Biologists link protein, seizure suppression

Research shows that seizure suppression was associated with an increase in COX-2 expression in neurons.

James Hewett, associate professor of biology, and Yifan Gong, a Ph.D. candidate in biology and neuroscience, have co-authored an article in the journal Neuroscience (Elsevier, 2018) about a protein in the brain called T-cell intracellular antigen-1 (TIA-1).

“TIA-1 is known for its ability to regulate gene expression during cellular stress,” says Hewett, who studies the processes that suppress the severe electrical storms in the brain, leading to seizures. “We suspected that TIA-1 was involved with seizure suppression, but our findings suggested something else.”

He and Gong are interested in the function of an enzyme in the brain called cyclooxygenase-2 (COX-2). This enzyme makes prostaglandins — chemical messengers that aid in the performance of normal tasks, including learning and memory.

“Our findings raise the possibility that the level of neuronal COX-2 expression in the brain may be a determinant of the seizure threshold [a natural set-point for electrical activity, above which seizures occur]. This suggests that a better understanding of the regulation of COX-2 expression in the brain can provide new insights into molecular mechanisms that suppress seizure-induction,” adds Hewett, a pharmacologist by training.

Prof. Ley Sander Discusses Preventing SUDEP and How to Build Research Around SUDEP: Video from CURE Frontiers in Research Seminar Series

Video is available from the CURE Frontiers in Research Seminar Series talk given by Professor Ley Sander, discussing SUDEP prevention and research.

Talk summary: Individuals with epilepsy, particularly those with uncontrolled epilepsy, are at a much greater risk of premature death than those without. In fact, the standardized mortality ratio in those with epilepsy is between 2 and 3. In the UK, the most common cause of epilepsy-related death is due to Sudden Unexpected Death in Epilepsy (SUDEP), which accounts for up to one-fifth of deaths in some series. SUDEP is more common in those with frequent convulsive seizures (particularly nocturnal seizures) and in those with drug-resistant epilepsy. While the causes of SUDEP are unknown, the most commonly suggested underlying mechanisms are cardiac arrhythmias, respiratory depression and “cerebral shutdown.” Because no preventative measures currently exist, an understanding of SUDEP risk factors, potential mechanisms and the effectiveness of preventative measures is essential. To this end, there are a multitude of opportunities available in the field of SUDEP research and these opportunities will be interactively discussed during the presentation.

Study: Clinical and Electrographic Features of Sunflower Syndrome

CONCLUSIONS: Valproate monotherapy continues to be the most effective treatment for Sunflower Syndrome and should be considered early. For patients who cannot tolerate valproate, higher doses of lamotrigine or polypharmacy should be considered. Levetiracetam monotherapy, even at high doses, is unlikely to be effective.

BACKGROUND: Sunflower Syndrome describes reflex seizures – typically eyelid myoclonia with or without absence seizures – triggered when patients wave their hands in front of the sun. While valproate has been recognized as the best treatment for photosensitive epilepsy, many clinicians now initially treat with newer medications; the efficacy of these medications in Sunflower Syndrome has not been investigated. We reviewed all cases of Sunflower Syndrome seen at our institution over 15 years to describe the clinical course, electroencephalogram (EEG), and treatment response in these patients.

METHODS: Search of the electronic medical record and EEG database, as well as survey of epilepsy providers at our institution, yielded 13 cases of Sunflower Syndrome between 2002 and 2017. We reviewed the records and EEG tracings.

RESULTS: Patients were mostly young females, with an average age of onset of 5.5 years. Seven had intellectual, attentional or academic problems. Self-induced seizures were predominantly eyelid myoclonia?±?absences and 6 subjects also had spontaneous seizures. EEG demonstrated a normal background with 3-4?Hz spike waves?±?polyspike waves as well as a photoparoxysmal response. Based on both clinical and EEG response, valproate was the most effective treatment for reducing or eliminating seizures and improving the EEG; 9 patients tried valproate and 66% had significant improvement or resolution of seizures. None of the nine patients on levetiracetam or seven patients on lamotrigine monotherapy achieved seizure control, though three patients had improvement with polypharmacy.

UC granted $1.75 million to develop potential cures for acquired epilepsy

Research scientist Jianxiong Jiang, PhD, doesn’t just want to treat acquired epilepsy…he hopes to prevent it.

“Epilepsy is a common neurological condition that afflicts nearly three million Americans and 50 to 60 million people globally. The disease is featured by epileptic seizures due to unusual hypersynchronization and hyperexcitability of a group of brain neurons,” says Jiang, an assistant professor at the University of Cincinnati (UC) James L. Winkle College of Pharmacy.

Jiang is the principal investigator on a $1.75 million grant from the National Institute of Neurological Disorders and Stroke (#R01NS100947) for a five-year preclinical study on the signaling pathways underlying the development of acquired epilepsy. Unlike the genetic forms of epilepsy, acquired epilepsy often directly results from neurological insults such as strokes, traumatic brain injuries, brain infections and brain tumors.

Jiang will track the alterations of some key inflammatory mediators within the brain in animal models and study their potential roles in the development of acquired epilepsy. Jiang says he feels confident that the goal of “no seizures, no side effects, no comorbidities” in the management of epilepsy will be ultimately achieved one day through the collaborative efforts among the epilepsy research community: “Successful completion of this study might lead to the identification of novel molecular targets for the prevention strategies of acquired epilepsy.”

Press Release: WVU Medicine Offers New Seizure-Reducing Device For Drug-Resistant Epilepsy

Another option besides medication is now available for adult and pediatric WVU Medicine patients with drug-resistant epilepsy. The new physician-guided SenTiva nerve stimulation device is implanted under the skin of the chest and sends mild electrical impulses to the brain to reduce the number of seizures, lessen the duration of seizures, and enable a faster recovery.

“This therapy shows our commitment at WVU Medicine to offering the latest and most advanced surgical interventions for epilepsy to our patients,” WVU Medicine neurosurgeon Nicholas Brandmeir, M.D., said. “SenTiva has the potential to improve seizure outcomes, provide more accurate monitoring of patients, and decrease the risk of sudden death from an epileptic seizure.”

Manufactured by the global medical technology company LivaNova, the SenTiva implantable generator is the first FDA-approved vagus nerve stimulation (VNS) therapy for use in patients age four and older. The coin-sized device is placed under the skin beneath the collar bone, and unseen wires connect it to the vagus nerve in the neck. The SenTiva generator is controlled by a wireless wand and a tablet to adjust therapy as needed. The device also monitors heart rate variations and a patient’s body position, which are commonly associated with seizures. When a patient feels a seizure coming on, he or she can activate the mild electrical impulses by holding a small magnet over the device implanted in the chest.

SenTiva is different from previous VNS generators in that it provides more specialized programming abilities. Based on each patient’s needs, a WVU Medicine adult or pediatric neurologist sets the frequency and duration of the electrical pulses on the device, and the patient typically goes about his or her normal routine unaware that any stimulation is occurring. Patients usually go home the same day as the procedure, but some may need to stay overnight for observation.

Study: Stiripentol improves long-term seizure frequency in 50% of patients with Dravet Syndrome: a 12-year observational study

Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, a Developmental Medicine & Child Neurology study found.

OBJECTIVE: To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome.

METHOD: A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded.

RESULTS: Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate.

INTERPRETATION: Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds: Frequency of status epilepticus is reduced in 40% of patients with Dravet syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs.

Clinical Trial: Neuroimaging Biomarker for Seizures

Brief Summary: This multi-site study will examine patients with epilepsy (ES) following head injury [i.e., posttraumatic epilepsy (PTE)] and posttraumatic psychogenic Non-epileptic seizures (PNES) and will compare them to patients with traumatic brain injury (TBI) who do not have seizures using functional neuroimaging.

Detailed Description: Numerous Veterans and civilians have seizures, which can be epileptic or nonepileptic in nature. Epileptic seizures are caused by abnormal brain cell firing. Nonepileptic seizures appear similar to epileptic seizures, but are associated with traumatic experiences and underlying psychological stressors. Both types of seizure are common and disabling, and many patients with seizures do not have adequate control resulting in loss of quality of life.

Impact: This grant application for the first study investigating mechanisms of PNES and PTE will provide increased understanding of neural circuitry in PTE and PNES, which can inform PTE and PNES treatments and could change clinical neurologic and psychiatric practice for PTE and PNES.

Anticipated study start date: March 1, 2018
Primary completion date: March 2021
Estimated study completion date: September 2011

Eligibility Criteria

Inclusion Criteria:

Inclusion criteria for PNES, ES and TBI (w/o PNES or ES) participants

  • Individuals with history of documented TBI (any severity).
  • Males and Females ages 18-60 years .
  • Women of child bearing potential, if currently using appropriate contraception.


Inclusion criteria of PNES and ES participants

  • Diagnosed by video/EEG with lone PNES or by EEG with lone ES.
  • Patients must have at least 1 PNES or 1 ES during the year prior to enrollment.


Exclusion Criteria:

Exclusion Criteria of PNES, ES and TBI (w/o PNES or ES) participants

  • Current or past year self-injurious behavior.
  • Current suicidal intent (BDI suicide question 9 score of >1).
  • Current or past year psychosis.
  • Pending litigation or current application for long term disability.
  • Active substance or alcohol use disorder (dependence), in past 3 months.
  • Serious illness requiring systemic treatment or hospitalization; the participant either completes therapy or is clinically stable on therapy, for at least 30 days prior to study entry.
  • Inability to fill out the self-report surveys.
  • Women who are or/are attempting to become pregnant during the study.
  • Ineligible or unwilling to complete MRI imaging.
  • Inability to document TBI.


Exclusion Criteria for PNES and ES participants

  • Inability or unwillingness to participate in CBT and assigned homework.
  • Currently enrolled in cognitive therapy aimed at PNES (Current CBT or other psychotherapy may be administered).
  • Concurrent mixed ES/PNES or equivocal video/EEG findings in discerning between ES and PNES will not be enrolled.

Study: CaV3.2 Calcium Channels Drives Sustained Burst-firing, which is Critical for the Spread of Absence Seizures in Reticular Thalamic Neurons

This research included the efforts of CURE grantee Stuart Cain.

Study findings support a role for thalamic reticular nucleus CaV3.2 T-type channels in spreading thalamocortical network seizures and setting the pacemaking frequency of SWDs.

Objective: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation (the spread of the seizure) and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN.

Methods: Pathophysiological contributions of CaV3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings.

Results: TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV3.2 mutation-sensitive splice variant. In vivo knock-down of CaV3.2 using direct thalamic injection of lipid nanoparticles containing CaV3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures.

News from Abroad: Xenon Pharmaceuticals Advances Second Proprietary Epilepsy Product into the Clinic with Initiation of XEN901 Phase 1 Clinical Trial

BURNABY, British Columbia — Xenon Pharmaceuticals Inc., a clinical-stage biopharmaceutical company, today announced the initiation of a Phase 1 clinical trial of its proprietary epilepsy product candidate, XEN901, which is an orally administered, small molecule, highly selective Nav1.6 sodium channel inhibitor. The Clinical Trial Application (CTA) for XEN901 was accepted by the Medicines & Healthcare products Regulatory Agency (MHRA) in the United Kingdom (UK), and the first subject has now been dosed in the Phase 1 clinical trial.

XEN901 is a potent, highly selective Nav1.6 sodium channel inhibitor being developed by Xenon for the treatment of epilepsy, including treatment resistant adult and pediatric focal seizures, as well as rare, pediatric forms of epilepsy, such as EIEE13, an early infantile epileptic encephalopathy associated with gain-of-function mutations in the SCN8A gene, which encodes the Nav1.6 sodium channel.

Dr. Simon Pimstone, Xenon’s President and Chief Executive Officer, said, “With the initiation of the XEN901 Phase 1 clinical trial, Xenon now has two anti-epileptic therapeutics in clinical development, each highly validated and with novel mechanisms of action. We believe this further supports our efforts to become a leader in the development of therapeutically differentiated alternatives to the anti-epileptic medications currently available, and we believe that XEN901 is the only selective Nav1.6 inhibitor currently in clinical development. Non-selective sodium channel inhibitors are broadly used for the treatment of focal seizures but are limited by their narrow therapeutic window. We anticipate that XEN901, as a highly selective Nav1.6 inhibitor, could offer an efficacious treatment with a better therapeutic index due to its improved target selectivity.”

Press Release: Final data from long-term study of CombiGene’s epilepsy treatment indicate clearly positive effects in the form of fewer and shorter seizures

Final data from CombiGene’s preclinical proof-of-concept-study (the long-term study) show that CombiGene’s candidate drug, CG01, has clear antiepileptic effects. The study has demonstrated that CG01 reduces the frequency and duration of epileptic seizures in treatment-responsive animals. A couple of the animals were completely free of seizures after being treated. No side effects have been observed in the study.

The study, which began in April 2017, has been conducted at Lund University under the direction of Professor Merab Kokaia, one of CombiGene’s scientific founders and head of the Epilepsy Centre at Lund University’s Faculty of Medicine. The principal aim of the study is to provide additional evidence of the antiepileptic effect of CombiGene’s candidate drug.