Posts Tagged Pharmacy
January 8, 2018
UC San Francisco neurologists have discovered monthly cycles of brain activity linked to seizures in patients with epilepsy. The finding, published online January 8 in Nature Communications, suggests it may soon be possible for clinicians to identify when patients are at highest risk for seizures, allowing patients to plan around these brief but potentially dangerous events.
“One of the most disabling aspects of having epilepsy is the seeming randomness of seizures,” said study senior author Vikram Rao, MD, PhD, an assistant professor of neurology at UCSF and member of the UCSF Weill Institute for Neurosciences. “If your neurologist can’t tell you if your next seizure is a minute from now or a year from now, you live your life in a state of constant uncertainty, like walking on eggshells. The exciting thing here is that we may soon be able to empower patients by letting them know when they are at high risk and when they can worry less.”
Epilepsy is a chronic disease characterized by recurrent seizures — brief storms of electrical activity in the brain that can cause convulsions, hallucinations, or loss of consciousness. Epilepsy researchers around the world have been working for decades to identify patterns of electrical activity in the brain that signal an oncoming seizure, but with limited success. In part, Rao says, this is because technology has limited the field to recording brain activity for days to weeks at most, and in artificial inpatient settings.
At UCSF Rao has pioneered the use of an implanted brain stimulation device that can quickly halt seizures by precisely stimulating a patient’s brain as a seizure begins. This device, called the NeuroPace RNS® System, has also made it possible for Rao’s team to record seizure-related brain activity for many months or even years in patients as they go about their normal lives. Using this data, the researchers have begun to show that seizures are less random than they appear. They have identified patterns of electrical discharges in the brain that they term “brain irritability” that are associated with higher likelihood of having a seizure.
- Adequate intake of choline during pregnancy could provide cognitive benefits for offspring
- Powerful imaging technique sheds light on how the brain responds to vascular injury
- Callous-unemotional traits linked to brain structure differences in boys, not girls
The new study, based on recordings from the brains of 37 patients fitted with NeuroPace implants, confirmed previous clinical and research observations of daily cycles in patients’ seizure risk, explaining why many patients tend to experience seizures at the same time of day. But the study also revealed that brain irritability rises and falls in much longer cycles lasting weeks or even months, and that seizures are more likely to occur during the rising phase of these longer cycles, just before the peak. The lengths of these long cycles differ from person to person but are highly stable over many years in individual patients, the researchers found.
The researchers show in the paper that when the highest-risk parts of a patient’s daily and long-term cycles of brain irritability overlap, seizures are nearly seven times more likely to occur than when the two cycles are mismatched.
Rao’s team is now using this data to develop a new approach to forecasting patients’ seizure risk, which could allow patients to avoid potentially dangerous activities such as swimming or driving when their seizure risk is highest, and to potentially take steps (such as additional medication doses) to reduce their seizure risk, similar to how people with asthma know to take extra care to bring their inhalers when pollen levels are high.
“I like to compare it to a weather forecast,” Rao said. “In the past, the field has focused on predicting the exact moment a seizure will occur, which is like predicting when lightning will strike. That’s pretty hard. It may be more useful to be able tell people there is a 5 percent chance of a thunderstorm this week, but a 90 percent chance next week. That kind of information lets you prepare.”
The University of Utah College of Pharmacy’s Anticonvulsant Drug Development (ADD) Program has been awarded a five-year $19.5 million contract renewal with the National Institutes of Health (NIH) to test drugs to treat epilepsy, and the major focus of the project is to address needs that affect millions of people worldwide -identify novel investigational compounds to prevent the development of epilepsy or to treat refractory, or drug-resistant, epilepsy.
The ADD program began in 1975 and since then has tested the vast majority of drugs used to control seizures in patients with epilepsy, helping millions of people worldwide. Unfortunately, almost one-third of the estimated 50 million people with the disorder has refractory, or unresponsive, epilepsy that isn’t adequately controlled by medications currently available. The contract renewal, awarded through the National Institute of Neurological Disorders and Stroke (NINDS) to the U Department of Pharmacology and Toxicology, represents a shift in the mission to identify new therapies, according to ADD Director Karen S. Wilcox, Ph.D., professor and chair of pharmacology and toxicology and principal investigator of the contract.
“We’re proud that over the past 41 years, the ADD program has played a key role in identifying and characterizing many of the drugs now available to treat patients with epilepsy and to control their seizures,” Wilcox says. “Now, we’re looking for drugs that can modify or prevent the disease, particularly in those patients either with refractory epilepsy or at risk for developing epilepsy following a brain injury.”
Epilepsy is a group of neurological disorders characterized by a tendency for repeated seizures over time. It occurs when permanent changes in the brain result in abnormal or excessive neuronal activity in the brain. An estimated 2.9 million people in the United States and 50 million people worldwide have active epilepsy, according the Centers for Disease Control and World Health Organization. There is no cure for epilepsy and the mainstay of treatment is anti-seizure medications.
ADD is a long-standing program dedicated to testing drugs to treat epilepsy. It has received continuous funding from NINDS’ Epilepsy Therapy Screening Program (ETSP) (formerly known as the Anticonvulsant Screening Program) since its founding in 1974. In collaboration, the ETSP and the ADD Program have evaluated more than 32,000 compounds. ADD received the contract in a competitive bidding process. The renewal of the contractual relationship between the NINDS and the University of Utah reflects the ongoing commitment of the NIH and the ETSP to finding and developing novel therapies for epilepsy and represents a unique partnership between government, industry, and academia.
“The NIH-NINDS ETSP is pleased to continue the productive relationship with the University of Utah,” says Dr. John Kehne, a Program Director at NINDS and head of the ETSP. “These and other efforts supported by the NINDS will help to discover new pharmacotherapies to address the unmet medical needs of people living with epilepsy.”
In addition to its focus on evaluating potential candidate drugs for the treatment of therapy-resistant epilepsy, the mission of the ADD Program includes efforts to identify novel therapies for different types of epilepsy. The program also serves as a base for innovative basic research that sheds new light on the pathophysiology of epilepsy and provides a unique training environment for students, research fellows, and visiting scientists. Currently, the ADD program employ18 researchers, technicians, and staff. Cameron S. Metcalf, Ph.D is associate director and a co-Investigator of the contract and Peter J. West, Ph.D., and Misty D. Smith, Ph.D, research assistant professors of pharmacology and toxicology, are also co-investigators on the contract renewal.
Although there currently is no cure for epilepsy, Wilcox, who previously served as a co-Investigator of ADD before taking over as PI in 2016, believes that can be changed.
“The brain has remarkable plasticity throughout a person’s life,” she says. “If we learn enough about neuroscience and the details of how the brain works, it’s very possible to find a cure.”