Study Provides Insights on the Effects of Cannabidiol on Severe Form of Epilepsy, LGS

Results from a study published in the British Journal of Clinical Pharmacology may help explain why cannabidiol (CBD)—a chemical component of marijuana with no psychoactive properties—reduces the frequency of seizures in patients with a severe form of epilepsy. The effect may be explained by a drug-drug interaction between cannabidiol and the anti-seizure medication clobazam.

The form of epilepsy examined in the study is called Lennox–Gastaut syndrome. Investigators conducted clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on seizure frequency in patients with this syndrome.

“The effects of cannabidiol on seizure frequency in Lennox-Gastaut patients could be explained entirely through estimated elevations of blood levels of clobazam, which might mean that cannabidiol in itself may not have any, or at best limited, antiepileptic effects,” said senior author Geert Jan Groeneveld, MD, PhD, of the Centre for Human Drug Research, in The Netherlands.

Hemispherectomy in Adults and Adolescents: Seizure and Functional Outcomes in 47 Patients

Objective: To examine longitudinal seizure and functional outcomes after hemispherectomy in adults and adolescents.

Methods: This team reviewed 47 consecutive patients older than 16 years who underwent hemispherectomy between 1996 and 2016 at our center. Clinical, electroencephalographic (EEG), imaging, neuropsychological, surgical, and functional status data were analyzed.

Results: Thirty-six patients were 18 years or older at surgery; 11 were aged between 16 and 18 years. Brain injury leading to hemispheric epilepsy occurred before 10 years of age in 41 (87%) patients. At a mean follow-up of 5.3 postoperative years (median = 2.9 years), 36 (77%) had Engel class I outcome. Longitudinal outcome analysis showed 84% seizure freedom (Engel IA) at 6 months, 76% at 2 years, and 76% at 5 years and beyond, with stable longitudinal outcomes up to 12 years from surgery. Multivariate analysis demonstrated that acute postoperative seizures and contralateral interictal spikes at 6-month follow-up EEG were associated with seizure recurrence. Patients who could walk unaided preoperatively and had no cerebral peduncle atrophy on brain magnetic resonance imaging were more likely to experience worsening of motor function postoperatively. Otherwise, postoperative ambulatory status and hand function were unchanged. Of the 19 patients who completed neuropsychological testing, 17 demonstrated stable or improved postoperative outcomes.

Significance: Hemispherectomy in adults is a safe and effective procedure, with seizure freedom rates and functional outcome similar to those observed in children.

Gene Therapy for Epilepsy Shows Promise in Animal Models

A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. The researchers demonstrated that this strategy is capable of suppressing seizures at their site of origin on demand in animal models.

The study was conducted at Charité – Universitätsmedizin Berlin, Germany and the Medical University of Innsbruck, Austria. The method is now being optimised for clinical trials.

The technique involves the selective delivery of a specific gene to nerve cells within the area of the brain where the epileptic seizures originate.

The gene is delivered via an adeno-associated virus (AAV), which then provides the cells with the information they need to synthesise dynorphins: naturally produces peptides that modulate neural activity.

Professor Christoph Schwarzer, one of the lead researchers, said: “High-frequency stimulation of the nerve cells, such as that seen at the beginning of a seizure, results in the release of stored dynorphins. Dynorphin dampens signal transduction and as a result, the epileptic seizure doesn’t spread… As the cells will only release this substance when needed, this type of gene therapy is referred to as ‘release-on-demand’.”

Using an animal model, the researchers were able to show that this gene therapy is capable of suppressing epileptic seizures for several months.

Moreover, no side effects were observed, which the researchers suggest is due to the site-specific release of dynorphin and its short duration of action.

Phases of Seizures

Kootenai Health in Idaho Unveils Epilepsy Monitoring Unit

The facility is designed to allow patients to safely experience seizures while medical staff make observations.

A state of the art facility designed to treat people with seizures has finally arrived at Kootenai Health. The facility, which required years of planning and preparation, will hopefully cut down on months-long waiting times for local patients.

Called an epilepsy monitoring unit, or EMU, the facility is designed to allow patients to safely experience seizures while medical staff make observations. Specifically, epileptic patients who are experiencing challenges treating their seizures will undergo monitoring in EMUs.

“It’s amazing. It’s absolutely amazing,” said Judy Hayton, Kootenai Health’s Neurodiagnostics lab manager, of the new facility. The hospital’s four EMU rooms opened last June.

Study Finds Fewer Google Searches for Epilepsy Surgery Over 15-Year Period

BACKGROUND: Epilepsy surgery is an effective treatment for drug-resistant epilepsy. Some centers have noticed changes in referral patterns.

AIM: The aim of this study was to determine if online infodemiological data related to epilepsy surgery reflect reported changes in referrals to surgical centers.

METHODS: Google Trends and Pageview analysis of temporal trends of searches conducted in Google and Wikipedia for epilepsy surgery, using key search terms such as “epilepsy surgery” and terms related to pathology, operation type, and investigative practice.

RESULTS: Over the 15-year time period studied by Google trend analysis, when the initial three-year epoch and final three-year epoch are compared, a 56.1% decline in search volume for “epilepsy surgery” was observed. Vagus nerve stimulation and laser ablation are increasingly searched items. Pageview analysis shows that temporal lobe epilepsy remains the most commonly searched subtype of epilepsy and hippocampal sclerosis was searched for more than focal cortical dysplasia.

CONCLUSION: This study suggests a lower search interest over time in epilepsy surgery, and various associated terms, with increased interest in vagus nerve stimulation and laser ablation procedures over time. There is no clear indication from these data regarding the apparent shift from mesial temporal cases to an increase in extratemporal case workload.

Zogenix Announces New Positive Data for Its Investigational Drug FINTEPLA® in Dravet Syndrome

Zogenix, Inc. announced positive new data for its investigational drug, FINTEPLA® (ZX008, fenfluramine), for the treatment of seizures associated with Dravet syndrome. The data were presented in five scientific posters, available here, at the recent Childhood Neurology Society (CNS) Congress. The posters include data showing long-term, clinically meaningful reduction in convulsive seizure frequency in young Dravet syndrome patients (under 6 years of age) in an ongoing Open-Label Extension (OLE) study, as well as data from a post-hoc analysis showing clinically meaningful and profound reduction in the frequency of high-risk tonic-clonic (grand-mal) seizures in Dravet syndrome patients treated in two previously completed Phase 3 clinical trials. Other data include the results of a Phase 1 study to assess the potential drug-drug interaction of fenfluramine and cannabidiol (CBD).

“These data continue to demonstrate the significant clinical impact Fintepla has shown in studies of Dravet syndrome patients,” said Bradley Galer, M.D., Executive Vice President and Chief Medical Officer at Zogenix. “These new results clearly show the impact this drug candidate has had on some of the most vulnerable patients, those who are younger than 6 years of age, as well as those suffering from generalized tonic-clonic seizures, a recognized risk factor for sudden unexplained death in epilepsy (SUDEP).”

Study Examines Which Antiepileptic Drug is Best for New-Onset Epilepsy in the Elderly

Objective: To estimate the comparative efficacy and safety of antiepileptic drugs (AEDs) in the elderly with new-onset epilepsy.

Methods: The research team searched electronic databases for randomized controlled trials (RCTs) of monotherapy AEDs to treat epilepsy in elderly. The following outcomes were analyzed: seizure freedom and withdrawal from the study for any cause at 6 and 12 months; withdrawal from the study for any adverse event (AE) at 12 months; and occurrence of any AE at 12 months. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA) and mean ranks.

Results: Five RCTs (1425 patients) were included. Included AEDs were carbamazepine immediate- and controlled-release (CBZ-IR, CBZ-CR), gabapentin (GBP), lacosamide (LCM), lamotrigine (LTG), levetiracetam (LEV), phenytoin (PHT), and valproic acid (VPA). At the pairwise and network meta-analyses, there were no differences in any of the comparison according to 6- and 12-month seizure freedom. The treatment with CBZ-IR and CBZ-CR was associated with a higher risk of withdrawal than LTG, LEV, or VPA, and CBZ-IR had the overall highest probability of discontinuation across all AEDs. According to SUCRA, the following had the greatest likelihood ranking best for seizure freedom at 6 and 12 months: LCM, LTG, and LEV. CBZ-CR and CBZ-IR had the highest probabilities of being worst for the 12-month retention. CBZ-IR, CBZ-CR, and GBP had the highest probabilities of withdrawal from the study for AEs and VPA had the highest probability of being the best-tolerated option.

Significance: Although no significant difference in efficacy was found across treatments, lacosamide, lamotrigine, and levetiracetam had the highest probability of ranking best for achieving seizure freedom. Carbamazepine immediate- and controlled-release showed a poor tolerability profile, leading to higher withdrawal rates compared to levetiracetam and valproic acid.

CURE Discovery: Understanding and Treating NMDA Receptor-Associated Epilepsy

Key Takeaways:

  • Researchers are studying whether off-label treatment with certain FDA-approved drugs can improve seizure control for individuals whose epilepsy is caused by over-activation of NMDA-R.
  • The CURE-funded team is researching previously unstudied mutations in GRIN genes and using this information to determine who might benefit from off-label treatment with NMDA-R blockers.
  • Interested families with a genetic diagnosis of a GRIN mutation and epilepsy can enroll in this important study. Contact Jenifer Sargent at Jenifer.Sargent@childrenscolorado.org for more information.

Deep Dive:

Dr. Stephen Traynelis

Can off-label use of certain FDA-approved drugs which reduce NMDA-R function

improve seizure control in patients with epilepsy caused by over-activation of NMDA-R? That is the question a CURE-funded study by Dr. Stephen Traynelis at Emory University and his team aims to answer.

Dr. Traynelis and his collaborators, Drs. Sooky Koh, Ann Poduri, and Tim Benke, will assess if epilepsy caused by over-activation of a protein in the brain, called the N-methyl-D-aspartate receptor (NMDA-R), can be improved when patients with GRIN mutations are treated off-label by their clinicians with certain FDA-approved NMDA-R blockers. They also hope to determine if treatment with these drugs has any positive effects on developmental progress in addition to improved seizure control.

NMDA-R is an essential component of electrical signaling in the brain and is made from proteins encoded by the GRIN family of genes.1 Because GRIN genes provide the blueprint for NMDA-R, mutations in these genes can impact how the NMDA-R works. Not all of these mutations cause over-activation of the NMDA-R, so in the first part of this project, the researchers are investigating each human GRIN mutation that has not been studied before by re-creating them in the laboratory and evaluating how they affect NMDA-R activity. This information will then be used to determine who might benefit from off-label treatment with drugs that reduce NMDA-R function.

People with GRIN variants that data suggest produce a strong over-activation of the NMDA-R might be candidates for treatment by their physician with NMDA-R blockers. Those with GRIN variants that reduce activity of the NMDA-R or produce complex actions which are difficult to clearly categorize would not be expected to benefit from treatment.

The investigators have created a registry where families affected by GRIN mutations can sign up to participate. The registry collects medical history data and records that are stored without any identifying information to protect the privacy of each participant. Following analysis of a patient’s mutation status, a report is shared with their clinician who will judge whether it is in the patient’s best interest to be considered for off-label treatment. Treatment could then be offered to the family and is based on treatment guidelines Dr. Traynelis and his collaborators have developed.

The team will follow up with a retrospective analysis of treatment efficacy. That is, the investigators will go back and analyze medical records, EEG data, seizure history, and other relevant data for people who received off-label treatment from their physicians to understand how well the treatment worked. This data will also allow an assessment of whether particular GRIN mutations may benefit more from the treatment than others.

This study is expected to provide data for a clinical trial that could lead to new therapies for these difficult to treat epilepsies. In a previously published study, the investigators treated a child with early-onset epileptic encephalopathy associated with a mutation in GRIN2A with the drug memantine and found a substantial reduction in his seizure burden after treatment for a year.2 Additional studies provided more mixed results, creating a need to better understand the utility of this approach.

The team is looking to enroll additional families in this important study. If you or anyone you know with a genetic diagnosis of a GRIN mutation and epilepsy are interested in participating, please contact Jenifer Sargent at Jenifer.Sargent@childrenscolorado.org to learn more about the study.

1 Hansen KB, Feng Y et. al., J Gen Physiol. 2018 Aug 6; 150(8): 1081–1105
2 Pierson TM, Yuan H et. al., Ann Clin Transl Neurol. 2014 Mar 1;1(3):190-198

Cannabis-based Zygel Helps Reduce Seizures in Childhood Epilepsy Syndromes, Trial Reports

A cannabis-based gel formulation developed by Zynerba Pharmaceuticals can significantly reduce seizures by up to six months in children and adolescents with developmental and epileptic encephalopathies, according to Phase 2 trial data.

Developmental and epileptic encephalopathies, or DEE, is an umbrella term that includes a heterogeneous group of rare pediatric epilepsy syndromes, such as Dravet and Lennox-Gastaut syndrome, among others.

The open-label BELIEVE 1 clinical trial was designed to explore the long-term safety and efficacy of Zygel in children and adolescents with DEE. To date, the study has enrolled, by invitation, 48 participants between 3 and 16 years old, who had confirmed DEE as classified by the International League Against Epilepsy.

The participants were initially dosed daily with 250 or 500 mg of Zygel, based on their weight, but the dosage could be increased up to a maximum of 1,000 mg daily. The treatment was directly applied to the skin (transdermal delivery) on the shoulders and upper arms.

Zygel was generally well-tolerated, and the safety profile was consistent with data from previous clinical studies.

NeuCyte to Advance Novel Compound for Treatment of Refractory Epilepsy and Related Neurological Disorders

NeuCyte, Inc. announced that it has entered into an exclusive license agreement with Trillium Therapeutics to advance an undisclosed preclinical compound with potential utility in treating refractory epilepsy in the form of Dravet syndrome and related disorders.

The compound covered by this agreement has demonstrated highly encouraging activity during studies conducted by the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP). It demonstrates a superior safety and anti-seizure efficacy profile over NINDS benchmark anti-epileptic drugs (AEDs) in eleven animal models. It has also demonstrated broad efficacy in NIH animal studies for pharmaco-resistant epilepsy.  As a result, this novel agent has gained the prestigious NINDS Red Book status and been selected as a promising lead drug candidate.

“This compound is an exceedingly promising antiseizure drug which, although in preclinical development, is quite efficacious in a wide variety of highly predictive seizure models,” said Roger J. Porter, MD, Adjunct Professor of Neurology at the University of Pennsylvania, former Deputy Director of NINDS, former Chairman of the White House Committee on Brain and Behavioral Sciences, and former President of American Epilepsy Society. “It may prove very effective for patients with epilepsy.” As a first-in-class compound with unique mechanism of action profiles, this drug candidate is likely to have activity across a variety of indications. The favorable efficacy and safety profile has also been validated by NeuCyte’s proprietary in vitro human iPSC-derived models.