FDA-Approved Donepezil Protects Against Seizures in a Mouse Model of Dravet Syndrome

De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. This research team previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants.

In the present study, the team evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the FDA, in a mouse model of Dravet syndrome (Scn1a +/-). The team found that donepezil conferred robust protection against induced seizures in Scn1a +/- mutants.

Study Recommends Physicians and Healthcare Providers Better Educate Patients about Epilepsy and Cannabis

INTRODUCTION: Medical cannabis is increasingly discussed as an alternative treatment option in neurological diseases, e.g. epilepsy. Supporters and opponents base their propositions mostly on subjective estimates, they confuse cannabis in whole versus extracts and botanical versus synthesized.

METHODS: Two hundred seventy five patients with any kind of epilepsy (56% female, 44% seizure free, 91% on medication) answered a survey on the knowledge, expectations, fears, and willingness to be treated with medical cannabis. Data were analyzed with regard to patient characteristics and clinical data from patient files.

RESULTS: Overall, 70.5% of the patients were familiar with the possibility of medical cannabis treatment, 36.7% with its use in epilepsy. A minority of 10.9% gained the information from their physicians. The majority knew about organic compared to synthetic cannabis. The interest in further information is high (71.3%). Regression analysis (explaining 53.8% of the variance) indicated that positive expectations (in the order of relevance) were seizure control, relaxation, mood, and tolerability whereas fears mostly concerned addiction and delirant intoxication. Men showed a greater interest than women.

CONCLUSION: Many epilepsy patients knew about medical cannabis, were interested in this treatment, and wanted more information. Expectations, however, appear to be based on the connotations of the whole substance cannabis with tetrahydrocannabidiol and its commonly known effects. Unfortunately, patients did not get their information from physicians, but mostly by other sources. In order to avoid prejudices and potentially harmful self-medication, physicians and healthcare providers are called to become familiar with the substance and to inform patients adequately.

Therapy That Targets Underlying Cause of Dravet Syndrome Gets Orphan Drug Status

The FDA has granted Orphan Drug designation to STK-001 (Stoke Therapeutics) for the treatment of Dravet syndrome.

Dravet syndrome is a severe and progressive genetic epilepsy that starts within the first year of life and often leads to cognitive regression or developmental stagnation, ataxia, and speech impairment. The disease is characterized by frequent, prolonged and refractory seizures, in which approximately 85% of cases are due to a spontaneous, heterozygous loss of function mutations in the SCN1A gene.

STK-001 is an investigational antisense oligonucleotide that works by upregulating Nav1.1 protein expression from the non-mutant (wild type) copy of the SCN1A gene to restore physiological Nav1.1 levels. STK-001 is designed to address the underlying cause of Dravet syndrome, thereby reducing the occurrence of seizures and significant non-seizure comorbidities. The Company has generated preclinical data for STK-001 to demonstrate proof-of-mechanism.

Repeated, Intermittent, Acute Treatment of Seizure Clusters with Midazolam Nasal Spray Well-Tolerated

OBJECTIVE: To evaluate safety- and seizure-related outcomes with repeated intermittent use 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: In this open-label extension trial (ClinicalTrials.gov NCT01529034), patients aged 12 years or older and on a stable regimen of antiepileptic drugs who completed the original phase III, randomized controlled trial were enrolled. Caregivers administered MDZ-NS 5 mg when patients experienced SCs; a second dose could be given if seizures did not terminate within 10 minutes or recurred within 10 minutes-6 hours. Patients were monitored for treatment-emergent adverse events (TEAEs) throughout, and the main seizure-related outcome was treatment success, defined as seizure termination within 10 minutes and no recurrence 10 minutes-6 hours after drug administration.

RESULTS: Of 175 patients enrolled, 161 (92.0%) received one or more MDZ-NS dose, for a total of 1998 SC episodes. Median time spent by patients in the trial was 16.8 months (range = 1-55.7 months). TEAEs were experienced by 40.4% of patients within 2 days of drug administration and 57.1% overall. TEAEs reported by most patients (within 2 days and overall) were nasal discomfort (12.4%) and somnolence (9.3%). One patient each discontinued due to treatment-related nasal discomfort and somnolence. There were no patients with treatment-related respiratory depression, and none with TEAEs indicative of drug abuse or dependence. Treatment success criteria were met in 55% (1108/1998) of SC episodes after administration of a single 5-mg dose and in 80.2% (617/769) with the second dose. Treatment success was consistent over treated episode number.

SIGNIFICANCE: Repeated, intermittent, acute treatment of patients experiencing seizure clusters with midazolam nasal spray in the outpatient setting was well tolerated over an extended period, with maintenance of efficacy suggesting lack of development of tolerance.

Webinars: Two-Part Series on Rescue Medications

Seizures can be both unpredictable and unrelenting. When a seizure becomes an emergency, rescue medications provide immediate relief and help prevent the need for emergency care. While existing therapies do stop these epilepsy emergencies in many patients, some are still searching for an option that works for them.

In this two-part webinar series, you will gain insight on the different epilepsy emergencies, existing rescue medications,  promising research in this space, and what rescue therapies are currently in the pipeline. These webinars will feature leading experts in the field who have recently participated in rescue medication research trials.

In our first webinar on August 13, Dr. Kamil Detyniecki of the University of Miami will provide an overview of the different types of seizure emergencies, while also discussing the currently available rescue medications.

Our second webinar on September 10 features Dr. Nathan Fountain of the University of Virginia, who will explore the latest research on rescue medications. His presentation will include a look at the rescue medication pipeline and the new delivery methods which may become available to patients.

During a live Q&A at the end of each webinar, these leading experts will answer your questions such as:

  • What makes different delivery methods more or less effective for some patients?
  • Are rescue medications only for individuals who experience seizure clusters?
  • What are the potential risks associated with using rescue medications?

The first webinar will feature Dr. Kamil Detyniecki, Assistant Professor of the Clinical Neurology Epilepsy Division, at the University of Miami.  The second webinar will be presented by Dr. Nathan Fountain, Professor of Neurology and the Director of the Comprehensive Epilepsy Program at the University of Virginia.

European Medicine Agency Panel Backs Cannabis Drug for Severe Epilepsy

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has recommended approval of cannabidiol oral solution (Epidyolex, GW Pharma) as add-on therapy for seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome in conjunction with clobazam (multiple brands) for patients as young as 2 years.

The US FDA approved GW’s cannabidiol oral solution last year under the trade name Epidiolex, as reported by Medscape Medical News.

The CHMP’s positive opinion is based on results from four randomized, controlled phase 3 trials that included 714 patients with either LGS or Dravet syndrome. Results showed that add-on therapy with the cannabidiol product was more effective than placebo in reducing seizure frequency.

“This is a significant milestone for patients with LGS and Dravet syndrome as there remains a severe unmet medical need for these rare, lifelong forms of epilepsy,” Martin Brodie, MD, president of the International Bureau for Epilepsy, said in a news release from the drugmaker.

A Trial of Sertraline or Cognitive Behavior Therapy for Depression in Epilepsy

In this investigation involving 140 adult outpatients with epilepsy and current major depressive disorder, researchers assessed the effectiveness of sertraline vs cognitive behavior therapy (CBT) for depression, quality of life, seizures, and adverse treatment effects. Patients were randomized to sertraline or weekly CBT for 16 weeks. Investigators found that suicide risk at final evaluation was linked to persistent depression, but not sertraline or seizures.

After sertraline or CBT, remission of depression was seen in in over one-half of people. Improving depression benefits quality of life despite the epilepsy-related complex psychosocial disability. Serotonin reuptake inhibition in people with epilepsy does not seem to boost seizures or suicidality.

Overlook Medical Center Performs First NJ Surgery with ROSA Brain Robot

Atlantic Health System’s Overlook Medical Center announced on Monday its nationally recognized neurosurgery team is the first in New Jersey to pioneer the use of a new minimally invasive option for brain surgery — the ROSA Brain robot from Indiana-based Zimmer Biomet.

The ROSA Brain is a surgical navigation and positioning system, much like a GPS, that allows for precise spatial positioning and orientation of surgical instruments and tools.

According to Overlook, conventional neurosurgery for epilepsy requires a craniotomy, which is the surgical removal of part of the bone from the skull to expose the brain, so that electrodes can be placed to detect and record seizure activity.

Using the ROSA Brain robot, surgeons make tiny holes in the skull through which they insert the electrodes. The electrodes record brain activity and help pinpoint exactly which part of the brain is responsible for seizures. The robot also can assist in deep brain stimulation, trans-nasal and ventricular endoscopy and brain biopsies.

Due to the complexity of epilepsy surgery, only the most technically skilled neurosurgeons are trained to use the ROSA Brain robot, which does not require opening the skull, or even shaving the head.

Clinical Opinion: Earlier Employment of Polytherapy May Improve Outcomes

Modern pharmacotherapy for epilepsy consists of orderly, sequential drug trials, in which antiepileptic drugs (AEDs) are chosen under the concept of individual patient-oriented (or – tailored) pharmacotherapy.

Although monotherapy (using one drug at a time) has been established as the preferred mode of AEDs therapy in both newly diagnosed and drug resistant epilepsies, there are still lack of evidence to favor either monotherapy or polytherapy (using more than one drug at a time) in epilepsy, which has generated continuing controversies on the preferred mode of pharmacotherapy. However, each mode of pharmacotherapy may have both advantages and disadvantages, which are different and variable related to individual case scenario.

These researchers conducted a brief comparative overview between monotherapy and polytherapy to provide clues for earlier employment of polytherapy in each steps of sequential drug trials. Previous claims about the advantages of monotherapy over polytherapy are not supported but gradually losing its ground by the introduction of a large number of drugs carrying pharmacological advantages for combination therapy.

Current evidence stresses the importance of combining drugs having synergistic interactions for better outcome of polytherapy, which has not been considered in previous clinical investigations comparing monotherapy and polytherapy. It is likely that a significant improvement in the outcome of current AEDs therapy is feasible by earlier employment of polytherapy as well as identification of combination drug regimens carrying synergistic interactions.

At present, lamotrigine(LTG) and valproate(VPA) combination regimen is the only well documented synergistic regimen, but there are a long-list of candidate regimens requiring future trials in appropriate designs.

Epilepsy Research Findings: July 2019

This month’s edition of epilepsy news features recent research suggesting that inducing a seizure prior to surgery is just as effective for pinpointing the brain region where seizures originate as a spontaneous seizure as a spontaneous seizure. In addition, CURE Post-Traumatic Epilepsy initiative members Dr. Oleskii Shandra and Dr. Stefanie Robel published work indicating that the amount of a certain type of cell may increase in the brain following repeated, mild TBIs, causing epilepsy.

Safety updates on several anti-epileptic drugs were reported, including results showing pregabalin may be associated with increased suicidal behavior and other hazards, and that certain drugs used to treat epilepsy may increase the risk of dementia. Studies also highlight the need for improved counseling for safe and effective contraception for women with epilepsy, and the need for resources for people with epilepsy in low-income countries.

Summaries of all highlighted studies follow below. We have organized the findings into Research and Discoveries and Also Notable.

Research and Discoveries

Inducing Seizures to Stop Seizures
Learn More

Causing seizures by stimulating the brain may be a convenient and more cost-effective way to determine the brain region where seizures are originating prior to surgery.

New Research Could Help Predict Seizures Before They Happen
Learn More

A new study has found a pattern of molecules that appears in the blood before a seizure happens, which may lead to the development of an early warning system.

Pregabalin Associated with Increased Suicidal Behavior and Other Hazards 
Learn More

Gabapentinoids, a class of drugs used to treat epilepsy and other neurological disorders, are associated with an increased risk of suicidal behavior, unintentional overdoses, head/body injuries, and road traffic incidents and offences. Pregabalin was associated with higher hazards of these outcomes than gabapentin.

Study Furthers Understanding of the Development of Epilepsy Following Mild Traumatic Brain Injury (TBI)
Learn More

Featuring the work of CURE PTE Initiative members Dr. Oleskii Shandra and Dr. Stefanie Robel

A type of cell in the brain called an “atypical astrocyte” may increase following trauma, causing epilepsy following repeated, mild TBIs, according to a study by Drs. Oleskii Shandra and Stefanie Robel.

Even People with Well-Controlled Epilepsy May Be at Risk for Sudden Death
Learn More

Featuring the work of former CURE Grantee Elizabeth Donner

A new study shows the risk of Sudden Unexpected Death in Epilepsy (SUDEP) may apply to individuals whose epilepsy is well-controlled. Previous, smaller studies showed that SUDEP risk was highest among those with severe, difficult-to-treat epilepsy, however, this study suggests a sizeable minority of SUDEP occurred in patients thought to be treatment-responsive or to have benign epilepsies. The study found that SUDEP occurred in people who had not taken their last dose of epilepsy medication, those who were sleep deprived, and those who had not had a seizure in at least a year.

Anticholinergic Drugs May Increase Risk of Dementia 
Learn More

A study suggests that the possible link between anticholinergic drugs and an increased risk of dementia is strongest for certain classes of anticholinergic drugs, including antiepileptic drugs such as oxcarbazepine and carbamazepine.

Research into Cannabis Dosage Shows Reduced Seizures in Children with Severe Epilepsy
Learn More

Medicinal cannabis oil containing both cannabidiol (CBD) and a small amount of tetrahydrocannabinol (THC) can reduce or end seizures in children with severe, drug-resistant epilepsy, a study by the University of Saskatchewan has found.

Also Notable

The World Health Organization (WHO) Highlights the Scarcity of Treatment for Epilepsy in Low-Income Countries
Learn More

Three quarters of people living with epilepsy in low-income countries do not get the treatment they need, increasing their risk of dying prematurely and condemning many to a life of stigma, according to WHO.

Bringing Neuromodulation Therapies to Drug-Resistant Epilepsy Patients
Learn More

Researchers at the University of Alabama at Birmingham found that creating an epilepsy neuromodulation clinic improved access for patients and communication with referring physicians, achievement of expected outcomes for reducing or eliminating seizures, and the ability to train future providers in programming neuromodulation devices.

Encoded Therapeutics Gets $104M to Propel ‘Precision Gene Therapy’ for Dravet Syndrome
Learn More

Encoded Therapeutics received $104 million to fund a precision gene therapy for Dravet syndrome. The company will also use the funds to advance its preclinical programs and come up with new treatments for severe genetic disorders.

Improved Counseling Needed for Safe, Effective Contraception in Women With Epilepsy
Learn More

Over a third of women with epilepsy do not use highly effective contraception, despite the important, negative consequences of unintended pregnancy such as elevated risk of having offspring with congenital malformations. There is a need for more readily available information and counseling on safe and effective contraception for this community.