêutico , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/diagnóstico , Convulsões/complicações , Convulsões/tratamento farmacológico , Convulsões/diagnóstico , Epilepsia Generalizada/tratamento farmacológico , Encéfalo/diagnóstico por imagem , EletroencefalografiaRESUMO
OBJECTIVE: Epilepsy with myoclonic absences is a rare epilepsy syndrome with distinct features and high rates of drug resistance. Identifying this syndrome may help guide treatment decisions. We highlight clinical heterogeneity in this case series and two cases in which corpus callosotomy was performed. METHODS: Medical records were reviewed between 2017 and 2021 to identify demographics, comorbidities, age at onset, EEG findings, diagnostic evaluations, seizure semiologies, seizure frequency, anti-seizure medications, diet therapy and surgical treatments in patients with myoclonic absences. RESULTS: Ten patients were identified including twins with myoclonic absence status epilepticus. Forty percent had an atonic component, 20% presented with myoclonic absence status epilepticus and 60% had incomplete control of seizures at last follow-up visit. Two patients with epilepsy with myoclonic absences with atonia underwent corpus callosotomy; one patient was seizurefree eight months after surgery and the other had greater than 50% seizure reduction over a five-month period. SIGNIFICANCE: Phenotypic heterogeneity was evident based on seizure semiologies, comorbidities, seizure frequency and response to anti-seizure medications and non-medication treatments. Of patients with an atonic component, 75% did not achieve seizure freedom with medication alone. Corpus callosotomy was performed in two of these patients with encouraging seizure response thus far, however, the efficacy of this treatment should be further evaluated in a larger study.
Assuntos
Epilepsias Mioclônicas , Epilepsia , Estado Epiléptico , Idade de Início , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/cirurgia , Epilepsia/cirurgia , Humanos , Resultado do TratamentoRESUMO
Lafora disease is a severe form of progressive myoclonic epilepsy with autosomal recessive inheritance diagnosed by inclusion body in biopsy. A 26-year-old woman was admitted due to complaints of frequent twitches and fainting. The 0.5x0.3x0.3 cm axillary skin punch biopsy was subjected to routine histopathological evaluation. Cytoplasmic PAS-positive inclusion bodies were observed at the basal side of the eccrine and apocrine glands. The diagnosis of Lafora disease can also be made by the observation of the polyglycosan cytoplasmic inclusion bodies in the brain, liver and skeletal muscle biopsies. Although we need more work to understand the etiopathogenesis of Lafora disease, we would like to draw attention to the importance of skin biopsy in the differential diagnosis of young patients with clinically refractory epilepsy, myoclonus, and cognitive decline.
Assuntos
Epilepsias Mioclônicas/diagnóstico , Doença de Lafora/diagnóstico , Pele/patologia , Adulto , Biópsia , Epilepsias Mioclônicas/patologia , Feminino , Humanos , Doença de Lafora/genética , Microscopia EletrônicaRESUMO
A 38-year-old woman presented with a history of recurrent episodes of transient loss of consciousness (TLOC) with seizure-like activity and post-TLOC left sided paresis. Electroencephalogram and MRI of the brain were normal, and events were not controlled by anti-convulsant therapy. Tilt testing produced reflex mixed pattern vasovagal syncope, with exact symptom reproduction, including bilateral upper and lower limb myoclonic movements and post-TLOC left hemiparesis that persisted for 27 min. A witness for the tilt event confirmed reproduction of patients 'typical' TLOC event. Syncope is the most frequent cause of TLOC. Myoclonic movements during syncope are not uncommon and can be misdiagnosed as epilepsy. It is rare to experience paresis after syncope, which in this case, lead to misdiagnosis and unnecessary anti-convulsant treatment.
Assuntos
Eletroencefalografia/métodos , Epilepsias Mioclônicas/diagnóstico , Paralisia/diagnóstico , Educação de Pacientes como Assunto/métodos , Síncope Vasovagal , Teste da Mesa Inclinada , Adulto , Determinação da Pressão Arterial/métodos , Diagnóstico Diferencial , Feminino , Frequência Cardíaca/fisiologia , Humanos , Administração dos Cuidados ao Paciente/métodos , Síncope Vasovagal/diagnóstico , Síncope Vasovagal/fisiopatologia , Síncope Vasovagal/terapia , Teste da Mesa Inclinada/efeitos adversos , Teste da Mesa Inclinada/métodos , Inconsciência/diagnóstico , Inconsciência/etiologiaRESUMO
Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.
Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Dioxolanos/uso terapêutico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Testes Genéticos , Criança , HumanosRESUMO
Las encefalopatías epilépticas es un grupo de síndromes epilépticos caracterizados por el deterioro cognitivo más allá de lo esperado debido a la actividad epiléptica. Se caracterizan por presentar resistencia farmacológica grave, electroencefalogramas profundamente anormales, inicio en la niñez temprana, deterioro neurocognitivo, fenotipo variable y resonancia magnética de cerebro usualmente normal. Frecuentemente estos síndromes están genéticamente determinados. Su diagnóstico correcto y oportuno puede contribuir y guiar el consejo médico y terapia adecuada, influyendo así en el pronóstico a corto, mediano y largo plazo. En este artículo se revisan los hallazgos electroencefalográficos, genéticos y opciones terapéuticas más recomendadas, facilitando así la conducta clínica. Las encefalopatías epilépticas incluidas en este artículos abarcan los síndromes de Ohtahara, encefalopatia mioclónica temprana, epilepsia focal migratoria de la infancia, West, Dravet, estado mioclónico en encefalopatías no progresivas, Doose, Lennox-Gastaut, Landau-Kleffner y epilepsia con espiga-onda continuas durante el sueño de onda lenta.
Epileptic encephalopathies is a group of epileptic syndromes characterized by progressive cognitive impairment beyond the expected for the epilepsy activity. They are characterized by severe pharmaco-resistant epilepsy, severely abnormal electroencephalograms, early-age onset, neurocognitve impairment, variable phenotype and usually normal brain MRI. These syndromes are usually genetically determined. A correct and timely diagnosis could help and guide the medical counselling and the correct therapeutic approach improving the short, medium and long term outcomes. In this article we review the electroencephalographic and genetic findings along with the most recommended therapeutic options facilitating the clinical management. We include the following epileptic encephalopathy syndromes: Ohtahara, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West, Dravet, non-progressive myoclonic status, Doose, Lennox-Gastaut, Landau-Kleffner and continuous spike-wave during sleep epilepsy.
Assuntos
Humanos , Espasmos Infantis , Encefalopatias/genética , Epilepsias Mioclônicas/genética , Síndrome , Encefalopatias/classificação , Encefalopatias/diagnóstico , Encefalopatias/tratamento farmacológico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Eletroencefalografia , Anticonvulsivantes/classificação , Anticonvulsivantes/uso terapêuticoRESUMO
Dravet syndrome is a rare and severe encephalopathy that first presents in infancy with seizures refractory to conventional antiepileptic drugs. Forty-five percent of patients report four or more tonic-clonic seizures per month despite multidrug regimens. Fenfluramine, an amphetamine derivative, was initially developed as an appetite suppressant with a serotonergic mechanism of action. Clinical observation of a potential antiepileptic activity in a small homogeneous cohort of patients combined with a genetic workup of these patients led to the hypothesis of fenfluramine as a treatment for seizures in Dravet syndrome. This concept was successfully evaluated in a zebrafish model and led to a Phase 3 trial of fenfluramine to treat seizures in children with Dravet syndrome. Preliminary results of the trial suggest that fenfluramine may be a highly effective, well-tolerated treatment for patients with Dravet syndrome. This short review summarizes the history of use of fenfluramine from the initial clinical observations followed by preclinical studies and subsequent successful clinical trial. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond."
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Medicina de Precisão/métodos , Convulsões/tratamento farmacológico , Animais , Ensaios Clínicos Fase III como Assunto/métodos , Epilepsias Mioclônicas/diagnóstico , Humanos , Estudos Observacionais como Assunto/métodos , Medicina de Precisão/tendências , Convulsões/diagnóstico , Resultado do TratamentoRESUMO
The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood-brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is characterized by early infantile seizures, developmental delay, microcephaly, and ataxia. Recently, milder variants have also been described. The clinical picture of Glut1 defects and the understanding of the pathophysiology of this disease have significantly grown. A special form of transient movement disorders, the paroxysmal exertion-induced dyskinesia (PED), absence epilepsies particularly with an early onset absence epilepsy (EOAE) and childhood absence epilepsy (CAE), myoclonic astatic epilepsy (MAE), episodic choreoathetosis and spasticity (CSE), and focal epilepsy can be based on a Glut1 defect. Despite the rarity of these diseases, the Glut1 syndromes are of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms especially if it is started as early as possible. The present article summarizes the clinical features of Glut1 syndromes and discusses the underlying genetic mutations, including the available data on functional tests as well as the genotype-phenotype correlations. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".
Assuntos
Epilepsia/genética , Transportador de Glucose Tipo 1/genética , Transtornos dos Movimentos/genética , Mutação/genética , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/dietoterapia , Erros Inatos do Metabolismo dos Carboidratos/genética , Dieta Cetogênica/métodos , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/dietoterapia , Distúrbios Distônicos/genética , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/dietoterapia , Epilepsias Mioclônicas/genética , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/dietoterapia , Epilepsias Parciais/genética , Epilepsia/diagnóstico , Epilepsia/dietoterapia , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/dietoterapia , Epilepsia Tipo Ausência/genética , Humanos , Proteínas de Transporte de Monossacarídeos/deficiência , Proteínas de Transporte de Monossacarídeos/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/dietoterapiaRESUMO
PURPOSE OF REVIEW: For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy. RECENT FINDINGS: While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Maconha Medicinal/uso terapêutico , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Canabidiol/metabolismo , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Cannabis , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/metabolismo , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/metabolismo , Epilepsia/diagnóstico , Epilepsia/metabolismo , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/metabolismo , Humanos , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Síndrome de Lennox-Gastaut/metabolismo , Maconha Medicinal/metabolismo , Maconha Medicinal/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Estudos Retrospectivos , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Resultado do TratamentoRESUMO
OBJECTIVE: We report a large new family of familial cortical myoclonic tremor with epilepsy(FCMTE) from China and identify the possible causative gene(s) for the family. METHOD: Whole exome sequencing of blood genomic DNA from 4 patients and 2 unaffected family members were performed. Detected variants and their cosegregation were confirmed by Sanger sequencing. RESULTS: We identified c.20â¯Gâ¯>â¯C variant in the DCAF13 gene and c.983â¯Tâ¯>â¯C variant in the NOV gene cosegregating in the family. There was no additional cross-over in the family to narrow to one gene. The two DCAF13 and NOV gene variants are located on 8q23.3 and 8q24.12, which is consistent with the location 8q23.3-q24.13 reported previously for a group of Japanese families. The DCAF13 variant is located in alternative transcription start site(TSS) and the function of alternative TSS is unknown. The missense NOV variant is near the C terminus in a site that is highly conserved across species. It was predicted to be deleterious on protein function. CONCLUSIONS: In this study, we identify two novel variants in the DCAF13 and NOV genes associated with FCMTE in Asian populations. The interval between two variants is 15.6Mb, which is very close to each other. Future studies of additional families with this phenotype are warranted to confirm whether it is rare bigenic or monogenic inheritance.
Assuntos
Povo Asiático/genética , Epilepsias Mioclônicas/genética , Sequenciamento do Exoma/métodos , Variação Genética/genética , Proteína Sobre-Expressa em Nefroblastoma/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Sequência de Aminoácidos , Epilepsias Mioclônicas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
PURPOSE: Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy (SMEI), is a rare genetic disorder that results in severe childhood-onset epilepsy. Children with DS initially present with seizures in the first year of life that are often associated with fevers. With age, multiple seizure types develop. There are few reports and no guidelines regarding palliative surgical treatment for DS. Therefore, we reviewed our surgical experience with DS. METHODS: We conducted a retrospective review of all patients with genetically confirmed DS who underwent either vagal nerve stimulator (VNS) implantation or corpus callosotomy (CC) from May 2001 to April 2014 at our institution. All inpatient and outpatient relevant documentation were reviewed. Demographic information, genetic mutation, operation performed, and preoperative and postoperative seizure frequency were recorded. Inclusion criteria required greater than one-year postoperative follow-up. RESULTS: Seven children with DS were assessed. Six patients were treated with VNS and one patient was treated with CC. In one child, VNS was followed by CC as a secondary procedure. Therefore, in total, eight surgeries were performed on seven patients during the study period. At least 1 year elapsed from presentation to our hospital and surgery for all patients. Average time after the first seizure to VNS was 4.1 years, and the average time after the first seizure to CC was 7.6 years. The mean age of patients undergoing VNS implantation was 4.3 years, and the mean age for patients undergoing CC was eight. Average follow-up for all seven patients was 6.6 years. Seizures were decreased in five of the six patients with VNS and decreased in the two patients after CC. Four of the six patients who had VNS implanted had a greater than 50 % reduction in seizure frequency, and one of the six patients who had VNS implanted had a less than 50 % reduction in seizure frequency. One patient did not respond effectively to the VNS and had very limited change in seizure frequency. Both patients who had a CC had a greater than 50 % reduction in seizure frequency. CONCLUSIONS: Both VNS and CC in patients with DS can be effective at reducing seizure frequency. Patients with DS may benefit from earlier and more aggressive surgical intervention. Studies using larger patient cohorts will help clarify the role that surgery may play in the multidisciplinary approach to controlling seizures in DS. Further studies will help determine the appropriate timing of and type of surgical intervention.
Assuntos
Corpo Caloso/cirurgia , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/cirurgia , Cuidados Paliativos/tendências , Estimulação do Nervo Vago , Eletroencefalografia/tendências , Epilepsias Mioclônicas/fisiopatologia , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Epilepsia/cirurgia , Feminino , Humanos , Lactente , Masculino , Estimulação do Nervo Vago/tendênciasAssuntos
Medula Óssea/patologia , Epilepsias Mioclônicas/diagnóstico , Doença de Gaucher/diagnóstico , Adulto , Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Feminino , Doença de Gaucher/complicações , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/genética , Glucosilceramidase/uso terapêutico , Humanos , Fenótipo , Mutação Puntual , RecidivaRESUMO
De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate-to-severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide-based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 Wiley Periodicals, Inc.
Assuntos
Heterozigoto , Deficiência Intelectual/genética , Mutação , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Criança , Pré-Escolar , Constipação Intestinal/diagnóstico , Constipação Intestinal/genética , Constipação Intestinal/patologia , Análise Mutacional de DNA , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/patologia , Expressão Gênica , Haploinsuficiência , Luxação do Quadril/diagnóstico , Luxação do Quadril/genética , Luxação do Quadril/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Fenótipo , Estrabismo/diagnóstico , Estrabismo/genética , Estrabismo/patologia , Gêmeos MonozigóticosRESUMO
OBJECTIVES: Eyelid myoclonia (EM), without or with absences (EMA), is induced by eye closure (ECL)-associated generalized paroxysms of polyspikes and waves. Although considered as an epileptic syndrome, it has been listed as a type of seizure in the recent epilepsy classifications, perhaps because of its clinical heterogeneity. In this study, we aimed to specifically study the clinical and electroencephalogram (EEG) features and the prognosis of long-term followed-up adult patients with EMs and to determine common points between EMAs, idiopathic generalized epilepsies (IGEs), and symptomatic epilepsies. METHODS: Between 1996 and November 2011, 61 adult patients with EMs with or without absences and bilateral EEG paroxysms were retrospectively enrolled in the study and followed up for 1-34 years (mean: 5.8 years). RESULTS: According to patient history, seizure semiology, and EEG findings, we classified the patients having EM seizures into three main groups. In group 1 (n=31), all patients had prominent EMs with or without absences associated with upward rolling of eyeballs. The second group included 20 patients with EM seizures associated with generalized tonic-clonic seizures (GTCSs) and/or massive myoclonias. The third group of 7 patients had varying diagnosis of symptomatic epilepsies. In the first group with pure EMA, the diagnosis was more delayed than in the other groups (p=0.01). In the group with pure EMA, EMs continued in adulthood (p=0.00), and only 24% of patients were seizure-free, which was considered poor prognosis. On EEG, occipital (n=3) and frontal (n=4) focal discharges were found in the group with pure EMA. Interestingly, 2 patients with symptomatic epilepsy with frontal lesions also had EM seizures. CONCLUSION: The patients with pure EMA have many similarities to patients with IGEs. We also demonstrated that EMs could be seen as a seizure type in symptomatic epilepsies. Eyelid myoclonia with absences meets the criteria for an epileptic syndrome with the early onset and long duration of seizures, special seizure type, specific EEG findings, possibility of cognitive impairment, precipitating modalities, photosensitivity, and presence of family history, suggesting a strong genetic background.
Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsia Generalizada/diagnóstico , Mioclonia/diagnóstico , Convulsões/diagnóstico , Adulto , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Mioclonia/complicações , Mioclonia/fisiopatologia , Estudos Retrospectivos , Convulsões/complicações , Convulsões/fisiopatologia , Síndrome , Adulto JovemRESUMO
Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.
Assuntos
Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Receptor 1 de Folato/genética , Deficiência de Ácido Fólico/tratamento farmacológico , Leucovorina/uso terapêutico , Mutação de Sentido Incorreto , Mutação Puntual , Atrofia , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/patologia , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/genética , Diagnóstico Precoce , Eletroencefalografia , Epilepsias Mioclônicas/líquido cefalorraquidiano , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Feminino , Receptor 1 de Folato/deficiência , Deficiência de Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Piridoxina/uso terapêutico , Irmãos , Tetra-Hidrofolatos/líquido cefalorraquidianoRESUMO
Introduction: Dravet syndrome (DS) is one of the most intractable forms of epilepsy that begins in infancy. This syndrome is characterized by beginning with complex febrile seizures (FS) in a healthy infant and progresses to refractory epilepsy with psychomotor regression. The detection of a SCN1A mutation encoding the sodium channel can confirm the diagnosis. Objective: To report 3 confirmed cases of genetically DS. Case reports: We describe 3 girls diagnosed with complex FS that started when they were between 2 and 7 months old. FS were frequent, hemi generalized and myoclonic associated with recurrent febrile status epilepticus (SE). Despite FS and SE recurrence, the psychomotor development, electrophysiological studies and magnetic resonance imaging (MRI) of the brain were normal. After a year, they developed afebrile seizures progressing to refractory epilepsy with developmental regression. A molecular study detected SCN1A mutation confirming DS. The specific antiepileptic treatment and prevention of febrile episodes allowed partial control of epilepsy with some recovery of psychomotor skills. Conclusions: The high frequency complex FS associated with recurrent SE in a previously healthy infant should alert about the possibility of DS. Molecular diagnostics helps us to establish a drugs and non-drug therapies treatment, as well as long-term prognosis and genetic counseling.
Introducción: El Síndrome de Dravet (SD) es una de las formas más intratables de epilepsia que debuta en lactantes con convulsiones febriles (CF) complejas recurrentes que evolucionan posteriormente a epilepsia refractaria con regresión psicomotora. La detección de una mutación del canal de Sodio (SCN1A) permite certificar el diagnóstico. Objetivo: Reportar 3 casos de SD confirmados genéticamente. Casos clínicos: Se describen 3 niñas con diagnóstico de CF complejas iniciadas entre los 2 y 7 meses de edad. Las CF eran frecuentes, hemigeneralizadas, mioclónicas asociadas a status epilepticus (SE) febriles recurrentes. A pesar de la recurrencia de CF y SE, tanto el desarrollo psicomotor como los estudios electrofisiológicos y la resonancia magnética (RM) cerebral, fueron normales. Posterior al año iniciaron crisis afebriles que evolucionaron a epilepsia refractaria con regresión del desarrollo. El estudio molecular detectó la mutación SCN1A confirmando SD. El tratamiento antiepiléptico específico y la prevención de cuadros febriles permitieron un control parcial de la epilepsia con recuperación de algunas habilidades psicomotoras. Conclusiones: La alta frecuencia de CF complejas asociadas a SE recurrentes en un lactante previamente sano, debe alertar sobre la posibilidad de un SD. El diagnóstico molecular nos permite instaurar un tratamiento antiepiléptico y terapias no farmacológicas además de un pronóstico a largo plazo y consejería genética.
Assuntos
Criança , Pré-Escolar , Feminino , Humanos , Lactente , Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/diagnóstico , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Imageamento por Ressonância Magnética , Mutação , Estado Epiléptico/diagnósticoRESUMO
The paper reported on a case of severe myoclonic epilepsy of infancy (SMEI) associated with a probable autoimmune lymphoproliferative syndrome variant (Dianzani autoimmune lymphoproliferative disease) (DALD). A male patient with typical features of SMEI and a SCN1A gene variant presented in the first year of life with multiple lymph nodes, palpable liver at 2 cm from the costal margin, neutropenia, dysgammaglobulinemia, relative and sometimes absolute lymphocytosis. Subsequently the patient presented with constantly raised IgA in serum and positive antinuclear and thyroid antimicrosomal antibodies. The diagnosis of probable autoimmune lymphoproliferative syndrome was made; arthritis, skin and throat blisters, which appeared subsequently led to the diagnosis of linear IgA disease. On the basis of these unique associations, the Authors hypothesized that autoimmunity may be partly responsible of the severe epileptic symptomatology, perhaps mediated by autoantibodies against sodium channels or by accompanying cytotoxic T-lymphocytes. Corticosteroid treatment ameliorated the epilepsy and laboratory tests. Future studies will be necessary to evaluate the relevance of autoimmunity in SMEI.
Assuntos
Síndrome Linfoproliferativa Autoimune/diagnóstico , Epilepsias Mioclônicas/diagnóstico , Corticosteroides/uso terapêutico , Síndrome Linfoproliferativa Autoimune/fisiopatologia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/fisiopatologia , Humanos , Imunoglobulina A/sangue , Lactente , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Linfócitos T/imunologiaRESUMO
Benign myoclonic epilepsy in infancy, classified among the generalised idiopathic epilepsies, is characterised by the occurrence of myoclonic seizures in the first three years of life in otherwise normal infants. Some authors have described cases of myoclonic seizures as a reflex response to sudden unexpected tactile or acoustic stimuli and this clinical entity has been proposed as a separate nosographic syndrome, referred to as "reflex myoclonic epilepsy in infancy" (RMEI). We reviewed all published articles and case reports on RMEI in order to clarify clinical and electroencephalographic findings, with particular attention to outcome and treatment. RMEI appears to be a benign variant of idiopathic myoclonic epilepsy in infancy with specific features that occur in neurologically and developmentally normal children. This rare clinical entity is often under-described and under-diagnosed, and for this reason should be brought to the attention of paediatricians in order to avoid extensive investigations and reassure parents of the lack of long-term complications.
Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsia Reflexa/diagnóstico , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsia Reflexa/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Som/efeitos adversos , TatoRESUMO
The aim of this study was to develop and perform a preimplantation genetic diagnosis (PGD) assay discriminating between wild-type and mutant alleles in two families with germline mosaicism. Family 1 had two children affected with severe myoclonic epilepsy (SCNA1A del exons 1-22). Family 2 had two children with tuberous sclerosis (TSC2 C1327T) and two healthy children. Neither mutation was detected in genomic DNA derived from the parents in either family. Informative microsatellite markers flanking SCNA1A and TSC2 along with the identified mutations were used to construct haplotypes. For tuberous sclerosis, single spermatozoa were analysed using a multiplex assay that included six informative markers and the TSC2 mutation. In family 1, deletion in the maternal allele was detected in the affected child. In family 2, both affected children and one healthy child shared the same paternal allele. To confirm mutant paternal transmission, single spermatozoa were analysed for the mutation along with six markers. Of 44 single spermatozoa, four showed the mutant T allele, allowing linkage between the mutation and the genetic markers. Both families delivered healthy children following IVF/PGD. In conclusion, germline mosaicism complicates allele assignment when constructing haplotypes for PGD. Sperm analysis is a useful tool for verifying allelic linkage.
Assuntos
Epilepsias Mioclônicas/diagnóstico , Mutação em Linhagem Germinativa , Mosaicismo , Diagnóstico Pré-Implantação/métodos , Espermatozoides/metabolismo , Esclerose Tuberosa/diagnóstico , Alelos , Epilepsias Mioclônicas/embriologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/metabolismo , Éxons , Saúde da Família , Feminino , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Linhagem , Análise de Célula Única , Esclerose Tuberosa/embriologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
We describe a boy (aged 2 years and 7 months) with hemimegalencephaly who developed myoclonic status, which improved dramatically after total callosotomy. The patient experienced seizures beginning at age 2 days, at which time electroencephalography revealed a right unilateral burst suppression pattern, and cranial magnetic resonance imaging revealed an enlarged right hemisphere. At age 8 months, habitual seizures increased to more than daily frequency. At the same time, myoclonic status epilepticus appeared with frequent erratic, partial, massive myoclonic seizures and clouding of consciousness. These signs were accompanied by diffuse spike and spike-wave patterns on electroencephalography, indicating myoclonic status in nonprogressive encephalopathy. Total callosotomy performed at age 10 months resulted in the complete disappearance of myoclonic status and prominent decrease in habitual seizures. This description of hemimegalencephaly is the first, to our knowledge, in which total callosotomy alleviated myoclonic status epilepticus. Although the mechanism of myoclonic status epilepticus remains unknown, our results suggest that cortico-cortical pathways are involved in this type of myoclonic status.