News and research from the departments of Neurology, Neurosurgery and PsychiatryNeural Networks

Fall 2009

childrenshospital.org/neuroscience

We are pleased to introduce Neural Networks, a triannual Children’s Hospital Boston Neuroscience Program newsletter sponsored by the departments of Neurology, Neurosurgery and Psychiatry.

This inaugural issue focuses on epilepsy, a common disorder that affects one percent of children. A child with severe intractable epilepsy pres-ents a great challenge. When medications are not enough to stop the seizures, more drastic measures must be considered, including neuro-surgical removal of the epileptic source. Since this involves excision of pathologic regions of brain, great care must be taken to identify adjacent normal brain structures to avoid injuries that could leave the child with life-changing neurological sequelae.

An integrated multidisciplinary approach is needed, bringing together the expertise of neurologists, neurophysiologists, neuropsychologists, neuroradiologists and neurosurgeons to identify the source of seizures. Specialized care from neuroanesthesiologists, neurocritical care and neurological nursing help the child through a complex and prolonged hospitalization. This combined effort allows the team to zero in on the source of the seizures, so that successful neurosurgical removal of the source can achieve the ultimate goal: a life without seizures.

Going forward, Neural Networks will focus on the latest developments in science and clinical care within the Neuroscience Program at Children’s. We will highlight clinical innovations and research in neuroscience, and show how advanced care teams translate these advances into technolo-gies and treatments that tackle diseases of the nervous system. We will focus on the challenges of caring for children with life-long disabilities, and the skilled and compassionate caregivers who work tirelessly to improve their lives.

We hope you enjoy our first issue.

David R. DeMaso, MD, chair of Psychiatry Scott L. Pomeroy, MD, PhD, chair of Neurology R. Michael Scott, MD, chair of Neurosurgery

Pinpointing epilepsyGwendolyn 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-ent medications, the Guays met with Blaise Bourgeois, MD, director 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.

Diagnostic evaluation 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 Bourgeois. “The hope is that you can go in and remove the trigger.” While this kind of surgery is the most effective treatment—and epi-lepsy’s only real cure—only about 5 percent of patients are surgery candidates.

Using the latest brain imaging devic-es, the epilepsy team searched for the source of Gwen’s seizures as well as areas housing her crucial functions, like movement, language or memory.

Neurophysiologists conducted a week-long session of 24-hour video electroencephalogram (VEEG) monitor-ing, recording the electrical activity of Gwen’s brain through 26 electrodes. Results suggested a left brain focal point, but weren’t conclusive. Sophisticated brain imaging tests—a Positron Emission Tomography (PET) scan that tracked chemical activity, Single Photon Emission Computerized Tomography (SPECT) scan which tracks blood flow, and a Magnetic Resonance Imaging (MRI) which painted a three-dimensional picture—provided addition-al clues. Together, the results suggested the left temporal lobe.

Understanding what impact a resection would have and its prox-imity to healthy tissue were also important. Special attention was paid to language and memory—skills traditionally housed in the left temporal lobe, close to Gwen’s epileptic area. To clarify which parts of her brain controlled these, doctors performed a Wada test. They numbed one whole side of Gwen’s brain, causing the opposite half 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 tasks. She couldn’t speak or remember when her brain’s left side was asleep.

continued on page 3

From leFt, Scott Pomeroy, MD, PhD, R. Michael Scott, MD and David R. DeMaso, MD

gwen and dr. Bourgeois

2 Neural Networks | Fall 2009 | childrenshospital.org/neuroscience

For the past two decades, Frances Jensen, MD, of the Department of Neurology and Program of Neurobiology at Children’s has been learning why most infants seem immune to anticonvulsants and developing new treatments specific to their biology.

Beginning in the laboratory, she stud-ied the brain’s molecules and modeled epilepsy in animals. Then, with Children’s Pathology Department, Jensen made corresponding observations in human tis-sue. Collectively, her findings revealed just how different the physiology and biochemistry of a baby’s brain are from an adult’s. “It’s practically a different spe-cies,” Jensen says.

Adult brains are balanced between two states, excitation and inhibition. But Jensen and others have shown that the rapidly developing infant brain is more inclined toward excitation.

“A baby’s increased brain activity is designed to create new connections that are the underpinnings of learning,” Jensen explains. “But this turns out to be a dou-ble-edged sword. There are certain dis-eases, such as epilepsy, that are caused by over-activation of the brain.”

Most anticonvulsant drugs—developed for adults—increase inhibition. Yet the developing brain doesn’t have many of the inhibitory synapses that the medica-tions target. “This physiologic difference explains why current medications are not effective for infants,” Jensen says.

Jensen returned to the lab with this knowledge. In animal models of early-life seizures, she found that blocking a certain kind of excitatory receptor—something rare-ly tried, since most drugs target inhibitory receptors—prevented further seizures and stopped all of their long-term consequences.

The drug she used, called topiramate, has been approved by the FDA to control seizures in adults and in children over age 3. Unfortunately, it doesn’t yet exist in IV form and will take several years to develop for clinical trials.

Seeking other options, Jensen worked with pediatric neurologist Kevin Staley, MD, chief of Pediatric Neurology at Massachusetts General Hospital, to explore the other half of the equation: how inhibition might be boosted in infants to block seizures.

Conventional anticonvulsants mimic the action of GABA, a natural inhibitory mes-senger, by activating GABA receptors on the surface of brain cells. In adult cells, this

opens channels so chloride moves into the cell, giving it a negative charge that makes it less excitable and inhibits seizure activity. But in babies’ cells, chloride concentration is already high, so when GABA receptors open, chloride flows out of the cell, toward the area of low concentration. This wrong-way chloride flow creates a paradoxical excitatory reaction that may actually wors-en seizures.

“An infant’s GABA receptors are actu-ally doing the opposite of what they do in adults,” Jensen says. “Their brains wants so much to be excitable, they’re even using classical inhibitory receptors to bring about excitation.”

But how? Jensen and Staley found the answer in two molecules that regulate cells’ chloride levels. One, called KCC2, transports chloride out of cells; the other, NKCC1, brings chloride in. In adult rats, KCC2 predominates in nerve cells, keep-ing internal chloride concentrations low;

thus, when GABA receptors are activated, chloride comes in, with an inhibitory effect. But in newborn rats, they found very little KCC2.

Examining brain tissue from babies and young children who had died, they found the same pattern in humans: KCC2 was initially absent in the upper part of the brain where the seizures originated, but rose over the first year of life. Conversely, NKCC1 levels were high during the fetal and newborn periods, falling during the first year of life.

“NKCC1 is expressed unopposed in the immature brain, likely keeping cel-lular chloride levels high,” says Jensen. “We thought that blocking NKCC1 and its inward transfer of chloride, might get immature neurons to act like older neurons and give GABA a chance to do its job.”

Fortuitously, research had shown that an existing drug called bumetanide blocks NKCC1 in the kidney. If it did the same in the brain, perhaps it could keep chloride levels low inside newborns’ nerve cells and allow them to respond to anticon-vulsants. A trial in baby rats confirmed the idea, showing that bumetanide suc-cessfully blocked seizures. Even better, when combined with the anticonvulsant phenobarbital, which works poorly when given alone, bumetanide was even more effective.

putting Bumetanide to the test It’s been more than 60 years since a new medication has been available to treat infant seizures, but using molecular discoveries from Frances Jensen, md, Kevin staley, md, and others, Janet soul, md, of the Department of Neurology and her clinical colleagues in Neurology and Neonatology will soon begin enrolling newborns with perinatal asphyxia who are at risk for seizures in a pilot study of bumetanide.

It’s a tricky trial, since those first hours of life are critical and treatment needs to start quickly. As soon as babies arrive at Children’s Hospital Boston and are found to qualify, Dr. Soul’s team will enroll them and place EEG leads on their heads to determine if they are having seizures. For the babies whose sei-zures persist despite a first dose of the standard medicine phenobarbital, two thirds of the babies will receive the study drug bumetanide with the next dose of phenobarbital, while one third of the babies will receive a second dose of the standard medicine phenobarbital alone (standard or ‘control’ group).

Over the next 48 hours, Dr. Soul’s team will perform continuous EEG monitoring and data collection to see if the seizure activity stops. Lab tests and clinical monitoring will determine how the drug is metabo-lized and how well it’s tolerated. Magnetic resonance imaging will determine if there is any brain injury. Dr. Soul will then evaluate the infants every few months to assess their neurologic development. Finally, at 18 months of age, the children will undergo detailed developmental testing for cognitive or motor problems, and assessment of whether they are continuing to have seizures. If all goes well, Drs. Soul and Jensen hope this pilot study will lead to a large multicenter trial.

To learn more about this study, contact Dr. Soul directly at 617-355-8994.

Understanding the neonatal brainBumetanide mechanism of action

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childrenshospital.org/neuroscience | Fall 2009 | Neural Networks 3

Benjamin warf, md, began his career as a pediatric neurosurgeon at Children’s Hospital Boston in 1991 as the first Pediatric Fellow in Neurological Surgery. A large contributor to the research and

treatment of hydrocephalus in developing countries, Dr. Warf helped found the only pediatric neurosur-gery unit in SubSaharan Africa, and went on to be the first to identify neonatal infection as the chief cause of pediatric hydrocephalus in a developing country. His technique for the primary treatment of hydrocephalus in infants has been adopted in many different centers around the world and will hope-fully lead to the avoidance of shunt-dependence in the majority of children.

Jonathan lipton, md, phd joins the Department of Neurology and Division of Sleep Medicine as an Assistant in Neurology, Staff Physician, and Instructor at Harvard Medical School. His

research is focused on understanding the relation-ship between sleep, neurodevelopmental disorders and cellular stress pathways using animal models of the human disease Tuberous Sclerosis Complex. Dr. Lipton has received funding support from the Tuberous Sclerosis Alliance, William Randolph Hearst Foundation, and the American Academy of Neurology.

Yoon-Jae cho, md, is currently an Instructor in Neurology at Harvard Medical School, Assistant in Neurology at Children’s Hospital Boston, and a Consultant in Pediatric Oncology at Dana-Farber

Cancer Institute. He has a clinical and research focus in pediatric brain tumors and has received a Young Investigator Award through the Pediatric Brain Tumor Foundation. He is currently work-ing on his post-doctoral research in our Division of Neuroscience, combining computational and bench experiments to understand mechanisms of tumorigenesis in pediatric brain tumors. In addition, Dr. Cho has received funding from the National Organization of Rare Disorders as a co-investigator studying the genetic basis of Moyamoya syndrome.

M e e t o u r n e w s p e c i a l i s t s

Neurosurgeons needed a detailed map of her brain’s functions—millimeter by millimeter—which required implanting subdural strips of silicon, studded with 108 electrodes. “It’s the most accurate data you can get,” says Bourgeois. A few days later, with scores of fine wires coming neatly out of Gwen’s head, doc-tors performed a cortical stimulation test; they asked her questions while applying small shocks to each electrode in turn, temporarily rendering that part of her brain useless. If she failed a task, doctors knew that the part of her brain receiv-ing the stimulus was being used for that thought process. Results were good: They zeroed in on the epilepsy, and the areas right around it didn’t seem to be used for language. But whether Gwen’s memory would be safe was still unclear.

Team discussionWith the “blueprint” of Gwen’s brain in hand, the team began an hours-long debate about whether to proceed with surgery. Neurologists, neurosurgeons, radi-ologists, nurses and psychologists exam-ined the monitoring and imaging results and debated the likelihood of success. “We had lots of concerns about Gwen’s memory,” says Bourgeois. “If we took out functional tissue, she wouldn’t be able to recall or retain words.” But that possibility had to be balanced against the risks of liv-

ing with such debilitating seizures. “Most of my patients tell me that having even one seizure a week ruins their lives,” says Bourgeois. “Living with her seizures would be a constant worry and self-esteem issue for her as she got older.”

Meanwhile, the team made a sig-nificant discovery. Just days before her scheduled surgery, a specialized high-powered MRI revealed a cortical abnor-mality in Gwen’s left temporal lobe, near the hippocampus but not involving it. “It was a big reassurance and we recom-mended her for the surgery with a very high certainty that it would be a success,” says Bourgeois. And the procedure did go

smoothly: Gwen’s neurosurgeon removed the electrodes that mapped her brain, and easily located the epileptic tissue.

“Grids and strips can be risky, but Gwen clearly benefited from it,” says her neurosurgeon Joseph Madsen, MD. “The collective data from all of Gwen’s tests correlated with the abnormal cortex seen on her MRI, outlining a very clear cut area for me. My job is to remove the bad tissue, but I couldn’t do that without the expertise of our team.”

Within the week, the Guays left for home. Gwen will return for regular follow-up visits, but all signs point toward a seizure-free future.

Pinpointing epilepsycontinued From page 1

using research to improve care Once grids and strips were placed on Gwen’s brain, several teams of researchers were poised to gather much more information about how the brain works. Two studies Gwen participated in while undergoing subdural EEG monitoring are described below.

Facial expressions With the MIT Media Lab, Children’s researchers are conducting a trial investigat-ing how certain brain signals suggest certain emotional states. Because facial expressions frequently precede seizures, they expanded their data collection to epilepsy patients. Findings may uncover new treatment options for patients who do not qualify for epilepsy surgery.

Vision Hongye liu, phd, and gabriele Kreimen, phd, msc, want to understand how the brain iden-tifies things so quickly. By interpreting signals through electrodes, as Gwen watched Disney movies, they could tell what she was looking at by correlated what she was actually seeing with what her brain said she was seeing. This data may help develop brain-machine interfaces for people with vision loss as well as help epileptologists identify attributes and bad brain.

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Neural Networks issue no. 1, Fall 2009 | published by the departments of neurology, neurosurgery and psychiatry Editor: nikki shimshock | Contributors: erin graham, abby williams | Designer: patrick Bibbins 300 Longwood Avenue, Boston, MA 02115 | 857-218-4835 | neuroscience@childrens.harvard.edu childrenshospital.org/neuroscience | © Children’s Hospital Boston, 2009. All rights reserved.

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Children’s Hospital Boston is ranked #1 in Neurology and Neurosurgery by U.S.News & World Report.

Children’s Hospital Boston is the primary pediatric teaching hospital of Harvard Medical School

Patients seeing a gen-eral neurologist for up to 12 months who have yet to gain control over their seizures, likely need specialized treatment from a Level 4 epilepsy center.

Diagnostic and treatment options have increased greatly for people with epilepsy over the past decade. It’s not only possi-ble, but expected, that treatment will stop seizures and their side effects from occur-ring. With the abundance of resources for both health care providers and recipients, the approach to subspecialty epilepsy care has been revisited and reorganized by the National Association of Epilepsy Centers as outlined below.

Most patients with epilepsy are treated within the first two levels of care, either

initially by the primary care physician or secondly by a general neurologist. If sei-zures persist, patients are referred to third level specialty epilepsy centers for basic medical, neuropsychological and psycho-social services. Some of these centers implant vagus nerve stimulators. They may also offer noninvasive evaluation for epilepsy surgery, but they do not perform these surgeries.

Patients needing intracranial evaluation or another complex resective epilepsy surgery must go to a Level 4 epilepsy center. Providing the highest level of care, they offer more complex forms of inten-sive neurodiagnostic monitoring, more extensive medical, neuropsychological, and psychosocial treatment, as well as resective epilepsy surgery and intracranial electrodes. The minimum requirements for a Level 4 epilepsy center include a staff with at least two board-certified neu-rologists with expertise in epilepsy, clinical

neurophysiology, registered EEG or certi-fied Long-Term-Monitoring Technologists (REEGT or CLTM), video-EEG monitoring, selection of patients for epilepsy surgery, and the pharmacology of anticonvulsant drugs.

Our highly-skilled staff at Children’s Hospital Boston exceeds these require-ments, with ten epileptologists, seven EEG/LTM technologists, and an extensive care team that includes eight nurse prac-titioners, research nurses, clinical nurse specialist, clinic nurses, neuropsycholo-gists, social workers and a nutritionist. Our staff, along with our state-of-the-art technology that includes 24 hour /7days a week EEG video monitoring, provides patients with the highest level of epilepsy care and treatment. We encourage physi-cians to send complex patients to Level 4 centers as quickly as possible because early intervention plays a crucial role in positive outcomes.

by Blaise Bourgeois, md

why send your patients to a level 4 epilepsy center?