This month’s epilepsy news includes a recent study that documents the potential risk of suicide in people with epilepsy who experience hallucinations and what treating physicians can do to intervene. Another important study for clinicians and families to be aware of suggests that there may be an increased risk of death among Alzheimer’s patients who take antiepileptic drugs (AEDs).

In FDA news, Fintepla® (fenfluramine) was approved for the treatment of seizures associated with Dravet syndrome in patients age 2 and older. While this is exciting news, we recommend that families considering this treatment option review the full FDA statement first.

Lastly, highlights from two interesting studies are presented. The first suggests an unexpected therapeutic effect of listening to Mozart’s piano compositions in people with epilepsy. The second details the development of a novel noninvasive method of mapping seizure foci in preparation for epilepsy surgery.

Summaries of these research discoveries and news highlights are below.

Research News

• Hallucinations and Suicide Risk: Approximately 8% of people with epilepsy experience hallucinations unrelated to their seizures. This study showed that 65% of these individuals had a diagnosable mental illness and 53% had attempted suicide at least once. The data suggest that hallucinations are critical markers of suicide risk and emphasize the importance of clinicians routinely asking about hallucinations and assessing the mental state of their patients with epilepsy. Learn more
• Alzheimer’s Disease and Antiepileptic Drugs: A Finnish study suggests that use of AEDs increases the rate of death among those who suffer from Alzheimer’s disease. According to this study, older AEDs increase the probability of death compared to more recently developed ones. Although researchers cautioned that the reasons for prescribing the AED could partly explain the data, they also stressed the need for close monitoring of adverse effects. Learn more
• New Therapy for Dravet Syndrome Approved: The FDA recently approved Zogenix’s Fintepla® (fenfluramine) for the treatment of seizures associated with Dravet syndrome in patients older than 2 years of age. Individuals who are prescribed this drug do need to undergo cardiac monitoring, due to the risk of two specific cardiac concerns. Learn more
• The Magic of Mozart: An intriguing yet preliminary study found that daily listening to one of Mozart’s piano sonatas reduced the frequency of seizures in people with epilepsy. Importantly, nothing else was changed, including the dosage of their AEDs. While these results are promising, the next step is to conduct larger studies with more patients over a longer period of time. Learn more
• Epilepsy Surgery: A recently described approach to finding the area in the brain responsible for a person’s seizures does not require invasive brain surgery, but instead combines artificial intelligence and 76 scalp electrodes. This method has been shown to be just as effective at pinpointing the location and extent of the seizure source as implanted electrodes. Learn more

National funding for epilepsy research is in jeopardy. Scientists are facing extreme challenges due to COVID-19 and its impact on funding. Critically important research hangs in the balance. Donate today to support continued scientific progress aiming to create a world without epilepsy.

Abstract, published in Seizure

Purpose: This study aimed to analyze the therapeutic effect of sirolimus on seizures in pediatric patients with tuberous sclerosis.

Methods: Researchers first compared the efficacy of controlling seizures in all patients after they had taken sirolimus for one year, and then we performed a subgroup analysis based on whether the administered antiepileptic drugs (AEDs) were changed to determine whether the efficacy was associated with changes of AEDs.

Results: A total of 91 eligible children were enrolled. The response rate was 78.0% (71/91), and 47.2% (43/91) of all patients were became seizure-free. The improvement in seizure control before and after treatment with sirolimus was significant. In the AEDs unaltered group, 34 were responders (34/45, 75.6%), of which 24 were seizure-free (24/34, 70.6%). In the AEDs-altered group, 37 were responders (37/46, 80.4%), of which 19 were seizure-free (19/37, 51.4%). There was no significant difference between the two groups for reductions in rate of seizure frequency. In the patients with refractory epilepsy, treatment with sirolimus was also effective. Further analysis showed that age was an important factor affecting outcome of epilepsy.

Conclusions: Sirolimus has a significant effect on seizures associated with tuberous sclerosis complex (TSC), with no or only moderate adverse events after long-term administration. Sirolimus could be used as the first-line medication for pediatric patients with TSC-associated epilepsy.

Abstract, published in Epilepsy Research

Purpose: To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to brivaracetam in the add-on treatment of focal-onset seizures. Focal seizures are those that begin in a single area of the brain, which can then spread to the rest of the brain (secondarily generalization) and often be accompanied by violent convulsions (tonic-clonic).

Results: Eight RCTs (four comparing perampanel to placebo and four comparing brivaracetam to placebo) were included. For patients taking concomitant levetiracetam (Keppra®), which is chemically similar to brivaracetam, perampanel showed a significantly better responder rate compared to brivaracetam. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found.

Conclusions: Perampanel and brivaracetam are effective for the add-on treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam.

Abstract, published in Epilepsia

Objective: The RNS System® is a direct brain-responsive neurostimulation system that is approved by the US FDA for adults with drug-resistant seizures that begin in one area of the brain, based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System.

Results: One hundred fifty patients met the criteria for analysis. The average reduction in seizures was 67% at 1 year, 75% at 2 years, 82% at 3 years or more, and 74% at last follow-up (average = 2.3 years). Thirty-five percent of patients had a ?90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, location of seizure onset, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9%; five of the six patients had an implant site infection, and one had a bone infection. Lead revisions were required in 2.7%, and 2.0% of patients had a subdural hemorrhage (a collection of blood outside the brain), none of which had long-lasting neurological consequences.

Significance: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming of the RNS device.

Abstract, published in Epilepsy & Behavior

Purpose: Lamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with dizziness, impaired coordination, and double vision may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when seen in the emergency department (ED), leading to unnecessary cost and delayed management. We investigated the frequency of stroke evaluation for symptoms associated with LTG toxicity and attempted to identify factors leading to this expensive evaluation.

Results: Thirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their average age was 62 years (range: 43-79) as compared with 47 years for all patients treated with LTG. The average daily LTG dose was 621 mg (range: 300-900 mg). A LTG serum concentration was requested on the day of evaluation in 7 instances, though the result was never available until at least the next day. In 4 instances, the LTG level was drawn 1-3 days after the patient had been seen. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration >20.

Conclusions: Emergency departments will frequently call a stroke alert for patients taking LTG and having symptoms consistent with LTG toxicity, particularly in seniors at greater risk of stroke. This adds not only expense but also radiation and contrast exposure from computed tomography (CT) studies. We recommend that a rapid LTG assay be made available and always ordered in patients receiving LTG, avoiding the considerable expense of an unnecessary stroke evaluation.

Abstract, published in Epilepsy & Behavior

Objective: Delayed or missed doses are unavoidable in the pharmacotherapy of epilepsy and significantly compromise the efficacy of antiepileptic drug treatment. An inappropriate remedial regimen can cause seizure relapse or serious adverse events. This study investigated the effect of delayed or missed doses on the metabolism of valproic acid (VPA) in patients with epilepsy and established remedial dosing recommendations for nonadherent patients.

Methods:. The following four remedial strategies were investigated for each delayed dose: A) A partial dose or a regular dose is taken immediately; a regular dose is taken at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed dose and a partial dose are taken; the next scheduled time is skipped, and the regular regimen is resumed. D) Double doses are taken when missed one dose or two doses, and the regular regimen at the subsequent scheduled time is resumed.

Results: The recommended remedial dose was related to the delay duration and daily dose. Remedial dosing strategies A and B were almost equivalent, whereas strategy C was recommended when the delayed dose was close to the next scheduled dose. strategy D was only suggested for delayed two doses.

Press release, published by Monash University

In 2010, Professor Patrick Kwan from Monash University’s Department of Neuroscience, led an international team researching the causes and outcomes of epilepsy patients in rural China. A decade later the results indicate that at least one million Chinese people with epilepsy could be candidates for a standard operation that may leave them seizure-free.

The study, published in Neurology, incorporated 600 epilepsy patients from across four rural provinces in China from July 2010 and December 2012, with each participant undergoing an MRI and other tests looking for abnormalities in brain imaging. Of those, 108 were found to have lesions that could potentially be cured by surgery.

“In a best-case scenario, around 70-80% of them would be seizure-free – often after enduring seizures uncontrolled by medications for 20 years or more,” Professor Kwan said.

The participants were assessed by local primary care doctors trained by provincial neurologists in main hospitals to use a standardized questionnaire and take patient histories. The patients then traveled to provincial centers to have tests including MRIs and blood taken, for use in later research into genetic causes for epilepsy.

Professor Kwan said those patients identified as potential surgery candidates would need to undergo further tests including video-EEGs and neuropsychological assessments to ensure surgery would be effective, with the actual operation only taking three to four hours.

The same standard operation is carried out for suitable patients routinely around the world including Australia, UK and US.

“Extrapolating out the study results, potentially at least a million people could benefit from the operation – that’s a huge surgical treatment gap,” Professor Kwan said. “These findings are significant, highlighting the magnitude of the unmet needs for epilepsy surgery in China.

“Hopefully this information demonstrates a quantifiable need. By raising awareness we hope to influence policymakers to provide more resources in epilepsy care, including proper evaluation in specialist centers and proceeding to surgery if deemed appropriate.”

###

The multicenter study was conducted with international collaborators in London, Shanghai and Beijing, and was funded by the National Institutes of Health (US) and Chinese Ministry of Science and Technology.

The statistical analysis in the study was conducted by Dr Zhibin (Ben) Chen (joint first author) from Monash University’s Department of Neuroscience. Also instrumental in the study were; joint first author Dr Indran Davagnanam, Dr Chandrashekar Hoskote, Professor John Duncan and Professor Josemir (Ley) Sander from UCL, Dr Wenzhi Wang from Beijing Neurosurgical Institute, and Associate Professor Ding Ding from Shanghai’s Fudan University.

Professor Kwan is a medical specialist in neurology, an internationally recognized expert in epileptology and antiepileptic drug development, and is the head of the Comprehensive Epilepsy Program at the Alfred Hospital in Melbourne.

For Media Enquiries please contact:

E: media@monash.edu
T: +61 (0) 425 725 836

Summary, published in Epilepsy Open

Objective: To evaluate the success of initiation of “add-on” brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam.

Methods: In this retrospective non-interventional study conducted in specialized epilepsy centers across Germany, patients initiated “add-on” brivaracetam between 15 February and 31 August 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months and withdrew at least one AED either before/within 6 months after brivaracetam initiation.

Results: 506 patients had at least one brivaracetam dose and were included in the safety set (SS). 470 patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation and were included in the full analysis set (FAS) for effectiveness analyses. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (Keppra® [(49.4%)]. 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure-free. In the SS, 34.6% of patients reported treatment-emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug-related. Incidences of behavioral AEs before and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs).

Significance: Brivaracetam was effective and well-tolerated in patients who required a change in AED drug regimen and initiated “add-on” brivaracetam in German clinical practice.

Abstract, published in Seizure

Purpose: For status epilepticus, the choice of antiepileptic drugs for second-line treatment after benzodiazepine remains controversial: although both phenytoin and fosphenytoin are recommended, it not unknown which is better. Using a nationwide inpatient database in Japan, we compared the efficacy and safety of these two drugs.

Method: An observational study identified adult patients who had been admitted for status epilepticus and who had received intravenous diazepam (Valium®) on the day of admission from January 1, 2011 through December 31, 2015.

Results: The analysis examined data from 5265 patients: 2969 patients received phenytoin; 2296 received fosphenytoin, on the day of admission. No significant difference was found for use of a vasopressor, which is a drug to treat low blood pressure, or for mechanical ventilation, on the day of admission; in-hospital mortality; length of hospital stay; or total hospitalization cost. Higher age, comorbidity of cardiac diseases and lower body mass index were associated significantly with increased vasopressor use, whereas the dose of phenytoin equivalents and the choice of fosphenytoin were not.

Conclusions: This nationwide observational study found no evidence that fosphenytoin provides higher efficacy or safety than phenytoin for treatment of status epilepticus in adults after diazepam. Age, cardiac disease, and low body mass index were identified as independent risk factors for vasopressor use in both phenytoin and fosphenytoin.