High Incidence of Persistent Subtherapeutic Levels of the Most Common AEDs in Children with Epilepsy Receiving Polytherapy

BACKGROUND: Low levels of AEDs can be secondary drug-drug interactions or related to irregular intake due to poor treatment adherence. This latter behavior is highly suspected in ambulatory pediatric epileptic patients when controls of AEDs are subtherapeutic. However, it cannot be considered for inpatients during long periods of hospitalization. A few isolated case reports have documented persistent low levels (PLL) of AEDs in hospitalized epileptic children, but no population study has currently been reported.

OBJECTIVE: The aim of this study was to document the incidence of PLL of the most common AEDs – phenytoin (PHT), phenobarbital (PHB), valproic acid (VA), and carbamazepine (CBZ) – in pediatric epileptic in- and outpatients (PEP).

METHODS: 21,040 plasma levels of the aforementioned AEDs from 3279 PEP were retrospectively analyzed. Plasma levels of AEDs were measured by an automated method using trademarked commercial kits with their corresponding quality control programs. Randomized samples were also controlled by HPLC methods. Only cases with more than 3 controls were included in the study.

RESULTS: A high rate of PLL of PHT was detected in in- (71.7%) and outpatients (74.1%), while PLL of PHB, VA, and CBZ were detected in a lower proportion. Rates of PLL of PHT were similar in in- and outpatients. PLL of PHB was more commonly observed in outpatients while PLL of VA and CBZ were more frequently seen in inpatients. In some hospitalized patients receiving polytherapy, PLL of at least one AED were documented during a long time.

DISCUSSION: Treatment non-adherence could be present in part of the outpatients, but cannot explain the persistent low levels observed in a group of inpatients as described here. The recently described “pharmacokinetic hypothesis” of pharmaco-resistant epilepsy should be addressed in cases with antiepileptic drug persistent low levels, particularly in hospitalized cases. Perhaps, instead of stopping the subtherapeutic medication, the increasing doses of this antiepileptic drugs and/or administration of inhibitors of CYP and P-glycoprotein, could help to achieve its therapeutic range, allowing a better pharmacologic effect and avoiding the development of more severe complications, such as status epilepticus or SUDEP.

History of Depression and Psychosis Increases Risk of Developing Intolerable Psychiatric and Behavioral Side Effects to Antiepileptic Drugs


PURPOSE: To determine rates of cross-sensitivity of intolerable psychiatric and behavioral side effects (IPBSEs) among commonly used antiepileptic drugs (AEDs) in adult patients with epilepsy.

METHODS: IPBSE was defined as a psychiatric or behavioral side effect attributed to AED use that led to a decrease in dose or cessation of an AED. Cross-sensitivity was calculated and was defined as the likelihood of developing IPBSE to a specific AED given IPBSE to another AED. Our sample consisted of 2312 adult patients that were prescribed 2 or more AEDs. Non-AED confounders and were controlled for in all analyses.

RESULTS: Among the 2312 patients, 20.2% of patients who had taken at least 2 AEDs had IPBSE(s) attributed to at least one AED; 3.5% had IPBSE to two or more AEDs. History of treated depression and psychosis were found to be significant predictors (p < 0.001) of developing IPBSE and were controlled for in all AED-specific analyses. Cross-sensitivity was seen between LEV and ZNS (p < 0.001). There was a significant increase in odds of experiencing IPBSE to LEV (41.5%; OR = 2.7; p < 0.001) or ZNS (22.1%; OR = 3.5; p < 0.001) given a patient had IPBSE to another AED compared to having no IPBSE to other AEDs (20.5% and 7.5%, respectively). CONCLUSION: History of depression and psychosis increased risk of developing intolerable psychiatric and behavioral side effects to antiepileptic drugs. The probability of experiencing intolerable psychiatric and behavioral side effects increased for a patient taking levetiracetam or zonisamide if the patient experienced intolerable psychiatric and behavioral side effects to another antiepileptic drugs. Our results may be clinically useful for predicting intolerable psychiatric and behavioral side effects associated with certain antiepileptic drugs.

Clinical Trial: Assessment of Effect of Vagal Nerve Stimulator (VNS) on Electrocorticograms Recorded by Responsive Neurostimulator (RNS) in Patients With Drug Resistant Epilepsy

Brief Summary: This study will investigate whether a Vagal Nerve Stimulator (VNS) causes measurable desynchronization and reduces epileptiform activity, such as spikes and seizures, in electrocorticograms (ECOGs) recorded by a Responsive Neurostimulator (RNS) in patients who have both devices implanted.

Specific aims of the study:

  • Evaluate the change in frequency of epileptiform discharges during active VNS stimulation compared to interstimulation baseline periods
  • Evaluate the change in frequency of seizures during active VNS stimulation compared to interstimulation baseline periods
  • Evaluate the change in the number of RNS activations during active VNS stimulation compared to interstimulation baseline periods
  • Evaluate the change in synchronization of background ECoG (electrocorticogram) during VNS stimulation compared to interstimulation baseline periods


Estimated study start date: August 1, 2018
Estimated study completion date: December 1, 2018

Eligibility Criteria:

Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: Yes
Sampling Method: Non-Probability Sample

Inclusion Criteria:

  • A patient of the University of Colorado Hospital Epilepsy clinic;
  • Have had either VNS and/or RNS implanted;
  • Age 18 years to 75 years.


Exclusion Criteria:

  • Not capable of making a medical decision;
  • Unable to comprehend study details, or
  • Unable to adequately communicate secondary to intellectual or language barrier.


Xenon Expands Ion Channel Neurology Pipeline With Addition Of Xen496, A Phase 3 Ready Potassium Channel Modulator For The Treatment Of Epilepsy

Xenon Pharmaceuticals Inc., a clinical stage, neurology-focused biopharmaceutical company, today reported the expansion of its ion channel product pipeline with XEN496 (active ingredient ezogabine), a Kv7 potassium channel modulator for the potential treatment of epilepsy. Based on feedback from the U.S. Food and Drug Administration (FDA), Xenon anticipates initiating a single, pivotal Phase 3 clinical trial in approximately mid-2019 examining XEN496`s efficacy as a precision medicine treatment of KCNQ2 epileptic encephalopathy (KCNQ2-EE) or EIEE7, which is a rare, severe, pediatric epilepsy caused by loss-of-function missense mutations in the KCNQ2 gene that encodes for the Kv7.2 channel. Published case reports where physicians have used ezogabine in infants and young children with KCNQ2-EE suggest that XEN496 may be efficacious in this often hard-to-treat patient population.

Ezogabine, also known as retigabine, is the only anti-epileptic drug previously approved by the FDA with a mechanism of action that potentiates Kv7-mediated potassium current. Ezogabine was originally approved by the FDA in June 2011 as an adjunctive treatment for adults with focal seizures with or without secondary generalization. GlaxoSmithKline (GSK) marketed ezogabine in various jurisdictions – as Potiga in the U.S. and Trobalt in Europe – but withdrew the drug from the market worldwide in June 2017 citing commercial reasons.

Dr. Simon Pimstone, Xenon`s Chief Executive Officer, said, “We have done an immense amount of diligence leading up to the addition of XEN496 to our novel and robust pipeline of ion-channel, anti-epileptic drugs. Based on feedback from key opinion leaders, advocacy groups, pre-existing literature, and promising data generated to date, we believe there is tremendous support for us to vigorously pursue the development and commercialization of XEN496 in order to reach the pediatric KCNQ2-EE patient population as rapidly as possible.”

Improving Electronic Care For Young Outpatients Who Have Epilepsy


PURPOSE: The purpose of this study was to review electronic tools that might improve the delivery of epilepsy care, reduce medical care costs, and empower families to improve self-management capability.

METHOD: We reviewed the epilepsy-specific literature about self-management, electronic patient-reported or provider-reported outcomes, on-going remote surveillance, and alerting/warning systems.

CONCLUSIONS: The improved care delivery system that we envision includes self-management, electronic patient (or provider)-reported outcomes, on-going remote surveillance, and alerting/warning systems. This system and variants have the potential to reduce seizure burden through improved management, keep children out of the emergency department and hospital, and even reduce the number of outpatient visits.

Brain-Protein Study Could Lead To New Epilepsy Drugs

Research identifying the role of a specific protein in the brain in triggering epileptic seizures could spark creation of a new family of medications to help patients with the disease, according to Dr. Gabriel Martz, director of the Epilepsy Center at the Hartford HealthCare Ayer Neuroscience Institute.

The research, published in a recent issue of the academic journal Nature Communications, suggests that the protein collybindin, previously not thought to be relevant in the brain activity that activates or inhibits seizures, could actually play a role. A new medication, he says, could target the collybindin or its binding site in the brain to help curb seizures.

“We have many drugs on the market but most work in fairly similar ways,” Dr. Martz says. “This could lead to a new way of approaching the problem and of reducing cortical excitability, which many people think is the route of the problem of seizures.”

The research, conducted by neuroscientists at the University of Nevada, Las Vegas, expands the understanding of the signaling between neurons in epilepsy. Regulating the proteins in the brain that control cell signaling may lead to better therapies for stopping or preventing seizures entirely.

“This is a new piece in a big and age-old puzzle,” Dr. Martz says. “It is a stepping-off point for other research that will likely teach us more about how the brain works and may help improve the treatment for seizures, depending on whether medications that work on this protein can be identified and would be safe to take.”

Aquestive Therapeutics Announces Tentative FDA Approval for Sympazan™ (clobazam) Oral Film

Aquestive Therapeutics, Inc. announced Sympazan™ (clobazam) oral film has received tentative approval by the US Food and Drug Administration (FDA), for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older. Currently, clobazam is marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

“We saw a need in the LGS community for a simpler, more consistent way to administer a full dose of clobazam – and we are now one step closer to bringing this important treatment to patients, caregivers and physicians,” said Keith J. Kendall, Chief Executive Officer of Aquestive Therapeutics. “This tentative approval for Sympazan is a key milestone for Aquestive, as it represents the first in a series of late stage proprietary products Aquestive plans to commercialize once they are approved. We believe Sympazan and our other products in development solve important therapeutic problems, and will meaningfully improve the lives of patients and their caregivers.”

Electronic Pump Delivers Drugs to the Brain to Stop Seizures

Researchers have engineered an electronic drug delivery tool that pumps seizure-stopping molecules directly to the source of the problem in the brain. The device, reported in the journal Science Advances, offers an alternative to conventional, systemic drugs that can cause unwanted side effects throughout the body.

The device, a microfluidic ion pump, uses an electrical potential to move drug molecules from a reservoir on the device across a short channel and out the tip of the device. The pump can be implanted in the brain at the site of a problem, such as a focal point of a seizure, where it will deliver the drug when needed.

The pump technology is based on the concept of electrophoresis: the transport of molecules through a fluid or gel under the influence of an electrical field. When a voltage is applied, electrons withdraw from the source electrode, and positively charged ions—in this case positively charged drug molecules—are driven out of the reservoir, across the ion-conducting membrane, and out of the device for delivery

ZX008 Reduces Convulsive Seizures in Majority of Patients with Lennox-Gastaut Syndrome in Pilot Study

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a drug-resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX008 (fenfluramine HCl oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open-label, dose-finding study of add-on ZX008 in patients with LGS (NCT02655198).

METHODS: Eligible treatment-refractory patients with LGS aged 3-18 years with ?4 documented convulsive seizures (CS) in the prior 4 weeks were administered adjunctive ZX008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long-term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram.

RESULTS: Thirteen patients were enrolled (mean age = 11.7 years, range = 3-17). Ten (77%) patients completed 20 weeks of ZX008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS; median reduction was 60% in the 10 completers. Eight patients (62%) had a ?50% CS reduction; three (23%) patients had a ?75% reduction. Nine (69%) patients entered the long-term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ?50% reduction, and three (33%) patients had a ?75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed.

SIGNIFICANCE: ZX008 provided clinically meaningful reduction (?50%) in convulsive seizure frequency in the majority of patients with Lennox-Gastaut syndrome in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.