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In the Clinic-Multiple Sclerosis in Children
Children with Radiologically-Isolated Syndrome Tend to Convert Quickly to MS

ARTICLE IN BRIEF

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AXIAL FLAIR images demonstrate (A) an infratentorial hyperintensity within the cerebellar white matter in a child with radiologically-isolated syndrome (RIS) at baseline (other lesions not shown) and (B) juxtacortical and ovoid hyperintensities (arrows) in a different child. (C) Sagittal FLAIR image from the child shown in B demonstrates hyperintensities extending over the long axis of the lateral ventricles and oriented perpendicularly to the corpus callosum (arrows, other lesions not shown). To date, neither child has developed a first clinical event consistent with CNS demyelination.

Researchers found that among children with radiologically-isolated syndrome, two factors in particular predicted whether a child would progress to MS: the presence of two or more unique oligoclonal bands in cerebrospinal fluid and spinal cord lesions on magnetic resonance imaging.

Children who were found incidentally on magnetic resonance imaging (MRI) to have radiologically-isolated syndrome (RIS) are at high risk for developing multiple sclerosis (MS) and tend to progress to a first clinical event more quickly than do adults with RIS, according to a retrospective study of 38 children published in the September 25 edition of Neurology: Neuroimmunology & Neuroinflammation.

The study found that two factors in particular predicted whether a child would progress to MS: the presence of two or more unique oligoclonal bands in cerebrospinal fluid (CSF) and spinal cord lesions on MRI. The children in the study had originally undergone MRI for other reasons.

Lead author Naila Makhani, MD, assistant professor of pediatrics and neurology and director of the Pediatric MS Program at Yale University, told Neurology Today that “previously we didn't know much about happens to children with radiologically-isolated syndrome” and, in fact, criteria for diagnosing RIS have only been established for adults, not children.

“Our study highlights the importance of the detection of RIS in children,” she and her coauthors wrote. Professional guidelines are needed to specify how best to evaluate children for RIS, they said, so that those at high risk for developing MS are identified and monitored.

The study authors also noted “the incidental finding of abnormalities in MRI scans of the brain and spinal cord have become more common due to the use of MRI in the evaluation of a wide range of medical conditions in children. Some of these abnormalities are highly suggestive of central nervous system (CNS) demyelination based on their size, location within the white matter and shape,” the study said.

Prior research has shown that 34 percent of adults with RIS develop a first clinical event within five years, the paper noted, and 59 percent had radiological evolution within 2.7 years. It had not been known whether the same patterns of progression to MS hold true for children.

STUDY DESIGN

To examine that question, the researchers conducted a historical cohort study with 38 children under age 18 who were seen at one of 16 collaborating MS centers in six countries between December 1995 and March 2016. The children, who had no symptoms indicative of demyelinating disease, had undergone neuroimaging evaluations related to other issues, most commonly headache.

Their incidental MRI abnormalities were consistent with CNS demyelination that met 2010 MRI criteria for dissemination in space (DIS) for MS. (White matter abnormalities were ovoid, well-circumscribed homogenous foci with or without involvement of the corpus callosum; T2 hyperintensities measuring 3 mm or greater in accordance with 2010 DIS criteria; and were not consistent with a vascular pattern.) About half of the children in the study also met the criteria for the adult definition of RIS published in 2009.

The most common lesion type was periventricular, and at least one such lesion was identified in all the children. Spinal cord imaging was done in 29 of the 38 children, and of those, five (17 percent) had spinal lesions. Some, but not all, of the children underwent CSF testing.

In a mean follow-up of 4.8 years, the investigators reported that a first clinical event consistent with CNS demyelination occurred in 16 children (42 percent) within a median of two years; changes in radiological findings occurred in 23 children (61 percent) within just over a year; and children who had two or more unique oligoclonal bands detected in CSF and spinal cord lesions on MRI were more likely to progress to a first event compared to those who did not have those factors.

Five of the children in the study were treated with immunomodulatory therapy for MS to prevent or delay a first clinical event, a number too small to determine any clinically meaningful event.

“Although this work does not address the issue of whether children with RIS should be treated with disease-modifying agents, we hope that an accurate classification of the risk of clinical symptoms in children with RIS will help in the development of consensus guidelines that are urgently need to optimize clinical care in this population,” the researchers wrote.

Two immunomodulatory agents, dimethyl fumarate and teriflunomide, are being tested in multicenter trials to determine if they can prevent or delay clinical evolution of disease in adults with RIS.

Dr. Makhani said the question of using immunomodulatory agents in children with RIS is complicated because “we are dealing with a developing immune system and we don't know what effect these drugs are having in the long term.”

EXPERT COMMENTARY

Patricia K. Coyle, MD, FAAN, professor and vice chair of the department of neurology at Stony Brook University, said the findings argue for conducting a thorough workup of every pediatric individual with MRI findings suggestive of RIS, including doing a spinal fluid analysis and MRI imaging of the spinal cord.

Dr. Coyle, director of Stony Brook's MS Comprehensive Care Center, said some practitioners are reluctant to do lumbar punctures, in part because the procedure is perceived as invasive and difficult, but she said the new study indicates that valuable information can be gleaned. She recommended having a comprehensive checklist to allow doctors to better rule in or rule out RIS.

“MS can declare itself in young people, who may have had the disease a number of years before it is identified,” Dr. Coyle said.

Moses Rodriguez, MD, FAAN, professor of neurology and immunology at Mayo Clinic, said the finding that progression to the first clinical event happens quickly in children with RIS “is really telling us that there is something unique about this disease in children.”

“It does seem to be much more aggressive and cause more attacks” than in adults, he said.

Dr. Rodriguez said it had long been assumed that MS was a disease of adulthood, but awareness is growing that MS can happen in even very young children.

“Children may not present with optic neuritis,” he said. More typically the path toward diagnosis begins with a mother saying that something does not seem quite right with the child, or his grades are dropping, he said. Headache may be another reason for seeking evaluation.

As part of the U.S. Network of Pediatric Multiple Sclerosis Centers, Dr. Rodriguez is involved in a multicenter study that is prospectively following more than 700 children from the time they are identified with RIS or MS to determine how they fare clinically, radiologically and from a cognitive perspective. Among the questions they look at are these: “How do they do in school? Do they do as well in college as normal kids?” Dr. Rodriguez said.

Dr. Rodriguez said that studying MS in children could turn out to be more conducive to identifying causes of the disease because family and patient reports related to potential environmental influences, such as infections and Vitamin D deficiency, may be more reliable early on rather than long after the fact. He said he expects the multicenter prospective study “to provide new insights into MS.”

Wendy Vargas, MD, assistant professor of neurology and director of the pediatric MS and neuroimmunology program at Columbia University, said it was noteworthy that the newly published study from Yale identified two factors that make it more likely that a child with RIS will convert to MS — the presence of lesions on spinal cord MRI and oligoclonal bands in CSF. She said doing a comprehensive evaluation that includes those tests is warranted when a brain MRI turns up suspicious white matter lesions. But she said how best to manage children found to have RIS is not clear.

Given how quickly a first clinical event can develop, “The question is, ‘Do we start treatment?’ The jury is still out. We have to wait and see what the data show in adults.”

“Given the high rates of conversion to MS found in this study, these children must be monitored frequently with clinical visits and MRIs. Since the median time to radiological conversion was one year, I would say that yearly MRIs are warranted in these children. I personally would want to see a child like this in the office every six months to a year to monitor for symptoms,” Dr. Vargas said. “If a child is having symptoms consistent with MS, that certainly changes my approach because then it is not just a radiologic pattern. The symptoms actually help you make the diagnosis of MS, in which case treatment is warranted promptly following diagnosis.”

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DR. NAILA MAKHANI said professional guidelines are needed to specify how best to evaluate children for radiologically-isolated syndrome, so that those at high risk for developing MS are identified and monitored.

Jayne Ness, MD, PhD, professor of neurology and neurobiology and director of the Center for Pediatric Onset Demyelinating Disease Clinic at the University of Alabama at Birmingham, agreed, adding that the goal is to “have a precise diagnosis and a diagnosis as soon as we can without over diagnosing MS.”

“Parents are understandably worried when they are told that an MRI obtained for headache or seizure unexpectedly looks like MS, yet the child does not yet have any symptoms that fit with MS,” she said. “The follow-up MRIs and subsequent testing are very anxiety-provoking for some families.”

She said CSF testing can help sort out whether there is some other explanation for abnormal white spots on MRI, such as NMDA receptor antibody and other autoimmune encephalitides, CNS vasculitis or infectious etiologies.

“I tell residents we have to be open to all possibilities,” Dr. Ness said.

LINK UP FOR MORE INFORMATION:

• Makhani N, Lebrun C, Aksel S, et al; for the Observatoire Francophone de la Sclérose en Plaques (OFSEP), Société Francophone de la Sclérose en Plaques (SFSEP) and the Radiologically Isolated Syndrome Consortium (RISC). The radiologically isolated syndrome in children: Clinical and radiological outcomes http://nn.neurology.org/content/4/6/e395.short. Neurol Neuroimmunol Neuroinflamm 2017;4(6):e395.