ARTICLE IN BRIEF
Investigators identified specific differences between children with multiple sclerosis and monophasic acquired demyelinating syndrome in the expected growth and atrophy of the cerebellum.
Scientists at the Montreal Neurological Institute of McGill University and their collaborators have devised a novel way to quantify cerebellar volume in children diagnosed with acquired demyelinating syndrome (ADS) and to use these data to distinguish children destined for a diagnosis of multiple sclerosis (MS) from those children who experience a monophasic (transient) illness.
The idea to study cerebellar volume emerged from recent studies showing that children diagnosed with MS have more prominent inflammatory lesions in the posterior fossa than those in newly diagnosed adults.
Katrin Weier, MD, a post-doctoral research fellow, and her colleagues, identified specific differences between children with MS and those with monophasic ADS in the expected growth and atrophy of the cerebellum. Their findings were presented at the AAN Annual Meeting in Philadelphia.
Dr. Weier's laboratory is participating in a multicenter longitudinal study, headed by Brenda L. Banwell, MD, formerly of the University of Toronto and now chief of the Division of Neurology at Children's Hospital of Philadelphia and a professor of neurology at the Perelman School of Medicine at the University of Pennsylvania.
The goal of the 10-year prospective study, which has been following Canadian children diagnosed with clinically isolated syndrome and monophasic ADS, is to identify risk factors and MRI features that identify children with MS and distinguish them from children with monophasic ADS.
“The cerebellum has not previously been the focus of research in MS,” said Dr. Weier. “We wanted to look deeper in the cerebellum and try to see discrete patterns. We wanted to know whether any cerebellar dysfunctions, for example, coordination or ocular motor problems, are correlated with any pathology observed on the scan.”
THE TECHNIQUE, RESULTS
Dr. Weier and her colleagues measured the volume of the cerebellum, along with its gray and white matter compartments, using information from the MRI scans and the presence of infratentorial lesions.
After plotting the volumes on a graph and plugging them into their statistical model to generate a growth curve, they could see patterns of change over time.
So far, they analyzed 449 longitudinal MRI scans from 93 children ages five to 18, all of whom had multiple scans over the years. They also referenced scans from 35 healthy matched children, and an additional 350 MRI scans from children four to 18 years old who were part of a longitudinal developmental study at the National Institutes of Health.
The mean follow-up period was 2.9 years. Of these, 69 children were diagnosed with monophasic ADS and 24 children with MS.
According to Dr. Weier, both monophasic ADS and MS patients had an inverted U-shaped developmental trajectory for total cerebellar volume and cerebellar grey matter volume (CGV). It peaked at around 13 years for girls and 17 years for boys, and then declined. In all cases, boys had significantly larger volumes compared with girls (p< 0.01).
A significant age-by-gender effect was seen for CGV (p=0.001). A significant age-by-diagnosis interaction (p=0.005) was found for cerebellar white matter volume (CWV), showing a reduction of CWV in MS patients, whereas the CWV plateaued in monophasic ADS patients over time.
Dr. Weier said that the effect of infratentorial lesions was significantly different between groups (p=0.04), with CWV affected only in the MS group. Thus, “even after a single event the cerebellum does not reach its expected size,” said Dr. Weier. “There is about a 5 percent volume loss among those with MS,” she added. (The statistical analysis represents an average of the total number of patients in the study.) The failure of growth in cerebellar white matter trajectories is different for patients that have monophasic ADS or MS, with MS patients demonstrating a clear loss of cerebellar white matter.
Dr. Weier noted that cerebellar volume growth changes over time and is different for each sex.
“Both monophasic ADS and MS in childhood lead to impaired age-expected growth of the entire cerebellum and by subsequent actual cerebellar atrophy,” said Dr. Weier. “The involvement of the cerebellum in motor, cognitive, and affective processes may lead to subtle changes in a child's developmental trajectory.”
One possible explanation for the findings, said Dr. Weier, is that “MS patients have more lesions in the posterior fossa than those patients with monophasic ADS, and this might explain the white matter volume difference. There might be additional ongoing processes, some that we can't yet detect with MRI, which may explain the differences. This is just the beginning of our analysis. We need much more information to interpret what is happening and why.
“For now, we can say that there is a volume difference but how much impact it has clinically we just don't know,” said Dr. Weier. The next step is to see whether they can correlate this volume difference with clinical disability, she added.
Commenting on the new study, Tanuja Chitnis, MD, director of the Partners Pediatric MS Center at Massachusetts General Hospital, said that pediatric MS has been challenging to diagnose. “Until recently, there has been no standard definition,” she said, adding that a consensus panel created a working definition in 2007, which was updated last year. “This has helped in accurately diagnosing pediatric MS.”
Still, “it is difficult to know which patients with their first demyelinating attack will go on to be diagnosed with MS. It helps to distinguish features in kids with monophasic ADS and clinically isolated syndrome from those with MS.”
This latest study shows that “there are new lesions and brain atrophy that occur in children with MS, and brain growth is delayed. Cerebellar growth is more impaired in children with MS versus those with monophasic ADS. We did not know that cerebellar growth is impaired.”
While she said it is still too early to use this tool clinically to measure brain volume, “it does mean that brain changes occur early in pediatric MS and it could potentially have an impact on the disease course. If cerebellar growth is impaired, it can cause functional problems in life.
“We may need to think about ways to prevent cerebellar volume decline,” she added. “The lesions in the brain influence white matter growth and may be responsible, in part, for the delays in cerebellar growth.”
John R. Corboy, MD, FAAN, professor of neurology at the University of Colorado School of Medicine and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus, said that there has not been a long enough follow-up period “to see whether this marker holds up over time.” But, added Dr. Corboy, who serves on the Neurology Today editorial advisory board, “it will be important to be able to distinguish between these events and MS. We don't want to start on a $50,000-a-year treatment on a 10-year-old. I will hold judgment to see if the finding can be replicated.”
EXPERTS: ARE THE FINDINGS READY FOR CLINICAL USE?
This study was selected by members of the Neurology Today editorial advisory board as one of the noteworthy papers from the AAN Annual Meeting.