Absence epilepsy

The C67BLIlO spsfsps mouse mutant displays generalized absence seizure-like behavior. In these mice, glutamic acid decarboxylase activity is reduced in the oortex and hippocampus. Tritiated flunitrazepam binding (sH-flu) is reduced in these areas, as well as in midbrain, cerebellum, and pons-medulla. Quantitative [SH]-flunitraxepam binding autoradiography confirms these observations. GABA uptake by synaptosomes from spsisps mice is also reduced in all the areas studied. Potassium-stimulated, Ca*+-dependent release of radioactivity from synaptosomes preloaded with ['*Cl-GABA is reduced in the hippocampus, increased in midbrain and pons-medulla, but remains unaltered in the cortex, These results suggest region-specific alterations in GABAergic neurotransmission that may be responsible for the absence-like seizures in C57BLIlO sps/sps mice.

In 1945, Lennox was the first to describe the epileptic states mainly expressed by various degrees of consciousness disturbance, which have their onset in children who present epileptic absences correlated with ictal EEG patterns of spike-wave complex discharges at about 3 Hz. As the clinical picture seemed to be similar to an uninterrupted series of absences, this led to the definition "Petit Mal Status" (PMS). Many authors have subsequently reported that PMS can occur in epileptic subjects who have never presented absences (and even in subjects without a previous history of epilepsy) and that the related EEG pictures were characterised by paroxysmal generalized activity of various morphology, but hardly ever consisted of the continuous rhythmic spike-wave or polyspike-wave complexes at 3 Hz found in petit mal absences. Finally, in reporting the onset and recurrence of this condition typically in adults and the elderly, some authors have proposed the existence of a particular form of PMS (dependent on different types of pathologic factors and characterising a specific syndrome of this age) that is different from that of the "real PMS" typical of childhood and related to petit mal absences. This paper describes fifteen patients in whom the onset of the condition occurred at different ages, and who seem to exemplify the various possible clinical expressions of PMS, with the aim of making a contribution towards the better nosographic definition of this epileptic condition. On the basis of our study, we sustain that the so-called PMS is a seizure type of Idiopathic Generalized Epilepsy which may appear at nearly all ages, and may occur in isolation or in association with other epileptic manifestations, but cannot itself be considered as characterising one or more age-dependent syndromes.

Spike-wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. GAERS and Wag/Rij rat strains exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies about the Sprague-Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2-3 month old naïve female Sprague-Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest and they continued for months. Males exhibited SWDs only after 3 months of age, consistent with previous reports . Housing in atypical lighting during early life appeared to facilitate the incidence SWDs. SWDs were often accompanied by behaviors similar to stage 1-2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to theta rhythm during exploration for a given animal, typically 7-8 Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>250 Hz) during SWDs, suggesting neuronal activity in hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague-Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal and cortical neurons in does not prevent SWDs, at least in this animal

We read with interest the paper by Destina Yalcin et al. 1 describing four patients with eyelid myoclonia associated with absences, myoclonic jerks and generalized tonic-clonic seizures (GTCS), and showing electroclinical features compatible with the diagnosis of either eyelid myoclonia with absences (EMA) and juvenile myoclonic epilepsy (JME). The authors suggest that EMA and JME are dynamic syndromes tending to evolve into one another. 1 However, few points need further discussion.

Background and purposesTo determine the prevalence of SLC2A1 mutations in children with early‐onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure‐free with anti‐epileptic drug (AED) monotherapy (group I) and those who needed add‐on treatment of a second AED (group II).MethodsWe reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3 years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient.ResultsEighty‐four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first‐degree family history for genetic generalized e...

Results: Among 33 children with absence epilepsy starting before 3 years of life, there were 20 boys and 13 girls. Mean seizure onset was at 28.0 ± 8.3 (range: 8-36) months of life. Two children displayed borderline intellectual functioning at long-term follow-up. Twenty-eight (85%) patients showed excellent response to therapy. Three subjects evolved into a different form of idiopathic generalized epilepsy (IGE). No SLC2A1 mutation was identified in 20 (60.6%) patients tested. The main clinical features of patients with early-onset absences did not differ from those of CAE except for increased prevalence of males (p = 0.002) and longer treatment duration (p = 0.001) in the former. Conclusions: Strong similarities in the electroclinical features and outcome between children with early-onset absences and those with CAE support the view that these conditions are part of the wide spectrum of IGE.

Carefully selected patients with drug-resistant epilepsy may be candidates for resective surgery. Neuroimaging, including positron emission tomography (PET), magnetic resonance imaging (MRI), and ictal single-photon emission computed tomography (SPECT), are important clinical tools for presurgical seizure focus localization. MRI is an essential part of evaluation for patients with epilepsy. Structural studies may show focal abnormalities such as mesial temporal sclerosis or focal cortical dysplasia, which are the pathological substrates of seizure initiation. Functional localization data from arterial spin labeling for cerebral blood flow and spike-triggered or resting-state signal acquisition are potentially valuable as well. PET and SPECT usually only are performed for patients being considered for surgery. PET may show decreased interictal glu-

Purpose of Study: IEM are relatively rare causes of seizures in infants and children. L-serine deficiency that occurs in IEM is determined by a mutation in the genes encoding the enzymes involved in L-serine synthesis. The purpose of the study, through the example of a clinical case, was to emphasize the importance of metabolic screening evaluation of children with drug-resistant seizures for the fastest possible initiation of targeted treatment, thus preventing and minimizing the rate of complications. Materials and methods: Presentation of a clinical case of a 4-year-old boy hospitalized a lot of times in the Neurology Department of our hospital due to polymorphic epileptic seizures, resistant to combined anticonvulsant treatment (Levetiracetam, Valproic Acid, Clonazepam), associated with cognitive and verbal decline, secondary to seizures. During the genetic testing for IEM, the c.777A>T mutation was detected in exon 7 of the PSAT1 genea gene involved in the coding of the PSAT enzyme that participates in the synthesis of L-serine, thus its severe deficiency is associated with the clinical picture of our patient. Results: After the treatment with L-serine with a dose of 500 mg/kg/day divided into 3 doses, the child's condition clinically improved. Seizures disappeared after 2 months of treatment with a positive cognitive and verbal dynamics. Conclusions: Early diagnosis of seizures occurring in IEM is essential, as many IEMs are potentially treatable, and seizure control can only be achieved when they are properly treated.

We studied a patient with a history of absence attacks in childhood in whom an absence status with bilateral spike-and-wave discharges developed after a top-of-the-basilar syndrome. Surprisingly, even though the ischemic lesion involved the left thalamus alone, spike-andwave discharges were recorded from the two hemispheres. Three days after antiepileptic treatment (sodium valproate 500 mg 3 times a day) began, electroenceplalographic recordings and consciousness became normal.

The article summarises the role of input and consequent phasic events in the dynamism of non-rapid eye movement (NREM) sleep and in homeostatic slow-wave economy during sleep. Then, an overview of the mechanism of how micro-arousals in NREM sleep gate epileptic events in absence epilepsy (AE) and in sporadic and autosomal dominant nocturnal frontal lobe epilepsy (NFLE/ADNFLE) is presented. The ictal type of generalised spike-wave discharges (SWDs) are associated with a special vigilance level in between NREM, rapid-eye movement (REM) and wake state. This transitional state is characterised by input-driven bidirectional fluctuations. Among them, SWDs are linked to A1 type A phases of CAP and therefore seem to be associated with shifts towards NREM sleep (sleep induction). In ADNFLE (and presumably in NFLE), micro-arousals release epileptic events in NREM sleep probably due to epileptic sensitisation of the cholinergic arousal system by the known acetylcholine (ACh) receptor mutations affecting the arousal system, giving rise to the epileptic (and also parasomniac) episodes. In both kinds of these system epilepsies (AE and NFLE), epileptic events can be released by phasic events during NREM sleep. The difference is that absences are activated in reactive states with a sleep-promoting, antiarousal effect, while in NFLE the epileptic disorder is interwoven with the cholinergic arousal function. The role of arousal/antiarousal in NFLE and AE fits nicely with the hypothesis that these epilepsies are disorders of two antagonistic thalamo-frontal systems involved in functions NREM sleep and wakefulness.

The distinction between typical absences and hypomotor seizures in patients having frontal lesions is difficult. In focal epilepsy, generalized-like interictal discharges can reflect either a coexistent generalized epileptic trait or a secondary bilateral synchrony. Using combined measures of the EEG and blood oxygenation level dependent (BOLD) activity, we studied a 50-year-old patient with both absence-like and symptomatic focal motor seizures. Focal activity induced activation in the lesional area and deactivation in the contralateral central cortex. Generalized spike-and-wave discharges (GSWDs) resulted also in perilesional activation, and multifocal symmetrical cortical and thalamic activations, and deactivation in associative cortical areas. Although the central cortex was involved during both types of epileptic activity, electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) revealed distinct neuronal networks at the time of the focal or generalized discharges, allowing a clear-cut differentiation of the generators. Whether the patient had distinct epileptic syndromes or distinct electrographic patterns from the lesional trigger remains debatable.

The distinction between typical absences and hypomotor seizures in patients having frontal lesions is difficult. In focal epilepsy, generalized-like interictal discharges can reflect either a coexistent generalized epileptic trait or a secondary bilateral synchrony. Using combined measures of the EEG and blood oxygenation level dependent (BOLD) activity, we studied a 50-year-old patient with both absence-like and symptomatic focal motor seizures. Focal activity induced activation in the lesional area and deactivation in the contralateral central cortex. Generalized spike-and-wave discharges (GSWDs) resulted also in perilesional activation, and multifocal symmetrical cortical and thalamic activations, and deactivation in associative cortical areas. Although the central cortex was involved during both types of epileptic activity, electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) revealed distinct neuronal networks at the time of the focal or generalized discharges, allowing a clear-cut differentiation of the generators. Whether the patient had distinct epileptic syndromes or distinct electrographic patterns from the lesional trigger remains debatable.

In vivo extracellular and intracellular recordings were performed from thalamocortical (TC) neurones in a genetic model of absence epilepsy (genetic absence epilepsy rats from Strasbourg) during spontaneous spike and wave discharges (SWDs). Extracellularly recorded single units (n= 14) fired either a single action potential or a high frequency burst of up to three action potentials, concomitantly with the spike component of the spike‐wave complex. Three main events characterized the intracellular activity of twenty‐six out of twenty‐eight TC neurones during SWDs: a small amplitude tonic hyperpolarization that was present throughout the SWD, rhythmic sequences of EPSP/IPSPs occurring concomitantly with the spike‐wave complexes, and a small tonic depolarization at the end of the SWD. The rhythmic IPSPs, but not the tonic hyperpolarization, were mediated by activation of GABAA receptors since they reversed in polarity at ‐68 mV and appeared as depolarizing events when recording with KC...

In the present study, the effects of the acetylcholinesterase (AChE) enzyme inhibitor rivastigmine (RIVA) on spike-wave discharges (SWDs), memory impairment, anxiety-like behavior, and the transient receptor potential vanilloid 1 (TRPV1) gene expression were investigated in genetic absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. After tripolar electrodes were implanted on the WAG/Rij rats’ skulls, single doses of 0.125, 0.25, 0.5, 1, and 2 mg/kg RIVA were intraperitoneally (i.p.) administered, and electrocorticogram (ECoG) recordings of SWDs were recorded for three hours before
and after injections. Additionally, once significant doses were determined in acute studies, WAG/Rij rats were administered low-dose (0.5 mg/kg) and high-dose (2 mg/kg) of RIVA for 21 consecutive days and SWDs were recorded. Learning-memory
abilities (Y-maze test), anxiety-like behavior (elevated plus maze test), and TRPV1 gene expression were determined and compared in 8-month-old WAG/Rij and age-matched Wistar rats. Acute RIVA administration dose-dependently reduced the total number of SWDs and was even entirely inhibited at 1 and 2 mg/kg RIVA doses. On the other hand, long-term high-dose RIVA administration increased the total number of SWDs. Long-term high-dose RIVA treatment reduced learning-memory and anxiety-like behavior in WAG/Rij rats, while only anxiety-like behavior decreased in Wistar rats. TRPV1 gene expression increased in WAG/Rij rats and decreased in Wistar rats with long-term RIVA administration. These data indicate that the sudden increase of acetylcholine (ACh) causes a significant decrease in absence seizures. In contrast, prolonged maintenance
of ACh elevation causes an increase in absence seizures, probably by altering the expression of channels such as TRPV1.

Sleep is an essential innate but complex behaviour which is ubiquitous in the animal kingdom. Our knowledge of the distinct neural circuit mechanisms that regulate sleep and wake states in the brain are, however, still limited. It is therefore important to understand how these circuits operate during health and disease. This review will highlight the function of mGlu5 receptors within the thalamocortical circuitry in physiological and pathological sleep states. We will also evaluate the potential of targeting mGlu5 receptors as a therapeutic strategy for sleep disorders that often co-occur with epileptic seizures.

Childhood absence epilepsy (CAE) is one of the most frequent epilepsies in infancy. The first-line recommended therapy for CAE is based on the prescription of the narrow spectrum ethosuximide and the broad spectrum valproic acid which have similar efficacy in the first 12 months. Nevertheless, some anti-epileptic drugs (AEDs) may worsen seizure duration and type in this syndrome. In line with this, we have been faced with a case of identical twins with CAE and early exposure to different antiseizure drugs leading to divergent outcomes. From this, we hypothesized that the first AED to treat CAE may determine the long-term prognosis, especially in the developing brain, and that some situations leading to drug-resistance may be explained by an inappropriate first AED. Therefore, we investigated this hypothesis by using a genetic mouse model of absence epilepsy (BS/Orl). Mice received a first appropriate or inappropriate AED followed by the same appropriate AED. Our data demonstrate that an inappropriate first AED has a negative impact on the long-term efficacy of a second appropriate AED. This work supports the necessity to effectively diagnose epileptic syndromes prior to medication use, particularly in children, in order to prevent the deleterious effects of an inappropriate initial AED.

– The recommended treatment for juvenile myoclonic epilepsy (JME) is valproate (VPA). Recently, topiramate and lamotrigine have also been shown to be effective. The objective of this study was to evaluate the efficacy and tolerability of zonisamide (ZNS) in the treatment of JME. We retrospectively analyzed the records of 15 patients (three M, 12 F, ages 11-20 years) diagnosed with JME at our institution during 2001-2003, and treated with ZNS. General-ized tonic-clonic (GTC), myoclonic and absence seizure response was as-sessed. The ZNS dose range was 200-500 mg/day (2.0-8.5 mg/kg/day). ZNS was started as the first drug, and as monotherapy, in 13 and was added to VPA in two patients. Follow-up range was 2-24 months (mean 12 months). Overall, 80 % of patients on ZNS monotherapy showed good control ( ≥ 50 % seizure reduction). Sixty-nine, 62 and 38 % of patients were free of GTC, myoclonic, and absence seizures, respectively. Seizure control was achieved within four to eight weeks of a...

We studied the effectiveness of anterior callosotomy in 43 patients whose follow-up period averaged 39 months. These patients had intractable generalized seizures, characterized by a combination of seizure patterns, most frequently drop attacks with generalized tonic-clonic, generalized tonic, and absence seizures. Overall, drop attacks were the most frequent (31/43 or 7296) and the most disabling seizure pattern (27143 or 63%); they were also the most likely to benefit from anterior callosotomy (70%). Patients with lateralized changes tended to have a better result than did those without lateralization, but patients with synchronous and symmetrical spike and wave discharges also benefited. The preoperative intelligence quotient and the etiological factors were not predictors of outcome. There was a correlation between the extent of section and the results; patients with section of the anterior two thirds had a better result, compared with those who had section of the anterior half. Oguni H, Olivier A, Andermann F, Comair J. Anterior callosotomy in the treatment of medically intractable epilepsies: a study of 43 patients with a mean follow-up of 39 months. Ann Neurol 1991;30:357-364 Over the last 10 years, there has been a considerable resurgence of interest in the use of callosotomy for the surgical treatment of intractable epilepsy. This operation was first carried out in the human in 1940 by Van Wagenen and Herren [ l ] with encouraging results, but the operation never became widely accepted. Bogen and Vogel 12, 31 reintroduced it in the early 1960s, but again, in spite of its demonstrated effectiveness, it was never practiced routinely because of its high morbidity. In the last 16 years, Wilson and his colleagues [4-61, using a microsurgical approach in selected patients with intractable epilepsies, have shown satisfactory results in seizure control as well as an important reduction in morbidity. Since then, physicians at several centers employed callosotomy for the treatment of patients with uncontrollable epilepsy and reported promising results in those patients who were not candidates for classic resective surgery {7-141. The purpose of this report is to present the results of anterior corpus callosotomy performed at the Montreal Neurological Institute (MNI). Materials and Methods Patient Selection Since 1981, we carried out a total of 63 anterior callosotomies for a variety of forms of intractable epilepsy. Fifteen patients who had a combined frontal corticectomy and callosotomy were excluded from this study, leaving 48 patients. One patient had the diagnosis of Lafora disease made after surgery and was also excluded. Forty-three patients were followed for more than 1 year and are included in the analysis. Twenty patients were male and 23, female. Their ages at the time of surgery ranged from 7.8 to 60.0 years, with a mean of 23.5 years. The duration of epilepsy ranged from 4.9 to 46.0 years, with a mean of 18.8 years. Follow-up ranged from 15 to 98 months, with a mean duration of 39 months. Selection criteria for anterior callosotomy were as follows { l 5 , 161: (1) the presence of intractable generalized or partial seizures with secondary generalization, not responding to medical treatment; (2) a malignant seizure pattern leading to injury, deterioration, or both, more particularly consisting of drop or akinetic attacks, especially of the tonic type, with rigid unpreventable falling; and (3) absence of a single resectable epileptogenic area.

Summary Objective: Eyelid myoclonia with absences (EMA) or Jeavons syndrome characterized by eyelid myoclonia (EM) (with or without absences), eye closure‐induced EEG paroxysms, and photosensitivity. We conducted an open‐label trial of levetiracetam in EMA. Patients and Methods: Patients were recruited in different Italian Epilepsy Centres. Levetiracetam was administrated at starting dose of 10 mg/kg/day up to 50–60 mg/kg/day in two doses. Treatment period included a 5–6 week up‐titration phase and a 12‐week evaluation phase. The number of days with EM (i.e., days with seizures, DwS) and number of generalized tonic–clonic seizures (GTCS) were evaluated. Analysis of intent‐to‐treat population was performed using Fisher's and Wilcoxon tests. Results: Thirty‐five patients (23 F) with a mean age of 19 ± 6 years were recruited. Twenty‐seven had previously undergone one to five adequate trials of antiepileptic drugs. The median number of DwS/month was 12 ± 8.2. Twenty‐one patients exp...

Seizures, arising from a variety of neurological conditions beyond epilepsy, pose significant health risks, including injury, prolonged episodes, and status epilepticus, which can be fatal if untreated. The SeizureShield is a cutting-edge transdermal device designed to autonomously detect and respond to all types of seizures, regardless of their origin. Using continuous EEG monitoring, the device identifies abnormal brain activity and promptly delivers a pre-loaded dose of lorazepam, a fast-acting anticonvulsant, to halt the seizure. The SeizureShield employs a miniature EEG sensor near the mastoid area for optimal seizure detection and a micro-needle array for rapid lorazepam delivery. This technology offers real-time intervention, significantly reducing the risk of status epilepticus, neurological damage, and mortality. With a 94% success rate in terminating acute seizures when administered within 10 minutes, the SeizureShield provides a life-saving solution that empowers individuals with seizures, improving their autonomy and safety, particularly in regions with limited access to timely medical care.

Pharmacological and functional data suggest the existence of uridine (Urd) receptors in the central nervous system (CNS). In the present study, simultaneous extracellular single unit recording and microiontophoretic injection of the pyrimidine nucleoside Urd was used to provide evidence for the presence of Urd-sensitive neurons in the thalamus and the cerebral cortex of Long Evans rats. Twentytwo neurons in the thalamus (24% of recorded neurons) and 17 neurons in the cortex (55%) responded to the direct iontophoresis of Urd. The majority of Urd-sensitive neurons in the thalamus and cortex (82% and 59%, respectively) increased their firing rate in response to Urd. In contrary, adenosine (Ado) and uridine 5 -triphosphate (UTP) decreased the firing rate of all responding neurons in the thalamus, and the majority of responding neurons in the cortex (83% and 87%, respectively). Functional relevance of Urd-sensitive neurons was investigated in spontaneously epileptic freely moving Long Evans and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Intraperitoneal (i.p.) injection of 500 mg/kg Urd decreased epileptic activity (210-270 min after injection) in both rat strains. Intraperitoneal administration of 1000 mg/kg Urd decreased the number of spike-wave discharges (SWDs) between 150-270 min and 90-270 min in Long Evans and WAG/Rij rats, respectively. The effect of Urd was long-lasting in both rat strains as the higher dose significantly decreased the number of SWDs even 24 h after Urd injection. The present results suggest that Urd-sensitive neurons in the thalamus and the cerebral cortex may play a role in the antiepileptic action of Urd possibly via modulation of thalamocortical neuronal circuits.

To characterize the genetic basis of spike-wave discharges (SWDs) detected by electroencephalography (EEG) in C3H/He mice, substrains of C3H mice were evaluated by EEG and sensitivity to ethosuximide. Crosses with the SWD-negative strain C57BL/6J were performed to map the underlying gene(s). C3H/He substrains exhibited a modest incidence (average of 19 SWDs per hour) of 7-8 Hz SWDs when at rest, compared with the C3HeB/Fe subline (four SWDs per hour). In the mapping backcross, however, many mice showed a very high incidence (50 -220 SWDs per hour) throughout the recording period. SWDs were first detected at 3.5 weeks of age, were associated with behavioral arrest, were suppressed by ethosuximide, and were strongest in the cerebral cortex and thalamus. The major C3H determinant of SWDs, spkw1 (spike-wave 1), mapped to chromosome (Chr 9), and together with a C57BL/6J determinant on Chr 8, spkw2, accounted for more than one-half of the phenotypic variation in the backcross mice. The modest SWD incidence in C3H/He mice and the high incidence in backcrosses implies that SWD could be a confounding variable for other behaviors. Because C3H/He mice have no other brain abnormalities, they are an attractive alternative for studying idiopathic absence epilepsy.

Absence seizures occur in several types of human epilepsy and result from widespread, synchronous feedback between the cortex and thalamus that produces brief episodes of loss of consciousness. Genetic rodent models have been invaluable for investigating the pathophysiological basis of these seizures. Here, we identify tetratricopeptide-containing Rab8binteracting protein (TRIP8b) knockout mice as a new model of absence epilepsy, featuring spontaneous spike-wave discharges on electroencephalography (EEG) that are the electrographic hallmark of absence seizures. TRIP8b is an auxiliary subunit of the hyperpolarization-activated

Background: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, I h , which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown. Methodology/Principal Findings: We investigated the effects of Kcne2 gene deletion on I h properties and excitability in ventrobasal (VB) and cortical layer 6 pyramidal neurons using brain slices prepared from Kcne2 +/+ and Kcne2 2/2 mice. Kcne2 deletion shifted the voltage-dependence of I h activation to more hyperpolarized potentials, slowed gating kinetics, and decreased I h density. Kcne2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with HCN1 or 2. Kcne2 deletion also increased input resistance and temporal summation of subthreshold voltage responses; this increased intrinsic excitability enhanced burst firing in response to 4-aminopyridine. Burst duration increased in corticothalamic, but not thalamocortical, neurons, suggesting enhanced cortical excitatory input to the thalamus; such augmented excitability did not result from changes in glutamate release machinery since miniature EPSC frequency was unaltered in Kcne2 2/2 neurons. Conclusions/Significance: Loss of KCNE2 leads to downregulation of HCN channel function associated with increased excitability in neurons in the cortico-thalamo-cortical loop. Such findings further our understanding of the normal physiology of brain circuitry critically involved in cognition and have implications for our understanding of various disorders of consciousness.

CHD2 gene has been described in association with different types of childhood myoclonic epilepsy and is emerging as a gene involved in photosensitivity alone or combined with epilepsy. Recent studies suggest that CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity and in particular with self-induced seizures. We report the case of a child with CHD2 mutation and mild developmental impairment that since the age of 3 years started with myoclonic seizures apparently well responding to antiepileptic drugs and that subsequently developed intractable self-induced seizures. Through an accurate Video-EEG polygraphic analysis, we demonstrated that seizures are related to an abnormal increase of epileptiform activity after eye-closure or loss of fixation as observed in the Fixation-Off Sensitivity (FOS) phenomenon. In conclusion our study adds relevant features of the CHD2-epilepsy phenotype and c...

γ-Hydroxybutyric acid (GHB) is a naturally occurring γ-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABA B receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABA B receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABA B receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABA B receptor-mediated actions of GHB are caused by GHB itself acting directly on GABA B receptors or by a GHB-derived GABA pool (or both).

In the modern industrialized countries every year several hundred thousands of people die due to sudden cardiac death. The individual risk for this sudden cardiac death cannot be defined precisely by common available, noninvasive diagnostic tools like Holter monitoring, highly amplified ECG and traditional linear analysis of heart rate variability (HRV). Therefore, we apply some rather unconventional methods of nonlinear dynamics to analyze the HRV. Especially, some complexity measures that are based on symbolic dynamics as well as a new measure, the renormalized entropy, detect some abnormalities in the HRV of several patients who have been classified in the low risk group by traditional methods. A combination of these complexity measures with the parameters in the frequency domain seems to be a promising way to get a more precise definition of the individual risk. These findings have to be validated by a representative number of patients.

In an experimental model of hemorrhagic shock resulting m the death of almost all rats within 20-30 mln, centrally actwc cholinomlmetlc drugs are reported to induce a prompt, sustained and dose-dependent ~mprovement m blood pressure and survival rate claimed to be due to nlcotmic, but not muscarlnlC actions In the present study, chohnerglc receptor agomst, oxotremorlne (50/xg/kg, i v.) increased mean arterml pressure (from 22 +_ 1 to 123 +_ 3 mm Hg) and 60 mm-survlval rate (from 0% to 92%) m rats bled to hypovolemlc shock. Atropme (2 mg/kg, i v.) pretreatment inhibited the pressor effect ot oxotremorlnc significantly, but did not modify its effect on survwal rate. On the other hand, pretreatment with mecamylamme (50 #g, 1 c v) almost abolished the reduction m mortality rate, but lnh~blted the pressor effect of oxotremorme, partially These results m&catc that oxotremorlne-lnduced pressor response and decrease in mortahty in rats w~th severe hemorrhagic shock are primarily medmted via central muscarlmc and nlCOtlmC receptors, respectively. AV3V region was previously reported to be revolved m pressor and natrluretlc effects of ~c.v carbachol m normotenslve rats. In the present study, the electrolytic les~ons of AV3V regxon significantly inhibited oxotremorlne-mduced increases m both blood pressure and survwal rate m rats subjected to hemorrhagic shock These findings indicate that AV3V region plays a major role m chohnergic car&ovascular control m hypotensive animals as well as normotenslves.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P meta 5 2.5 3 10 29 , OR[T] 5 0.81) and 17q21.32 (rs72823592, P meta 5 9.3 3 10 29 , OR[A] 5 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P meta 5 9.1 3 10 29 , OR[T] 5 0.68) and at 1q43 for JME (rs12059546, P meta 5 4.1 3 10 28 , OR[G] 5 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P meta 5 4.0 3 10 26) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate

Objective-To examine the relationship between genotype and phenotype in idiopathic generalized epilepsies (IGEs) using a novel approach that focuses on seizure type rather than syndrome. Methods-The authors evaluated whether the genetic effects on myoclonic seizures differ from the genetic effects on absence seizures. For this purpose, they studied 34 families containing 2 or more members with IGEs and assessed whether the number of families concordant for seizure type exceeded that expected by chance. The authors performed a similar analysis to examine the genetic contributions to juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and childhood absence epilepsy (CAE). Results-The observed number of families concordant for seizure type (myoclonic, absence, or both) was greater than expected (20 vs 7.51; p < 0.0001). The observed number of families concordant for syndrome was greater than expected when JME was compared with absence epilepsies (JAE +CAE) (17 vs 11.9; p < 0.012) but not when JAE was compared with CAE (8 vs 6.82; p = 0.516). Conclusions-These results provide evidence for distinct genetic effects on absence and myoclonic seizures, suggesting that examining the two seizure types separately would be useful in linkage studies of idiopathic generalized epilepsies. The approach presented here can also be used to discover other clinical features that could direct division of epilepsies into groups likely to share susceptibility genes.

Objective: To examine the genetic relationships among epilepsies with different seizure types—myoclonic, absence, and generalized tonic-clonic—within the idiopathic generalized epilepsies (IGEs).Background: Careful phenotype definition in the epilepsies may allow division into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups.Methods: Using the approach that found evidence of distinct genetic effects on myoclonic vs absence seizures in families from the Epilepsy Family Study of Columbia University, the authors examined an independent sample of families from Australia and Israel. They also examined the familial clustering of generalized tonic-clonic seizures (GTCs) within the IGEs in two combined data sets. Families were defined as concordant if all affected members had the same type of seizure or IGE syndrome, as appropriate for the analysis performed.Results:...

Introduction-A crucial issue in the genetic analysis of idiopathic generalized epilepsy (IGE) is deciding on the phenotypes that are likely to give the greatest power to detect predisposing variants. A complex inheritance pattern and unclear nature of the genotype-phenotype correlation makes this task difficult. In the absence of much definitive genetic information to clarify this correlation, we inferred the putative effects of predisposing genes by studying the clustering of various phenotypic features, both clinical and electrophysiological, within families. Methods-We examined the distribution of clinical features among relatives of a proband in 70 French-Canadian families with a minimum of two affected individuals with a clear diagnosis of IGE and then, using concordance analysis, identified the relative genetic influences on IGE syndrome, seizure type, age-at-onset, and EEG features. Results-The mean number of affected individuals with IGE per family was three. One-third of relatives had the same syndrome as the proband. 16-22.5% of relatives of a proband with one of the absence syndromes had juvenile myoclonic epilepsy (JME). Conversely, 27% of relatives of probands with JME had an absence syndrome. 15% of relatives displayed the exact constellation of seizure types as the proband. Concordance analysis demonstrated greater clustering within families of IGE syndrome, seizure type, and age-at-onset than would be expected by chance. Significant concordance was not evident for EEG features. Discussion-There was a large degree of clinical heterogeneity present within families. However we found evidence for clustering of a number of clinical features. Further refinement of the phenotypes used in genetic studies of complex IGE is necessary for progress to be made.

Nonconvulsive status epilepticus (NCSE) is a medical emergency, which is diagnosed most frequently with the routine use of EEG in the pediatric emergency and intensive care units. Data from eight patients, ranging from 2.8-15 years old (median 8.7 years), treated with the diagnosis of NCSE were evaluated on clinical basis. The patients attended the hospital with acute confusional state ranging from sudden onset of verbal cooperation insufficiency to aimless-meaningless behavior and confusion without any motor component of seizure. While five of the cases were diagnosed and followed up with epilepsy, the other three had no history of epilepsy. No reason was detected that could cause acute encephalopathy. EEG examinations during acute confusional state showed partial or generalized continuous electrographic seizure activity lasting at least 30 minutes without clinical seizure activity. After administration of intravenous antiepileptic medication, the confusional states of the patients recovered, and the EEG examinations showed normal baseline activity with significantly diminished discharges or complete normal waveform. Nonconvulsive status epilepticus should be considered in all children admitted to the hospital with acute unexplained encephalopathy, whether they have a history of epilepsy or not. Emergent EEG examination should be a routine part of evaluation in these children for the diagnosis and treatment of NCSE.

Recent research has revealed more evidence supporting the positive effects of music on humans and animals. However, evidence of music's effects on improving epilepsy in animals is sparse. This study aimed to clarify the influence of Mozart's music in Long Evans rats, which are characterized by spontaneous absence epilepsy (SAE) and high-voltage rhythmic spike (HVRS) discharges. Methods: Continuous electroencephalograms comprised of HVRS discharges, and behavioral performance were recorded in Long Evans rats (n = 5) before, during, and after exposure to the Mozart's Sonata for Two Pianos in D Major, K.448 (Mozart K.448). The same evaluation was repeated after they had been subjected to daily exposure of the music for 20 days. Results: Seizure frequencies and spontaneous HVRS discharges were reduced in all of the SAE rats during and after music exposure compared with the pre-music stage. The average seizure frequencies were 79.8 ± 24.6, 48 ± 15.2, and 33 ± 12.1/h before, during, and after music

Recent research has revealed more evidence supporting the positive effects of music on humans and animals. However, evidence of music's effects on improving epilepsy in animals is sparse. This study aimed to clarify the influence of Mozart's music in Long Evans rats, which are characterized by spontaneous absence epilepsy (SAE) and high-voltage rhythmic spike (HVRS) discharges. Methods: Continuous electroencephalograms comprised of HVRS discharges, and behavioral performance were recorded in Long Evans rats (n = 5) before, during, and after exposure to the Mozart's Sonata for Two Pianos in D Major, K.448 (Mozart K.448). The same evaluation was repeated after they had been subjected to daily exposure of the music for 20 days. Results: Seizure frequencies and spontaneous HVRS discharges were reduced in all of the SAE rats during and after music exposure compared with the pre-music stage. The average seizure frequencies were 79.8 ± 24.6, 48 ± 15.2, and 33 ± 12.1/h before, during, and after music

A seizure is a clinical manifestation of presumed or proved abnormal electrical activity in the brain. A first seizure can range from a fleeting subjective experience such as déjà vu or a twitch (myoclonic jerk) through to a tonic-clonic convulsion. Some seizure manifestations overlap with normal phenomena. A single seizure may be provoked (with an acute precipitant that may or may not recur) or unprovoked (idiopathic or of unknown cause). Epilepsy is defined as more than one seizure. This article focuses on the diagnosis of first seizures and differentiation from their "mimics" in adults. The diagnosis is correct in only two thirds of cases or less and relies almost exclusively on the clinical history. 1-9 Information for patients, particularly regarding risks of recurrence, investigation and treatment, driving, and mortality, will be discussed. This review uses older seizure terminology, 10 11 as this is better understood by most readers and succinctly conveys important clinical concepts. Where the revised terminology differs, this is noted in the text and the supplementary table. 12 How common are first seizures? Few data about the frequency of minor (non-convulsive) first seizures exist. Many minor first seizures are unrecognised. The recorded incidence of first seizure (provoked and unprovoked) in Europe is approximately 70 per 100 000 per year, 13 14 with twice that incidence in poorer countries. 15-17 Febrile seizures are the "first seizure" with the highest worldwide incidence (50 per 100 000 per year), usually occurring in the first three years of life. 18

Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1a receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

Peripheral injection of bacterial lipopolysaccharide (LPS) facilitates 8-10 Hz spike-wave discharges (SWD) characterizing absence epilepsy in WAG/Rij rats. It is unknown however, whether peripherally administered LPS is able to alter the generator areas of epileptic activity at the molecular level. We injected 1 mg/kg dose of LPS intraperitoneally into WAG/Rij rats, recorded the body temperature and EEG, and examined the protein expression changes of the proteome 12 h after injection in the frontoparietal cortex and thalamus. We used fluorescent two-dimensional differential gel electrophoresis to investigate the expression profile. We found 16 differentially expressed proteins in the fronto-parietal cortex and 35 proteins in the thalamus. It is known that SWD genesis correlates with the transitional state of sleep-wake cycle thus we performed meta-analysis of the altered proteins in relation to inflammation, epilepsy as well as sleep. The analysis revealed that all categories are highly represented by the altered proteins and these protein-sets have considerable overlap. Protein network modeling suggested that the alterations in the proteome were largely induced by the immune response, which invokes the NFkB signaling pathway. The proteomics and computational analysis verified the known functional interplay between inflammation, epilepsy and sleep and highlighted proteins that are involved in their common synaptic mechanisms. Our physiological findings support the phenomenon that high dose of peripheral LPS injection increases SWD-number, modifies its duration as well as the sleep-wake stages and decreases body temperature.

A longitudinal prospective approach was used to investigate clinical correlations of interictal occipital paroxysms with or without fixation-off sensitivity (FOS). Occipital paroxysms were recorded in the electroencephalograms (EEGs) of 76 children with heterogeneous clinical conditions including seizures in 39 patients. Occipital paroxysms with FOS (42 patients) were only fractionally more frequent than non-FOS (34 patients) and were not specific of any clinical condition. Although present and FOS-related in all 11 children with benign childhood epilepsies with occipital paroxysms (CEOP), they were also frequently encountered in symptomatic occipital epilepsy 6. The differentiation of CEOP from other syndromes established on clinical grounds could also be aided by the analysis of background EEG activity that was frequently significantly more abnormal in symptomatic than CEOP. Clinical characteristics and ictal seizure semiology as well as follow-up clearly distinguish two type of idiopathic CEOP syndromes: (1) early onset type or Panayiotopoulos syndrome characterized by excellent prognosis and rare, prolonged nocturnal seizures with tonic deviations of the eyes and vomiting, and (2) late onset or Gastaut type showing a common ictal visual symptomatology, co-occurrence of migraine, diurnal complex partial seizures and less favourable EEGclinical prognosis.

Objectives: Thrombospondins, which are known to interact with the a 2 d subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). Methods: We measured the transcripts of thrombospondin-1 and a 2 d subunit, and protein levels of a 2 d, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPI-NOMICS-CoGIE Consortium. Results: Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. Significance: These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs.

Objectives: Thrombospondins, which are known to interact with the α2δ subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). Methods: We measured the transcripts of thrombospondin-1 and α2δsubunit, and protein levels of α2δ, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of pre-symptomatic and symptomatic WAG/Rij rats and in two control strains by real-time PCR and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium. Results: Thrombospondin-1 mRNA levels were largely reduced in the ventrobasal thalamus of both pre-symptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in non-epileptic controls, whereas the frequency of CACNA2D1 was unchanged.

GLUT-1 deficiency syndrome (GLUT-1 DS) is a disorder of cerebral glucose transport associated with early infantile epilepsy and microcephaly. We report two boys who presented with refractory absence epilepsy associated with hypoglycorrhachia, both of whom have genetically confirmed GLUT-1 DS. We propose that these children serve to expand the phenotype of GLUT-1 DS and suggest that this condition should be considered as a cause of refractory absence seizures in childhood.

Using the gamma-butyrolactone (GBL) rat model of absence seizures, this study investigated the functional connectivity of the hippocampus, thalamus and cerebral cortex before and during absence seizures. Methods: Functional connectivity between the hippocampus, thalamus and sensory and motor cortecies, were examined by the temporal correlations of the resting state blood-oxygen-level-dependent (BOLD) signal. Functional connectivity between these regions was calculated at baseline, 5 min after saline injection, and at 5, 20 and 52 min after GBL injection. This time interval spans the onset of behaviours including chewing and staring spells associated with GBL-induced absence seizures, along with the onset and suppression of spike-andwave discharges (SWDs). Results: Overall there was an increase in functional connectivity across most regions. The functional connectivity generally decreased over time and it returned to baseline 52 min post-GBL injection. Functional connectivity of the thalamus to the sensory and motor cortecies increased during absence seizure. The results revealed enhanced connectivity of the left dorsal hippocampus and the thalamus shortly after GBL injection, which coincided with the appearance of SWDs in this rat model. Significance: Increased functional connectivity between the hippocampus and the thalamus suggests that the hippocampus participates in the GBL model of absence seizures. Involvement of the hippocampus during absence seizure has implications for studies into the mechanisms in cognitive impairments in patients with absence epilepsy.

Murine brain is an excellent tool for studying protein expression and brain function in mammals. Although mice are an extensively used model to recapitulate various pathological conditions, the proteome of the normal mouse brain has not been yet reported. In the present study, we identified the total proteins of different parts of the brain of CB7BL/6 mice, a widely used strain, by applying proteomic methodologies. The adult mouse brain was dissected anatomically into the following regions: frontal cortex, olfactory bulb, hippocampus, midbrain, cerebellum, hypothalamus and medulla. Total protein extracts of these regions were separated by two-dimensional gel electrophoresis and analyzed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry, following in-gel digestion with trypsin. Protein identification was carried out by peptide mass fingerprint. Thus, 515 different single-gene products were identified in total, 54 expressed specifically in the olfactory b...