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Pamela and Randall Kromm remember the moment during Cammy's birth when a lack of oxygen caused their daughter's brain to swell and become consumed with seizure activity. "We knew something awful had happened," says Pamela. Less than a day later, Cammy was transported to Children's Hospital Boston's Neonatal Intensive Care Unit (NICU), where she was put on an anticonvulsant and examined by a team of neonatal neurologists. "Here was my full-term baby who, a week before, during a prenatal exam, had been perfect, but was all of a sudden hooked up to machines and drugged up. I remember thinking, 'This is the worst nightmare I could ever have.'"
After nine days in Children's NICU, Cammy had an MRI that showed a pattern of hypoxic-ischemic encephalopathy (HIE), or brain damage due to a shortage of oxygen. Although she didn't have full-blown bodily convulsions, her brain was wracked with damaging electrical activity.
Since both HIE and seizures affect each child uniquely, the extent of Cammy's neurologic damage was unknown. "We truly knew nothing about her future state at the time," Pamela remembers. "Would she have mental retardation? Would she need to be in a wheelchair forever? Would she be able to feed herself?"
The kind of non-visible seizure activity Cammy still suffers from can pose a major threat to both brain function and development. "Usually, by the time a child turns 3 or 4, it becomes much clearer what kind of problems she'll have long-term," says Janet Soul, MD, the neurologist who treated Cammy at Children's for six years. Developmental milestones can turn into stumbling blocks at that age, and Cammy showed significant delays with language, coordination and fine motor skills. Today, at age 7, she can speak only simple sentences, and it's unclear how well she understands what she's seeing and how much her memory is affected.
Doctors aren't sure to what extent Cammy's irreversible cognitive impairments come from of the initial episode of asphyxia, but it's likely that her continued seizure activity has exacerbated her brain injury.
Frances Jensen, MD, of the Department of Neurology and Program in Neurobiology at Children's, is studying the long-term effects of these early seizures. "We're showing that shortly after certain kinds of seizures occur, changes in the brain networks begin to happen that in some cases can result in severe cognitive problems and learning deficits later in life," she says.
Ultimately, Jensen hopes to avoid the lifelong complications of severe newborn seizures—which can include mental retardation, cerebral palsy and autism—by halting them as early as possible—ideally in the first hours after birth.
Despite the fact that newborn seizures are quite common, affecting 80,000 babies each year in the United States, and despite growing knowledge of their long-term effects, a drug to stop them has yet to be developed. Standard antiseizure medications are usually ineffective. "It's long been known that these seizures are highly resistant to treatment," Jensen says. "And yet for 60 years, we haven't changed the way we treat babies—we give them hand-me-down drugs created for adults."
For the past two decades, Jensen has been learning why most infants seem immune to anticonvulsants, and developing new treatment approaches specific to the biology of infants. Her work began in the laboratory, studying the brain at the molecular level and modeling epilepsy in animals. Then, collaborating with Children's Pathology Department, Jensen made corresponding observations in human tissue. Collectively, her findings have revealed just how different the physiology and biochemistry of a baby's brain are from an adult's. "It's practically a different species," Jensen says.
Adult brains are balanced between two states: excitation and inhibition, in which electrical activity is increased and dampened down, respectively. Each brain cell builds receptors at its synapses that can receive excitatory or inhibitory signals. But Jensen and others have shown that the rapidly developing brain of a baby 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 double-edged sword. There are certain diseases, such as epilepsy, that are caused by over-activation of the brain."
There are two ways to stop a seizure: reducing excitation or increasing inhibition. Most anticonvulsant drugs—developed for adults—increase inhibition. Yet the developing brain doesn't have many of the inhibitory synapses that the medications target. "This physiologic difference explains why current medications are simply not a rational therapeutic strategy for infants," Jensen says.
Taking what she had learned about the infant brain and what might quell its seizures, Jensen went back to the lab. In animal models of early-life seizures, she found that if she blocked a certain kind of excitatory receptor—something rarely tried, since most drugs target inhibitory receptors—she was able to prevent further seizures. Better still, she stopped all of their long-term consequences.
The drug she used, called topiramate, has already 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 more years to develop for clinical trials.
Seeking other options, Jensen teamed up with pediatric neurologist Kevin Staley, MD, chief of Pediatric Neurology at Massachusetts General Hospital, to explore the other side of the equation: the inhibition problem. How could inhibition be boosted in infants, and could this block seizures?
Jensen and Staley knew that conventional anticonvulsants work by mimicking the action of GABA, a natural inhibitory messenger, by activating receptors for GABA on the surface of brain cells. In adult cells, this opens up tiny channels that allow chloride to move into the cell. This influx gives the cell a negative charge that makes it less excitable, inhibiting 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 worsen seizures.
"We found that a baby's GABA receptors are actually doing the opposite of what they do in adults," Jensen says. "The baby brain wants so much to be excitable, it's even using its 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, keeping 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.
"We found that NKCC1 is expressed unopposed in the immature brain, likely keeping cellular chloride levels high," says Jensen. "We thought that perhaps if we blocked NKCC1 and its inward transfer of chloride, we could get immature neurons to act like older neurons and give GABA a chance to do what it's supposed to do."
Fortuitously, research had shown that an existing drug called bumetanide blocks NKCC1 in the kidney. If it did in the same in the brain, Jensen and Staley reasoned, perhaps it could keep chloride levels low inside newborns' nerve cells and allow them to respond to anticonvulsants. A trial in baby rats confirmed their idea and showed that bumetanide successfully blocked seizures. Even better, when they combined it with the anticonvulsant phenobarbital, which works poorly when given alone, bumetanide was even more effective.
Interestingly, bumetanide is already used as a diuretic, and epidemiologic studies have found that adults taking diuretics are less likely to have seizures. Moreover, bumetanide has been shown to be safe for use in infants. The promise for treating seizures in newborns seemed huge.
Jensen approached Soul and her clinical colleagues in Neurology and Neonatology to embark on what could be the final step: a clinical trial. This spring, Soul will begin to enroll about 50 newborns at risk for early seizures. It's a tricky trial to do, since those first hours of life are critical and treatment needs to start quickly. As soon as the babies arrive at Children's and are found to qualify for the trial, researchers will enroll them, place EEG leads on them and start them on conventional phenobarbital treatment. Two thirds of the babies will also receive bumetanide.
Over the next 48 hours, Soul and her colleagues 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 metabolized and how well the infants tolerate it. Magnetic resonance imaging will be performed to determine if there is any brain injury. Soul will then evaluate the infants every few months to assess their neurologic development and determine whether they are still having seizures. Finally, between 18 and 22 months of age, the children will undergo detailed developmental testing for cognitive or motor problems. If all goes well, Soul and Jensen hope this pilot study will lead to a large multicenter trial.
"I've always been interested in the mechanisms of injury on a cellular level," says Jensen. "But this translational part is especially exciting. At Children's, we have world-class basic neuroscientists, but we also have the ability to look at human tissue, extrapolate findings from animal to human and finally, of course, enroll our patients in clinical trials. There couldn't be a more ideal environment to put it all together."
Cammy today is an enthusiastic, gregarious daddy's girl who loves Elmo and is almost always smiling. She has made remarkable strides, largely due to her parents' dedication to helping her learn. They've been teaching her through Verbal Behavior, a system of repetitive presentations of material known to work well in children with autism.
"Cammy is showing progress, but if we could have controlled the seizures better early on, she might be starting from a higher baseline now," says her father, Randall. "We hold out hope that some of the research findings will have relevance for older kids."
In the meantime, Cammy regularly comes to Children's to see ophthalmology, neurology, occupational therapy and developmental medicine specialists. Her last EEG showed sleep seizure activity 95 percent of the time, so she's taking a new combination of drugs in hopes of smoothing out some of that activity.
"We know there is no magic pill," says Pamela. "But it's amazing to think that they're working on something that could help other children lead better lives. It would be quite a breakthrough—and help so many families."
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