SCN2A Pathogenic Variants and Epilepsy: Heterogeneous Clinical, Genetic and Diagnostic Features

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.

Therapeutic possibilities of coriaria myrtifolia L. in high dilutions

Background: Homeopathy literature shows references about Coriaria myrtifolia L. at some important Homeopathic Materia Medica: Allen,TF [1], Voisin H [2] and Vijnovsky B [3]. Those reports are unsatisfactory to fulfill a contemporary standardized study basis on: origin and description, preparation, medicine general action, sensations and modalities; demanding a broader investigation. Aims: Identify therapeutic possibilities on Coriaria myrtifolia L. from ratifying and broadening the homeopathic materia medica knowledge. Methodology: Literature review on botanical, biochemical and pharmacological data [4-12]. The use of plant in various fields since XVIII century and analyzes of clinical-toxicological reports described in medical reviews published. Results: Coriaria myrtifolia L. is a toxic shrub, growing wild in western Mediterranean region. The entire plant contains a sesquiterpene-lactone called coriamyrtin, a potent convulsivant neurotoxin. Clinical manifestations of acute intoxication includes: Central Nervous System – generalized tonic-clonic seizures, recurrent, which may evolve to status epilepticus, coma, apnea and death. Respiratory Tract – respiratory depression due to anoxia, respiratory arrhythmia alternating with apnea, respiratory muscles tetanization evolving to respiratory arrest. Cardiovascular System – central excitatory action which may initially promote increased blood pressure followed by heart failure, as a result of the seizures, due to anoxia and acidosis, leading to cardiac arrest. Gastrointestinal Tract – nausea, vomiting and stomach pains that precede seizures; since there is no evidence of toxin direct action on mucosa, those symptoms may relate to Central Nervous System action (attributed to impairment of cranial nerve VIII). Knowledge of these aspects gave us possibility to build a Coriaria myrtifolia L. materia medica with broader clinical indications. Conclusion: Coriaria myrtifolia L. is a valuable source to be used in high dilutions as medicine indicated for epileptic syndromes treatment, characterized by tonic-clonic seizures, mainly presenting a malignant tendency, with recurrent seizures, which may evolve to status epilepticus and potential mortality risk. Among the clinical indications proposed stand out etiologies of great incidence at emergency rooms such as metabolic or vascular primary disorders, or resulting from systemic diseases (diabetes, hepatopathy, nephropathy), encephalitis and meningitis with or without Acquired Immunodeficiency Syndrome, withdrawal syndrome from alcohol or drugs, exogenous poisoning, poisoning or overdose of alcohol or drugs, traumatic brain injury and intracranial expanding lesions.

Cerebral dominance in an unusual case of Landau-Kleffner syndrome

Landau-Kleffner syndrome (LKS) is described by the International Classification of Epileptic Syndromes since 1985 as a constellation of clinical and electrographic signs, including acquired aphasia, regression of language milestones and seizures, along with sleep-activated paroxysms on electroencephalogram which can progress to electrographic status epilepticus of sleep. In this case, a 7-year-old boy presented with an atypical history of new-onset aphasia and regression of language milestones with rare seizures. However, there was an electrographic mismatch in the form of right-sided epileptiform activity and continuous spike and wave of sleep pattern. Detailed speech analysis and perusal of the history revealed a possibly ambidextrous child with right hemispheric language dominance, and he was diagnosed with LKS and treated. This report illustrates the many pitfalls in the diagnosis and treatment of this rare epileptic syndrome.

Probability of Remission of the Main Epileptic Syndromes in Childhood

Aim To determine the long-term probability of remission without antiepileptic treatment of common epileptic syndromes and of children without a specific syndromic diagnosis. Patients and methods All children less than 14 years old with 2 or more unprovoked seizures seen at our hospital between June 1, 1994, and March 1, 2011 (n = 680), were included and prospectively followed up until August 15, 2020. Syndromic diagnosis was made retrospectively but blinded to subsequent evolution, employing the data available at 6 months after diagnosis and under predefined operational criteria. Results The Kaplan-Meier estimate of the probability of achieving a remission period of at least 5 years, with neither seizures nor antiepileptic treatment at 14 years was 97% for well-defined childhood epilepsy with centrotemporal spikes, 82% for uncertain childhood epilepsy with centrotemporal spikes, 85% for well-defined Panayiotopoulos syndrome, 88% for uncertain Panayiotopoulos syndrome, 93% for nonfamilial self-limited infantile epilepsy, 100% for familial self-limited infantile epilepsy, 86% for absence epilepsy, 6% for juvenile myoclonic epilepsy, 71% for cryptogenic West syndrome, 72% for patients with no associated neurologic deficits and no specific syndromic diagnosis, 65% for symptomatic West syndrome, and 40% for patients with associated neurologic deficits and no specific syndromic diagnosis. Conclusions The study results highlight the long-term outcomes of the main epileptic syndromes and also of the patients with no syndromic diagnosis.

Towards a Treatment for Neuroinflammation in Epilepsy: Interleukin-1 Receptor Antagonist, Anakinra, as a Potential Treatment in Intractable Epilepsy

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.

Modern approach to diagnosis and treatment of seizures in newborns and early age children

The article is devoted to the topical problem of neonatology and pediatric neurology — the diagnosis and treatment of seizures in newborns and young children. The work presents an algorithm for the diagnosis and treatment of epileptic seizures in children. It is indicated that the therapeutic effect of most antiepileptic drugs consists of modulation of voltage-gated and ligand-gated channels of membranes of neurons of the cerebral cortex, enhancement of inhibitory synaptic transmission or inhibition of activating synaptic transmission. The issues of the pharmacokinetics and pharmacodynamics of antiepileptic drugs are considered, taking into account the age characteristics of the child's body, in particular, newborns and early age children. The problems of drug interaction were discussed. The properties of individual antiepileptic drugs, which are used in newborns and young children, are considered. Emphasized are «polar» differences in the work of phenobarbital, which depend on the stage of epileptogenesis, namely: suppression of epileptiform activity at the early stage of epileptogenesis and its enhancement in the already formed epileptic focus (epileptic system). The literature data on the differentiated treatment of certain epileptic syndromes are presented. The issues on the prospects for the treatment of genetically determined diseases, which are accompanied by seizures associated with metabolic disorders, are considered. The modern high-tech methods of treatment of these diseases are noted. The role of diet therapy, co-factor therapy in the treatment of hereditary metabolic disorders, in particular, the ketogenic diet as a method of alternative treatment for drug-resistant epilepsy in children, is shown. No conflict of interest was declared by the authors. Key words: newborn, epilepsy, epileptic encephalopathy, treatment, antiepileptic drugs, review.

Monogenic Epilepsies: Channelopathies, Synaptopathies, mTorpathies, and Otheropathies

Epilepsy has been historically defined as the recurrence of two or more seizures, together with typical electroencephalogram (EEG) changes, and significant comorbidities, including cardiac and autonomic changes, injuries, intellectual disability, permanent brain damage, and higher mortality risk. Epilepsy may be the consequence of several causes, including genetic anomalies, structural brain malformations, hypoxic–ischemic encephalopathy, brain tumors, drugs, and all contributing factors to the imbalance between excitatory and inhibitory neurons and modulatory interneurons which in turn provoke abnormal, simultaneous electric discharge(s) involving part, or all the brain. In the pregenetic, pregenomic era, in most cases, the exact cause of such neuronal/interneuronal disequilibrium remained unknown and the term “idiopathic epilepsy” was used to define all the epilepsies without cause. At the same time, some specific epileptic syndromes were indicated by the eponym of the first physician who originally described the condition (e.g., the West syndrome, Dravet syndrome, Ohtahara syndrome, and Lennox–Gastaut syndrome) or by some characteristic clinical features (e.g., nocturnal frontal lobe epilepsy, absence epilepsy, and epilepsy and mental retardation limited to females). In many of these occurrences, the distinct epileptic syndrome was defined mainly by its most relevant clinical feature (e.g., seizure semiology), associated comorbidities, and EEGs patterns. Since the identification of the first epilepsy-associated gene (i.e., CHRNA4 gene: cholinergic receptor neuronal nicotinic α polypeptide 4), one of the genes responsible for autosomal dominant nocturnal frontal lobe epilepsy (currently known as sleep-related hypermotor epilepsy) in 1995, the field of epilepsy and the history of epilepsy gene discoveries have gone through at least three different stages as follows: (1) an early stage of relentless gene discovery in monogenic familial epilepsy syndromes; (2) a relatively quiescent and disappointing period characterized by largely negative genome-wide association candidate gene studies; and (3) a genome-wide era in which large-scale molecular genetic studies have led to the identification of several novel epilepsy genes, especially in sporadic forms of epilepsy. As of 2021, more than 150 epilepsy-associated genes or loci are listed in the Online Mendelian Inheritance in Man database.

The Antiepileptic Drugs Therapy Practice in Epileptic Patients: What Does Evidence Show?

Introduction: Though studies regarding epilepsy have been conducted in different parts of the world, there is a scarcity of established studies regarding treatment outcomes among patients with epilepsy. Therefore, the aim of this review is to assess antiepileptic drug therapy among patients with epilepsy. This will help in exploring the existing AEDs therapy practice including the outcomes. Methods: Using different search engines like EndNote (Pubmed), Google, Google Scholar and Hinari, literatures were searched for review. Different literatures like, research reports, articles, documents, books and internet findings relevant to this study were reviewed. Findings and discussion: Outcome of AEDs therapy is affected by several factors including patient-related factors, disease related factors and drug related factors. The selection of the most appropriate AEDs for a patient with seizures depends upon the accurate classification of the seizures, the type of epilepsy or epileptic syndromes, and drug such as availability and accessibility of drugs, their efficacy, side effect and comfort use as well as patient factors. So, the selection of AED therapy at present is an empirical process, based on seizure and patient-specific variables and a working knowledge of available AEDs, including AED mechanism of action, pharmacokinetics, drug-drug interactions, and medication side effects and ultimately the treatment outcomes. Conclusion: It is recommended that researchers need to focus on further longitudinal and interventional studies in providing adequate evidence about the cause-effect relationship between the AEDs therapy practice and seizure control.