Lisuride Shows Promise as Dravet Syndrome Treatment, Zebrafish Study Suggests

Lisuride, an anti-parkinson medicine with demonstrated anti-seizure effects, was able to stop epileptic activity in a model of convulsant Dravet syndrome zebrafish, researchers report. The study with that finding, “Drug repurposing for Dravet syndrome in scn1Lab?/? mutant zebrafish,” was published in Epilepsia.

Recent studies have used a zebrafish model of Dravet syndrome to reveal the role of pharmacologic modulation of the serotonin (5-HT) system in treating drug-resistant seizures. Serotonin is a chemical known as a neurotransmitter (used to transmit messages between nerve cells). It plays a key role in the central nervous system (CNS) and the body’s function in general.

“With the aim to bring novel therapeutics to the market together with reducing the costs associated with traditional de novo drug development, many efforts are underway to repurpose existing drugs,” researchers wrote.

As such, investigators from the University of Leuven in Belgium, preformed a literature search on already marketed medicines that could affect the serotonin system.

They found three compounds that filled these criteria: rizatriptan (a headache medicine, brand name Maxalt), lisuride (antiparkinson medicine, brand names Dopergin, Proclacam, and Revanil) and efavirenz (an anti-HIV medicine, brand name Sustiva, among others).

They then investigated the feasibility of repurposing the above-mentioned marketed medicines as anti-epileptic drugs, particularly in difficult-to-treat epilepsy conditions like Dravet syndrome.

Fenfluramine, a Serotonin-Releasing Drug, Prevents Seizure-Induced Respiratory Arrest and is Anticonvulsant in the DBA/1 Mouse Model of SUDEP

OBJECTIVE: Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure-induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure-induced respiratory arrest (S-IRA) in DBA/1 mice.

METHODS: The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz-induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi-square test.

RESULTS: Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S-IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20-40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S-IRA susceptibility occurred, which were long-lasting (less than or equal to 48 hours). The median effective dose (ED50 ) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg.

SIGNIFICANCE: This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and seizure-induced respiratory arrest susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block seizure-induced respiratory arrest selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

Omega-3 Supplementation Associated With Fewer And Shorter Seizures In Epileptics

A triple-blind trial reported in Clinical and Translational Medicine found a benefit for supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) among men and women with intractable seizures.

The trial included 50 patients with treatment-resistant epilepsy who received a placebo or 180 milligrams (mg) EPA plus 120 mg DHA twice daily for 16 weeks. Seizure frequency and duration, and blood levels of the inflammatory factors tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) were assessed at the beginning and end of the trial.

FDA to Review Cenobamate for the Treatment of Partial-Onset Seizures

The FDA has accepted for filing the New Drug Application (NDA) for cenobamate (SK Life Science), an investigational antiepileptic drug being developed for the treatment of partial-onset seizures in adults.

The NDA submission includes results from a clinical trial program which included over 1900 patients. Adjunctive treatment with cenobamate was found to significantly decrease seizure frequency in 2 well-controlled studies, however cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported in early clinical development among the first patients exposed to the drug. In December 2018, results from a large Phase 3 safety study showed that among the 1037 patients exposed to cenobamate, no cases of DRESS were identified; reducing the starting dose and slowing titration rate appeared to reduce the risk.

Pregabalin Effective in Reducing Seizure Frequency in Children with Focal Onset Seizures

In this double-blind, randomized, placebo-controlled, international study, researchers assessed the effectiveness and safety of pregabalin as adjunctive treatment for children (aged 4-16 years) with partial-onset seizures, termed focal onset seizures for this investigation. The criteria for selection included focal onset seizures and a stable regimen of 1 to 3 antiepileptic drugs. Pregabalin 2.5 mg/kg/d, 10 mg/kg/d or placebo were used in the study, with doses increased to 3.5 or 14 mg/kg/d for subjects weighing <30 kg. According to findings, pregabalin 10 mg/kg/d was effective in reducing the seizure frequency in children with focal onset seizures vs placebo, and both doses of pregabalin were generally safe and well tolerated. Common adverse events included somnolence, increased weight and increased appetite.

Ohio State Leading World’s First Study Using Focused Ultrasound to Treat Epilepsy

In a first-in-world clinical trial, researchers at The Ohio State University College of Medicine are studying how well focused ultrasound surgery works in adults with a specific type of epilepsy whose seizures are not controlled by medication.

Up to 10 adults with the “medically refractory lobe focal onset” type of epilepsy will be enrolled in this study. The technique uses magnetic resonance-guided focused ultrasound through an intact skull to reach tissue deep in the brain without incisions or radiation. With this technology, 1,024 ultrasound beams pass through the scalp, skull and brain tissue without causing any harm and converge at a focal point to ablate specific brain tissue involved in epilepsy.

“We’re pursuing this clinical trial because we know there’s a large unmet clinical need. More than 20 million people worldwide live with uncontrollable seizures because no available treatment works for them,” said neurosurgeon Dr. Vibhor Krishna, who is leading the study at The Ohio State University Wexner Medical Center and Ohio State’s Neurological Institute. “Our goals are to test the safety of this procedure and study changes in seizure frequency in these patients.”

Evidence Suggests Epilepsy Should Not Automatically Preclude Treatment with ADHD Medication

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) affects 10%-30% of individuals with epilepsy, yet concerns remain regarding the safety of ADHD medication in this group. The objective of this study was to examine the risk of acute seizures associated with ADHD medication in individuals with epilepsy.

METHODS: A total of 21 557 individuals with a seizure history born between 1987 and 2003 were identified from Swedish population registers. Within this study population, researchers also identified 6773 youth (<19 years of age) who meet criteria for epilepsy, and 1605 youth with continuous antiepileptic drug (AED) treatment.

ADHD medication initiation and repeated medication periods were identified from the Swedish Prescribed Drug Register between January 1, 2006 and December 31, 2013. Acute seizures were identified via unplanned visits to hospital or specialist care with a primary seizure discharge diagnosis in the Swedish National Patient Register during the same period. Conditional Poisson regression was used to compare the seizure rate during the 24 weeks before and after initiation of ADHD medication with the rate during the same 48 weeks in the previous year. Cox regression was used to compare the seizure rate during ADHD medication periods with the rate during nonmedication periods. Comparisons were made within-individual to adjust for unmeasured, time constant confounding.

RESULTS: Among 995 individuals who initiated ADHD medication during follow-up, within-individual analyses showed no statistically significant difference in the rate of seizures during the 24 weeks before and after medication initiation, compared to the same period in the previous year. In the full study population 11,754 seizure events occurred during 136,846 person-years and 1,855 individuals had at least one ADHD medication period.

ADHD medication periods were associated with a reduced rate of acute seizures (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.57-0.94), compared to nonmedication periods within the same individual. Similar associations were found in youth with epilepsy and continuous AED treatment, when adjusting for AEDs, and across sex, age, and comorbid neurodevelopmental disorders.

SIGNIFICANCE: This study found no evidence for an overall increased rate of acute seizures associated with ADHD medication treatment among individuals with epilepsy. These results suggest that epilepsy should not automatically preclude patients from receiving ADHD medications.

Implantable Device Shows Potential as Epilepsy Treatment

Motivated by the need for an effective and well-tolerated epilepsy therapy, a research team from the University of Ferrara and Gloriana Therapeutics has developed an implantable device that delivers high and consistent levels of therapeutic protein directly to the brain. The slender device can be implanted into diseased areas of the brain where it secretes protein through its permeable distal tip.

Giovanna Paolone and colleagues have investigated the use of this Gloriana targeted cellular delivery system to deliver glial cell line-derived neurotrophic factor (GDNF) — a protein that may help suppress epileptic activity — directly to the hippocampus of epileptic rats.

Overall, these results support ongoing development and pre-clinical evaluation of this technology, paving the way for eventual clinical translation into a new treatment for epilepsy.

Safety and Effectiveness of Stereotactic Laser Ablation for Epileptogenic Cerebral Cavernous Malformations

OBJECTIVE: Magnetic resonance (MR) thermography-guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs.

METHODS: We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow-up.

RESULTS: All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5-52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow-up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure-free from SLA alone became so following intracranial electrode-guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling.

SIGNIFICANCE: In a consecutive retrospective series, magnetic resonance thermography-guided stereotactic laser ablation was an effective alternative to open surgery for epileptogenic cerebral cavernous malformations. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. Stereotactic laser ablation presents no barrier to subsequent open surgery when needed.

FDA Approves First Generic Version of Sabril to Help Treat Seizures in Adults and Pediatric Patients with Epilepsy

The FDA approved the first generic version of Sabril (vigabatrin) 500 mg tablets for treating complex partial seizures, also called focal seizures, as an adjunctive therapy in patients 10 years and older who have responded inadequately to several alternative (refractory) treatments.

“Prioritizing the approval of generic drugs to compete with medicines that face little or no competition is a key part of our efforts to support access and reduce drug costs to patients,” said FDA Commissioner Scott Gottlieb, MD. “The availability of high-quality generic alternatives of critically important medicines, once the period of patent protection or exclusivity has ended on the brand drug, helps advance access and saves consumers billions of dollars each year.”

Dr. Gottieb goes on to say, “We know there has been past interest in developing a generic alternative to this product. Earlier this year, we also highlighted this drug, along with many others, on a list of off-patent, off-exclusivity branded drugs without approved generics, to clarify that there were no patents or exclusivities that should impede its approval.

“Today’s action demonstrates that there is an open pathway to approving products like this one. We’re especially focused on new policies aimed at making the generic review process more predictable, efficient and lower cost so we can entice more generic firms to enter this space, and help facilitate more generic drug launches after generic approvals. We know it’s not enough just to approve a record number of generic medicines. We also want to see firms launch these products so that patients can benefit from their availability, and we intend to take steps to advance these goals.”