Epilepsy Research Findings: January 2019

This month’s news features work done in part by one of our grantees, Dr. Gemma Carvill. The research identified a genetic variant which activates a poisonous piece of genetic code, possibly leading to seizures. In addition, research found a 70% reduction in seizures in rats given stem cell brain implants compared to rats without implants.

In treatment-related advances, two clinical studies found positive results in pursuit of new treatments for epilepsy and related conditions.

Summaries of all highlighted studies follow below. We’ve organized the findings into three categories: Treatment Advances, Diagnostic Advances, and Research Discoveries.

Treatment Advances

Ovid Therapeutics Announces Phase 1b/2a Results of OV935/TAK-935 in Adults with Rare Epilepsies

Ovid Therapeutics announced results from a 12-week, Phase 1b/2a clinical trial of OV935/TAK-935 that enrolled 18 adults with rare developmental and epileptic encephalopathies who were not successfully treated with available treatment regimens. The trial achieved its primary endpoint of safety and tolerability, as well as showed OV935 was generally well tolerated.

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Improved Everyday Executive Function with Fenfluramine HCL Oral Solution (FINTEPLA®): Results from a Phase 3 Study in Children and Young Adults with Dravet Syndrome

In a Phase 3 study of individuals with Dravet syndrome, fenfluramine showed significant and clinically meaningful improvements in behavior regulation and emotion regulation, as well as planning and organization.

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Diagnostic Advances

An Improved Tool for Lennox-Gastaut Syndrome Screening

The complex clinical presentation and progression of Lennox-Gastaut syndrome (LGS) can complicate the accurate diagnosis of this severe, lifelong, childhood-onset epilepsy, often resulting in suboptimal treatment. As described in Epilepsy & Behavior, the Refractory Epilepsy Screening Tool for LGS (REST-LGS) may be a valuable clinical tool for identifying patients with LGS.

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Research Discoveries

Epilepsy Study Points to Promising New Uses for Existing Drugs

In a study published in Annals of Clinical and Translational Neurology, University of Iowa researchers tested candidate drugs from a list of FDA-approved drugs not currently being used to treat epilepsy. The researchers found three — a diabetes drug, a hypertension medication, and an antiparasitic therapy — which significantly reduced seizure-like movement in zebrafish.

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Groundbreaking Stem Cell Brain Implant Helps Fight Epilepsy in Rats

As described in the journal Proceedings of the National Academy of Sciences, researchers at Texas A&M University found that rats given stem cell brain implants suffered 70% fewer seizures than those without. The investigation demonstrated that grafting certain cells derived from human-induced pluripotent stem cells into the brain can help alleviate seizures, as well as improve brain function.

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Study Highlights Potential Benefits of Continuous EEG Monitoring for Infant Patients

A recent retrospective study evaluating continuous electroencephalography (cEEG) of children in intensive care units found a higher than anticipated number of seizures. The work also identified several conditions closely associated with the seizures and suggests cEEG monitoring may be a valuable tool for helping to identify and treat neurological problems in patients who are 14 months old or younger.

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HudsonAlpha Scientists Identify “Poisonous” Piece of Genetic Code Causing Infant Seizures

Featuring the Work of CURE Grantee Gemma L. Carvill, PhD

Scientists at the HudsonAlpha Institute for Biotechnology, along with collaborators from across the country, identified a variant in the SCN1A gene which causes a poisonous piece of genetic code, called a poison exon, to be included in the final instructions for making the crucial SCN1A protein. When the poison exon is incorporated, it prematurely cancels the protein’s production, disrupting neural function and leading to seizure disorders.

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Childhood Seizures and Risk of Psychiatric Disorders in Adolescence and Early Adulthood: a Danish Nationwide Cohort Study

A study published in The Lancet found that children with epilepsy and febrile seizures – with and without concomitant epilepsy – are at increased risk of developing a broad range of psychiatric disorders in later life. Clarification of the underlying mechanisms attributable to these associations is needed to identify potential options for prevention.

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Two Possible New Ways to Treat Silent Seizures in Children

As early as 3 months of age, infants with Dravet syndrome start having convulsive seizures, during which their arms and legs jerk repeatedly. As they become toddlers, another type of seizure – the silent seizure – begins to appear. A recent study published in Cell Reports characterizes silent seizures in a mouse model of Dravet syndrome and identifies the brain area which could be targeted to stop them.

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Wireless ‘Pacemaker for the Brain’ Could Be New Standard Treatment for Neurological Disorders

A new neurostimulator developed by engineers at UC Berkeley can listen to and stimulate electric current in the brain at the same time, potentially delivering fine-tuned treatments to patients with diseases like epilepsy and Parkinson’s. The device is called the WAND and works like a “pacemaker for the brain,” monitoring the brain’s electrical activity and delivering electrical stimulation if it detects something amiss.

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Use of Common Epilepsy Drug in Pregnancy Tied to ADHD in Kids

When a woman with epilepsy uses the anti-seizure drug valproate during a pregnancy, the odds her baby will develop attention-deficit/hyperactivity disorder (ADHD) rise, a new study suggests. The Danish report can’t prove valproate causes ADHD in these cases, only that there’s an association. The findings were published online in JAMA Network Open.

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Central Nervous System Lymphatic Unit, Immunity and Epilepsy: Is There a Link?

The recent definition of a network of lymphatic vessels in the meninges surrounding the brain and the spinal cord has advanced our knowledge on the functional anatomy of fluid movements within the central nervous system (CNS). Meningeal lymphatic vessels, along dural sinuses and main nerves, contribute to the cerebrospinal fluid (CSF) drainage, integrating the cerebrovascular and periventricular routes, and forming a circuit that we here outline as the CNS-lymphatic unit. The latter is important for parenchyma waste clearance, brain homeostasis, and the regulation of immune or inflammatory processes within the brain.

Disruption of fluid drain rules may promote or sustain CNS disease, conceivably applicable to epilepsy where extracellular accumulation of macromolecules and metabolic by-products occur at the interstitial and perivascular spaces.

Poor Mental Health Support for Children in Epilepsy Clinics, National Audit in England and Wales Shows

Almost 9 in 10 Health Boards and Trusts in England and Wales do not enable mental health provision within epilepsy clinics. This is despite research showing that children with epilepsy are four times more likely to experience a mental health problem than their peers.

This is a finding in the new Epilepsy12 National Audit report from the Royal College of Paediatrics and Child Health (RCPCH). The report also found that nearly a quarter of Health Boards and Trusts are failing to provide routine and comprehensive care planning for children with epilepsy.

The report also highlighted areas of improvement. The number of epilepsy specialist nurses (ESNs) across England and Wales has increased significantly since 2014, when the last audit was published. ESNs are a key part of the epilepsy team, providing essential support to children and young people and their families.

Heart Rate, Movement Detect Nocturnal Seizures in Epilepsy

Measurement of heart rate and movement using a multimodal bracelet sensor may be effective for detecting nocturnal seizures of varying types in patients with epilepsy, according to results of a multicenter, prospective study published in Neurology.

Patients with an intellectual disability and a history of more than 1 major nocturnal seizure per month who resided in a long-term care facility at an epilepsy center in the Netherlands were enrolled (n=28). A bracelet was worn by all participants on the upper arm during sleep for up to 2 to 3 months. Heart rate or movement detected nocturnal seizures via photoplethysmography or 3-dimensional accelerometry, respectively. Investigators identified seizures as being tonic-clonic, generalized tonic >30 seconds, hyperkinetic, or others (eg, clusters [>30 minutes] of short myoclonic/tonic seizures).

Limitations of this study include its small cohort size and the inclusion of only patients residing in long-term care facilities in the Netherlands, which may likely limit the ability to extrapolate the findings across the broader epilepsy population.

“The multimodal sensor might be of help in preventing [sudden unexpected death in epilepsy],” the researchers added. “Although comparative studies are lacking, combining [heart rate and accelerometry] seems more effective for detecting major seizures because of the shortcomings of current audio detection.”

Embrace Smartband

Embrace by Empatica Receives First of Its Kind FDA Clearance in Epilepsy for Children

Embrace by Empatica has received 510(k) clearance from the FDA for use in children. Embrace is an epilepsy smartband that detects patterns in motion and physiological signals that may be associated with generalized tonic-clonic seizures, and immediately alerts caregivers. It is the first non-EEG based physiology signal seizure monitoring system to be cleared by the FDA for use in a pediatric population, highlighting the challenges and complicated processes that come with this type of testing for children.

This clearance represents a significant advancement in expanding availability to this cutting-edge seizure monitoring technology for families living with epilepsy. It is a fantastic piece of news to start 2019 for the global epilepsy population, as it means parents now have easy access to an officially clinically validated technology. The clearance for children is not only a positive development for families, but also for doctors, providing them with reliable technology that can assist in patient treatment and care.

New Key Mechanism of Epileptic Seizures Revealed

Scientists investigated the changes in the temporal lobe cortex of a rat brain during prolonged epileptic seizures. Despite the complex interaction of neural signals, biologists and physicists managed to build their mathematical model and identified the key factor leading to the seizures. This work was supported by the Russian Science Foundation and published in Frontiers in Cellular Neuroscience.

A person subject to epilepsy suffers from occasional convulsive seizures. The condition when the seizures follow each other after a short time is called epistatus and considered to be particularly dangerous. Although scientists know that this happen due to excessive excitation of neurons in the brain, the cause of such excitation remains unclear.

In the new study, the researchers examined the signaling processes in the cortex of the temporal lobe before and after the seizures. This area was chosen on purpose since the epilepsy associated with it is the most common. Scientists conducted their research on a rat brain cut placed in a special pro-epileptic solution that mimics convulsions in the patient’s brain tissue. To study the excitability of neurons, scientists analyzed the currents that occur in the brain cells stimulated by electricity, before and after a 15-minute epistatus.

Determinants of Health and Wellbeing in Refractory Epilepsy and Surgery: The Patient Reported, ImpleMentation sciEnce (PRIME) Model

This paper offers a new way of understanding the course of a chronic, neurological condition through a comprehensive model of patient-reported determinants of health and wellbeing: The Patient Reported ImpleMentation sciEnce (PRIME) model is the first model of its kind to be based on patient-driven insights for the design and implementation of initiatives that could improve tertiary, primary, and community healthcare services for patients with refractory epilepsy, and has broad implications for other disorders.

PRIME focuses on: patient-reported determinants of health and wellbeing, pathways through care, gaps in treatment and other system delays, patient need and expectation, and barriers and facilitators to high-quality care provision; PRIME highlights that in the context of refractory epilepsy, patients value appropriate, clear, and speedy referrals from primary care practitioners and community neurologists to specialist healthcare professionals based in tertiary epilepsy centers. Many patients also want to share in decisions around treatment and care, and gain a greater understanding of their debilitating disease, so as to find ways to self-manage their illness more effectively and plan for the future.

Here, PRIME is presented using refractory epilepsy as the exemplar case, while the model remains flexible, suitable for adaptation to other settings, patient populations, and conditions; PRIME comprises six critical levels: 1) The Individual Patient Model; 2) The Patient Relationships Model; 3) The Patient Care Pathways Model; 4) The Patient Transitions Model; 5) The Pre- and Postintervention Model; and 6) The Comprehensive Patient Model.

Each level is dealt with in detail, while Levels 5 and 6 are presented in terms of where the gaps lie in our current knowledge, in particular in relation to patients’ journeys through healthcare, system intersections, and individuals adaptive behavior following resective surgery, as well as others’ views of the disease, such as family members.

Wireless ‘Pacemaker for the Brain’ Could be New Standard Treatment for Neurological Disorders

A new neurostimulator developed by engineers at UC Berkeley can listen to and stimulate electric current in the brain at the same time, potentially delivering fine-tuned treatments to patients with diseases like epilepsy and Parkinson’s.

The device, named the WAND, works like a “pacemaker for the brain,” monitoring the brain’s electrical activity and delivering electrical stimulation if it detects something amiss.

These devices can be extremely effective at preventing debilitating tremors or seizures in patients with a variety of neurological conditions. But the electrical signatures that precede a seizure or tremor can be extremely subtle, and the frequency and strength of electrical stimulation required to prevent them is equally touchy. It can take years of small adjustments by doctors before the devices provide optimal treatment.

How a Web-Based Model Helps Predict Epilepsy Risk

Seizures can be scary for parents and children, but researchers from the Netherlands have developed a new model that can help determine the risk of epilepsy and guide future clinical pathways.

For children who have had 1 or more seizures, the model may help to determine the risk a child has of receiving a diagnosis of epilepsy, according to the report. The study, published in Pediatrics, details how the model was developed and tested.

Epileptic seizures can be underestimated in children because clinical symptoms vary so widely and initial interictal electroencephalogram (EEG) may have limited sensitivity, the report notes.

Psychiatric Comorbidities go Untreated in Patients with Epilepsy: Ignorance or Denial?

Psychiatric comorbidities are common in patients with epilepsy (PWE). Depression and anxiety are the most prevalent of these comorbidities and are associated with worse quality of life. Several screening tools are available to identify and follow up these conditions. However, time constrains in outpatient clinic visits and limited access to mental healthcare professionals discourage clinicians to use them.

This paper discusses the advantage and limitations of screening tools and makes a compelling argument for neurologists to take an active role in the diagnosis and treatment of common psychiatric comorbidities in PWE. This article is part of the Special Issue Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy.