1,721,098 research outputs found
Towards an evidence-based treatment of pediatric status epilepticus: still a mountain to climb.
No full textNO ABSTRACT AVAILABL
Epilepsy in inherited neurotransmitter disorders: Spotlights on pathophysiology and clinical management.
No full textInborn errors of neurotransmitter metabolism are ultrarare disorders affecting neurotransmitter biosynthesis, breakdown or transport or their essential cofactors. Neurotransmitter dysfunctions could also result from the impairment of neuronal receptors, intracellular signaling, vesicle release or other synaptic abnormalities. Epilepsy is the main clinical hallmark in some of these diseases (e.g. disorders of GABA metabolism, glycine encephalopathy) while it is infrequent in others (e.g. all the disorders of monoamine metabolism in exception for dihydropteridine reductase deficiency). This review analyzes the epileptogenic mechanisms, the epilepsy phenotypes and the principle for the clinical management of epilepsy in primary and secondary inherited disorders of neurotransmitter metabolism (disorders of GABA, serine and glycine metabolism, disorders of neurotransmitter receptors and secondary neurotransmitter diseases)
Novel Genes of Early-Onset Epileptic Encephalopathies: From Genotype to Phenotypes.
No full textBACKGROUND:Early-onset epileptic encephalopathies are severe disorders in which seizure recurrence impairs motor, cognitive, and sensory development. In recent years, next-generation sequencing technologies have led to the detection of several pathogenic new genes.
METHODS AND RESULTS:A PubMed search was carried out using the entries "early onset epileptic encephalopathies," "early infantile epileptic encephalopathies," and "next generation sequencing." The most relevant articles written on this subject between 2000 and 2015 were selected. Here we summarize the related contents concerning the pathogenic role and the phenotypic features of 20 novel gene-related syndromes involved in the pathogenesis of early-onset epileptic encephalopathy variants.
CONCLUSIONS:Despite the increasing number of single early-onset epileptic encephalopathy genes, the clinical presentations of these disorders frequently overlap, making it difficult to picture a systematic diagnostic evaluation. In any case, a progressive approach should guide the choice of molecular genetic investigations. It is suggested that clinicians pay particular attention to mutated genes causing potentially treatable conditions in order to take advantage of expert counseling
Clinical approach to neurodegenerative disorders in childhood: an updated overview.
No full textNeurodegenerative disorders include a group of severe diseases that share a core including a gradual loss of previously acquired motor, sensory and cognitive functions. In pediatric age, the main diagnostic issues are the discrimination between the loss of previously acquired competencies and the lack of achievement of specific developmental milestones. An ideal classification of these disorders could be based on the combination of genetic, clinical and neuroimaging features. Diagnostic workup should be organized with a special attention to the few diseases with an available and effective therapeutic treatment. The present paper reports a proposal of classification that is based on the prominently involved structure and summarizes the hallmarks for clinical approach and therapeutic management
The impact of next generation sequencing in the diagnostic work-up of pediatric epilepsies: a single centre observational cohort study
No full textBackground Next generation sequencing techniques (targeted gene panels, whole exome sequencing and whole genome sequencing) allowed an increase of molecular diagnosis of genetic epilepsies, an expansion of the phenotypic spectrum of several epileptic syndromes and an optimization of the correlated diagnostic work-up.
Aim of the study: To characterize the epilepsy phenotypes that could be associated with a better detection rate of targeted next generation sequencing for pathogenic/likely pathogenic variants.
Patients and methods: A retrospective cohort analysis was performed on 58 patients (28 males and 30 females; mean age=9,06 ± 6,97 years) who underwent targeted next generation sequencing gene for epilepsy between 2015 and 2018. Data about demographic features, seizures semiology and evolution during follow-up, associated neurological and non-neurological features, EEG and MRI characteristics were collected. These variables were evaluated and compared in: - patients with epileptic encephalopathies (seizures causing developmental impairment- A group); -patients with developmental encephalopathies including epilepsy (developmental impairment preceding epilepsy- B group); - patients with isolated idiopathic epilepsy without signs of encephalopathy (no developmental impairment- C group).
Results: Pathogenic or likely pathogenic variants were assessed in 18/58 patients (13/18 were de novo) with a detection rate of 31,03% in the whole sample (51,6% in the B group; 11,1% in group C and 0% in the A group). Genes with pathogenic/likely pathogenic mutations were represented by: SCN1A (in 3 patients), IQSEC2 (in 2 patients), PRICKLE1, GABRB3, SLC2A1, MFF, SCN1B, KCTD7, CDKL5; FOXG1, SYNGAP1, ATP1A3, GRIN2A, PRRT2 and CACNA1A (one affected patients for each one of these genes). Atypical phenotypes were associated with variants involving SCN1A, KCTD7, PRICKLE1 and PRRT2. Molecular diagnosis addressed positively therapeutic choices in 13/18 patients with an optimization of seizures control.
Conclusions: Patients with developmental encephalopathies including epilepsy should undergo targeted next generation sequencing since the first stages of diagnostic work-up
Lennox-Gastaut Syndrome: A State of the Art Review.
Full text linkLennox-Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients
Genes of Early-Onset Epileptic Encephalopathies: From Genotype to Phenotype
No full textEarly-onset epileptic encephalopathies are severe disorders in which cognitive, sensory, and motor development is impaired by recurrent clinical seizures or prominent interictal epileptiform discharges during the neonatal or early infantile periods. They include Ohtahara syndrome, early myoclonic epileptic encephalopathy, West syndrome, Dravet syndrome, and other diseases, e.g., X-linked myoclonic seizures, spasticity and intellectual disability syndrome, idiopathic infantile epileptic-dyskinetic encephalopathy, epilepsy and mental retardation limited to females, and severe infantile multifocal epilepsy. We summarize recent updates on the genes and related clinical syndromes involved in the pathogenesis of early-onset epileptic encephalopathies: Aristaless-related homeobox (ARX), cyclin-dependent kinase-like 5 (CDKL5), syntaxin-binding protein 1 (S7XBP1), solute carrier family 25 member 22 (SLC25A22), nonerythrocytic alpha-spectrin-1 (SPTAN1), phospholipase C beta 1 (PLC beta 1), membrane-associated guanylate kinase inverted-2 (MAG12), polynucleotide kinase 3'-phosphatase (PNKP), sodium channel neuronal type 1 alpha subunit (SCN1A), protocadherin 19 (PCDH19), and pyridoxamine 5-prime-phosphate oxidase (PNPO). (C) 2012 Published by Elsevier Inc
Diagnostic work-up and therapeutic options in management of pediatric status epilepticus
No full textBACKGROUND:
Status epilepticus (SE) is a life-threatening neurologic disorder comprising prolonged and unremitting crisis, and two or more series of seizures without complete intercritical recovery.
DATA SOURCES:
We reviewed the literature through a Pubmed/Medline research using key words including status epilepticus, antiepileptic drugs and children, in order to revise and compare international/national protocols and to examine pediatric guidelines in SE management.
RESULTS:
Neurologic impairment and SE etiology seem to be the most independent risks for mortality. A deep semiologic evaluation is essential to addressing diagnostic work-up. Ematochemical parameters, plasma levels of antiepileptic drugs and clinically oriented toxic/metabolic screening should be mandatory for investigating both causes and effects of SE. Electroencephalography is clearly helpful to characterize focal from generalized SE and to distinguish epileptic events from pseudoseizures, and it is deal to find nonconvulsive SE. Neuroimaging techniques could detect epileptogenic lesions (such as cortical malformations, tumors, demyelinating disorders or strokes) but are common in practice to find negative or controversial results. Pharmacologic management can be essentially arranged in three stages: benzodiazepines for early SE (lasting less than 30 minutes), phenytoin/fosphenytoin, phenobarbital, valproate, levetiracetam or lacosamide for established SE (30-90 minutes), and anesthetics for refractory SE (more than 90 minutes).
CONCLUSIONS:
Status epilepticus is the most common neurologic emergency in childhood. A systematic diagnostic work-up and a three steps based therapeutic approach is required at this age
Update on the treatment of vitamin B6 dependent epilepsies
No full textIntroduction: Vitamin B6 dependent epilepsies are a group of treatable diseases (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects) responding to pyridoxine or pyridoxal-5I-phosphate. Areas covered: A critical review was conducted on the therapeutic management of all the reported patients with genetically confirmed diagnoses of diseases affecting vitamin B6 metabolism and presenting with pyridoxine or pyridoxal-5I-phosphate dependent-seizures. Data about safety and efficacy were analyzed as well as the management of supplementation with pyridoxine or pyridoxal-5I-phosphate both in the acute phases and in the maintenance therapies. The authors also analyzed alternative therapeutic strategies for ALDH7A1 deficiency (lysine-restricted diet, arginine supplementation, oligonucleotide antisense therapy, upstream inhibition of aminoadipic semialdehyde synthase). Expert opinion: The administration of pyridoxine or pyridoxal-5I-phosphate should be considered in all intractable seizures also beyond the first year of life. Lysine restricted diet and arginine supplementation should be introduced in all the confirmed ALDH7A1 deficient patients. Pre or post-natal supplementation with pyridoxine should be given in familial cases until an eventual molecular genetic disconfirmation. Minor data about alternative therapies are available for other disorders of vitamin B6 metabolism
Paediatric sudden unexpected death in epilepsy: From pathophysiology to prevention
No full textSudden unexpected death in epilepsy (SUDEP) is a fatal event, occurring in patients with epilepsy, in which seizures may or may not precede the exitus, and no other potential causes of death are identifiable. The proposed pathophysiological mechanisms for SUDEP include cardio-respiratory dysfunctions, brainstem arousal system impairment, and dysregulation in the neurotransmitter/neuromodulator systems. This narrative review provides an overview of primary research on SUDEP in paediatric populations. Some studies report an incidence of paediatric SUDEP which is about five times lower than in adults (between 0.02 and 0,34 per 1,000 person-years) even if more recent studies suggested similar incidence rates than in adulthood (between 1.20 / 1,000 and 1.45 / 1,000 person per years). Risk factors for SUDEP in children include genetic predisposition, neurological comorbidities, epilepsy phenotype, adequacy/adherence to treatment, adequate supervision by caregivers and access to adequate health care support. The early identification of risk factors, the definition of reliable biomarkers and the building of efficacious preventive strategies, including parental/caregiver counselling, novel technological devices, and pharmacological treatments, may reduce the risk of paediatric SUDEP
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