UAB researchers release new research findings on effect of CBD oil at national Epilepsy Society Meetings

 jerzy groupLeslie Perry, M.D., Jerzy Szaflarski, M.D., Ph.D., and Tyler Gaston, M.D., are among the UAB researchers presenting findings of the CBD oil studies.

BIRMINGHAM, Ala. – Cannabidiol oil, also known as CBD oil, reduces the frequency and severity of seizures in children and adults with severe, intractable epilepsy, according to findings presented by researchers from the University of Alabama at Birmingham at the American Epilepsy Society 70th Annual Meeting.

UAB researchers presented eleven abstracts, or research findings, at the meeting. A key finding was that CBD provided a significant reduction in frequency of seizures for a majority of the patients in the study, and that approximately two-thirds of patients saw a greater than 50 percent reduction in severity.

“It is encouraging that both frequency and severity of seizures appear to improve in the majority of patients in our study, patients who have limited treatment options,” said Jerzy P. Szaflarski, M.D., Ph.D., professor in the Department of Neurology and director of the UAB Epilepsy Center. “Our research adds to the evidence that CBD may reduce frequency of seizures, but we also found that it appears to decrease the severity of seizures, which is a new finding.”

The results were based on an open-label study of 81 patients — 42 children and 39 adults — who experienced four or more seizures per month. UAB launched the studies of CBD oil as a treatment for severe, intractable seizures in April 2015. The studies, an adult study at UAB and a pediatric study at Children’s of Alabama, were authorized by the Alabama Legislature in 2014 by legislation known as Carly’s Law.

After one month of beginning CBD therapy, 68 percent of the patients had experienced a greater than 25 percent reduction in seizure frequency; 58 percent had a greater than 50 percent reduction; 36 percent had a greater than 75 percent reduction and 9 percent were seizure-free. Those results were maintained at three and six months.

To assess seizure severity, researchers led by Jenifer DeWolfe, M.D., associate professor of neurology, used the Chalfont Seizure Severity Scale, a questionnaire given prior to therapy and re-administered at intervals throughout treatment. Fifty-seven patients were followed for three months: 67 percent experienced a more than 50 percent decrease in seizure severity, while 33 percent did not. Of 47 patients followed for six months, 64 percent had a greater than 50 percent decrease in seizure severity and 36 percent did not.

 “These are encouraging results, but it is important to note that each patient may respond differently to CBD, and the dose for optimal seizures control varies,” said Martina Bebin, M.D., professor of neurology and co-primary investigator of the CBD studies. “There appears to be an optimal CBD dose range where the patient achieves maximum benefit. If outside this CBD dosing range, the seizure frequency may not improve and may even increase. More research is needed, including determining why and how CBD helps some people with epilepsy but not others.”

Among the other UAB abstracts presented at the AES meetings:

·         CBD oil was associated with an improvement in mood, an effect independent of the extent of seizure reduction. Lead author Pongkiat Kankirawatana, M.D., professor of pediatrics, says CBD oil may have overall positive effects on mood, which should be further investigated in patients with epilepsy and other chronic conditions in controlled studies.

·         A study led by Szaflarski and Bebin found that the optimum dose in both children and adults was between 20 and 25 mg/kg/day.

·         Jane Allendorfer, M.D., assistant professor of neurology, found that CBD, in a selected group of patients with epilepsy who experienced overall improved seizure control, has the potential for positive cognitive effects that are associated with corresponding fMRI signal changes.

·         One abstract reports on an interaction between warfarin, a drug used as an anticoagulant, and CBD. This underscores the importance of monitoring appropriate laboratory work in patients receiving CBD oil along with other medications, according to study lead Brannon Vines, M.D., a clinical neurophysiology fellow.

·         Significant drug interactions were identified between CBD and commonly-used medications for epilepsy, including clobazam, rufinamide, topiramiate, zonisamide and eslicarbazepine. This study, led by neurology fellow Tyler Gaston, M.D., emphasizes the importance of monitoring anti-epilepsy drug levels during treatment with CBD. 

·         Electrical discharges measured by EEG decreased significantly after initiation and maintenance of CBD, particularly in pediatric patients, according to a study led by Leslie Grayson, M.D., a neurology fellow.

·         Using fMRI imaging, Amber Gregory, a graduate student in psychology, showed that persons with epilepsy showed gains in working memory that were associated with a shift in neural recruitment as examined with functional MRI.

·         An abstract aimed at examining associations between social determinants of health, such as age, gender and socioeconomic factors against health status, quality of life and mood states showed that higher age and low income were associated with lower health ratings among epilepsy patients, according to study led Magdalena Szaflarski, Ph.D., assistant professor of sociology.

The studies are designed to test the safety and tolerability of CBD oil in patients with intractable seizures. CBD oil, a derivative of the cannabis plant, is delivered orally as an oily liquid.

The oil used in the studies is produced under stringent requirements of the United States Food and Drug Administration by a licensed pharmaceutical company. It contains only traces of THC, the psychoactive component of marijuana. The process developed by GW Pharmaceuticals guarantees the consistency of the product that is provided to study participants.


By Bob Shepherd
UAB Media Relations

energy drinksVenkatraman says the drink contains a high level of caffeine, along with a variety of other ingredients, many of which are associated with increases in blood pressure.Investigators at the University of Alabama at Birmingham have presented the first case study of a patient experiencing a hemorrhagic stroke — a brain bleed — following consumption of an energy drink.

In an article in press in the American Journal of Emergency Medicine, the UAB physicians detail the case of a 57-year-old man who developed an intracranial hemorrhage within 15 minutes of drinking a popular energy drink.

The patient presented at a local emergency department and was transferred to the stroke unit at UAB with symptoms of sensory changes (tingling and numbness) in the right arm and leg, along with ataxia (shaky gait and movement). A CT scan revealed a small hemorrhage near the left thalamus.

“The man reported that his symptoms began about 15 minutes after drinking an energy drink, the first time he had consumed this particular product, as he was about to do yardwork,” said Anand Venkatraman, M.D., a fourth-year resident in the Department of Neurology at UAB and the lead author of the study.

Venkatraman says the drink contains a high level of caffeine, along with a variety of other ingredients, many of which are associated with increases in blood pressure.

“This particular drink contains several supplements for which we have little understanding of their potential interactions with each other or with caffeine,” Venkatraman said. “One is structurally similar to amphetamines, and several are known to stimulate the sympathetic nervous system.”

The sympathetic nervous system regulates what is known as the “flight or fight” response. When faced with an urgent, potentially dangerous situation, the body gears up to either take extraordinary action (fight) or run away (flight).

“The body begins to marshal all of its resources to respond to the situation at hand — boosting strength and alertness, for example — in part by raising blood pressure to increase blood flow,” Venkatraman said. “For a patient who may be at risk for vascular disease, this increase in blood pressure could be potentially dangerous, as a rise in blood pressure can affect an already weakened blood vessel to the point that it ruptures.”

Ingredients in the drinks that are suspected to influence the sympathetic nervous system include β-phenylethylamine hydrochloride, yohimbine and green tea extract. 

“These ingredients are supplements and, as such, are not regulated by the government to the same degree that medications are,” Venkatraman said. “We don’t have good information on dosing for some of these supplements. We don’t know how much is too much, for example, especially in populations with varying degrees of risk.”

Another issue is serving size. The manufacturer’s label says the bottle contains two servings, but the patient reported that he drank the full 8 oz. bottle at one time, a behavior that Venkatraman believes is common.

“The warning here is that we do not fully understand how some of these ingredients interact with other compounds,” Venkatraman said. “Nor do we have enough information on maximum dosages, especially for individuals with underlying health issues. Consumers need to be aware of the ingredients in the drinks if they choose to use them, and check with their physician if they have questions. They should also follow the manufacturer’s recommendations.”

 In this case, the patient had a history of elevated blood pressure and was at increased risk for vascular disease. Several months after the incident, the patient reported that he still had some residual effects from the incident.

“I am not anti-energy drink,” Venkatraman said. “In fact, I use them myself on occasion. But I strongly urge consumers to read the label and be informed. Don’t take unnecessary risks with your health. There is potential for a serious outcome.”

Contributing authors to the study are Angela Shapshak, M.D., associate professor of neurology, and Ayaz Khawaja, M.D., now a fellow in neurology at Harvard Medical School.

By Bob Shepherd
UAB Media Relations
   
nita limdi labNita Limdi, Ph.D., Pharm.D., professor of NeurologyA quick, precise genetic test can significantly reduce the risk of cardiovascular events by helping to identify more effective medication for some heart patients, according to new findings presented Nov. 15 at the American Heart Association’s Scientific Sessions in New Orleans. Investigators from the University of Alabama at Birmingham collaborated on the multisite study, which was led by researchers at the University of Florida.

Each year, more than 1 million coronary stents are placed in patients with heart disease. After the stent is put in place, patients are prescribed a combination of two anti-platelet medications to reduce the risk of heart attacks or strokes. The most commonly used combination is aspirin and clopidogrel, or Plavix. However, about 25-30 percent of patients have a gene variant that limits or prevents their body’s ability to activate clopidogrel, putting them at a higher risk for major adverse cardiovascular events.

In the new study, UAB investigators joined researchers from seven other institutions to combine data from 1,815 patients. All patients received genetic testing at the time of their stent placement and were followed for one year after the stent procedure.

Thirty percent of patients carried the gene variant that limits or prevents their body’s ability to activate clopidogrel. Based on that genotype, 60 percent of these patients were prescribed alternative anti-platelet medication, which reduced the number of deaths, heart attacks or strokes by nearly half compared with those who continued taking clopidogrel.

“This is the first large U.S.-based collaborative study assessing the implementation of a genetic test in the provision of personalized cardiovascular medicine,” said Nita Limdi, Pharm.D., Ph.D., professor in the UAB Department of Neurology and interim director of the UAB Hugh Kaul Personalized Medicine Institute. “Personalized medicine is about using an individual patient’s information, including genetic data, to tailor treatment.”

“In addition to the current implementation study, research from ongoing clinical trials may help provide additional evidence on effectiveness of genotype-guided therapy,” said Brigitta Brott, M.D., professor in the Division of Cardiovascular Disease in the Department of Medicine.

In addition to identifying the optimal anti-platelet therapy for stent patients, the genetic testing can be done efficiently. Overall, across the nine sites, genetic information was available in about one day. At UAB, the molecular diagnostic laboratory led by Shuko Harada, M.D., associate professor in the Department of Pathology, provided genotype results in 70 minutes, allowing physicians to make changes to the prescriptions immediately.   

“This study demonstrates the power and the promise of genotype-guided therapy in delivery of personalized medicine,” said Limdi. “Genetic testing can be done in real time, guidance on tailoring treatment can be incorporated into the clinical care, and that patient outcomes can be tracked to assess whether genotype-guided therapy improves patient outcomes. Evidence from such studies will collectively inform broader implementation of personalized medicine.”

"Genetic testing can be done in real time, guidance on tailoring treatment can be incorporated into the clinical care, and that patient outcomes can be tracked to assess whether genotype-guided therapy improves patient outcomes. Evidence from such studies will collectively inform broader implementation of personalized medicine.”

The study was conducted through a collaborative genomic medicine network funded by the National Institutes of Health and known as Implementing Genomics in Practice, or IGNITE. Collaborating sites are the University of Florida, Vanderbilt University Medical Center, University of Alabama at Birmingham, University of North Carolina, the University of Maryland-Baltimore, the University of Pittsburgh, the University of Illinois-Chicago, Indiana University-Indianapolis, Sanford Health, Duke University and the University of Pennsylvania.

UAB efforts are supported in part by UAB’s Health Service Foundations’ General Endowment Fund, Hugh Kaul Personalized Medicine Institute, and a grant from the National Heart, Lung, and Blood Institute.

By Bob Shepherd
UAB Media Relations

    UAB and Auburn will team up for a study of magnetic resonance imaging techniques that could enhance epilepsy surgery.  

brain scan verhoefAn MRI image showing the hippocampus of a patient with epilepsy.A $2.6 million, five-year grant from the National Institutes of Health will allow researchers at the University of Alabama at Birmingham and Auburn University to see whether a newly developed magnetic resonance imaging technique will provide more detailed images of the brains of epilepsy patients.

One of the keys to the study will be to see whether the new technique will allow less powerful but more available 3 tesla — or 3T — MRI machines to produce images as clear as the more powerful but fairly rare 7T MRI machines.

“Most MRI machines used for clinical imaging have a field strength of 3T or less,” said Lawrence Ver Hoef, M.D., associate professor in the UAB Division of Epilepsy in the Department of Neurology and principal investigator of the new study. “UAB has several 3T machines, and they are fairly common in hospitals and clinics throughout the state. There is only one 7T machine in Alabama, located at Auburn University, and there are less than 20 in North America.”

The more powerful 7T machines can produce more detailed images, but they are expensive and difficult to use. Due to these limitations, 7T machines are used primarily for research, not clinical care, according to Thomas S. Denney Jr., Ph.D., director of the Auburn University MRI Research Center and a co-investigator.

“The overarching goal is to see whether we can create images on a 3T machine that are as good as or better than we can achieve with a 7T machine, and we anticipate this study will help us verify this new approach,” Denney said.

MRI images are used frequently in epilepsy care. Surgery to remove small sections of the brain responsible for causing seizures is a highly specialized, tailored procedure, and physicians need precise imaging to determine which patients are good candidates for surgery and to minimize unwanted side effects. UAB is the only institution in Alabama that offers epilepsy surgery.

“The hippocampus in particular is a frequent locus for seizures, and it is a most difficult area to image with fine detail,” Ver Hoef said. “There is often a loss of clarity of the internal structures of the hippocampus with traditional MRI. Diagnosis is difficult if not impossible without clear images.”

Previous research done in Ver Hoef’s lab developed a new technique for MRI imaging of the hippocampus referred to as high-resolution, multiple image co-registration and averaging. This technique produces image resolution on a 3T machine that could previously be done only with a 7T machine.

“By altering some parameters and using conventional techniques in an unconventional way, we were able to develop a method for capturing high-resolution images that clearly and consistently visualized the internal architecture of the hippocampus,” he said.

Now, Ver Hoef and his collaborators at Auburn will test the new method by performing MRI imaging on 40 epilepsy patients using the new technique with the 3T MRI machines at UAB and comparing the results to those gained by traditional images from the 7T machine in Auburn.

“If we can show that we can get suitable images from the 3T machines, then we will have a significant improvement in the ability of MRI images to aid in pre-surgical evaluation of these patients,” Denney said. “If it doesn’t work, we reinforce the argument that the field needs more 7T machines for clinical use, which is an expensive proposition.”

 

A second aim of the study will be to see whether changes in the hippocampus could serve as a biomarker for the disease. Using the 3T and 7T machines, the investigators will test two groups of subjects, one with epilepsy well-controlled through medication and one with poorly controlled epilepsy, to see whether differences in the image clarity of the internal architecture are predictive of more severe disease.

 

In collaboration with Farah Lubin, Ph.D., associate professor in the UAB Department of Neurobiology and co-investigator of the new study, a third aim will attempt to see if the investigators can identify an epigenetic biomarker that could help in the future diagnosis of epilepsy. Epigenetics refers to genetic changes not encoded in DNA, but caused by external, environmental factors. Biomarkers are detectable, measurable signs that can be used to diagnose or treat disease.

Ver Hoef says the lack of definition seen in the hippocampus may be the result of astrogliosis, an increase in glial cells called astrocytes, which enlarge and proliferate when nearby neurons die through excitotoxic injury, one of the hallmarks of temporal lobe epilepsy. The researchers will study the brain tissue removed from the hippocampus during epilepsy surgery and compare it to the MRI brain images.

“We anticipate that there will be enhanced astrogliosis in certain layers of the hippocampus in those patients,” Ver Hoef said. “We will collaborate with Dr. Lubin, to measure epigenetic gene regulation and protein levels in the cells within these layers. No one has ever done layer-specific measurements of this type in epilepsy patients before.”

“We will look for correlations between what Dr. Ver Hoef sees on MRI images and what we find in our analysis of brain tissue,” Lubin said. “The hope is that, by employing clinical observation and imaging with laboratory analysis, we will be able to identify and confirm the presence of a biomarker that could provide valuable information for future diagnoses.”

“This is really an exploratory aim of the study,” Ver Hoef said. “Dr. Lubin will try to determine whether there is evidence of epigenetic changes and whether those changes will serve as a biomarker. If we get to a point where we can treat disease by restoring epigenetic balance, this may allow cells to heal themselves, which would be an exciting prospect in the treatment of disease.”

The study is a collaboration of the Alabama Advanced Imaging Consortium, of which Auburn and UAB are founding members. The AAIC promotes collaboration, project management and support between the major research centers in the field of imaging in Alabama.

 
Bob Shepherd
UAB Media Relations