Form Of Idiopathic Epilepsy Research Articles

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research.

The electrographic hallmark of childhood absence epilepsy (CAE) and other idiopathic forms of epilepsy are 2.5–4 Hz spike and wave discharges (SWDs) originating from abnormal electrical oscillations of the cortico-thalamo-cortical network. SWDs are generally associated with sudden and brief non-convulsive epileptic events mostly generating impairment of consciousness and correlating with attention and learning as well as cognitive deficits. To date, SWDs are known to arise from locally restricted imbalances of excitation and inhibition in the deep layers of the primary somatosensory cortex. SWDs propagate to the mostly GABAergic nucleus reticularis thalami (NRT) and the somatosensory thalamic nuclei that project back to the cortex, leading to the typical generalized spike and wave oscillations. Given their shared anatomical basis, SWDs have been originally considered the pathological transition of 11–16 Hz bursts of neural oscillatory activity (the so-called sleep spindles) occurring during Non-Rapid Eye Movement (NREM) sleep, but more recent research revealed fundamental functional differences between sleep spindles and SWDs, suggesting the latter could be more closely related to the slow (<1 Hz) oscillations alternating active (Up) and silent (Down) cortical activity and concomitantly occurring during NREM. Indeed, several lines of evidence support the fact that SWDs impair sleep architecture as well as sleep/wake cycles and sleep pressure, which, in turn, affect seizure circadian frequency and distribution. Given the accumulating evidence on the role of astroglia in the field of epilepsy in the modulation of excitation and inhibition in the brain as well as on the development of aberrant synchronous network activity, we aim at pointing at putative contributions of astrocytes to the physiology of slow-wave sleep and to the pathology of SWDs. Particularly, we will address the astroglial functions known to be involved in the control of network excitability and synchronicity and so far mainly addressed in the context of convulsive seizures, namely (i) interstitial fluid homeostasis, (ii) K+ clearance and neurotransmitter uptake from the extracellular space and the synaptic cleft, (iii) gap junction mechanical and functional coupling as well as hemichannel function, (iv) gliotransmission, (v) astroglial Ca2+ signaling and downstream effectors, (vi) reactive astrogliosis and cytokine release.

The study of sodium and potassium channel gene single-nucleotide variation significance in non-mechanical forms of epilepsy

BackgroundEpilepsy is one of the most common and heterogeneous neurological diseases. The main clinical signs of the disease are repeated symptomatic or idiopathic epileptic seizures of both convulsive and non-convulsive nature that develop against a background of lost or preserved consciousness. The genetic component plays a large role in the etiology of idiopathic forms of epilepsy. The study of the molecular genetic basis of neurological disorders has led to a rapidly growing number of gene mutations known to be involved in hereditary ion channel dysfunction. The aim of this research was to evaluate the involvement of single-nucleotide variants that modify the function of genes (SCN1A, KCNT1, KCNTС1, and KCNQ2) encoding sodium and potassium ion channel polypeptides in the development of epilepsy.ResultsDe novo mutations in the sodium channel gene SCN1A c.5347G>A (p. Ala1783Thr) were detected in two patients with Dravet syndrome, with a deletion in exon 26 found in one. Three de novo mutations in the potassium channel gene KCNT1 c.2800G>A (p. Ala934Thr), were observed in two patients with temporal lobe epilepsy (TLE) and one patient with residual encephalopathy. Moreover, a control cohort matched to the case cohort did not reveal any SNVs among conditionally healthy individuals, supporting the pathogenic significance of the studied SNVs.ConclusionOur results are supported by literature data showing that the sodium ion channel gene SCN1A c.5347G>A mutation may be involved in the pathogenesis of Dravet syndrome. We also note that the c.2800G>A mutation in the potassium channel gene KCNT1 can cause not only autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) but also other forms of epilepsy. To treat pathogenetic mutations that accelerate the function of sodium and potassium ion channels, we recommend ion channel blockade drug therapy.

Efficacy of levetiracetam monotherapy in epilepsy associated with benign epileptiform discharges of childhood

Aim. To analyze efficacy of levetiracetam monotherapy in patients with epilepsy associated with benign epileptiform discharges of childhood (BEDC). Materials and methods. We examined 29 pediatric patients with idiopathic and symptomatic BEDC-associated epilepsy, including continuous spike-and-wave epileptiform activity during slow-wave sleep (CSWS) in the stage of clinical remission. Of those, 12 children received antiepileptic treatment with valproic acid, and 17 children received levetiracetam. The examination included passive awake EEG recordings (with functional tests) as well as daytime sleep EEG recordings (within 60 minutes). Results. Levetiracetam was no less efficient in monotherapy of BEDC-associated epilepsy (including the CSWS patterns) than the traditionally used valproic acid, especially in idiopathic forms of epilepsy. Conclusion. Levetiracetam can be recommended for the first-choice basic anti-epileptic monotherapy treatment.

Features of treatment of focal epilepsia in adults

Now it is quite difficult to determine the true cause of the development of epilepsy. This is especially true of idiopathic and cryptogenic forms, which develop for no apparent reason. In such a process, there are no changes in the brain, or other conditions that can trigger the development of pathology. If there is an idiopathic form of epilepsy, the patient is supposed to get a disability. This is due to the fact that this disease leads to a significant limitation of a person in his work activity. We will not expand on how epilepsy is treated in the complex, because with each individual focal diagnosis the doctor prescribes his own set of drugs. But we will only talk about general principles. So, in most cases, the disease can be cured without surgery, only medicamentously. This does not mean, however, the rejection of social and therapeutic assistance, without which it will be difficult for a person to adapt in the society.

FEATURES OF TREATMENT OF FOCAL EPILEPSIA IN ADULTS

Now it is quite difficult to determine the true cause of the development of epilepsy. This is especially true of idiopathic and cryptogenic forms, which develop for no apparent reason. In such a process, there are no changes in the brain, or other conditions that can trigger the development of pathology. If there is an idiopathic form of epilepsy, the patient is supposed to get a disability. This is due to the fact that this disease leads to a significant limitation of a person in his work activity. We will not expand on how epilepsy is treated in the complex, because with each individual focal diagnosis the doctor prescribes his own set of drugs. But we will only talk about general principles. So, in most cases, the disease can be cured without surgery, only medicamentously. This does not mean, however, the rejection of social and therapeutic assistance, without which it will be difficult for a person to adapt in the society.

Physiological mechanisms of simulated purposeful activities of patients with epilepsy

We examined 102 patients with symptomatic, cryptogenic, and idiopathic forms of epilepsy in order to investigate the physiological mechanisms providing the efficiency of purposeful activity in patients with this disease. Three clusters of patients were formed with the use of the Gorbov-Shulte performance test. The patients of "low efficiency" cluster were characterized by the lack of habituation mechanisms in the activity of afferent systems and mechanism of motor response; the activity rate of stress adaptation systems and the rate of intrasystemic tension during the preparation to purposeful activities were higher than in patients of "intermediate" and "high performance" clusters.

JUVENILE MYOCLONIC EPILEPSY: A FOCUS ON THE EFFICACY OF THERAPY AND THE RATE OF RELAPSES ACCORDING TO LONG-TERM FOLLOW-UP DATA

Juvenile myoclonic epilepsy (JME) is a type of adolescent-onset idiopathic generalized epilepsy with the appearance of massive myoclonic seizures and, in most cases, generalized convulsions occurring chiefly in the period after awakening. It is assumed that there is a two-locus (dominant and recessive) model of inheritance of JME; moreover, the dominant gene is located on the short arm of chromosome 6. JME is one of the most common types of epilepsy and most frequent among idiopathic generalized epilepsies. Its rate is 5 to 11 % of all types of epilepsy with some female predominance. The diagnosis of JME creates no problems in typical cases. The disease is generally manifested by a concurrence of myoclonic (usually in the hands) and generalized clonic-tonic-clonic seizures occurring during waking. Typical absences and epileptic myoclonus of the eyelid are rarer. Seizures are clearly provoked by sleep deprivation. As in other types of idiopathic epilepsy, the patients’ neurological status is normal; no intellectual disabilities are observed. This type of epilepsy is well treatable and, when initial monotherapy is correctly used, sustainable remission occurs immediately in the vast majority (75–85 %) of the patients with JME. However, the problem of these patients, unlike that of patients with many forms of idiopathic epilepsy, is that sleep pattern disturbance, missing a dose of antiepileptic drugs (AED), or therapy refusal give rise to relapse of seizures in the vast majority of patients even in long-term remission. Due to the fact that the data available in the literature on the efficacy of therapy in patients with JME and particularly on the results of its discontinuation are contradictory, the authors of the paper conducted an investigation to determine therapeutic effectiveness and the frequency of relapse of seizures in patients with JME during a long-term follow-up. The study enrolled 106 JME patients who had been regularly followed up at the Saint Luka’s Institute of Pediatric Neurology and Epilepsy for 3 to 28 years (mean 8.6 years). The authors detailed the clinical characteristics of the disease and the results of the investigation in the observed patients. The investigation showed that JME was the second common type (next to rolandic epilepsy) among all idiopathic epilepsies. Clinical remission lasting 3 years or longer was achieved in the vast majority of cases (89.6 %); however, clinical and electroencephalographic remission was in only 22 % of the patients. Treatment was not absolutely ineffective in any of the cases. Monotherapy for JME was used in most patients (79 %), duotherapy in 17 % and polytherapy (3 AEDs) in 4 %. Valproate was most commonly used as monotherapy for JME (56 %); levetiracetam and topiramate were more rarely in 13 and 8 %, respectively. Unfortunately, despite the high effect of treatment, the recurrence rate during or after discontinuation of AED therapy (which was gradually done under guidance of video-assisted electroencephalographic monitoring at least 3–4 years after remission) was very high (92 %). The recurrence risk was highest when the dose was reduced by more than 50 % and within the first year after therapy discontinuation. Multiple attempts to discontinue the treatment were made at an interval of an average of 4.3-years of remission in a number of patients. The authors identified a number of factors increasing the recurrence risk after withdrawal of an AED.

Quality of life of children with epilepsy (neuropsychiatric and social aspects)

Epilepsy is one of the most common neurological diseases in childhood and adolescence. It is on the third place in the structure of diseases of the nervous system. The social significance of this disease is determined by the highest percentage in disability of patients. Currently, many leading national and foreign epileptologists expresses the same opinion that the one of the most important purposes in helping patients with epilepsy is to improve their quality of life. Cognitive disorders play a leading role in disturbances of patients’ adaptation in the community, so their role can be more considerable in disability than seizures, thus impairing the quality of life. The most common cognitive disorders in patients with epilepsy include memory impairment, retarded intellectual development and attention deficit disorder. In recent years, a special interest is given to the introduction of neuropsychological methods in studying the brain organization of higher mental functions in children with epilepsy. Analysis of neuropsychological features and characteristics of cognitive disorders with various forms of idiopathic epilepsy is of particular interest.

The diagnosis of idiopathic epilepsy in children based on the algorithm of molecular-genetic studies

To study mutations and polymorphisms in the sodium channels genes, determining the development of idiopathic epilepsy (IE). The study of SCN1A gene by direct Sanger sequencing in 53 patients and targeted resequencing of the regions of 34 genes in 40 patients with different clinical forms of IE was performed. Seven mutations (c.3022G>T, c.3637C>T, c.1144G>T, c.80G>C, c.1603C>T, c.2427G>A and c.1131A>C) were detected among 53 patients by direct Sanger sequencing of SCN1A gene. The mutations of SCN1A gene (2 - nonsense mutation, 5 - missense mutation) were identified in 7/40 (17.5%) patients with epilepsy using high-performance sequencing, Mutations in sodium channel genes encoding other subunits: SCN1B, SCN2A, SCN9A were identified in 6 patients. As epileptic encephalopathy is polygenic, it is important to conduct genetic testing of more genes (primarily sodium channel genes - SCN1B, SCN2A, SCN9A etc.) using special gene panels to find the molecular defect in DNA.

Problems of Rational Therapy for Epilepsy during Pregnancy

Epilepsy is one of the most frequent neurological disorders. In these circumstances, more than 25% of the patients are women of reproductive age. The aim of our research was to analyze the effectiveness and safety of antiepileptic therapy in women with epilepsy during pregnancy and to analyze the pregnancies’ outcomes. We included in our research 121 pregnancies of 101 women aged at the moment of childbearing about 26.9 ± 4.57 years old. Idiopathic forms of epilepsy were predominant among all causes—47.1% (р

Synapsin II and Rab3a Cooperate in the Regulation of Epileptic and Synaptic Activity in the CA1 Region of the Hippocampus

Some forms of idiopathic epilepsy in animals and humans are associated with deficiency of synapsin, a phosphoprotein that reversibly associates with synaptic vesicles. We have previously shown that the epileptic phenotype seen in synapsin II knock-out mice (SynII(-)) can be rescued by the genetic deletion of the Rab3a protein. Here we have examined the cellular basis for this rescue using whole-cell recordings from CA1 hippocampal pyramidal cells in brain slices. We find that SynII(-) neurons have increased spontaneous activity and a reduced threshold for the induction of epileptiform activity by 4-aminopyridine (4-AP). Using selective recordings of glutamatergic and GABAergic activity we show that in wild-type neurons low concentrations of 4-AP facilitate glutamatergic and GABAergic transmission in a balanced way, whereas in SynII(-) neurons this balance is shifted toward excitation. This imbalance reflects a deficit in inhibitory synaptic transmission that appears to be secondary to reduced Ca(2+) sensitivity in SynII(-) neurons. This suggestion is supported by our finding that synaptic and epileptiform activity at SynII(-) and wild-type synapses is similar when GABAergic transmission is blocked. Deletion of Rab3a results in glutamatergic synapses that have a compromised responsiveness to either low 4-AP concentrations or elevated extracellular Ca(2+). These changes mitigate the overexcitable phenotype observed in SynII(-) neurons. Thus, Rab3a deletion appears to restore the excitatory/inhibitory imbalance observed in SynII(-) hippocampal slices indirectly, not by correcting the deficit in GABAergic synaptic transmission but rather by impairing excitatory glutamatergic synaptic transmission.

Клиническая характеристика когнитивных расстройств у больных с эпилепсией

Изучена структура когнитивных расстройств у 72 больных — 38 (I группа) с симптоматической эпилепсией и 34 (II группа) с идиопатической эпилепсией, средний возраст которых составил 48 ± 25,3 года. Показано, что у больных с различными формами эпилепсии могут встречаться когнитивные нарушения, частота и выраженность которых зависит как от типа судорожных припадков, так и от вида и длительности приема антиэпилептических препаратов. Показано, что симптоматическая и идиопатическая формы эпилепсии имеют ряд различий по нейропсихологическим показателям.

Sam Berkovic: a need for answers

Sam Berkovic: a need for answers

The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins

The concept of epilepsy and seizure disorders caused by autoantibodies to specific neuronal membrane proteins has developed significantly during the past few years. Antibodies to cell-surface membrane proteins such as voltage-gated potassium channels or N-methyl-D-aspartate receptors, or to glutamic acid decarboxylase, are found in patients with different forms of limbic encephalitis, and in a few patients with epilepsy as their main or only condition. Many of these patients do not show a good response to conventional antiepileptic drugs, but respond to immunotherapies. By contrast, studies of other antibodies in idiopathic forms of epilepsy, or epilepsy associated with systemic lupus erythematosus or coeliac disease, have not in general disclosed consistent, clinically helpful results. There are a growing number of specific antibodies associated with new onset epilepsy. These patients are likely to have an immune-mediated disorder that may benefit from immunotherapies. In autoimmune diseases such as systemic lupus erythematosus or coeliac disease, antibodies to specific membrane targets may also prove to be important in the future.

Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2

Benign familial infantile seizures (BFIS) is a form of idiopathic epilepsy characterized by clusters of afebrile seizures occurring around the sixth month of life and a favorable outcome. Linkage analysis has revealed that three chromosomal segments, 19q12-q13.1, 16p12-q12, and 2q23-31, are linked to this disorder. We report here a large Chinese family in which all 17 affected members had had infantile seizures with onset at age 2-4 months, with two of these also manifesting seizures later in life accompanied with either choreoathetosis or myokymia. Linkage analysis in this family confirmed a previous report of genetic heterogeneity in BFIS - since linkage was excluded at the above-mentioned known BFIS loci - and suggested a possible linkage to the KCNQ2 gene, which is believed to be a voltage gated potassium channel gene responsible for benign familial neonatal seizures (BFNS). Sequencing of the KCNQ2 gene revealed that all 17 affected family members carried a heterozygous Gly-to-Val (G271V) mutation in the conserved pore region that resulted from a guanine-to-thymine transition in exon 5 of KCNQ2. The same mutation with a comparable localization in the KCNQ3 (G310V) gene has been found in BFNS patients. The same conserved amino acid was also found to be mutated in the KCNQ1 gene in a family with Long QT Syndrome.

Theoretical Investigation of the Neuronal Na + Channel SCN1A: Abnormal Gating and Epilepsy

Epilepsy is a paroxysmal neurological disorder resulting from abnormal cellular excitability and is a common cause of disability. Recently, some forms of idiopathic epilepsy have been causally related to genetic mutations in neuronal ion channels. To understand disease mechanisms, it is crucial to understand how a gene defect can disrupt channel gating, which in turn can affect complex cellular dynamic processes. We develop a theoretical Markovian model of the neuronal Na + channel Na V1.1 to explore and explain gating mechanisms underlying cellular excitability and physiological and pathophysiological mechanisms of abnormal neuronal excitability in the context of epilepsy. Genetic epilepsy has been shown to result from both mutations that give rise to a gain of channel function and from those that reduce the Na + current. These data may suggest that abnormal excitation can result from both hyperexcitability and hypoexcitability, the mechanisms of which are presumably distinct, and as yet elusive. Revelation of the molecular origins will allow for translation into targeted pharmacological interventions that must be developed to treat syndromes resulting from divergent mechanisms. This work represents a first step in developing a comprehensive theoretical model to investigate the molecular mechanisms underlying runaway excitation that cause epilepsy.

Neuroimaging abnormalities in children with an apparent first unprovoked seizure

Objective: To determine the incidence and type of neuroimaging abnormalities in children presenting with a first seizure. Methods: In a prospective observational study, 411 children with a first afebrile seizure were seen between 1983 and 1992. Imaging studies were performed in 218 (53%). For this analysis we examined the most sensitive neuroimaging study performed which included 159 computed tomography scans and 59 magnetic resonance imagings (MRI). Results: Four children were found to have lesions requiring intervention (brain tumor in two, neurocysticercosis in two). The remaining 407 were enrolled in a follow-up study of children with a first unprovoked seizure. After a mean follow-up of >10 years, none have developed clinical evidence of a tumor. In these 411 children, 45 (21%) of 218 imaging studies were abnormal. The most common abnormalities were focal encephalomalacia ( n=16) and cerebral dysgenesis ( n=11). Although children with partial seizures were more likely to be imaged (64%) than children with generalized seizures (43%) ( P<0.001), the fraction of abnormal imaging studies was similar in both groups. Six children with a normal neurological examination who were initially classified as cryptogenic were subsequently found to have errors of cerebral migration on MRI. The incidence of lesions requiring acute intervention in children presenting with a first seizure is low. A significant proportion will have neuroimaging abnormalities particularly on MRI. Conclusions: Neuroimaging should be considered in any child with a first seizure who does not have an idiopathic form of epilepsy.

REVIEW ■ : The Genetic Basis of Epilepsy: Mutant Alleles of Ligand- and Voltage-Gated Ion Channels

Idiopathic epilepsies are a heterogenous group of conditions characterized by different types of seizures, ages of onset, and EEG features. By definition, idiopathic epilepsies show no underlying cause other than a possible inherited predisposition. For most syndromes, especially the common ones, the mode of inheritance is complex rather than monogenetic. However, some rare idiopathic epilepsies show an autosomal dominant mode of inheritance, and genetic studies have been most successful in these diseases. Thus far, genes underlying the rare syndromes of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), benign familial neonatal convulsions (BFNC), and generalized epilepsy with febrile seizures plus (GEFS+) have been cloned. The first genes that were identified code for different types of ion channel proteins. Thus, it is likely that ion channels play an important role in the etiology of complex inherited forms of idiopathic epilepsies. A detailed under standing of the pathophysiological implications of these results could have important implications for the de velopment of target-specific antiepileptic drugs. NEUROSCIENTIST 5:295-301, 1999

Concordance of clinical forms of epilepsy in families with several affected members. Italian League Against Epilepsy Genetic Collaborative Group.

Evidence for genetic heterogeneity in epilepsy is strong. We evaluated the concordance of clinical forms in the same family in a series of families with several cases of idiopathic epilepsy, collected as part of the Study on the Genetics of Epilepsy of the Italian League against Epilepsy (LICE). The studied families had at least three members affected by an idiopathic form of epilepsy in one or more generations. Seventy-four families (with a total of 296 affected members) have been analyzed; two families had cases with benign neonatal familial convulsions (BNFC); in 25% of the remaining families all members were affected by the same clinical form, 13.9% had a prevalent clinical form with only one affected member with a different seizure type, 36.1% had two clinical forms, and 25% had three forms of epilepsy in the same family. There are no clinical differences in the form of epilepsy between the families concordant for one clinical form and families with two or three clinical forms of idiopathic epilepsies. The distribution of the clinical form in the affected relatives in our families showed the higher concordance with the proband in febrile convulsions (FC, 70.8%) and in epilepsy with generalized tonic-clonic seizures (EGTC, 63.0%). FC and EGTC were highly diffused in the affected relatives in the families with other forms of idiopathic epilepsy, above all in the more distantly related affected family members. In our families we observed a rare associated between childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy (JME).(ABSTRACT TRUNCATED AT 250 WORDS)

The idiopathic form of West syndrome.

The clinical and electroencephalographic data of 31 children with cryptogenic West syndrome (WS), selected from a series of 103 WS patients, with a follow-up between 4 and 12 years, were studied retrospectively to verify whether this group included patients who fulfilled the criteria for an idiopathic etiology. The results identified a possible idiopathic etiology in 17 patients (55%), who had a family history of other forms of idiopathic epilepsy or febrile convulsions, or who developed, during the follow-up, an EEG genetic trait such as a photoconvulsive response or spike-and-wave discharges, or rolandic spikes. All 17 children had a favorable outcome and all had normal neuropsychological development. Four children (13%) fulfilled the criteria for a true cryptogenic etiology, a causative lesion being suspected, but never proved. At the end of the follow-up all four had seizures, or developmental delay or both, all signs that suggest an underlying cerebral lesion. The other 10 children, representing 32% of the cryptogenic cases, had a good prognosis, with early disappearance of spasms and hypsarrhythmia, and normal neurological development, but none had an EEG epileptic trait or family history of epilepsy or febrile convulsions; although they could have had an idiopathic WS, this was not proved. We conclude that among the children classified as having a cryptogenic WS, many--in our series at least 55%--fulfill the criteria for an idiopathic etiology.