A Review of Hyperventilation Activation in Diagnosis and Management of Childhood Absence Epilepsy.

Childhood absence epilepsy is one of the most prevalent pediatric epilepsy syndromes, but diagnostic delay is common and consequential. Childhood absence epilepsy is diagnosed by history and physical examination including hyperventilation with electroencephalography (EEG) used to confirm the diagnosis. Hyperventilation produces generalized spike-wave discharges on EEG in >90% of patients with childhood absence epilepsy and provokes clinical absence seizures consisting of brief loss of consciousness typically within 90 seconds. Child neurologists report a high volume of referrals for children with "staring spells" that strain already limited health care resources. Resources are further strained by the use of EEG for monitoring antiseizure medication effectiveness with unclear benefit. In this review, we examine the safety and efficacy of hyperventilation activation as a tool for the diagnosis and management of childhood absence seizures.

Neuronal rhythmicity and cortical arousal in a mouse model of absence epilepsy.

OBJECTIVES: Absence seizures impair psychosocial function, yet their detailed neuronal basis remains unknown. Recent work in a rat model suggests that cortical arousal state changes prior to seizures and that single neurons show diverse firing patterns during seizures. Our aim was to extend these investigations to a mouse model with studies of neuronal activity and arousal state to facilitate future fundamental investigations of absence epilepsy. METHODS: We performed in vivo extracellular single unit recordings on awake head-fixed C3H/HeJ mice. Mice were implanted with tripolar electrodes for cortical electroencephalogram (EEG). Extracellular single unit recordings were obtained with glass micropipettes in the somatosensory barrel cortex, while animals ambulated freely on a running wheel. Signals were digitized and analyzed during seizures and baseline. RESULTS: Neuronal activity was recorded from 36 cortical neurons in 19 mice while EEG showed characteristic 7-8 Hz spike-wave discharges. Different single neurons showed distinct firing patterns during seizures, but the overall mean population neuronal firing rate during seizures was no different from pre-seizure baseline. However, the rhythmicity of neuronal firing during seizures was significantly increased (p < 0.001). In addition, beginning 10s prior to seizure initiation, we observed a progressive decrease in cortical high frequency (>40 Hz) EEG and an increase in lower frequency (1-39 Hz) activity suggesting decreased arousal state. SIGNIFICANCE: We found that the awake head-fixed C3H/HeJ mouse model demonstrated rhythmic neuronal firing during seizures, and a decreased cortical arousal state prior to seizure onset. Unlike the rat model we did not observe an overall decrease in neuronal firing during seizures. Similarities and differences across species strengthen the ability to investigate fundamental key mechanisms. Future work in the mouse model will identify the molecular basis of neurons with different firing patterns, their role in seizure initiation and behavioral deficits, with ultimate translation to human absence epilepsy.

A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation.

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings' father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.

A preclinical study to determine the anti-epileptic effect of biotin on maximal electroshock (MES) and pentylenetetrazole (PTZ) models in albino rats.

OBJECTIVES: Vitamin B7(biotin) is not synthesized in our body and is retrieved from some food products like eggs, liver, pork and leafy vegetables and as well as microbes of gut. Deficiency of biotin majorly leads to loss of hair, rashes over skin, lethargy and seizures. It is noted that biotin is an anti-oxidant and negates free radical effects. Biotin is also involved in carbon dioxide metabolism and it might alter seizure threshold. Studies also suggest its effect on lipid metabolism as well. So, the primary objective of this study was to assess the efficacy of biotin in maximal electric shock (MES) induced generalized tonic-clonic seizures (GTCS) and pentylenetetrazole (PTZ) induced absence seizures. The secondary objective is to study the effect of combined treatment of biotin and sodium valproate on seizures as well as plasma lipid profile in rats. METHODS: In our study 30 albino Wistar rats each were used in MES and PTZ model respectively. 30 rats were divided equally into following groups: I - distilled water (negative control) II - distilled water (positive control) III - sodium valproate (300 mg/kg) IV - biotin (10 mg/kg/day) V - biotin (10 mg/kg) + sodium valproate (150 mg/kg). RESULTS: We observed that the tonic hind limb extension was significantly reduced in the treatment group in MES model. Nitric oxide levels were also seen raised in combination group in MES model and all the treated groups in PTZ model. Biotin treated group showed increased high-density lipoproteins and reduced low density lipoproteins and triglycerides. CONCLUSIONS: Biotin had an additive effect to sodium valproate in both the models of epilepsy in rats. Further, it was also able to counteract hyperlipidemia cause by sodium valproate.

The landscape of drug resistant absence seizures in adolescents and adults: Pathophysiology, electroclinical spectrum and treatment options.

The persistence of typical absence seizures (AS) in adolescence and adulthood may reduce the quality of life of patients with genetic generalized epilepsies (GGEs). The prevalence of drug resistant AS is probably underestimated in this patient population, and treatment options are relatively scarce. Similarly, atypical absence seizures in developmental and epileptic encephalopathies (DEEs) may be unrecognized, and often persist into adulthood despite improvement of more severe seizures. These two seemingly distant conditions, represented by typical AS in GGE and atypical AS in DEE, share at least partially overlapping pathophysiological and genetic mechanisms, which may be the target of drug and neurostimulation therapies. In addition, some patients with drug-resistant typical AS may present electroclinical features that lie in between the two extremes represented by these generalized forms of epilepsy.

BAER-101, a selective potentiator of α2- and α3-containing GABAA receptors, fully suppresses spontaneous cortical spike-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS).

BAER-101 (formerly AZD7325) is a selective partial potentiator of α2/3-containing γ-amino-butyric acid A receptors (GABAARs) and produces minimal sedation and dizziness. Antiseizure effects in models of Dravet and Fragile X Syndromes have been published. BAER-101 has been administered to over 700 healthy human volunteers and patients where it was found to be safe and well tolerated. To test the extent of the antiseizure activity of BAER-1010, we tested BAER-101 in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model, a widely used and translationally relevant model. GAERS rats with recording electrodes bilaterally located over the frontal and parietal cortices were used. Electroencepholographic (EEG) signals in freely moving awake rats were analyzed for spike-wave discharges (SWDs). BAER-101 was administered orally at doses of 0.3-100 mg/kg and diazepam was used as a positive control using a cross-over protocol with a wash-out period between treatments. The number of SWDs was dose-dependently reduced by BAER-101 with 0.3 mg/kg being the minimally effective dose (MED). The duration of and total time in SWDs were also reduced by BAER-101. Concentrations of drug in plasma achieved an MED of 10.1 nM, exceeding the Ki for α2 or α3, but 23 times lower than the Ki for α5-GABAARs. No adverse events were observed up to a dose 300× MED. The data support the possibility of antiseizure efficacy without the side effects associated with other GABAAR subtypes. This is the first report of an α2/3-selective GABA PAM suppressing seizures in the GAERS model. The data encourage proceeding to test BAER-101 in patients with epilepsy.

Atypical absence seizures and gene variants: A gene-based review of etiology, electro-clinical features, and associated epilepsy syndrome.

Atypical absence seizures are generalized non-convulsive seizures that often occur in children with cognitive impairment. They are common in refractory epilepsy and have been recognized as one of the hallmarks of developmental epileptic encephalopathies. Notably, pathogenic variants associated with AAS, such as GABRG2, GABRG3, SLC6A1, CACNB4, SCN8A, and SYNGAP1, are also linked to developmental epileptic encephalopathies. Atypical absences differ from typical absences in that they are frequently drug-resistant and the prognosis is dependent on the etiology or related epileptic syndromes. To improve clinicians' understanding of atypical absences and provide novel perspectives for clinical treatment, we have reviewed the electro-clinical characteristics, etiologies, treatment, and prognosis of atypical absences, with a focus on the etiology of advancements in gene variants, shedding light on potential avenues for improved clinical management.

Epilepsias generalizadas idiopáticas / Idiopathic generalized epilepsies

Resumen Las epilepsias generalizadas idiopáticas (EGI) son un grupo de epilepsias generalizadas edad de pendientes, subgrupo de las Epilepsias genéticas generalizadas(EGG), con hallazgos electro-clínicos característicos y herencia poligénica. Las EGI inclu yen las cuatro epilepsias generalizadas clásicas más comunes de las EGG: la epilepsia de ausencias de la infancia (EAI), epilepsia de ausencias juveniles (EAJ), epilepsia mioclónica juvenil (EMJ) y la epilepsia con crisis tónico clónicas generalizadas. Clínicamente caracterizadas por la presencia de una o una com binación de crisis de ausencias, mioclonías, tónica-clónicas omioclónica-tónica-clónicas con patrón elec troencefalográfico de punta onda lenta de 2.5 a 6cps y activación con la hiperventilación y fotoestimula ción, Sobresalen de las EGG por compartir atributos particulares como el buen pronóstico con control frecuente de las crisis, la no evolución a encefalopa tías epilépticas, frecuente superposición clínica entre las tres primeras, pudiendo evolucionar entre ellas; la probabilidad y edad de remisión varía en cada una.Más del 80% se controlan adecuadamente con medicamentos anticrisis de amplio espectro como el ácido valproico y pueden empeorar con bloqueadores de sodio o gabaérgicos. Si bien los pacientes son previamente sanos con neurodesarrollo normal, frecuentemente se asocian con trastornos del ánimo, déficit de atención e hiperactividad (TDAH) y problemas del aprendizaje pero no presentan déficit cognitivo. El reconocimiento de este grupo de EGI es importan te para el uso adecuado del recurso, evitando estudios innecesarios, adecuada orientación del pronóstico y un tratamiento óptimo.

Abstract Idiopathic generalized epilepsies (IGE) is a group of epilepsies age-dependent, a subgroup of EGG genetic generalized epilepsies, with electro-clinical features and polygenic inheritance. Four syndromes comprising the IGEs: childhood absence epilepsy (CAD), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures epilepsy. Clinically characterized by the presence of one or a combination of absence seizures, myoclonus, tonic-clonic, or myoclonic-tonic-clonic with common electroencephalographic pat terns of 2.5-5.5 Hz generalized spike-wave and activated by hyperventilation or photic stimulation. They generally have a good prognosis for seizure control, not evolve to an epileptic encephalopathy. Frequent clinical overlap between the first three, being able to evolve between them; the probability and age of remission varies in each one. About 80% responding to broad-spectrum anti-seizure drugs such as valproic acid, may worsen with sodium or GABAergic blockers. Development is typically normal; however, they are frequently associated with mood disorders, attention-deficit/hyperactivity disorder (ADHD), and learning dis abilities, but do not have cognitive deficits. The recognition of this group of EGI is important for the adequate use of the resources, avoiding unnecessary studies, adequate orientation of the prognosis and an optimal treatment.

Therapeutic Outcomes and Prognostic Factors in Childhood Absence Epilepsy

BACKGROUND AND PURPOSE: Childhood absence epilepsy (CAE) is one of the most common types of pediatric epilepsy. It is generally treated with ethosuximide (ESM), valproic acid (VPA), or lamotrigine (LTG), but the efficacy and adverse effects of these drugs remain controversial. This study compared initial therapy treatment outcomes, including VPA-LTG combination, and assessed clinical factors that may predict treatment response and prognosis. METHODS: Sixty-seven patients with typical CAE were retrospectively enrolled at the Korea University Medical Center. We reviewed patients' clinical characteristics, including age of seizure onset, seizure-free interval, duration of seizure-free period, freedom from treatment failure, breakthrough seizures frequency, and electroencephalogram (EEG) findings. RESULTS: The age at seizure onset was 7.9±2.7 years (mean±SD), and follow-up duration was 4.4±3.7 years. Initially, 22 children were treated with ESM (32.8%), 23 with VPA (34.3%), 14 with LTG (20.9%), and 8 with VPA-LTG combination (11.9%). After 48 months of therapy, the rate of freedom from treatment failure was significantly higher for the VPA-LTG combination therapy than in the three monotherapy groups (p=0.012). The treatment dose administrated in the VPA-LTG combination group was less than that in the VPA and LTG monotherapy groups. The shorter interval to loss of 3-Hz spike-and-wave complexes and the presence of occipital intermittent rhythmic delta activity on EEG were significant factors predicting good treatment response. CONCLUSIONS: This study showed that low-dose VPA-LTG combination therapy has a good efficacy and fewer side effects than other treatments, and it should thus be considered as a firstline therapy in absence epilepsy.

The sleep-wakefulness cycle of Wistar rats with spontaneous absence-like epilepsy / O ciclo vigília-sono de ratos Wistar portadores de epilepsia espontânea tipo ausência

Possible interactions between the sleep-wakefulness cycle and a new kind of spontaneous epilepsy, expressed as absence-like seizures and spike-wave bursts in FMUSP rats, are evaluated. The electro-oscillograms of some cortical and subcortical regions of the brain were recorded, as well as head, rostrum/vibrissae and eye movements. Recordings were performed uninterruptedly during 24 hours. The seizures were mostly concentrated in the wakefulness state but they could occur in any other phase, including paradoxical sleep. After the seizure, the rats usually returned to the same phase that was interrupted, although they often returned to wakefulness. There was an intense fragmentation of the sleep-wakefulness cycle. The incidence of each cycle phase was significantly reduced, except S III of synchronized sleep and paradoxical sleep, thus maintaining the overall duration and architecture of the sleep -wakefulness cycle. The fragmentation of the cycle seems to be due to an impairment of the very processes that generate sleep and wakefulness. Electrophysiological and behavioral profiles of the FMUSP rats recommend accurate and comprehensive study of the animal model owing to its resemblance to seizures in humans and also to discrepancies with existing genetic or experimental epilepsy models.

A razão principal desta investigação foi estudar a arquitetura do ciclo vigília-sono numa cepa de ratos Wistar (FMUSP-rats) portadores de epilepsia espontânea tipo ausência. Foram utilizados 10 ratos Wistar adultos, que receberam eletrodos em regiões corticais e subcorticais, nos músculos trapézios e nos epicantos oculares, pelos quais registramos os eletroscilogramas continuamente por 24 horas, dos quais foram analisados os registros eletroscilográficos e demais parâmetros da arquitetura do ciclo vigília-sono. As crises ocorriam preferencialmente durante o período escuro, coincidindo com a maior prevalência de estados de vigília. O ciclo vigília-sono sofreu intensa fragmentação nos ratos epilépticos, e a duração média de algumas fases do sono foi mais prolongada nos ratos epilépticos do que nos sadios. As manifestações eletrofisiológicas das crises assumiram várias formas, predominando, porém, os complexos espícula-onda (de 7 a 9,5 Hz) o que se assemelha muito à faixa de oscilação das ondas teta. As características eletrofisiológicas e comportamentais da epilepsia que estudamos recomendam o estudo acurado e abrangente desse modelo de síndrome epiléptica, por sua semelhança com as crises encontradas em humanos, mas também por algumas discrepâncias em relação a modelos de epilepsia genética ou experimental já existentes.

Lamotrigine for absence seizures in children and adolescents：a systematic review / 药学实践杂志

Objective To assess the efficacy and safety of lamotrigine for absence seizures in children and adolescents . Methods Databases of PubMed ,the Cochrane Library ,EMbase ,CENTRAL ,VIP ,WanFang ,CBM and CNKI were electron-ically searched till August ,2014 for clinical trials on lamotrigine for absence seizures in children and adolescents .All literature were screened by two reviewers independently according to the inclusion and exclusion criteria .The data was extracted ,and the methodological quality was assessed .Then ,meta-analysis was performed using RevMan 5 .2 .Results Seven trials were in-cluded involving a total of 721 patients .The results of methodological qualities were two studies rated as A-class ,three studies rated as B-class and two studies rated as C-class .Meta-analysis results showed that the efficacy of lamotrigine monotherapy for absence seizure in children and adolescents was better than placebo ,but efficacy of lamotrigine was lower than valproic acid and ethosuximide .The adverse reaction rates of lamotrigine were with no significant difference compared with valproic acid and et-hosuximide .Conclusion Lamotrigine monotherapy was effective for absence seizures in children and adolescents and was well tolerated .Lamotrigine was a good choice for patients that are intolerable to valproic acid or ethosuximide .

Clinical and electroencephalographic characteristics of a cohort of patients with epilepsy and absence seizures / Características clínicas e eletrencefalográficas de uma coorte de pacientes com epilepsia com crises de ausência

BACKGROUND: Epileptic syndromes with absence seizures (AS) possess unique clinical and electroencephalographic (EEG) characteristics. In typical or atypical AS, ictal phenomenology may include various characteristics. Vídeo-EEG monitoring enables findings to be correlated with ictal phenomenology. OBJECTIVE: To evaluate the different AS in a cohort of patients with drug-resistant epilepsy (DRE) based on the International League against Epilepsy (ILAE)'s 2006 classification, to correlate with ictal phenomenology recorded and to apply the Panayiotopoulos criteria. METHOD: This study included patients with criteria of AS followed up at the Epilepsy Clinic. A dual, cross-sectional cohort study was carried out between 2005 and 2008. Patients receiving care in the Epilepsy Program of the HUCFF-UFRJ, who had been investigated by video-EEG and who presented clinical and EEG criteria for absence seizures, typical or atypical, according to the criteria defined by the ILAE, were included in the study, independent of age onset, the review of clinical history, age onset, family history, epilepsy onset and evolution, seizures phenomenology, antiepileptic drugs response and neuroimaging studies were used to classify the patients among the different epileptic syndrome associated to absence seizures. RESULTS: Typical absences were more frequent (71.4 percent) than atypical absences. Cases of juvenile absence epilepsy were the most frequent (19 percent) in this series, followed by childhood absence epilepsy (14.4 percent) and juvenile myoclonic epilepsy (4.8 percent). In 14 patients (66.67 percent), diagnosis was modified from focal epilepsy to primary generalized epilepsy. Clinical and EEG diagnosis of absence epilepsy resulted in a dramatic improvement in the control of seizures following modification of diagnosis and indication of an appropriate antiepileptic drug. CONCLUSION: Our results show that typical AS are more frequent than atypical. AS was ...

Síndromes epilépticas com crises de ausência (CA) possuem características clínicas e eletroencefalográficas (EEG) únicas. Nas crises de ausência típica ou atípica, a fenomenologia ictal pode incluir características que podem levar ao erro diagnóstico e à indicação de drogas antiepilépticas que pioraram o quadro. Quando esses pacientes são referidos a um Programa de Epilepsias para investigação, a monitorização por vídeo-EEG permite correlacionar os achados eletrográficos com a fenomenologia ictal. OBJETIVO: Identificar em uma coorte de pacientes com epilepsia fármaco-resistente (EFR), pacientes com CA segundo critérios propostos pela Liga Internacional contra a Epilepsia (ILAE) de 2006, correlacionar a fenomenologia ictal ao EEG e aplicar os de critérios Panayiotopoulos neste grupo. MÉTODO: Estudo de corte transversal incluiu doentes encaminhados ao Programa de Epilepsia do HUCFF-UFRJ entre 2005 e 2008, investigados por vídeo-EEG e que apresentavam os critérios clínicos e EEG para CA típicas ou atípica; a revisão da história clínica, idade início, história familiar de epilepsia, evolução, a fenomenologia ictal, resposta a drogas antiepilépticas e estudos de neuroimagem foram utilizados para classificar os pacientes entre as diferentes síndromes epilépticas associadas a CA. RESULTADOS: As CA típicas foram mais freqüentes (71,4 por cento) do que as atípicas. Casos de epilepsia ausência juvenil ocorreram em 19 por cento desta série, seguido por epilepsia ausência infantil (14,4 por cento) e epilepsia mioclônica juvenil (4,8 por cento). Em 14 pacientes (66,67 por cento), o diagnóstico de epilepsia focal epilepsia foi modificado para epilepsia generalizada primária. A mudança do diagnóstico de epilepsia focal para epilepsia com CA, seguido da troca para DAE adequadas, resultou em melhoria no controle de crises. CONCLUSÃO: Nossos resultados mostram que as CA típicas são mais freqüentes do que as atípicas. Em 10 pacientes, a aplicação dos critérios ...

Enfoque electroclínico de las epilepsias generalizadas idiopáticas con ausencias: [revisión] / Electrolytic approach of idiopathic generalized epilepsies with absences: [review]

La primera descripción de las crisis de ausencias data de 1705. Sin embargo, aún persiste el desconocimiento y la confusión en relación con algunos aspectos conceptuales, de clasificación, terminológicos, diagnósticos, pronósticos y de tratamiento de las diferentes formas de epilepsias con ausencias. El objetivo fundamental de esta publicación es tomar en consideración las denominadas epilepsias generalizadas idiopáticas con ausencias, en los aspectos clínicos y electroencefalográficos. Se realizó una revisión y actualización del tema.

The first description of absence seizures dates back to 1705. However, the lack of knowledge and confusion still persist as regards some aspects of concept, classification, terminology, diagnosis, prognosis and treatment of the different forms of epilepsies with absences. The fundamental purpose of this publication was to take into consideration the so-called idiopathic generalized epilepsies with absences in the clinical and electroencephalographic aspects. The topic was reviewed and updated.