Scientists at the Virginia Tech Carilion Research Institute have solved a 125-year-old mystery of the brain, and, in the process, uncovered a potential treatment for acquired epilepsy.
Since 1893, scientists have known about enigmatic structures called perineuronal nets wrapped around neurons, but the function of the nets remained elusive.
Now, a research team led by Harald Sontheimer, the director of the VTCRI Center for Glial Biology in Health, Disease, and Cancer and the executive director of the School of Neuroscience, part of the Virginia Tech College of Science, has determined the nets modulate electrical impulses in the brain. What’s more, brain seizures can occur if the nets are dissolved.
A research team led by Harald Sontheimer (right), a professor at the Virginia Tech Carilion Research Institute, has discovered mysterious brain structures called perineuronal nets to help modulate electrical impulse activity in the brain. The team, which include first author and postdoctoral fellow Bhanu Tewari (left), may be able to target the nets to treat some cases of acquired epilepsy. Credit: Virginia Tech
The discovery, published today in Nature Communications, has implications in various forms of acquired epilepsy, a type of seizure disorder that results from brain lesions caused by trauma, infection, or tumors in the brain.
“We started by investigating tumor-associated epilepsy, and we accidentally learned something else important about how the brain works in disease and in health,” Sontheimer said.
The researchers initially made their finding in a mouse model of epilepsy caused by the deadly brain cancer known as glioblastoma, the first symptom of which is often a seizure.
Glioblastoma is tnly cancer whose growth is restricted by space. Since the skull blocks the cancer from expanding outward, the tumor produces an excitatory chemical neurotransmittercalled glutamate in excessive amounts that kills neighboring healthy cells to make room to grow.
The researchers saw that glutamate targeted brain cells producing a different chemical neurotransmitter called “GABA,” that usually calms neurons by inhibiting them from firing electrical impulses once the messages are relayed. Without GABA, the brain becomes too excited and can seize.
In addition to glutamate, the tumor also secretes an enzyme aimed at destroying the surrounding extracellular matrix, a gel-like substance that holds brain cells in place. Glioblastomas are highly malignant and notoriously invasive—the enzyme is the knife that cuts the cancer’s tethers and lets it migrate freely.
“Unexpectedly, we also saw the enzyme attacking the perineuronal nets,” Sontheimer said, noting that the nets are primarily found wrapped around the GABA-secreting inhibitory neurons, which help prevent seizures. “It was a surprise to see this bystander effect of seizure activity once the neurons were stripped of their nets.”
Italian neurobiologist Camillo Golgi was the first to identify perineuronal nets in 1893, but he misunderstood their function. Golgi called the nets “corsets,” and said they most likely impeded messaging between neurons.
To the contrary, Sontheimer found the nets enabled messaging. The neurons covered by perineuronal nets have a reduced membrane capacitance or ability to store electrical charge, meaning that they can fire an impulse and reload up to twice as fast as non-netted neurons.
When the inhibitory neurons suddenly lose their perineuronal nets, the results can be catastrophic. The researchers applied the enzyme to brains without tumors and saw that on its own, the enzymatic degradation of the perineuronal nets was enough to induce seizures—even when the neurons were left intact.
“Without the perineuronal nets, inhibitory neurons would fire too slowly and therefore inhibition becomes too little, too late, and a seizure will occur—even in otherwise healthy brains,” Sontheimer said, noting that the enzyme can devour a perineuronal net in less than 30 minutes. “No one thought that these structures would have such a profound effect on how normal processes operate.”
Now, the researchers are studying how perineuronal nets might play a role in other forms of acquired epilepsy, which can result from head injury or brain infection. Such elucidation could lead researchers to discover potential pharmacological solutions.
“Importantly, the finding that tumor-induced disruption in perineuronal nets contributes to imbalanced inhibitory neurotransmission suggests a new target for therapeutic intervention to control tumor-associated seizures,” said H. Steve White, a professor and chair of the Department of Pharmacy in the University of Washington’s School of Pharmacy in Seattle, Washington.
White, a renowned expert in epilepsy and anticonvulsant drug development research, was not involved in Sontheimer’s study.
“Although additional studies are needed, it is likely that the findings reported by Dr. Sontheimer and his team are applicable to other forms of acquired epilepsy where brain injury is associated with a heightened inflammatory response,” White said, noting that the implications for treatment and prevention of epilepsy are particularly striking since current therapies are aimed at controlling seizures. “While controlling the symptoms of the disease is significant, the results of this study suggest a possible path toward modifying the development and progression of epilepsy, which would lessen the overall burden to the patient.”
More than 50 million people worldwide have epilepsy, according to the World Health Organization. About a third of those individuals don’t respond to current anti-epileptic treatments.
“If we confirm our hypothesis that digested perineuronal nets are responsible for other forms of acquired epilepsy, then a potential treatment could be an enzyme inhibitor,” Sontheimer said.
He noted that one such an inhibitor is already approved by the FDA for other uses but he also cautioned that there’s a significant amount of research to conduct before their hypothesis is confirmed.
“We need new approaches to treat epilepsy. I think this could be an effective way to control seizures,” Sontheimer said. “And we solved a 125-year-old neuroscience mystery! This is what basic science is all about—keeping an open and observant mind to answer questions old and new.”
Resective epilepsy surgery is a viable option to help improve both seizure control and adaptive functioning in patients with Lennox-Gastaut syndrome, according to an article published in Pediatrics.
To evaluate the long-term outcomes for patients with Lennox-Gastaut syndrome who had undergone resective epilepsy surgery, researchers reviewed 90 patient case reports for surgeries performed at the Severance Children’s Hospital from 2003 to 2014 and managed them for at least 2 years following. Patients were between 3 and 23.5 years old at the time of surgery (mean±SD: 9.3±4.4) with 0.7 to 20.1 years from the time of first seizure to surgery (7.2±4.3). The most common pathologic finding was malformation of cortical development, which was noted in 62.3% (n=57) of patients.
Better social competence and adaptive behavior was achieved by seizure-free patients at post-surgery follow-ups compared with patients with persistent seizures
During the post-operative follow-up period, 50% (n=45) of patients had no seizures and 16.7% (n=15) had infrequent seizures. Of the 21 patients who underwent hemispherectomies, 71.4% (n=15) achieved seizure-free outcomes, compared with 45.1% (23 out of 51) of patients who underwent multilobar resections, and 38.9% (7 out of 18) of those who had single lobar resections. Among the 22.2% (n=20) of patients with negative findings on high-resolution MRIs, 40% (8 out of 20) became seizure-free following resective surgery. Better social competence and adaptive behavior, as indicated by social quotients, was achieved by seizure-free patients at both the second and third post-surgery follow-ups (2-3 years and 4-6 years, respectively) compared with patients with persistent seizures (P <.05).
The study investigators concluded that “[c]areful preoperative investigations can be used to steer the course of LGS in patients toward seizure-free status and better outcomes in adaptive functioning and social competence. Resective surgery should be actively used to treat patients with LGS with suspected focal epileptic pathology.”
The immune system normally protects a person from infections by making specialised agents called antibodies which normally recognise “foreign targets” and destroy them. Doctors utilise this function through vaccinations, which are used for immunization.
Sometimes, the immune system can become “over-excited” and instead of attacking foreign bodies it attacks its own tissues, causing a disease, which is called an autoimmune disease. Researchers believe that this occurs in a small, but significant, number of patients with epilepsy.
In a previous study funded by ERUK, Dr Bethan Lang and colleagues showed that autoimmune antibodies against certain brain proteins were present in a number of types of epilepsy. Using this project grant funding, the research team were able to build on their previous work by investigating whether the immune system has a role to play in the generation/maintenance of epilepsy.
The researchers enrolled patients with specific types of epilepsy and ran a series of tests including understanding, awareness, and a blood test, and combined these with a careful clinical history. They evidence of these destructive autoantibodies in over 10% of patients. Some patients have now been treated with drugs which alter or “deaden-down” the immune-system, instead of, or as well as, the more standard anti-epileptic drugs. The initial results are promising, suggesting that these drugs may be suitable for patients with epilepsy who test positive for autoantibodies. This study has led to a significant change in clinical practice, in that additional tests are not carried out for specific autoimmune proteins.
Using the results from histories, the researchers are now determining if there are symptoms common to patients with autoantibodies. This would help doctors identify which patients might benefit from immunomodulatory therapy.
Prof Lang said: “When we first suggested that autoimmunity could have a role in epilepsy, we were told that it was unlikely and we were roundly dismissed. Through the foresight of research funders such as ERUK we have shown that autoantibodies do indeed play an important role in some forms of epilepsy. Appropriate treatments with drugs that modulate the immune system are now used to treat some of these patients with good clinical outcome.”
This is the final report for a project grant awarded in 2012 for £149,916 to Professor Bethan Lang, Professor Sarosh Irani, Dr Jane Adcock, Dr Holger Kramer, and Professor Arjune Sen at the University of Oxford.
Unplanned pregnancy in women who have epilepsy may double the risk for spontaneous fetal loss, according to a new study.
Investigators from the Harvard Neuroendocrine Unit at Massachusetts General Hospital in Boston, Massachusetts, examined the Epilepsy Birth Control Registry (EBCR) in order to determine whether a planned pregnancy is a determinant for spontaneous fetal loss in women with epilepsy. They also hoped to assess other risk factors that could potentially be modified, such as maternal age, pregnancy spacing, and antiepileptic drug categories.
The team pulled demographic, epilepsy, antiepileptic drug, contraceptive, and reproductive data from the EBCR between 2010 and 2014 and found 1144 female patients with epilepsy between the ages of 18 and 47 years to include in their analysis.
Further analysis revealed that 65% of pregnancies in women with epilepsy included in the study were unplanned, the investigators wrote. This rate was higher than the 45% to 51% range seen in the general US population between 2001 and 2011. Minority race and younger age were risk factors for both cohorts and a third of the pregnancies occurred when the women were not taking contraception.
European predictions indicate that maternal exposure to antiepileptic drug polytherapy, the presence of major congenital malformation in 1 parent, previous spontaneous fetal loss, and maternal age are risk factors for spontaneous fetal loss.
The investigators used the following predicted risk factors: pregnancy planning, age, and antiepileptic drugs use. Spontaneous fetal loss was the outcome for 180 of 794 pregnancies the investigators studied. The risk of spontaneous fetal loss was greater for unplanned vs planned pregnancies. Furthermore, the risk of spontaneous fetal loss was greater when unplanned pregnancies were entered alone, and when adjusted for maternal age, interpregnancy interval, and antiepileptic drug category. Additionally, maternal age and interpregnancy interval were independent risk factors. The use of antiepileptic drugs was not an independent risk factors, according to the investigators.
Those women younger than 18 years had the highest rate of spontaneous fetal loss while the risks for the other cohorts varied. Women aged 18 to 27 years had a 29% risk; women 28 to 37 years, had a 20% risk; and women 38 to 47 years had a 25% risk.
Of the 368 women with epilepsy who had more than 1 pregnancy, the risk for spontaneous fetal loss was greater when the time between pregnancies was less than 1 year, compared with latencies greater than 1 year, the study authors wrote.
The frequencies of spontaneous fetal loss among women with epilepsy who did and did not use antiepileptic drugs during pregnancies were similar, at 28% and 27%, respectively. About a quarter of women received monotherapy, while another quarter received polytherapy.
Despite practice guidelines suggestions that women with epilepsy achieve seizure control prior to conception—which requires planning—about two-thirds of these pregnancies are unplanned. Thus, the investigators shared that “unplanned pregnancy may increase the risk of spontaneous fetal loss in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables.”
“In view of the finding of increased risk for spontaneous fetal loss in unplanned pregnancies in women with epilepsy, and because a history of spontaneous fetal loss in women with epilepsy may increase the risk that subsequent live-born offspring will develop epilepsy, the finding warrants prospective investigation with medical record verification of pregnancy outcomes,” the authors concluded.
With funding from NIH Phase II SBIR grant, Neuroene Therapeutics will take the next steps toward bringing their vitamin K analogues for drug-resistant epilepsy to clinical trial
Neuroene Therapeutics, a start-up company founded by mitochondrial biologist Sherine S. L. Chan, Ph.D. and medicinal chemist C. James Chou, Ph.D. of the Medical University of South Carolina, has received a $1.5 million NIH Phase II Small Business Innovation Research grant to optimize vitamin K analogues that could improve seizure control in patients with drug-resistant epilepsy. Richard Himes, Ph.D., a chemist at the College of Charleston, serves as the company’s Chief Scientific Officer.
Photo: Dr. Chan and Dr. Chou are the founders of Neuroene Therapeutics, an MUSC start-up company that was awarded a 1.5M SBIR Phase II grant to develop a novel anti-seizure compound for drug-resistant epilepsy.
Of the 3.4 million Americans estimated to have epilepsy, one third do not receive adequate seizure control with current medications, either because the drugs do not work for them or because they cannot tolerate the drug’s side effects.
The SBIR grant will enable Neuroene Therapeutics to test the efficacy and safety of its lead compounds, which are analogues of a naturally occurring form of vitamin K that is essential for mitochondrial and neuronal health.
“Mitochondria are the powerhouses of the cell, and the brain needs a lot of energy for its function. A particular form of vitamin K protects the integrity of the mitochondria and helps them produce enough energy for brain cells,” explained Chan.
The form of vitamin K needed by the brain is not the same as the vitamin K we get from foods in our diet. The vitamin K we eat must first be processed by intestinal bacteria before transport to the brain, and then within neurons must be converted into the specific form of Vitamin K that is needed for mitochondrial and neuronal health.
Because the compound developed by Neuroene Therapeutics mimics this specific form of Vitamin K that the neuron needs (not the ingested form) and because it travels directly to the brain, it bypasses the need for transport systems.
“Unlike other vitamin K analogues, which require additional processing before they are in a usable form, our compounds are a direct substitute for the active form and go directly to the brain where they are needed,” said Chou.
Early testing of these vitamin K analogues by the MUSC investigators with pilot funding from the South Carolina Clinical and Translational Research Institute, a Clinical and Translational Science Awards hub funded by the National Institutes of Health, showed significantly reduced seizure activity with little toxicity in a zebrafish model. Testing in mouse seizure models at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program confirmed those findings.
With assistance from the MUSC Foundation for Research Development, Chan and Chou established Neuroene Therapeutics in 2015 and received a patent on their lead compounds earlier this year.
The current SBIR award will enable additional testing of the compounds’ efficacy and safety at the University of Utah’s Anticonvulsant Drug Development Program, directed by Karen Wilcox, Ph.D., which has robust rodent models of drug-resistant epilepsy. By the end of the two years of SBIR funding, Neuroene Therapeutics will have identified the lead compound to take forward into clinical trial.
Although Neuroene Therapeutics is focused currently on developing its lead compound for drug-resistant epilepsy, Chan and Chou are also studying whether vitamin K analogues could improve outcomes in other difficult-to-treat neurological diseases. They already have some promising preclinical data in Parkinson’s disease and mitochondrial DNA depletion syndrome. In addition, they speculate that the compounds could also be relevant to Alzheimer’s disease.
Apolipoprotein E4, one of the strongest genetic risk markers for late-onset Alzheimer’s disease, has a role to play in vitamin K transport. It is possible, then, that mitochondrial dysfunction due to insufficient transport of vitamin K could be implicated in Alzheimer’s and, if so, these brain-penetrating vitamin K analogues could bypass the transport process, thus improving mitochondrial health and disease outcome.
About Neuroene Therapeutics
Neuroene Therapeutics is a startup biotechnology company developing novel Vitamin K-based therapeutics for neurological disorders such as epilepsy. The company originated from collaborative research between Medical University of South Carolina investigators C. James Chou, Ph.D., and Sherine Chan, Ph.D., who cofounded and continue to lead Neuroene Therapeutics. Visit us at neuroenetherapeutics.com.
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 700-bed medical center, which includes a nationally recognized Children’s Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic programs or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.
About the South Carolina Clinical and Translational Research Institute
The South Carolina Clinical and Translational Research (SCTR) Institute is the catalyst for changing the culture of biomedical research, facilitating sharing of resources and expertise, and streamlining research-related processes to bring about large-scale, change in the clinical and translational research efforts in South Carolina. Our vision is to improve health outcomes and quality of life for the population through discoveries translated into evidence-based practice.
About MUSC Foundation for Research Development
FRD has served as MUSC’s technology transfer office since 1998. During that period, FRD has filed patent applications on more than 400 technologies, resulting in over 150 U.S issued patents. Additionally, FRD has executed more than 150 licenses and spun out more than 50 startup companies. MUSC startups have had products approved by the FDA and acquired by publicly traded corporations while attracting substantial investment dollars into South Carolina. Innovations from MUSC, including medical devices, therapies and software, are positively impacting health care worldwide. Please visit us online at frd.musc.edu.
A new high-tech bracelet, developed by scientists from the Netherlands, detects 85 percent of all severe nighttime epilepsy seizures. That is a much better score than any other technology currently available.
The researchers involved think that this bracelet can reduce the worldwide number of unexpected nighttime fatalities in epilepsy patients.
They published the results of a prospective trial in the scientific journal Neurology.
SUDEP, sudden unexpected death in epilepsy, is a major cause of mortality in epilepsy patients. People with an intellectual disability and severe therapy resistant epilepsy, may even have a 20 percent lifetime risk of dying from epilepsy.
Although there are several techniques for monitoring patients at night, many attacks are still being missed.
Consortium researchers have therefore developed a bracelet that recognizes two essential characteristics of severe attacks: an abnormally fast heartbeat, and rhythmic jolting movements. In such cases, the bracelet will send a wireless alert to carers or nurses.
The research team prospectively tested the bracelet, known as Nightwatch, in 28 intellectually handicapped epilepsy patients over an average of 65 nights per patient. The bracelet was restricted to sounding an alarm in the event of a severe seizure.
The patients were also filmed to check if there were any false alarms or attacks that the Nightwatch might have missed.
This comparison shows that the bracelet detected 85 percent of all serious attacks and 96 percent of the most severe ones (tonic-clonic seizures), which is a particularly high score.
For the sake of comparison, the current detection standard, a bed sensor that reacts to vibrations due to rhythmic jerks, was tested at the same time. This signaled only 21 percent of serious attacks. On average, the bed sensor therefore remained unduly silent once every 4 nights per patient.
The Nightwatch, on the other hand, only missed a serious attack per patient once every 25 nights on average. Furthermore, the patients did not experience much discomfort from the bracelet and the care staff were also positive about the use of the bracelet.
These results show that the bracelet works well, says neurologist and research leader Prof. Dr. Johan Arends. The Nightwatch can now be widely used among adults, both in institutions and at home.
Arends expects that this may reduce the number of cases of SUDEP by two-thirds, although this also depends on how quickly and adequately care providers or informal carers respond to the alerts. If applied globally, it can save thousands of lives.
The Nightwatch was developed by a consortium with the following members: Kempenhaeghe epilepsy centre, Eindhoven University of Technology, the Foundation for Epilepsy Institutions in the Netherlands (SEIN), UMC Utrecht, the Epilepsy Fund, patient representatives and LivAssured. This company has been established to market the Nightwatch and has been involved in the R&D since 2014.
The creation of the Nightwatch was initiated by Kempenhaeghe and Eindhoven University of Technology. The development has taken some 20 years. Its principle is based on an idea of Arends and some of his colleagues.
Whereas the Nightwatch still generates separate alarms based on the two sensors (heart rate sensor and motion sensor), the Tele-epilepsy Consortium is already investigating how the two can work intelligently together to achieve even better alerts.
The consortium is also working on improving alarm systems based on sound and video, which can be combined with alarm systems via the bracelet in the future. In time, the aim is to make the interpretation of the signals patient-specific.
According to scientists from Ohio state University (USA), the brains of people with epilepsy in a special way responds to music compared to people without this disease. Researchers believe that the music for patients with epilepsy can be used as a method of therapy that complements traditional treatment.
This writes the Chronicle.info with reference to medikforum.ru.
As the scientists explain, in the majority of cases (80%) the development of epilepsy cause the processes that occur in the temporal lobe of the brain. This part of the brain determines the sensitivity to the music.
Specialists carried out the experiments, which involved 21 patients with epilepsy. Volunteers play music works Coltrane and Mozart, and in those moments, for the activity of their brains was monitored by a sensitive scanning technique. In the control group listened to music participants without the disease.
These trials demonstrated that in patients with epilepsy brain waves are synchronized with the musical frequencies much more often than those who do not have this diagnosis. In General, according to scientists, the brain of epileptics are much more receptive to musical harmony and its activity in the form of corresponding reaction from them has been more intense.
The authors of the project expressed that music therapy can be a very promising method in the treatment of epilepsy. Previous research scientists from the medical school of the University of Maryland in the USA have shown that listening to music has a tremendously positive effect on the vascular system and improves blood circulation.
Regular exposure to stress can impact our physical and mental health, but how does it actually affect our brains? One new Harvard Medical School study answers that question.
According to new research, high levels of stress hormones can impact how well the brain functions.
Stress — especially when we experience it on a regular basis — takes a significant toll on our minds and bodies.
It can make us feel more irritable and constantly tired, and it impacts our ability to focus.
Chronic stress can also interfere with our sleep patterns, appetite, and libido, and it can also exacerbate a range of health conditions.
These include diabetes, heart disease, and gastrointestinal problems.
One study that Medical News Today covered earlier this year, in fact, saw that even minor levels of distress can increase a person’s risk of chronic disease.
What impact does stress have on the brain in physiological and cognitive terms? Researchers from Harvard Medical School in Boston, MA, have explored this question and reported their answer in the journal Neurology.
The stress hormone affects memory
In their study, the researchers worked with participants with an average age of 49 and no diagnosis of dementia.
At baseline, the investigators asked each participant to undergo a psychological exam. They also assessed each participant’s memory and thinking abilities. For the purpose of the study, they assessed these abilities again after an average period of 8 years.
Furthermore, at the beginning of the study, all the volunteers provided blood samples. The team collected them in the morning, after an appropriate fasting period, so that the blood test results would be accurate.
Specifically, the researchers were interested in measuring the participants’ levels of blood cortisol, which is a hormone released chiefly in response to stress. After assessing cortisol levels, the investigators divided the participants into groups according to their results.
They categorized participants as having high, middle, or low levels of cortisol, where middle levels corresponded to the normal cortisol level range of 10.8–15.8 micrograms per deciliter.
The researchers found that people with high levels of blood cortisol had much poorer memory when compared with peers with normal cortisol levels. Importantly, impaired memory was present in these individuals even before obvious symptoms of memory loss set in.
These results remained consistent even after the investigators had adjusted for relevant modifying factors, such as age, sex, smoking habit, and body mass index (BMI).
“Cortisol affects many different functions,” notes study author Dr. Justin B. Echouffo-Tcheugui, from Harvard Medical School, “so it is important to fully investigate how high levels of the hormone may affect the brain.”
Researchers from the University of California, Irvine School of Medicine, have found that a rare gene mutation alters brain development in mice, impairing memory and disrupting the communication between nerve cells. They also show memory problems could be improved by transplanting a specific type of nerve cell into the brain. The findings were published today in Neuron.
“Mutations in hundreds of genes have been linked to neurodevelopmental disorders, many of which have devastating behavioral consequences that cannot be managed with available treatment options,” explained Robert Hunt, Ph.D., assistant professor of Anatomy & Neurobiology, who led the study with Young Kim, Ph.D., a postdoctoral fellow. “Now, a major challenge in the field is to identify the underlying cause for each of these rare genetic disorders so that new, disease-specific therapies can be developed.”
The UCI team focused on the gene CHD2, which scientists believe modifies the structure of chromatin—the coiled complex of DNA and proteins—and controls expression of hundreds of other genes. Normally, humans have two copies of the CHD2 gene. However, in some cases, one copy is lost, which can lead to developmental disorders such as intellectual disability, epilepsy or autism.
To mimic the human disorder and better understand how CHD2 is involved in brain development, Hunt and his colleagues created mice that possess only one functioning copy of the CHD2 gene. Remarkably, the mice had severe memory problems and an increase in electrical oscillations in the brain, features similar to the condition in people.
A closer look at the animals’ brains revealed an abnormal development of brain circuitry, including changes in the way neurons communicate with each other, and fewer inhibitory interneurons, which control the activity of brain circuits. The mouse neurons also showed differences in the expression of more than 100 other genes associated with neurodevelopmental disorders. In the embryo, many of the altered genes are involved in critical biological processes like neurogenesis, but in adult animals, genes associated with neuronal activity and synapse function were changed. That insight indicated CHD2 may play different roles in early brain development and adulthood.
The findings prompted Hunt’s team to transplant embryonic progenitor cells capable of generating inhibitory internerneurons into the brains of the mutant mice. They targeted the hippocampus, a brain region critical for learning and memory, for cell transplantation.
“Inhibitory neurons regulate oscillatory rhythms that are required for memory functions,” Hunt said. “We’ve been developing a similar interneuron cell therapy for epilepsy, so we naturally thought of trying this approach in mice with CHD2 mutation.”
In the UCI study, the transplanted inhibitory cells migrated throughout the hippocampus and generated new interneurons, in effect replacing the brain cells that were missing in the mutant mice. In addition to having more inhibitory nerve cells, the treated mice showed a dramatic improvement in hippocampal-dependent memory.
“At least in principle, it should be possible to develop targeted therapies for genetic disorders like CHD2 mutation,” Hunt said. “That would be great, because in many cases, the medications that are currently available offer no therapeutic value at all.”
While the new research offers an important step toward understanding the role of CHD2 in brain development and function, further studies are necessary before interneuron progenitors can be used for cell therapy in the clinic. The Hunt lab next aims to evaluate brain wiring in the mouse model more closely and to explore how CHD2 mutations affect different neuronal pathways.
A large international research team has discovered a new genetic cause for a severe, difficult-to-treat childhood epilepsy syndrome. Spontaneous mutations in one gene disrupt the flow of calcium in brain cells, resulting in epileptic overactivity. The team’s research in patients also found clues to potential medical treatments for the rare condition.
“Even though variants in this gene were only just discovered to cause disease, we already have a good understanding of how changes in the gene’s associated protein affect brain function—causing neural overactivity in epilepsy,” said first author Katherine L. Helbig, MS, CGC, a research genetic counselor in the Neurogenetics Program in the Division of Neurology at Children’s Hospital of Philadelphia (CHOP). “Furthermore, although much follow-up research remains to be done, we found that there is a possibility that specific anti-seizure medications could reduce this overactivity in some patients.”
The senior authors of this large international study, published online today in the American Journal of Human Genetics, were Heather C. Mefford, MD, Ph.D., of the University of Washington, and Holger Lerche, MD, of the University of Tuebingen, Germany. The full research team included nearly 100 scientists, from Europe, Canada, China, Australia, New Zealand and the United States.
Katherine L. Helbig, MS, LCGC, is a genetic counselor in the Division of Neurology at Children's Hospital of Philadelphia. Credit: Children's Hospital of Philadelphia
The research team focused on disease-causing changes in the CACNAIE gene, long suspected to play a key role in how neurons regulate their electrical activity, but not previously known to cause human disease. This study was the first to link the gene to human epilepsy. By doing next-generation sequencing in 30 infants and young children with severe epilepsy, the team pinpointed disease-causing variants in CACNA1E. In most cases, the gene variants were de novo—present in the affected children, but not found in their parents. De novo variants are being increasingly found in severe childhood epilepsies.
“The fact that we were able to identify 30 patients at this stage of research indicates that we could be looking at a more common cause of genetic epilepsy than we would have initially assumed,” said Helbig. She added, “This research enables us to give some families an answer as to why their child has severe epilepsy. It also offers the potential that we can build on this knowledge to find new strategies for treatment.”
In addition to having difficult-to-treat epilepsy, most of the affected children had severe developmental delays, low muscle tone, contractures starting at birth and movement disorder. “Many of the children were initially thought to have a severe muscular condition because of their contractures,” said Helbig. “We were surprised to find that a genetic epilepsy had such severe symptoms.” Helbig is a specialist genetic counselor in CHOP Neurology, which has deep experience in investigating and treating genetic epilepsies.
The de novo mutations disrupt a calcium channel in brain cells, causing the channel to activate too easily or to inactivate too slowly, and giving rise to epilepsy. In some cases, the study team found the increase in calcium current was too high to measure.
Most of the 30 patients did not respond to any anti-epileptic medications, except for a few who responded to the medication topiramate, known to target the CACNA1E channel. Further systematic work, said Helbig, will investigate this finding and other aspects of their research, with the aim of translating their knowledge into targeted precision therapies for children with severe genetic epilepsy.
A follow-up study of Danish babies with neonatal hyperbilirubinaemia* who had been treated with phototherapy discovered a modest increase in the risk of childhood epilepsy. The finding has now been replicated in a large database analysis from the United States. Phototherapy is associated with an increase in the likelihood of epilepsy by 30% to 40% and the risk seems to be greater in boys than girls.
Phototherapy (light treatment) is the process of using light to eliminate bilirubin in the blood, many time used on newborn babies with jaundice.
* A condition characterized by an abnormal increase of BILIRUBIN in the blood, which may result in JAUNDICE. Bilirubin, a breakdown product of HEME**, is normally excreted in the BILE or further catabolized before excretion in the urine.
**An iron-containing compound of the porphyrin class that forms the nonprotein part of hemoglobin and some other biological molecules.
Study finds significant changes in how seizure medications are metabolized during the different trimesters of pregnancy
BRIGHAM AND WOMEN’S HOSPITAL
During pregnancy, the numerous physiological changes a woman’s body undergoes can alter the way medications are metabolized, the rate at which they are cleared, and their overall effectiveness. Many women continue taking antiepileptic drugs (AEDs) during pregnancy, but while many studies address their safety, it has been unclear if the drug’s effectiveness may be altered during pregnancy. A new study by investigators from Brigham and Women’s Hospital examined whether pregnancy-related changes may influence how effectively five common AEDs prevent seizures and found that AED clearance significantly changes by the first trimester for the most commonly used medication and by the second trimester for two others. Their results are published in Neurology.
“We want to be able to give the exact dose of a drug that keeps a woman seizure-free and keeps her and her baby safe, but there are relatively few studies that have examined pregnancy-related changes in AED metabolism for us to know how to adjust this dose,” said lead author P. Emanuela Voinescu, MD, PhD, associate neurologist in the Department of Neurology at BWH. “We sought to fill that gap about changes in AED metabolism during the different trimesters of pregnancy.”
The team investigated five commonly used drugs, including levetiracetam – one of the most widely used medications during pregnancy – oxcarbazepine, topiramate, phenytoin, and valproate.
The prospective, observational study, started by senior author Page Pennell, MD, while at Emory University, consisted of 40 women with epilepsy who were planning to conceive or were less than 16 weeks pregnant, and who chose to continue their AEDs during pregnancy. Study visits occurred every one to three months and for the first postpartum year. Drug clearance values, the dose required to maintain a certain blood serum concentration, were obtained via blood draw at baseline and during pregnancy. Seizure occurrence and frequency were recorded throughout the study.
Researchers found that the metabolic changes affecting levetiracetam started early, in the first trimester, and drug clearance remained elevated during the second and third trimesters. In contrast, they found that oxcarbazepine and topiramate had elevated clearance starting in the second trimester. This is important because if drug clearance increases, patients may need to be prescribed a higher or more frequent dose of their antiepileptic medication.
“It is already a challenge to be pregnant and our patients have to deal with epilepsy on top of it. It requires a little more work because of all the frequent blood draws and medication adjustments” said Voinescu. “It would be nice to be able to simplify their management by having more scientific guidelines in place regarding how to adjust medication doses during pregnancy to keep them seizure-free and to keep their babies safe.”
Funding for this work was supported by an NIH Specialized Center of Research (P50MH 68036) NCRR M01-RR00039, NINDS and NICHD (U01 NS038455), the American Brain Foundation, American Epilepsy Society and the Epilepsy Foundation as the Susan Spencer Clinical Research Training Fellowship and the Karger Fund.
Paper cited: Voinescu, E et al. “Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy” Neurology DOI:10.1212/WNL.0000000000006240
Monitoring patients with severe epilepsy in residential care facilities during the night was associated with a much lower rate of sudden unexplained death in epilepsy (SUDEP), a new study found.
“Our study was conducted in patients with severe epilepsy and learning difficulties in a residential care institution,” senior author Roland D. Thijs, MD, Stichting Epilepsie Instellingen Nederland, commented to Medscape Medical News. Nocturnal monitoring of such patients varies “hugely” between different institutions, he noted. “There are no guidelines on this, so each center makes their own decisions on monitoring within their budgets.
“Our results now provide enough evidence for some initial guidance on this — that these patients should receive nocturnal monitoring, probably with an acoustic listening device as the first step,” he added.
In an accompanying editorial, Orrin Devinsky, MD, Daniel Friedman, MD, New York University Langone Medical Center, New York City, and Frank M. C. Besag, FRCP, East London National Health Services Foundation Trust, Bedford, United Kingdom, say the study provides additional evidence that certain populations of patients with epilepsy should be monitored during sleep to prevent SUDEP.
They suggest that better SUDEP prevention could be brought about by “focused monitoring…at high-risk times for individual patients (when their convulsive seizures are most likely) and when SUDEP is most common (sleep).
“Because 85% – 90% of SUDEPs are unwitnessed, it seems as if witnesses can prevent SUDEP. Observations in epilepsy units suggest that peri-ictal intervention could mitigate deleterious consequences of seizures,” they add. “For instance, earlier stimulation and oxygen application by a nurse is associated with shorter postictal coma and EEG suppression. An untrained caregiver, who simply turns a postictal patient on their side and frees the airway and stimulates the patient by calling their name, may prevent SUDEP.”
In their article, Thijs and colleagues note that SUDEP is mostly a sleep-related, unwitnessed event, and although the incidence of SUDEP is substantial, at 3.6 to 3.8 per 1000 person-years, recommendations for nocturnal supervision are lacking.
For this nested case-control study, the researchers reviewed records of all people who died during a 25-year period at two residential care facilities (one in the Netherlands and one in the United Kingdom). Participants were adults with severe epilepsy; >90% had convulsive seizures, and 50% were receiving three or more antiepileptic drugs. The patients also had intellectual disabilities.
The Dutch center had the most intensive nocturnal monitoring. This included a central acoustic detection system that covered all residents, as well as bed motion sensors and video monitoring for those suspected of having had unwitnessed nocturnal events during the study period.
The UK center had no central nocturnal seizure detection system, but the institutional protocol recommended that all residents be physically checked once every 15 or 30 minutes.
The researchers identified 60 patients who died of SUDEP and 198 matched control persons from the same institutions. Results showed that people who died of SUDEP were more likely to have had nocturnal convulsive seizures in general (77% of patients vs 33% of control persons; P< .001). In addition, the frequency of nocturnal convulsive seizures was higher among patients who died by SUDEP.
The total SUDEP incidence was 3.53 per 1000 patient-years, although the incidence differed widely between the two centers.
At the UK center, which was the center with less intensive nocturnal monitoring, the incidence of SUDEP was nearly threefold higher (6.12 vs 2.21 per 1,000 patient-years). This difference was not explained by other factors, such as seizure severity.
The authors point out that this study has five times more person-years of data than previous studies. They write that the results confirm that the occurrence of nocturnal convulsive seizures, as well as a high frequency of such seizures, are independent risk factors for SUDEP.
They say the strong association between SUDEP and sleep is explained by two factors: prone position, and the absence of a witness.
“Most SUDEP cases are found in the prone position, which is remarkable as people seldom are prone after nonfatal convulsive seizures,” they write. “When an individual is in the prone position after a seizure, respiratory dysfunction may lead to apnea and asystole, which should normally evoke an arousal response. Postictal coma might, however, prevent arousal and thus the resumption of ventilation, consequently leading to SUDEP.”
Nursing interventions, including repositioning and oxygen administration, have been reported to significantly shorten the duration of respiratory dysfunction after a convulsive seizure, they add. “Further study of the mechanisms involving nursing interventions (other than cardiopulmonary resuscitation) may help prevent postictal coma or even SUDEP,” the authors note.
They conclude that this study and two previous reports “suggest that nocturnal supervision is protective for SUDEP.”
Of the two previous reports, the first was a case-control study in which patients who died by SUDEP were less likely to have had a roommate or to have been given a listening device compared with the control patients. The second was a cohort study of children with severe epilepsy and intellectual disabilities. In this study, all 14 SUDEP deaths occurred while the students were not under the supervision of the boarding school because they had left the school or were on leave.
The authors point out that the variation in nocturnal supervision among the two sites in the current study were predominantly explained by the implementation of an acoustic detection system in the Dutch center. “Acoustic detection systems are often useful, as in 85% of tonic-clonic seizures, an ictal cry is heard,” they add.
To Medscape Medical News, Thijs said acoustic listening devices “would be a good first step. Other measures could be added if it is thought seizures are being missed with the acoustic device.”
He said the study results could not be extrapolated to patients living at home. “Our population was made up of patients with severe epilepsy and learning disabilities in residential care. This is a very specialized set of circumstances. We need to study the home setting separately.”
In their editorial, Devinsky, Friedman, and Besag agree that the data from the study fall far short of establishing a mandate that all patients with epilepsy be monitored. They note that more research is needed on night-time monitoring strategies and SUDEP prevention. They also write of “the relative value of different strategies, the absolute value of any strategy, which populations are most important to monitor, and which populations may be least important to monitor.
“Worldwide, there are around 60 million people with epilepsy and 80,000 SUDEPs per year,” they write. “If we monitor every person with epilepsy every night, how many false alarms will we create, with lost sleep and anxiety for the patient and caregiver? How many SUDEPs will we prevent? How much guilt will result from not responding quickly to an alarm?”
They conclude that SUDEP research “should move from observational and retrospective case-control studies to prospective preventive studies.”
Source: MedScape by S. Hughes from Neurology. Published online September 21, 2018.
The rate of miscarriage was doubled in women with epilepsy whose pregnancies were unplanned, a survey of Epilepsy Birth Control Registry participants found.
Among women with epilepsy, spontaneous fetal loss occurred in 35% of unplanned versus 16% of planned pregnancies, reported Andrew Herzog, MD, MSc, of Beth Israel Medical Center in Boston, and colleagues in JAMA Neurology.
“This is important because unplanned pregnancy is very common among women with epilepsy, more common than in the general population,” Herzog told MedPage Today.
About 65% of pregnancies in women with epilepsy are unplanned, despite epilepsy practice guidelinesthat suggest these women “plan pregnancies to occur when they have achieved optimal seizure control on the minimum effective dosage of antiepileptic drugs and take folic acid supplement before conception to achieve optimal maternal and fetal outcomes,” Herzog added.
Reasons behind these practice guidelines have been evident for years: prenatal exposure to valproate (Depakote) has been tied to autism and impaired cognitive development in children, prompting FDA warnings about using the drug during pregnancy. And while research indicates that newer anti-epileptic drugs like levetiracetam (Keppra) or topiramate (Topamax) during pregnancy are not linked to reduced cognitive abilities in children, a recent study showed that women on anti-seizure medications who did not take folic acid supplements before conceiving had a substantially increased risk of children with autistic traits.
“Discussion about the importance of planned pregnancies should be part of standard care by neurologists carrying for teens and women with epilepsy,” said Page Pennell, MD, of Brigham and Women’s Hospital in Boston, who was not involved with the study.
“To increase the likelihood of a planned pregnancy, the neurologist should also be directly engaged in education of the patient and her other healthcare providers if the anti-seizure medicine prescribed interacts with hormonal contraceptives and lowers their efficacy,” Pennell told MedPage Today. “In those situations, long-acting reversible contraceptives such as intrauterine devices should be encouraged.”
In this study, researchers conducted a web-based retrospective survey from 2010 to 2014 on women with epilepsy from the Epilepsy Birth Control Registry. The average age of survey respondents was 28.5 years; nearly 4 in 10 had household incomes of $25,000 or less, and minority women represented 8.7% of participants.
Respondents reported that 794 pregnancies had occurred: 530 were unplanned (66.8%) and 264 were planned (33.2%). Among 653 unaborted pregnancies, the risk for spontaneous fetal loss was greater for unplanned (n=137 of 391, 35.0%) than planned (n=43 of 262, 16.4%) pregnancies (RR 2.14, 95% CI 1.59-2.90, P<0.001).
Regression analysis identified an interpregnancy interval of less than 1 year and conception age under 18 or over 37 years as predictors of spontaneous fetal loss. Miscarriage frequencies were comparable among women who did and did not use antiepileptic drugs during pregnancy.
“The Epilepsy Birth Control Registry has previously published that a substantial minority of women with epilepsy do not use highly effective contraception despite their increased risk for having offspring with major congenital malformations,” Herzog said. “The current findings strengthen the need for the education of patients and healthcare providers in this regard.”
The researchers listed several important limitations to the study, including its reliance on self-reported information not verified by medical records. Stigmatized health information tends to be underreported, they pointed out, and it’s possible women reported fewer induced abortions in favor of miscarriage, despite survey anonymity and the option to not answer questions about pregnancy outcome. Minority women also were underrepresented in the sample.
This study was funded by the Epilepsy Foundation and Lundbeck. Researchers reported relationships with the Epilepsy Foundation and Lundbeck.
We share this article since we all know stress is a trigger for seizures. EpilepsyUShort-lived feelings of stress are a regular part of daily life. When these feelings become chronic, or long-lasting, they can severely impact a person’s health.
In this article, we look at what chronic stress is, how to identify it, and the medical consequences it can have. We also describe ways to manage stress, including medical treatments, and when to see a doctor.
What is chronic stress?
Signs of chronic stress can include headaches, fatigue, and low self-esteem.
Stress is a biological response to demanding situations. It causes the body to release hormones, such as cortisol and adrenaline.
These hormones help prepare the body to take action, for example by increasing the heart and breath rates. When this occurs, a doctor might describe a person as being in a state of heightened alertness or arousal.
Many factors can trigger a stress response, including dangerous situations and psychological pressures, such as work deadlines, exams, and sporting events.
The physical effects of stress usually do not last long. However, some people find themselves in a nearly constant state of heightened alertness. This is chronic stress.
Some potential causes of chronic stress include:
Chronic stress puts pressure on the body for an extended period. This can cause a range of symptoms and increase the risk of developing certain illnesses.
Signs and symptoms
Chronic stress affects the whole body. It can have several physical or psychological symptoms, which can make functioning on a daily basis more challenging.
The type and severity of symptoms vary considerably from person to person.
Signs and symptoms of chronic stress can include:
irritability, which can be extreme
difficulty concentrating, or an inability to do so
rapid, disorganized thoughts
changes in appetite
a perceived loss of control
loss of sexual desire
frequent infections or illnesses
Over long periods, chronic stress can contribute to the development of a range of physical and mental disorders, including:
Chronic stress can contribute to high blood pressure.
high blood pressure
a weakened immune system
post-traumatic stress disorder, or PTSD
Chronic stress can seem overwhelming, and a person may feel unable to regain control over their life.
However, a number of strategies can help to reduce stress levels and improve well-being.
Some methods for managing stress include:
Understanding the signs and symptoms. These indications can vary, but if a person can recognize their own signals of stress, they will be better able to manage them.
Speaking to friends and family. They can provide emotional support and the motivation to take action.
Identifying triggers. It is not always possible to avoid triggers of stress. However, taking note of specific triggers can help a person to develop coping and management strategies, which may involve reducing exposure.
Exercising regularly. Physical activity increases the body’s production of endorphins, which are chemicals that boost the mood and reduce stress. Exercise can involve walking, cycling, running, working out, or playing sports.
Trying mindfulness. People who practice this form of meditation use breathing and thought techniques to create an awareness of their body and surroundings. Research suggests that mindfulness can have a positive impact on stress, anxiety, and depression.
Improving sleep quality. Getting too little sleep or sleep of poor quality can contribute to stress. Try to get at least 7 hours every night, and set regular times for going to sleep and waking up. Avoid caffeine, eating, and intense physical activity in the hours before bed.
It can also help to unwind before sleeping, by listening to music, reading a book, taking a warm bath, or meditating, for example.
If strategies such as those listed above are not helping, it is important to see a healthcare professional for advice and support. A doctor may recommend psychological therapy, such as cognitive behavioral therapy (CBT).
One established aim of CBT is to help people deal with chronic stress. In structured sessions, a therapist works to enable a person to modify their behaviors, thoughts, and feelings concerning stressors.
CBT can also help a person develop tools and coping mechanisms to manage stress responses.
Sometimes, a doctor recommends medications to help treat some symptoms of chronic stress. For example, they may prescribe antidepressants to treat anxiety or depression. For people with trouble sleeping, doctors may prescribe sedatives.
When to see a doctor
Do not try to deal with chronic stress alone. If self-help strategies are not working, a doctor can provide support and advice about treatment options. They can also refer a person to a more specialized healthcare provider, such as a psychologist or psychiatrist.
Anyone feeling overwhelmed by stress should see a doctor as soon as possible, especially if they are having suicidal thoughts or using drugs or alcohol to cope.
Stress is a regular part of daily life. Short-lived stress is generally harmless, but when it lasts and becomes chronic, it can cause a range of symptoms. It can also contribute to the development of physical and mental disorders.
Self-help techniques include identifying triggers, developing coping and avoidance strategies, reaching out to friends and family, and practicing mindfulness.
If these techniques are not working, or if stress is becoming overwhelming, a person should speak to a healthcare professional.
Source: Article by A. Kandola Reviewed by T. Legg, PhD, CRNP
The US Food and Drug Administration (FDA) has granted expanded approval of perampanel (Fycompa, Esai Inc) for the treatment of “partial-onset seizures (POS) with or without secondary generalized seizures” in patients as young as 4 years, the manufacturer reports.
The expanded indication is for both monotherapy and adjunctive use in patients 4 years of age and older.
The drug was initially approved in 2012 as adjunctive treatment for POS. This was followed in 2015 by approval as adjunctive treatment for primary generalized tonic-clonic seizures in patients with epilepsy who were at least 12 years of age, and in 2017 as monotherapy for POS with or without secondary generalized seizures in the same age group.
To date, the drug “is approved in 55 countries and has treated more than 200,000 patients worldwide across all indications,” the company reported in a press release.
The new approval for the antiepileptic drug (AED) includes both film-coated tablet and oral suspension formulations. The former is available in 2-, 4-, 6-, 8-, 10-, and 12-mg doses; the latter is available at a dose of 0.5 mg/mL.
“Taking an AED as prescribed every day is a critical part of reaching the goal of seizure freedom for pediatric patients,” Jesus Eric Piña-Garza, MD, pediatric neurologist at TriStar Medical Group Children’s Specialists, Nashville, Tennessee, said in the same release.
“With Fycompa, children and their parents now have a once-daily dosing option with a long half-life that can fit into their increasingly busy lives,” added Piña-Garza.
AMPA Receptor Antagonist
It is currently estimated that approximately 470,000 US children have epilepsy. Of these, up to 40% will have uncontrolled seizures even with existing treatments.
The company notes that “breakthrough seizures” can also occur because of a number of factors, including illness, loss of sleep, and missed medication doses.
“Fycompa has a long half-life and in a pharmacokinetic study, it has been demonstrated that in the event of a missed dose, plasma levels remain relatively stable,” it adds.
The drug is a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist.
In addition to past phase 3 trials of adults with POS, two safety studies of children with epilepsy aged 4 to 11 years have been conducted. In the safety studies, 225 pediatric patients received the drug at baseline, 110 were exposed to the drug for at least 6 months, and 21 were exposed for at least a year. Adverse reactions “were similar to those seen in patients 12 years of age and older,” the company reports. It adds that final results of these studies will be presented at an upcoming medical meeting.
The company notes that perampanel, “like other AEDs, may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.” It also may cause psychiatric problems, such as new or worse aggressive behavior or hostility, hallucinations, paranoia, confusion, extreme changes in mood, or memory difficulties.
Other adverse events (AEs) may include dizziness, sleepiness, increased risk for falls, and serious allergic reactions. The most commonly reported AEs include dizziness, tiredness, irritability, falls, nausea and vomiting, and weight gain.
The US Drug Enforcement Administration has designated the product as a federally controlled substance (CIII).
A recent study conducted by Duquesne University professor John Tomko has linked high dosages of the epilepsy drug Gabapentin to opioid abuse. Based on the findings of the study, Tomko recommends prescribing and distributing Gabapentin with more scrutiny and oversight.
Gabapentin, brand name Neurontin, has been formally approved by the Food and Drug Administration (FDA) to treat symptoms of epilepsy, such as seizures and post herpetic neuralgia, a type of pain caused by shingles. According to Tomko, however, Gabapentin has been used off-label (i.e., not approved by the FDA) to treat other ailments such as back pain, anxiety, bipolar disorder, migraines and more.
Tomko’s study found that subjects in UPMC Mercy’s Behavioral Health units were twice as likely to test positive for illicit drug abuse and Hepatitis C when they were taking more than 1800 milligrams of Gabapentin a day.
Courtesy of John Tomko
John Tomko is an associate professor at the university’s School of Pharmacy.
Tomko noted that these off-label prescriptions of Gabapentin are often unclear.
“Many of these off-label uses have little positive data supporting their use or may even have outcomes that do not support their use,” Tomko said. “Previous works have shown that patients may be using [Gabapentin] to enhance the effect of illicit opiates or opiate replacement treatments such as methadone or buprenorphine.”
It is this link between Gabapentin and opiates with which Tomko’s study was concerned. The study was first prompted by a correlation between patients visiting UPMC Mercy’s mental health units who tested positive for drugs of abuse, and who had also been prescribed Gabapentin for off-label purposes. While other previous studies have shown that Gabapentin is often abused, Tomko’s study sought to provide a model that can predict opiate abuse when a patient requests a high dose of Gabapentin from his or her doctor.
The study, which lasted from December 2015 to January 2017, focused on all patients admitted to UPMC Mercy Behavioral Health units. Tomko’s research found that, of the 23.3 percent of patients who were prescribed Gabapentin, only 6.7 percent were taking the drug for an FDA-approved purpose. This, combined with the fact that 67.2 percent of Gabapentin users were taking 1800 milligrams a day or more, suggested to researchers that there was a problem with the use of Gabapentin among patients. Of particular note was the fact that 9 percent of patients prescribed Gabapentin were doing so with an “undetermined reason for use,” according to Tomko.
Tomko stressed that this study identifies Gabapentin as a drug used to enhance the effect of opioids, rather than as a gateway drug to opioid abuse itself. Being the first study of its kind to provide a predictive model for drug abuse, Tomko hopes that the findings of his study will cause doctors to consider prescribing Gabapentin with more scrutiny.
“If a patient is persistent in their requests, a physician may wish to inquire more about the reasons for the request and perhaps even request a urine drug screen to rule out illicit substance use,” Tomko said.
He believes that the findings of this study support potentially considering Gabapentin as a controlled substance by the Drug Enforcement Administration.
Douglas J. Bricker, dean of the School of Pharmacy at Duquesne, praised Tomko and his study.
“The research conducted by Tomko provides primary care physicians and other healthcare prescribers with pertinent information to recognize that patients who are prescribed or who ask for higher doses of Gabapentin should be aware of the association between this behavior and Substance Use Disorders,” Bricker said. “In this era of extensive opioid misuse, having predictive warning tools … can be very beneficial in combating the overuse and misuse of opioids.”
Tomko’s study adds not only to the existing body of work surrounding Gabapentin and its potential for misuse, but also provides a clear indication that high doses of the drug — often prescribed for unclear or off-label purposes — is linked to abuse of opioids.
Tomko and his team hope that this study will help physicians recognize more subtle signs of substance abuse and will raise awareness of substance use disorders.
Treating newborns for jaundice with phototherapy could increase the child risk of developing epilepsy, especially in boys, according to a study.
Researchers analyzed data from 499,642 children born between 1995 and 2011 in the Kaiser Permanente Northern California healthcare system and followed up for an average of 8 years. The findings were published in the September Pediatrics journal.
Photo: A study found treating newborns for jaundice with phototherapy could increase the child risk of developing epilepsy. Photo by Dr. Hudson/Wikimedia Commons
“Phototherapy may have delayed adverse effects that should make us more cautious about using it, and not use it in babies who don’t need it,” first author Dr. Thomas Newman, professor emeritus of epidemiology and biostatistics and pediatrics at University of California San Francisco said in a press release.
Neonatal jaundice affects up to 84 percent of term newborns, according to the American Academy of Family Physicians.
Jaundice develops from the build-up of bilirubin, which is a yellow pigment in the bloodstream. Bilirubin normally is a byproduct of the breakdown of red blood cells, but at high levels the compound is toxic to brain cells and can cause permanent damage.
The peak bilirubin levels are about three to seven days after birth. Then, livers mature and become capable of processing the compound. Also, mothers will begin producing higher-calorie mature milk, which helps increase bilirubin excretion.
Phototherapy lowers bilirubin levels. Blue light is absorbed through their skin, and then changes the shape of the bilirubin molecules and renders them water-soluble. They are more easily excreted.
In the study 37,683 of the children — or 7.6 percent — received phototherapy.
In the treated group, about 1.24 children per 1,000 per year received at least one seizure diagnosis and at least one prescription for an antiepileptic drug. That compared with 0.76 per 1,000 per year in the untreated group.
After statistical adjustment for factors that might lead to phototherapy and seizures, those exposed to the therapy had a 22 percent higher risk of experiencing these outcomes.
“It looks like phototherapy increases the risk of seizures in boys, but we can’t say whether it does so in girls,” Newman said.
Physicians sometimes will administer phototherapy even if a baby’s bilirubin levels likely will fall naturally, said Newman.
“Phototherapy is sometimes done during the birth hospitalization to try to reduce the chances of having to draw more bilirubin levels and treat with phototherapy later,” he said. “That would make sense if we were sure phototherapy were harmless. But data like these suggest that we should treat only babies that really need phototherapy now, not those who might need it later.”
The American Academy of Pediatrics recommends phototherapy based on gestational age, sex and time since delivery for the treatment as well as risk factors of significant bruising, exclusive breastfeeding, anemia and a sibling with a history of neonatal jaundice.
Thursday, September 27 marks a historic day. Today the DEA (United States Drug Enforcement Administration) scheduled the first marijuana based medication.
Epidiolex(r) is a FDA approved medication that is made up of highly-purified, plant-derived cannabidiol (CBD) in a proprietary oral solution of pure plant-derived cannabidiol or CBD and was scheduled today at a “V”. Epidiolex(R) will be used for, early-onset, treatment-resistant epilepsy syndromes including Dravet syndrome, Lennox-Gastaut syndrome (LGS) and Tuberous Sclerosis Complex (TSC). The release of the drug will mark the first time that such a prescription drug has been made available to the U.S. public and now is available for sale in the U.S. The company needs to finalize the product label for the drug and expects to have it ready for customers in six weeks. Greenwich Biosciences, GWPH’s U.S. subsidiary, will be marketing the drug in America.
This scheduling is historic in that level V is reserved for drugs, substances, or chemicals defined as drugs with lower potential for abuse than other schedules. Example: Schedule V drugs are generally used for antidiarrheal, antitussive, and analgesic purposes. Some examples of Schedule V drugs are cough preparations with less than 200 milligrams of codeine or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin.
We also hope this will open the door on how marajuania is schedule. Currently it is a “Level I”, consistent with heroin and other addictive drugs. This scheduling has made it very restrictive to nearly impossible to gain access to it for valid medical research. Example, Epidiolex(r) was developed in the UK prior to U.S. FDA approved medical trials.
For more on understanding scheduling read on.
What is Drug Scheduling
Drugs, substances, and certain chemicals used to make drugs are classified into five (5) distinct categories or schedules depending upon the drug’s acceptable medical use and the drug’s abuse or dependency potential. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs have a high potential for abuse and the potential to create severe psychological and/or physical dependence. As the drug schedule changes– Schedule II, Schedule III, etc., so does the abuse potential– Schedule V drugs represents the least potential for abuse. A Listing of drugs and their schedule are located at Controlled Substance Act (CSA) Scheduling or CSA Scheduling by Alphabetical Order. These lists describes the basic or parent chemical and do not necessarily describe the salts, isomers and salts of isomers, esters, ethers and derivatives which may also be classified as controlled substances. These lists are intended as general references and are not comprehensive listings of all controlled substances.
Please note that a substance need not be listed as a controlled substance to be treated as a Schedule I substance for criminal prosecution. A controlled substance analogue is a substance which is intended for human consumption and is structurally or pharmacologically substantially similar to or is represented as being similar to a Schedule I or Schedule II substance and is not an approved medication in the United States. (See 21 U.S.C. §802(32)(A) for the definition of a controlled substance analogue and 21 U.S.C. §813 for the schedule.)
Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted medical use and a high potential for abuse. Some examples of Schedule I drugs are:
Schedule II drugs, substances, or chemicals are defined as drugs with a high potential for abuse, with use potentially leading to severe psychological or physical dependence. These drugs are also considered dangerous. Some examples of Schedule II drugs are:
Combination products with less than 15 milligrams of hydrocodone per dosage unit (Vicodin), cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, and Ritalin
Schedule III drugs, substances, or chemicals are defined as drugs with a moderate to low potential for physical and psychological dependence. Schedule III drugs abuse potential is less than Schedule I and Schedule II drugs but more than Schedule IV. Some examples of Schedule III drugs are:
Products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone
Schedule IV drugs, substances, or chemicals are defined as drugs with a low potential for abuse and low risk of dependence. Some examples of Schedule IV drugs are:
Schedule V drugs, substances, or chemicals are defined as drugs with lower potential for abuse than Schedule IV and consist of preparations containing limited quantities of certain narcotics. Schedule V drugs are generally used for antidiarrheal, antitussive, and analgesic purposes. Some examples of Schedule V drugs are:
cough preparations with less than 200 milligrams of codeine or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin
According to a recent study, just a few minutes of light exercise can give your brain an immediate push in the right direction, helping to improve memory.
Exercise and the hippocampus
In the past, studies have revealed that exercise can enhance some aspects of cognitive ability and improve memory performance. Also, adults who are more physically active tend to have increased hippocampal volume.
In order to find out why exercise might benefit the hippocampus and memory performance, some scientists have asked whether physical activity stimulates the growth of new brain cells in the hippocampus (known as neurogenesis).
The hippocampus, which is a brain structure that sits within the temporal lobe, is of particular interest to researchers trying to understand this problem.
Vital for learning and memory, the hippocampus is particularly sensitive to stress.
Recently, a team from the University of California, Irvine and the University of Tsukuba in Japan ran some experiments to investigate whether exercise may enhance memory over a much shorter space of time: minutes, rather than days or weeks.
The study authors explain that it certainly is possible that brain cell growth could be stimulated by exercise, but there might also be a quicker mechanism involved that runs in parallel.
The authors wanted to chart any measurable improvements to memory-based brain activity in the first few minutes following light exercise. Their findings were published recently in the journal Proceedings of the National Academy of Sciences.
So, to investigate, 36 healthy young adult participants carried out just 10 minutes of light exercise. The team then used high-resolution functional MRI to measure any changes in brain activity.
Instant brain benefits
The brain imaging showed improved connectivity between the dentate gyrus, which is part of the hippocampus that is thought to play a role in laying down new episodic memories, and cortical areas involved in detailed memory processing.
Also, when the researchers tested the participants using a memory recall test, the increased connectivity correlated with improved memory performance.
“What we observed is that these 10-minute periods of exercise showed results immediately afterward.” Project co-leader Michael Yassa
Yassa believes that it is “encouraging to see more people keeping track of their exercise habits — by monitoring the number of steps they’re taking, for example,” he explains. “Even short walking breaks throughout the day may have considerable effects on improving memory and cognition.”
“The hippocampus is critical for the creation of new memories; it’s one of the first regions of the brain to deteriorate as we get older […] Improving the function of the hippocampus holds much promise for improving memory in everyday settings.” MichaelYassa
Finding that light exercise could have a measurable impact on the parts of the brain responsible for memory is the first step; but next, we need to develop a clearer understanding of the ideal amount of activity necessary to make a real and lasting difference.
As Yassa says, “Clearly, there is tremendous value to understanding the exercise prescription that best works in the elderly so that we can make recommendations for staving off cognitive decline.”
In conclusion, the next time you have misplaced something important, it might be worth trying 10 minutes of yoga; it certainly won’t hurt.