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Results from Clinical Trial Show Promise for Children with PCDH19 Epilepsy

Epilepsy Research - Sat, 10/01/2016 - 04:58

Please note that Epilepsy Research UK does not endorse/promote individual epilepsy treatments or pharmaceutical companies.

Marinus Pharmaceuticals has announced the results of a phase two clinical trial evaluating its drug candidate, ganaxolone, for the treatment of PCDH19 epilepsy. They show that ganaxolone was generally safe, well-tolerated and reduced seizure frequency in most participants.

In a press release, Dr Michael G. Chez, Paediatric Neurologist at Sutter Medical Center in Sacramento, California, and an investigator in the trial said: “The benefit that ganaxolone provided in reducing seizures is clinically meaningful for these difficult-to-treat patients with a severe, rare epilepsy… In addition to seizure reduction, the patients that I treated with ganaxolone displayed improved behavior and cognitive skills during treatment.”

“A drug that can lessen seizure burden and behavioral comorbidities caused by this disease would be welcomed by patients, their families and the medical community,” he added.

The study enrolled 11 girls with PCDH19 epilepsy, aged 4 to 15 years. The children were first observed for a period of 12-weeks to assess their seizure frequency, and then given ganaxolone for 26 weeks.

The results showed that seizure frequency was reduced in seven participants (64%) following treatment with ganaxolone. In addition, eight subjects (73%) had more seizure-free days during treatment with ganaxolone than during the 12-week period prior to the start of treatment.

The company is now enrolling participants with other forms of paediatric genetic epilepsies, such as CDKL5 and Lennox-Gastaut Syndrome.

PCDH19 epilepsy is a rare form of genetic epilepsy that mostly affects girls. It is characterised by early onset seizures and cognitive and behavioural difficulties.

The condition is caused by a mutation in the PCDH19 gene, located on the X-chromosome. This causes the protein the gene encodes for, which supports communication between the cells of the nervous system, not to function properly or to be absent altogether.

Although there are currently no approved drugs to treat this form of epilepsy, in 2015, the US Food and Drug Administration granted orphan drug designation to ganaxolone, which will help accelerate its development as a potential treatment.

Author: Dr Özge Özkaya

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Value of video monitoring for nocturnal seizure detection in a residential setting

Epilepsia - Fri, 09/30/2016 - 05:50
Summary Objective

Following a sudden death at a residential care unit, the Dutch Health and Care Inspectorate advised intensification of the use of video monitoring (VM) at the unit. We assessed whether VM resulted in increased identification of seizures that required clinical intervention.

Methods

The unit provides care for 340 individuals with refractory epilepsy and severe learning disabilities. Acoustic detection systems (ADSs) cover all individuals; 37 people also have a bed motion sensor (BMS) and 46 people with possible nocturnal seizures are now monitored by VM. During a 6-month period, in all cases of a suspected seizure we asked the caregivers to specify which device alerted them and to indicate whether this led to an intervention. Staff costs of VM were estimated using payroll information.

Results

We identified 1,208 seizures in 37 individuals: 4 had no nocturnal seizures and 393 (33%) seizures were seen only on video. In 169 (14%) of 1,208 seizures an intervention was made and this included 39 (10%) of 393 seizures seen only on video. When compared to seizures observed with an ADS or BMS, seizures seen only on video were more often tonic seizures (71% vs. 22%, p < 0.001) and occurred mostly in the beginning or at the end of the night (40% vs. 26%, p < 0.001). The extra staff costs of monitoring was 7,035 euro per seizure seen only on video and leading to an intervention.

Significance

VM facilitates nocturnal surveillance, but the costs are high. This underscores the need for development of reliable seizure detection devices.

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Scientists track unexpected mechanisms of memory

Science Daily - Thu, 09/29/2016 - 14:05
Our brains hold on to memories via physical changes in synapses, the tiny connections between neurons. Unexpected molecular mechanisms by which these changes take place have now been revealed by new research.
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Molecule Involved in Memory and Learning Could Be Key in Temporal Lobe Epilepsy

Epilepsy Research - Thu, 09/29/2016 - 09:36

A new study, conducted by researchers at Duke University and the Max Planck Florida Institute for Neuroscience, could shed light on how certain types of epilepsy develop in the brain. This in turn could help scientists find new approaches to treat the condition. The study is published in the leading scientific journal, Nature.

Co-Senior Author, Dr James McNamara, at Duke University, commented: “We’re beginning to unlock some of the mysteries underlying both the acquisition of a memory in the normal brain, as well as how a normal brain is transformed into an epileptic brain.”

Using a mouse model, Dr McNamara and his team developed a molecular sensor that can track, in real time, the activity of a receptor called trkB, which is involved in the way neurons grow. The researchers were able to activate the trkB receptor by using a signalling molecule called glutamate, which plays a crucial role in the formation of memory. Interestingly, in mice where the trkB receptor was missing, neurons failed to grow in response to glutamate.

Researchers in Dr McNamara’s laboratory had previously shown that TrkB is also involved in some cases of temporal lobe epilepsy (TLE), and that inhibiting trkB signalling shortly after the first seizure could prevent the development of TLE in mice.

In TLE seizures originate in the temporal lobe – the region of the brain that is important for the formation of short-term memory. TLE is thought to occur when glutamate is released at higher levels and for longer than normal.

The team is currently working on understanding what happens after trkB is activated using the new molecular sensor that they developed.

Author: Dr Özge Özkaya

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New Animal Model of Epilepsy Could Help Develop Novel AEDs

Epilepsy Research - Thu, 09/29/2016 - 09:25

Researchers at Florida Atlantic University and The Scripps Research Institute,  in the US, have developed a new animal model of epilepsy that will allow the screening of hundreds of thousands of potential antiepileptic compounds. This work is published in the leading scientific journal, Plos One

The team, led by Dr Ken Dawson-Scully, genetically modified microscopic worms called C. elegans and were able to chemically or electrically induce short seizures in their nervous systems.

When they treated the animals with antiepileptic drugs (AEDs) that are already approved for use in humans, they saw that their recovery from seizures improved.

Dr Dawson-Scully commented: “The fact that … these worms react well to antiepileptic drugs, makes this new assay a perfect model for high-speed drug screens.” He also noted that, with this new approach, testing potential new AEDs would cost a fraction, both in money and time, compared with existing models.

AEDs are efficient in controlling seizures in approximately two thirds of people with epilepsy. Some people with drug-resistant epilepsy might be eligible for surgery, where the area of the brain in which seizure arise is removed; however this is a highly invasive approach. Being able to test new compounds in a fast and cost-effective way could dramatically speed up the process of developing new AEDs that may benefit a larger number of people.

C. elegans has been used as a model organism for decades to study the genetic and molecular mechanisms of many conditions, including neurological disorders.

Author: Dr Özge Özkaya

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500 year-old Genetic Mutation May Be Responsible for EAST Syndrome

Epilepsy Research - Thu, 09/29/2016 - 09:10

EAST syndrome is a genetic condition that includes epilepsy, lack of voluntary muscle coordination including gait abnormality, deafness caused by hearing nerve problems and salt loss caused by kidney problems. It can result from a number of changes (mutations) in a gene called KCNJ10, which encodes a type of potassium ion channel. The mutations cause the channels to lose their function.

Although there are 14 different mutations associated with EAST syndrome, one of these is much more frequent than the others and, interestingly, is found mainly in people of Pakistani origin.

In order to establish whether a ‘founder effect’ – a loss of genetic variation occurring when a new population is established by a very small number of individuals – exists in the Pakistani population, researchers from University College London genetically analysed 12 people with EAST syndrome from seven families and compared them with ethnically matched healthy controls.

The team found that all of the people with EAST syndrome had an identical group of genes very close to their KCNJ10 gene mutation, which they had inherited from one of their parents. This group of genes was completely absent in the healthy individuals. Based on additional information including the size of the Pakistani population and the frequency of EAST syndrome, the researchers estimated that this mutation must have occurred 20 generations or 500 years ago.

The researchers, who published their findings in the scientific journal Molecular Genetics & Genomic Medicine concluded that knowing the mutation in a given population can help better diagnose the condition. This way, families can be offered better genetic counselling.

Author: Dr Özge Özkaya

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Diagnostic utility of invasive EEG for epilepsy surgery: Indications, modalities, and techniques

Epilepsia - Wed, 09/28/2016 - 08:12
Summary

Many patients with medically refractory epilepsy now undergo successful surgery based on noninvasive diagnostic information, but intracranial electroencephalography (IEEG) continues to be used as increasingly complex cases are considered surgical candidates. The indications for IEEG and the modalities employed vary across epilepsy surgical centers; each modality has its advantages and limitations. IEEG can be performed in the same intraoperative setting, that is, intraoperative electrocorticography, or through an independent implantation procedure with chronic extraoperative recordings; the latter are not only resource intensive but also carry risk. A lack of understanding of IEEG limitations predisposes to data misinterpretation that can lead to denying surgery when indicated or, worse yet, incorrect resection with adverse outcomes. Given the lack of class 1 or 2 evidence on IEEG, a consensus-based expert recommendation on the diagnostic utility of IEEG is presented, with emphasis on the application of various modalities in specific substrates or locations, taking into account their relative efficacy, safety, ease, and incremental cost-benefit. These recommendations aim to curtail outlying indications that risk the over- or underutilization of IEEG, while retaining substantial flexibility in keeping with most standard practices at epilepsy centers and addressing some of the needs of resource-poor regions around the world.

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Women with epilepsy initiating a progestin IUD: A prospective pilot study of safety and acceptability

Epilepsia - Wed, 09/28/2016 - 07:56
Summary Objective

Effective contraception enables women with epilepsy (WWE) to plan their pregnancies and improve outcomes for themselves and their children. Although popular among all women, complex drug interactions limit the efficacy and safety of oral contraceptives (OCs) for WWE. We sought to explore the safety, acceptability, and pharmacokinetic impact of a progestin-containing intrauterine device (IUD) in WWE.

Methods

We enrolled 20 women with well-controlled epilepsy and a stable antiepileptic drug (AED) regimen and who were initiating a progestin-containing IUD (levonorgestrel 52 mg) in a prospective, observational study. For each AED, we compared the trough concentration before IUD insertion to the trough concentration 3 weeks, and 3 and 6 months later. Participants recorded seizures in a daily paper diary. We compared seizures that occurred during the month before IUD insertion to those occurring in the 6 months thereafter. Participants completed an acceptability questionnaire at 3 and 6 months.

Results

Participants’ average age was 28 years; 60% were nulligravid. They reported a history of multiple seizure types. During the baseline month, 75% were seizure-free and the remainder reported between one and three seizures. Fourteen received monotherapy and six received polytherapy. Lamotrigine use was most common (n = 12). AED trough concentrations remained stable during the 6 months after IUD insertion, without clinically meaningful deviations from baseline. Diary data showed that seizure frequency worsened in 3, and remained unchanged in 13 and improved in 4 after IUD insertion. Subjectively, no participant believed the IUD worsened her seizure control. All participants were either somewhat or very satisfied with the IUD throughout the study. All participants continued the IUD use at 6 months. No pregnancies occurred.

Significance

This pilot study suggests that the progestin-containing IUD is a safe and acceptable long-acting contraceptive for WWE.

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Early epilepsy increases risk of later comorbid ADHD in autism

Clinical Neurology News - Wed, 09/28/2016 - 07:44

VIENNA – Early-onset idiopathic epilepsy occurring before age 7 years nearly doubles the likelihood that a child with autism spectrum disorder will later develop comorbid...

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Neuropsychological performance and seizure control after subsequent anteromesial temporal lobe resection following selective amygdalohippocampectomy

Epilepsia - Wed, 09/28/2016 - 07:42
Summary Objective

Selective amygdalohippocampectomy (sAHE) is a well-established treatment for temporal lobe epilepsy, commonly with favorable neuropsychological outcome. Yet, it is still unknown if subsequent resection of the anteromesial temporal lobe (AMTLR), when necessary, deteriorates neuropsychological performance in this selected group of patients. Thus, we evaluated the clinical and neuropsychological data of patients who, due to insufficient seizure control after sAHE, received a subsequent ipsilateral AMTLR and compared these findings with patients who did not receive a second resection (control group).

Methods

Patients’ characteristics and neuropsychological data were assessed and analyzed in the reoperated as well as in the control group at each step of treatment. Experienced neuropsychologists conducted the standardized examination focusing on verbal, figural and working memory, speech fluency and attention. Preoperative diagnostics included further continuous video-electroencephalography monitoring, high-resolution magnetic resonance imaging and functional transcranial Doppler sonography.

Results

Eighty patients having received sAHE in our center from 11/2007 to 02/2013 were included in this study. Seventeen of these patients underwent subsequent AMTLR. Thirteen of these were available for follow-up after the second surgery and twelve had a comprehensive neuropsychological testing at all three steps. Analyzing the neuropsychological data revealed no significant differences compared with controls. On the individual level, the data demonstrated that improvement in a subdomain was more frequent than decline, if the performance had already deteriorated after the first procedure. Seizure control improved significantly (p < 0.001) in all patients after subsequent AMTLR resulting in seven patients being seizure-free at follow-up.

Significance

Subsequent AMTLR following sAHE can be a safe procedure to improve seizure outcome in selected patients. In our series the risk for further neuropsychological deterioration after the second procedure was low. The neuropsychological performance after the sAHE can be a valuable criterion to advise patients who are eligible for a second surgery on their risk of further cognitive decline.

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Increasing the Levels of Certain Fats in the Brain Could Suppress Epileptic Seizures

Epilepsy Research - Tue, 09/27/2016 - 10:23

Increasing the levels of certain fat molecules in the brain could suppress epileptic seizures, according to a new ground-breaking study carried out by two collaborating groups in Belgium. The work is published in the leading scientific journal, Nature Structural & Molecular Biology.

The team focused their efforts on a protein called TBC1D24, since mutations in the gene that encodes it cause severe epilepsy. An almost identical protein called Skywalker exists in the fruit fly Drosophila melanogaster, an organism widely used to study different biological pathways and diseases.

The researchers had previously shown that Skywalker plays a vital role in maintaining communication between brain cells. In the current study, they successfully mapped the three dimensional structure of the Skywalker protein and found that it binds to specific fat molecules in the brain of the flies.

This led them to think that increasing the levels of these fats in the flies that have a faulty Skywalker gene may improve the effects of the fault. In fact, they found that the epileptic seizures completely disappeared in these flies.

In a press release, Prof Verstreken, a senior author on the study, said: “Our work shows that increasing specific brain fats at the synapses of patients with a TBC1D24 mutation is a possible strategy for preventing epileptic seizures. And although our work focuses on people with TBC1D24 mutations, we think that our findings could be relevant to various forms of epilepsy.”

Co-senior author, Professor Wim Versées, added: “Our two research groups will now continue to collaborate in order to seek out strategies for increasing the concentration of specific fats in the brain to prevent epileptic seizures. This research stems from cross-pollination between structural biology, biochemistry and genetics, so we will certainly continue down this interdisciplinary route.”

Author: Dr Özge Özkaya

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The 'worm' holds the key to treating epilepsy: New possibilities for rapid drug discovery

Medical News Today - Tue, 09/27/2016 - 08:00
Current methods to control epilepsy are not only inefficient but haven't improved in more than 150 years when the first anticonvulsant drug was developed.
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Scientists track down possible new treatment for epilepsy

Medical News Today - Tue, 09/27/2016 - 03:00
Increasing the concentration of specific fats in the brain could suppress epileptic seizures.
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The 'worm' holds the key to treating epilepsy

Science Daily - Mon, 09/26/2016 - 14:30
Current methods to control epilepsy are not only inefficient, but haven’t improved in more than 150 years when the first anticonvulsant drug was developed. Researchers have opened up the possibilities for rapid drug screens to treat seizures in the near future by developing the smallest whole-animal electroconvulsive seizure model using a microscopic nematode worm.
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Scientists track down possible new treatment for epilepsy

Science Daily - Mon, 09/26/2016 - 11:51
Increasing the concentration of specific fats in the brain could suppress epileptic seizures, ground-breaking new research shows. On the basis of this discovery, scientists were able to completely suppress epileptic seizures in fruit flies.
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The molecular and phenotypic spectrum of IQSEC2-related epilepsy

Epilepsia - Mon, 09/26/2016 - 02:32
Summary Objective

IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants.

Methods

Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians.

Results

Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic–clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut–like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features.

Significance

The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

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HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption

Epilepsia - Mon, 09/26/2016 - 01:55
Summary Objective

Oxcarbazepine (OXC) is a widely used antiepileptic drug for the treatment of partial seizures that was developed through structural variation of carbamazepine. Although OXC has a lower risk of cutaneous adverse drug reactions (cADRs) than carbamazepine, cADRs ranging from maculopapular eruption (MPE) to the more severe Stevens-Johnson syndrome and toxic epidermal necrolysis still limit the use of OXC in some patients. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine-induced cADRs have been identified. However, the HLA-related genetic risk factors associated with OXC-induced cADRs are unknown.

Methods

A total of 40 patients who experienced OXC-induced MPE and 70 patients who were tolerant to OXC treatment were included in the study. Genomic DNA was extracted from the peripheral blood of these patients, and high-resolution HLA genotyping was performed.

Results

The HLA-B*40:02 and HLA-DRB1*04:03 alleles were significantly associated with OXC-induced MPE compared with the OXC-tolerant group (odds ratio [OR] 4.33, p = 0.018 and OR 14.64, p = 0.003, respectively) and the general Korean population (OR 4.04, p = 0.001 and OR 3.11, p = 0.019, respectively). The HLA-B*15:01 genetic frequency was significantly lower in the OXC-MPE group compared to the OXC-tolerant group (OR 0.18, p = 0.016) and the Korean population (OR 0.22, p = 0.030). The allele frequencies of well-known HLA-related risk factors for carbamazepine-induced cADRs (HLA-B*15:02, A*31:01 and B*15:11) were not different among the three groups.

Significance

This study is the first to demonstrate an association of HLA-B*40:02 and HLA-DRB1*04:03 with OXC hypersensitivity using a large cohort of patients with OXC-induced MPE. These findings should be confirmed in future studies in different ethnic groups.

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