WASHINGTON, DC—The incidence of stroke among children is steadily increasing, although the condition is still underdiagnosed, according to Gabrielle deVeber, MD. And while current antithrombotic therapies are safe, they are not completely effective, she reported.

“In the last 10 years, there's been a rapid progression of research and interest [in ischemic stroke due to vascular occlusion],” said Dr. deVeber. “And we still face numerous challenges. This is a rare and heterogeneous condition. Neonates are not little children; children are not little adults.… There’s a wealth of data out there on stroke, but it can only be selectively extrapolated to pediatric patients. In childhood stroke, we see rare and unusual situations as the norm.”

Dr. deVeber is the Research Institute Director of the Children’s Stroke Program and Associate Professor of Pediatrics at the University of Toronto. She presented her findings at the 31st National Meeting of the Child Neurology Society.

“A BIG PROBLEM”

In the 1970s, ischemic stroke occurred at a rate of 0.6 per 100,000 children per year. That number doubled to 1.2 per 100,000 children in the 1980s. In the 1990s, a study from France found a prevalence of 8.0 per 100,000 children per year. Currently, arterial ischemic stroke combined with sinovenous thrombosis is occurring at a rate of at least 3.3 per 100,000 children a year, according to the Canadian Pediatric Ischemic Stroke Registry.

“What’s very important is that there are 620 children [in the registry] with arterial stroke, and 25% were newborns,” Dr. deVeber said. “So if you look at the incidence rate for newborns, it's about one in a thousand based on those data. For sinovenous thrombosis, where we have 161 children, 43% were newborns, and that gives an incidence in newborns of about one in 2,000 per live birth. So that’s very, very impressive and helps define for us the fact that this is a large burden of illness and a big problem, particularly considering that survivors live many decades with the neurologic sequelae and risk of recurrence in these conditions.”

Dr. deVeber offered a number of reasons as to why the incidence is increasing, including heightened awareness, improved radiographic techniques, and that more patients are surviving what were previously considered lethal conditions. As a result, those children are predisposed to stroke. “But I think counteracting that latter point is the fact that we’ve come closer and closer to preventing primary strokes in those populations,” she said.

The registry shows that more than 75% of children who present with acute arterial stroke are diagnosed later than 24 hours after the onset of symptoms. Furthermore, 10% of children with a first-index arterial ischemic stroke have had a preceding transient ischemic attack or even a preceding arterial stroke. “So not only are we delaying the diagnosis, we are actually missing it and the opportunity to prevent further events,” Dr. deVeber remarked.

THE KEYS FOR DIAGNOSIS

Dr. deVeber pointed out that in older children with stroke, hemiparesis and focal signs are evident, but in the newborn, seizures alone are the norm. Because the brain is not developed in newborns, future deficits may not be evident, she added, cautioning physicians accordingly: “In the neonatal nursery, do not give a good prognosis to parents who have a child without hemiparesis [following stroke], because as the brain myelinates and matures, you’ll see the emergence of hemiparesis in about a third [of patients].” For sinovenous thrombosis, the same is true in that newborns are different than older children. “But the important point here is that given the pathophysiology of the disease, most of the signs are diffuse for sinovenous thrombosis, even in older infants and children.”

An abundance of new neuroimaging techniques is currently helping researchers better understand and detect stroke in children. Diffusion weighted magnetic resonance imaging (MRI) may be the most important clinically useful tool because it shows early cytotoxic edema, said Dr. deVeber. “Prior to the regular MRI, it tells you that this area of the brain is probably destined for permanent infarction.” Vascular imaging is also valuable, because half of children with stroke have a vasculopathy or disease attacking an artery. Perfusion weighted imaging, Doppler ultrasound, and, in newborns especially, diffusion weighted imaging are all very important methods by which to detect early changes, she said.

In a child, there are predisposing and triggering factors for stroke, which are multiple and often overlapping. “You can’t stop looking just because you found an obvious cause,” she said. “You need to do a full work-up and find the full burden of risk factors for that child because some are treated differently than others.” According to the registry, 26% of older infants and children with stroke have no identifiable risk factors. “So there’s clearly a large target for research. I’m sure that over the next 10 years that 26% is going to go down.”

WHAT TREATMENTS WORK?

One means of preventing poststroke damage is antithrombotic therapy, she said. In one study, Dr. deVeber and colleagues found that of 115 older infants and children, none who took aspirin had a major bleed or complication and none who took low-molecular-weight heparin had a major bleed or developed Reye’s syndrome. A study by StrŠter et al found no major bleeds or complications in 135 children given low-dose low-molecular-weight heparin or aspirin. “The bottom line is these treatments appear to be safe,” she said. “The largest reason for noncompliance in our population for aspirin therapy is the concern about Reye’s syndrome. The message needs to get out to the parents and pharmacists that Reye’s syndrome at these doses has not yet been reported.”

Dr. deVeber said that only a randomized controlled trial will decide whether one of these therapies works better than another. “We will be developing those. That's really our end point and our next goal.”

HOW EFFECTIVE IS t-PA IN CHLDREN?

Another potentially useful, but controversial, treatment for children is t-PA, she said. One problem is that most children do not present to the hospital within three hours, the recommended window for treatment. In addition, she said, “There is a wide differential for acute hemiplegia in children, unlike in an adult.… So we can’t really know if these are children with stroke in many cases. And there is poor emergency access to t-PA in pediatric hospitals. It is a potentially very effective medication, but the use of this medication in a nonstandardized way, in particular with protocol violations where it’s given after three to six hours, could deep-six this treatment for the future. If we get a couple of initial bleeds, that will be it, this drug will never be studied in children.”

No neuroprotective strategies for treating stroke in children are currently approved, she said. However, approaches beyond drugs, such as fever control, seizure control, and blood pressure and blood glucose control, can make a big difference. In addition, emerging rehabilitation strategies, adjunctive therapies, and pharmacologic mechanisms such as amphetamines may be of benefit to children with stroke.

WHAT DOES THE FUTURE HOLD?

The goal of the clinical research in this area is to build randomized controlled trials, noted Dr. deVeber. But sufficient data on treating children with stroke must be gathered first, and one way to help accomplish that is to interest the research organizations funding adult stroke. “Our sell to them is that by studying the immature brain and the mechanisms for recovery in the immature brain, where we know plasticity is such an active process, we may be able to better understand what goes on in the mature brain and to find better strategies for treatment.

“The light at the end of the tunnel and the optimism are there. The understanding is advancing, and it’s improving through collaborations,” she said.

NR

—Colby Stong

Suggested Reading
Lanthier S, Carmant L, David M, et al. Stroke in children: the coexistence of multiple risk factors predicts poor outcome. Neurology. 2000;54:371-378.
StrŠter R, Kurnik K, Heller C, et al for the Childhood Stroke Study Group. Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study. Stroke. 2001;32: 2554-2558.

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