Author Interviews, Epilepsy / 19.12.2019 Interview with: Steve S. Chung MD Epilepsy Neurology Banner University Medical Center University of Arizona, Phoenix, AZ What is the background for this study? Response: Prior studies have shown that midazolam nasal spray (MDZ-NS) is superior to placebo in providing rapid, sustained seizure control and a favorable safety profile when administered to patients experiencing seizure clusters, a type of seizure emergency impacting an estimated 150,000 patients in the U.S. with uncontrolled epilepsy. To explore the influence of concomitant antiepileptic drugs (AEDs) on treatment outcomes, we conducted a post hoc analysis of a Phase III trial to evaluate the tolerability and efficacy of midazolam nasal spray in patients 12 years of age and older with seizure clusters, according to concomitant enzyme-inducing AED (EIAED)/non-enzyme-inducing AED (NEIAED) status and by the number of concomitant AEDs. (more…)
Author Interviews, Epilepsy / 19.12.2019 Interview with: Eun Jung Choi, MD, PhD; Senior Director, New Product Launch, Neurology UCB What is the background for this study? Response: Patients experiencing seizure clusters, a type of seizure emergency impacting an estimated 150,000 patients in the U.S. with uncontrolled epilepsy, are at risk for potentially serious consequences including hospitalization, mortality, physical injury, neurological damage, and status epilepticus. Although unmet needs of seizure clusters are intuitively well accepted, the burden of seizure clusters has not been well characterized and evaluated in a systemic matter. As a result, the seizure cluster patients are overlooked, and burden of seizure clusters is under-recognized. So we systematically assessed the clinical, humanistic, and economic burden associated with seizure clusters to provide the comprehensive body of evidence about burden of seizure clusters. (more…)
Author Interviews, Epilepsy, NEJM, NIH / 11.12.2019 Interview with: Robin Conwit, M.D Program Director, Division of Clinical Research NIH: National Institute of Neurological Disorders and Stroke What is the background for this study? Response: Approximately one-third of patients with intractable status epilepticus do not respond to benzodiazepines, often the first line medications given in the emergency department, leaving doctors to decide among three commonly prescribed anti-convulsants. In this study all of the anti-convulsants were equally effective. The trial gives doctors a way to clear the air of arguments that one of these drugs works any better than the others, or that any one of them is a lot safer.  It gives doctors a reason to choose a dosing strategy in status epilepticus for levetiracetam, which has otherwise been controversial and non-standard.   (more…)
Author Interviews, Epilepsy, Nutrition / 23.07.2019 Interview with: Geoffrey W. Abbott PhD Department of Physiology and Biophysics, Bioelectricity Laboratory, School of Medicine, University of California What is the background for this study? Response: The main focus of my laboratory is the study of potassium ion channels - proteins that coordinate electrical activity in all organisms. When human potassium channels do not function properly, it can result in pathologically discordant electrical activity, and diseases such as cardiac arrhythmia, myotonia, and epilepsy - depending on whether the affected potassium channel is in the heart, skeletal muscle or brain, for example. T here are existing drugs that directly regulate ion channels for therapeutic benefits, including one - retigabine - that opens neuronal potassium channels in the KCNQ family, to treat epilepsy. Retigabine causes side effects including turning the skin blue, and was withdrawn from clinical use in 2017. Retigabine may make a comeback because a form of epilepsy was recently discovered, arising from mutations in the KCNQ2 gene, that is associated with severe developmental delay and seizures. In my lab, we are interested in discovering new therapeutic agents that might more safely fix dysfunction in KCNQ2 and other potassium channels. We turned to plants as a possible source of compounds. We are interested both in explaining the underlying mechanism of traditional botanical medicines, and also discovering unanticipated therapeutic chemicals synthesized naturally by plants.  (more…)
Author Interviews, Epilepsy, FDA / 29.05.2019 Interview with: Dr. Steven S. Chung, MD Executive Director and Program Chair Neuroscience Institute and Director of the Epilepsy Program Banner – University Medical Center What is the background for this study? How is Nayzilam different from other treatments for epilepsy? Who/How is it administered?  Response: NAYZILAM is the first medication and only FDA-approved nasal option for treating seizure clusters. NAYZILAM allows for administration by a non-healthcare professional to patients when a seizure cluster occurs, which could provide significant value to patients who currently have limited treatment options for SC. The effectiveness of NAYZILAM was established in a randomized, double-blind, placebo-controlled trial (Study 1; NCT 01390220). Study 1 was conducted in two phases: an open-label Test Dose Phase followed by a randomized, double-blind, placebo-controlled, Comparative Phase. In the Test Dose Phase, tolerability was assessed in 292 patients. Patients were excluded from participation in the Comparative Phase if they failed to meet pre-defined blood pressure, heart rate, sedation, electrocardiogram, and peripheral oxygen saturation criteria. In the Comparative Phase, 201 patients treated a single seizure cluster episode in an outpatient setting. Numerical differences in favor of NAYZILAM were observed on each of the components of the treatment success responder definition; termination of seizure(s) within 10 minutes after initial dose of study drug (80.6 versus 70.1%) and the absence of seizure recurrence between 10 minutes and 6 hours after the initial dose of study drug (58.2 versus 37.3%). Study 1 also evaluated the occurrence and time to next seizure after the initial blinded dose of study drug. A smaller proportion of NAYZILAM-treated patients experienced the next seizure within 24 hours after the initial blinded dose of study drug (37.3% versus 46.3%). NAYZILAM-treated patients experienced a statistically longer time-to-next-seizure than the placebo group.   (more…)
Author Interviews, Epilepsy, Genetic Research, JAMA, Pediatrics / 12.04.2019 Interview with: Dr. Ahmad Abou Tayoun, PhD Clinical Molecular Geneticist Director of the Genetics Laboratory Al Jalila Children’s United Arab Emirates What is the background for this study?   Response: In this study, we provide data in favor of using an exome-based testing approach, where parental samples can be readily accessible, for early onset epilepsy patients. The exome test includes all coding genes in the human genome. Although we perform exome sequencing on those patients, we demonstrate that a first tier analysis should include targeted interpretation of ~100 genes strongly associated with the disease. This analysis provides diagnoses in ~11% of the patients. Follow up parental testing on a limited number of patients (n=15) that had inconclusive results, revealed de novo (new mutations) variant status, leading to upgrade to positive reports in 7 patients and adding ~5% to the overall diagnostic yield. (more…)
Author Interviews, Epilepsy, Neurological Disorders, NYU, Pharmaceutical Companies / 17.05.2018 Interview with: Patel, M.D. Section Chief of Neurology Interim Division Chief of Neurology Nationwide Children’s Hospital What is the background for this study? Response: The study evaluated kids and adults with an epilepsy syndrome (Lennox Gastaut Syndrome – LGS) that is often difficult to treat and does not respond well to current medical treatment.  The study was a double blind randomized control trial evaluating how well a plant based, liquid solution, cannabidiol (CBD) product made by Greenwich Biosciences called Epidiolex helped to treat drop seizures (the most common seizure type in LGS) and how safe it was compared to placebo.  Two doses (10 mg/kg/day and 20 mg/kg/day) were evaluated compared to placebo. (more…)
Alzheimer's - Dementia, Author Interviews, Cognitive Issues, Epilepsy / 12.04.2018 Interview with: Britta Haenisch, PhD Pharmacoepidemiology in Neurodegenerative Disorders German Center for Neurodegenerative Diseases, DZNE What is the background for this study? What are the main findings? Response: Antiepileptic drugs (AEDs) have been shown to affect cognition by suppressing neuronal excitability and increasing inhibitory neurotransmission. Previous studies suggested that AEDs may be associated with cognitive adverse effects. Therefore, we evaluated the association between AED use and incident dementia and Alzheimer’s disease (AD). We utilized large longitudinal datasets from Finnish health registers and from German health insurance data. The case-control analyses was adjusted for several potential confounders like comorbidities and polypharmacy. The inclusion of a lag time between . Antiepileptic drugs use and dementia diagnosis allowed minimization of protopathic bias. Our study provides an association between regular prescription of  antiepileptic drugs with known cognitive adverse effects and the occurrence of dementia and AD in patients aged 65 years and older.  (more…)
Author Interviews, Epilepsy, JAMA / 10.04.2018 Interview with: Dr Hayley Gorton PhD MPharm MRPharmS FHEA Research Associate Centre for Pharmacoepidemiology and Drug Safety Research Division of Pharmacy & Optometry| Faculty of Biology, Medicine & Health University of Manchester What is the background for this study? What are the main findings? Response: It is already known that people with epilepsy are at a higher risk of death than those without epilepsy but we didn’t know much about the risks of different types of death. Unnatural death (mainly accident and suicide) accounts for a very small number of all deaths but, compared to people without epilepsy, people with epilepsy are three times more likely to die by accident and twice as likely to die by suicide. Within these broad categories, persons with epilepsy are five times more likely to die specifically by accidental poisoning with medication, and three times more likely to die by intentionally poisoning themselves with medication. Opioid painkillers and medicines for mental illness were the ones most commonly used in poisoning deaths among people with epilepsy and those without epilepsy. Antiepileptic drugs were taken relatively infrequently-they were involved in about 10% of poisoning deaths in people with epilepsy.  (more…)
Author Interviews, Epilepsy, NEJM, Neurological Disorders, Pediatrics, Surgical Research / 25.10.2017 Interview with: Dr. Manjari Tripathi Professor, Epileptology, Neurology Dr. P Sarat Chandra, Chief epilepsy Neurosurgeon AIIMS, New Delhi What is the background for this study?:
  1. Surgery for drug resistant epilepsy (DRE) is an accepted procedure for children and there have been multiple surgical series and surgical techniques published in literature. However, till date there are no randomized controlled trials (RCT) available to objectively demonstrate the safety and efficacy of surgical therapy in children with DRE. There are till date only 2 randomized trials for adult patients with drug resistant epilepsy (both for mesial temporal sclerosis only, Wiebe S et al, New Eng J Med, 2001 & Engel J et al, JAMA, 2012).
  2. Children constitute a significant proportion of patients undergoing surgical therapy for DRE (close to 50% in tertiary centers). They have unique problems associated due to uncontrolled epilepsy and some of these include epileptic encephalopathy and status epilepticus. In addition, surgery is also associated with problems like hypothermia, issues related to blood loss etc. Thus the senior author (Manjari Tripathi) and her team felt that a RCT would be very important to objectively assess the role of surgery and hence designed this study.
Author Interviews, Endocrinology, Epilepsy / 17.10.2017 Interview with: Dr. Samba Reddy, Ph.D., R.Ph., FAAPS, FAAAS, FAES Professor Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center What is the background for this study? What are the main findings? Response: For the past two decades, D. Samba Reddy, PhD, RPh, professor of neuroscience and experimental therapeutics at the Texas A&M College of Medicine, has been searching for answers to catamenial epilepsy, a subset of chronic epilepsy that causes a dramatic increase in seizures during women’s menstrual periods. Although this condition has been documented for millennia, there is currently no effective treatment for catamenial seizures, leaving many women and their families desperate for answers. In this report, the researchers discovers the neuro-code for treating women with menstrual period-linked epilepsy. A unique platform has been created for clinical trials for catamenial seizures with synthetic neurosteroid agents. (more…)
Author Interviews, Epilepsy, JAMA, Karolinski Institute, OBGYNE, Pediatrics, Weight Research / 06.04.2017 Interview with: Neda Razaz-Vandyke, PhD, MPH Postdoctoral Fellow Reproductive Epidemiology Unit Karolinska Institutet What is the background for this study? What are the main findings? Response:   There is a growing concern about long-term neurological effects of prenatal exposure to maternal overweight and obesity. The etiology of epilepsy is poorly understood and in more than 60% of cases no definitive cause can be determined. We found that maternal overweight and obesity increased the risks of childhood epilepsy in a dose-response pattern. (more…)
Author Interviews, Epilepsy, Pharmacology / 28.02.2017 Interview with: Robert Lutjens, PhD Head of Discovery at Addex Therapeutics Geneva, Switzerland What is the background for this study? What are the main findings? Response: Metabotropic glutamate receptors represent an attractive therapeutic target for various neurologic conditions. In particular, the metabotropic glutamate receptor subtype 2 (mGlu2) can affect excitatory synaptic transmission by decreasing glutamate release. As excess gluatamate is observed in epilepsy, targeting mGlu2 could lead to new avenues of therapy. Positive allosteric modulators (PAMs) of mGlu2 could be valuable candidate drugs as they do not directly activate receptors. Therefore, they may avoid tachyphylaxis and side effects emerging from direct receptor agonism.  The publication summarizes the effects obtained when the mGlu2 receptor is activated using an agonist or PAM, such as ADX71149, in the 6Hz psychomotor seizure test, considered to be the most relevant model of pharmacoresistant limbic seizures. The data show that while seizures are reduced when mGlu2-acting compounds are administered alone, their combination with the antiseizure drug levetiracetam (LEV) result in a potent reduction of doses required to produce full efficacy, which is important because higher doses of LEV are associated with dose-limiting side effects, such as aggression, nervousness/anxiety, somnolence and fatigue. In this study, a fixed dose of ADX71149 was seen to increase the potency of LEV, leading to an approximate 35-fold increase in its potency. Conversely, using a fixed dose of LEV with varying doses of ADX71149 resulted in an approximate 14-fold increase in ADX71149 potency. (more…)
Author Interviews, Epilepsy, JAMA, Mayo Clinic, Neurological Disorders / 23.09.2016 Interview with: Brian Nils Lundstrom, MD, PhD Department of Neurology Mayo Clinic Rochester, Minnesota What is the background for this study? What are the main findings? Response: About as many people have drug-resistant focal epilepsy as have multiple sclerosis, and treatment options are limited. This study describes an alternative treatment option that has proven very helpful for the majority of participants. Electrical stimulation is delivered continuously via implanted electrodes to the region of brain where seizures start. The electrical stimulation decreases the seizure-related discharges from the brain, and for about 40% of patients their disabling seizures were completely stopped. (more…)
Author Interviews, Epilepsy, Neurological Disorders, PLoS / 30.05.2016 Interview with: Amanda Sierra, PhD Research Professor and Group Leader Ramón y Cajal Fellow Achucarro Basque Center for Neuroscience Laida Bidea Bizkaia Science and Technology ParkAmanda Sierra, PhD Research Professor and Group Leader Ramón y Cajal Fellow Achucarro Basque Center for Neuroscience Laida Bidea Bizkaia Science and Technology Park Zamudio, Bizkaia, Spain What is the background for this study? What are the main findings? Dr. Sierra: Microglia phagocytosis of apoptotic cells is at the core of the brain regenerative response to recover the homeostasis of the brain parenchyma after damage because it prevents the spillover of toxic intracellular contents and is actively anti-inflammatory. However, while neuronal death is widespread in neurodegenerative diseases (Alzheimer´s, Parkinson´s, multiple sclerosis) and well as in ischemic and traumatic brain injuries, we have a complete lack of knowledge of the efficiency of microglial phagocytosis in the diseased brain. In this paper we have discovered that microglia have a generalized response to apoptotic challenges: when confronted to a rise in the number of newborn cells, microglia display a combination of different strategies to boost their phagocytic output: increase the phagocytic capacity of each cell, recruit more cells to become phagocytic, or increase the total number of microglia (Abiega et al., PLoS Biol 2015). Thus, microglia have a very large potential for phagocytosis that could be summoned when needed. To our surprise, however, in pathological conditions such as epilepsy (mouse and human), microglial phagocytosis was blocked. We have made use of the adult neurogenic cascade, where newborn cells undergo apoptosis naturally and are engulfed by “unchallenged microglia” (Sierra et al. Cell Stem Cell 2010), to establish the baseline of microglial phagocytosis efficiency. Whereas in physiological conditions microglia phagocytose over 90% of the apoptotic cells and remove them in under 1.5h, soon after the seizures it only engulfed 10% of the apoptotic cells and took up to 6h to digest them. This is the first quantification of microglial phagocytosis efficiency in the diseased mouse and human brain.. The block in phagocytosis was a rather complex phenomenon related to an impaired recognition (reduction of phagocytosis receptors) as well as impaired motility and targeting (reduced basal motility). We have also shown that the impairment is mediated at least partially by altered ATP microgradients: ATP is not only a neuro- and gliotransmitter widely released during seizures but is also a well-known “find-me” signal released by apoptotic cells. Thus, during seizures microglia became “blinded” by the neuronal hyperactivity and could not find the apoptotic cells. In addition, we have shown that impairing phagocytosis releases the break on the inflammatory response. In fact, the impaired microglia were in a pro-inflammatory state and produced more cytokines such as tumor necrosis factor alfa (TNFa) or interleukin-1beta (IL-1b), which are well known neurotoxic and epileptogenic factors. (more…)
Author Interviews, Epilepsy, NYU / 01.05.2016 Interview with: Jacqueline French, MD Professor, Department of Neurology Director Translational Research& Clinical Trials Epilepsy NYU Langone Medical Center What is the background for this study? Dr. French:  Tuberous sclerosis complex (TSC) is a disease associated with abnormal cell growth, caused by dysfunction of the TSC1 or TSC2 genes and dysruption of the MTOR pathway, which leads to cortical malformations, neuronal hyperexcitability, and seizures. Seizures in patients with TSC often start within the first year of life, and tend not to respond to traditional treatments. Everolimus is a marketed drug that has been used to treat other manifestations of TSC (including giant cell tumors of the brain, renal angiomyolipomas, and angiofibromas of the skin). This study was a placebo-controlled add-on study of everolimus for the treatment of refractory seizures in children and adults with epilepsy.Following an 8-week baseline phase, patients aged 2-65 years (stratified by age) with TSC and refractory seizures on 1-3 antiepileptic drugs were randomized to EVE LT or HT Cmin target ranges or placebo, and treated in an 18 week Core Phase (6-wk titration + 12-wk maintenance). Primary endpoints were change from baseline in average weekly frequency of TSC-seizures (seizures not previously shown to be generalized in onset by EEG), expressed as response rate (≥50% reduction [RR]), and percentage reduction. What are the main findings? Dr. French:  Overall, 366 patients were randomized to EVE LT (n=117), HT (n=130), or placebo (n=119). The median percentage reduction in TSC-seizures was significantly greater with EVE LT (29.3%, P=0.003) and HT (39.6%, P<0.001) vs placebo (14.9%). RR was also significantly greater with EVE LT (28.2%, P=0.008) and HT (40%, P<0.001) vs placebo (15.1%). The most frequent ≥10% all grade adverse events (AEs) reported with EVE LT/HT vs placebo included stomatitis (28.2%/30.8% vs 3.4%), diarrhea (17.1%/21.5% vs 5%), mouth ulceration (23.9%/21.5% vs 4.2%), nasopharyngitis (13.7%/16.2% vs 16%), upper respiratory tract infection (12.8%/15.4% vs 12.6%), aphthous ulcer (4.3%/14.6% vs 1.7%), and pyrexia (19.7%/13.8% vs 5%). Discontinuations due to AEs (5.1%/3.1% vs 1.7%) were low. (more…)
Author Interviews, Epilepsy / 21.02.2016 Interview with: Dr. Samba Reddy, PhD, RPh, FAAPS Professor Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan, TX Medical Research: What is the background for this study? What are the main findings? Dr. Reddy: Neurosteroids are a group of neuroactive compounds present in the brain. They are known to modulate ionotropic post-synaptic GABA-A receptors, which are the primary mediators of fast inhibitory neurotransmission in the brain. Hence, the neurosteroid—GABA-A receptor system is a critical axis for controlling neuronal excitability in certain brain disorders, such as anxiety and epilepsy. There is new evidence that such neurosteroids can strongly activate extrasynaptic GABA-A receptors, which are located outside of the synapses mainly on soma, dendrites and axons. However, the neurosteroid structure requirement for functional activation of extrasynaptic receptors remains largely unexplored.  In this study, we identified a consensus neurosteroid pharmacophore model at extrasynaptic GABA-A receptors for activation of tonic current and seizure protection. (more…)
Author Interviews, Epilepsy, Neurological Disorders, Stroke / 20.02.2016 Interview with: Alexander Merkler, MD Fellow in neuro critical care Weill Cornell Medical College and New York-Presbyterian Hospital, New York Medical Research: What is the background for this study? What are the main findings? Dr. Merkler:  Patients with stroke often ask about what type of problems they may expect in the future. As neurologists, we often warm our patients about the risk for recurrent stroke, infections, clots, eating difficulty, and depression. Although seizures are a well-known complication of stroke, there was little data regarding the long-term rate of seizures in patients who have a stroke. Therefore, we sought to evaluate the long-term risk of seizures following stroke in order to better advise physicians and patients on the likelihood of developing seizures after suffering a stroke. We identified over 600,000 patients with stroke and found that the rate of seizures after stroke is high – 15.3% of all patients with stroke will develop seizures. Patients who have hemorrhagic stroke face an even higher rate of seizures – 24% of patients with hemorrhagic type stroke will develop seizures. The rate of seizures after ischemic stroke was significantly higher than previous literature - 13.5% of patients with an ischemic stroke had a seizure in our study. (more…)
Author Interviews, Epilepsy, Lancet, Pharmacology / 15.02.2016 Interview with: Dr. Michael Privitera MD Professor of the Department of Neurology and director of the Epilepsy Center University of Cincinnati Neuroscience Institute  Medical Research: What is the background for this study? What are the main findings? Dr. Privitera: Generic substitution of medications has saved the American health care system billions of dollars per year. However, based on a series of uncontrolled studies, patients and clinicians share concerns that generic substitution of antiepileptic drugs may lead to loss of efficacy or emergence of adverse effects. To answer this question we undertook a prospective, randomized study that tested bioequivalence of two generic products of the antiepileptic drug lamotrigine. Lamotrigine was identified in several publications as a possible source of problems after generic switches. FDA studies test a single generic versus the brand name product in a single dose study in normal volunteers. We designed a study that would be most likely to show a difference between generics if one existed. We compared the two generic lamotrigine products showing the most difference in prior testing in patients with epilepsy taking the drug daily using rigorous pharmacokinetic methods. Each patient took each of the two generics for 2 four week periods. Our study showed the two generics were essentially indistinguishable and easily met bioequivalence standards. No patient had loss of seizure control or unexpected adverse effects. (more…)
Author Interviews, Epilepsy, Technology / 11.12.2015 Interview with: Dr. Frances Hutchings Interdisciplinary Computing and Complex BioSystems School of Computing Science, Newcastle University Newcastle upon Tyne, United Kingdom Medical Research: What is the background for this study? Response: Temporal lobe epilepsy is a prevalent and disruptive disorder, which is often treated with surgical removal of epileptic tissue when medication fails to repress seizures. In around a third of cases surgery is unsuccessful at preventing seizures. The aim of this study is to seek ways to improve surgery success rates by giving a better prediction of where seizures are starting and spreading on an individual patient basis, using an individual’s brain imaging data. Surgery is simulated in the model to provide a prediction of a procedures effectiveness at reducing seizures. Medical Research: What are the main findings? Response: Using patient Diffusion Tensor Imaging data to reconstruct the brain as a network, locations commonly implicated in temporal lobe epilepsy were found by the model to be most vulnerable to seizures. Simulations of surgery (following a commonly used surgery procedure) in patient models predicted a surgery success rate close to 70%, matching clinical observations. Subject specific surgery simulations were also tried, following individual predictions from the model of which regions to remove for which person. These showed far greater improvements in seizure likelihood than regular surgery. This is a preliminary study and there is much to be done to improve the predictive success, and also to ensure that model predicted subject specific surgery regions are safe to remove. Nonetheless it is a significant move towards computer aided patient specific surgery planning to improve outcomes. (more…)