What's Current?

Localization Value of Seizure Semiology Analyzed by the Conditional Inference Tree Method

Epilepsy Research Journal - Mon, 06/01/2015 - 00:00
Careful history taking, with accurate interpretation of seizure semiology, is an important first step in the diagnosis and prediction of prognosis, as well as the choice of appropriate treatment for patients with epilepsy (Noachtar and Peters, 2009). Before the introduction of EEG and neuroimaging, direct observation of seizures was the only diagnostic approach available for patients with epilepsy. Therefore, the diagnosis and classification of epileptic seizures were based solely on clinical observations and detailed reports of seizure semiology (Reynolds, 2001; Hogan and Kaiboriboon, 2003).
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Investigation of in common epilepsy phenotypes

Epilepsy Research Journal - Mon, 06/01/2015 - 00:00
Mutations in GRIN2A, coding for the alpha2 subunit of the NMDA glutamate receptor, were recently identified in pediatric patients with epilepsy-aphasia spectrum disorders including benign focal epilepsies with centrotemporal spikes (CTS) (Carvill et al., 2013; Lemke et al., 2013; Lesca et al., 2013). Most patients were described with epileptic phenotypes belonging to the more severe end of the spectrum of idiopathic focal epilepsies (IFE) such as atypical Rolandic epilepsy, atypical benign partial epilepsy (ABPE), epileptic aphasia (Landau-Kleffner syndrome, LKS) and electrical status epilepticus in slow-wave sleep (ESES).
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EEG characteristics predict subsequent epilepsy in children with their first unprovoked seizure

Epilepsy Research Journal - Sat, 05/30/2015 - 00:00
One of the most important risk factors for seizure recurrence is the electroencephalogram (EEG) characteristics of children with a first unprovoked seizure. However, the nature of the relationship between the risk factors for subsequent epilepsy and EEG characteristics, especially the localization of EEG paroxysmal abnormalities (PAs), remains unclear. The importance of EEG characteristics, especially the localizations of PAs, as predictors for subsequent epilepsy in children with a first unprovoked seizure was investigated.
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Perineuronal net degradation in epilepsy

Epilepsia - Fri, 05/29/2015 - 13:38
Summary Objective

We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin-positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE.

Methods

The pilocarpine chemoconvulsant rodent epilepsy model was used to characterize the degradation of the aggrecan component of the PN in the hippocampus following SE. Chondroitinase ABC (ChABC) was used to degrade the PN in mice. Onset, number, and duration of pentylenetetrazole (PTZ)–induced seizures were assessed.

Results

The loss of the PN in the hippocampus following SE is at least partially related to degradation of the aggrecan PN component by MMP activity. Forty-eight hours after SE, a neoepitope created by MMP cleavage of aggrecan was present and concentrated around parvalbumin-positive interneurons. The increase in aggrecan cleavage products was found at 48 h, 1 week, and 2 months after SE, with different fragments predominating over time. We demonstrate ongoing aggrecan proteolysis and fragment accumulation in the hippocampus of adult control rats, as well as in SE-treated animals. Degradation of the PN alters the seizure response to PTZ. ChABC treatment caused an increase in myoclonic seizures following PTZ administration, a delayed onset of Racine stage 4/5 seizure, and a decreased duration of Racine stage 4/5 seizure.

Significance

Status epilepticus increases MMP proteolysis of aggrecan, pointing to MMP activity as one mechanism of PN degradation post-SE. There is accumulation of aggrecan fragments in adult rat hippocampus of both control and SE-exposed animals. Loss of the PN was associated with increased numbers of myoclonic seizures; it also, delayed and shortened the duration of Racine stage 4/5 seizures, suggesting a complex relationship between the PN and seizure susceptibility.

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Antiepileptic drugs alter the expression of placental carriers: An in vitro study in a human placental cell line

Epilepsia - Fri, 05/29/2015 - 13:38
Summary Objective

Antiepileptic drugs (AEDs) affect the expression of carriers for drugs and nutrients at several blood-tissue barriers, but their impact on placental carriers is largely unknown. Our aim was to study the effects of AEDs in human placental cells on the expression of carriers for hormones, nutrients, and drugs: folate placental uptake carriers (reduced folate carrier, RFC; folate receptor α, FRα) and efflux transporters (breast cancer resistance protein, BCRP and multidrug resistance protein 2) and thyroid hormone uptake transporters (l-type amino acid transporter-LAT1 and organic anion transporting polypeptides-OATPs).

Methods

The human trophoblast BeWo cells were incubated with phenytoin (PHT), valproic acid (VPA), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), or their vehicles at concentrations that mostly represent their therapeutic range. RT-PCR and western blot analysis were utilized to study the effects of AEDs on carriers’ mRNA and protein expression, respectively. The activity of BCRP was evaluated by accumulation studies.

Results

Compared with controls, VPA-treated cells displayed half the levels of RFC mRNA and protein (p < 0.05) and up to 2.7-fold increases in BCRP mRNA and protein expression (p < 0.05), together with enhanced BCRP activity. PHT increased the expression of BCRP and LAT1 by 2.9-fold and 2.5-fold, respectively (p < 0.01). LTG modulated the levels of FRα transcript and protein, whereas LEV altered those of RFC, LAT1, and OATPs 1A2 and 4A1. CBZ affected carrier expression at the mRNA but not the protein level. All the AEDs altered to a modest extent the transcription of nuclear receptors known to regulate transporter expression.

Significance

These findings suggest a possible effect of AEDs on placental transport mechanisms for folate and thyroid hormones as well as those involved in the elimination of potential toxins from the fetus. Identification of AED effects on the placental barrier could be a first step toward a more rational pharmacotherapy and supplemental therapy in pregnant women with epilepsy.

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The GIRK2 subunit is involved in IS-like seizures induced by GABAB receptor agonists

Epilepsia - Fri, 05/29/2015 - 13:37
Summary Objective

Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABABR) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein–coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABABR-mediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response duration) phenotype induced in the Ts mice by GABABR agonists.

Methods

GIRK2−/−, +/−, and +/+ mice were treated with γ-butyrolactone (GBL), a pro-drug of the GABABR agonist γ-hydroxybutyric acid, and the specific GABABR agonist baclofen (BAC) under continuous EEG monitoring. These drugs induce epileptiform bursts, extensor spasms, and an electrodecremental response (EDR) in Ts mice at low doses, and in wild-type mice at high doses. A dose–response curve was ascertained with two treatment groups: GBL (100, 200, and 400 mg/kg) and BAC (4, 8, 12, and 16 mg/kg). We determined the baseline, the presence and duration of electrodecremental epochs (EDEs), and quantified acute epileptic extensor spasms.

Results

Analysis of EEG and behavior of GIRK2−/−, +/−, and +/+ mice after treatment with GABABR agonists and antagonists, indicate that GIRK2−/− mice are highly resistant to GABABR agonist–induced EEG and behavioral changes.

Significance

These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms.

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Midazolam as an anticonvulsant antidote for organophosphate intoxication—A pharmacotherapeutic appraisal

Epilepsia - Fri, 05/29/2015 - 13:33
Summary Objective

This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication.

Methods

Benzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action.

Results

Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic γ-aminobutyric acid (GABA)A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings.

Significance

In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence.

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What are the minimum requirements for ketogenic diet services in resource-limited regions? Recommendations from the International League Against Epilepsy Task Force for Dietary Therapy

Epilepsia - Fri, 05/29/2015 - 13:32
Summary

Despite the increasing use of dietary therapies for children and adults with refractory epilepsy, the availability of these treatments in developing countries with limited resources remains suboptimal. One possible contributory factor may be the costs. There is often reported a significant perceived need for a large ketogenic diet team, supplements, laboratory studies, and follow-up visits to provide this treatment. The 2009 Epilepsia Consensus Statement described ideal requirements for a ketogenic diet center, but in some situations this is not feasible. As a result, the International League Against Epilepsy (ILAE) Task Force on Dietary Therapy was asked to convene and provide practical, cost-effective recommendations for new ketogenic diet centers in resource-limited regions of the world.

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Ketogenic diet exhibits anti-inflammatory properties

Epilepsia - Sat, 05/23/2015 - 03:23
Summary

The ketogenic diet (KD) is an established treatment for refractory epilepsy, including some inflammation-induced epileptic encephalopathies. In a lipopolysaccharide (LPS)–induced fever model in rats, we found that animals given the KD for 14 days showed less fever and lower proinflammatory cytokine levels than control animals. However, KD rats exhibited a decrease in circulating levels of arachidonic acid and long-chain n-3 polyunsaturated fatty acids (PUFAs), suggesting that the anti-inflammatory effect of KD was probably not due to an increase in anti-inflammatory n-3 PUFA derivatives. These properties might be of interest in some conditions such as fever-induced refractory epileptic encephalopathy in school-aged children.

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Oxidative stress is an aggravating factor in Lafora rare disease

Medical News Today - Fri, 05/22/2015 - 10:00
Neurodegenerative Lafora disease usually becomes apparent through seizures during adolescence and puberty and occurs as a consequence of defects in glycogen metabolism and in the cellular...
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Anterior temporal lobectomy compared with laser thermal hippocampectomy for mesial temporal epilepsy: a threshold analysis study

Epilepsy Research Journal - Thu, 05/21/2015 - 00:00
Mesial temporal lobe epilepsy (mTLE) is the most common indication for epilepsy surgery, accounting for 17-31% of surgical procedures (Pasquier et al., 2002; Piao et al., 2010). Anterior temporal lobectomy (ATL), introduced in 1968 by Falconer and Taylor, is the most common surgical procedure for mTLE (Falconer and Taylor, 1968) and entails removing 4-6cm of the anterior temporal lobe including the amygdala and hippocampus. Randomized controlled trials (RCT) have demonstrated a significantly greater seizure freedom and improved quality of life (QoL) after surgery compared with medical management alone, with 60-80% of patients achieving effective seizure control (Engel et al., Wiebe et al., 2001).
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Task force offers recommendations on epilepsy treatments in women and girls

Medical News Today - Tue, 05/19/2015 - 12:00
The anti-epilepsy drug valproate should be avoided whenever possible in women who may become pregnant due to a high risk of malformations and developmental problems in babies who are exposed to the...
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Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography

Epilepsia - Tue, 05/19/2015 - 01:48
Summary Objective

Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions.

Methods

Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded.

Results

Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording.

Significance

About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

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Comparison of lacosamide concentrations in cerebrospinal fluid and serum in patients with epilepsy

Epilepsia - Tue, 05/19/2015 - 01:46
Summary Objective

This study was carried out to estimate the exposure of the central nervous system (CNS) to the antiepileptic drug (AED) lacosamide, under steady state conditions, in patients with epilepsy who take oral lacosamide alongside up to three other AEDs.

Methods

Twenty-seven serum and cerebral spinal fluid (CSF) samples were collected from 21 patients receiving lacosamide for the treatment of epilepsy (50–600 mg/day over two or three doses). This included 23 time-matched pairs of serum and CSF samples from 19 patients. The concentration of lacosamide in each sample was determined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Linear regression was used to characterize the relationship between the CSF-to-serum ratio of lacosamide concentration and the time since dosing, the daily lacosamide dose, or the daily dose normalized by volume of distribution (Vd, approximated to total body water), and between the drug concentrations in each compartment (CSF vs. serum).

Results

Concentrations of lacosamide in CSF (mean ± standard deviation [SD] 7.37 ± 3.73 μg/ml, range 1.24–14.95, n = 27) and serum (mean ± SD 8.16 ± 3.82 μg/ml, range 2.29–15.45, n = 27) samples showed a good correlation over the dose range investigated. The mean CSF-to-serum ratio of lacosamide concentrations was 0.897 ± 0.193 (range 0.492–1.254, n = 23 time-matched pairs) and was independent of lacosamide dose.

Significance

Drug concentrations in the CSF are often used to indicate those in the brain interstitial fluid. In patients with epilepsy who follow a stable oral AED dosing regimen, lacosamide concentration in CSF is approximately 85% of that found in serum, suggesting that serum may be a valuable indicator of lacosamide concentration in the CNS.

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Epileptogenesis and epileptic maturation in phosphorylation site-specific SNAP-25 mutant mice

Epilepsy Research Journal - Tue, 05/19/2015 - 00:00
Epilepsy, a chronic neurological disorder that is characterized by recurrent spontaneous seizures due to neuronal hyperactivity in the brain, is the most common serious neurological condition, affecting more than 50 million people world-wide (Sander 2003). Between 70 and 80% of people with epilepsy will go into remission, and the remaining patients will continue to have seizures and will be resistant to antiepileptic drugs (AEDs). Thus, development of new AEDs and new method of treatment are urgently required.
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Announcements

Epilepsia - Mon, 05/18/2015 - 05:18
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