Childhood Absence Research Articles

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.

A - 63 Sotos Syndrome: a Case Study

Abstract Objective Sotos syndrome is a genetic disorder characterized by pre and postnatal overgrowth and a non-progressive neurological disorder frequently accompanied by intellectual disability. The estimated prevalence is 1:14,000 live births; however, misdiagnosis is common due to features being attributable to other conditions. This case study highlights the broad range of symptom presentation in individuals with Sotos syndrome and adds to the limited available literature on this rare condition. Method The patient is a 26-year-old female with no prior neuropsychological testing presenting with concerns for cognitive functioning, regression of skills, and emotional/behavioral dysregulation. Concerns were raised for an underlying autism spectrum disorder. She presents with large stature, prominent facial configuration, and hypotonia. Developmental history was significant for delayed motor and language milestones. She has a history of absence seizures in childhood and was evaluated by neurology and medical genetics and diagnosed with Sotos syndrome. Results The patient’s overall intellectual functioning was in the exceptionally low range with a personal strength in verbal skills. Her neurocognitive results and low adaptive skills are indicative of a moderate intellectual disability. The patient’s developmental history, social difficulties, restrictive interests, and repetitive behaviors met criteria for autism spectrum disorder. Another notable finding was frequent starring spells in which she became unresponsive for approximately 15 seconds. Conclusion Delayed motor and language milestones, hypotonia, behavioral problems, and intellectual disability are common in individuals with Sotos syndrome and were present in the patient. Seizures and scoliosis are less common in individuals diagnosed, for which she was referred to a neurologist for further work-up.

Association of epilepsy and neurological impairments with homozygous recessive missense mutations found in the genes responsible for ganglioside biosynthesis (ST3GAL5) and calcium voltage-gated channels (CACNA1H) - insights through molecular dynamic simulations

With over 2.2 million cases, the incidence rate of epilepsy in Pakistan is far higher than the rest of the world due primarily to the frequent, traditionally imposed cousin marriages. In the present study, comprehensive whole exome sequencing (WES) analyses of a three-generation family with four affected members presenting ‘unexplained’ childhood absence epilepsy (CAE), seizures and dementia, was performed in a quest to identify heritable, epilepsy-causal gene variants to better aid in carrier screening and genetic counselling. The WES data was generated, analyzed, and validated through Sanger’s sequencing, molecular dynamic simulation (MDS) analysis, and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) studies. Two homozygous recessive, missense mutations in ST3GAL5 (c.311A > G, p. His104Arg) and CACNA1H (c.6230G > A, p. Arg2077His) genes, earlier regarded as benign or of uncertain significance, have been identified as a potential etiology. Comparative MDS and free binding energy calculations revealed substantial structural perturbations in mutant forms of ST3GAL5 leading to decreased binding and reduced catalytic activity of the p.His104Arg and two other functional variants (p.Val74Glu and p.Arg288Ter) when compared with wild type. Our findings reinforce that WES analyses may uncover ‘hidden’, heritable variants and together with MDS and MM/GBSA may provide plausible clues to answer the unexplained causes of epilepsy for an effective management and better patient outcome. Further, revisit of epilepsy-associated mutational landscape in population context is imperative as the variants with ‘benign’ tags may turn out to be ‘non-benign’, when exist in combination with other benign. Communicated by Ramaswamy H. Sarma

Relationship Between Electroencephalography and Seizure Outcome in Typical Absence Seizures in Children

BackgroundTypical absence seizures (TAS) are seen in idiopathic generalized epilepsy. Electroencephalography (EEG) contributes to syndrome characterization and counseling in an area where genetics does not currently play a significant role. Prominent interictal EEG findings are seen in juvenile absence epilepsy (JAE) and are thus thought to be associated with less favorable outcome in any TAS case despite lack of evidence. Our study evaluates EEG findings and their association with seizure outcomes in children with TAS. MethodsRetrospective cohort study of 123 children over 10 years with extensive EEG analysis and medical record review. Phone interviews ascertained longer-term outcomes. EEG reviewers were unaware of outcomes. ResultsTotal cohort included 123 children with phone review completed in 98. Median follow-up was 5 years 9 months. Seizure freedom was seen in 59% off antiseizure medicines (ASMs). Interictal findings included focal discharges in 29%, fragments of spike-wave (SW) discharges in 82.1%, and generalized interictal discharges in 63.4%. Interictal SW was more likely in those who slept (100%, 18 of 18) versus those who did not (57%, 60 of 105) (P < 0.001). Outcome analysis found no associations between focal or generalized interictal findings and seizure freedom, relapse off ASM, occurrence of other seizure types, or response to first ASM. ConclusionFocal and generalized interictal EEG discharges are common in children with TAS and are not associated with poorer outcomes. These interictal findings were traditionally associated with JAE rather than childhood absence epilepsy and were thus believed to be associated with potentially poorer outcome, which is probably not the case.

Preictal neuronal and vascular activity precedes the onset of childhood absence seizure: direct current potential shifts and their correlation with hemodynamic activity.

The neurovascular mechanisms underlying the initiation of absence seizures and their dynamics are still not well understood. The objective of this study was to better noninvasively characterize the dynamics of the neuronal and vascular network at the transition from the interictal state to the ictal state of absence seizures and back to the interictal state using a combined electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and diffuse correlation spectroscopy (DCS) approach. The second objective was to develop hypotheses about the neuronal and vascular mechanisms that propel the networks to the 3-Hz spikes and wave discharges (SWDs) observed during absence seizures. We evaluated the simultaneous changes in electrical (neuronal) and optical dynamics [hemodynamic, with changes in (Hb) and cerebral blood flow] of 8 pediatric patients experiencing 25 typical childhood absence seizures during the transition from the interictal state to the absence seizure by simultaneously performing EEG, fNIRS, and DCS. Starting from before the onset of the SWD, we observed a transient direct current potential shift that correlated with alterations in functional fNIRS and DCS measurements of the cerebral hemodynamics detecting the preictal changes. Our noninvasive multimodal approach highlights the dynamic interactions between the neuronal and vascular compartments that take place in the neuronal network near the time of the onset of absence seizures in a very specific cerebral hemodynamic environment. These noninvasive approaches contribute to a better understanding of the electrical hemodynamic environment prior to seizure onset. Whether this may ultimately be relevant for diagnostic and therapeutic approaches requires further evaluation.

Difficult to treat absence seizures in children: A single-center retrospective study.

ObjectivesThe aim of this study was to analyse the characteristics of typical absence seizures (AS), myoclonic AS and AS with eyelid myoclonia in children and to find associations between these characteristics and difficult to treat absence seizures (DTAS).MethodsThis was a single-center retrospective study. Electronic health records of pediatric patients with a clinical diagnosis of AS treated at a single tertiary epilepsy center between January 2013 and June 2020 were reviewed. Clinical characteristics, seizure information, ASM, and therapeutic response of patients were recorded. All patients were followed up for at least 1 year. DTAS were defined as failure to achieve remission after treatment with at least 2 anti-seizure medications (ASM), regardless of whether remission was achieved eventually in the study period.ResultsData from 131 patients were available for analysis. Remission was achieved after the first ASM treatment in 81 (61.8%) patients, and eventually in 120 (91.6%) during the study period. Epilepsy was classified as DTAS in 18 (13.7%) patients. AS were more often difficult to treat in patients with myoclonic AS and AS with eyelid myoclonia (40.0%), compared with patients with typical AS (11.4%; p = 0.012, 95% CI 1.480–25.732). A positive family history of epilepsy (p = 0.046; 95% CI 1.021–8.572), a higher seizure frequency (p = 0.023, 95% CI 1.009–1.126) prior to ASM treatment, and longer time between seizure onset and treatment onset (p = 0.026; 95% CI 1.006–1.099) were also associated with DTAS.SignificanceOur study suggests that several clinical characteristics of AS are associated with DTAS. One of these was the time between onset of AS and initiation of ASM treatment, which can be shortened with better care, suggesting that early diagnosis and treatment may improve prognosis in pediatric patients with AS. These findings remain to be confirmed in larger prospective studies.

Electro-clinical relationship and source analysis of absence seizures in childhood

Electro-clinical relationship and source analysis of absence seizures in childhood

Testicular androgens determining the incidence of spike-wave discharges in taiep rats: A model of H-ABC leukodystrophy

Absence seizures are characterized as a generalized type of epilepsy that occurs during childhood. Importantly, absence seizures in children often discontinue after puberty. There is limited availability of animal models in which electroencephalography (EEG) can be performed in the long term; however, two absence seizure models, GAERS and WAG/Rij albino rats, are available. The taiep rat is a myelin mutant rat with tubulinopathy due to a tubulin β 4A gene mutation and characteristic spike-wave discharges (SWDs) that mimic absence seizure epilepsy in humans and the above rat models. This study aimed to analyze spike-wave discharges after an orchiectomy was performed on postnatal day (PND) 2 or PND 90 in adult rats; and SWDs was recorded in both groups on PND 104. The results suggest that androgens play a critical role in susceptibility to SWDs. In fact, orchiectomy during the neonatal period significantly reduced the frequency of spike-wave discharges. However, if an orchiectomy was performed in adulthood, then SWDs were significantly increased. The mean duration of spike-wave discharges did not differ among the groups tested. Acute administration of testosterone (1 mg/kg) did not change the frequency or duration of spike-wave discharges in the control group or both orchiectomized groups. Overall, this study is the first to show a dichotomic influence of testicular androgens on spike-wave discharges. These findings will have implications in children with this type of generalized epilepsy and may explain the disappearance of absence epilepsy in two-thirds of patients after puberty.

Which antiseizure medications are effective for absence seizure in children and adolescents? A Cochrane Review summary with commentary.

The aim of this commentary is to discuss the published Cochrane Review ‘Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents’ by Brigo et al.,a under the direct supervision of the Cochrane Epilepsy Group. This Cochrane Corner is produced in agreement with Developmental Medicine & Child Neurology by Cochrane Rehabilitation. Absence seizures account for 10% to 17% of all seizures in children and adolescents.2 Absence seizures present as short sudden episodes of loss of awareness and can be divided into typical absence seizure, atypical absence seizure, and absence seizures with special features.3, 4 Sodium valproate, ethosuximide, and lamotrigine are three antiseizure medications commonly used to treat absence seizures. Ethosuximide is indicated only for the treatment of generalized absence seizure, whilst valproate and lamotrigine are used in other types of seizures. Non-systematic reviews have suggested that ethosuximide and sodium valproate are equally effective, while lamotrigine is considered as a second-line drug, reserved for intractable absence seizure.5 Accidental injury is a common complication of absence seizure; around 20% of adolescents with absence seizure were reported to suffer an injury during an absence seizure.6 This could impact their rehabilitation process and thus prescribing antiseizure medication based on evidence is important. The aim of this Cochrane Review was to determine the best choice of antiseizure medication for children and adolescents with typical absence seizure between ethosuximide, valproate, and lamotrigine compared with placebo and each other. The population addressed in this review were children and adolescents up to 16 years of age with typical absence seizure. The interventions studied were sodium valproate, ethosuximide, or lamotrigine as monotherapy or add-on treatment. The intervention was compared with placebo or with one another. The primary study outcomes were proportion of seizure-free participants at 1 month, 3 months, 6 months, 12 months, and 18 months after randomization; 50% or greater reduction in the frequency of seizures; and incidence of adverse effects. Secondary study outcomes included normalization of electroencephalogram (EEG) and/or negative hyperventilation test. The review authors searched the Cochrane Register of Studies (CRS) and MEDLINE (OVID) up to September 2020. The CRS Web included randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups. The authors also contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline), and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine, and ethosuximide respectively. They also reviewed references of identified studies and retrieved relevant studies. The review authors did not include any new studies in the present review. The review authors assessed five full-text reports for possible inclusion. However, the studies were excluded for the following reasons: three studies were commentaries; one a review; and another one not relevant to the current review. This current review is based on the eight studies (691 participants) from the 2019 review. The review authors did not perform meta-analysis due to the different methodologies used in the included studies. The authors concluded that ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with absence seizure with regards to both efficacy and tolerability. If absence and generalized tonic–clonic seizures coexist, valproate should be preferred, as ethosuximide is inefficacious on tonic–clonic seizures. The conclusions remain the same as the previous update as there was no new study found since the last version of the review was published. The review would influence the choice of antiseizure medication that should be prescribed for children and adolescents with typical absence seizure. Children with absence seizure are also at risk of having behaviour/psychiatric status, and psychosocial and cognitive function issues including attention, memory, and learning disability.7-9 This group of patients will often require multidisciplinary rehabilitation management. Selecting the best treatment for absence seizure is very important to optimize the outcome and improve the quality of life in patients with absence seizure. Poorly controlled absence seizure will lead to accidental injury and may influence the outcome of coordinated multidisciplinary rehabilitation management. Another issue to consider relates to females of child-bearing age, as a proportion of the adolescents will require antiseizure medication beyond the age group studied.10 There is a need to improve the design of randomized controlled trial research in this area to provide more concrete evidence to guide decision-making as most of the trials included in the systematic review are of poor methodological quality. The authors thank Cochrane Rehabilitation and Cochrane Epilepsy Group for reviewing the contents of the Cochrane Corner. The authors have stated that they had no interests that could be perceived as posing a conflict or bias.

Historical Context Changes Pathways of Parental Influence on Reproduction: An Empirical Test from 20th-Century Sweden

Several studies have found that parental absences in childhood are associated with individuals’ reproductive strategies later in life. However, these associations vary across populations and the reasons for this heterogeneity remain debated. In this paper, we examine the diversity of parental associations in three ways. First, we test whether different kinds of parental availability in childhood and adolescence are associated with women’s and men’s ages at first birth using the intergenerational and longitudinal Uppsala Birth Cohort Study (UBCoS) dataset from Sweden. This cultural context provides a strong test of the hypothesis that parents influence life history strategies given that robust social safety nets may buffer parental absences. Second, we examine whether investments in education help explain why early parental presence is associated with delayed ages at first birth in many post-industrial societies, given that parents often support educational achievement. Third, we compare parental associations with reproductive timing across two adjacent generations in Sweden. This historical contrast allows us to control for many sources of heterogeneity while examining whether changing educational access and norms across the 20th-century change the magnitude and pathways of parental influence. We find that parental absences tend to be associated with earlier first births, and more reliably so for women. Many of these associations are partially mediated by university attendance. However, we also find important differences across cohorts. For example, the associations with paternal death become similar for sons and daughters in the more recent cohort. One possible explanation for this finding is that fathers start influencing sons and daughters more similarly. Our results illustrate that historical changes within a population can quickly shift how family affects life history.

Association between GABRG2 rs211037 polymorphism and idiopathic generalized epilepsies: a meta-analysis

BackgroundWe performed this meta-analysis to investigate the association between GABRG2 rs211037polymorphism and the risk for idiopathic generalized epilepsies (IGEs).MethodsMedline, Embase, Cochrane Library and Chinese National Knowledge Infrastructure (CNKI) databases were searched for eligible studies (until May 5, 2020) on the association between GABRG2 rs211037 polymorphism and IGE. The odds ratios were calculated using a fixed or random model in STATA 15.0 software. Subgroup analyses for ethnicity, age, source of controls, type of seizure syndrome and therapeutic responses were conducted.ResultsWe found no significant associations between GABRG2 rs211037 polymorphism and the susceptibility to IGEs. In addition, no significant association was detected between GABRG2 rs211037 polymorphism and drug resistance in IGE patients. The results did not change after stratification by Asian population, healthy controls, children, juvenile myoclonic epilepsy, and childhood absence epilepsy.ConclusionThe current studies indicated that the GABRG2 rs211037 polymorphism was not related to susceptibility or drug resistance of IGE. Further well-designed studies are needed to verify the results.

Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents.

This is an updated version of the Cochrane Review previously published in 2019. Absence seizures (AS) are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with AS. To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures (AS), when compared with placebo or each other. For the latest update we searched the Cochrane Register of Studies (CRS Web, 22 September 2020) and MEDLINE (Ovid, 1946 to September 21, 2020). CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with AS: ethosuximide, sodium valproate, lamotrigine, or placebo. Outcome measures were: 1. proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; 2. individuals with a 50% or greater reduction in seizure frequency; 3. normalisation of EEG and/or negative hyperventilation test; and 4. adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). We used GRADE quality assessment criteria to evaluate the certainty of evidence for the outcomes derived from all included studies. On the basis of our selection criteria, we included no new studies in the present review. Eight small trials (total number of participants: 691) were included from the earlier review. Six of them were of poor methodological quality (unclear or high risk of bias) and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from randomised controlled trials (RCTs) to support a specific effect on AS for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in 453 children with newly diagnosed childhood absence epilepsy found that at 12 months, seizure freedom was higher in patients taking ethosuximide (70/154, 45%) than in patients taking lamotrigine (31/146, 21%; P < 0.001), with no difference between valproate (64/146, 44%) and ethosuximide (70/154, 45%; P > 0.05). In this study, the frequency of treatment failures due to intolerable adverse events was significantly different among the treatment groups, with the largest proportion of adverse events in the valproic acid group (48/146, 33%) compared to the ethosuximide (38/154, 25%) and the lamotrigine (29/146, 20%) groups (P < 0.037). Overall, this large study demonstrates the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. This study provided high certainty of the evidence for outcomes for which data were available. However, the certainty of the evidence provided by the other included studies was low, primarily due to risk of bias and imprecise results because of the small sample sizes. Hence, conclusions regarding the efficacy of ethosuximide, valproic acid and lamotrigine derive mostly from this single study. Since the last version of this review was published, we have found no new studies. Hence, the conclusions remain the same as the previous update. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with AS. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures.

Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

Hyperventilation-induced high-amplitude rhythmic slowing: A mimicker of absence seizures in children

PurposeHyperventilation (HV) in children can lead to HV-induced high-amplitude rhythmic slowing (HIHARS) on the EEG (electroencephalogram) which is sometimes associated with altered awareness (AA) and concomitant semiological features. Our aims were to determine the frequency of HIHARS in children, to assess if the associated semiological features were temporally related to HV, and to evaluate if specific semiological features can differentiate HIHARS with AA from absence seizures. MethodsConsecutive children with suspected new onset seizure(s) underwent HV and awareness testing during video-EEG acquisition. Hyperventilation-induced high-amplitude rhythmic slowing was defined as 2.5- to 5-Hz generalized rhythmic slowing with amplitude ≥100 μv lasting for ≥3 s. The associated semiological features were compared between the group of children with HIHARS and AA, an age- and gender-matched control group without HIHARS, and in children who experienced absence seizures during HV. ResultsOne hundred sixteen children with a mean age of 9.8 years were included. Hyperventilation-induced high-amplitude rhythmic slowing occurred in 39 children (33.6%) with AA documented in 30 (76.9%). The probability of developing AA during HIHARS was significantly and positively correlated with the HIHARS duration. The frequencies of HIHARS were not significantly different between children diagnosed with seizure(s) and those with nonepileptic spells. Hyperventilation cessation and staring did not occur in any child of the control group. Fidgeting and yawning were significantly more common in the group with HIHARS with AA while staring and blinking were significantly more frequent in the group of children with absence seizures. ConclusionsWe ascertained that HIHARS with AA is a relatively common occurrence in children and most likely represents an age-related nonepileptic phenomenon. When associated with fidgeting or yawning, it can help differentiate this phenomenon from absence seizures. However, recording the concomitant presence of generalized spike wave discharges on the EEG remains essential to confirm the diagnosis of absence seizures.

The efficacy and safety of lamotrigine for absence seizures in children and adolescents: A systematic review and meta-analysis

AimsThis systematic review and meta-analysis of randomized controlled trials (RCTs) systematically explored the effectiveness and safety of lamotrigine for absence seizures in children and adolescents. MethodsKeywords searches were conducted in Pubmed Embase Cochrane Central Register of Controlled Trials Wanfang CNKI from inception through March 2019. The RCTs comparing lamotrigine with other drugs and/or placebo for the treatment of absence seizures in children and adolescents were considered in this study. The study was conducted adhering to PRISMA guidelines. ResultsEight RCTs (n = 787) were included in our study. Among these studies, one study (N = 45 patients) used placebo as a control and seven studies (N = 742 patients) used positive drug controls. For effectiveness, there was significant difference between lamotrigine and valproate [OR = 0.42, 95%CI (0.28–0.63), I2 = 0%] or ethosuximide [OR = 0.34, 95%CI (0.22–0.53), I2 = 0%]. For adverse effects (AEs), there was no significant difference between lamotrigine and valproate [OR = 1.17, 95%CI (0.59, 2.32), I2 = 0%] or ethosuximide [OR = 0.75, 95%CI (0.47, 1.19), I2 = 92%], and the most common adverse effects of lamotrigine were Rash (7.88%), Fatigue (6.50%) and Headache (6.50%). ConclusionsAccording to current evidence, LTG is less effective than VPA and ESM, however, based on its relative safety, LTG might be reasonably tried as initial therapy in children and adolescents at risk of significant adverse effects from VPA and ESM, and future well-designed studies are needed to confirm our findings.

Historical trend toward improved long-term outcome in childhood absence epilepsy

We retrospectively analyzed published studies to investigate historical trends in outcome of childhood absence epilepsy (CAE). We included patients based on onset of absence seizures in childhood, 3 Hz bilateral spike-wave discharges on EEG, and availability of seizure-free outcome data. The primary endpoint was seizure-freedom off medications by study publication year. We also analyzed relationships between seizure-freedom and 1. treatment medication, and 2. CAE diagnostic criteria. We included 29 studies published 1945–2013, encompassing 2416 patients. Seizure-freedom off medications was higher for studies after 1985 versus before 1975 (82% versus 35%; p < 0.001). Ethosuximide and valproate were used more commonly after 1985, and patients previously treated with ethosuximide or valproate had higher seizure-freedom off medications than those treated only with other medications (64% versus 32%; χ2>10; p < 0.001). Although differences in diagnostic criteria for early vs. later studies did not reach statistical significance, later studies tended to use normal EEG background (p = 0.09) and absence of comorbid disorders (p = 0.09) as criteria more commonly. These findings demonstrate that seizure-freedom off medications has improved in published CAE studies after 1985. Our results are limited due to retrospective analysis. Further work is needed with prospective, controlled trials to establish factors leading to improved long-term prognosis in CAE.

Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents.

This is an updated version of the Cochrane Review previously published in 2017.Absence seizures (AS) are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with AS. To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures (AS), when compared with placebo or each other. For the latest update we searched the Cochrane Register of Studies (CRS Web, 29 May 2018), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 29 May 2018), ClinicalTrials.gov (29 May 2018) and the WHO International Clinical Trials Registry Platform (ICTRP, 29 May 2018). Previously we searched Embase (1988 to March 2005) and SCOPUS (1823 to 31 March 2014), but this is no longer necessary because randomised controlled trials (RCTs) and quasi-RCTs in Embase and SCOPUS are now included in CENTRAL. No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with AS: ethosuximide, sodium valproate, lamotrigine, or placebo. Outcome measures were: (1) proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test; and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). We used GRADE quality assessment criteria to evaluate the certainty of evidence derived from all included studies. On the basis of our selection criteria, we included no new studies in the present review. Eight small trials (total number of participants: 691) were included from the earlier review. Six of them were of poor methodological quality (unclear or high risk of bias) and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from RCTs to support a specific effect on AS for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in 453 children with newly diagnosed childhood absence epilepsy found that at 12 months, the freedom-from-failure rates for ethosuximide and valproic acid were similar and were higher than the rate for lamotrigine. The frequency of treatment failures due to lack of seizure control (P < 0.001) and intolerable adverse events (P < 0.037) was significantly different among the treatment groups, with the largest proportion of lack of seizure control in the lamotrigine cohort, and the largest proportion of adverse events in the valproic acid group. Overall, this large study demonstrates the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. The risk of bias for this study was low. We rated the overall certainty of the evidence available from the included studies to be moderate or high. Since the last version of this review was published, we have found no new studies. Hence, the conclusions remain the same as the previous update. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with AS. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.

EEG of asymptomatic first-degree relatives of patients with juvenile myoclonic, childhood absence and rolandic epilepsy: a systematic review and meta-analysis.

Rolandic (RE), childhood absence (CAE) and juvenile myoclonic (JME) epilepsy encompass centrotemporal sharp waves, 3-Hz spike waves and >3-Hz spike or polyspike waves, respectively. Evidence abounds for genetic roles in all three syndromes, yet involved genes for the vast majority of patients remain unknown. It has long been proposed that while each disease is genetically complex, its specific EEG trait may represent a genetically simpler endophenotype. This meta-analysis of the literature focuses on the frequency of EEG traits in clinically unaffected first-degree relatives towards determining inheritance patterns of the EEG endophenotypes. We used the Preferred Reporting Items for Systematic Review and Meta-Analysis for protocols (PRISMA-P) and searched Medline, EMBASE, CINHAL and the Cochrane Central Register of Controlled Trials. Following extensive screening, 15 studies were included with a total of 3,858 asymptomatic relatives. The prevalence of 'abnormal' EEG waves was 21%, 42% and 33% for JME, CAE and RE, respectively, close to what would be expected based on Mendelian inheritance. However, breaking down the reported EEG abnormalities, most consisted not of the respective EEG signature traits -prevalences of which were as low as 5%- but of non-specific EEG 'abnormalities'/variants. Prevalence of non-specific EEG 'abnormalities'/variants in the general population ranges from 0.1 to 10%. Underlying this 100-fold-wide range is a spectrum of what is considered 'abnormal' or variant. The prevalences of 'abnormalities'/variants in asymptomatic siblings in RE, CAE and JME significantly exceed even the highest value in the general population and fall within Mendelian expectations. These results suggest that EEG 'abnormalities'/variants shared with the general population are enriched in the three syndromes and are endophenotypes inherited in a genetically simple near-Mendelian fashion. Future work with modern EEG variant definitions should uncover genetic variants contributing to neuronal hypersynchrony in epilepsy.

Electroclinical Features of Generalized Paroxysmal Fast Activity in Typical Absence Seizures

Generalized paroxysmal fast activity (GPFA) is a diffuse, paroxysmal, frontal predominant activity described in patients with generalized epilepsies. Studies specifically focusing on electroclinical features of typical absence seizures in children have not reported any GPFA-like features. We sought to identify GPFA in children with typical absence seizures, study its incidence, characteristic electroclinical features, and effect on their epilepsy. We performed a retrospective review of electroencephalograms of children with diagnosis of absence epilepsy. A total of 173 subjects were identified. In subjects with GPFA on their electroencephalograms, GPFA characteristics were collected (i.e., predominant location, duration, amplitude, frequency, provocation factors, and if GPFA was followed by spike-wave discharges). In GPFA-positive subjects, further data sets were collected examining their demographics, duration of epilepsy, and pharmacoresponsiveness to epilepsy. Generalized paroxysmal fast activity was identified in 10 subjects (5.78%) with female to male ratio of 9:1. Median age of subjects was 17 years, and median duration of illness was 9.5 years. Mean maximum GPFA amplitude was 88.3 μV with posterior predominance in 9/10 subjects. Generalized paroxysmal fast activity frequency ranged between 11 and 20 Hz with duration of 1 to 4 seconds. Generalized paroxysmal fast activity was provoked with eye closure, hyperventilation, and photic stimulation. Antiseizure medications had no effect on GPFA, and epilepsy was well controlled in most subjects. Generalized paroxysmal fast activity is uncommon in children with typical absence seizures and has medium voltage, posterior predominance, and marked female preponderance. Generalized paroxysmal fast activity is seen during both pharmacoresponsive and drug-resistant epilepsy, and is not affected by antiseizure medications. It may serve as an independent marker of lifelong epilepsy.

Amantadine for the Treatment of Refractory Absence Seizures in Children.

Introduction:Childhood epilepsy is a generalized epilepsy syndrome with a favorable response to antiepileptic drugs; however, a small percentage of typical absence seizures remain refractory to drugs. We studied the safety and efficacy of amantadine in children with refractory absence seizures.Materials and Methods:Of 48 children with typical absence seizures attending the outpatient department of a tertiary care neurological center over a period of 3 years from July 2013 to June 2016, 4 children who were refractory to standard treatment for at least 1 year were selected and were started on amantadine 4–6 mg/kg/day, after obtaining informed consent.Observations:The children, aged between 7 and 14 years, had more than 10 episodes of seizures per day in spite of polytherapy with valproate, lamotrigine, clonazepam, levetiracetam, and topiramate in various combinations. Electrographically, all showed the typical generalized 3 Hz spike wave discharges activated by hyperventilation. All the children became seizure free within 1 week after starting amantadine, and there was improvement in their school performance. The children continue to remain seizure free for 6–30 months now. No significant adverse effects were observed on addition of amantadine.Discussion:Amantadine can be tried as a safe add-on drug for children with absence epilepsy refractory to multiple drugs. Further multicenter trials may be needed to prove its effectiveness, as the numbers are small.