MONTREAL—Pediatric-onset acute demyelination provides a unique window for studying environmental exposure and disease mechanisms involved in multiple sclerosis (MS), said Brenda Banwell, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis. Some of the triggers being studied in children include viral exposure (eg, Epstein-Barr virus [EBV]) and vitamin D deficiency.

“Pediatric acute demyelination provides an opportunity to look at a population of individuals presenting at a time when they have had a relatively limited environmental experience, when the immune attack may be directed at the primary target involved in the MS disease process with a reduced possibility of secondary immune responses to injured tissue,” said Dr. Banwell, Associate Professor of Pediatrics (Neurology) and Director of the Pediatric Multiple Sclerosis and Demyelinating Disease Program at the Hospital for Sick Children, University of Toronto. In pediatric MS, the targets become available to the immune system potentially at a time when the environmental exposures, or triggers of the disease, are still operative.

Dr. Banwell and colleagues obtained data from the Canadian National Pediatric Demyelinating Disease Study, a prospective study involving 23 sites across Canada. Children with a first demyelinating event were enrolled at presentation and underwent a comprehensive clinical, genetic, pathobiologic, and neuroimaging assessment, which was performed at three, six, and 12 months, and then annually thereafter.

EBV as a Possible Trigger
A viral pathogen of interest as a potential trigger of MS is EBV. “EBV has a very powerful effect on our immune system; when you acquire EBV infection, you never really lose it,” she said. “It becomes part of our B-cell repertoire, and it’s a part of our repertoire that we have to tightly control.”

She described a study of 137 children with MS and 96 controls matched by age and geographic region who underwent standardized assays for immunoglobulin G antibodies directed against EBV, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus.

“We found that when you compare children with MS to non-MS participants, the MS children do indeed have higher titer reactions to the EBV protein,” she said. A greater percentage of children with MS were in the high-titer group (area under the curve > 195), compared with age-matched, EBV-positive healthy controls (40% vs 18%).

Serial samples demonstrated that “high titers persist,” she said. “It’s not a transient phenomenon.”

Is Vitamin D Insufficiency Linked to MS?
More than 80% of the children with MS were seropositive for EBV infection, a significantly higher rate than that observed in controls. Children with MS did not differ from controls in seroprevalence of the other viruses studied.

The high rate of MS in Canada may be related to vitamin D insufficiency, said Dr. Banwell. Canada has one of the highest rates of MS in the world, and distance from the equator is one variable that has been shown to be associated with MS prevalence. One of the more popular theories is that suboptimal vitamin D synthesis in the skin may play a role in the pathobiology of MS.

Therefore, Dr. Banwell and colleagues evaluated vitamin D status in 117 children with a first attack of demyelination who were enrolled in the Canadian National Pediatric Demyelinating Disease Study; 98 had monophasic acquired demyelination syndrome (ADS) at the time of the study, and 19 were diagnosed with MS.

The mean serum level of 25-hydroxyvitamin D was 61.3 nmol/L at presentation in the children with monophasic ADS, which was significantly greater than the 44.2-nmol/L mean level at presentation in the children who were later diagnosed with MS. The mean level of serum 25-hydroxyvitamin D value for the entire group of 117 children was 58.5 nmol/L, “well below what is considered to be a reasonable vitamin D level in serum, which is 75 nmol/L,” said Dr. Banwell.

More than 75% of the entire cohort were vitamin D–insufficient. Of the children in the lowest quartile of serum 25-hydroxyvitamin D level (≤ 34.8 nmol/L), 28% were diagnosed with MS, compared with 7% of children with serum 25-hydroxyvitamin D levels in the highest quartile (> 76.3 nmol/L).

Assessing Immunologic Biomarkers
Several immunologic biomarkers and their association with pediatric MS have also been studied. Dr. Banwell’s research team conducted one such study of serum biomarkers in children with clinically isolated syndrome and age- and gender-matched healthy children. In this study, children with demyelination had higher levels of matrix metalloproteinase (a marker of potential immune cell entry into the CNS), reduced levels of tumor necrosis factor–related apoptosis-inducing ligand, which is a potential biomarker of reduced apoptosis of inflammatory cells, and reduced levels of interleukin 10 (indicating a reduction in anti-inflammatory activity), compared with healthy controls.

—Wayne Kuznar

Exploring Viral, Environmental, and Immunologic Bases for Multiple Sclerosis