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Genetic Changes that Cause Loss of a Certain Type of Memory Can Also Protect Against Epilepsy

Epilepsy Research - Fri, 12/02/2016 - 09:11

A new biological mechanism that damages only a specific type of memory can provide protection against epilepsy according to a study published in the scientific journal Cerebral Cortex.

The biological pathway involves a genetic modification in a protein called eEF2K, which regulates the expression of other proteins. According to the authors, the eEF2K protein could be a potential new target for antiepileptic drugs (AEDs).

The findings came by chance while the team of international researchers were trying to isolate molecular components involved in long-term memory whilst working on learning and memory.

Using a mouse model, the researchers made a molecular change to the eEF2K gene, which resulted in the complete lack of the protein that the gene encodes for. They then tested the mice behaviourally to assess their memory.

They saw that the lack of eEF2K protein caused damage to a specific type of memory called context memory, whilst keeping consolidation of other types of memory intact.

When they further analysed the brains of these animals, the researchers found that a certain part of a receptor called GABAAR and another protein called synapsin2b were over expressed. The over expression of GABAAR causes the nerve cells to be less active while the overexpression of synapsin2b causes them to be more active.

In a press release, one of the authors of the study, Elham Taha, explained: “We realized that, surprisingly, the change in the general translation control element, eEF2K, changes the excitation/inhibition ratio in a specific area of the brain. This area as well as the molecules whose expression changed are associated with epilepsy. For example, mutation in synapsin2b in humans or a decline in its expression may lead to epilepsy.”

As a next step, the researchers genetically-engineered mice with epilepsy that lacked eEF2K protein, to find out if eEF2K down-regulation decreases seizure activity. EEG tests revealed that these animals did not have any seizures.

The scientists also sought to find out whether chemically (rather then genetically) inhibiting the eEF2K protein would have the same effect. They gave mice with epilepsy (that had low levels of synapsin2b) a substance that inhibits the expression of eEF2K protein. They noticed that the mice did not experience any seizures during the following week.

For both the genetic and chemical methods, when the researchers looked at the expression of synapsin2b they saw that the levels had been brought to normal as a result of eEF2K absence/inhibition.

In the future, the researchers want to find ways to block the expression of eEF2K in only certain nerve cells “in order to improve our understanding of the basis of epilepsy and to create new possibilities for treating the disease.”

Author: Dr Özge Özkaya

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Link found between epilepsy drugs and birth defects

Science Daily - Tue, 11/29/2016 - 14:58
For most women who have epilepsy, continuing their medication during pregnancy is important for their health. Over the last 25 years, research has shown that children exposed to these medications in the womb can be at a higher risk of having a malformation or birth defect.
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Children With Congenital Heart Disease Have a Higher Risk of Epilepsy

Epilepsy Research - Tue, 11/29/2016 - 08:50

The risk of epilepsy is higher in children with congenital heart disease (CHD) compared with the general population, even if the condition is mild and does not require surgical intervention, according to a study published in the scientific journal, Circulation.

This finding suggests that epilepsy in children with CHD may be a consequence of  ‘non-surgical’ factors, such as an insufficient supply of oxygen to the brain during development and subsequent brain abnormality. However, the authors do speculate the existence of a genetic link between congenital heart disease and epilepsy.

For the study, the team, led by Dr Morten Olsen, identified children born with CHD between 1980 and 2010, using data from population-based registries covering all hospitals in Denmark. All of the children that were included in the study were diagnosed with CHD by the age of 15. For each child with CHD, the scientists identified 10 healthy children who were the same age and sex for comparison.

The results showed that there were 15,222 children born and diagnosed with CHD in Denmark during this period. A little more than half of them (51%) were male and 49% were female. Five percent of the children were diagnosed with epilepsy by the time they were 15 years of age. When only children born with CHD without extra-cardiac (outside of the heart) malformations were considered, this figure was 3%. It was more likely for children with CHD to develop epilepsy before the age of five than after the age of five.

The likelihood of developing epilepsy was not influenced by the age of the child when they had heart surgery, but it was highest among children who underwent multiple surgeries. However the risk of epilepsy was also higher than in the general population for children with mild CHD who did not undergo surgery.

Although it was previously known that neurological complications are associated with congenital heart disease, this is the first study that examined the long-term risk of epilepsy in people with congenital heart defects compared with the general population.

Previous work has identified genetic mutations that may link CHD with neurodevelopmental disabilities. According to the authors “there may be an as-yet-undiscovered genetic explanation for the heightened risk of epilepsy in the [CHD] population”.

It is important to note that the increased risk of epilepsy that was observed in this study could be linked to other factors such as the mother having epilepsy, and the foetus being exposed to antiepileptic drugs in the mother’s uterus. However in the group with CHD that was analysed, the proportion of mothers with epilepsy was very low and so it is unlikely to be the only mechanism explaining the increased risk of epilepsy.

Author: Dr Özge Özkaya

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Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies

Epilepsia - Tue, 11/29/2016 - 04:00
Summary Objective

To examine the 30-day risk of hospitalization with hyponatremia associated with carbamazepine, valproic acid (V), phenytoin (P), or topiramate (T) use compared to nonuse in the outpatient setting among older adults.

Methods

We conducted two population-based, retrospective cohort studies in Ontario, Canada, between 2003 and 2015 using administrative health care databases of older adults. The first study compared carbamazepine users to a propensity-score matched group of antiepileptic drug nonusers, whereas the second compared V-P-T users to a propensity-score matched group of antiepileptic nonusers. The primary outcome was hospitalization with hyponatremia within 30 days of an antiepileptic prescription.

Results

The baseline characteristics between matched groups were similar in both cohorts. Carbamazepine use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (82/21,191 [0.39%] versus 30/63,573 [0.05%]; relative risk [RR] 8.20, 95% confidence interval [CI] 5.40–12.46). Similarly, V-P-T use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (34/20,155 [0.17%] versus 26/40,310 [0.06%]; RR 2.62, 95% CI 1.57–4.36).

Significance

Older adults prescribed carbamazepine and V-P-T have a higher risk of being hospitalized with hyponatremia compared to other adults with similar indicators of baseline health who were not prescribed antiepileptic drugs. Physicians should be mindful of this risk; when a patient presents to a hospital with symptomatic hyponatremia these drugs should be considered as potential causes.

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Modifying AEDs Used by Patients During Vagal Nerve Stimulation Does Not Improve Outcome

Epilepsy Research - Mon, 11/28/2016 - 04:14

Changing people’s antiepileptic drugs (AEDs) during vagal nerve stimulation (VNS) does not seem to improve their outcomes, according to a study published in the journal Acta Neurochirurgica.

On the basis of this finding, the authors suggest that keeping the same AEDs following the implantation of a VNS device may help optimise its parameters and could improve its effectiveness.

In order to assess the influence of medication change following the implantation of a VNS device, researchers at University Hospital La Princesa, in Madrid, compared two groups of people with epilepsy treated with VNS, with and without medication changes.

They analysed a total of 85 people with epilepsy who were treated with VNS between 2005 and 2014. The AEDs given to 43 of the participants was not modified following the implantation of the VNS device, while the decision to make a change in medication was left to the neurologist in the case of the remaining 42 people.

Eighteen months after implantation, more than half of all the patients (54.1%) had at least a 50% reduction in seizure frequency. When the researchers compared patients whose medication was not modified following the procedure with the patients whose medication was modified, they found that in the first group (medication not modified) 63% of patients had at least 50% reduction in their seizures. This figure was 45.2% in the second group (medication modified).

The researchers concluded that there were no statistical differences in the reduction of seizure frequency between people whose medication was changed, and those whose medication remained the same, following implantation of a VNS device.

A VNS device (or stimulator) is a small device containing a generator that is implanted in the left side of the chest. It sends regular electrical impulses to the left vagus nerve in the neck and it is used to try and prevent seizures in people who don’t respond to medication alone. During the 12-18 months following the implantation of  VNS device, a neurologists will usually change the patient’s antiepileptic drugs (AEDs), which makes it difficult to know whether any reduction in seizure frequency is due to VNS or the change in medication.

Author: Dr Özge Özkaya

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Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus

Epilepsia - Sat, 11/26/2016 - 01:40
Summary

Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders. Liquid chromatographic procedures coupled with electrospray tandem mass spectrometry and routine laboratory investigations were performed. Significantly lower AP levels were found in the CSF of patients affected by SE (−30%; p < 0.05, Mann-Whitney test). Notably, AP was not detectable in 28 of 41 patients affected by SE (p < 0.01 vs. controls, Fisher's exact test). In serum, AP levels did not differ in the two considered groups. Conversely, PS was present at similar levels in the investigated groups. Finally, differences in AP levels could not be explained by a variation in CSF albumin content. These findings indicate that AP is defective in the CSF of patients affected by SE. This phenomenon was not dependent on carriers for steroids, such as albumin.

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Identifying the epileptogenic zone in interictal resting-state MEG source-space networks

Epilepsia - Sat, 11/26/2016 - 01:35
Summary Objective

In one third of patients, seizures remain after epilepsy surgery, meaning that improved preoperative evaluation methods are needed to identify the epileptogenic zone. A potential framework for such a method is network theory, as it can be applied to noninvasive recordings, even in the absence of epileptiform activity. Our aim was to identify the epileptogenic zone on the basis of hub status of local brain areas in interictal magnetoencephalography (MEG) networks.

Methods

Preoperative eyes-closed resting-state MEG recordings were retrospectively analyzed in 22 patients with refractory epilepsy, of whom 14 were seizure-free 1 year after surgery. Beamformer-based time series were reconstructed for 90 cortical and subcortical automated anatomic labeling (AAL) regions of interest (ROIs). Broadband functional connectivity was estimated using the phase lag index in artifact-free epochs without interictal epileptiform abnormalities. A minimum spanning tree was generated to represent the network, and the hub status of each ROI was calculated using betweenness centrality, which indicates the centrality of a node in a network. The correspondence of resection cavity to hub values was evaluated on four levels: resection cavity, lobar, hemisphere, and temporal versus extratemporal areas.

Results

Hubs were localized within the resection cavity in 8 of 14 seizure-free patients and in zero of 8 patients who were not seizure-free (57% sensitivity, 100% specificity, 73% accuracy). Hubs were localized in the lobe of resection in 9 of 14 seizure-free patients and in zero of 8 patients who were not seizure-free (64% sensitivity, 100% specificity, 77% accuracy). For the other two levels, the true negatives are unknown; hence, only sensitivity could be determined: hubs coincided with both the resection hemisphere and the resection location (temporal versus extratemporal) in 11 of 14 seizure-free patients (79% sensitivity).

Significance

Identifying hubs noninvasively before surgery is a valuable approach with the potential of indicating the epileptogenic zone in patients without interictal abnormalities.

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A novel c132-134del mutation in Unverricht-Lundborg disease and the review of literature of heterozygous compound patients

Epilepsia - Sat, 11/26/2016 - 01:30
Summary

Unverricht-Lundborg disease or progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disease caused by mutation of the cystatin B gene (CSTB), located on chromosome 21q22.3. The most common mutation is an expansion of unstable dodecamer repetition (CCCCGCCCCGCG), whereas other types of mutations are rare. Among these, heterozygous compound mutations are described to induce a more severe phenotype than that of homozygous dodecameric repetition. We report two siblings affected by heterozygous compound mutations carrying a novel mutation of the deletion of three nucleotides in exon 2 of the gene in position 132–134 of the coding sequence (c.132-134del) in the allele not including the dodecamer repetition. This mutation results in the loss of two amino acid residues and insertion of an asparagine in position 44 (p.Lys44_Ser45delinsAsn). Our patients presented a very different clinical picture. The male patient had a severe myoclonus, drug-resistant epilepsy and psychiatric comorbidity, while his affected sister had only very rare seizures and sporadic myoclonic jerks at awakening. The revision of literature about heterozygous compound EPM1 patients confirms this gender phenotypic expressivity, with female patients carrying less severe symptoms than male patients. These data lead to the hypothesis of complex gender-specific factors interacting with CSTB expressivity in EPM1 patients.

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The burden of premature mortality of epilepsy in high-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy

Epilepsia - Sat, 11/26/2016 - 01:25
Summary

Since previous reviews of epidemiologic studies of premature mortality among people with epilepsy were completed several years ago, a large body of new evidence about this subject has been published. We aim to update prior reviews of mortality in epilepsy and to reevaluate and quantify the risks, potential risk factors, and causes of these deaths. We systematically searched the Medline and Embase databases to identify published reports describing mortality risks in cohorts and populations of people with epilepsy. We reviewed relevant reports and applied criteria to identify those studies likely to accurately quantify these risks in representative populations. From these we extracted and summarized the reported data. All population-based studies reported an increased risk of premature mortality among people with epilepsy compared to general populations. Standard mortality ratios are especially high among people with epilepsy aged <50 years, among those whose epilepsy is categorized as structural/metabolic, those whose seizures do not fully remit under treatment, and those with convulsive seizures. Among deaths directly attributable to epilepsy or seizures, important immediate causes include sudden unexpected death in epilepsy (SUDEP), status epilepticus, unintentional injuries, and suicide. Epilepsy-associated premature mortality imposes a significant public health burden, and many of the specific causes of death are potentially preventable. These require increased attention from healthcare providers, researchers, and public health professionals.

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Rapid and safe response to low-dose carbamazepine in neonatal epilepsy

Epilepsia - Sat, 11/26/2016 - 01:15
Summary Objective

To evaluate treatment responses in benign familial neonatal epilepsy (BFNE).

Methods

We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes.

Results

Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures. Mutations or deletions of KCNQ2 were found in 14, and of KCNQ3 in 2, of the 19 patients. In all patients, seizures began at 2–5 days of life and occurred multiple times per day. Four patients developed status epilepticus. Seizures were focal, alternating between hemispheres, and characterized by asymmetric tonic posturing associated with apnea and desaturation, followed by unilateral or bilateral asynchronous clonic jerking. Twelve of 19 patients were treated with multiple medications prior to seizure cessation. Seventeen of (88%) 19 patients were seizure-free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization (p < 0.01). No side effects of CBZ were reported. All patients had normal development and remain seizure-free at a mean follow-up period of 7.8 years (6 months–16 years).

Significance

This study provides evidence that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus. We propose that CBZ should be the drug of choice in benign familial neonatal seizures.

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Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus

Epilepsia - Sat, 11/26/2016 - 01:10
Summary Objective

The maturation of adult-born granule cells and their functional integration into the network is thought to play a key role in the proper functioning of the dentate gyrus. In temporal lobe epilepsy, adult-born granule cells in the dentate gyrus develop abnormally and possess a hilar basal dendrite (HBD). Although morphological studies have shown that these HBDs have synapses, little is known about the functional properties of these HBDs or the intrinsic and network properties of the granule cells that possess these aberrant dendrites.

Methods

We performed patch-clamp recordings of granule cells within the granule cell layer “normotopic” from sham-control and status epilepticus (SE) animals. Normotopic granule cells from SE animals possessed an HBD (SE+HBD+ cells) or not (SE+HBD− cells). Apical and basal dendrites were stimulated using multiphoton uncaging of glutamate. Two-photon Ca2+ imaging was used to measure Ca2+ transients associated with back-propagating action potentials (bAPs).

Results

Near-synchronous synaptic input integrated linearly in apical dendrites from sham-control animals and was not significantly different in apical dendrites of SE+HBD− cells. The majority of HBDs integrated input linearly, similar to apical dendrites. However, 2 of 11 HBDs were capable of supralinear integration mediated by a dendritic spike. Furthermore, the bAP-evoked Ca2+ transients were relatively well maintained along HBDs, compared with apical dendrites. This further suggests an enhanced electrogenesis in HBDs. In addition, the output of granule cells from epileptic tissue was enhanced, with both SE+HBD− and SE+HBD+ cells displaying increased high-frequency (>100 Hz) burst-firing. Finally, both SE+HBD− and SE+HBD+ cells received recurrent excitatory input that was capable of generating APs, especially in the absence of feedback inhibition.

Significance

Taken together, these data suggest that the enhanced excitability of HBDs combined with the altered intrinsic and network properties of granule cells collude to promote excitability and synchrony in the epileptic dentate gyrus.

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Depression in young people affects the stomach, anxiety the skin

Medical News Today - Fri, 11/25/2016 - 09:00
Mental disorders and physical diseases frequently go hand in hand. For the first time, psychologists at the University of Basel and Ruhr University Bochum have identified temporal patterns in young...
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Connection found between memory mechanisms, resistance to epilepsy

Science Daily - Fri, 11/25/2016 - 08:43
A genetic change in the protein eEF2K creates resistance to epileptic attacks, thereby creating the possibility of a new treatment for the disease, show the surprising results of a new study.
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Children with Epilepsy on the Ketonic Diet Should Have their Blood Selenium Levels Closely Monitored

Epilepsy Research - Fri, 11/25/2016 - 05:00

An olive oil-based ketogenic-diet leads to a decline in selenium levels in children with drug-resistant epilepsy, according to a study published in the journal of Biological Trace Elements Research.

Previous research has shown that low amount of selenium, an element found in trace amounts in the blood that, may increase the risk of seizures. Therefore the levels of selenium in the blood of children with epilepsy who are on a ketogenic diet should be closely monitored.

For the study, the team led by Dr Orkide Guzel, at Behçet Uz Children Hospital in Izmir, Turkey, enrolled a total of 110 children with drug-resistant epilepsy, aged between three and 12 years, who were on ketogenic diet for at least 12 months.

The researchers measured the level of selenium in the children’s blood before the start of ketogenic diet treatment (baseline) and again at three, six and 12 months.

The results showed that although there were no significant differences in the level of selenium in the blood of the children after three months of treatment with ketogenic diet, selenium levels were significantly lower at six and 12 months compared with pre-treatment levels.

Almost half of the children (54 out of 110) were diagnosed with selenium deficiency, defined as selenium levels lower than 48 micrograms per litre, and treated with selenium supplements.

“The decline of the serum selenium concentrations after 6 and 12 months of ketogenic diet suggests that patients on this highly prescriptive dietary treatment need close monitoring of this trace element,” the authors wrote.

Author: Dr Özge Özkaya

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