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Epilepsy drug therapies to be improved by new targeted approach

Medical News Today - Wed, 05/17/2017 - 03:00
New research from the University of Liverpool, in collaboration with the Mario Negri Institute in Milan, published in the Journal of Clinical Investigation, has identified a protein that could help...
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Professor Helen Cross is announced as new President of Epilepsy Research UK

Epilepsy Research - Mon, 05/15/2017 - 05:52

Epilepsy Research UK is proud and pleased to announce the appointment of Professor Helen Cross as President of the organisation.  Professor Cross has long been involved in the organisation being Chair of Trustees between 2005 and 2011.  We are delighted that Professor Cross has now agreed to be President of the organisation.

About Professor Cross
Professor Helen Cross is The Prince of Wales’s Chair of Childhood Epilepsy and Honorary Consultant in Paediatric Neurology at UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, and Young Epilepsy, Lingfield.

She is currently Clinical Advisor to the Children’s Epilepsy Surgery Services (CESS) (2012-present), is Chair of the Medicines for Children Research Network Neurosciences Clinical Study Group (2012-present), Chair of the Evidence Update of the NICE Guidelines for Epilepsy (2013) and was recently elected Secretary General of the ILAE to serve 2013-2017.

She is on the Editorial Board of Epileptic Disorders, Epilepsy Research, Developmental Medicine Child Neurology and European Journal of Paediatric Neurology.

 

Professor Cross qualified from Birmingham University in 1984, trained in paediatrics in Birmingham and subsequently in paediatric neurology in London, obtaining her PhD in 1998.

Her former roles include:

  • Chair of the ILAE Commission for Paediatrics (2005 – 2009)
  • Assistant Secretary to the Board of the European Paediatric Neurology Society (2005 – 2009)
  • Chair of the Trustees of Epilepsy Research UK (2005 – 2011)
  • President of the British Paediatric Neurology Association (2008 – 2011)
  • Clinical Advisor to the update of the NICE guidelines on diagnosis and management of the epilepsies in adults and children (2009 – 2012)
  • International League Against Epilepsy (ILAE) Commission for European Affairs, (2009 – 2013)
  • ILAE Co-Chair of the sub-committee for ILAE Task Force for Global Outreach (2009 – 2013)
  • Chair of the Task Force for Paediatric Epilepsy Surgery (2001-2013).

Professor Cross has published widely on seizure, neuropsychological and behavioural outcomes in children who have undergone surgical resection for treatment of their epilepsy.  Her research has focused on improving outcomes for children with early onset epilepsy. Her early research was into improving imaging techniques to determine areas of likely seizure onset in children with drug resistant focal epilepsy and has developed an epilepsy surgery programme based on her research.

She conducted the first randomized controlled trial of the ketogenic diet in the treatment of children with drug resistant focal epilepsy and is endeavouring to conduct the same in the very young and adults. Recognising there was little in the way of control data with regard to neurodevelopmental progress, she initiated the North London Epilepsy in Infancy study, where a cohort of children was recruited at diagnosis in the first two years of life, and has been followed to at least three years. She is now aiming to conduct a similar study over a wider geographical area, also examining phenotypes and genotypes.

She is also endeavouring to examine mechanisms of cognitive impairment – in particular examining the relationship of sleep to memory consolidation.

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Epilepsia - Sat, 05/13/2017 - 03:43
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Epilepsia - Sat, 05/13/2017 - 03:43
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BGG492 as an adjunctive treatment in patients with partial-onset seizures: A 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension

Epilepsia - Sat, 05/13/2017 - 03:41
Summary Objectives

To evaluate dose–response relationship of BGG492 as add-on therapy to 1–3 antiepileptic drugs in patients with partial-onset seizures and to investigate safety and tolerability of BGG492.

Methods

This was a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study (core study) with a 30-week, flexible-dose, open-label extension. In the core study, patients were randomized (1:2) to placebo or BGG492 100 mg t.i.d. in cohort 1, and in cohort 2 patients were randomized (1:4) to placebo or BGG492 150 mg t.i.d. On completion of the core study, eligible patients entered the extension study. Primary outcome measures were total partial seizure frequency per 28 days (core study) and safety and tolerability (extension study).

Results

Overall, 93 patients were randomized (150 mg [n = 44]; 100 mg [n = 24]; placebo [n = 25]), and 81 (87.1%) completed the core study. Fifty-one patients entered and 43 (84.3%) completed the extension study. In the core study, no statistically significant dose–response trend among the BGG492 treatment groups (100 and 150 mg) was observed at the 4-week double-blind maintenance period (weeks 7–10); however, there was higher percent reduction in total partial seizure frequency in the BGG492 150 mg over placebo groups (37.32%; 95% confidence interval [CI] −18.90, 66.95). Dizziness, somnolence, and fatigue were the most common adverse events (AEs), higher in the BGG492 150 mg group than in the 100 mg and placebo groups (dizziness: 14 [31.8%] vs. 3 [12.5%] and 1 [4.0%]; somnolence: 7 [15.9%] vs. 1 [4.2%] and 1 [4.0%]; fatigue: 5 [11.4%] vs. 1 [4.2%] and 1 [4.0%]). During the open-label extension study, 39 (76.5%) patients on BGG492 had AEs, and the most commonly experienced AEs were dizziness (14 [27.5%]) and somnolence (9 [17.6%]).

Significance

There was no significant dose–response trend in the BGG492 treatment groups (100 and 150 mg); however, higher percent reduction over placebo was observed in the BGG492 150 mg group. Safety and tolerability data were consistent with the known safety profile for BGG492, and no new safety risks were identified.

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Why do some images cause seizures while others do not?

Epilepsy Research - Thu, 05/11/2017 - 06:19

A new study has investigated why it is that some images can cause seizures in people with photosensitive epilepsy while other images don’t.

We know that in people with photosensitive epilepsy, flashing lights can cause seizures. The impact of such provocative visuals can be quite staggering. In 1997, for example, a certain Pokémon episode triggered seizures in 685 people in Japan, and in 2012, the promotional video for the Olympics had to be taken down from the website because it caused seizures in multiple epileptic patients.

However, seizures can also be caused by static images, with no motion or flicker. New research set out to examine why that is. A team of international researchers reviewed the literature available in the field of neurophysiology to see if the neural responses in a healthy visual cortex can predict how people with photosensitive epilepsy might respond to static images.

The study, led by Dora Hermes, of the University Medical Center (UMC) Utrecht in the Netherlands, and published in the journal Current Biology, has looked into the role of gamma oscillations in the brain.

Their review focused on gamma oscillations induced by the spatial features of some static images, such as those depicting black and white bars.

The repetitive pattern of brain activity of gamma oscillations takes place when people are exposed to these images. In fact, the authors note that these images can cause headaches and migraines in photosensitive people as well as discomfort in perfectly healthy people.

“Our findings imply that in designing buildings, it may be important to avoid the types of visual patterns that can activate this circuit and cause discomfort, migraines, or seizures. Even perfectly healthy people may feel modest discomfort from the images that are most likely to trigger seizures in photosensitive epilepsy.” Said Dr Hermes.

Gamma brain oscillations can be measured with the help of a simple electroencephalogram, and they have been known to scientists since the 1980s. However, researchers have not yet agreed on the role that these oscillations play in perception, thought, or generally in neural processing.

Gamma oscillations occur in the brain only upon viewing certain images, however, which runs counter to the hypothesis that they may be key to neural processing. For instance, images of grating patterns cause strong gamma oscillations, but images of clouds or natural landscapes do not. Why this happens remains largely unknown.

The authors conclude that these grating patterns are most likely to induce seizures, and they suggest various ways in which the images can be adjusted so as to avoid producing gamma oscillations in the brain.

“The likelihood that a [photosensitive seizure] is induced by viewing a grating can be reduced by decreasing the size of the grating [pattern], by reducing the contrast, by superimposing a second grating [pattern] to create a plaid or checkerboard, or by superimposing noise. Both sine and square wave gratings are provocative whereas chromatic contrast alone […] is not.”

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Erratum to “Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study” [Epilepsy Res. 131 (2017) 70–75]

Epilepsy Research Journal - Wed, 05/10/2017 - 00:00
The publisher regrets that during the publication of this article Table 6 was inadvertently laid out incorrectly. Table 6 is hereby republished with the correct layout. The publisher would like to apologise for any inconvenience caused.
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Child- and parent-reported quality of life trajectories in children with epilepsy: A prospective cohort study

Epilepsia - Tue, 05/09/2017 - 08:31
Summary Objective

To describe the developmental trajectories of quality of life (QoL) in a large cohort of children with epilepsy, and to assess the relative contribution of clinical, psychosocial, and sociodemographic variables on QoL trajectories.

Methods

Five assessments during a 28-month prospective cohort study were used to model trajectories of QoL. Participants were recruited with their parents from six Canadian tertiary centers. A convenience sample of 506 children aged 8–14 years with epilepsy and without intellectual disability or autism spectrum disorder were enrolled. A total of 894 children were eligible and 330 refused participation. Participating children were, on average, 11.4 years of age, and 49% were female. Nearly one third (32%) had partial seizures. At baseline, 479 and 503 child- and parent-reported questionnaires were completed. In total, 354 children (74%) and 366 parents (73%) completed the 28-month follow-up. QoL was measured using the child- and parent-reported version of the Childhood Epilepsy QoL scale (CHEQOL-25).

Results

Child-reported QoL was fitted best by a six-class model and parent-reported QoL by a five-class model. In both models, trajectories remained either stable or improved over 28 months. Of these children, 62% rated their QoL as high or moderately high, defined as at least one standard deviation above the average CHEQOL-25 score. Greater family, classmate, and peer social support, fewer symptoms of child and parent depression, and higher receptive vocabulary were identified as the most robust predictors of better QoL (all p < 0.001).

Significance

Most children with epilepsy and their parents reported relatively good QoL in this first joint self- and proxy-reported trajectory study. Findings confirm the heterogeneous QoL outcomes for children with epilepsy and the primary importance of psychosocial factors rather than seizure and AED-specific factors in influencing QoL. These predictors that are potentially amenable to change should now be the focus of specific intervention studies.

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Why do some images cause seizures while others do not?

Medical News Today - Tue, 05/09/2017 - 03:00
New research examines why some static images - that is, without any motion or flicker - can trigger seizures in people with photosensitive epilepsy.
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Mesial temporal lobe epilepsy diminishes functional connectivity during emotion perception

Epilepsy Research Journal - Tue, 05/09/2017 - 00:00
Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of refractory epilepsy in adults, and is now considered as a complex network disease that affects widely distributed brain regions organized in networks in the afflicted hemisphere (Berg et al., 2010 and Jokeit et al., 1997). Consistent with structural and functional abnormalities extending far beyond the mesial temporal lobe (Bernhardt et al., 2013), deficits in neuropsychological functions relying on large-scale networks such as memory (Bell et al., 2011), language (Bartha-Doering and Trinka, 2014) and executive functions (Stretton and Thompson, 2012) are a common characteristic of MTLE.
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People with epilepsy frequently suffer from anxiety and depression but we are not sure why.

Epilepsy Research - Mon, 05/08/2017 - 09:03

A recent study at the University of Sydney has looked into the prevalence of depression and anxiety disorders in people with epilepsy.  The study carried out by Dr. Louise Sharpe and her colleagues was a meta-analysis and looked at 27 previously published research papers on the subject.

Dr. Sharpe said: “It is often thought that depression is more common than anxiety in people with epilepsy.  Our results suggest that in clinical practice depression is more often diagnosed than anxiety disorders. However, in studies using structured interviews, depression and anxiety were equally common.”

The researchers found that 20% percent of people with epilepsy had anxiety disorders while 23% suffered from depression.  However, the severity of people’s epilepsy did not seem to effect the prevalence of anxiety or depression.

The big difference came with how the anxiety disorder had been diagnosed. Unstructured clinician assessments resulted in a prevalence of 8%, while a structured clinical interview gave a prevalence of 27%.

“This suggests that people with epilepsy who have anxiety may be under-diagnosed in practice,” said Dr Sharpe. “We need to understand more about anxiety in epilepsy so that it can be identified more readily and effective treatments can be developed.”

The study’s findings also challenge the assumption that psychiatric disorders are more common in people with drug-resistant epilepsy. Researchers said the detection and management of such disorders — particularly anxiety disorders — among people with remains neglected.

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Enriched environment attenuates behavioral seizures and depression in chronic temporal lobe epilepsy

Epilepsia - Mon, 05/08/2017 - 03:20
Summary Objective

Temporal lobe epilepsy (TLE) is commonly associated with depression, anxiety, and cognitive impairment. Despite significant progress in our understanding of the pathophysiology of TLE, it remains the most common form of refractory epilepsy. Enriched environment (EE) has a beneficial effect in many neuropsychiatric disorders. However, the effect of EE on cognitive changes in chronic TLE has not been evaluated. Accordingly, the present study evaluated the effects of EE on chronic epilepsy–induced alterations in cognitive functions, electrophysiology, and cellular changes in the hippocampus.

Methods

Status epilepticus (SE) was induced in 2-month-old male Wistar rats with lithium and pilocarpine. Six weeks' post SE, epileptic rats were either housed in their respective home cages or in an enrichment cage (6 h/day) for 14 days. Seizure behavior was video-monitored 2 weeks before and during exposure to EE. Depression-like behavior, anxiety-like behavior, and spatial learning and memory were assessed using the sucrose preference test (SPT), elevated plus maze (EPM), and Morris water maze (MWM), respectively. Delta and theta power in the CA1 region of hippocampus was assessed from recordings of local field potentials (LFPs). Cellular changes in hippocampus were assessed by histochemistry followed by unbiased stereologic analysis.

Results

EE significantly reduced seizure episodes and seizure duration in epileptic rats. In addition, EE alleviated depression and hyperactivity, and restored delta and theta power of LFP in the hippocampal CA1 region. However, EE neither ameliorated epilepsy-induced spatial learning and memory deficits nor restored cell density in hippocampus.

Significance

This is the first study that evaluates the role of EE in a chronic TLE model, where rats were exposed to EE after occurrence of spontaneous recurrent seizures (SRS). Given that 30% of TLE patients are refractory to drug treatment, therapeutic strategies that utilize components of EE could be designed to alleviate seizures and psychiatric comorbidities associated with TLE.

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Weather as a risk factor for epileptic seizures: A case-crossover study

Epilepsia - Mon, 05/08/2017 - 02:57
Summary Objective

Most epileptic seizures occur unexpectedly and independently of known risk factors. We aimed to evaluate the clinical significance of patients’ perception that weather is a risk factor for epileptic seizures.

Methods

Using a hospital-based, bidirectional case-crossover study, 604 adult patients admitted to a large university hospital in Central Germany for an unprovoked epileptic seizure between 2003 and 2010 were recruited. The effect of atmospheric pressure, relative air humidity, and ambient temperature on the onset of epileptic seizures under temperate climate conditions was estimated.

Results

We found a close-to-linear negative correlation between atmospheric pressure and seizure risk. For every 10.7 hPa lower atmospheric pressure, seizure risk increased in the entire study population by 14% (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.01–1.28). In patients with less severe epilepsy treated with one antiepileptic medication, seizure risk increased by 36% (1.36, 1.09–1.67). A high relative air humidity of >80% increased seizure risk in the entire study population by up to 48% (OR 1.48, 95% CI 1.11–1.96) 3 days after exposure in a J-shaped association. High ambient temperatures of >20°C decreased seizure risk by 46% in the overall study population (OR 0.54, 95% CI 0.32–0.90) and in subgroups, with the greatest effects observed in male patients (OR 0.33, 95% CI 0.14–0.74).

Significance

Low atmospheric pressure and high relative air humidity are associated with an increased risk for epileptic seizures, whereas high ambient temperatures seem to decrease seizure risk. Weather-dependent seizure risk may be accentuated in patients with less severe epilepsy. Our results require further replication across different climate regions and cohorts before reliable clinical recommendations can be made.

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Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany

Epilepsia - Mon, 05/08/2017 - 02:47
Summary Objective

To evaluate factors predicting efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice.

Methods

A multicenter, retrospective cohort study recruiting all patients who started BRV between February and November 2016 with observation time between 3 and 12 months.

Results

Of a total of 262 patients (mean age 40, range 5–81 years, 129 male) treated with BRV, 227 (87%) were diagnosed to have focal, 19 (7%) idiopathic generalized and 8 (3%) symptomatic generalized epilepsy, whereas 8 (3%) were unclassified. The length of exposure to BRV ranged from 1 day to 12 months, with a median retention time of 6.1 months, resulting in a total exposure time to BRV of 1,504 months. The retention rate was 79.4% at 3 months and 75.8% at 6 months. Efficacy at 3 months was 41.2% (50% responder rate) with 14.9% seizure-free for 3 months and, at 6 months, 40.5% with 15.3% seizure-free. Treatment-emergent adverse events were observed in 37.8% of the patients, with the most common being somnolence, dizziness, and behavioral adverse events (BAEs). BAE that presented under previous levetiracetam (LEV) treatment improved upon switch to BRV in 57.1% (20/35) and LEV-induced somnolence improved in 70.8% (17/24). Patients with BAE on LEV were more likely to develop BAE on BRV (odds ratio [OR] 3.48, 95% confidence interval [CI] 1.53–7.95).

Significance

BRV in broad clinical postmarketing use is a well-tolerated anticonvulsant drug with 50% responder rates, similar to those observed in the regulatory trials, even though 90% of the patients included had previously been exposed to LEV. An immediate switch from LEV to BRV at a ratio of 10:1 to 15:1 is feasible. The only independent significant predictor of efficacy was the start of BRV in patients not currently taking LEV. The occurrence of BAE during previous LEV exposure predicted poor psychobehavioral tolerability of BRV treatment. A switch to BRV can be considered in patients with LEV-induced BAE.

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Prolonged epileptiform EEG runs are associated with persistent seizures in juvenile myoclonic epilepsy

Epilepsy Research Journal - Mon, 05/08/2017 - 00:00
Juvenile myoclonic epilepsy (JME) is the most common form of idiopathic generalized (genetic) epilepsy (Syvertsen et al., 2017). Seizure onset usually occurs around puberty with early morning myoclonic jerks. The majority of patients develop generalized tonic-clonic seizures and 20-40% has absence seizures (Commission, 1989; Genton et al., 2013; Janz, 1989; Kasteleijn- Nolst Trenité et al., 2013). EEG is the most useful supplementary diagnostic method. Valproate is effective in the majority of patients (Gesche et al., 2017; Penry et al., 1989), but reproductive toxicity limits its use in women.
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Anticonvulsant profile of the neuroactive steroid, SGE-516, in animal models

Epilepsy Research Journal - Sun, 05/07/2017 - 00:00
Since the discovery of phenobarbital in 1912 and the development of benzodiazepines in the 1950s, drugs that enhance GABAergic signaling have been used for the treatment of seizure disorders (Magiorkinis et al., 2014). In addition, over a dozen new pharmacotherapies with varying mechanisms of action have been developed to treat seizures in the last twenty years. Whereas these newer therapies have generally demonstrated improved safety and tolerability, approximately one third of patients with epilepsy continue to struggle with uncontrolled seizures (Tellez-Zenteno et al., 2014).
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Computer technology increasingly important in study of epilepsy

Epilepsy Research - Fri, 05/05/2017 - 11:37

Two recently published studies show just how important the use of computer technology and modelling have become in the study of epilepsy.

A study being carried out at Newcastle University is using a brain model to explore the cause of different epileptic seizure onset patterns. According to the study, at the onset of an epileptic seizure, differing characteristics of brain tissue surrounding the seizure’s origin site may determine which of two main patterns of brain activity will be seen. Electrical activity in the brain at the start of an epileptic seizure typically follows either a “low amplitude fast” pattern or a “high amplitude slow” pattern. Patients whose seizures follow the high amplitude slow pattern have a higher risk of continuing seizures after surgical treatment. However, the mechanisms underlying these different patterns are unclear.

To better understand the onset patterns, Yujiang Wang of Newcastle University, UK, and colleagues used a previously developed computer model that can simulate brain activity at the start of a seizure. The model output suggested that the onset pattern of a seizure may be determined not by brain tissue at the site where the seizure originates, but by characteristics of the surrounding “healthy” brain tissue.

The simulation showed that the high amplitude slow pattern occurs when surrounding brain tissue has higher excitability; that is, the brain cells have a stronger response to stimulation and can react immediately to the initiation of a seizure. Meanwhile, the low amplitude fast pattern is associated with tissue of lower excitability, which is only slowly penetrated by seizure activity.

These findings suggest why the different onset patterns are associated with different treatment outcomes. Surgical removal of seizure-triggering brain tissue may be enough to prevent seizure activity in nearby low-excitability tissue. However, high-excitability tissue may still be stimulated by alternative trigger sites after surgery, providing a possible explanation for the worse outcomes experienced by patients whose seizures follow the high amplitude slow pattern.

Next, the researchers plan to study seizure onset patterns in greater detail. “We hope to contribute towards the overall goal of associating patterns seen in seizures with an understanding of the underlying mechanism,” Wang says. “This would not only help our understanding of seizures in general, but may be useful for patient stratification in terms of treatment options.”

In a second study being carried out at Boston Children’s Hospital could enable more patients with epilepsy to benefit from surgery when medications do not help. The approach streamlines the seizure monitoring process required for surgical planning, making surgery a more feasible and less risky option for patients.

Currently, for some patients, pinpointing the diseased brain areas where their seizures originate requires invasive surgery to place grids of electrodes on the brain’s surface. This is followed by long-term electroencephalography (EEG) monitoring – typically for a week – while doctors wait for a seizure to happen. Then, patients must undergo a second brain operation to remove the diseased tissue.

The new technology, developed by Joseph Madsen, MD, Director of Epilepsy Surgery at Boston Children’s Hospital, and Eun-Hyoung Park, PhD, a computational biophysicist in the Department of Neurosurgery, could allow patients to be monitored in one short session, without the need to observe an actual seizure. Patients could then proceed directly to surgery, avoiding a second operation.

Effective use of this technology could cut the cost and risk by more than half by reducing the current two-stage procedure to one-stage, the researchers say.  “We know that the diseased brain network responsible for the seizures is there all along,” says Madsen. “So rather than wait for the patient to have a seizure, we set out to find patterns of interaction between various points in the brain that might predict where seizures would eventually start.”

To identify the brain areas causing the seizures, Madsen and Park applied a special algorithm to analyze patients’ interictal EEG data – data captured between their seizures. They randomly selected 25 patients with hard-to-treat epilepsy who previously had long-term EEG monitoring at Boston Children’s, and analyzed data from the first 20 seizure-free minutes of the patients’ EEGs.

Their algorithm, known as Granger causality analysis, is based on a statistical approach developed Sir Clive Granger (for which he won the Nobel Prize in Economics in 2003). Madsen and Park adapted the Granger method, originally used for economic forecasting, to calculate the probability that activity at one brain location predicts subsequent activity at other brain locations strongly enough to be considered causative. Their analysis generated a map of the causal relations in each patient’s epileptogenic network, which Park and Madsen superimposed over images of the brain.

They then showed that the brain regions predicted to be causing seizures strongly correlated with actual causative regions on seizure EEGs – as read by ten board-certified epileptologists, usually many days later.
Madsen and Park have shown that their calculations can be done quickly enough to allow data obtained in the operating room to potentially influence surgical decision-making. They now are investigating how the Granger causality method can best augment readings of EEGs by trained neurophysiologists.  “We still need to validate and refine our approach before it can be used clinically,” notes Madsen. “But we are hopeful that these advanced computer applications can help us treat more children with epilepsy – with less risk and lower cost.”

Article: Granger Causality Analysis of Interictal iEEG Predicts Seizure Focus and Ultimate Resection, Eun-Hyoung Park, PhD Joseph R. Madsen, MD, Neurosurgery, doi: 10.1093/neuros/nyx195, published 2 May 2017.

Article: Mechanisms underlying different onset patterns of focal seizures, Wang Y, Trevelyan AJ, Valentin A, Alarcon G, Taylor PN, Kaiser M, PLOS Computational Biology, doi: 10.1371/journal.pcbi.1005475, published 4 May 2017.

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