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.

A female researcher with a silver ponytail looks through a microscope.

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.

Study Finds No Clear Genomic or Clinical Predictors of Lacosamide Response in Refractory Epilepsies

Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. This study examined predictors of lacosamide response in a real world clinical setting.

Methods: This research team tested the association of clinical predictors with treatment response using regression modelling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes.

Results: Most patients (479/483) were treated with LCM in addition to other AEDs. The results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. The research team then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 non-responders (less than 25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis.

Significance: No genetic predictor of lacosamide response was identified. Patients with refractory genetic generalized epilepsy might benefit from treatment with lacosamide.

Oral Cannabidiol Epidyolex Approved in Europe as Add-on Treatment for Dravet, Lennox-Gastaut Syndromes

The European Commission has approved Epidyolex (cannabidiol) as an add-on therapy to clobazam (brand names Onfi and Sympazan) for the treatment of seizures associated with Dravet syndrome and Lennox?Gastaut syndrome (LGS) in patients 2 and older.

This decision, which follows the favorable opinion of the Committee for Medicinal Products for Human Use — an arm of the European Medicines Agency (EMA) — is valid in all 28 E.U. member countries, along with Norway, Iceland, and Liechtenstein. The U.S. Food and Drug Administration had reached a similar decision to approve the treatment, under the brand name Epidiolex, in June 2018.

GW Pharmaceuticals’ Epidyolex is a purified and oral form of cannabidiol (CBD), the most common non-psychoactive cannabinoid compound in the cannabis plant. CBD is able to mimic natural compounds by acting on brain receptors, which may cause seizures when faulty.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

CBD Alleviates Seizures in Animal Model of Angelman Syndrome, a Severe Neurodevelopmental Condition

University of North Carolina School of Medicine researchers show that CBD may alleviate seizures and normalize brain rhythms in Angelman syndrome, a rare neurodevelopmental condition. Published in the Journal of Clinical Investigation, the research conducted using Angelman syndrome animal models shows that CBD could benefit kids and adults with this serious condition, which is characterized by intellectual disability, lack of speech, brain rhythm dysfunction, and deleterious and often drug-resistant epilepsy.

“There is an unmet need for better treatments for kids with Angelman syndrome to help them live fuller lives and to aid their families and caregivers,” said Ben Philpot, Ph.D., Kenan Distinguished Professor of Cell Biology and Physiology and associate director of the UNC Neuroscience Center. “Our results show CBD could help the medical community safely meet this need.”

Scientific Method Called “dCas9-Based Scn1a Gene Activation” Lessens Febrile Seizures in Dravet Syndrome Mice

Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism.

Here, researchers tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue the decrease in Scn1a gene in a mouse DS model and restore physiological levels of its gene product, the Na v 1.1 voltage-gated sodium channel. The team screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system.

This study identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Na v 1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, thus rescuing their ability to fire. To test the therapeutic potential of this approach, the team delivered the Scn1a-dCas9 activation system to DS pups using adeno-associated viruses. Parvalbumin interneurons recover their firing ability and febrile seizures were significantly attenuated.

The research team claims that their results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach in Dravet syndrome and other disorders resulting from altered gene dosage.

Epilepsy surgery: The Earlier the Better, Overview Study Suggests

Jointly with the Swedish Council for Assessment of Health Technology and Social Services (SBU), Kristina Malmgren and her colleagues have compiled a systematic literature overview and meta-analysis of studies investigating associations between early or later operations and the chances of seizure freedom. This meta-study has formed part of the basis for the national guidelines on epilepsy recently adopted by the Swedish National Board of Health and Welfare, and the results have now been published in the highly reputed journal Neurology.

Today, there is sound scientific support for the view that people with drug resistant epilepsy, compared with their prospects if they continue to receive drug treatment only, have better prospects of being seizure free, or of the frequency of attacks being greatly reduced, if they can undergo surgical treatment for their epilepsy.

“Earlier studies have shown that a lot of people who are operated on for epilepsy have had it for many years — often half their lives. It has been shown that being operated can mitigate many of the adverse consequences of the epilepsy. There are also certain studies providing evidence that the chances of post-operative seizure freedom improve if the person undergoes the surgery at an earlier stage, compared with a later one,” Malmgren says.

The meta-analysis comprises 12 studies that examined the outcomes of surgery on patients who had previously had epilepsy for between two and 20 years. The probability of being spared from attacks was 15-21 per cent higher for those who were operated on at an earlier stage. However, the authors point out that the degree of evidence for the studies included was low, since these were observation studies of only average quality. “The duration of the epilepsy is the only known predictor of freedom from attacks following surgery for epilepsy that can be influenced. The study therefore underlines the importance of people with drug resistant epilepsy being investigated for a possible epilepsy operation as soon as possible.”

Diacomit is Effective as Add-on Therapy to Reduce Refractory Seizures in Dravet, Review Study Finds

Diacomit (stiripentol) is an effective add-on oral therapy to reduce the frequency and duration of seizures in patients with Dravet syndrome, a review study has found.

The study, “Stiripentol: A Novel Antiseizure Medication for the Management of Dravet Syndrome,” was published in the journal Annals of Pharmacotherapy.

Diacomit, marketed by Biocodex, is a new type of anticonvulsive medication that has been shown to reduce the frequency of seizures in patients with Dravet syndrome, especially when administered in combination with other antiseizure medications, such as Onfi (clobazam), Depacon (valproate), and topiramate (sold as Topamax among other names), or with dietary interventions such as the ketogenic diet (low-carbohydrate, high-fat diet).

This new antiseizure therapy received the designation of orphan drug in 2001 from the European Medicines Agency, followed by its approval in Europe as an add-on therapy in 2007. The U.S. Food and Drug Administration approved Diacomit in 2018 as an add-on therapy for the treatment of seizures in children with Dravet syndrome who are 2 years of age or older and already taking Onfi.