VIPS II Study Homes In on Pediatric Arterial Ischemic Stroke

Arterial ischemic stroke (AIS) in childhood is rare and often unrecognized, occurring in about 2.4 per 100,000 U.S. children annually. Recurrence poses a particular challenge: One month after an initial event, about 7 percent of children have another stroke, with the recurrence rate climbing to about 12 percent after one year. In the presence of an arteriopathy, however, this risk is increased fivefold versus an “idiopathic stroke,” with the highest risk of recurrence within the first three months after the index stroke.

Better understanding of the potential etiology of recurrence risk is the focus of the second Vascular Effects of Infection in Pediatric Stroke (VIPS II) study, which is currently underway at 17 centers in the U.S. (including Cleveland Clinic), Canada and Australia.

VIPS II follows the first VIPS trial, which found that the greatest predictor of stroke recurrence is arteriopathy, underscoring its importance as a target for secondary stroke prevention in this population. Using cutting-edge testing techniques on blood samples and throat swabs from patients, VIPS II investigators anticipate better defining the roles of infection and inflammation on arteriopathy to help inform treatment decisions following an initial AIS.

One common and unique pattern of arteriopathy seen in children involves a focal narrowing of the distal internal carotid artery, or proximal middle cerebral artery, known as focal cerebral arteriopathy (FCA) of childhood (see image below), notes pediatric cerebrovascular specialist Neil Friedman, MBChB.

“We learned in VIPS I that abnormal blood vessels pose the greatest risk for a recurrent arterial ischemic stroke in children, but we really don’t understand the underlying basis very well,” says Dr. Friedman, Director of Pediatric Neurosciences at Cleveland Clinic and a co-investigator in both VIPS I and VIPS II. “VIPS I identified infection as a risk factor for a first AIS in children, but key questions remain: Is infection and/or inflammation potentially implicated in FCA? Should we treat children with steroids or antibiotics after a stroke to prevent a second one? We aim to find out in the current VIPS study.”

Focal cerebral arteriopathy of childhood. Cerebral angiogram showing focal irregularity of the left internal carotid artery terminus measuring approximately 3.6 mm in length, with associated stenosis, and mild to moderate flow limitation.

Lessons from first VIPS trial

VIPS I prospectively followed 355 children with AIS at 37 international centers from 2009 to 2014. During median follow-up of two years, one child died, 40 children had a recurrent AIS and none had a hemorrhagic stroke. Findings of VIPS I, which were published in late 2015 in Stroke, included the following:

• Risk factors for first childhood AIS included recent infection, undervaccination and low socioeconomic status.
• The only identified predictor of recurrence was the presence of an arteriopathy.
• Arteriopathy increased the risk of recurrence fivefold compared with idiopathic AIS.
• One-year recurrence rates were 32 percent for moyamoya, 25 percent for focal or transient cerebral arteriopathy and 19 percent for arterial dissection.

VIPS II study design

Initiated in September 2016, VIPS II is anticipated to last five to six years. About 150 patients ages 29 days through 18 years will be recruited within 72 hours of having an arteriopathic, cardioembolic or idiopathic stroke. In addition, 150 controls (75 healthy and 75 ill children) will be matched by age and site.

The study will collect throat swabs at the time of the stroke. Blood samples will be taken within four to seven days, again one to six weeks later, and again at two to 12 months. Parents will be interviewed within the first week after the stroke, then annually. All imaging performed during clinical care, including brain MRIs and vascular imaging of the intracranial arteries, will be available to study investigators.

Serum and throat swabs will be analyzed for known and novel pathogens using next-generation sequencing, a high-throughput technique that matches RNA in a sample to pathogen sequences in a gene database.

Luminex™ immunoassays will also be used to detect 26 possible immune mediators to discern whether distinct analyte signatures are associated with an alternative pathway of inflammation in arteriopathic AIS compared with cardioembolic or idiopathic stroke.

Gene expression profiling will also be conducted to identify molecular correlates of stroke heterogeneity.

Battling AIS: Prevention, recognition, treatment

In addition to recurrence risk, the first VIPS trial examined other facets of AIS related to prevention and diagnosis:

• Risk factors for childhood AIS were discussed in a 2015 paper in Neurology; infection was found to act as a trigger, while routine vaccinations appeared protective.
• Factors to aid in diagnosing childhood arteriopathy were discussed in a 2014 article in Stroke. The authors concluded that although clinical data and follow-up imaging help, diagnosis remains a challenge.
• Diagnosing childhood arteriopathy subtypes was further discussed in a 2017 paper in the American Journal of Neuroradiology.

“With the consequences of childhood stroke so often devastating and lifelong, it is critical to find out as much as we can about it and develop strategies to prevent it, recognize it when it occurs and prevent further recurrence,” says Dr. Friedman.

He adds that dedicated pediatric cerebrovascular experts and collaborative efforts by a network of institutions are what allow invaluable research to be conducted on this rare condition.

Dr. Friedman emphasizes that large institutions have important unique capabilities to deal with rare and complex neurological events such as childhood stroke. “At Cleveland Clinic, we are fortunate to have an adult stroke team with the latest treatments for vascular interventions available at all times that can be quickly mobilized for pediatric cases,” he observes.