The epidemiology of the epilepsies in children

The epilepsies are a heterogeneous collection of neurological conditions and syndromes characterized by recurrent, unprovoked, paroxysmal seizure activity. There are several types of epileptic seizures and syndromes that are unique to children, including infantile spasms, Lennox-Gastaut syndrome and absence seizures. Febrile seizures and neonatal seizures, while not epilepsy, are relatively common types of seizures in infants and children and are likely markers of risk of later epilepsy. Thus, it is important to consider the epidemiological features of the epilepsies as they occur specifically in infants and children. The purpose of this review is to summarize what is currently known about the epidemiology of the childhood epilepsies and to identify promising areas for further population-based studies. The epilepsies are an important cause of neurological morbidity in children. The average annual rate of new cases (incidence) of epilepsy is approximately 5-7 cases per 10,000 children from birth to age 15 years, and in any given year, about 5 of every 1,000 children will have epilepsy. There is evidence that the incidence of the epilepsies in some populations of children may be decreasing over time, and this possibility merits further investigation. Factors that are known to increase risk of the epilepsies in children include congenital malformations of the central nervous system (CNS), moderate or severe head trauma, CNS infections, certain inherited metabolic conditions, and genetic factors. However, these account for only 25% to 45% of cases, and thus, the etiology of most cases of the epilepsies remains obscure. The paucity of well-controlled etiological studies is due largely to formidable methodological problems in conducting epidemiological studies of the epilepsies. The prognosis for seizure control is generally good, although children with remote symptomatic seizures and those with additional neurological disabilities do less well.     

Epilepsy genes: the link between molecular dysfunction and pathophysiology

Our understanding of the genetic basis of epilepsy is progressing at a rapid pace. Gene mutations causing several of the inherited epilepsies have been mapped, and several more are likely to be added in coming years. In this review, we summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, emphasizing how genetic defects may correlate with the pathophysiological mechanisms of brain hyperexcitability. Mutations leading to epilepsy have been identified in genes encoding voltage- and ligand-gated ion channels (benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, generalized epilepsy with febrile seizures "plus"), neurotransmitter receptors (Angelman syndrome), the molecular cascade of cellular energy production (myoclonic epilepsy with ragged red fibers), and proteins without a known role in neuronal excitability (Unverricht-Lundborg disease). Gene defects can lead to epilepsy by altering multiple and diverse aspects of neuronal function.     

Seizure types, epilepsy syndromes, etiology, and diagnosis

The clinical manifestation of epileptic seizures may vary widely from patient to patient, depending on the region of the brain involved. Over the centuries, many seizure classification systems have been used, and the current most widely used classification system is that of the International League Against Epilepsy (ILAE). The ILAE system divides seizures into those of partial onset and those of generalized onset, depending on whether the initial clinical manifestations indicate that one cortical region or both hemispheres are involved at the onset of the seizure. Partial seizures are then divided into simple partial seizures, in which a fully conscious state is retained, or complex partial seizures, in which consciousness is impaired. A more recent classification system based purely on symptom features and signs has been proposed, and this system may provide advantages for localization, and especially for surgical evaluation. Epilepsy is a condition characterized by recurrent unprovoked seizures. Epilepsy may be idiopathic, cryptogenic, or symptomatic. Idiopathic epilepsies are generally genetic, and while many such syndromes have been described, advances in molecular genetics will undoubtedly reveal many more syndromes in the near future. Cryptogenic epilepsies are those in which an underlying cause is suspected, but the etiology remains undetected. Epilepsies for which there is an underlying structural cause or major metabolic derangement are considered symptomatic. Common causes and diagnostic evaluation are described in this article.     

The debt of neuropsychology to the epilepsies.

Both neuropsychology and psychology in general have been enhanced markedly by brain-behavior models derived from the study of the epilepsies. A significant body of neuropsychological concepts originated or were confirmed through epilepsy-based treatment and research. These concepts include the peri-Rolandic homunculus, the role of the hippocampal-temporal lobe complex in cognitive memory, hemisphere plasticity for speech in childhood, the intracarotid amytal procedure for determining hemisphere memory patency, and hemisphere-based models of cognition confirmed through human commissurotomy. Personality and social-emotional research in epilepsy are additional areas in which new conceptual models grounded in psychological science can both repay our debt to the epilepsies and provide much needed psychological research and treatment.     

Behavioral aspects of epilepsy in children with mental retardation

Epilepsy and mental retardation, two relatively common childhood conditions, are both associated with a wide range of behavioral disorders. This article reviews the behavioral disturbances found in children with epilepsy, mental retardation, and both conditions. The behavioral disturbances found in children with epilepsy are associated with seizure-related, cognitive, developmental, and psychosocial factors. Although children with mental retardation also demonstrate a broad spectrum of behavioral disturbances, children with specific mental retardation syndromes have better-defined patterns of psychopathology. The presence of epilepsy and mental retardation seems to increase the severity of psychopathology. Further studies are needed, however, to define better the interaction of these two conditions and how they impact the behavior of children.     

A Systematic Review of Psychiatric and Psychosocial Comorbidities of Genetic Generalised Epilepsies (GGE)

Psychiatric disorders and associated poor psychosocial outcomes are recognised to be a common sequelae of epilepsy. The extent to which this is true of genetic generalised epilepsies (GGE), particularly syndromes other than juvenile myoclonic epilepsy (JME) is unclear. This systematic review synthesises findings regarding psychiatric and associated comorbidities in adults and children with GGE. Systematic review yielded 34 peer-reviewed studies of psychiatric and psychosocial outcomes in adults and children with GGE. Clinically significant psychiatric comorbidity was reported in over half of all children and up to a third of all adults with GGE. There was no evidence to support the presence of personality traits specific to JME or other syndromes; rather rates mirrored community samples. A small number of studies report poor psychosocial outcomes in GGE, however the interpretation of these findings is limited by paucity of healthy comparison groups. Some evidence suggests that anti-epileptic drug polytherapy in children and seizure burden at all ages may constitute risk factors for psychopathology. Findings highlight the importance of early screening so as not to overlook early or developing symptoms of psychopathology.     

Die neuen Klassifikationen von epileptischen Anfällen und Epilepsien

In 2010 the classification and terminology committee of the International League Against Epilepsy (ILAE) presented a revised proposal for the classification of epileptic seizures and epilepsy, which is also available as a German translation. In 2016 this commission presented an operational classification of epileptic seizures and new concepts for the classification of epilepsy. The essential amendments and aspects of this new classification system in comparison to the previous classification of epileptic seizures and epilepsy are briefly summarized and exemplified by two case reports.     

Psychoses in epilepsy

The heterogenous psychoses in epilepsies, caused by well known conditions, are not rare but associated with regularly a few of seizure-types not with the nature and development of attacks. Polar transitional ranks and converging courses of schizophrenic (accentuated) syndromes in epilepsies and idiopathic schizophrenias are rather frequent. Also (sub-)acute schizophrenic psychoses are corresponding to the complete palette of first and second rank symptoms (K. Schneider) of idiopathic schizophrenias. After manifestations of epilepsy these syndromes can appear at any time. It is given a profile of risks. Progressive avoidance of a. phenylaceturea, b. mixtures of antiepileptics did not put an end to psychotic syndromes: Long-term therapies with 1. Polytherapy, 2. Primidone and Phenytoin (dosedependant) as well as 3. Ethosuximide (-monotherapy) cause a disorder of feed back mechanisms, especially a disturbed regulation of vigilance and sleeping-waking-cycle and their psychological correlates. Carbamazepine and Sodium Valproate are, plasma-level-controlled of preventive antipsychotic effect. Selected neuroleptics of rather slight epileptogenic potency are of going down importance. Benzodiazepines are required mostly in prepsychotic syndromes, Lithium compounds in selected cases. There is no more alternative seizures or psychosis.     

Effectiveness and safety of epilepsy surgery: what is the evidence?

Evidence from a recent randomized controlled trial of surgical versus medical therapy of temporal lobe epilepsy proves that antero-mesial resection is safe and more effective than medical therapy. The number of patients needed to treat for one patient to become free of disabling seizures is two, which is superior to most interventions in neurology. A meta-analysis of non-randomized trials gives almost identical results; about two-thirds of patients become seizure-free, compared with only 8% with medical therapy. The results are remarkably similar among studies from different parts of the world. Quality of life improves early after epilepsy surgery, the improvements are both statistically and clinically significant, and they are sustained. Surgical morbidity with clinically important permanent sequelae is 2%. Epilepsy surgery remains underutilized in developed countries and it does not exist in all but a few developing countries. Current randomized trials are underway to explore the effect of early surgery versus optimum medical therapy on the prevention of disability in patients with mesial temporal lobe epilepsy, and to examine the effectiveness of novel interventions, such as minimally invasive surgery and brain stimulation.     

自由基在癫痫发生及其治疗中的研究现状与进展

癫痫是一组包括许多不同症状的综合征,其主要特征是对反复出现的无明显诱因的发作的易感性。无论动物实验还是临床观察均表明癫痫时伴有活跃的自由基反应,自由基与癫痫的发生发展有着密切的联系。清除自由基,阻断自由基反应无疑为癫痫的治疗开辟了新的途径。本文就自由基在癫痫发生及其治疗中的研究现状与进展作一概述。目前应用自由基清除剂治疗癫痫尚处于临床试验阶段,但我们可以预见,进一步探索癫痫发生的自由基病理机制,开发有效清除自由基的药物具有广阔的前景,并将为人类最终战胜癫痫提供有力的帮助。     

Comparison between two opposite homicidal syndromes (Syndrome e vs. limbic psychotic trigger reaction)

Two syndromes with opposite kinds of homicidal acts also implicate opposite activation of frontal lobe and limbic systems. I. Fried's “Syndrome E” refers to planned, ideologically-motivated mass murders, committed in groups and accompanied by “elation.” Implicated are heightened functioning of certain frontal lobe regions with certain reduced limbic involvement . In contrast, A. A. Pontius' “Limbic Psychotic Trigger Reaction” delineates unplanned, motiveless homicidal acts (so far 17 cases) committed by a single loner with flat affect, implicating a partial limbic seizure hyperactivation with fleeting psychosis and brief secondary dysfunctioning of certain frontal regions.     

Drug treatment of epilepsy: when does it fail and how to optimize its use?

Although modern community-based studies have shown that a majority of people with newly diagnosed epilepsy will enter long-term remission, seizures remain refractory to treatment in a substantial proportion of this population--perhaps as much as 40%. A consensus is being reached that, for operational purposes, pharmacoresistance can be suspected when two appropriately chosen, well-tolerated, first-line antiepileptic drugs (AEDs) or one monotherapy and one combination regimen have failed due to lack of efficacy. Poor prognostic factors include lack of response to the first AED, specific syndromes, symptomatic etiology, family history of epilepsy, psychiatric comorbidity, and high frequency of seizures. These observations suggest that prognosis can often be determined early in the course of the disorder. We propose a management paradigm that aims to maximize the chance of successful AED therapy, including the early use of "rational polytherapy" for patients not responding to monotherapy, and to identify efficiently patients suitable for "curative" resective surgery, in particular those with mesial temporal lobe epilepsy. An orderly approach to each epilepsy syndrome will optimize the chance of perfect seizure control and help more patients achieve a fulfilling life.     

Classroom performance and adaptive skills in children with epilepsy

The relationships of age at onset, seizure syndrome, seizure type, and seizure frequency, respectively, to the classroom performance and adaptive skills of 131 children with epilepsy were studied. The Teacher Report Form of the Child Behavior Checklist was completed by the children's teachers. Hierarchical multiple regression analyses were conducted on ratings of academic subject areas and overall adaptive skills. Significant results were obtained for English/Language, Reading, Mathematics, overall School Performance, Learning, Happy, and Total Adaptive skills. Epilepsy syndrome and frequency of seizures were significantly related to some of these analyses, with amounts of variance accounted for ranging from 11% to 23%. Children with secondary generalized epilepsy performed significantly worse than children with other epilepsy syndromes. The results suggest that a seizure disorder associated with a diffuse or multifocal brain insult can produce problems in achievement and school adaptation as manifested on a day-to-day basis. Suggestions for future research are presented.     

Epilepsie – eine potenziell chirurgisch behandelbare Erkrankung

Epilepsy is one of the most frequent neurological diseases in adults. First line therapy consists of antiepileptic drugs. However, up to 50?% of patients with focal epilepsy do not adequately respond to medical therapy. After failure of two first-line drugs, patients should be referred to a comprehensive epilepsy center for evaluation of the possibility for epilepsy surgery. The noninvasive phase 1 includes history with eye witness report, clinical examination, structural and functional imaging techniques, simultaneous video-EEG monitoring as well as a neuropsychological examination. An invasive phase 2 can be added in cases with incongruent results. Subdural strip and grid electrodes as well as stereotactically implanted depth electrodes give more detailed information on seizure origin and spread. Detailed planning of the surgical approach is of utmost importance. In patients with temporal lobe epilepsy, seizure freedom can be achieved in 60–80?% of cases after epilepsy surgery.     

Lateralization of auditory rhythm length in temporal lobe lesions

In the visual modality, short rhythmic stimuli have been proven to be better processed (sequentially) by the left hemisphere, while longer rhythms appear to be better (holistically) processed by the right hemisphere. This study was set up to see if the same holds in the auditory modality. The rhythm task as originally designed by Seashore was computerized and is part of the Fepsy Neuropsychological battery. This task was performed by 85 patients with intractable temporal lobe epilepsy (left TLE = 32; right TLE = 53) enrolled in the Dutch Collaborative Epilepsy Surgery Program. They performed the task before and 6 months after surgery. The task consists of 30 pairs of rhythmic patterns in 3 series of 10 items. The series contains patterns of 5, 6, or 7 notes. The purpose is to indicate whether the two patterns are the same or different. Reaction times are also measured. If the hypothesis is true, the short-item sequence will be better processed by patients with right temporal lobe epilepsy (nonimpaired left temporal lobe), the longer sequence will be better processed by the left temporal epilepsy group (nonimpaired right temporal lobe). No overall laterality effect on rhythm perception could be found and no difference was found between both test moments. IQ did not correlate with rhythm performance. However, there was an interaction effect of laterality and rhythm length on performance and reaction time. This effect can be explained by the increase after the operation of the score of the left focus group and a decrease in the right focus group on the longer rhythms. This effect was somewhat less strong in the reaction times: a clear tendency for faster reaction times after surgery in the left and longer reaction times in the right focus group. The effect could not be explained for by the difference in extent of resection in either temporal lobe. This study showed that memory for and discrimination of auditory rhythm is dependent on which hemisphere is used in processing. The effect could be demonstrated for the right hemisphere, which uses a holistic processing of stimuli, which outperforms the left in rhythms consisting of a long sequence. In left temporal resections an improvement occurs on the longer rhythms and in right temporal resections the performance on the longest rhythms decreases.     

Use of operational criteria in an office practice for diagnosis of children referred for evaluation of learning or behavior disorders

100 consecutively referred school-age children were evaluated for learning or behavior disorders. 45 children had one of three classical neurological syndromes of epilepsy, sensorineural deafness, or childhood migraine. The 26 children with epilepsy required medication adjustment to improve behavior or learning. Operational criteria for childhood depression, specific learning disability, developmental hyperactivity, and Gilles de la Tourette syndrome were used to establish the correct diagnosis in 55 children. 32 children had a single diagnosis, while 23 children fulfilled the criteria of two diagnostic categories. The diagnostic categorization permitted specific counseling of the child and family, development of a proper school program, and correct pharmacotherapy (when indicated).     

Structural and functional imaging in children with partial epilepsy

Imaging plays an increasingly important role in the evaluation of children with complex partial seizures. Most partial epilepsy, especially of temporal lobe origin, begins during childhood. Structural imaging with high-resolution MRI can help identify the etiology of partial seizure disorders in many children. MRI studies also show the more widespread effect of seizures on brain structure. Progressive volume loss of the hippocampal formation in some patients with temporal lobe epilepsy provides evidence that continued seizures may be associated with progressive neuronal injury. FDG-PET studies show regional decreases in glucose consumption in the cortical zone from which seizures arise. Functional abnormalities often are more extensive than the seizure focus. Studies in children with recent-onset epilepsy show that metabolic abnormalities are considerably less common than in adults with partial epilepsy, supporting the notion that in some patients there may be progressive metabolic changes that occur with continued seizures. Functional MRI may be used to identify language areas in children with partial epilepsy. fMRI language tasks reliably identify the dominant hemisphere for language dominance when compared to the intracarotid amytal procedure. Tests of verbal fluency and semantic decision identify frontal lobe language areas, while reading text paradigms and auditory passage paradigms are better for identifying temporal language areas. A panel of paradigms is best used to identify language areas in children being considered for epilepsy surgery. fMRI is a valuable tool for elucidating the impact of chronic neurologic disease states on the functional organization of language networks during development.     

Sleep and arousal mechanisms in experimental epilepsy: epileptic components of NREM and antiepileptic components of REM sleep

Neural generators related to different sleep components have different effects on seizure discharge. These sleep-related systems can provoke seizure discharge propagation during nonrapid eye movement (NREM) sleep and can suppress propagation during REM sleep. Experimental manipulations of discrete physiological components were conducted in feline epilepsy models, mostly in the systemic penicillin epilepsy model of primary generalized epilepsy and the amygdala kindling model of the localization-related seizure disorder, temporal lobe epilepsy. The sleep-wake state distribution of seizures was quantified before and after discrete lesions, systemic and localized drug administration, and/or photic stimulation, as well as in relation to microdialysis of norepinephrine. We found that (1) neural generators of synchronous EEG oscillations--including tonic background slow waves and phasic "arousal" events (sleep EEG transients such as sleep spindles and k-complexes)--combine to promote electrographic seizure propagation during NREM and drowsiness, and antigravity muscle tone permits seizure-related movement; (2) neural generators of asynchronous neuronal discharge patterns reduce electrographic seizures during alert waking and REM sleep, and skeletal motor paralysis blocks seizure-related movement during REM; (3) there are a number of similarities between amygdala-kindled kittens and children with Landau-Kleffner Syndrome (LKS) that suggest a link among seizures, sleep disorders, and behavioral abnormalities/regression.     

Childhood Epilepsy and Autism Spectrum Disorders: Psychiatric Problems, Phenotypic Expression, and Anticonvulsants

Epilepsy and autism spectrum disorders (ASDs) frequently co-occur during childhood, however, the characteristics of psychiatric or behavioural problems in these children remains largely unknown. This article contributes to these discussions by reporting on the prevalence and presentation of psychiatric or behavioural problems in children with epilepsy and ASDs, as well as on the use of anticonvulsants in these children. The current evidence suggests that children with epilepsy and ASDs may present with a distinct clinical profile, with a greater number of developmental difficulties, and a more severe expression of the ASD phenotype that can not solely be accounted for by level of intellectual functioning. Positive effects of anticonvulsants on behavioural symptoms associated with ASDs were also reported, though pharmacoresistance and a lack of clear treatment guidelines may contribute to an elevated risk of adverse side effects. In relation to clinical presentation and management there is a need for careful consideration of potential interaction effects between disorder specific factors (e.g., age of seizure onset/ASD diagnosis), cognitive characteristics (e.g., intellectual functioning, memory), and psychosocial variables (e.g., coping strategies). Ultimately however, many conclusions are tentative and this review highlights the need for more empirically validated research on children with epilepsy and ASDs.     

Understanding the delay before epilepsy surgery: who develops intractable focal epilepsy and when?

Intractable temporal lobe epilepsy that is surgically treated in adulthood is a disorder whose onset frequently occurs during childhood and early adolescence. The average duration of epilepsy prior to surgery is on the order of 20 years. The long delay between onset and surgery has at least two components: time from onset to intractability and time from evidence of intractability to surgery. The first interval is prolonged >10 years especially if the onset is during childhood. This suggests a complex natural history that we have not fully appreciated as well as a potential window of opportunity for early secondary intervention. The second interval is also prolonged, especially if onset was during childhood. Reasons for this are not fully clear but may include a reluctance to consider surgery and perhaps difficulty deciding whether seizures are sufficiently intractable to warrant surgery especially after what may have been a relatively benign initial course. Factors involved in the second delay need to be better understood so that surgical interventions can be appropriately targeted early rather than late, thereby reducing serious social, psychological, and educational consequences associated with uncontrolled seizures.