Research reveals how altered brain networks can lead to seizures, offering new treatment strategies for epilepsy

An international team of scientists, led by mathematicians from the University of Exeter’s Living Systems Institute, have developed a ground-breaking new method that can identify regions of brain tissue most likely to generate seizures in people with epilepsy.

The innovative new method, which utilizes mathematical modelling, offers the potential to complement existing clinical approaches and could lead to enhanced surgical outcomes.

The new research is published in leading scientific journal, PLOS Computational Biology on August 17 2017.

Epilepsy, which affects around 1 in 100 people worldwide, is predominantly treated by a range of medications. However, in around a third of cases people do not experience adequate seizure control through drugs and alternative therapies are sought. In some instances surgery is an option, however long-term seizure freedom is only achieved in around 50% of cases.

In their latest research the team used statistical methods to determine how different regions were connected from the electrical recordings of the brain. They then used advanced mathematical modelling to study which regions of the brain contribute most greatly to generating seizures and whether their removal would result in the brain being seizure free. The idea being that if brain surgeons targeted these regions the outcome of surgery would be enhanced.

Dr Marinho Lopes, a Research Fellow at the University of Exeter funded by the Medical Research Council and lead author of the research said: “What is truly exciting about our findings is that common network forms appear to underpin the generation of seizures and we can now identify the specific brain regions involved in forming those networks for different individuals providing optimised surgical strategies.”

For the research, the team analysed a database of EEG recordings taken from 16 individual patients who had already undergone surgery for epilepsy. They found certain brain regions connected with each other preferentially over other less connected regions to form a “rich club” network.

The researchers then demonstrated mathematically that targeting these “rich-clubs” through removing well connected nodes would result in fewer seizures occurring. Returning to the clinical data they found evidence to support their mathematical observations: when surgery removed a greater proportion of the ‘rich-club’, people experienced fewer or no seizures long-term.

Professor John Terry, from the University of Exeter and senior author of the paper added:  “Mathematics can often appear esoteric, yet it is a powerful tool to reveal information about the workings of the brain that would be otherwise hidden to brain surgeons.  Our findings offer hope of new strategies for treating drug-resistant epilepsies and we shall redouble our efforts to advancing our understanding further still.”

An optimal strategy for epilepsy surgery: Disruption of the rich-club?  Is published in PLOS Computational Biology.

Eisai epilepsy data presented at the American Academy of Neurology (AAN) annual meeting‏

 Data show that seizure control improves regardless of age, sex and ethnicity in drug-resistant patients with primary generalised tonic-clonic (PGTC) seizures treated with once-daily adjunctive Fycompa^®(perampanel) at doses up to 8mg per day.]  These data are one of a number of perampanel and Inovelon^® (rufinamide) abstracts presented this week at the American Academy of Neurology (AAN) Annual Meeting Vancouver, Canada.

The results show that a change in seizure frequency from baseline is greater with perampanel than with placebo across all groups and similar for placebo between age, sex, and ethnicity. Data are obtained from a double-blind, placebo-controlled Phase III study in 162 patients with idiopathic generalised epilepsy (IGE) (81 each on either perampanel or placebo) who have confirmed PGTC seizures.

“These data confirm that adjunctive perampanel provides effective management of seizures in all groups of IGE patients studied with primary generalised tonic-clonic seizures,” comments Bernhard Steinhoff, Medical Director and Executive Chief Physician, Kork Epilepsy Centre, Germany.

Post-hoc analysis of this Phase III study of adjunctive perampanel for primary tonic-clonic seizures across age, sex and ethnicity shows similar median percent change from baseline in primary generalised tonic-clonic seizure frequency for age (age <18y nbsp="" span="">-88.0%; age ≥18−<65y nbsp="" span="">-74.4%), sex (males, -53.3%; females, -83.0%) and ethnic groups (White, -65.5%; Asian/Pacific, -79.1%).  The 50% responder rate is also similar across age (age <18y 53.8="" age="" span="">-<65y 54.3="" 58.8="" 66.2="" 68.2="" 71.7="" acific="" and="" asian="" ethnic="" females="" groups="" hite="" males="" sex="" span="">

Perampanel has shown efficacy in, and is indicated for the adjunctive treatment of partial-onset seizures with or without secondarily generalised seizures in adult and adolescent patients from 12 years of age with epilepsy; and for the adjunctive treatment of primary generalised tonic-clonic seizures in adult and adolescent patients from 12 years of age with idiopathic generalised epilepsy. 

Abstract P2.024 17 April 08:30-17:30 PDT Krauss et al[iii]

Data presented from this Phase III study in PGTC seizures explores the relationship between perampanel exposure, primary generalised tonic-clonic seizure outcomes, and treatment-emergent adverse events (TEAEs) in patients with uncontrolled primary generalised      tonic-clonic seizures. Response rate increases, and responder probability is predicted to increase with increased perampanel exposure.  Concomitant use of enzyme-inducing anti-epileptic drugs (EIAED) reduces perampanel exposure, and perampanel exposure is higher in patients with hostility/aggression-related TEAEs than in those without, although the concentrations overlap substantially.³

Abstract P2.045 17 April 08:30-17:30 PDT French J et al

Data from an external review was used for the first time to ensure the appropriate classification of trial participants⁴ withprimary generalised tonic-clonic seizures in the Phase III perampanel PGTC trial. An independent group review eliminated almost a third (29.9%) of patients, initially considered eligible, from inclusion in perampanel’s pivotal study 332.  Without this review the interpretability of results may otherwise be compromised.⁴  

Abstract P2.044 17 April 08:30-17:30 PDT Tsong et al 

With the advent of newer medications for primary generalised tonic-clonic seizures the standard of care (SOC) has changed over time while trial designs remain similar over time, according to a systematic literature review of published data during 1989-2014 of different anti-epileptic drug (AED) trials versus placebo for adjunctive treatment of primary generalised tonic-clonic seizures. The latest trial, the perampanel Phase III study 332⁵ includes a standard of care that is weighted to the most recently approved drugs for primary generalised tonic-clonic seizures such as topiramate, lamotrigine, levetiracetam, and valproate.  

Abstract P5.405 20 April 08:30-19:00 PDT Perucca et al

In patients with partial seizures, results of an extension study shows that treatment with perampanel for three or four years significantly improves seizure control, and is well tolerated as an adjunctive treatment At three years’ exposure to perampanel, median seizure reduction is 61.98% and at four years’ exposure is 70.63%.  The largest median percent decrease during the last year of treatment occurs in patients with secondarily generalised seizures at baseline – at three years, seizure reduction is 87.96% and at four years is 100%.

“We are proud to share these data on the use of perampanel to manage partial-onset seizures and primary generalised tonic-clonic seizures, both seizure types with life-limiting outcomes where treatment with perampanel can make a real difference, Eisai is committed to the exploration of effective treatments for people affected by epilepsy,” comments Neil West, Vice President, Global Neurology Business Unit, Eisai EMEA.

Abstract P2.056 17 April 08:30-17:30 PDT Striano et al[viii] Abstract P2.043 17 April 08:30-17:30 PDT Ng et al

A sub-group analysis of another Phase III trial shows that rufinamide demonstrates favourable efficacy as adjunctive treatment for adults with Lennox-Gastaut syndrome (LGS), a severe and rare form of childhood-onset epilepsy, which affects nearly 208,000 people in Europe.  Median change from baseline in seizure frequency was -31.5% for rufinamide (n=21) versus +22.1% for placebo (n=21), this represents a statistically significant difference in favour of rufinamide (p=0.008).

Further data reported at AAN 2016⁹ in 138 people with LGS aged 4-37, shows no evidence of tolerance to rufinamide during short-term and long-term treatment.    Larger median decreases in both total and tonic-atonic seizure frequency for rufinamide versus placebo are evident as early as two weeks and over the course of treatment for rufinamide (total: -20.6%−-43.1%; tonic-atonic: -22.8%−-50.3%) than for placebo (total: 1.3%−-1.5%; tonic-atonic: -1.3%−1.0%), which suggests a fast onset of action and lack of short-term tolerance to rufinamide.

Rufinamide efficacy continues up to three years.  Over the course of open-label treatment from 3-36 months, progressive median decreases in seizure frequency for total seizures are -31.6% to -79.3% and for tonic-atonic seizures are -41.9% to-76.1%.⁹

Rufinamide is currently indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in children four years and older. Effective Lennox-Gastaut Syndrome management and compliance to treatment is of key importance to patients, as the condition is characterised by a high number of seizures - up to 70 seizures a day.  The condition often persists into adulthood and most people with this condition will have developmental delay, mental retardation, and moderate to severe learning disabilities, in addition to physiological and behavioural problems.

The development of perampanel and rufinamide demonstrates Eisai’s commitment to the therapeutic area of epilepsy and further exemplifies the company’s contribution to addressing the diversified needs of and increasing the benefits provided to patients and their families as shown by its human health care mission.

Entrevista con el dr Christian Elger: "El 20% de los casos de epilepsia están incontrolados"

El 20% de los casos de epilepsia están incontrolados. Una enfermedad que afecta a unos 50 millones de personas en todo el mundo y cuyas causas concretas aún no están claras. Así nos lo afirma en entrevista exclusiva el dr. Christian Elger( Universidad de Bonn, Alemania) durante el Congreso de la Academia Europea de Neurología( EAN 2015) celebrado en Berlin.
El especialista intervino en un Seminario sobre epilepsia, organizado por la compañía EISAI. En el mismo se presentaron los últimos avances producidos con  el manejo del Fycompa( Peramparel), de mayor toleración en los pacientes en comparación con otros fármacos antiepilépticos.

www.noticiadesalud.blogspot.com
@acedotor
@cuquita1982

Entrevista con el dr Martin Holtkamp sobre el estudio EPOS centrado en la epilepsia

En Berlin durante el Congreso de la Academia Europea de Neurología( EAN 2015) las compañías EISAI y BIAL han presentado los resultados del estudio EPOS. En 8 países europeos se han desarrollado test de control especial de la epilepsia utilizando el medicamento Zebinix.
En el seminario para periodistas celebrado en Berlin estuvo presente NOTICIAS DE SALUD que entrevistó al dr. Martin Holtkamp( University Hospital Charite de Berlin) y coordinador médico del estudio. Declaraciones exclusivas que arrojan un atisbo de positiva luz para los pacientes de epilepsia a la hora de ser tratados medicamente con estos avances en fármacos.

www.noticiadesalud.blogspot.com
@acedotor
@cuquita1982 

Early Warning System for Seizures Could Cut False Alarms

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 Epilepsy affects 50 million people worldwide, but in a third of these cases, medication cannot keep seizures from occurring. One solution is to shoot a short pulse of electricity to the brain to stamp out the seizure just as it begins to erupt. But brain implants designed to do this have run into a stubborn problem: too many false alarms, triggering unneeded treatment. To solve this, Johns Hopkins biomedical engineers have devised new seizure detection software that, in early testing, significantly cuts the number of unneeded pulses of current that an epilepsy patient would receive.

Sridevi V. Sarma, an assistant professor of biomedical engineering, is leading this effort to improve anti-seizure technology that sends small amounts of current into the brain to control seizures.
"These devices use algorithms -- a series of mathematical steps --to figure out when to administer the treatment," Sarma said. "They're very good at detecting when a seizure is about to happen, but they also produce lots of false positives, sometimes hundreds in one day. If you introduce electric current to the brain too often, we don't know what the health impacts might be. Also, too many false alarms can shorten the life of the battery that powers the device, which must be replaced surgically."
Her new software was tested on real-time brain activity recordings collected from four patients with drug-resistant epilepsy who experienced seizures while being monitored. In a study published recently in the journal Epilepsy & Behavior, Sarma's team reported that its system yielded superior results, including flawless detection of actual seizures and up to 80 percent fewer alarms when a seizure was not occurring. Although the testing was not conducted on patients in a clinical setting, the results were promising.
"We're making great progress in developing software that is sensitive enough to detect imminent seizures without setting off a large number of false alarms," Sarma said. Further fine-tuning is under way, using brain recordings from more than 100 epilepsy patients at The Johns Hopkins Hospital, where several epilepsy physicians have joined in the research. Sarma said that within two to four years she hopes to see her system incorporated into a brain implant that can be tested on people with drug-resistant epilepsy.
"There is growing interest in applying responsive, or closed-loop, therapy for the treatment of epileptic seizures," said Gregory K. Bergey, M.D., professor of neurology and director of the Johns Hopkins Epilepsy Center. "Devices to do this have been tested in humans, but for this therapy to be useful for the patient with epilepsy requires early detection of abnormal brain activity that is destined to become a seizure. Detection has to be within seconds of seizure onset, before the seizure spreads to cause disabling symptoms such as alteration of consciousness."
He added, "Developing detection methods that can both provide this early detection and yet not be triggered by brain activity that will not become a clinical seizure has been a real challenge. Dr. Sarma's group appreciates how important this is. The application of their detection algorithms has produced promising preliminary results that warrant further study of more seizures in more patients."
In trying to solve the seizure false-alarm problem, Sarma drew on her training in electrical engineering, particularly a discipline called control theory. "We decided to start with the origin of the signal in the brain," she said.
Sarma's team compared electrical data from the brains of epilepsy patients before, during and after seizures. The researchers looked at how this activity changed over time, particularly when a seizure began. "We wanted to figure out when would be the optimal time to step in with treatment to stop the seizure," she said. The team members "trained" their system to look for that moment without setting off false alarms.
Ideally, Sarma would someday like to see her software embedded in a microchip that would continually check electrical activity in the brain and launch electrical stimulation whenever a seizure is just beginning to form. The device would operate as a closed loop system, resembling a thermostat that keeps a room's temperature at a constant, comfortable level.
Sarma's interest in brain disorders developed relatively late in her education. She earned a bachelor's degree from Cornell University in electrical engineering, then master's and doctoral degrees at MIT, both in electrical engineering and computer science. During her doctoral studies, however, she pursued a minor in neuroscience. For a class, she conducted a case study of her aunt, who had developed Parkinson's disease at age 29 and had trouble managing it with medication. Watching her aunt's condition was an emotionally draining experience, Sarma said, and she wondered if anything in her own training could help. "I really wanted to understand the neurobiological circuitry of this disease," she said.
That led Sarma to learn more about deep brain stimulation, the use of electric pulses to treat brain disorders such as Parkinson's and epilepsy. She completed a postdoctoral fellowship in MIT's Brain and Cognitive Sciences Department and became a neuroscience research associate affiliated with Massachusetts General Hospital and Harvard Medical School.
In 2009, Sarma joined the faculty of Johns Hopkins' Department of Biomedical Engineering, which is shared by the School of Medicine and the Whiting School of Engineering. She also is a core faculty member in the university's Institute for Computational Medicine. In 2011, Sarma was named a recipient of a Faculty Early Career Development Award from the National Science Foundation.
Her team's new system for seizure detection with reduced false alarms is protected by a patent obtained through the Johns Hopkins Technology Transfer office.

Sridevi Sarma’s research focuses on a system with three components: electrodes implanted in the brain, which are connected by wires to a neurostimulator or battery pack, and a sensing device, also located in the brain implant, which detects when a seizure is starting and activates the current to stop it. (Credit: Illustration by Greg Stanley/JHU)

**Published in "SCIENCE DAILY"