What's Current?

Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome

Epilepsia - Sat, 12/24/2016 - 02:05
Summary Objective

Two major classes of SCN1A variants are associated with Dravet syndrome (DS): those that result in haploinsufficiency (truncating) and those that result in an amino acid substitution (missense). The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation–positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment.

Methods

We sequenced all exons and intron–exon boundaries of SCN1A in our cohort, investigated differences in the distribution of truncating and missense variants, tested for associations between variant type and phenotype, and compared these patterns with those of cohorts with milder epilepsy and healthy individuals.

Results

Unlike truncation variants, missense variants are found at higher density in the S4 voltage sensor and pore loops and at lower density in the domain I–II and II–III linkers and the first three segments of domain II. Relative to healthy individuals, there is an increased frequency of truncating (but not missense) variants in the noncoding C-terminus. The rate of cognitive decline is more rapid for patients with truncation variants regardless of age at seizure onset, whereas age at onset is a predictor of the rate of cognitive decline for patients with missense variants.

Significance

We found significant differences in the distribution of truncating and missense variants across the SCN1A sequence among healthy individuals, patients with DS, and those with milder forms of SCN1A-variant positive epilepsy. Testing for associations with phenotype revealed that variant type can be predictive of rate of cognitive decline. Analysis of descriptive medication data suggests that in addition to conventional drug therapy in DS, bromide, clonazepam and topiramate may reduce seizure frequency.

Categories: What's Current?

Verbal memory after temporal lobe epilepsy surgery in children: Do only mesial structures matter?

Epilepsia - Sat, 12/24/2016 - 02:01
Summary Objective

Previous findings have been mixed regarding verbal memory outcome after left temporal lobectomy in children, and there are few studies comparing verbal memory change after lateral versus mesial temporal lobe resections. We compared verbal memory outcome associated with sparing or including the mesial structures in children who underwent left or right temporal lobe resection. We also investigated predictors of postsurgical verbal memory change.

Methods

We retrospectively assessed verbal memory change approximately 1 year after unilateral temporal lobe epilepsy surgery using a list learning task. Participants included 23 children who underwent temporal lobe surgery with sparing of the mesial structures (13 left), and 40 children who had a temporal lobectomy that included resection of mesial structures (22 left).

Results

Children who underwent resection from the left lateral and mesial temporal lobe were the only group to show decline in verbal memory. Furthermore, when we considered language representation in the left temporal resection group, patients with left language representation and spared mesial structures showed essentially no change in verbal memory from preoperative to follow-up, whereas those with left language representation and excised mesial structures showed a decline. Postoperative seizure status had no effect on verbal memory change in children after left temporal lobe surgery. Finally, we found that patients with intact preoperative verbal memory experienced a significant decline compared to those with below average preoperative verbal memory.

Significance

Our findings provide evidence of significant risk factors for verbal memory decline in children, specific to left mesial temporal lobe epilepsy. Children who undergo left temporal lobe surgery that includes mesial structures may be most vulnerable for verbal memory decline, especially when language representation is localized to the left hemisphere and when preoperative verbal memory is intact.

Categories: What's Current?

TRPC3 channels play a critical role in the theta component of pilocarpine-induced status epilepticus in mice

Epilepsia - Sat, 12/24/2016 - 02:00
Summary Objective

Canonical transient receptor potential (TRPC) channels constitute a family of cation channels that exhibit a regional and cell-specific expression pattern throughout the brain. It has been reported previously that TRPC3 channels are effectors of the brain-derived neurotrophic factor (BDNF)/trkB signaling pathway. Given the long postulated role of BDNF in epileptogenesis, TRPC3 channels may be a critical component in the underlying pathophysiology of seizure and epilepsy. In this study, we investigated the precise role of TRPC3 channels in pilocarpine-induced status epilepticus (SE).

Methods

The role of TRPC3 channels was investigated using TRPC3 knockout (KO) mice and TRPC3-selective inhibitor Pyr3. Video and electroencephalography (EEG) recording of pilocarpine-induced seizures were performed.

Results

We found that genetic ablation of TRPC3 channels reduces behavioral manifestations of seizures and the root-mean-square (RMS) power of SE, indicating a significant contribution of TRPC3 channels to pilocarpine-induced SE. Furthermore, the reduction in SE in TRPC3KO mice is caused by a selective attenuation of pilocarpine-induced theta activity, which dominates both the preictal phase and SE phase. Pyr3 also caused a reduction in the overall RMS power of pilocarpine-induced SE and a selective reduction in the theta activity during SE.

Significance

Our results demonstrate that TRPC3 channels unequivocally contribute to pilocarpine-induced SE and could be a novel molecular target for new anticonvulsive drugs.

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Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Epilepsia - Sat, 12/24/2016 - 01:40
Summary Objective

Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV.

Methods

Radioligand binding studies were carried out using [3H]BRV and [3H]LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue.

Results

The modulator increased the binding of both radioligands but by different mechanisms. For [3H]BRV, the increase was driven mainly by an increase in affinity, whereas for [3H]LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect.

Significance

These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein.

Categories: What's Current?

Erratum to “Safety, efficacy and outcome-related factors of perampanel over 12months in a real-world setting: The FYDATA study” [Epilepsy Res. 126 (2016) 201–210]

Epilepsy Research Journal - Thu, 12/22/2016 - 00:00
The publisher regrets that during the publication of this article Table 1 was inadvertently laid out incorrectly. Table 1 is hereby republished with the correct layout.
Categories: What's Current?

Study Sheds Light Onto How Flashing Images May Trigger Epileptic Seizures

Epilepsy Research - Wed, 12/21/2016 - 11:48

A new study published in the scientific journal, NeuroImage, may help explain how rhythmic stimulations at certain frequencies such as flickering images can lead to epileptic seizures.

In a press release, Senior Author Dr Marc Goodfellow, at the University of Exeter, said: “Our findings help to elucidate mechanisms of the generation and spreading of epileptic seizures in the brain”.

The team used a mathematical model of brain dynamics, to study how seizures are generated. They showed that neuronal tissue displays epileptic-like activity when exposed to enhanced stimulation of certain frequencies. These may be generated by the brain’s own activity or come from the outside such as flashing images.

According to the researchers, this is the result of the ability of neuronal tissue to undergo resonance. Visual stimulation with frequencies close to alpha rhythm, a type of electrical activity in the brain that has a frequency of 8–13 Hz, may interfere with the natural alpha activity occurring in a region of the brain called the visual cortex. This can lead to an increase in the amplitude of the electrical discharges in a “snowball effect” that triggers an epileptic seizure.

“This work shows that the temporal characteristics of the random activity of the brain can have profound effects on its behaviour,” said Co-author Dr Jordi Garcia-Ojalvo, at Universitat Pompeu Fabra, in Barcelona.

Dr Goodfellow added: “This research provides further insight into ways that communication within brain networks can possibly lead to the occurrence of seizures.”

According to the authors, future improvements in computational modelling may help develop tools that are useful for the treatment of epilepsy.

Author: Dr Özge Özkaya

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Categories: What's Current?

Rabbi Lionel Blue

Epilepsy Research - Wed, 12/21/2016 - 05:06

Rabbi Lionel Blue passed away on 19th December, aged 86. Rabbi Blue was diagnosed with epilepsy at age 57 and was one of the first people to talk openly about the condition and how it affected his life.   

Rabbi Blue was a greatly valued friend of Epilepsy Research UK. He served as Vice President of the Epilepsy Research Foundation, and latterly Epilepsy Research UK, from 1997 until his retirement due to failing health in 2015.

Through his radio broadcasting, Rabbi Blue enriched the lives of untold individuals with his warm and witty ‘Thought for the Day’. Using the same empathetic skills, Rabbi Blue led several successful Radio 4 Appeals on behalf of Epilepsy Research UK. In doing so, he raised awareness and improved the public’s understanding of epilepsy. We are grateful that he found the time in his busy schedule to support the epilepsy cause.

Our condolences go to all his family, friends and colleagues. We at Epilepsy Research UK, and across the wider epilepsy world, owe Rabbi Lionel Blue a huge debt of thanks.

Categories: What's Current?

Professor Brian Neville

Epilepsy Research - Tue, 12/20/2016 - 12:09

It is with great sadness that we announce the death of Professor Brian Neville, Emeritus Professor of Paediatric Neurology at University College London – Institute of Child Health (UCL-ICH). 

Brian was a great ambassador for epilepsy and dedicated his life to improving the lives of children and young people with the condition. He held the first Prince of Wales’s Chair of Childhood Epilepsy, integrating research between the epilepsy unit at UCL-ICH, Great Ormond Street Hospital and Young Epilepsy.

Brian’s association with Epilepsy Research UK has been a long one. He had been a valuable friend, colleague and trustee of the Fund for Epilepsy before it merged with Epilepsy Research Foundation in 2007 at which point he became a trustee for the newly-formed Epilepsy Research UK. In 2013 Brian became Epilepsy Research UK President.

Brian’s distinguished career leaves a long legacy as a champion and pioneer for the needs of children with epilepsy: pushing for early detection and treatment, initiating an epilepsy surgery programme, and being instrumental in launching an emergency therapy for prolonged or repeated seizures. He is remembered fondly by the young people he treated and the young clinicians and researchers he nurtured.

Our thoughts at this time are with Brian’s family and friends, to whom we offer our sincere condolences and our immense gratitude that Brian chose to work in the field of epilepsy.

 

Categories: What's Current?

Absence Seizures Could Be Prevented, Experimental Study Suggests

Epilepsy Research - Tue, 12/20/2016 - 05:02

It may be possible to reduce, stop or even prevent absence seizures, the most common form of childhood epilepsy, according to a study published in the leading scientific journal Neuron.

Using an advanced technology called optogenetics and a rodent model, researchers at Stanford University School of Medicine showed that it is possible to trigger seizures by inducing synchronized, rhythmic activity within a particular structure in the brain called the thalamocortical tract. Importantly, they also demonstrated that disrupting this activity is sufficient to terminate the seizures.

For the study the team, led by Dr Jeanne Paz, inserted a gene that encodes for a light-sensitive cell-surface protein into a set of nerve cells situated in the thalamocortical tract of rat and mice models of absence seizures. This way, the scientists were able to prevent these cells from firing by shining a yellow light onto them.

In a press release, Dr John Huguenard,one of the authors of the study said:

“A single pulse of yellow light was enough to generate rhythmic firing activity throughout the cortex, in both hemispheres of the brain”.

The researchers then inserted a different kind of light sensitive protein into the brain of the rodents, which made  thalamocortical neurons more excitable when blue light was shone onto them. This disrupted their collective firing synchrony and seizure activity was blocked.

“Our study shows that the thalamus is a choke point whose involvement is essential to the maintenance of absence seizures,” said Dr Paz.

The authors suggested that treatments that are capable of guiding excitatory thalamocortical nerve cells from a tightly synchronized firing pattern (pro-seizure) to a more chaotic one could stop absence seizures.

Absence seizures, also called petit-mal seizures, are a form of epilepsy that is mostly seen in children aged between six to 15. They account for about 1 in 20 cases of epilepsy and are characterized by a sudden loss of consciousness that can last for up to 15 seconds, accompanied by a freezing in place.

Absence seizures are thought to be caused by patterns of rhythmic nerve-cell firing activity that originate in one area of the brain and then spread to the rest of the brain. A nerve circuitry called the thalamocortical tract is involved in this type of seizure.

Author: Dr Özge Özkaya

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Categories: What's Current?

Why exposure to rhythmic stimulation at certain frequencies facilitate epileptic seizures

Science Daily - Mon, 12/19/2016 - 13:44
New research proposes an explanation for the occurrence of epileptic seizures as a result of the exposure to certain stimuli.
Categories: What's Current?

Neural Stem Cells Found in Brain Tissue Removed During Epilepsy Surgery

Epilepsy Research - Mon, 12/19/2016 - 09:56

Researchers at the University of Gothenburg, in Sweden, have found neural stem cells in epileptic brain tissue where they normally do not reside. This work is published in the scientific journal, Cerebral Cortex.

Neural stem cells are immature cells in the brain that are able to mature into neurons, astrocytes (non-neuronal support cells) or oligodendrocytes (producers of myelin, which is needed for effective neuronal signalling). They are normally found in the hippocampus, an area of the brain that is involved in learning and memory, and in the subventricular domains.

This finding helps improve scientists’ understanding of how the brain responds to epilepsy.

The team, led, Dr Milos Pekny, analysed the brain tissue obtained from people with drug-resistant epilepsy who underwent surgery. In eight out of 14 tissue samples (57%), they discovered neural stem cells in areas where these types of cells are not normally found.

According to the authors of the study, “This may point to a greater plasticity in the epileptic tissue, which to some extent can be compared to the brain tissue of a newborn.”

When the scientists cultured the brain samples, they saw that the cells that gave rise to neural stem cells were not astrocytes as was previously thought.

New neurons are formed in the brain of adults throughout life. These originate from neural stem cells that are found in the subventricular zone, hippocampus and striatum of the brain. Experiments conducted on mice have shown that in neurological conditions such as brain injury or stroke, astrocytes exhibit neural stem cell-like properties. This study shows that this is not the case in the human brain, at least not in epilepsy.

Author: Dr Özge Özkaya 

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Categories: What's Current?

Time to onset of sustained ≥50% responder status in patients with focal (partial-onset) seizures in three phase III studies of adjunctive brivaracetam treatment

Epilepsia - Sun, 12/18/2016 - 09:10
Summary

Time to onset of sustained ≥50% responder status (SRS) was assessed for the pooled patient population receiving brivaracetam (BRV) 50, 100, or 200 mg/day or placebo in three randomized phase III studies (NCT00464269, NCT00490035, and NCT01261325). Patients were aged ≥16 years with well-characterized focal (partial-onset) seizures (FS) uncontrolled by 1–2 concomitant antiepileptic drugs. After an 8-week baseline period, patients received study drug without up-titration for a 12-week (84-day) treatment period. A patient was a sustained ≥50% responder on a particular day if they completed the entire treatment period through day 84 and was a ≥50% responder (based on percent reduction in FS frequency from baseline) both on that day and every successive day until day 84 (end of treatment period). In the pooled efficacy population (N = 1,160), 15.5%, 18.1%, and 19.4% of patients taking BRV 50, 100, or 200 mg/day, respectively, achieved SRS on day 1 versus 6.7% for placebo (p < 0.001). Statistically significant SRS was also achieved for most of the BRV-treated groups in the three separate studies. This suggests that BRV has an early, sustained onset of action in a subset of responders. The incidence of adverse events during the first week was similar to that in the overall treatment period.

Categories: What's Current?

Ictal asystole: A systematic review

Epilepsia - Sun, 12/18/2016 - 09:10
Summary Objective

To comprehensively analyze ictal asystole (IA) on a large number of subjects.

Methods

We performed a systematic review of case report studies of patients diagnosed with IA (1983–2016). Each included case was characterized with respect to patient history, IA seizure characteristics, diagnostic workup, and therapy. In addition, comparative analyses were also carried out: two alignments were developed based on the delay between epilepsy onset and IA onset (“new-onset” if <1 year, “late-onset” if ≥1 year) and asystole duration (asystole was “very prolonged” if lasted >30 s).

Results

One hundred fifty-seven cases were included. All patients had focal epilepsy. In 7% of cases IA developed during a secondary generalized tonic–clonic seizure. Both the seizure-onset zone and the focal seizure activity at asystole beginning were usually temporal (p < 0.001 and p = 0.001, respectively) and were lateralized to the left hemisphere in 62% (p = 0.005 and p = 0.05, respectively). Asystole duration was 18 ± 14 s (mean±SD) (range 3–96 s); 73% of patients had late-onset, 27% had new-onset IA. Compared to late-onset IA, new-onset IA was associated with female gender (p = 0.023), preexisting heart condition (p = 0.014), focal seizure activity at asystole beginning (p = 0.012), normal neuroimaging (p = 0.013), normal interictal EEG (p < 0.001), auditory aura (p = 0.012), and drug-responsive epilepsy (p < 0.001). “Very prolonged” asystole was associated with secondary generalized tonic–clonic seizures (p = 0.003) and tended to occur in extratemporal lobe seizures (p = 0.074). No IA-related death was reported.

Significance

Characteristics considered to be typical of IA (focal, left temporal seizures appearing on grounds of a long-lasting, intractable epilepsy) seem only partially legitimate. We suggest that in new-onset IA, female gender and a preexisting heart condition could serve as predispositions in an otherwise benign epilepsy. We speculate that in late-onset IA, male-predominant changes in neuronal networks in chronic, intractable epilepsy and an accompanying autonomic dysregulation serve as facilitating factors.

Categories: What's Current?

Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior

Epilepsia - Sun, 12/18/2016 - 09:10
Summary Objective

Perampanel (PER), a selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonist, exhibits broad-spectrum anticonvulsant activity in several seizure models, but its potential disease-modifying effects have not been investigated. Because of the relevance of AMPA receptors in epileptogenesis and psychiatric comorbidities, we studied the effects of PER in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and depressive-like comorbidity.

Methods

We investigated the effects of acute, subchronic, and chronic treatment with PER (0.25–3 mg/kg) on absence seizures, their development, and related psychiatric/neurologic comorbidity in WAG/Rij rats. Depression-related behavior was studied by using the forced swimming and the sucrose preference test; anxiety-related behavior by using the open field and elevated plus maze test; and memory by using the passive avoidance test.

Results

PER (3 mg/kg/day orally for 17 weeks starting from P30) significantly reduced the development of absence seizures at 6 months of age (1 month after treatment withdrawal), but this effect was not maintained when reassessed 4 months later. Attenuated absence seizure development was accompanied by reduced depressive-like behavior in the forced swimming test (FST), whereas no effects were observed on anxiety-related behavior and memory. Subchronic (1 and 3 mg/kg/day orally for 1 week) and acute PER (0.25–1 mg/kg, i.p.) dosing did not affect established absence seizures and behavior.

Significance

These results suggest that AMPA receptors are involved in mechanisms of epileptogenesis in an established model of absence epilepsy, and that these mechanisms differ from those responsible for seizure generation and spread when epilepsy has become established.

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Premature mortality of epilepsy in low- and middle-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy

Epilepsia - Sun, 12/18/2016 - 09:10
Summary

To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low- and middle-income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank-defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7–45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3–7.2) among higher-quality population-based studies. Clinical cohort studies yielded 7.1 (range 1.6–25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5–75.5%) derived from population-based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high-income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.

Categories: What's Current?

Research at Stanford locates absence epilepsy seizure 'choke point' in brain

Medical News Today - Fri, 12/16/2016 - 09:00
A particular structure in the brain is a "choke point" for a type of epileptic seizure that affects mostly children, Stanford University School of Medicine investigators have found.
Categories: What's Current?

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