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A novel animal model of acquired human temporal lobe epilepsy based on the simultaneous administration of kainic acid and lorazepam

Epilepsia - Fri, 02/03/2017 - 04:03
Summary Objective

Kainic acid (KA) is a potent glutamate analog that is used to induce neurodegeneration and model temporal lobe epilepsy (TLE) in rodents. KA reliably induces severe, prolonged seizures, that is, convulsive status epilepticus (cSE), which is typically fatal without pharmacologic intervention. Although the use of KA to model human epilepsy has proven unquestionably valuable for >30 years, significant variability and mortality continue to confound results. These issues are probably the consequence of cSE, an all-or-nothing response that is inherently capricious and uncontrollable. The relevance of cSE to the human condition is dubious, however, as most patients with epilepsy never experienced it. We sought to develop a simple, KA-based animal model of TLE that avoids cSE and its confounds.


Adult, male Sprague-Dawley rats received coincident subcutaneous injections of KA (5 mg) and lorazepam (0.25 mg), approximately 15.0 and 0.75 mg/kg, respectively. Continuous video–electroencephalography (EEG) was used to monitor acute seizure activity and detect spontaneous seizures. Immunocytochemistry, Fluoro-Jade B staining, and Timm staining were used to characterize both acute and chronic neuropathology.


Acutely, focal hippocampal seizures were induced, which began after about 30 min and were self-terminating after a few hours. Widespread hippocampal neurodegeneration was detected after 4 days. Spontaneous, focal hippocampal seizures began after an average of 12 days in all animals. Classic hippocampal sclerosis and mossy fiber sprouting characterized the long-term neuropathology. Morbidity and mortality rates were both 0%.


We show here that the effects of systemic KA can be limited to the hippocampus simply with coadministration of a benzodiazepine at a low dose. This means that lorazepam can block convulsive seizures without truly stopping seizure activity. This novel, cSE-free animal model reliably mimics the defining characteristics of acquired mesial TLE: hippocampal sclerosis and spontaneous hippocampal-onset seizures after a prolonged seizure-free period, without significant morbidity, mortality, or nonresponders.

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Different Mutations in the Same Gene Can Result in Epilepsy or Autism

Epilepsy Research - Thu, 02/02/2017 - 05:00

Mutations in a gene called SCN2A can cause either infantile epilepsy or autism spectrum disorder (ASD) according to a new study published in the journal Biological Psychiatry.

SCN2A is responsible for making a protein called NaV1.2 in the brain. NaV1.2 determines the electrical properties of neurons and their ability to communicate with each other, especially during early brain development. Mutations in SCN2A that cause a reduction in NaV1.2 activity lead to ASD, whereas mutations that cause increased activity of NaV1.2 lead to epilepsy.

In a press release, one of the senior authors of the study Dr Stephan Sanders said: “The genetics of neuropsychiatric disease is often complicated, but here we have a single gene in which specific mutations can cause either infantile seizures or autism in a consistent and predictable manner. This gives us an opportunity to understand both what these disorders have in common and what makes them different.”

In this study, the researchers from the University of California San Francisco, Lawrence Berkley National Laboratory and the University of Puerto Rico, analysed 11 different mutations in the SCN2A gene that were originally discovered in children with ASD. The team studied how those mutations affected the function of NaV1.2 in human cells grown in the laboratory.

They saw that all mutations reduced the activity of the protein, but depending on their location on the gene, they either inhibited the production of the protein or blocked its function. The researchers then used these data to develop computer models predicting how these mutations, together with those that had previously been reported to cause infantile seizures, would affect the behaviour of nerve cells, especially during development.

They found that while the mutations seen in children with infantile seizures made the neurons more excitable, those seen in children with ASD made them “unwilling” to send electrical signals.

The lead author of the study, Dr Roy Ben-Shalom said: “It was remarkable to see how consistently neuronal function was disrupted by these different mutations [which] all affected the [protein] in slightly different ways, but they ended up affecting neurons in almost exactly the same way.”

According to the authors, these findings are a first step toward understanding how different subtle changes in neuronal function inside the mother’s womb might lead to the development of either a seizure-prone brain or an autism-prone brain in infancy.

Author: Dr Özge Özkaya

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Radiofrequency thermocoagulation of the seizure-onset zone during stereoelectroencephalography

Epilepsia - Thu, 02/02/2017 - 02:11
Summary Objective

To assess long-term outcome and identify prognostic factors of radiofrequency thermocoagulation (RFTC) following stereoelectroencephalography (SEEG) explorations in particularly complex cases of focal epilepsy.


We retrospectively reviewed the medical charts, video-SEEG recordings, and outcomes for 23 patients (aged 6–53 years) treated with SEEG-guided RFTC, of whom 15 had negative magnetic resonance imaging (MRI) findings, and 10 were considered noneligible for resective surgery after SEEG. Two to 11 RFTCs per patient (mean 5) were produced by applying 40–50 V, 75–110 mA current for 10–60 s on SEEG electrode contacts within the epileptogenic region, which was very close to eloquent cortices in 12 cases. The general features, SEEG findings, and RFTC extent of the patients were analyzed to extract potential preoperative predictors of post-RFTC seizure outcomes.


After a mean follow-up of 32 months (range 2–119 months), eight patients experienced a ≥50% decrease of seizure frequency after RFTC (R+, 34.8%), of whom one had a sustained seizure freedom and 15 patients did not benefit from RFTC (R−, 65.2%). The presence of an MRI lesion was the only significant predictor of a positive outcome, whereas location of epilepsy, extent of interictal epileptiform discharges (IEDs) and of the seizure onset zone, induction of seizures by electrical stimulation, as well as the ratio of the coagulated sites did not show a significant correlation to the RFTC response. However, (sub-)continuous IEDs were more frequently found in R+ than in R− patients, thus suggesting that this EEG marker of the epileptogenic tissue might predict a positive outcome even in patients without obvious MRI lesion.


Our study confirms that RFTC, although less effective than resective surgery, can be a reasonable therapeutic option in complex cases where anatomic constraints make impossible any cortical resection. Further prospective studies are needed to better define RFTC indications and to optimize its methodology.

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