Cannabidiol Reduced Drop Seizures in Severe Epilepsy Disorder

MedicalResearch.com Interview with:

https://www.gwpharm.com/epilepsy-patients-caregivers/patientsAnup Patel, M.D.
Section Chief of Neurology
Interim Division Chief of Neurology
Nationwide Children’s Hospital


MedicalResearch.com: 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.

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Epilepsy Patients Have Small Increased Risk of Unnatural Death

MedicalResearch.com 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

Dr. Gorton

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

MedicalResearch.com: 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.  Continue reading

Early Surgery for Drug Resistant Epilepsy May Limit Cognitive Disabilities

MedicalResearch.com Interview with:
Dr. Manjari Tripathi Professor, Epileptology, Neurology
Dr. P Sarat Chandra, Chief epilepsy Neurosurgeon
AIIMS, New Delhi

MedicalResearch.com: 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.

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Maternal Obesity Linked To Increased Risk of Epilepsy in Offspring

MedicalResearch.com Interview with:
Neda Razaz-Vandyke, PhD, MPH
Postdoctoral Fellow
Reproductive Epidemiology Unit
Karolinska Institutet  

MedicalResearch.com: 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.

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mGlu2 receptor Agonist ADX71149 Plus Levetiracetam May Reduce Seizures With Fewer Side Effects

MedicalResearch.com Interview with:

Robert Lutjens, PhD Head of Discovery at Addex Therapeutics Geneva, Switzerland

Dr. Lutjens

Robert Lutjens, PhD
Head of Discovery at Addex Therapeutics
Geneva, Switzerland

MedicalResearch.com: 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.

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Chronic Subthreshold Cortical Stimulation to Treat Resistant Focal Epilepsy.

MedicalResearch.com Interview with:

Brian Nils Lundstrom, MD, PhD Department of Neurology Mayo Clinic Rochester, Minnesota

Dr. Brian Lundstrom

Brian Nils Lundstrom, MD, PhD
Department of Neurology
Mayo Clinic
Rochester, Minnesota

MedicalResearch.com: 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.

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Brain Cleaning Cells Have Important Role in Epilepsy

MedicalResearch.com 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

MedicalResearch.com: 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.

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New Neurosteroids May Target Refractory Epilepsy

MedicalResearch.com 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

Dr. Samba Reddy

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.

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Two Generic Lamotrigine Medications Demonstrate Bioequivalence in Epilepsy

MedicalResearch.com Interview with:

Dr. Michael Privitera MD Professor of the Department of Neurology and director of the Epilepsy Center University of Cincinnati Neuroscience Institute

Dr. Michael Privitera

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.

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Women With Epilepsy At Much High Risk Of Death During Delivery

MedicalResearch.com Interview with:
Sarah C. MacDonald, BS
Harvard T. H. Chan School of Public Health

MedicalResearch: What is the background for this study? What are the main findings?Response: Approximately 0.3-0.5% of all pregnancies are in women with epilepsy. While individual studies have suggested that women with epilepsy may be at increased risk for certain adverse outcomes in pregnancy, the risks have not been well quantified in large population based samples. We addressed this issue using a large retrospective sample of delivery hospitalizations from across the United States.The main findings were that women with epilepsy had a more than 10 fold increased risk of death during their delivery hospitalization as compared to the risk in women without epilepsy (80 deaths per 100,000 women with epilepsy vs. 6 deaths per 100,000 in women without epilepsy). We also found that women with epilepsy were at increased risk for a cesarean delivery, prolonged hospital stay, preeclampsia, preterm labor, stillbirth and other adverse outcomes.

MedicalResearch: What should clinicians and patients take away from your report?

Response: The findings from our work suggest that women with epilepsy are at a higher risk for many adverse outcomes during their delivery admission in hospital. While this is only one study, our work suggests that pregnancies in women with epilepsy may be high risk and that these patients may be best treated by physicians who are comfortable caring for these complex patients. While the relative risk of death in women with epilepsy was quite high, it is important to note that maternal death during delivery is still very rare, with only approximately 80 deaths for every 100,000 women with epilepsy.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Response: Our study was not designed to determine particular causes for the increased risks in women with epilepsy. Therefore further research is needed to understand why women with epilepsy are at a higher risk for adverse outcomes during delivery. Future research is also needed to determine the benefits of particular interventions. One possible route of improvement could be in triaging women with epilepsy to higher risk centers and following them closely throughout gestation and post-delivery.

Citation:

MacDonald SC, et al “Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States” JAMA Neurology 2015; DOI: 10.1001/jamaneurol.2015.1017

Sarah C. MacDonald, BSHarvard T. H. Chan School of Public Health (2015). Women With Epilepsy At Much High Risk Of Death During Delivery

Sleeping On Stomach May Increase Risk of Death in Epilepsy

James Tao, MD, Ph.D Assistant Professor Director, EEG Lab Department of Neurology, The University of Chicago, IL.MedicalResearch.com Interview with:
James Tao, MD, Ph.D
Assistant Professor Director, EEG Lab
Department of Neurology, The University of Chicago, IL.

Medical Research: What is the background for this study? What are the main findings?

Dr. Tao: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with chronic uncontrolled epilepsy. Patients often died in sleep, in bed, and unwitnessed. They were often found in prone position. These circumstances of SUDEP are remarkably similar to those of sudden infant death syndrome (SIDS). In our study, we found that 73% of 253 SUDEP patients were died in prone position. These findings suggest that sudden unexpected death in epilepsy may share the mechanisms similar to SIDS.

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