A major receptor found in the brain called PAR1 is involved in the regulation of anxiety-related behaviour, suggests a recent study, published in the journal Epilepsy and Behavior.
The study used an animal model of temporal lobe epilepsy (TLE), the most common type of focal epilepsy in adults, which is often associated with psychiatric complications such as depression and anxiety. However, the mechanism of anxiety-related deficits in people with epilepsy are unclear.
The findings are important because they suggest that PAR1-dependent signalling may be associated with emotional disorders in people with epilepsy and that targeting PAR1 signalling might open a new therapeutic avenue to help prevent cognitive problems related to anxiety in TLE.
The research, led by Dr Elena Isaeva at Bogomoletz Institute of Physiology in Kiev, Ukraine, involved inducing epilepsy in rats, which led to a decrease in anxiety-related behaviour of the animals and an increase in their general activity.
When the researchers blocked PAR1 shortly after inducing epilepsy, they saw that the normal anxiety-related behaviour of the animals was restored but the increase in their activity remained unchanged. In rats with epilepsy, blocking PAR1 had a less pronounced effect on memory recall than in control rats and also showed a modest beneficial effect on learning.
The team concluded that PAR1 inhibition in the normal brain is harmful whereas blocking PAR1 in animals with epilepsy may be therapeutic.
“The present study shows for the first time ……. the involvement of PAR1 in the regulation of anxiety-related behaviour”, the researchers wrote.
PAR1, or protease-activated receptor 1, is involved in behaviour and memory formation. It is expressed in areas of the brain that are important for processing emotional reactions and is implicated in the regulation of emotionally-motivated learning.
Author: Dr Özge Özkaya
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The American Academy of Neurology (AAN) has published new guidelines on mapping of the brain prior to epilepsy surgery, following a systematic review of available evidence.
The guidelines were published in the academy’s journal Neurology and compared results of functional magnetic resonance imaging (fMRI), a type of scan that assesses brain activity by measuring blood flow, with data obtained from the more commonly used intracarotid amobarbital procedure (or Wada test), where a drug called sodium amytal is injected into the main artery in the neck (called the carotid artery) to put one side of the brain to sleep.
Both procedures are aimed at locating brain regions involved in language and memory, to ensure that they are not affected by epilepsy surgery. Unlike the Wada test, which is an invasive method causing discomfort and has risks associated with it, fMRI is non-invasive and considered safe.
The principal author of the guidelines, Dr Jerzy Szaflarski, a neurologist at the University of Alabama, said in a press release: “Because fMRI is becoming more widely available, we wanted to see how it compares to the Wada test. While the risks associated with the Wada test are rare, they can be serious, including stroke and injury to the carotid artery.”
The researchers suggest that fMRI could be used as an alternative to the Wada test. However, it is difficult to generalise the recommendations to the wider population of people with epilepsy because much of the evidence in the review came from studies that recruited small numbers of patients with similar types of epilepsy from a single institution only.
According to Dr Szaflarski larger studies are needed to increase the quality of the evidence that is available. “Doctors should carefully advise patients of the risks and benefits of fMRI versus the Wada test,” he added.
Epilepsy surgery is an option for some people with epilepsy who do not respond to treatment with antiepileptic drugs. The seizure focus (the area of the brain where seizures are generated) may be removed or the spread of seizure activity may be reduced using different surgical techniques.
Author: Dr Özge Özkaya
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Adamas, a pharmaceutical company based in California, has announced the completion of a Phase1 clinical trial testing the drug candidate ADS-4101 for the treatment of partial onset seizures.
ADS-4101 is a new version of the existing antiepileptic drug (AED) lacosamide (Vimpat®) that is already approved by the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA). However ADS-4101 is designed to be taken once a day unlike Vimpat, which is usually taken twice a day. It is specially manufactured in an effort to improve seizure control when it is most needed and limit side effects at other times.
“With our confirmed understanding that epileptic seizures primarily occur during the day, we are developing ADS-4101 to deliver high concentrations of medicine during the day when seizures occur,” said Dr Gregory Went, the chairman and chief executive officer of Adamas Pharmaceuticals, in a press release. “We believe ADS-4101’s promising profile may potentially provide a clinically meaningful benefit to patients with epilepsy.”
The trial compared the safety, tolerability, and properties of four different versions of ADS-4101 in 24 healthy volunteers and compared them with lacosamide. According to the company, the best version will then be tested in further clinical trials. “We are encouraged by the results of this Phase 1 clinical trial in ADS-4101 and look forward to advancing the program in 2017,” Went said.
Dr Graeme Sills, chairman of the Board of Trustees of Epilepsy Research UK and Senior Lecturer in Pharmacology at the University of Liverpool, suggested that this report should be considered cautiously. “This is a very interesting concept but much more research is required before we can assess whether it will deliver genuine benefits for people with epilepsy whose seizures are not adequately controlled by existing drugs” he said.
Please note that Epilepsy Research UK does not endorse/promote individual epilepsy treatments or pharmaceutical companies.
Author: Dr Özge Özkaya
Click here for more articles about anti-epileptic drugs and pregnancy risks.
This year once again brings a fantastic events calendar with lots of exciting sporting events and challenges to get involved in! Proudly wear your green ERUK colours and make 2017 our best year yet!
Join Team ERUK
No matter what your ability there is something for everyone. Whether a 5K Fun Run, Sponsored Walk, Marathon or Cycle event there is loads to choose from, in all locations around the UK. If you’re feeling particularly brave why not sign up for a Parachute Jump too! Details of all the events we have places in can be found in our Event Pages.
Already have your own place? If you have your own place we would love you to join our team! There is no minimum sponsorship for own place runners, just email Jo to let us know you have your place and receive your fundraising pack.
Not able to run? How about volunteering to join our cheering squad for Team ERUK and help them reach the finish line! Contact Jo on 020 8747 5024 or email@example.com for details.
Every pound raised will help us to increase the amount of research we can fund and we really hope to have the biggest running team we’ve ever had out in force throughout 2017!
Jo Finnerty, Events Fundraiser says, “2016 brought some fantastic fundraisers, with Epilepsy Research UK being the Official Charity for the British 10K in July a particular highlight. Everyone who took part last year went to great lengths to raise awareness for epilepsy and madesponsorship to help boost the research that we can fund. It was a fantastic year!! I’m really looking forward to 2017 and supporting all those who are out flying the flag for Team ERUK. Each and every one of whom is helping us transform the lives of people with epilepsy and we’re so grateful for their support.”
Posterior cortex epilepsy surgery in childhood and adolescence: Predictors of long-term seizure outcome
We aimed to investigate the long-term seizure outcome of children and adolescents who were undergoing epilepsy surgery in the parietooccipital cortex and determine their predictive factors.Methods
We retrospectively analyzed the data of 50 consecutive patients aged 11.1 (mean) ± 5.1 (standard deviation) years at surgery. All patients but one had a magnetic resonance imaging (MRI)–visible lesion. Resections were parietal in 40%, occipital in 32%, and parietooccipital in 28% cases; 24% patients additionally underwent a resection of the posterior border of the temporal lobe. Etiology included focal cortical dysplasia in 44%, benign tumors (dysembryoplastic neuroepithelial tumor, ganglioglioma, angiocentric glioma, and pilocystic astrocytoma) in 32%, peri- or postnatal ischemic lesions in 16%, and tuberous sclerosis in 8% cases.Results
At last follow-up (mean 8 years, range 1.5–18 years), 60% patients remained seizure-free (Engel class I): 30% had discontinued and 20% had reduced antiepileptic drugs. Most seizure recurrences (71%) occurred within the first 6 months, and only three patients presented with seizures ≥2 years after surgery. Independent predictors of seizure recurrence included left-sided as well as parietal epileptogenic zones and resections. Longer epilepsy duration to surgery was identified as the only modifiable independent predictor of seizure recurrence.Significance
Our study demonstrates that posterior cortex epilepsy surgery is highly effective in terms of lasting seizure control and antiepileptic drug cessation in selected pediatric candidates. Most importantly, our data supports the early consideration of surgical intervention in children and adolescents with refractory posterior cortex epilepsy.
The increasing number of treatment options and the high costs associated with epilepsy have fostered the development of economic evaluations in epilepsy. It is important to examine the availability and quality of these economic evaluations and to identify potential research gaps. As well as looking at both pharmacologic (antiepileptic drugs [AEDs]) and nonpharmacologic (e.g., epilepsy surgery, ketogenic diet, vagus nerve stimulation) therapies, this review examines the methodologic quality of the full economic evaluations included. Literature search was performed in MEDLINE, EMBASE, NHS Economic Evaluation Database (NHS EED), Econlit, Web of Science, and CEA Registry. In addition, Cochrane Reviews, Cochrane DARE and Cochrane Health Technology Assessment Databases were used. To identify relevant studies, predefined clinical search strategies were combined with a search filter designed to identify health economic studies. Specific search strategies were devised for the following topics: (1) AEDs, (2) patients with cognitive deficits, (3) elderly patients, (4) epilepsy surgery, (5) ketogenic diet, (6) vagus nerve stimulation, and (7) treatment of (non)convulsive status epilepticus. A total of 40 publications were included in this review, 29 (73%) of which were articles about pharmacologic interventions. Mean quality score of all articles on the Consensus Health Economic Criteria (CHEC)-extended was 81.8%, the lowest quality score being 21.05%, whereas five studies had a score of 100%. Looking at the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), the average quality score was 77.0%, the lowest being 22.7%, and four studies rated as 100%. There was a substantial difference in methodology in all included articles, which hampered the attempt to combine information meaningfully. Overall, the methodologic quality was acceptable; however, some studies performed significantly worse than others. The heterogeneity between the studies stresses the need to define a reference case (e.g., how should an economic evaluation within epilepsy be performed) and to derive consensus on what constitutes “standard optimal care.”
Sodium selenate treatment improves symptoms and seizure susceptibility in a malin-deficient mouse model of Lafora disease
To search for new therapies aimed at ameliorating the neurologic symptoms and epilepsy developing in patients with Lafora disease.Methods
Lafora disease is caused by loss-of-function mutations in either the EPM2A or EPM2B genes. Epm2a−/− and Epm2b−/− mice display neurologic and behavioral abnormalities similar to those found in patients. Selenium is a potent antioxidant and its deficiency has been related to the development of certain diseases, including epilepsy. In this study, we investigated whether sodium selenate treatment improved the neurologic alterations and the hyperexcitability present in the Epm2b−/− mouse model.Results
Sodium selenate ameliorates some of the motor and memory deficits and the sensitivity observed with pentylenetetrazol (PTZ) treatments in Epm2b−/− mice. Neuronal degeneration and gliosis were also diminished after sodium selenate treatment.Significance
Sodium selenate could be beneficial for ameliorating some symptoms that present in patients with Lafora disease.
Towards prognostic biomarkers from BOLD fluctuations to differentiate a first epileptic seizure from new-onset epilepsy
The diagnosis of epilepsy cannot be reliably made prior to a patient's second seizure in most cases. Therefore, adequate diagnostic tools are needed to differentiate subjects with a first seizure from those with a seizure preceding the onset of epilepsy. The objective was to explore spontaneous blood oxygen level–dependent (BOLD) fluctuations in subjects with a first-ever seizure and patients with new-onset epilepsy (NOE), and to find characteristic biomarkers for seizure recurrence after the first seizure.Methods
We examined 17 first-seizure subjects, 19 patients with new-onset epilepsy (NOE), and 18 healthy controls. All subjects underwent clinical investigation and received electroencephalography and resting-state functional magnetic resonance imaging (MRI). The BOLD time series were analyzed in terms of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFFs).Results
We found significantly stronger amplitudes (higher fALFFs) in patients with NOE relative to first-seizure subjects and healthy controls. The frequency range of 73–198 mHz (slow-3 subband) appeared most useful for discriminating patients with NOE from first-seizure subjects. The ReHo measure did not show any significant differences.Significance
The fALFF appears to be a noninvasive measure that characterizes spontaneous BOLD fluctuations and shows stronger amplitudes in the slow-3 subband of patients with NOE relative first-seizure subjects and healthy controls. A larger study population with follow-up is required to determine whether fALFF holds promise as a potential biomarker for identifying subjects at increased risk to develop epilepsy.
We determined the role of the neurosteroid-sensitive δ subunit–containing γ-aminobutyric acid A receptors (δ-GABARs) in epileptogenesis.Methods
Status epilepticus (SE) was induced via lithium pilocarpine in adult rats, and seizures were assessed by continuous video–electroencephalography (EEG) monitoring. Finasteride was administered to inhibit neurosteroid synthesis. The total and surface protein expression of hippocampal δ, α4, and γ2 GABAR subunits was studied using biotinylation assays and Western blotting. Neurosteroid potentiation of the tonic currents of dentate granule cells (DGCs) was measured by whole-cell patch-clamp technique. Finally, the effects of inhibiting N-methyl-d-aspartate receptors (NMDARs) during SE on the long-term plasticity of δ-GABARs, neurosteroid-induced modulation of tonic current, and epileptogenesis were studied.Results
The inhibition of neurosteroid synthesis 4 days after SE triggered acute seizures and accelerated the onset of chronic recurrent spontaneous seizures (epilepsy). The down-regulation of neurosteroid-sensitive δ-GABARs occurred prior to the onset of epilepsy, whereas an increased expression of the γ2-GABAR subunits occurred after seizure onset. MK801 blockade of NMDARs during SE preserved the expression of neurosteroid-sensitive δ-GABARs. NMDAR blockade during SE also prevented the onset of spontaneous seizures.Significance
Changes in neurosteroid-sensitive δ-GABAR expression correlated temporally with epileptogenesis. These findings raise the possibility that δ-GABAR plasticity may play a role in epileptogenesis.
Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.
Several genes previously thought to be associated with only rare types of epilepsy seen in children are also involved in more common types of the condition, according to a study published in the scientific journal The Lancet Neurology.
This finding suggests that therapeutic approaches, which target the precise genetic cause of epilepsy and which are used to tackle rare forms of the condition may also be helpful in treating its more common forms.
“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures, which begin in one area of the brain, or generalized seizures,” said Dr James Riviello, Chief of Child Neurology at Columbia University, New York, in a press release. “Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of the epilepsy has guided our treatment choices.”
The study involved the comparison of all protein coding genes from 1,140 people with one of two common types of epilepsy – genetic generalised epilepsy and non-acquired focal epilepsy – with those from 3,877 people without epilepsy.
The researchers found that some people with non-acquired focal epilepsy had significantly more mutations in five specific genes that were previously thought to be associated with rare forms of the condition only. They estimated that these five genes contribute to epilepsy risk in approximately eight percent of people with this common form of the condition. A similar pattern was observed for genetic generalised epilepsy.
According to the authors, as more genes associated with a wide range of epilepsies are identified, more treatments that are targeted to an individual’s genetic subtype can be developed. In the future, with more samples being analysed, the researchers are hoping to find additional genetic variations that contribute to common epilepsies.
The research was coordinated by the Epi4K collaboration, an international consortium of doctors and scientists from around the world. The study was funded in part by Epilepsy Research UK and several UK researchers were involved, including Prof Mark Rees and Dr Graeme Sills, who are both trustees of Epilepsy Research UK.
Author: Dr Özge Özkaya
Click here for more articles about brain science including genetics.
Preclinical evaluation of intravenous NAX 810-2, a novel GalR2-preferring analog, for anticonvulsant efficacy and pharmacokinetics
Potential clinical utility of galanin or peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia due to galanin receptor subtype 1 (GalR1) activation. NAX 810-2, a galanin receptor subtype 2 (GalR2)-preferring galanin analog, possesses 15-fold greater affinity for GalR2 over GalR1 and protects against seizures in the mouse 6 Hz, corneal kindling, and Frings audiogenic seizure models. The purpose of these studies was to further evaluate the preclinical efficacy and pharmacokinetics of NAX 810-2 in mice.Methods
NAX 810-2 was administered by intravenous (i.v.; tail vein, bolus) injection to fully kindled (corneal kindling assay) or naive CF-1 mice (6 Hz assay and pharmacokinetic studies). Plasma NAX 810-2 levels were determined from trunk blood samples. NAX 810-2 was also added to human plasma at various concentrations for determination of plasma protein binding.Results
In the mouse corneal kindling model, NAX 810-2 dose-dependently blocked seizures following intravenous administration (median effective dose [ED50], 0.5 mg/kg). In the mouse 6 Hz (32 mA) seizure model, it was demonstrated that NAX 810-2 dose-dependently blocked seizures following bolus administration (0.375–1.5 mg/kg, i.v.; ED50, 0.7 mg/kg), with a time-to-peak effect of 0.5 h posttreatment. Motor impairment was observed at 1.5 mg/kg, i.v., whereas one-half of this dose, 0.75 mg/kg, i.v., was maximally effective in the 6 Hz test. Plasma levels of NAX 810-2 show linear pharmacokinetics following intravenous administration and a half-life of 1.2 h. Functional agonist activity studies demonstrate that NAX 810-2 effectively activates GalR2 at therapeutic concentrations.Significance
These studies further suggest the potential utility of NAX 810-2 as a novel therapy for epilepsy.
Seizure Detection and Neuromodulation: A Summary of Data Presented at the XIII Conference on New Antiepileptic Drug and Devices (EILAT XIII)
Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: Results from a pregnancy registry in South India
Kerala Registry of Epilepsy and Pregnancy had been prospectively evaluating the reproductive issues of women with epilepsy since April 1998. This analysis aimed to estimate the relative risk of major congenital malformations (MCM) to the registrants.Methods
All pregnancies with known outcome in this register until December 2013 were included. Malformation status was evaluated by antenatal ultrasonography, physical examination at birth, echocardiography, and abdomen ultrasonography at 3 months of age and a final review at 1 year of age.Results
There were 1,688 fetuses (singlets 1,643, twins 21, and triplet 1) resulting in 1,622 live births. All were born to women of Asian origin living in South India. The MCM rate for all live births was 6.84% (95% confidence interval [CI] 5.71–8.18) and for all pregnancy outcomes including fetal loss was 7.11% (95% CI 5.98–8.44). The MCM rates (mean with 95% CI) for exposed group were 6.4% (5.03–8.03) for monotherapy and 9.9% (7.37–13.13) for polytherapy; internal control group (women with epilepsy [WWE] not on antiepileptic drugs [AEDs] in first trimester) 5.6% (3.34–9.11), external control group (women without epilepsy or AED exposure in first trimester) 3.45% (1.94–6.07). Valproate monotherapy group had a dose-dependent relative risk for MCM of 2.6 (95% CI 1.30–5.20) compared to the external control group. The preliminary data on MCM rate for the nine total clobazam monotherapy (22.2%; 95% CI 6.2–54.7) signals increased risk that needs further validation on larger sample size. There was no association between MCM rate and maternal socioeconomic status, epilepsy syndrome, or use of folic acid in first trimester.Significance
This dataset from South India confirms the increased risk of MCM with exposure to AEDs, particularly polytherapy. A dose-dependent increased risk was observed with valproate. The increased risk associated with clobazam monotherapy is an important signal that needs to be confirmed in a larger sample.
We report on temporally clustered seizures detected from continuous long-term ambulatory human electroencephalographic data. The objective was to investigate short-term seizure clustering, which we have termed bursting, and consider implications for patient care, seizure prediction, and evaluating therapies.Methods
Chronic ambulatory intracranial electroencephalography (EEG) data collected for the purpose of seizure prediction were annotated to identify seizure events. A detection algorithm was used to identify bursts of events. Burst events were compared to nonburst events to evaluate event dispersion, duration and dynamics.Results
Bursts of seizures were present in 6 of 15 subjects, and detections were consistent over long-term monitoring (>2 years). Subjects with bursts of seizures had highly overdispersed seizure rates, compared to other subjects. There was a complicated relationship between bursts and clinical seizures, although bursts were associated with multimodal distributions of seizure duration, and poorer predictive outcomes. For three subjects, bursts demonstrated distinctive preictal dynamics compared to clinical seizures.Significance
We have previously hypothesized that there are distinct physiologic pathways underlying short- and long-duration seizures. Herein we show that burst seizures fall almost exclusively within the short population of seizure durations; however, a short duration event was not sufficient to induce or imply bursting. We can therefore conclude that in addition to distinct mechanisms underlying seizure duration, there are separate factors regulating bursts of seizures. We show that bursts were a robust phenomenon in our patient cohort, which were consistent with overdispersed seizure rates, suggesting long-memory dynamics.