Ketamine Shows Promise as Therapy for Brain Trauma and Mood Disorders
Jed Hartings, PhD, in his office. Behind him are a few of the studies he has published in the last year. Photo by Cindy Starr / Mayfield Clinic. Patients who are fighting for their lives as a result of conditions as diverse as major depression, stroke and traumatic brain injury may benefit from an established drug that is drawing new attention from researchers at the University of Cincinnati Neuroscience Institute. Ketamine, commonly used as an anesthetic, is showing promise in its ability to treat a subset of patients with bipolar disorder and to cause sudden improvement in people with depression who have not responded to other treatments. Equally exciting, neurotrauma researchers at the UC Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health, recently co-authored a study that showed that ketamine halted the damaging electrical activity known as brain tsunamis after traumatic brain injury and stroke. Cal Adler, MD “Ketamine is an anesthetic that is commonly used in children and widely used in veterinary practice,” says Cal Adler, MD, Associate Professor of Psychiatry and Behavioral Neuroscience and an expert at the UC Mood Disorders Center. “It is also a drug of abuse. ‘Special K,’ the club drug, is ketamine.” The drug is known to lower body temperature and to improve cerebral blood flow. It also can cause symptoms of disassociation – a feeling of an out-of-body experience – as well as hallucinations. Although it is being investigated as a potential therapy for patients with severe depression and anxiety disorders that do not respond well to other treatments, it is not currently prescribed by physicians at the UC Mood Disorders Center. Ketamine works by controlling glutamate, a neurotransmitter that normally plays an important role in memory and learning. If glutamate is present in excessive amounts, however, it overstimulates brain cells, causing them to die from “excitotoxicity.” Ketamine blocks the neuro-excitatory effects of glutamate by interfering with one of its receptors, known as NMDA (N-methyl D-aspartate). In scientific parlance, ketamine is an NMDA receptor antagonist, which means that it works by antagonizing, or inhibiting, the ability of the NMDA receptor to act. Because the NMDA receptor is involved in several areas of brain regulation, the result of this activity may have different results for different types of patients. Erik Nelson, MD “When you block this NMDA receptor, you get a sudden increase in signaling through a different receptor, AMPA, which is thought to underlie the rapid antidepressant effect,” says Erik Nelson, MD, Associate Professor of Psychiatry and Behavioral Neuroscience. Limiting glutamate might also slow the spread of damage following brain trauma or stroke. “Glutamate enables one cell’s firing to communicate with the next cell and cause it to fire as well,” explains Jed Hartings, PhD, Assistant Professor in the Department of Neurosurgery. “After a head injury or stroke, the brain becomes hyper-excitable, and we believe that an excess amount of glutamate or the disregulation of ions in the brain is what is causing them to fire too much. This disregulation can lead to seizures and also to electrical disturbances called spreading depolarizations (or brain tsunamis).” Decades of research in animal models have shown that blocking the NMDA receptor is the best way to stop spreading depolarizations. Last year, for the first time, Dr. Hartings and his colleagues from the international group COSBID (Co-Operative Studies of Brain Injury Depolarizations) accumulated brain-monitoring data of patients who had suffered spreading depolarizations after head trauma or stroke. During the observational, retrospective study, which included patients treated at the UC Medical Center, the researchers compared spreading depolarizations in patients who were treated with various medications during their hospitalization. “There was no intention to treat spreading depolarizations with ketamine,” Dr. Hartings said. “But some patients in the European population were given ketamine for other reasons. And we found that when that drug was given, the depolarizations stopped.” The group’s study was published in the August 2012 issue of the journal Brain. The next step for Dr. Hartings and his team is to conduct a study that administers ketamine to patients with an intention to treat spreading depolarizations. An application is in process with the U.S. Department of Defense. If the study is funded, Dr. Hartings said, it would be the first “selective inclusion trial” ever for a brain trauma therapy. Whereas study therapies for brain trauma previously have been given to all study participants, ketamine would be delivered only to those who are known to be experiencing spreading depolarizations. At the same time, the ability of ketamine and ketamine-like drugs to block the NMDA receptor is attracting widespread interest within the psychiatric community. UC is a study site for an investigational medicine that was discovered and is being developed by AstraZeneca Pharmaceuticals. The medication, given as an infusion (by IV) to study patients with treatment-resistant depression, resembles ketamine in that it blocks glutamate receptors, but its side-effects are fewer. Meanwhile, an NMDA antagonist called memantine is being used in the treatment of moderate to severe Alzheimer’s disease. In Alzheimer’s disease, as in neurotrauma, an excessive amount of glutamate appears to kill nerve cells through excitotoxicity. “The story of the NMDA antagonists is exciting, and we may be using more of these drugs therapeutically in the not-too-distant future,” Dr. Adler says. “We’re still pretty early in process, but ketamine represents the first really new treatment for depression since the advent of serotonin reuptake inhibitors (SSRIs). – Cindy Starr
Dr. Michael Privitera Answers 6 Common Questions about Epilepsy
Photo of Michael Privitera, MD, by UC Academic Health Center Communications Services. Seizures are among the most puzzling mysteries in medicine. They can occur any time, at any age and without any warning. Michael Privitera, MD, Director of the Epilepsy Center at the University of Cincinnati Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health, has developed a national reputation for explaining the mystery of seizures to the general public. After recent reports that the rapper Lil Wayne was hospitalized because of seizures, Dr. Privitera explained to MTV.com why a 30-year-old might suddenly develop an epileptic condition. Dr. Privitera was also recently interviewed by People magazine after Kelley Osbourne, the English singer and actress, suffered a seizure. Below, Dr. Privitera answers six of the most commonly asked questions about seizures. Q: What happens when I have a seizure? A: A seizure starts in the brain as an electrical disturbance in which nerve cells all fire at the same time instead of in a smooth, coordinated manner. The area in the brain where this electrical activity occurs will determine the seizure’s clinical appearance, or manifestation. For example, if the seizure starts in the part of the brain that controls motor function in the hand, the shaking may start in the hand. If it starts in a part of the brain that involves consciousness, the person may just blank out. And if the seizure discharge spreads to involve the entire brain, the individual may have a convulsive seizure, which is also known as a grand mal seizure. Q. Why does a person develop seizures? A: This is a difficult question because in about 50 percent of people we cannot tell. We simply will not be able to tell them what caused their seizure. The most common causes are related to head trauma or a severe infection that involves the brain, such as meningitis or encephalitis. Sometimes stroke or tumors can cause seizures. But in about half of patients, the MRI scan is normal and we do not really know why they have seizures. Sometimes there is a genetic factor in seizures, but this is less common than most people might think. The causes also differ substantially by age of onset. Q: What triggers a particular seizure? A: If someone has not had a seizure for six months and then has one out of the blue, they invariably want to know why it happened. And again, we have some ideas. Major triggers of seizures include sleep deprivation, not taking one’s medication or drinking alcohol. We believe that stress is another potential trigger. But very often we do not see a particular trigger, and the seizure has just happened. This is one of the research areas that we are keenly interested in: what makes people have seizures at a particular time, what is the role of stress as a trigger, and how can we predict when seizures will occur? Q: Why do I need to take medication every day if I have only had one or two seizures? A: This is a question we frequently hear from our patients who have been newly diagnosed, and the answer is related to the one above. Unfortunately, seizures are unpredictable and we do not have a good idea of exactly when one will occur. A seizure could happen when you are sitting down to dinner, but it also could happen while you a driving on a busy highway or walking down a flight of stairs. Because of that, people need to take medication every day to help protect the brain against future seizures. Q: Is it safe to have a baby if I have epilepsy? A: This is an area of research that Dr. Jennifer Cavitt is leading at the Epilepsy Center. As far as we know right now, all of the available seizure medicines have the potential to increase the risk of malformations for the baby. What is very clear is that some medicines are worse than others. We have identified the worst ones, and we know that women should almost never take them during pregnancy. We know that there are some medicines that seem to be less risky, and we try to use those whenever we can. Because the other problem is that having seizures during pregnancy is also a risk. The medicine has a risk to the baby, but not taking the medicine could increase the risk of seizures, which could be bad for the baby as well. That is the balance we have to strike. The UC Epilepsy Center was part of a major study that looked at the rate of serious birth defects in babies whose mothers were taking seizure medicine. The study also looked at IQ problems in those children. This was the first time anyone had done the most rigorous research necessary for IQ, because you have to check the mother’s IQ as well as the child’s. The IQ of the child is more closely correlated to the mother’s IQ than the father’s. Our study showed that the medicine, valproate (or Depakote) on average reduced children’s IQ by 9 points, which is a huge number. The other medicines either had no effect or one that was very small. The dose also played a role: the higher the dose, the greater the effect. We are doing a follow-up study now with the newer anti-seizure medicines. Q: How does my doctor know which medicine to prescribe for me? A: Most of the available medicines are approximately equal in their effectiveness at stopping seizures, as long as the main epilepsy syndrome is correctly identified. But their side-effect profiles are very different. So I talk to my patients and determine the side-effect profile that is best suited to them. For example, some seizure medicines can amplify depression, while others can make it better. So if a patient has a history of depression, I absolutely want to choose a seizure medicine that has a positive effect on depression.
Gardner Center Specialists Provide Answers for Essential Tremor
March is Essential Tremor Awareness Month, and everyone at the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders sends a vote of confidence and a word of encouragement to the more than 2,000 Gardner Center patients who are affected by this progressive neurological condition. The Gardner Center is a center of excellence at the UC Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health. Essential tremor is a movement disorder that is also known as familial tremor, benign essential tremor or hereditary tremor. It causes a rhythmic trembling of the hands, head, voice, legs or trunk and can make everyday activities, such as eating, drinking, dressing and writing difficult. Although it does not garner as much media attention as Parkinson’s disease, it is at least three to four times as common as Parkinson’s, affecting an estimated 3.9 to 14 percent of all elderly individuals. Katharine Hepburn is the most famous American to have coped with the condition. Although essential tremor has no definitive cure, up to two-thirds of patients have such mild symptoms that they do not require treatment. For the other third, treatment can involve medication and, in severe cases, surgery. “There are two first-line oral treatments for essential tremor,” explains Alberto Espay, MD, a UC Health neurologist and movement disorders specialist at the Gardner Center. “One is an anti-epileptic drug called Primidone. And the other is an anti-hypertensive drug called Propranolol. “It is an interesting situation in that you have two drugs that were really not designed for essential tremor but were given to patients for either epilepsy or hypertension. In the process, doctors discovered that patients who also happened to have essential tremor reported that their tremor improved while they were taking the drug. And that’s how we serendipitously have our two best drugs for essential tremor.” Symptoms progress slowly for most patients with essential tremor, but over time tremors can become severe. At the Gardner Center, those patients have the option of undergoing surgery, which is performed by neurosurgeons George Mandybur, MD, and Ellen Air, MD, PhD. Surgery targets the thalamus, the part of the brain that is overactive in patients with essential tremor. The most commonly performed surgical procedure is deep brain stimulation (DBS) surgery. During DBS tiny electrodes are implanted in a small part of the thalamus and connected to a programmable, battery-powered device that creates electric pulses. The device, which resembles a heart pacemaker, is implanted beneath the collar bone. The electrodes deliver a low-intensity current that continually pulses through the thalamus, neutralizing it without damaging it. In a less commonly performed procedure, surgeons use an electrode to ablate (destroy) the overactive part of the thalamus. Meanwhile, lifestyle changes may ease symptoms of essential tremor. Fredy J. Revilla, MD, Director of the Gardner Center and the James J. and Joan A. Gardner Family Chair, says that decreasing or eliminating the consumption of caffeine (e.g., coffee and caffeinated beverages) or other stimulants may reduce tremor, while hand and wrist exercises can promote hand stability. Although alcohol is known to reduce tremor, Dr. Revilla does not recommend alcohol consumption as a treatment because of the risk of alcohol dependence. Essential tremor differs from Parkinson’s disease in some important ways. Whereas fewer than 10 percent of people with Parkinson’s disease have a family history of the disease, more than 50 percent of patients with essential tremor have a family history of their condition. While Parkinson’s usually starts on one side of the body and remains asymmetrical when progressing to the other side, essential tremor usually affects both sides from the beginning. And while the tremor in Parkinson’s is usually confined to the hands and, to a lesser extent, the legs, essential tremor predominantly affects the hands but can also affect the head, jaw and voice. As many as 20 percent of patients with essential tremor may also go on to develop Parkinson’s disease, but researchers have not confirmed that essential tremor is a risk factor for Parkinson’s. The Essential Tremor Support Group welcomes patients treated at the Gardner Center. The group shares information about new studies, medication, coping and helpful hints from 2 to 4 p.m. on the second Sunday of each month, except in May, when it meets on the third Sunday. Meetings are held at Sycamore/Kettering Hospital on Leiter Road in Miamisburg, Ohio, about one mile from I-75. Come to Dining Room 2 on the lower level. Meetings are free and open to anyone with essential tremor, as well as families, caregivers and friends. For more information, contact Arlene Rosen in Cincinnati at (513) 791-5546 or [email protected] or Norma Doherty in Dayton at (973) 433-0153 or [email protected]. Learn more: Lacking a Michael J. Fox, Essential Tremor Advocates Tell Their Story >> – Cindy Starr
Dr. Ronald Warnick Honored with Tew Chair in Neurosurgical Oncology
From left, Ronald Warnick, MD, Wally Pagan, and John M. Tew, MD, at the Tew Chair celebration at the Queen City Club. Photo by Tonya Hines / Mayfield Clinic. The community that raised $2 million to create the John M. Tew, Jr., MD, Chair in Neurosurgical Oncology was sincerely thanked last Friday with a memorable evening highlighted by tributes, memories and pledges of stewardship. Attending the event were more than 100 dignitaries, donors and supporters of the Tew Chair, which was awarded to Ronald Warnick, MD, Professor of Neurosurgery and Radiation Oncology and Medical Director of the UC Brain Tumor Center at the UC Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health. The chair, a tribute to Dr. Tew, Professor of Neurosurgery, Radiology and Surgery at UC and Clinical Director of the UC Neuroscience Institute, was announced by Mario Zuccarello, MD, Professor and Chairman of the Department of Neurosurgery and the Frank H. Mayfield Chair for Neurological Surgery. The chair is an endowment at the UC College of Medicine that will fuel research in brain cancer and brain metastasis in perpetuity. “Tonight we gather here to acknowledge that we owe you an enormous debt of appreciation,” Dr. Tew told the audience. “We want to assure you that your hopes and the expectations that you have entrusted to us will be continuously respected by our extraordinary team of experts – experts who share your hope and passion for the future of science.” Dr. Tew said he wished to honor all those who donated financially to the Tew Chair’s endowment as well as “all the people who give of their talents, their resources, their efforts, their wisdom every day.” UC Trustee Ginger Warner read a proclamation from Governor John Kasich. Ginger Warner, a University of Cincinnati Trustee and friend of the Brain Tumor Center, read a proclamation from Ohio Governor John Kasich in which he recognized Dr. Warnick as the John M. Tew Chair, commended him for his commitment and dedication, and expressed his certainty that “you will change many lives in the coming years.” James Kingsbury, President and CEO of UC Health, described Dr. Tew as a thinker who envisioned a neuroscience institute built on centers of excellence that could serve the entire region. He said the UC Comprehensive Stroke Center, headed by Joseph Broderick, MD, which serves 26 area hospitals, was the best example of expanding the center concept to the region. The center concept today, he said, is central to UC Health’s interdisciplinary focus and to its conviction that, as the region’s only academic health center, “it should make an impact on all other hospitals and practices.” Mr. Kingsbury also praised Dr. Tew for ushering in a new generation of leaders, including Dr. Warnick. “Instead of developing the Brain Tumor Center himself, John said, ‘Ron Warnick, I want you to develop the center.’ John mentored him, encouraged him, and supported him … assisted him in how to develop an advisory council and how to raise funds, how to put together a business plan. So John began another legacy of not just doing things, but of helping train new leaders to do great things.” John Hutton, MD In another reflection, John Hutton, MD, Dean Emeritus of the UC College of Medicine, praised Dr. Tew for his “uncanny ability to spot and develop young talent.” That talent included Dr. Warnick, who was a rising young neurosurgeon when he caught Dr. Tew’s eye. “I was a brain tumor fellow at the University of California San Francisco with a job offer from the University of Pennsylvania,” Dr. Warnick recalled. “Just before signing the contract, I received a call from John Tew. It was the sheer force of his personality that persuaded me to visit Cincinnati. I arrived in 1991, and since then we have worked side by side on many important projects in neurosurgery and neuro-oncology.” A central tenet of the UC Brain Tumor Center is teamwork. From diagnosis through treatment and recovery, patients are evaluated and cared for by a multidisciplinary team. In keeping with that core value, Dr. Warnick recognized his colleagues “in the Mayfield Clinic, the UC Brain Tumor Center and the Community Advisory Council,” many of whom were in attendance, and thanked them for their support and guidance. He also thanked his patients, “whose courage and spirit are constant sources of inspiration.” To the community that had entrusted him with the Tew Chair, Dr. Warnick concluded, “I’m going to work tirelessly to exceed your expectations … I will make you proud.” – Cindy Starr
Coping with an Unwelcome Disorder: Lewy Body Dementia
For Dean Jennings, neurological disease arrived cloaked in disguise. It began with memory problems at work, which he hid from his wife and co-workers, then revealed itself with balance problems, a shuffling walking pattern and an unexpected fall on the tennis court. Dean’s initial diagnosis was “possible Parkinson’s disease,” and later he was treated with medications for Parkinson’s disease. But Dean’s true problem, which was diagnosed after Dean began experiencing hallucinations, was Lewy body dementia, which is related to both Parkinson’s and Alzheimer’s diseases. Judy Towne Jennings, PT, MA The story of Dean Jennings, a former patient of Andrew Duker, MD, a UC Health neurologist, is told in a new book for caregivers, Living with Lewy Body Dementia, by Dean’s widow, Judy Towne Jennings, PT, MA , of Cincinnati. Dr. Duker, who treated Dean at the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health, served as one of Ms. Jennings’s editors. Although Lewy body dementia, or LBD, does not receive as much publicity or attention as Alzheimer’s disease or Parkinson’s, it is the third most common cause of dementia after Alzheimer’s and vascular dementia, accounting for 10 to 25 percent of cases, according to the Alzheimer’s Association. The hallmark of the disease is the presence of Lewy bodies, normal proteins that become abnormally clumped together inside neurons, or brain cells. They are named after Dr. Frederick Lewy, the neurologist who discovered them while working in Dr. Alois Alzheimer’s laboratory and who first described them in 1912. Dr. Lewy discovered Lewy bodies in the brains of people with Parkinson’s disease. Lewy body dementia is typically diagnosed via symptoms, medical history and a complete laboratory workup that can rule out other causes of cognitive problems. Brain imaging does not reveal changes until the patient is in advanced stages of the disease. Brendan Kelley, MD “Individuals with Lewy body dementia can have difficulty in any of the cognitive domains, especially memory, visuospatial skills, and the ability to plan, anticipate and think abstractly,” says Brendan Kelley, MD, the Sandy and Bob Heimann Chair in Research and Education of Alzheimer’s in UC’s Department of Neurology and Medical Director of the UC Memory Disorders Center. “Other symptoms may include parkinsonism, visual hallucinations, fluctuations in attention and alertness during the day and sensitivity to temperature changes. Lewy body dementia also can be associated with sleep symptoms, such as acting out dreams at night.” The diagnosis of Lewy body dementia, Ms. Jennings writes, “felt like a torpedo piercing my chest.” Families facing this diagnosis receive the unwelcome news that Lewy body disease, unlike Parkinson’s, often involves a rapid, cognitive decline. How caregivers cope becomes an important part of the patient’s overall healthcare scenario. Andrew Duker, MD “Just as with Parkinson’s disease, every patient has his or her own version of Lewy body dementia, and each person will be affected differently by the disease,” Dr. Duker notes. “There will be good days and bad days, and with LBD the good and the bad can fluctuate even over hours within the same day. I advise caregivers to hold on to the good periods when they come and use them to help get through the bad periods.” The hallucinations that frequently occur can be especially traumatic for family members. Dr. Duker advises patience when a loved one is hallucinating. “Their brain is feeding them incorrect information, but to them what they are seeing is quite real,” he says. “If the hallucination is not frightening or threatening, choose your battles as to when or when not to try to explain what is real. If the hallucinations are frightening to them, tell the doctor, as there are medications that can help.” Dr. Duker strongly encourages caregivers to take respite time for themselves. “You cannot expect to care for your loved one 24 hours per day, seven days per week, without burning out.” Dr. Kelley stresses that treating contributing factors, including underlying medical disorders, psychiatric conditions, and sleep issues, is essential. “Exercise and other physical activity may be helpful, and patients are encouraged to remain socially and cognitively active,” he says. “Because both cognitive changes and parkinsonism can increase the risk of falls in those with Lewy body disease, taking steps to reduce the risk of falling is vital.” Ms. Jennings worked to maintain an “I-can attitude” for both her husband and herself. To help him navigate the household after his retirement from his work as an engineer, she writes that she “circled the start buttons on the dishwasher, labeled the stove burner and painted an arrow on the clothes dryer controls to help him visually see how to operate the appliances.” She also made the days more precious by scheduling outings, watching sporting events that her husband enjoyed, encouraging him to resurrect old hobbies (including his high school band instrument) and listening to audio books. “I always had a vacation looming in the future to keep my sanity,” Ms. Jennings writes. “Mostly, I was trying to encourage Dean to keep moving … We found many ‘carrots’ that inspired both of us to get out of bed each morning and make the decision to celebrate life.” – Cindy Starr
UCNI Celebrates its 2013 Healthcare Heroes
From left, Health Care Heroes honorees Christopher McPherson, MD, Yash Patil, MD, and George Atweh, MD. All are affiliated with the UC Brain Tumor Center and the UC Cancer Institute. Photos by Cindy Starr. Whether he received highest honors or simply the honor of being a finalist in the Cincinnati Business Courier’s 2013 Health Care Heroes event, Yash Patil, MD, was prepared to continue doing what he does best: provide compassionate and superior care to his patients with head and neck cancer at the UC Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health. “My 6-year-old asked what I would do if I didn’t win,” Dr. Patil told the packed ballroom at the Duke Energy Convention Center Tuesday evening. “I said, I’ll put on my scrubs and go to work tomorrow.” As it turned out, that humility and dedication to his patients helped make Dr. Patil a winner in the provider category. “I’m phenomenally humbled,” he said, during a short impromptu speech. “I’m privileged to be in this room with so many extraordinary individuals.” Dr. Patil, Assistant Professor in the Department of Otolaryngology-Head & Neck Surgery, was nominated by one of his grateful patients, Bill Budde, and Mr. Budde’s wife, Jayme, who helped Dr. Patil launch a support group for people with head and neck cancer. “Dr. Patil has given a voice to all of us, even those who are physically unable to speak,” the Buddes wrote in their nomination. “He is our hero—and his unselfish example has helped each of us who have been affected by this terrifying disease to find the little piece of hero in ourselves.” In turn, Dr. Patil praised the hundreds of patients he treats each year and the dozens each week who receive good news or sorrowful news about their prognoses. He commended the patients who have assisted and nurtured each other in the support group for people with oral cancers, which are painful and potentially disfiguring. Dr. Patil was joined by two additional cancer experts at the event: George Atweh, MD, Director of the UC Cancer Institute, who was a finalist in the manager category; and Christopher McPherson, MD, a specialist with the UC Brain Tumor Center who was a finalist in the innovator category. The Brain Tumor Center is part of both the Neuroscience and Cancer institutes. John Hawkins, MD, of the Lindner Center of HOPE John Hawkins, MD, left, Chief of Psychiatry and Deputy Chief of Research at the Lindner Center of HOPE, an affiliate of UCNI, was named the winner in the innovator category for efforts in the delivery and research of transcranial magnetic stimulation (TMS). The therapy, a treatment for medication-resistant depression, is a noninvasive procedure that uses an electromagnetic coil to stimulate nerve cells in the brain. It was approved by the Food and Drug Administration in 2008. Dr. Hawkins, Adjunct Associate Professor in the Department of Psychiatry and Behavioral Neuroscience, views the therapy as an important alternative for people who have not responded well to medications and psychotherapy. As a researcher, Dr. Hawkins is collecting data related to safety, patient outcomes and the most effective methods of delivering the treatment. “The Lindner Center of HOPE was the first healthcare organization in Ohio to provide TMS, and under the guidance of Dr. Hawkins, remains one of few that continue to do so,” says Paul Keck, MD, President and CEO at the Lindner Center. “To date, 26 individuals have received TMS, with 33 percent experiencing complete remission (healthy and recovered) of depression, and 62.5 percent at least partial improvement. These are impressive findings since nearly all individuals who have received TMS at the Center of HOPE had few if any other treatment alternatives. In this very real sense, TMS has offered genuine hope where none would have existed to people with depression.” Dr. McPherson, Associate Professor in the UC Department of Neurosurgery, was honored for his growing national role in the research and treatment of brain tumors. He is currently involved in 11 clinical trials that could lead to better treatments for malignant gliomas. Dr. McPherson is Cincinnati’s principal investigator in The Cancer Genome Atlas, a national study that seeks to map out the glioblastoma and gliomas tumors’ entire genomes in order to identify abnormalities at the molecular level that could be targets for therapies of the future. He is also Cincinnati’s principal investigator in the Ohio Brain Tumor Research Study, which is looking at risk factors for brain tumors. Dr. Atweh is the Koch Chair and Professor in the Department of Internal Medicine’s Division of Hematology/Oncology at UC. He also directs the adult cancer program at the UC Health Barrett Center and is Associate Director of adult medical oncology for the Cincinnati Cancer Consortium. Dr. Atweh was recruited to UC in March 2009 from Mt. Sinai Medical Center, where he headed up the hematology/oncology division and served as Interim Director of the Tisch Cancer Institute and Associate Director of the General Clinical Research Center. He studied medicine at the American University of Beirut and performed fellowships at Duke University and Yale University. — Cindy Starr
Tonic for the Brain: Arias from Cincinnati Opera
CCM student Tyler Alessi, left, and CCM graduate Samina Aslam, perform during a celebration of the UC Medical Center’s new partnership with Cincinnati Opera in the hospital’s lobby. Photos by Cindy Starr / Mayfield Clinic. The power of music, with all of its beauty and adjunct neurological benefits, swept through the lobby of the University of Cincinnati Medical Center (UCMC) on Wednesday as the hospital celebrated a new partnership with Cincinnati Opera. Among those enjoying the occasion – which included arias and Broadway tunes from four gifted young vocalists — were four specialists from the UC Neuroscience Institute who helped make it happen: Drs. Sid Khosla, Charles Kuntz, IV, John M. Tew, Jr., and Mario Zuccarello. The UC Neuroscience Institute is one of four institutes of the UC College of Medicine and UC Health. It is perhaps no surprise that the four neuroscientists share a passion for opera, a neurological triumph blending sight, sound, language, voice and soul. “Music involves the entire brain, or almost the entire brain,” said Dr. Khosla, Assistant Professor of Otolaryngology at UC and Director of the UC Health Voice and Swallowing Center. In a 2009 interview with CNN, Dr. Wendy Magee, International Fellow in Music Therapy at London’s Institute of Neuropalliative Rehabilitation, described music as a “mega-vitamin for the brain” that could influence and improve motor function, communication and even cognition. Voice specialist Sid Khosla, MD As such, researchers have found that music, with its complex and widespread neural pathways, enables some individuals with neurological diseases or disorders to rise above limitations in specific parts of the brain. The act of singing employs pathways that are different from those used in speaking, for example, and people who stutter, have suffered a stroke, or suffer from spasmodic dystonia may benefit from music therapy, a type of task-specific training, Dr. Khosla said. The movie, The King’s Speech, is an example where stuttering abates when music is playing in the background. “We have a lot of different theories about why we have task specificity as human beings, and they’re fascinating, but we don’t know for sure,” Dr. Khosla said. “The newer theories are evolving from brain imaging of the gray matter and the white matter tracts, which facilitate electrical connections between different parts of the brain.” At UC Health Drake Center, rehabilitation therapists employ music in the treatment of stroke survivors who suffer from aphasia, a language impairment that makes communication difficult. “Often folks cannot speak fluently, but if you give them a familiar song, they can sing it well,” said Paige Thomas, PT-MSR, NCS, MHA, manager of outpatient physical therapy and occupational therapy. “It helps tap into those rote and automatic speech patterns.” Alberto Espay, MD, a neurologist with the James J. and Joan A. Gardner Center for Parkinson’s Disease and Movement Disorders, says the rhythm and melody of music can replace some of the abnormal motor programs in the brains of patients with Parkinson’s disease “with more ‘harmonic,’ better sequenced programs.” The best example of this, Dr. Espay said, is seen in patients who have problems with gait and who are at risk of suddenly freezing in place while walking. These patients can experience a restoration of gait with music, Dr. Espay said. “The type of music that works best will vary from person to person. The optimal music is something that resonates with the patient and has a beat that is contagious enough that it can be brought to mind during potentially freezing moments.” Wednesday’s performers¹, current and former opera students from UC’s College-Conservatory of Music, performed a few selections that might do the trick, including the Toreador’s Song from Bizet’s Carmen², and the famous Brindisi drinking song from Verdi’s La Traviata. Samina Aslam performs Puccini. Other selections, including Puccini’s glorious “O mio babbino caro” from Gianni Schicchi, might play a healing role for patients with Alzheimer’s disease. Cathy Crain, Chairman of the Cincinnati Opera Board of Trustees, who attended the UCMC event, shared a story about her own mother, who suffers from Alzheimer’s. “My mother raised us all to love music, particularly opera, and now, when it’s a little hard for her to focus on things, if we put an opera on, she will actually sit for two hours and listen,” Ms. Crain said. “And it is the most wonderful thing. In fact, I get chills thinking about it, because she sits there and smiles the whole time. The music brings a peace and joy to her that’s incredible to see. It’s worth everything to me.” Ms. Thomas echoed that sentiment. “Everyone gets more excited and motivated when they hear a familiar song they enjoy,” she said. “That can be part of a social connection for folks. Music is one of the few things that pretty much everyone can participate in, either through humming, singing, dancing, tapping a foot, even when seated. We use music in our stroke and Parkinson’s wellness classes to help facilitate the mood of the class as well as give some rhythm to assist in movements.” The partnership between Cincinnati Opera and the UC Medical Center will result in 18 public performances over the next three years at the UC Medical Center for staff, visitors, patients and physicians. In return, UC Health will provide enhanced wellness and voice care, in the words of Opera Board President Bob Olson, “for our invaluable professional and amateur singers.” Brian Gibler, MD, President and CEO of the UCMC, said the partnership was something to sing about. “Researchers have long studied the curative benefits of music and how it stimulates the brain,” he said. “We can all agree that music influences our lives in many ways and is considered to be the universal language. Joining medicine and music, this new duet between two longstanding institutions can provide a diverse healing environment for our patients and their families, in perfect harmony.” Mr. Olson also announced that Cincinnati Opera and UCMC would once again team up on World Voice Day, a free public event scheduled for
Moving Forward after Major Stroke Trial: Endovascular Care for Some; More Research on Tap
Joseph Broderick, MD, international stroke expert and Research Director of UCNI.Photo by Mark Bowen Media. Joseph Broderick, MD, Research Director at the UC Neuroscience Institute, was in the spotlight last week as the Principal Investigator of an international clinical trial that compared outcomes of stroke patients who received a clot-dissolving drug (tPA) through an IV and those who also received endovascular therapy. The endovascular treatment involved either delivering tPA directly to the clot via a catheter threaded up from the groin to the brain, or using a catheter and an FDA-approved device to actually retrieve the clot. The clinical trial, the Interventional Management of Stroke III (IMS III), found that patients who received the high-tech endovascular treatment fared no better than those who received tPA through an IV, although the safety of the two approaches was very similar. The trial disappointed stroke specialists who had sought to provide a new solution to the problem of stroke caused by a blockage in major arteries supplying oxygen-rich blood to the brain. Dr. Broderick, the Albert Barnes Voorheis Professor and Chair of UC’s Department of Neurology and Rehabilitation Medicine, authored the study, which appeared in the New England Journal of Medicine. He discussed the study and its ramifications with multiple media outlets, including the New York Times, the Los Angeles Times and the Washington Post, at the International Stroke Conference 2013 last week in Honolulu. The study will likely change how some stroke patients are treated at the UC Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health. The majority of patients will continue to be treated with tPA through an IV, without additional endovascular care. However, a subset of patients — those with large clots in large arteries — will strongly be considered for treatment with endovascular methods. “Our study found that patients who have occlusions of the distal internal carotid artery did poorly with IV tPA and better with an endovascular approach, although the number of patients in that particular subgroup was small,” Dr. Broderick said. Stroke patients may also benefit from two additional developments. The first is the UC Stroke Team’s effort to start endovascular therapy sooner, so as to maximize its benefits. “We have made efforts to minimize the time to start endovascular therapy since patients treated earlier tended to do better,” Dr. Broderick said. “We need to do an even better job with this.” Andrew Ringer, MD The second development involves improvements in the clot-retrieval devices themselves. “I think the new generation of devices is clearly better in opening arteries than what we had for most of the IMS III study,” said Andrew Ringer, MD, Director of the Division of Cerebrovascular Surgery and Professor of Neurosurgery & Radiology at UC. “I’ve seen a big difference in my own cases.” Dr. Ringer and his colleagues at the Endovascular Neurosurgery Research Group, whose 20-plus members include the Mayo Clinic, Cornell University and the University of California, San Diego, have collected data on the effectiveness of a new FDA-approved flow-restoration device known as the Solitaire. A multi-center retrospective analysis of the self-expanding stent retriever was recently accepted by a peer-reviewed neurosurgical journal. Dr. Broderick agreed that the newer devices open arteries better than those studied in the IMS III trial. A lingering question, however, is whether these improvements “will translate into better clinical outcomes for patients compared to IV tPA or standard therapy in patients who are beyond the tPA treatment window of 3 to 4 ½ hours.” Pooja Khatri, MD One thing is certain: the UC Stroke Team will continue to be at the center of international research into the best methods for treating patients who suffer acute stroke. “We remain very eager to participate in trials that test the combined tPA/endovascular and IV tPA alone approaches,” Dr. Broderick said. “We are participating in the Therapy Trial, which uses one of the new stent-retriever devices as well as a device that aspirates the clot. “We are also working on our next trial designs to improve rapid opening of brain arteries in acute stroke. These trials will include a combination of medications and advances in new mechanical devices.” Pooja Khatri, MD, Associate Professor of Neurology and a neurologist at the UC Neuroscience Institute, is the medical principal investigator for the Therapy Trial, a multi-site U.S. study. –Cindy Starr
UC Researchers Hope Noninvasive Biomarkers Lead To Better Treatments for Glioblastoma
Researchers at the Brain Tumor Center at the University of Cincinnati Neuroscience Institute are zeroing in on noninvasive biomarkers that may soon help guide doctors’ treatment of the malignant brain tumor glioblastoma multiforme. The novel translational research, led by El Mustapha Bahassi, PhD, Research Assistant Professor of Medicine, in collaboration with Peter Stambrook, PhD, Professor in the Department of Molecular Genetics, Biochemistry and Microbiology, focuses on DNA that breaks off from the tumor and cycles through the bloodstream. The research, begun as a pilot study that also involved the UC Cancer Institute, was funded by UC and small foundation grants from the Mayfield Education & Research Foundation, the Shemenski Foundation and the LCS/Sahlfeld Foundation. The research kicked into a higher gear last week with the awarding of a $100,000 grant from the Center for Clinical and Translational Science Training (CCTST) and an additional $35,000 gift from the Shemenski Foundation. El Mustapha Bahassi, PhD During the pilot study, Dr. Bahassi and his team¹ sequenced the genomes of glioblastoma tumors that were surgically removed from 10 study participants. In a major innovation, the Cincinnati team then sought to identify genetic abnormalities in individual tumors and to follow those abnormalities through the bloodstream by taking simple blood tests. The researchers established preliminary evidence that by sequencing an individual’s tumor and tracking the tumor’s DNA through the blood, they could enable doctors to address three significant challenges posed by the aggressive cancer. Specifically, they could help doctors: Determine the sub-type of glioblastoma and the patient’s prognosis; Determine whether the tumor had recurred; and Determine whether indeterminate markings on MRI scans following treatment were a sign of necrosis or tumor recurrence. In the future, Dr. Bahassi hopes that determination of the glioblastoma sub-type will also enable doctors to provide patients with individualized treatments rather than the current one-size-fits-all constellation of therapies that are currently available. “Brain tumors in general, and glioblastoma in particular, are diseases of the genes,” Dr. Bahassi said. “We have come to appreciate that every tumor is different; every patient is different; and therefore, the cookie-cutter method of treatment is not working, and we need to find another way to do it. There is a need for personalized treatments or individualized therapies. The way we will accomplish this is through whole-genome sequencing of the tumor. We will find out everything about a tumor and then tailor the treatment to that tumor.” The research is of critical importance, because approximately 10,000 people are diagnosed with glioblastoma annually in the United States alone. Glioblastoma presents special problems for doctors because it is not solid and cannot be removed in one clean piece. The tumor is diffuse and infiltrative, and individual cells tend to survive surgery, radiation and traditional chemotherapy. As a result, the tumor often grows back near the site of the initial mass. In sequencing the ten glioblastoma tumors in the pilot study, at a cost of $2,300 per tumor, the team identified genomic defects that lead to glioblastoma, including: Duplications on chromosome 7, meaning that the patient has more copies of the chromosome than he needs. This is the home of the EGFR receptor, which can lead to amplified cell division and cancer. Deletions on chromosome 9, meaning that the patient has fewer copies than normal. This is the home of CDK2NA, a protein that acts as a tumor suppressor. Deletions on chromosome 10, the home of PTEN, a protein that prevents cells from growing too rapidly. The team further classified the 10 tumors studied into three subtypes, including a classic subtype in which three defects (EGFR, PTEN and CDK2NA) were all present. Those patients had particularly poor prognoses. “So not only did this study allow us to classify patients based on their genomic signatures, it also allowed us to have a prognosis of how well they would do,” Dr. Bahassi said. “Now if we can use these genomic defects as pathways to develop targets to treat those patients, then we will have accomplished our ultimate task.” The researchers will sequence and track tumor DNA in an additional 20 patients during the next several months. Their work will be facilitated by the ability of Dr. Bahassi’s lab to perform its own data analysis of the genome sequencing. Only a few sites nationally have this capability. In this secondary study researchers will also seek to confirm the therapeutic value of tracking tumor DNA in the bloodstream to determine recurrence. “As a physician, I don’t have a crystal ball when I’m treating a patient with glioblastoma,” said Ronald Warnick, MD, Medical Director of the UC Brain Tumor Center and Professor of Neurosurgery and Radiation Oncology. “Following treatment, I cannot tell whether I am seeing a recurrent tumor on a brain scan or necrosis. The only foolproof way to be sure is to perform surgery. In the future, however, we hope to confirm that we can monitor our patients’ status and determine recurrence through a simple, noninvasive blood test.” Dr. Warnick said that small foundation grants play a critical role in the type of pioneering research that Dr. Bahassi is leading. “You need seed money to do this type of work, to get the preliminary data that allows you to then apply for a grant from the National Institutes of Health,” he said. “There is a gap between a great idea, a smart person in the lab, and the acquisition of enough information that you can be successful in your application for a large federal grant. These small foundation grants serve as the catalyst.” The team’s success in tracking tumor DNA that circulates through the bloodstream also holds promise for other tumors. “I would like to use this technology to address other questions, to detect other abnormalities, such as brain metastasis,” Dr. Bahassi said. * * * ¹ Researchers John M. Furgason and Emily Cross; Neurosurgeons Ronald Warnick, MD, Christopher McPherson, MD, and Tracy Ansay, MD; Pathologist Ady Kendler, MD, and Clinical Trials Specialists Ruth Steele, Suzanne Sifri and Alison Kastl. * * *
2012: A Year for Superlatives and Appreciation
Photos by Cindy Starr, UC Academic Health Center Communications Services, Mark Bowen, Joe Simon, Tom Uhlman, Tine Hofmann, Tonya Hines, and Fresh View Studio. The physicians, researchers, managers and associates of the University of Cincinnati Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health, extend a heartfelt message of appreciation to all of our friends who have helped make 2012 such a memorable year. With your support, we have continued to accelerate our efforts to provide the best available treatments and family-centered care while aggressively pursuing new therapies and potential cures for neurological disease. Dr. Opeolu Adeoye and the telestroke robot. Our clinical, research and educational programs touched the lives of thousands of patients, caregivers and future physicians. In addition, millions of dollars have been donated and awarded in support of our research and patient education programs. Here are just a few highlights from 2012: A “telestroke” initiative came to fruition, enabling UC Stroke Team physicians at the University of Cincinnati Medical Center (UCMC) to “examine” stroke patients long-distance with the help of robots. The program includes UC Health West Chester Hospital and five partner hospitals (Dearborn County Hospital, Clinton Memorial Hospital, Fort Hamilton Hospital, Adams County Hospital, and Southwest Regional Medical Center in Brown County). More than 70 patients in remote locations have been served by Stroke Team specialists since the program began six months ago. More than 75 stroke survivors and their caregivers attended “Celebrating 200 Patients in the START Stroke Recovery Program” at UC Health Drake Center. START, which stands for Stroke Team Assessment & Recovery Treatment, helps survivors continue to recover months or even years after their stroke. Dr. Ronald Warnickand Ginger Warner The UC Neuroscience Institute opened what is believed to be the first neurosurgical acuity-adjustable patient unit in the nation. The 10 new patient rooms eliminate the need for patients to be transferred to different care settings as their recovery progresses following surgery. Instead, the room and nursing staff conform to the needs of the patient. Simultaneously, we renovated the corridors of our neuro floor as well as the family waiting area, which includes the Ginger and David Warner Patient Education Alcove. In collaboration with the UC Cancer Institute, we opened a new Neurological Complications of Cancer Clinic for patients with all types of cancer who are suffering neurological side-effects. We offered free hearing and voice screenings as well as screenings for oral, head & neck cancer risk. And we continued to offer educational outreach to the community by hosting the Midwest Regional Brain Tumor Conference, the Sunflower Revolution Parkinson’s Disease Symposium & Expo, and the Play It Safe Symposium & Expo. We hosted the biennial Princeton Stroke Conference, the premier and oldest academic stroke and cerebrovascular disease conference in the world; we hosted NBC war correspondent Charles Sabine, who made the life-altering decision to face up to his family history of Huntington’s disease and undergo genetic testing; and we hosted Dennis Choi, MD, PhD, Executive Vice President of the Simons Foundation, who called for “increased bandwidth” in the number of ideas that can be converted into active research and a more proactive role in disease philanthropy. UC neuroscientists and their affiliates were named one of eight U.S. academic partners of the nonprofit One Mind for Research, which is mounting a global quest to cure brain disease and eradicate the stigma associated with mental illness and brain injury. The partnership could lead to expanded research and study of combat-related brain injuries and other neurological conditions. Dr. Linda Théodor UC Health Team Haiti deepened its commitment to Bernard Mevs Hospital/Project Medishare, Haiti’s only hospital dedicated to intensive care and trauma, with an intensive two-week mission. Later in 2012, Dr. Linda Théodor, one of two full-time physicians at the Port-au-Prince hospital, came to the UC Medical Center to further her understanding of a modern neuroscience intensive care unit. Aphasia study participant’sfMRI scan Our clinician researchers published dozens of findings in peer-reviewed journals and continued their search for new treatments for challenging diseases. They warned that stroke in the young is rising. They began a first-in-human Phase I trial for recurrent glioma, a malignant brain tumor, while helping map the glioma’s genome through a national effort called The Cancer Genome Atlas. They helped the Michael J. Fox Foundation identify biomarkers of Parkinson’s disease progression. They strived to learn how to slow down or prevent the onset of mental illness. And with funding from the Charles L. Shor Foundation, they used smartphones to determine whether stress and seizures can be positively linked. Our Nuclear Medicine facility was approved by Eli Lilly and Company, Inc., to begin using the Amyvid™ radiomarker in positron emission tomography (PET) scans, opening up new opportunities for us to develop diagnostic and treatment studies in memory and stroke. Brendan Kelley, MD, the Sandy and Bob Heimann Chair in Research and Education of Alzheimer’s, continued evaluating the Revastigmine patch in patients with severe dementia from Alzheimer’s. The UC Brain Tumor Center earmarked $150,000 in proceeds from the Precision Radiotherapy Center in West Chester, Ohio, for three $50,000 pilot grants to support metastatic brain tumor research. UCNI also revived the UCNI Pilot Grant Fund, which will provide four $25,000 awards each year. In one of our many satisfying stories of hope, experts at the UC Epilepsy Center stopped Ryan’s chronic seizures with epilepsy surgery, enabling him to get a good, seizure-free night’s sleep for the first time in four years. Jollene Shirley, CNP, Nurse Practitioner for the Waddell Center We welcomed a cadre of talented new professionals to our team: researchers Atsuo Sasaki, PhD, who will study brain cancer and seek new treatments for primary and metastatic brain tumors; Richard Curry, MD, a neurologist and neuro-oncology specialist; and Hani Kushlaf, MD, a neurologist and specialist in neuromuscular disorders. We also welcomed nurse practitioners to the Memory Disorders Center and the Waddell Center for Multiple Sclerosis. Lisa Davis, PT, DPT, left, assists Carolina Hatton in a demonstration of the new