Fighting a rising tide
by Nancy Fliesler
Lori Watson thinks it was an infection that caused her to give birth to her son William prematurely, at just 28 weeks gestation. "They gave me an anti-contraction drug, and it worked for about 10 days," Lori remembers. "But then his heart rate started to climb, and they wanted to deliver him."
William's still-developing brain was irreversibly damaged. At 13 months old he was examined by Joseph Volpe, MD, neurologist-in-chief at Children's Hospital Boston and a world expert in neonatal neurology. Volpe diagnosed periventricular leukomalacia (PVL), a "softening" or thinning of the white matter around the ventricles, the brain's fluid-filled cavities. "He'll be awkward and uncoordinated," Volpe told Lori, "but he'll have a relatively normal existence."
The white matter that had thinned is myelin, the fatty coating that insulates nerve fibers, facilitating the travel of nerve impulses, from cell to cell. The loss of myelin has impeded communication between William's brain cells. As a result, he has cerebral palsy (CP), leaving some muscles weak and others rigid, and impairing his muscle control. He can walk with a walker, but he tires easily, and he needs help getting out of bed and getting dressed. PVL has also left William with learning disabilities, a slight speech impediment, and a limited field of vision, so he can't see well below nose level.
"The worst part is having kids call me retard all the time," says William, who is now 10. "I just call them retard right back."
William is one of a large and growing number of children surviving extreme prematurity only to be left with its long-term complications. PVL is the major brain injury in these infants, and its risk increases the more premature the baby. And cases are surging: more in vitro fertilizations and more multiple gestations are leading to more premature, very-low-birthweight infants. In the U.S., about 57,000 babies weighing less than 1,500 grams (3 pounds, 4 ounces) are born annually.
With medical advances, survival of these frail infants has increased from about 20 percent 15 years ago to nearly 90 percent today. But it's progress at a price: some 25 to 50 percent of surviv-ors develop cognitive, attentional and behavioral deficits, and about 10 percent have CP. In fact, about half of all new cases of CP now occur in survivors of prematurity.
Since PVL cannot be reversed, clinicians, family and child can only work to minimize the functional impairment it causes. "Do as much as you can, as soon as you possibly can," William's doctors advised.
Lori has a big box filled with William's medical files, with labels like Orthopedic, Neurosurgical, Eyes/Vision, Cognition, Communication, Neuropsych. Separate folders hold his many MRI scans and X-rays and others hold reams of insurance-related paperwork. "It's not just a medical file," Lori says. "It's the lifelong management of a case."
She ticks off William's interventions: twice-weekly physical therapy, twice-weekly occupational therapy, speech therapy, a part-time personal care attendant and a personal aide who accompanies William at school. Although William gets A's in most subjects, he has trouble with math and abstract thinking, so a special education teacher pulls him out of some classes to do one-on-one academics.
William has also undergone a series of orthopedic surgeries to reduce the spasticity (over-contraction) of his limb muscles and correct skeletal misalignments. Each procedure has improved his function’Äîhe can now bend his legs to walk up stairs, for example’Äîbut
has posed setbacks to his overall progress.
"He's been tantalizingly close to independent walking at various points," says Adre du Plessis, MD, William's primary neurologist at Children's, "but he's thrown back by the lengthy recovery after each new procedure."
Led by Volpe, Children's researchers are trying to find ways to prevent PVL. They meet weekly to exchange data from MRI scans of infants' brains, autopsies of brains from non-surviving infants, laboratory studies, and animal studies that simulate human PVL and test possible interventions.
PVL, they know, is caused by two kinds of insults that can occur during late pregnancy or birth. One is inflammation, usually sparked by an infection in the mother. The other is a decrease in oxygen supply and blood flow to the brain, known as hypoxia/ischemia. Premature babies are especially vulnerable to hypoxia/ischemia: their underdeveloped lungs often can't deliver enough oxygen, and they experience frequent dips in blood pressure. Inflammation can also cause blood pressure to fall, exacerbating hypoxia/ischemia or triggering new episodes.
"A lot of premature newborns have a stormy course," says Children's neurologist Frances Jensen, MD. "It's not uncommon for them to have repeated hypoxic/ischemic insults and multiple setbacks."
Both types of insult trigger a cascade of reactions in the baby's vulnerable brain, leading to death of the critical cells that produce myelin, known as oligodendroyctes. At the tender gestational age of 23 to 32 weeks, the high-risk period for PVL, babies' oligodendrocytes are rapidly developing and at the peak of their vulnerability—just when a variety of damaging factors are converging on them.
"The good news is that each of those factors could be blocked," Jensen says. "We're now trying to figure out how."
One of these factors is glutamate, the brain's major excitatory messaging chemical. Hypoxia/ischemia causes glutamate to pool in excess around the developing oligodendrocytes, essentially exciting them to death. At 23 to 32 weeks' gestation, Jensen has found, oligodendrocytes have an especially large number of receptors where glutamate can dock, making them exceptionally vulnerable to the onslaught. When too much glutamate docks, it causes a toxic rush of calcium into the cell.
This influx triggers another damaging factor: the release of toxic molecules known as reactive oxygen and nitrogen species. These molecules, also triggered by inflammation, attach themselves to compounds in the cell, disrupting its function, says Children's neurologist Paul Rosenberg, MD, PhD. Developing oligodendrocytes are uniquely susceptible because they don't yet have the enzymes to defend against their attackers. "We've looked at immature and mature oligodendrocytes and found more antioxidant enzymes in the mature cells," Rosenberg says.
Microglia are another looming threat. These are the brain's scavenger cells, going to injury sites and clearing away debris. Children's neuropathologist Hannah Kinney, MD, has shown that microglia are over-activated in the brains of babies with PVL, making a bad situation worse: they produce more reactive oxygen and nitrogen species and cause further glutamate accumulation. Compounding this scenario, Kinney has found that microglia are especially plentiful in the white matter during the window of vulnerability to PVL: at 23 to 36 weeks' gestation, the cells have not yet completed their natural outward migration toward the cortex, the outer layer of the brain.
It's as if the young oligodendrocytes had encountered the perfect storm.
Dire as the situation is, the Children's team can now take on the causes of PVL one by one. Jensen has shown, for example, that the anticonvulsant drug topiramate, which blocks the activation of glutamate receptors, can prevent white-matter injury in animals when given after a hypoxic/ischemic event. The drug is FDA-approved, but only for adults and children over age 3; it would need to be tested for safety in newborns and infants.
In cell studies, Rosenberg has shown that vitamin K can prevent reactive oxygen and nitrogen species from damaging young oligodendrocytes by boosting deficient antioxidant mechanisms. Vitamin K is already given to newborns to boost their clotting ability and has no known side effects.
Rosenberg speculates that higher doses might protect high-risk babies from PVL.
Rosenberg is also targeting several specific substances, like peroxynitrite, a reactive nitrogen species produced by activated microglia, and 12-lipoxygenase, an enzyme that seems to generate reactive oxygen species. Early test-tube and animal studies suggest that blocking these compounds may be protective.
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Meanwhile, du Plessis hopes that loss of white matter could be prevented, or its effects minimized, through changes in the care of premature babies. He believes that PVL's root cause is impaired regulation of blood flow in the brain. Normally, tiny muscle fibers dilate or contract the brain's blood vessels to keep this flow constant. du Plessis thinks these muscle fibers are insufficiently developed in premature babies, so that when the body's blood pressure rises or falls, the brain's blood flow begins to fluctuate as well, leading to hypoxia/ischemia. Certain interventions used in sick newborns may also compromise blood flow in the brain, compounding the problem, du Plessis theorizes.
In a study now nearing completion, du Plessis and colleagues intensively monitored 100 premature infants during their first days of life, measuring blood pressure, cerebral blood flow, blood oxygenation, heart rate, markers of inflammation and other variables to look for predictors of PVL. Sensitive MRI scans were used to detect PVL, and sophisticated imaging techniques were used to examine the structure and organization of brain tissue.
"If we can prove an association between PVL and disturbances in blood flow, we then need to identify clinical factors that predispose to these disturbed blood-flow patterns," says du Plessis. "If we can predict which babies are most at risk, we could enter them into clinical trials."
Such trials, if approved, could help refine neonatal care to minimize brain damage and also test promising drugs like topiramate. But before drug trials can proceed, or changes made in newborn care, more needs to be known. Drug trials in children always raise concerns about side effects, and when it comes to infants, particularly premature infants, there's concern about giving just about anything—especially something that affects the brain.
And in a newborn's brain, the pharmaceutical targets are constantly changing. "When you think of therapy, it's so important to think of developmental stage," says Jensen. "If a drug is given at the wrong time, the target may not be there—or the effect may be the opposite of what is wanted."
William also has a long road ahead. He's tried many innovative treatments, including Botox injections to relax his spastic muscles, and a whole-body Lycra suit designed to reduce muscle spasticity and improve his joint stability, gait and posture.
du Plessis helps Lori assess the many available therapies. "We wade through the specialists' opinions together and pick the best path," Lori says. "You have to focus on what you can realistically expect, what the child is willing to do and what's in the child's best interest."
Mostly, William just keeps moving.
Each afternoon, his personal care attendant, Wesley Prevost, helps him get off the school bus, does homework with him and sees that he gets some exercise. The exercise is vital: it keeps William's muscles from permanently tightening, limiting his range of motion and producing deformities.
"We do stuff he likes, like boxing, so he doesn't realize he's exercising," Wesley explains. "He's real strong; sneaky, too. You don't see it coming sometimes."
"As long as he's moving," says Lori.
"I am moving," announces William, wiggling his finger. "The joy is rushing through my veins!"
Joe Gross, William's physical therapist, is charged with helping him get the most out of his body. "He has problems with his pelvic muscles, hip muscles and glutes—they just don't fire properly," Joe tells Lori at the end of one session. "I want him faster, I want him more efficient, I want him getting on and off that school bus. He's got a lot of work to do."
For information on supporting the Department of Neurology,
contact Donna Richardson in the Children's Hospital Trust at
(617) 355-2061 or donna.richardson@chtrust.org.
