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    Neural Networks Neural Networks Document Transcript

    • childrenshospital.org/neuroscience Neural Networks News and research from the departments of Neurology, Neurosurgery and Psychiatry Fall 2009 Pinpointing epilepsy Gwendolyn Guay began staring into space and mumbling to herself when she was 4. Over time, her episodes became more frequent and stranger— she would become unresponsive for up to a min- ute, pressing her fingers together while making soft clucking sounds. A specialist in Maine diag- nosed Gwen with epilepsy. Gwen’s epilepsy proved to be intractable. After five years trying differ-From leFt, Scott Pomeroy, MD, PhD, ent medications, the Guays met with Blaise Bourgeois, MD, directorR. Michael Scott, MD and David R. DeMaso, MD of Children’s Hospital Boston’s Epilepsy Program, who leads a multi- disciplinary evaluation by a team of neurologists, neuropsychologists, radiologists, imaging specialists and neurosurgeons. We are pleased to introduce Neural Networks, a triannual Children’s Hospital Boston Neuroscience Program newsletter sponsored by the Diagnostic evaluation departments of Neurology, Neurosurgery and Psychiatry. The team’s goal was to pinpoint the “trigger point” causing the seizures and remove it. “It’s like trying to defuse a bomb,” says This inaugural issue focuses on epilepsy, a common disorder that affects Bourgeois. “The hope is that you can go in and remove the trigger.” one percent of children. A child with severe intractable epilepsy pres- While this kind of surgery is the most effective treatment—and epi- ents a great challenge. When medications are not enough to stop the lepsy’s only real cure—only about 5 percent of patients are surgery seizures, more drastic measures must be considered, including neuro- candidates. surgical removal of the epileptic source. Since this involves excision of Using the latest brain imaging devic- pathologic regions of brain, great care must be taken to identify adjacent es, the epilepsy team searched for the normal brain structures to avoid injuries that could leave the child with source of Gwen’s seizures as well as life-changing neurological sequelae. areas housing her crucial functions, like movement, language or memory. An integrated multidisciplinary approach is needed, bringing together Neurophysiologists conducted a the expertise of neurologists, neurophysiologists, neuropsychologists, week-long session of 24-hour video neuroradiologists and neurosurgeons to identify the source of seizures. electroencephalogram (VEEG) monitor- Specialized care from neuroanesthesiologists, neurocritical care and ing, recording the electrical activity of neurological nursing help the child through a complex and prolonged Gwen’s brain through 26 electrodes. hospitalization. This combined effort allows the team to zero in on the Results suggested a left brain focal gwen and dr. Bourgeois source of the seizures, so that successful neurosurgical removal of the point, but weren’t conclusive. Sophisticated brain imaging tests—a source can achieve the ultimate goal: a life without seizures. Positron Emission Tomography (PET) scan that tracked chemical activity, Single Photon Emission Computerized Tomography (SPECT) Going forward, Neural Networks will focus on the latest developments in scan which tracks blood flow, and a Magnetic Resonance Imaging science and clinical care within the Neuroscience Program at Children’s. (MRI) which painted a three-dimensional picture—provided addition- We will highlight clinical innovations and research in neuroscience, and al clues. Together, the results suggested the left temporal lobe. show how advanced care teams translate these advances into technolo- Understanding what impact a resection would have and its prox- gies and treatments that tackle diseases of the nervous system. We will imity to healthy tissue were also important. Special attention was focus on the challenges of caring for children with life-long disabilities, paid to language and memory—skills traditionally housed in the left and the skilled and compassionate caregivers who work tirelessly to temporal lobe, close to Gwen’s epileptic area. To clarify which parts improve their lives. of her brain controlled these, doctors performed a Wada test. They numbed one whole side of Gwen’s brain, causing the opposite half We hope you enjoy our first issue. of her body to go as limp as if she’d had a stroke. While each side was temporarily paralyzed, the doctors asked Gwen to perform David R. DeMaso, MD, chair of Psychiatry tasks. She couldn’t speak or remember when her brain’s left side Scott L. Pomeroy, MD, PhD, chair of Neurology was asleep. R. Michael Scott, MD, chair of Neurosurgery continued on page 3
    • Understanding the neonatal brainFor the past two decades, Frances Bumetanide mechanism of action thus, when GABA receptors are activated,Jensen, MD, of the Department of chloride comes in, with an inhibitoryNeurology and Program of Neurobiology effect. But in newborn rats, they found Illustration: Dzhala Ann Neurol, 2008at Children’s has been learning why most very little KCC2.infants seem immune to anticonvulsants Examining brain tissue from babies andand developing new treatments specific to young children who had died, they foundtheir biology. the same pattern in humans: KCC2 was Beginning in the laboratory, she stud- initially absent in the upper part of theied the brain’s molecules and modeled brain where the seizures originated, butepilepsy in animals. Then, with Children’s rose over the first year of life. Conversely,Pathology Department, Jensen made NKCC1 levels were high during the fetalcorresponding observations in human tis- opens channels so chloride moves into the and newborn periods, falling during thesue. Collectively, her findings revealed cell, giving it a negative charge that makes first year of life.just how different the physiology and it less excitable and inhibits seizure activity. “NKCC1 is expressed unopposed inbiochemistry of a baby’s brain are from But in babies’ cells, chloride concentration the immature brain, likely keeping cel-an adult’s. “It’s practically a different spe- is already high, so when GABA receptors lular chloride levels high,” says Jensen.cies,” Jensen says. open, chloride flows out of the cell, toward “We thought that blocking NKCC1 and Adult brains are balanced between two the area of low concentration. This wrong- its inward transfer of chloride, might getstates, excitation and inhibition. But Jensen way chloride flow creates a paradoxical immature neurons to act like older neuronsand others have shown that the rapidly excitatory reaction that may actually wors- and give GABA a chance to do its job.”developing infant brain is more inclined en seizures. Fortuitously, research had shown thattoward excitation. “An infant’s GABA receptors are actu- an existing drug called bumetanide blocks “A baby’s increased brain activity is ally doing the opposite of what they do in NKCC1 in the kidney. If it did the same indesigned to create new connections that adults,” Jensen says. “Their brains wants the brain, perhaps it could keep chlorideare the underpinnings of learning,” Jensen so much to be excitable, they’re even levels low inside newborns’ nerve cellsexplains. “But this turns out to be a dou- using classical inhibitory receptors to bring and allow them to respond to anticon-ble-edged sword. There are certain dis- about excitation.” vulsants. A trial in baby rats confirmedeases, such as epilepsy, that are caused But how? Jensen and Staley found the the idea, showing that bumetanide suc-by over-activation of the brain.” answer in two molecules that regulate cessfully blocked seizures. Even better, Most anticonvulsant drugs—developed cells’ chloride levels. One, called KCC2, when combined with the anticonvulsantfor adults—increase inhibition. Yet the transports chloride out of cells; the other, phenobarbital, which works poorly whendeveloping brain doesn’t have many of NKCC1, brings chloride in. In adult rats, given alone, bumetanide was even morethe inhibitory synapses that the medica- KCC2 predominates in nerve cells, keep- effective.tions target. “This physiologic difference ing internal chloride concentrations low;explains why current medications are noteffective for infants,” Jensen says. Jensen returned to the lab with thisknowledge. In animal models of early-life putting Bumetanide to the testseizures, she found that blocking a certain It’s been more than 60 years since a new medication has been available to treat infant seizures, but usingkind of excitatory receptor—something rare- molecular discoveries from Frances Jensen, md, Kevin staley, md, and others, Janet soul, md, ofly tried, since most drugs target inhibitory the Department of Neurology and her clinical colleagues in Neurology and Neonatology will soon beginreceptors—prevented further seizures and enrolling newborns with perinatal asphyxia who are at risk for seizures in a pilot study of bumetanide.stopped all of their long-term consequences. The drug she used, called topiramate, It’s a tricky trial, since those first hours of life are critical and treatment needs to start quickly. As soonhas been approved by the FDA to control as babies arrive at Children’s Hospital Boston and are found to qualify, Dr. Soul’s team will enroll themseizures in adults and in children over and place EEG leads on their heads to determine if they are having seizures. For the babies whose sei-age 3. Unfortunately, it doesn’t yet exist zures persist despite a first dose of the standard medicine phenobarbital, two thirds of the babies willin IV form and will take several years to receive the study drug bumetanide with the next dose of phenobarbital, while one third of the babies willdevelop for clinical trials. receive a second dose of the standard medicine phenobarbital alone (standard or ‘control’ group). Seeking other options, Jensen worked Over the next 48 hours, Dr. Soul’s team will perform continuous EEG monitoring and data collection towith pediatric neurologist Kevin Staley, see if the seizure activity stops. Lab tests and clinical monitoring will determine how the drug is metabo-MD, chief of Pediatric Neurology at lized and how well it’s tolerated. Magnetic resonance imaging will determine if there is any brain injury.Massachusetts General Hospital, to Dr. Soul will then evaluate the infants every few months to assess their neurologic development. Finally,explore the other half of the equation: at 18 months of age, the children will undergo detailed developmental testing for cognitive or motorhow inhibition might be boosted in infants problems, and assessment of whether they are continuing to have seizures. If all goes well, Drs. Soulto block seizures. and Jensen hope this pilot study will lead to a large multicenter trial. Conventional anticonvulsants mimic theaction of GABA, a natural inhibitory mes- To learn more about this study, contact Dr. Soul directly at 617-355-8994.senger, by activating GABA receptors onthe surface of brain cells. In adult cells, this2 Neural Networks | Fall 2009 | childrenshospital.org/neuroscience
    • continued From page 1Pinpointing epilepsy Neurosurgeons needed a detailed mapof her brain’s functions—millimeter bymillimeter—which required implanting using research to improve caresubdural strips of silicon, studded with Once grids and strips were placed on Gwen’s brain, several teams of researchers were poised to gather108 electrodes. “It’s the most accurate much more information about how the brain works. Two studies Gwen participated in while undergoingdata you can get,” says Bourgeois. A subdural EEG monitoring are described below.few days later, with scores of fine wirescoming neatly out of Gwen’s head, doc- Facial expressions With the MIT Media Lab, Children’s researchers are conducting a trial investigat-tors performed a cortical stimulation test; ing how certain brain signals suggest certain emotional states. Because facial expressions frequentlythey asked her questions while applying precede seizures, they expanded their data collection to epilepsy patients. Findings may uncover newsmall shocks to each electrode in turn, treatment options for patients who do not qualify for epilepsy surgery.temporarily rendering that part of her Vision Hongye liu, phd, and gabriele Kreimen, phd, msc, want to understand how the brain iden-brain useless. If she failed a task, doctors tifies things so quickly. By interpreting signals through electrodes, as Gwen watched Disney movies, theyknew that the part of her brain receiv- could tell what she was looking at by correlated what she was actually seeing with what her brain saiding the stimulus was being used for that she was seeing. This data may help develop brain-machine interfaces for people with vision loss as wellthought process. Results were good: They as help epileptologists identify attributes and bad brain.zeroed in on the epilepsy, and the areasright around it didn’t seem to be used forlanguage. But whether Gwen’s memory ing with such debilitating seizures. “Most smoothly: Gwen’s neurosurgeon removedwould be safe was still unclear. of my patients tell me that having even the electrodes that mapped her brain, and one seizure a week ruins their lives,” says easily located the epileptic tissue.Team discussion Bourgeois. “Living with her seizures would “Grids and strips can be risky, butWith the “blueprint” of Gwen’s brain be a constant worry and self-esteem issue Gwen clearly benefited from it,” saysin hand, the team began an hours-long for her as she got older.” her neurosurgeon Joseph Madsen, MD.debate about whether to proceed with Meanwhile, the team made a sig- “The collective data from all of Gwen’ssurgery. Neurologists, neurosurgeons, radi- nificant discovery. Just days before her tests correlated with the abnormal cortexologists, nurses and psychologists exam- scheduled surgery, a specialized high- seen on her MRI, outlining a very clear cutined the monitoring and imaging results powered MRI revealed a cortical abnor- area for me. My job is to remove the badand debated the likelihood of success. mality in Gwen’s left temporal lobe, near tissue, but I couldn’t do that without the“We had lots of concerns about Gwen’s the hippocampus but not involving it. “It expertise of our team.”memory,” says Bourgeois. “If we took out was a big reassurance and we recom- Within the week, the Guays left forfunctional tissue, she wouldn’t be able to mended her for the surgery with a very home. Gwen will return for regular follow-recall or retain words.” But that possibility high certainty that it would be a success,” up visits, but all signs point toward ahad to be balanced against the risks of liv- says Bourgeois. And the procedure did go seizure-free future. Meet our new specialists Benjamin warf, md, began Jonathan lipton, md, Yoon-Jae cho, md, is his career as a pediatric phd joins the Department currently an Instructor in neurosurgeon at Children’s of Neurology and Division Neurology at Harvard Medical Hospital Boston in 1991 as of Sleep Medicine as an School, Assistant in Neurology the first Pediatric Fellow in Assistant in Neurology, Staff at Children’s Hospital Boston, Neurological Surgery. A large Physician, and Instructor at and a Consultant in Pediatric contributor to the research and Harvard Medical School. His Oncology at Dana-Farber treatment of hydrocephalus in developing countries, research is focused on understanding the relation- Cancer Institute. He has a clinical and research Dr. Warf helped found the only pediatric neurosur- ship between sleep, neurodevelopmental disorders focus in pediatric brain tumors and has received gery unit in SubSaharan Africa, and went on to be and cellular stress pathways using animal models a Young Investigator Award through the Pediatric the first to identify neonatal infection as the chief of the human disease Tuberous Sclerosis Complex. Brain Tumor Foundation. He is currently work- cause of pediatric hydrocephalus in a developing Dr. Lipton has received funding support from the ing on his post-doctoral research in our Division country. His technique for the primary treatment of Tuberous Sclerosis Alliance, William Randolph of Neuroscience, combining computational and hydrocephalus in infants has been adopted in many Hearst Foundation, and the American Academy of bench experiments to understand mechanisms of different centers around the world and will hope- Neurology. tumorigenesis in pediatric brain tumors. In addition, fully lead to the avoidance of shunt-dependence in Dr. Cho has received funding from the National the majority of children. Organization of Rare Disorders as a co-investigator studying the genetic basis of Moyamoya syndrome. childrenshospital.org/neuroscience | Fall 2009 | Neural Networks 3
    • NONPROFIT ORG. U.S. Postage paid300 Longwood Avenue, Boston, MA 02115 Boston, Mass. Permit No. 59240why send your patients to a level 4 epilepsy center?Patients seeing a gen- initially by the primary care physician or neurophysiology, registered EEG or certi-eral neurologist for secondly by a general neurologist. If sei- fied Long-Term-Monitoring Technologistsup to 12 months who zures persist, patients are referred to third (REEGT or CLTM), video-EEG monitoring,have yet to gain control level specialty epilepsy centers for basic selection of patients for epilepsy surgery,over their seizures, medical, neuropsychological and psycho- and the pharmacology of anticonvulsantlikely need specialized social services. Some of these centers drugs.treatment from a Level implant vagus nerve stimulators. They Our highly-skilled staff at Children’s4 epilepsy center. may also offer noninvasive evaluation for Hospital Boston exceeds these require- Diagnostic and epilepsy surgery, but they do not perform ments, with ten epileptologists, seventreatment options have these surgeries. EEG/LTM technologists, and an extensiveincreased greatly for by Blaise Bourgeois, md Patients needing intracranial evaluation care team that includes eight nurse prac-people with epilepsy or another complex resective epilepsy titioners, research nurses, clinical nurseover the past decade. It’s not only possi- surgery must go to a Level 4 epilepsy specialist, clinic nurses, neuropsycholo-ble, but expected, that treatment will stop center. Providing the highest level of care, gists, social workers and a nutritionist.seizures and their side effects from occur- they offer more complex forms of inten- Our staff, along with our state-of-the-artring. With the abundance of resources for sive neurodiagnostic monitoring, more technology that includes 24 hour /7daysboth health care providers and recipients, extensive medical, neuropsychological, a week EEG video monitoring, providesthe approach to subspecialty epilepsy care and psychosocial treatment, as well as patients with the highest level of epilepsyhas been revisited and reorganized by the resective epilepsy surgery and intracranial care and treatment. We encourage physi-National Association of Epilepsy Centers electrodes. The minimum requirements cians to send complex patients to Levelas outlined below. for a Level 4 epilepsy center include a 4 centers as quickly as possible because Most patients with epilepsy are treated staff with at least two board-certified neu- early intervention plays a crucial role inwithin the first two levels of care, either rologists with expertise in epilepsy, clinical positive outcomes.Neural Networksissue no. 1, Fall 2009 | published by the departments of neurology, neurosurgery and psychiatry Children’s Hospital Boston is the Children’s Hospital Boston isEditor: nikki shimshock | Contributors: erin graham, abby williams | Designer: patrick Bibbins primary pediatric teaching hospital ranked #1 in Neurology and300 Longwood Avenue, Boston, MA 02115 | 857-218-4835 | neuroscience@childrens.harvard.edu of Harvard Medical School Neurosurgery by U.S.News & World Report.childrenshospital.org/neuroscience | © Children’s Hospital Boston, 2009. All rights reserved.