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.

The Winner by a Nose: Intranasal Midazolam

OBJECTIVE: To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs).

METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial ( ClinicalTrials.gov NCT01390220) with patients aged at least 12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours and time to next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout.

RESULTS: Of 292 patients administered a test dose, 262 patients were randomized and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = .0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = .0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = .0124). Sixteen (5.5%) patients discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced at least 1 TEAE.

SIGNIFICANCE: The midazolam administered as a single-dose nasal spray was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an seizure clusters in the outpatient setting and was associated with a favorable safety profile.

Antiepileptic Drugs: Evolution of Our Knowledge and Changes in Drug Trials

This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States.

The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints.

The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology.

The last period (1989-2019) was dominated by the introduction of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials.

Better Seizure Control with Ketogenic Diet in Infants with Genetic Epilepsy

Infants and young children with epilepsy due to a confirmed genetic abnormality had a better response to treatment with ketogenic diet compared to patients with other types of epilepsy, according to a review of 10-year experience at Ann & Robert H. Lurie Children’s Hospital of Chicago. Results were published in Scientific Reports.

“Overall, we observed that ketogenic diet continues to be a safe, effective and well-tolerated treatment for patients under 3 years of age with drug-resistant epilepsy,” says study author John Millichap, MD, an epilepsy specialist at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Based on our experience, clinicians could consider offering ketogenic diet earlier to infants diagnosed with genetic epilepsy, perhaps even before it becomes clear that the patient is not responding to anticonvulsant medication.”

Ketogenic diet is a high fat, low carbohydrate and protein restricted diet that is rigorously medically supervised. It is widely recognized as an effective treatment for epilepsy that does not respond to medications.

“The ketogenic diet helps control seizures by reducing fluctuations of blood sugar, which reduces hyper-excitability in the brain,” explains Dr. Millichap. “At Lurie Children’s we have used it since 1963.”

Antiepileptics Not Found to Improve Neurologic Outcome, Reduce Seizures in Spontaneous ICH

Antiepileptic drugs such as phenytoin, levetiracetam, and valproic acid may not result in improvements in neurologic outcomes or reductions in seizure activity in patients with spontaneous intracerebral hemorrhage (ICH), study results published in the Annals of Emergency Medicine suggest.

The study was a meta-analysis of 8 trials that included 4211 adult patients with spontaneous ICH. Only studies that compared prophylactic antiepileptic therapy vs no preventive therapy were included in the analysis.

A limitation of the meta-analysis was the inclusion of predominantly observational and retrospective studies.

The findings from this study do not appear to “support routine use of an antiepileptic drug for primary seizure prevention in adults with spontaneous intracerebral hemorrhage.” The study investigators do, however, believe that “there remains a need for further randomized data with consideration of patient injury severity.”

Is it a Tie at This Point in the Game? Efficacy of Levetiracetam and Phenytoin for the Second-Line Treatment of Convulsive Status Epilepticus

BACKGROUND: Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of pediatric convulsive status epilepticus in the United Kingdom; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of pediatric convulsive status epilepticus.

METHODS: This open-label, randomized clinical trial was undertaken at 30 United Kingdom emergency departments at secondary and tertiary care centers. Participants aged 6 months to less than 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomization schedule to receive levetiracetam (40 mg/kg over 5 minutes) or phenytoin (20 mg/kg over at least 20 minutes), stratified by center. The primary outcome was time from randomization to cessation of convulsive status epilepticus, analyzed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomization and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.

FINDINGS: Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomized participants were treated and had available data: 152 allocated to levetiracetam and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomization to cessation of convulsive status epilepticus was 35 minutes (interquartile range: 20 to not assessable) in the levetiracetam group and 45 minutes (24 to not assessable) in the phenytoin group (hazard ratio: 1.20, 95% confidence interval: 0·91-1.60; P = .20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral edema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]).

INTERPRETATION: Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of pediatric convulsive status epilepticus.

Shortage of Epilepsy Medicine to Continue Until End of October, Manufacturer Says

Teva has announced that its epilepsy medicine Gabitril will be out of stock in the UK until the end of October 2019 as part of a “Europe-wide issue”.

All strengths of the epilepsy medicine Gabitril (tiagabine; Teva) will be out of stock in the UK until the end of October 2019, the drug’s manufacturer has said.

In a statement by the Epilepsy Society, a UK charity for patients with epilepsy, published on 20 August 2019, Teva said it had extended its return to market date from 30 September 2019 to “the end of October [2019]” as a result of issues in the manufacturing process that it said are out of its control.

Teva’s statement added that the 10mg Gabitril tablets “may experience further disruption in supply in early 2020”.