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Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway

Epilepsia - 9 hours 18 min ago
Summary Objective

Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno)proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin.

Methods

The expression of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post-status epilepticus (SE) rat model for temporal lobe epilepsy (TLE). The effect of rapamycin was studied on (immuno)proteasome subunit expression in post-SE rats that were treated for 6 weeks. (Immuno)proteasome expression was validated in the brain tissue of patients who had SE or drug-resistant TLE and the effect of rapamycin was studied in primary human astrocyte cultures.

Results

In post-SE rats, increased (immuno)proteasome expression was detected throughout epileptogenesis in neurons and astrocytes within the hippocampus and piriform cortex and was most evident in rats that developed a progressive form of epilepsy. Rapamycin-treated post-SE rats had reduced (immuno)proteasome protein expression and a lower number of spontaneous seizures compared to vehicle-treated rats. (Immuno)proteasome expression was also increased in neurons and astrocytes within the human hippocampus after SE and in patients with drug-resistant TLE. In vitro studies using cultured human astrocytes showed that interleukin (IL)-1β-induced (immuno)proteasome gene expression could be attenuated by rapamycin.

Significance

Because dysregulation of the (immuno)proteasome system is observed before the occurrence of spontaneous seizures in rats, is associated with progression of epilepsy, and can be modulated via the mTOR pathway, it may represent an interesting novel target for drug treatment in epilepsy.

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Perisylvian, including insular, childhood epilepsy: Presurgical workup and surgical outcome

Epilepsia - 9 hours 20 min ago
Summary Objective

To report the presurgical workup, surgical procedures, and outcomes in a series of pediatric patients with drug-resistant epilepsy involving the perisylvian/insular regions.

Methods

We retrospectively assessed 16 pediatric patients affected by drug-resistant focal epilepsy involving perisylvian/insular regions, who consecutively underwent tailored resective surgery. All patients underwent a detailed presurgical workup, which included the analysis of the anatomoelectroclinical correlations with scalp electroencephalography (EEG) and/or with stereo-electroencephalography (SEEG), brain magnetic resonance imaging (MRI), and comprehensive cognitive and neuropsychological evaluations. After surgery, all patients underwent serial clinical and laboratory evaluations.

Results

Focal motor seizures restricted to perioral area, associated with symptoms related to the surrounding areas (as auditory hallucinations, unpleasant paresthesia, fear, and epigastric sensation), characterized the ictal semiology in 75% of patients. In 50%, autonomic manifestations were present and in 56% subjective manifestations were reported. The 50% of the patients underwent SEEG with insular sampling to better define the epileptogenic zone. In all patients, the insular cortex was always part of the epileptogenic zone, and tailored resections also involved, with variable degree, the frontal, parietal, and temporal opercula. Preoperatively, the neuropsychological assessment revealed impairments in specific cognitive functions and mild or moderate cognitive compromise in 88% of the patients. Postoperatively, one patient had permanent slight hemiparesis. At the most recent follow-up (median 39 months), seizure outcome was satisfactory in 69% of patients: seven patients were completely seizure-free (Engel class Ia), two were free of disabling seizure (class Ic), and two had rare disabling seizures (class II). The cognitive functioning remained unchanged in 62%, and improved in 38%.

Significance

The assessment of perisylvian/insular epilepsy in children is particularly challenging. However, tailored resections based on a careful presurgical evaluation, including SEEG recording, may lead to a good seizure control and to a better overall outcome.

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Impaired hippocampal glucose metabolism during and after flurothyl-induced seizures in mice: Reduced phosphorylation coincides with reduced activity of pyruvate dehydrogenase

Epilepsia - Tue, 06/20/2017 - 14:21
Summary Objective

To determine changes in glucose metabolism and the enzymes involved in the hippocampus ictally and postictally in the acute mouse flurothyl seizure model.

Methods

[U-13C]-Glucose was injected (i.p.) prior to, or following a 5 min flurothyl-induced seizure. Fifteen minutes later, mice were killed and the total metabolite levels and % 13C enrichment were analyzed in the hippocampal formation using gas chromatography–mass spectrometry. Activities of key metabolic and antioxidant enzymes and the phosphorylation status of pyruvate dehydrogenase were measured, along with lipid peroxidation.

Results

During seizures, total lactate levels increased 1.7-fold; however, [M + 3] enrichment of both lactate and alanine were reduced by 30% and 43%, respectively, along with a 28% decrease in phosphofructokinase activity. Postictally the % 13C enrichments of all measured tricarboxylic acid (TCA) cycle intermediates and the amino acids were reduced by 46–93%. At this time, pyruvate dehydrogenase (PDH) activity was 56% of that measured in controls, and there was a 1.9-fold increase in the phosphorylation of PDH at ser232. Phosphorylation of PDH is known to decrease its activity.

Significance

Here, we show that the increase of lactate levels during flurothyl seizures is from a source other than [U-13C]-glucose, such as glycogen. Surprisingly, although we saw a reduction in phosphofructokinase activity during the seizure, metabolism of [U-13C]-glucose into the TCA cycle seemed unaffected. Similar to our recent findings in the chronic phase of the pilocarpine model, postictally the metabolism of glucose by glycolysis and the TCA cycle was impaired along with reduced PDH activity. Although this decrease in activity may be a protective mechanism to reduce oxidative stress, which is observed in the flurothyl model, ATP is critical to the recovery of ion and neurotransmitter balance and return to normal brain function. Thus we identified promising novel strategies to enhance energy metabolism and recovery from seizures.

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Regulation of kindling epileptogenesis by hippocampal Toll-like receptors 2

Epilepsia - Tue, 06/20/2017 - 08:55
Summary

This study examined whether Toll-like receptors 2 (TLR2) contribute to rapid kindling epileptogenesis. A TLR2 agonist, lipoteichoic acid (LTA), LTA antibody (LTA-A), or normal saline (control) was administered daily over 3 consecutive days, unilaterally into ventral hippocampus of adult male Wistar rats. Thirty minutes after the last injection, the animals were subjected to a rapid kindling procedure. The ictogenesis was gauged by comparing afterdischarge threshold (ADT) and afterdischarge duration (ADD) before the treatments, after the treatments prior to kindling, and 24 h after kindling. Kindling progression and retention were analyzed using video recording. The results showed that before kindling, LTA produced an ADT reduction. Neither LTA nor LTA-A affected baseline ADD. On kindling progression, LTA accelerated occurrence of generalized seizures, whereas LTA-A delayed this effect. Treatment with LTA-A reduced the number of secondary generalized complex partial seizures. Twenty-four hours after kindling, the rats of both the saline and LTA groups showed increased hippocampal excitability as compared with prekindling parameters. Administration of LTA-A prevented kindling-induced increase of hippocampal excitability. Immunostaining revealed that LTA-A attenuated the inflammatory response produced by seizures. These findings suggest that the activation of TLR2 in the hippocampus may facilitate limbic epileptogenesis.

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Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease

Epilepsia - Tue, 06/20/2017 - 08:54
Summary Objective

This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes.

Methods

Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed.

Results

A total of 14 patients were included. For the whole group, median (range) age at disease onset was 3.0 (2.0–3.8) years. Epilepsy was the most commonly reported presenting symptom (in 50% [seven of 14] of patients), occurring at the age of 3.2 (2.6–3.8) years. First seizure was myoclonic in 36% (five of 14) of patients, followed by generalized tonic–clonic in 29% (4 of 14), atonic in 22% (three of 14), and focal with motor signs in 14% (two of 14). All patients walked independently at the age of 12.0 (11.0–18.0) months, but delayed speech or regression of acquired verbal skills was present in 100% of patients at 3 years. EEGs revealed a photoparoxysmal response (PPR) on intermittent photic stimulation in 93% (13 of 14) of patients. PPR was present from the first EEG, which was performed at 3.6 (3.1–4.0) years, in 43% (six of 14) of patients; it was documented at low (1–3 Hz) stimulation frequencies in 69% (nine of 13) and took the form of a flash-per-flash response in 69% (nine of 13). First brain MRI at the age of 3.8 (3.0–5.1) years revealed cerebellar atrophy in 100% (14 of 14) of patients and alteration of the periventricular white matter signal in the posterior hemispheric region in 79% (11 of 14).

Significance

Early photosensitivity (typically PPR at low stimulation frequencies of 1–3 Hz) is a hallmark of CLN2 disease. This diagnosis should be considered in a child presenting with any type of seizure, and particularly if it is accompanied by delayed speech and/or ataxia or MRI abnormalities (posterior white matter signal alteration or cerebellar atrophy).

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Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction

Epilepsia - Tue, 06/20/2017 - 08:54
Summary

A recent article by Farrell et al. characterizes the phenomenon, mechanisms, and treatment of a local and severe hypoperfusion/hypoxia event that occurs in brain regions following a focal seizure. Given the well-established role of cerebral ischemia/hypoxia in brain damage and behavioral dysfunction in other clinical settings (e.g., stroke, cerebral vasospasm), we put forward a new theory: postictal hypoperfusion/hypoxia is responsible for the negative consequences associated with seizures. Fortunately, inhibition of two separate molecular targets, cyclooxygenase-2 (COX-2) and l-type calcium channels, can prevent the expression of postictal hypoperfusion/hypoxia. These inhibitors are important experimental tools used to separate the seizure from the resulting hypoperfusion/hypoxia and can allow researchers to address the contribution of this phenomenon to negative outcomes associated with seizures. Herein we address the implications of this postictal stroke-like event in acute behavioral dysfunction (e.g., Todd's paresis) and sudden unexpected death in epilepsy (SUDEP). Moreover, anatomic alterations such as increased blood–brain barrier permeability, glial activation, central inflammation, and neuronal loss could also be a consequence of repeated hypoperfusion/hypoxic events and, in turn, underlie chronic interictal cognitive and behavioral comorbidities (e.g., memory deficits, anxiety, depression, and psychosis) and exacerbate epileptogenesis. Thus these seemingly disparate and clinically important observations may share a common point of origin: postictal hypoperfusion/hypoxia.

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Poll shows that almost 50% of people forget to take their medication at least once a month

Epilepsy Research - Tue, 06/20/2017 - 06:52

Patient adherence to medication regimes is a large problem across the world.  Across all medicines, it has been estimated that up to 75% of people do not take their medicines properly.  This could be a problem in epilepsy as a lowering of the medication in the bloodstream could lead to breakthrough seizures.  We wanted to know how often people who receive our e-newsletter felt that they adhered to their medication regimes.  The results were interesting.  Please bear in mind that this was a self-selecting poll of 125 people and so any results must be read in that way.  They were also asked to estimate for themselves how many times in the last month that they had forgotten to take their medication altogether or had taken it at a different time to that which had been recommended.

  1. Of the 125 respondents, almost 90% were responsible for their own epilepsy medication while just 9% were responsible for someone else’s medicine (as a carer or parent).
  2. 90% of the respondents had to take their medications two or more times a day with the majority having to take medication twice a day.
  3. Half of our respondents were taking just one medication while 28% took two medications.  Almost a quarter of our respondents are taking 3, 4 or more medications for their epilepsy each day.

When we asked about how often the respondents forgot to take their medication altogether or at the wrong time in the past month:

  1. 52% said they had not forgotten to take their medication or give someone medication at all.
  2. Just over 20% said they had forgotten once in the last month.
  3. 25% said they had forgotten twice or more in the last month.
  4. 54% said they had not forgotten to take their medicine at the right time in the past month.
  5. 15% said they had taken their medicine at the wrong time once in the last month.
  6. Over a quarter said they had taken their medicine at the wrong time twice or more in the last month.

Here are some simple tips to help you remember to take your medicine.

Take the poll and help us gather more information.

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Leanne Bowman skydives to support research – could you?

Epilepsy Research - Tue, 06/20/2017 - 05:06

Leanne Bowman is shown here flying the flag for Epilepsy Research UK in a Tandem Skydive to raise vital funds for the only national charity exclusively dedicated to funding research. Leanne wanted to do something a little bit different to raise funds as her brother has suffered from epilepsy for over 10 years so it’s something close to her heart. She wishes to thank everyone who has supported her by their kind donations.

If you would like to skydive for epilepsy research or try another challenge you can find more details here

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Leading Grimsby law firm raising money for Epilepsy Research UK in memory of Robert Abba.

Epilepsy Research - Mon, 06/19/2017 - 06:13

Staff at a leading law firm are to saddle up and drop 200 ft in memory of a Grimsby student.  Robert Abba, 22, died after suffering an epileptic fit at home in Scartho.

His mother Rachel works for Bridge McFarland solicitors and colleagues will take in such landmarks as Lincoln Castle and Grimsby Dock Tower as they run, cycle, skydive and abseil to raise money in the memory of Robert.  The money will go to help Epilepsy Research UK find out more about epilepsy and SUDEP – Sudden Unexpected (Unexplained) Death in Epilepsy. Around 87 people are diagnosed with epilepsy each day and SUDEP claims around 600 lives every year.

Read more 

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Is a micro-gene a factor in epileptic seizures?

Epilepsy Research - Mon, 06/19/2017 - 05:01

Seizures in epilepsy can be caused by genetic factors or they can be triggered by injury.  While we know that all brains are capable of generating seizures we do not know why some brains do not develop them.  A good example is epilepsy that develops as a result of an ischemic stroke.  Only some of the people who have an ischemic stroke will develop epilepsy so it has long been conjectured that there are also other factors at play.

Researchers at the Hebrew University in Jerusalem believe they may have found one of these factors in the form of a micro-gene.

The research, that has been published in the journal Proceedings of the National Academy of Sciences, started out from the hypothesis that healthy brains do not have seizures when exposed to flashing lights or other triggers because of so-called short RNAs, otherwise known as rapidly inducible microRNAs.

MicroRNAs are a class of RNA – that is, one of the macromolecules needed for all forms of life, together with DNA and proteins – that have the ability to suppress the genetic expression of certain proteins.

Prof. Hermona Soreq and her team tested their hypothesis through a genetically designed a type of mouse that produces very large amounts of a microRNA called miR-211.

The overexpression of miR-211 taking place in the mice’s forebrain was engineered in such a way that it could be lowered with the antibiotic doxycycline.  Soreq, along with colleagues at the Ben-Gurion University of the Negev in Israel and Dalhousie University in Canada, managed to suppress the excess of miR-211 in the transgenic mice by using doxycycline, which brought the levels to normal.

After 4 days, they recorded the mice’s brain activity using electrocorticography. They found that the mice reacted to the miR-211-suppressing doxycycline by having nonconvulsive seizures, as well as by accumulating miR-134 in the forebrain.

The new study revealed that once they had their levels of miR-211 lowered, the mice showed signs of epilepsy and a propensity for convulsions. They displayed a hypersensitivity to compounds that induce epilepsy, such as the miR-134.

This suggests that miR-211 has a neuroprotective role and is key in preventing epileptic seizures in genetically modified mice.

“Dynamic changes in the amount of miR-211 in the forebrains of these mice shifted the threshold for spontaneous and pharmacologically induced seizures, alongside changes in the cholinergic pathway genes,” Prof. Soreq explains.

“It is important to discover how only some people’s brains present a susceptibility to seizures, while others do not, even when subjected to these same stressors. In searching for the physiological mechanisms that allow some people’s brains to avoid epilepsy, we found that increased levels of microRNA 211 could have a protective effect.” Prof. Hermona Soreq

The scientists hope that their discovery will help the medical research community to develop new treatments for epilepsy. Such therapies might work by raising the levels of miR-211 in human brains.

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How to record high-frequency oscillations in epilepsy: A practical guideline

Epilepsia - Fri, 06/16/2017 - 13:05
Summary Objective

Technology for localizing epileptogenic brain regions plays a central role in surgical planning. Recent improvements in acquisition and electrode technology have revealed that high-frequency oscillations (HFOs) within the 80–500 Hz frequency range provide the neurophysiologist with new information about the extent of the epileptogenic tissue in addition to ictal and interictal lower frequency events. Nevertheless, two decades after their discovery there remain questions about HFOs as biomarkers of epileptogenic brain and there use in clinical practice.

Methods

In this review, we provide practical, technical guidance for epileptologists and clinical researchers on recording, evaluation, and interpretation of ripples, fast ripples, and very high-frequency oscillations.

Results

We emphasize the importance of low noise recording to minimize artifacts. HFO analysis, either visual or with automatic detection methods, of high fidelity recordings can still be challenging because of various artifacts including muscle, movement, and filtering. Magnetoencephalography and intracranial electroencephalography (iEEG) recordings are subject to the same artifacts.

Significance

High-frequency oscillations are promising new biomarkers in epilepsy. This review provides interested researchers and clinicians with a review of current state of the art of recording and identification and potential challenges to clinical translation.

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UCL Neuroscience Symposium

Epilepsy Research - Fri, 06/16/2017 - 10:21

Today – Friday 16th – we have been at the annual UCL (University College London) Neuroscience Symposium.  It is immensely popular and attracts almost around 800 delegates.  Epilepsy Research UK projects were in evidence and I had the opportunity to meet some of our current researchers as well as young researchers that we would like to encourage in order to keep their skills in the field of epilepsy.

You can find more details of the UCL Symposium and download the abstract booklet here.

 

Dr Stephanie Schorge explains her research to an interested symposium delegate.

Dr Gabriele Lignani – Epilepsy Research UK Fellowship holder with details of his preliminary findings.

Among the Epilepsy Research UK funded researchers was Dr Stephanie Schorge who was presenting some details of her work on gene therapy and refractory epilepsy.  We also met Dr Gabriele Lignani who has just been awarded an Epilepsy Research UK Fellowship.  Dr Ligani was presenting his work on how to increase promoter activity to treat intractable epilepsy.  We also ran into Albert Snowball from the UCL Institute of Neurology who was presenting his work on gene therapy for epilepsy using non-integrating lentiviral delivery of an engineered potassium channel gene.  The  Institute of Neurology at UCL has a worldwide reputation and as an organisation, we are proud to help fund some of the fantastic work that is going on there.

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Nonintravenous rescue medications for pediatric status epilepticus: A cost-effectiveness analysis

Epilepsia - Fri, 06/16/2017 - 02:19
Summary Objective

To quantify the cost-effectiveness of rescue medications for pediatric status epilepticus: rectal diazepam, nasal midazolam, buccal midazolam, intramuscular midazolam, and nasal lorazepam.

Methods

Decision analysis model populated with effectiveness data from the literature and cost data from publicly available market prices. The primary outcome was cost per seizure stopped ($/SS). One-way sensitivity analyses and second-order Monte Carlo simulations evaluated the robustness of the results across wide variations of the input parameters.

Results

The most cost-effective rescue medication was buccal midazolam (incremental cost-effectiveness ratio ([ICER]: $13.16/SS) followed by nasal midazolam (ICER: $38.19/SS). Nasal lorazepam (ICER: −$3.8/SS), intramuscular midazolam (ICER: −$64/SS), and rectal diazepam (ICER: −$2,246.21/SS) are never more cost-effective than the other options at any willingness to pay. One-way sensitivity analysis showed the following: (1) at its current effectiveness, rectal diazepam would become the most cost-effective option only if its cost was $6 or less, and (2) at its current cost, rectal diazepam would become the most cost-effective option only if effectiveness was higher than 0.89 (and only with very high willingness to pay of $2,859/SS to $31,447/SS). Second-order Monte Carlo simulations showed the following: (1) nasal midazolam and intramuscular midazolam were the more effective options; (2) the more cost-effective option was buccal midazolam for a willingness to pay from $14/SS to $41/SS and nasal midazolam for a willingness to pay above $41/SS; (3) cost-effectiveness overlapped for buccal midazolam, nasal lorazepam, intramuscular midazolam, and nasal midazolam; and (4) rectal diazepam was not cost-effective at any willingness to pay, and this conclusion remained extremely robust to wide variations of the input parameters.

Significance

For pediatric status epilepticus, buccal midazolam and nasal midazolam are the most cost-effective nonintravenous rescue medications in the United States. Rectal diazepam is not a cost-effective alternative, and this conclusion remains extremely robust to wide variations of the input parameters.

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Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol

Epilepsia - Thu, 06/15/2017 - 01:00
Summary

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 ± 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.

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