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New Method Could Pinpoint More Accurately Where Seizures Arise

Epilepsy Research - Fri, 11/11/2016 - 04:46

Researchers in the US and China have developed a new brain implant that can monitor the activity of individual brain cells at a much higher resolution than was previously possible. Their work is published in the leading scientific journal, Science Advances

According to Senior Author Dr György Buzsáki, at New York University, the implant could help recognise pathological activities in the brain such as epilepsy.

This could potentially be beneficial in epilepsy surgery, where pinpointing the exact origin or ‘focus’ of seizures (for removal) is vital, but often difficult. It could also assist with other therapeutic strategies that specifically target particular areas of the brain.

The implant, which the scientists called ‘NeuroGrid’, is a very thin (four micrometre thick) polymer grid that can record electrical signals from an area of 420 mm2. It has 120 conductive electrodes connected to a silicon chip, which amplifies the signal coming from the brain and sends it to a computer.

The new system offers several advantages over existing set-ups, for example it is cheaper and more comfortable than rigid electrode grids, which need to stay on the brain for up to two weeks, potentially causing inflammation.

The researchers tested the new grid in people who were undergoing epilepsy surgery, by temporarily inserting it onto the surface of the brain and recording electrical activity. They found that the grid was able to record individual brain cells ‘firing’.

Dr Mikhail Lebedev, a neuroscientist at Duke University, who was not involved in the study, commented that the new technique could “allow (neuroscientists) to localize the epileptic focus more accurately”.

It is important to note that the technique is still in its infancy and more work is needed before it can be used in the clinic. The researchers are hoping to make the grid smaller, and to take longer recordings from the brains of people with epilepsy.

Author: Dr Özge Özkaya

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Analysis of Genetic Variations Could Help Develop New Therapies for Epilepsy

Epilepsy Research - Thu, 11/10/2016 - 13:49

A new study, published in the  American Journal of Human Genetics, sheds light onto how variations in genes can influence the activity of important proteins in the brain and may lead to neurological disorders.

The study focused on two genes called GRIN2A and GRIN2B, which are linked to epilepsy, intellectual disability and a number of other neurological conditions. These genes encode for two components – known as the GluN2A and GluN2B domains-of NMDA receptors, which play a crucial role in communication between brain cells.

Genetic variants in GluN2A and GluN2B are seen in the ‘general’ population without necessarily affecting the function of the NMDA receptor. However some rare variants do disrupt NMDA receptor activity, causing neurological disorders.

During the study the team, led by Dr Hongjie Yuan, at Emory University School of Medicine, in Atlanta, assessed genetic variation in the GluN2A and GluN2B ‘domains’, using data from the Exome Aggregation Consortium (ExAC). This is a large database that combines DNA sequences from more than 60,000 unrelated people. They were particularly interested in finding out what parts of the GLuN2 domains are most susceptible to disease-causing variations (identified via other gene databases).

They discovered that three different regions on theGluN2 domains – the region that binds to the molecules that activate the receptor; the region that anchors the receptor to the cell surface and the region that links the two domains – are particularly vulnerable to genetic variation. In other words, variations that cause functional problems in the NMDA receptor are more likely to be found in the sections of DNA that encode these areas.

In a press release, co-senior author Dr Stephen F. Traynelis, said:”This is one of the first analyses like this, where we’re mapping the spectrum of variation in a gene onto the structure of the corresponding protein. We’re able to see that the disease mutations cluster where variation among the healthy population disappears.”

In order to better understand how genetic variations in the GluN2 domains can affect the function of the NMDA receptor, the researchers explored 25 rare genetic GluN2A and GluN2B variants that had already been linked to different neurologic conditions, including epilepsy and intellectual disability. They found most of the GluN2A variants in the DNA of people with epilepsy, and most of theGluN2B variants in the DNA of people with intellectual disability with or without seizures.

Using the DNA, and genetic techniques, the team discovered that the effects of the GluN2 variants were complex and sometimes opposing. For example variants that resulted in both the receptor losing its function or acquiring function when it shouldn’t were associated with similar neurological conditions.

According to the authors, understanding how variants in GLuN2A and GluN2B cause disruption of NMDA receptor function could help scientists develop new strategies to restore it. These strategies could potentially serve as new treatments for epilepsy and other neurological conditions

Author: Dr Özge Özkaya

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Huperzine A provides seizure protection in genetic epilepsy models

Science Daily - Thu, 11/10/2016 - 12:53
The compound huperzine A can increase resistance to induced seizures in mouse models of genetic epilepsy, scientists have found. In particular, huperzine A shows potential for protecting against febrile seizures, which are a feature of both Dravet syndrome, a severe form of childhood epilepsy, and a related condition, GEFS+ (genetic epilepsy with febrile seizures plus).
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Epilepsia - Thu, 11/10/2016 - 02:42
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Epilepsia - Thu, 11/10/2016 - 02:42
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Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant

Epilepsia - Wed, 11/09/2016 - 15:54
Summary

Variants in KCNQ2 encoding for Kv7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies, ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2-related epilepsy: infantile spasms without prior neonatal seizures associated with a gain-of-function gene variant. With use of an international registry, we identified four unrelated patients with the same de novo heterozygous KCNQ2 c.593G>A, p.Arg198Gln (R198Q) variant. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4 and 6 months. At last follow-up (ages 3–11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, Kv7.2 and Kv7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered subcellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures.

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How brain surgery eliminates seizures in epilepsy patients

Science Daily - Tue, 11/08/2016 - 14:53
Surgery is an option for patients who do not respond to medications and have epileptic scar tissue that can be removed safely. In 60 to 70 percent of surgery patients, seizures are completely eliminated, and the success rate likely will improve as imaging and surgical techniques improve.
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New Antiepileptic Drug Candidate Discovered

Epilepsy Research - Tue, 11/08/2016 - 14:26

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

Researchers at Elli Lilly and Co., in Indiana, have discovered a new compound that specifically targets neural circuits involved in epilepsy and could potentially be developed into an antiepileptic drug (AED). The findings are published in the leading scientific journal, Nature Medicine.

The compound, known as CERC-611, selectively blocks a protein associated with a receptor called AMPA found in the forebrain, an area involved in the generation of focal seizures. As the AMPA-associated protein is absent in most other parts of the brain, it is thought that blocking it will not cause side effects such as dizziness, lack of muscle coordination and falling (which are seen with other drugs that block the AMPA receptor directly).

Dr Michael Rogawski, a professor of neurology and pharmacology at the University of California, said:”Targeting these receptors may lead to improved antiseizure efficacy, safety and tolerability, and make a significant impact on treatment outcomes. No prior epilepsy treatment targets a subset of brain receptors involved in seizure generation in a regionally-selective fashion.”

The researchers tested the specificity of the compound in brain tissue obtained form an epilepsy patient. They then tested it in rodent models of epilepsy and found that it prevented multiple seizures without causing motor side effects.

Dr Uli Hacksell, CEO of Crecor, the company that is developing the potential drug said: “We believe CERC-611 has the potential to provide a true advancement in epilepsy therapy.”

The company hopes to file an investigational new drug application with the US Food and Drug Administration (FDA), and start a phase one clinical trial to test the compound, in 2017.

Author: Dr Özge Özkaya

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Increased subcortical oligodendroglia-like cells in pharmacoresistant focal epilepsy in children correlate with extensive epileptogenic zones

Epilepsia - Tue, 11/08/2016 - 06:09
Summary Objective

Cortical resections in epilepsy surgery tend to involve multiple lobes in children, compared to adults, partly due to underlying pathology. Oligodendroglia-like cells (OLCs) have been observed in surgical specimens from children with pharmacoresistant epilepsy. We hypothesize that OLCs recruit multiple-lobe epileptogenic zones in pediatric pharmacoresistant focal epilepsy.

Methods

We examined the surgical specimens from 30 children who underwent epilepsy surgery (1.8- to 16.9-years-old; mean age 9.7 years). Immunohistochemical assays of OLCs were performed using Olig2, which is a marker of OLC. OLC populations in three sites (gray matter, gray–white matter junction, and white matter) were counted. We also performed immunohistochemical staining with neuronal nuclear antigen (NeuN) and glial fibrillary acidic protein (GFAP) for neuronal and astroglial markers, respectively. NeuN- and GFAP-positive cells were distinguished from OLCs. OLC results were compared with seizure types, scalp and intracranial video–electroencephalography (EEG), magnetic resonance imaging (MRI), surgical resection area, histopathologic diagnosis, and seizure outcome.

Results

Histopathologic diagnosis consisted of 14 cases of focal cortical dysplasia (FCD; type I; 4, type II; 9, type III; one); 6 cases of oligodendrogliosis; 6 cases of astrocytic gliosis; 2 cases of hyaline protoplasmic astrocytopathy; and 2 cases of tuberous sclerosis. Fifteen children (50%) underwent multiple-lobe resections after intracranial video-EEG. There was a positive correlation between the number of resected electrodes and the OLC population in the white matter (correlation coefficient 0.581, p = 0.001) and at the gray–white matter junction– (correlation coefficient 0.426, p = 0.027). OLC populations in both areas were increased significantly in nine children with epileptic spasms (ES) (gray–white matter junction [p = 0.021] and white matter [p = 0.025]), and nine nonfocal ictal scalp EEG findings (gray–white matter junction [p = 0.04] and white matter [p = 0.042]). The OLC population in white matter was significantly increased in children with 11 nonfocal interictal scalp EEG findings (p = 0.01), with 15 multiple-lobe resections (p = 0.028).

Significance

Pharmacoresistant epilepsy in children with increased OLCs presented with nonfocal epileptiform discharges on scalp EEG and ES, and they required multiple-lobe resections. We found increased populations of subcortical OLCs in the extensive epileptogenic zone.

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Correlation of FDG-PET hypometabolism and SEEG epileptogenicity mapping in patients with drug-resistant focal epilepsy

Epilepsia - Tue, 11/08/2016 - 05:44
Summary Objective

Interictal [18F]fluorodeoxyglucose–positron emission tomography (FDG-PET) is used in the presurgical evaluation of patients with drug-resistant focal epilepsy. We aimed at clarifying its relationships with ictal high-frequency oscillations (iHFOs) shown to be a relevant marker of the seizure-onset zone.

Methods

We studied the correlation between FDG-PET and epileptogenicity maps in an unselected series of 37 successive patients having been explored with stereo-electroencephalography (SEEG).

Results

At the group level, we found a significant correlation between iHFOs and FDG-PET interictal hypometabolism only in cases of temporal lobe epilepsy. This correlation was found with HFOs, and the same comparison between FDG-PET and ictal SEEG power of lower frequencies during the same epochs did not show the same significance.

Significance

This finding suggests that interictal FDG-PET and ictal HFOs may share common underlying pathophysiologic mechanisms of ictogenesis in temporal lobe epilepsy, and combining both features may help to identify the seizure-onset zone.

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Risk of epilepsy and autism in full and half siblings—A population-based cohort study

Epilepsia - Tue, 11/08/2016 - 05:12
Summary Objective

Epilepsy and autism spectrum disorder (ASD) often occur together in the same individual. However, it remains unknown whether siblings of children with ASD have an increased risk of epilepsy and vice versa. This study determines the risk of ASD and epilepsy among younger siblings of children with ASD and epilepsy.

Design

The study included all children born in Denmark between January 1, 1980 and 31 December 2006 who participated in follow-up until December 31, 2012 (1,663,302 children). We used Cox regression to calculate the adjusted hazard ratio (aHR) and the Kaplan-Meier method to calculate the cumulative incidence.

Results

The overall aHR of epilepsy in younger siblings increased by 70% (aHR 1.70, 95% confidence interval [CI] 1.34–2.16%) if the older sibling had ASD compared with siblings where the older sibling did not have ASD. The cumulative incidence of epilepsy at 20 years of age was 2.54% (95% CI 1.97–3.26%) if the older sibling had ASD, whereas the cumulative incidence of epilepsy at 20 years of age was 1.63% (95% CI 1.60–1.66%) if the older sibling did not have ASD. The overall aHR of ASD in younger siblings increased by 54% if the older sibling had epilepsy (aHR 1.54, 95% CI 1.32–1.80) compared with siblings where the older sibling did not have epilepsy. The cumulative incidence of ASD at 20 years of age was 2.06% (95% CI 1.84–2.32%) if the older sibling had epilepsy, whereas the cumulative incidence of ASD at 20 years of age was 1.27% (95% CI 1.25–1.29%) if the older sibling did not have epilepsy.

Significance

The cross-disorder sibling risk of epilepsy and ASD was increased for the two disorders, which suggests that genes or environmental factors shared by family members may play a causal role in the co-occurrence of ASD and epilepsy.

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Poor children with epilepsy may face social hurdles

Science Daily - Mon, 11/07/2016 - 11:29
In a population-based Canadian study of children with epilepsy, each of whom had access to universal health care, those from poor families had the same medical course and remission rate as their wealthier counterparts, but they had a less favorable social outcome as adults.
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Metabolic injury in a variable rat model of post–status epilepticus

Epilepsia - Mon, 11/07/2016 - 11:12
Summary Objective

In vivo studies of epilepsy typically use prolonged status epilepticus to generate recurrent seizures. However, reports on variable status duration have found discrete differences in injury after 40–50 min of seizures, suggesting a pathophysiologic sensitivity to seizure duration. In this report we take a multivariate cluster analysis to study a short duration status epilepticus model using in vivo 7T magnetic resonance spectroscopy (MRS) and histologic evaluation.

Methods

The Hellier Dudek model was applied with 45 min of status epilepticus after which the animals were imaged twice, at 3 days and 3 weeks post–status epilepticus. Single voxel point resolved spectroscopy (PRESS) MRS was used to acquire data from the dentate gyrus and CA3 region of the hippocampus, assessing metabolite ratios to total creatine (tCr). In a subset of animals after the second imaging study, brains were analyzed histologically by Nissl staining.

Results

A hierarchical cluster analysis performed on the 3-day data from 21 kainate-treated animals (dentate gyrus voxel) segregated into two clusters, denoted by KM (more injured, n = 6) and KL (less injured, n = 15). Although there was no difference in kainate dosing or seizure count between them, the metabolic pattern of injury was different. The KM group displayed the largest significant changes in neuronal and glial parameters; the KL group displayed milder but significant changes. At 3 weeks, the KL group returned to normal compared to controls, whereas the KM group persisted with depressed N-acetyl aspartate (NAA)/tCr, glutamate/tCr, and increased inositol/tCr and glutamine/tCr. The classification was also consistent with subsequent histologic patterns at 3 weeks.

Significance

Although a short status period might be expected to generate a continuous distribution of metabolic injury, these data show that the short Hellier Dudek model appears to generate two levels of injury. The changes seen in segregated groups persisted into 3 weeks, and can be interpreted according to neuronal and glial biomarkers consistent with histology results.

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Label-free multiphoton microscopy reveals altered tissue architecture in hippocampal sclerosis

Epilepsia - Mon, 11/07/2016 - 10:33
Summary

The properties and structure of tissue can be visualized without labeling or preparation by multiphoton microscopy combining coherent anti-Stokes Raman scattering (CARS), addressing lipid content, second harmonic generation (SHG) showing collagen, and two-photon excited fluorescence (TPEF) of endogenous fluorophores. We compared samples of sclerotic and nonsclerotic human hippocampus to detect pathologic changes in the brain of patients with pharmacoresistant temporomesial epilepsy (n = 15). Multiphoton microscopy of cryosections and bulk tissue revealed hippocampal layering and micromorphologic details in accordance with reference histology: CARS displayed white and gray matter layering and allowed the assessment of axonal myelin. SHG visualized blood vessels based on adventitial collagen. In addition, corpora amylacea (CoA) were found to be SHG-active. Pyramidal cell bodies were characterized by intense cytoplasmic endogenous TPEF. Furthermore, diffuse TPEF around blood vessels was observed that co-localized with positive albumin immunohistochemistry and might indicate degeneration-associated vascular leakage. We present a label-free and fast optical approach that analyzes pathologic aspects of HS. Hippocampal layering, loss of pyramidal cells, and presence of CoA indicative of sclerosis are visualized. Label-free multiphoton microscopy has the potential to extend the histopathologic armamentarium for ex vivo assessment of changes of the hippocampal formation on fresh tissue and prospectively in vivo.

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