Study Finds Antiepileptic Drug Withdrawal Increases the Likelihood for Epileptic Seizures but Does Not Prolong Seizure Duration

PURPOSE: To systematically evaluate the duration of focal onset seizures under medication withdrawal as a function of drug half-life.

METHODS: Adults with drug resistant focal epilepsy and invasive electroencephalographic (iEEG) recording between 01/2006 and 06/2016 (n = 128) were identified. Patients with multifocal or unknown epileptic foci were excluded, as well as subclinical seizures, isolated auras, or status epileptic. Antiepileptic drugs (AEDs) were withdrawn upon admission. The seizure duration was determined based on the invasive EEG data, and the latency since start of the monitoring was noted in hours. A negative binomial mixed model was used to compare the seizure durations before and after a cut-off, which was set at 2.5 half-lives of the individual anticonvulsive medication as this is thought to separate therapeutic and ineffective drug levels.

RESULTS: In total, 70 patients were included in the study and the duration of 672 seizures analyzed. On average, the patients were treated with 2.36 ± 0.78 AEDs. The individual cut-off of 2.5 half-lives was on average reached after 95.02 ± 80.18 h. The seizure frequency (321 vs. 351) and the rate of generalization (15.6% vs. 16.8%) was comparable before and after the individual cut-off point. The mean seizure duration was not statistically significantly prolonged after 2.5 half-lives by a factor of 1.168 for focal onset seizures (p = 0.090) and a factor of 1.091 for secondary generalized seizures (p = 0.545).

CONCLUSIONS: Although AED withdrawal increases the likelihood for epileptic seizures, it did not prolong the seizure duration, nor did it increase the rate of secondary generalization in this study.

Detecting Subtle Epileptogenic Lesions in MRI-Negative Pediatric Epilepsy

Children with drug-resistant focal epilepsy and focal cortical dysplasia who undergo complete resection of Morphometric Analysis Program (MAP)-positive regions are more likely to experience seizure-free outcomes compared with children who receive no or partial resection, according to a study published in the European Journal of Neurology.

Using a 2002 to 2015 surgical database, researchers included a consecutive cohort of pediatric patients with drug-resistant focal epilepsy and focal cortical dysplasia who underwent epilepsy surgery before 21 years of age, had a preoperative 1.5T or 3T MRI, had a negative presurgical MRI, and had 12 or more months of postsurgical follow-up data (n=78).

MAP on T1-weighted volumetric MRI was used to perform MRI postprocessing, and the researchers compared these data with an age-specific normal pediatric population (n=370). Surgical outcome and pathology data were also used to confirm the pertinence of MAP-positive areas.

Approximately 56% of patients (n=44) demonstrated positive MAP regions. In the 3- to 5-year, 5- to 10-year, 10- to 15-year, and 15- to 21-year-old age groups, the MAP-positive rates were 100% (2 of 2), 77% (13 of 17), 63% (15 of 24), and 40% (14 of 35), respectively. Approximately 45% of patients with temporal resection and 63% of patients with extratemporal resection had MAP-positive rates. Compared with patients with no or partial resection of the MAP-positive regions, patients who received complete resection of MAP-positive regions were more likely to experience a seizure-free outcome (P <.001).

Marinus Pharmaceuticals Initiates Phase 3 Study in Children with PCDH19-Related Epilepsy

Marinus Pharmaceuticals announced it is initiating a single global pivotal Phase 3 clinical study (Violet Study) evaluating oral ganaxolone in children with PCDH19-related epilepsy (PCDH19-RE), a rare genetic epilepsy. If successful, the Violet Study is intended to support the regulatory filings for approval of ganaxolone in this underserved and refractory patient population.

The Violet Study is a global, double-blind, randomized, placebo-controlled pivotal Phase 3 clinical study evaluating ganaxolone in children with PCDH19-RE. The study will enroll up to 70 patients between the age of 1 and 17 with a confirmed PCDH19 mutation. All patients that meet eligibility will be stratified into one of two biomarker groups and randomized (ganaxolone or placebo) within each stratum. The trial will consist of an 8-week prospective baseline period to collect seizure data, followed by a 17-week double-blind treatment phase.

Patients randomized to ganaxolone will titrate over four weeks to a dose of up to 600 mg of ganaxolone oral liquid suspension three times a day and maintain that dose for the following 13-weeks. After the double-blind period, all patients who meet certain eligibility requirements will have the opportunity to receive ganaxolone in an open label phase of the study. The company expects to begin screening patients for enrollment into the study in the second quarter of 2019 and data from the study are estimated to be available in 2021.

FutureNeuro Partners with UCB to Give Clinicians Insights into Epilepsy Treatments

FutureNeuro has partnered with UCB to unlock the power of healthcare data to inform improvements in clinical care of people with epilepsy.

Based on aggregated clinical data analytics, the project will provide insights into disease progression and responses to treatment, which can be used to determine risk factors and inform treatment planning for individuals living with epilepsy.

Clinicians, researchers and data scientists will collaborate to complete a feasibility study to demonstrate the potential of the Irish National Epilepsy eHealth System (Electronic Patient Record (EPR) and Electronic Patient Portal) as a tool to support better clinical analytics. Ultimately, the eHealth project has the potential to promote a model of proactive and personalised care which can prevent disease deterioration and tailor treatment to individual’s needs.

Michigan’s First Patient Treated with Thalamic Deep Brain Stimulation for Epilepsy at Henry Ford Health System

A Grayling-area man is the first in Michigan with a complete Deep Brain Stimulation (DBS) system surgically implanted for the treatment of epilepsy. Neurosurgeon Jason Schwalb, MD, with help from the team at the Henry Ford Comprehensive Epilepsy Center, implanted targeted electrodes in 32-year-old Steven Rennie’s brain on Feb. 12, and a pacemaker-like device known as an internal pulse generator in his chest on Feb. 28.  

The electrodes are attached to the internal pulse generator, their power source, via thin extension cords below the skin. Together, these components make a complete DBS system – something that provides hope for Rennie, who has not seen a significant reduction in symptoms from other epilepsy treatments.

Epilepsy-Specific Internet Intervention (Emyna) May Help Improve Mental Health and Quality of Life Among People with Epilepsy

Objective: Depression and anxiety are highly prevalent among people with epilepsy (PwE) but often remain unrecognized and treated inadequately. Effective psychosocial treatments such as cognitive behavioral therapy (CBT) are rarely available to most PwE, which is one reason electronically delivered CBT (eCBT) is regarded as promising. This study examined an eCBT intervention, termed Emyna, that was tailored to suit the needs of PwE. It includes CBT?related content on depression, stress and anxiety, seizure triggers and auras, and lifestyle habits. The trial examined the efficacy of Emyna in reducing symptoms of depression (primary outcome) and anxiety as well as improving quality of life.

Methods: Participants (N = 200) with epilepsy, a diagnosis of a depressive disorder, and at least moderate depressive symptoms were randomized to Emyna or care as usual. At baseline and after 3, 6, and 9 months, participants were invited to complete online questionnaires. The primary outcome was improvement of depressive symptoms at 3 months.

Results: Relative to the control group, intervention group participants experienced significantly greater improvements in depression, anxiety, stress, social?occupational impairment, and epilepsy?related quality of life, in both intention?to?treat (ITT) and per?protocol analyses. In ITT analyses, effects of medium magnitude were observed, as measured by the Patient Health Questionnaire–9 items (Cohen d = 0.54, 95% confidence interval [CI] = 0.25-0.82, P < 0.001) and the Neurological Disorders Depression Inventory for Epilepsy (d = 0.51, 95% CI = 0.23?0.79, P < 0.01). At 3 months, intervention group participants also reported fewer illness?related days off work and fewer days hospitalized over the preceding months, compared to control group participants, whereas no such differences were present at baseline (P > 0.30).

Significance: These findings showed that Emyna, used adjunctively to usual care, could help improve mental health, social?occupational functioning, and quality of life among people with epilepsy. The program provides an additional treatment option that could produce clinically relevant symptom reductions and reduce key cost drivers (ie, hospitalization rates and illness?related inability to work).

Invited Commentary: Ketamine Should Be Started Earlier in the Course of Human Status Epilepticus as a Neuroprotectant

Ketamine is currently being used as an anesthetic/antiepileptic drug in refractory status epilepticus. To validate its use, 2 clinical trials are recruiting patients. However, preclinical studies of its use in chemically induced status epilepticus in rodents have shown that it is remarkably neuroprotective, through N-methyl-d-aspartate–receptor blockade, even when given after the onset of status epilepticus. Human studies have shown that status epilepticus–induced brain damage can be caused by a glutamate analogue and that it occurs in the same brain regions as in the animal studies.

Researchers therefore propose that ketamine be started early in the course of human status epilepticus as a neuroprotectant and that it be continued until epileptic discharges are eliminated. Using it as an anesthetic/antiepileptic drug late in the course of refractory status epilepticus only ensures that it is given after widespread brain damage has occurred.

Neuroelectrics Announces Positive Results for Treatment of Medication-Resistant Epilepsy Using Starstim™

At the recent American Epilepsy Society Annual Meeting in New Orleans, Neuroelectrics Corporation presented positive results from its clinical trial treating patients with drug resistant epilepsy with Starstim™, a device that uses mild electric currents applied on the scalp to calm abnormal activity of the brain. Of the seventeen patients that completed the study, treatment with Neuroelectrics’ Starstim™ device resulted in a reduction in seizure frequency of at least 40% from baseline in 75% of the patients, measured eight weeks after treatment. Also, no device-related adverse events were reported during the study.

Neuroelectrics sponsored the FDA-approved investigational device study of its Starstim™ product (NCT02866240) at Boston Children’s Hospital, with adult patients being referred from nearby Beth Israel Deaconess Medical Center. A parallel study following the same protocol was conducted at the National Institute of Neurology and Neurosurgery in Mexico City.

All patients enrolled in the study had not responded to at least two anti-epileptic medications, and for many the next step would be brain surgery to resect the region of the brain where the seizures originate. The treatment protocol used 20 minutes of daily stimulation applied for 10 days times over two weeks, followed by an eight-week monitoring period to measure seizure frequency.

Cannabidiol Reduces Seizures in Patients with Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). This study is an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial.

Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.

Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). 35 patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. 88% of patients/caregivers reported an improvement in the patient’s overall condition per the Subject/Caregiver Global Impression of Change scale.

Significance: In this study, long-term add-on cannabidiol treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Zogenix Submits New Drug Application to FDA and Marketing Authorization Application to European Medicines Agency for FINTEPLA® for the Treatment of Dravet Syndrome

Zogenix, Inc. announced it has completed its rolling submission of a New Drug Application (NDA) to the FDA and submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for FINTEPLA (ZX008, low-dose fenfluramine) for the treatment of seizures associated with Dravet syndrome. Dravet syndrome is an intractable and difficult-to-treat epilepsy that begins in infancy and is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, and cognitive impairment.

Both applications are based on data from two pivotal Phase 3 trials in Dravet syndrome and an interim analysis from an ongoing open-label extension study, which included 232 patients treated for up to 21 months.