Fragile Beginnings

by Adam Wolfberg, MD

  Carmel and Martin often wondered if their data was too good to be true. If they were on to something of significant clinical importance, where was the recognition? Where were the competitors? “Why don’t we have a horde of neurologists knocking on our door every day saying, ‘We should try this in kids’?” Martin asked.

  But they didn’t; the clinical community largely ignored their work, and Carmel and Martin were left to envisage the clinical trials they would do in the future. They vowed to do them, even if they had to do them alone.

  There were bad days. Rats are great for research—they grow to maturity quickly, have most of the same organ systems as humans, and are cheap—but the translation only goes so far, and that recognition makes animal research a lonely endeavor. Although he refused to see it as a bad omen, as his research with rats intensified Carmel developed a brutal allergy to the rats; his arms broke out in angry hives and his nose began to run every time he handled the creatures. (At least I’m not allergic to children, Carmel thought morosely.) Most days, however, were exciting. The research was fascinating, and so far they had found none of the hypothesis-killing discoveries Jack Martin had worried about.

  Chapter 12. Living the Dream

  Predictably, when Larissa got her left hand back after her cast was taken off, she went back to using it, and her impaired right hand went from starring in the Birmingham hand camp to playing a decidedly supporting role. It wasn’t that her right hand couldn’t reach up and open the refrigerator door; it was just so much easier for her left hand. Testing at the end of the monthlong session showed she had made enormous gains, but we were warned that unless we kept up with her home program—a set of activities designed to reinforce and strengthen the progress she had made—those gains would be lost, at least in part.

  Kelly and I made a modest effort to keep up with the home program, but within a month, it was forgotten amid the demands of getting the kids to school and then bathed and to bed in the evening. It is unrealistic to expect a five-year-old to remember to use her right hand for certain activities when it is simpler to use her left, and so Righty didn’t receive the attention it deserved.

  Three years later, in the summer of 2010, we returned to the heat of Birmingham to do the program again. Our furnished apartment, in a completely different complex, looked pretty much the same as the last one. We were lucky enough to get Reggi back. She was even pregnant again.

  “Your right hand has really improved,” the therapist who did Larissa’s intake evaluation told her.

  “We didn’t do a great job of keeping up with the home program,” I volunteered.

  “One way or another, her right hand has gained a lot of ground,” the therapist said.

  The other difference was that Larissa was now eight and was able to articulate her own goals for the program. She wanted to learn to tie her shoes because she found it embarrassing to be the only one in her class who had to ask for help, and she wanted to learn to zipper her coat—again, this skill would grant her another degree of independence. She also wanted to learn to ride a bike.

  A therapist near our home in Newton had started teaching Larissa to type; the question was whether she should be taught to use two or three fingers of her right hand or write it off entirely and be taught one-handed typing. Reggi disagreed with both suggestions.

  “I think she can use all of her fingers,” Reggi said, and over the four weeks, she showed Larissa how those fingers of her right hand could learn to independently strike the keys of both a computer and a pink Barbie piano.

  She concentrated intensely and learned during the course of two weeks to pick up a Yahtzee die between her thumb and index finger, turn her hand over, and drop the cube into the palm of her hand. I told her how impressed I was.

  “Great job,” I said as I watched Larissa struggle (successfully) to pedal her bike up a shallow hill in the parking lot outside our apartment. “Super work.”

  A year earlier Kelly had gone back to work, so she and I split the month—I spent the first two weeks in Birmingham with Larissa; Kelly was there for weeks three and four.

  “I never hear her complain. Never,” Kelly told me on the phone from Birmingham one night after Larissa had gone to bed. “And she tries so hard to do whatever Reggi tells her. But I have to tell you that it is very painful to watch her work so hard to do with her right hand what most children take for granted.”

  Kelly thought back over the years—over the hundreds of doctors visits and the thousands of exercises with her physical therapists that were invariably scheduled for after school, when most kids were playing with friends or running around in the backyard.

  “She inspires me,” Kelly said. “She really does, because she’s always so positive and never feels sorry for herself. But it makes me feel bad for her.”

  While Larissa was with Reggi, and after Larissa went to bed at night, Kelly worked on her dissertation—now entering its ninth year in process. Kelly was finally confident she would finish it.

  “It’s not that I regret one minute of it,” she had said several times over the years. “I’d make the same choice again.”

  Measured by any metric, Kelly has succeeded. Larissa is a bright child, verbal and funny, and she’s a hardworking student who attends the same mainstream school as her sister Hannah. She read early, spoke early, and, like many of her classmates, has some difficulty with her handwriting.

  To be fair, she seems to have some problems coordinating her perception of objects with her ability to draw, and her paintings and drawings resemble what you might expect from a child two or three years younger. But artistry aside, she stands out for her humor and her personality, not for her right hand. In the indignities of her disability—shoe-tying, basketball shooting, monkey-bar scooting, painting—Larissa is reminded endlessly about what she can’t do. But in the context of everything she can do, these issues fade into the background.

  Science is incremental, and from the perspective of a career, success can be measured one paper at a time. Jason Carmel was publishing, and after finishing his residency he found himself a full-time research position—another sign of career success.

  It seemed appropriate that Carmel’s research had outgrown his brother’s injury—the most obvious disease target was now cerebral palsy, although the approach of using stimulation to strengthen brain-spinal connections might have a role in the treatment of spinal cord injury. Carmel had come to terms with the fact that his research would not cure David’s inability to move or feel below his chest, and during the years since his injury, David had come to terms with this too.

  But at times, when the welts rose and the rats misbehaved, Carmel was sobered by the recognition that he was modeling cerebral palsy and spinal cord injury in a six-inch rodent with a wire stuck into its brain through some modeling cement. So many questions remained unanswered, beginning with whether the rat was even an appropriate animal model for the human diseases Carmel really wanted to treat. Humans rely on their corticospinal tracts much more than rats do, and it would take studies in humans, perhaps years in the future, to determine exactly how well these exciting animal-model results translate into children like Larissa.

  It was probably impractical to implant an electrode in a child’s brain, so Carmel focused on finding a safe and noninvasive way to stimulate neurons. The best option at that point seemed to be transcranial magnetic stimulation (TMS), a cousin-technology to magnetic resonance imaging (MRI) that uses mild magnetic fields to create gentle electrical currents that can stimulate the brain. Best of all, TMS had an established track record in pediatrics.

  “I don’t think we have any illusions that we’re going to take a kid with severe hemiparesis or quadriparesis and get them playing on the high school basketball team,” Carmel said. “But we could make some important contributions to the quality of these kids’ lives.”

  Science,
increasingly, was a team sport, and Carmel had joined colleagues who shared his vision of therapy that combined stimulation of the brain with training of the injured limb. Carmel focused on direct stimulation of the brain, but Martin had shown that exercise of the disconnected limb was critical, so Carmel teamed up Andy Gordon, a scientist who had a training program for children with cerebral palsy that combined aspects of the Birmingham system—he used a sling instead of a cast to immobilize the unaffected arm—with two-handed activities.

  Together, Carmel, Gordon, and Kathleen Friel, another colleague who was pioneering research using MRI to pinpoint the exact extent of brain injury in children with cerebral palsy, were bullish about their prospects of making the first significant advance in therapy for cerebral palsy in a generation. “We have the tools, and we understand the circuitry,” said Carmel. “And because the therapies—TMS and constraint therapy—are known to be safe, what’s really exciting is that we can get going now.”

  Carmel planned a clinic focused on cerebral palsy and other neurologic disorders unlike anything that exists today. A kid like Larissa might be evaluated soon after going home from the hospital using Friel’s advanced MRI sequences to pinpoint the location and extent of her injury. Then she might come in each week, strap into a TMS helmet, and spend a couple of hours training to do specific tasks while targeted magnetic waves create precise electrical currents that stimulate neurons on the right side of her brain, making the learning process easier, faster, and more effective. Because TMS may work even without exercise, it might be possible to start TMS much earlier than exercise therapy—which requires the cooperation of the child—can begin.

  “Given the cat studies and what we know about the human corticospinal system as a bilateral system early on that starts to prune itself back to a single-sided system, our ability to use electrical stimulation during that early time when kids cannot participate in physical therapy could be very, very important,” Carmel said enthusiastically.

  However, will noninvasive stimulation be as effective as the implanted wire that will never be tried in humans? Will the window of plasticity in children stay open long enough that kids will benefit from these treatments? “I’m never going to be able to treat a newborn baby with an intraventricular hemorrhage, or even an adult in the first week after they injure their spine,” Carmel acknowledged. “Will this work when children are two, or twelve? As a neurologist, these are incredibly important questions.”

  Are there side effects that won’t be discovered until human studies begin? Research is rife with great ideas that had unanticipated consequences once studies moved from rodents to humans. But it’s hard not to get really excited.

  “When we first do TMS, we are expecting modest effects,” Carmel said, downplaying his hopes. “But as we better understand the circuitry, and understand which kids respond, we expect the efficacy will go up, and any chance of side effects will go down. Even early on we expect to make meaningful contributions to people’s recovery.”

  Sarah Habib isn’t much of a movie fan, but she loves a musical with a melodic score. When a movie becomes overstimulating or her surroundings create too much visual input, Sarah simply takes off her glasses. It’s a way to keep the world out, a strikingly effective way of reducing stimulation.

  It eludes her parents just how far these coping mechanisms go. Sarah appears to be unencumbered with disappointment that she can’t climb play structures like her contemporaries and doesn’t have playdates. Is she aware of how different she is from the other first-graders? Are her cognitive limitations such that she doesn’t even notice? Unlike Larissa, who discusses right-sided disability and also offers myriad clues to her awareness of her difference, Sarah’s thoughts are obscure to her parents and to the other children and adults who try to interact with her.

  “How do you know?” Kim asks. “If Sarah hears me say she can’t do something, then of course she’s not going to be able to do that.”

  “For me, it was about three years before I really understood that, okay, there are some things she is never going to be able to do,” acknowledges David.

  He would never admit to being disappointed—it would sound like a betrayal of his daughter—but David is matter-of-fact. “I’ve never been a parent in any other way,” he says. “I adapt to what she needs.”

  Kim finishes his thought. “We just say, ‘How can the situation be the best that it can be?’ ”

  Down on the floor of the living room, empty of furniture that could get in the way of Sarah’s play or practice walking, David sits, legs spread in front of him, across from Sarah, who has gotten him to play her favorite game: ball. The blue rubber ball flies back and forth. David rolls it across the floor to Sarah, who stops it, picks it up, and heaves it toward David, sometimes with a bounce, in his general direction. It’s a game she could play forever.

  “Ball,” Sarah says.

  “Ball,” David agrees.

  Kim sees incremental progress. “Every week she does something different, I’m telling you. It’s a new word, or better drawing. When people haven’t seen her in a while, they’re like, ‘Wow, she does that now!’ And guess what, now she’s potty trained.”

  Kim is always looking for signs of hope, like the advertisement on the subway wall.

  There was the time the family and Kim’s parents went to an antique store on Sarah’s birthday. Kim’s mother wanted to buy Sarah a gift, and Kim was all kinds of skeptical about the likelihood of finding an appropriate present for a little girl in an antique store. “My mother was showing her all of these old music boxes, and there was one with a unicorn, a teddy bear, and a star on it.” Kim’s mother wound it up, opened the top, and played the tune for Sarah. “Sarah signed I love the song to my mother,” Kim said. “I wasn’t paying attention, but my mother brings the music box over to where David and I are standing and is insistent that she’s found a gift for Sarah, and goes to purchase it. We get the music box home and Sarah pulls it out and opens the top and it plays ‘To dream the impossible dream,’ from Man of La Mancha.

  “You see: Sarah’s living the impossible dream.”

  Without a lot of enthusiasm, Steve Ringer was trying to find a word to describe the current state of newborn medicine, long years after the heady days when his colleagues discovered surfactant. “Elegant,” he said. “I think we are trying to make care more elegant.”

  Hospitals were pouring enormous resources into checklists and other low-tech systems to reduce errors and preventable complications, and Ringer’s NICU was in the thick of it, making sure that every time a central vein catheter was placed in one of the babies, a regimented set of guidelines, procedures, and sterilization techniques were carefully followed. The meetings that were needed to get everyone to contribute to the protocol were mind-numbing. Then there were four layers of hospital administration to go through to get approval for the new system. Finally, a skeptical group of residents, nurses, and fellows had to be won over, trained, and policed.

  But Ringer had to acknowledge that it worked. The problem of catheter-line infections pretty much disappeared. No one knew exactly how, because, of course, everyone had always used a sterile technique. It was a mystery, but a pleasant one, even if Ringer couldn’t take credit for this obvious success. This was an example of elegant medicine—more standardized, evidence-based, methodical, boring.

  The paperwork demands of the job increased too as the hospital asked for more documentation, and the health department and other supervisory agencies wanted to track diseases, infections, and outcomes with greater granularity. This part was frustrating.

  After the big discoveries were behind them and newborn medicine doctors turned to the critical task of fine-tuning their field, they realized that it was no longer adequate to publish papers reporting the experience of one hospital. Surfactant was so meaningful that it took only a few dozen babies to show that the stuff worked. Bu
t it is a truism of statistics that when a therapy’s effect is expected to be relatively small, a very large number of participants need to be enrolled in the study. So to prove that, for example, 40 percent oxygen supplementation is better than 50 percent oxygen supplementation, a very large number of babies are needed.

  Enter the Vermont Oxford Network, founded in 1988 with the specific purpose of improving the quality and safety of care in the NICU. The idea was simple, brilliant, and oh-so-tedious: All using the same precise criteria, NICUs would collect hundreds of pieces of information on how they cared for their tiny patients and record the outcomes—from infections to intraventricular hemorrhage, from retinopathy of prematurity to death—and send it in to the central office in Burlington. Expert statisticians culled through the data, merged it together, and then sent each participating NICU a confidential report that allowed the unit to compare itself with other units around the country and, eventually, around the world. By 2010, more than eight hundred units participated in the process.

  Over time, this cumbersome bureaucratic system transformed care in newborn medicine. It became common practice for units with higher-than-normal rates of respiratory complications to seek advice from units that had the lowest rates of complications. Experts from centers with the best results were invited to visit lower-performing centers, and best practices emerged, were published in scientific journals, and then trickled down across the country and around the world.

  It didn’t always work. Ringer participated in one program run by the Vermont Oxford Network that identified a package of best practices used by the NICUs with the lowest rates of chronic lung disease and took it to NICUs that had the highest rates of this common complication. When the results were evaluated years later, the group determined that even though the lagging NICUs had succeeded in implementing many of the recommended best practices, this had had no impact on chronic lung disease itself. “Something immeasurable was going on in those units,” Ringer said. “And we were as yet too stupid to understand exactly what it was.”