Screening MRIs Find Clinically Significant Pathology in Children With Neurofibromatosis 1

Jacquelyn K. Beals, PhD

November 12, 2009

November 12, 2009 (Honolulu, Hawaii) — The authors of a study assessing the use of screening magnetic resonance imaging (MRI) to diagnose central nervous system (CNS) pathology and other CNS malformations in children with neurofibromatosis 1 (NF1) suggest that centers skilled in pediatric sedation and imaging might reconsider the use of MRIs to identify clinically significant NF1 pathologies.

The report was presented by Cynthia J. Tifft, MD, PhD, from the Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, in Bethesda, Maryland, here at the American Society of Human Genetics 59th Annual Meeting.

NF1 is an autosomal dominant disease that occurs in approximately 1 person in 3500. It is caused by mutations in a tumor suppressor gene, NF1. The normal gene product, neurofibromin, negatively regulates a gene involved in cell division. However, mutant neurofibromin is unable to regulate this activity, permitting excessive cell division and tumor formation.

Among the many symptoms of NF1 are café au lait spots, freckles, neurofibromas (nearly always benign) that can develop along nerves anywhere in the body, macrocephaly, scoliosis, seizures, hypertension, learning disabilities, and optic nerve gliomas.

This study is the first to assess CNS pathology in screening MRIs of patients and to look at other CNS malformations, observed Dr. Tifft in her presentation. The goal is to see whether screening MRIs are of value in identifying clinically useful outcomes.

A major focus in this study was the diagnosis of optic pathway gliomas, which occur in 15% of NF1 children. The current recommendation for children with NF1 is careful annual ophthalmological evaluations to assess visual acuity and visual fields. "If you're in a center that does them a lot, that can be effective," Dr. Tifft told Medscape Pathology. "And if you find an abnormality in visual acuity or something, then do an MRI scan looking for optic pathway gliomas." However, this recommendation did not consider additional pathologies that can be detected by MRI scans.

Of the 190 patients (median age, ~6.3 years) who met the criteria for NF1 and qualified for the study, 34 had findings that required ongoing monitoring or clinical intervention. These findings included 20 optic pathway gliomas, some in a single optic nerve, and 9 other CNS tumors. Five of the optic pathway gliomas were treated with chemotherapy; none of the other CNS tumors required treatment. The MRI scans also detected stenosis of the internal carotid artery in 3 patients, 2 of whom needed surgery.

"The uniqueness of this study is that no one has looked at all pathology in the brain — not just the tumors," Dr. Tifft observed. "There are lots of people who have looked at tumors, but no one's sort of taken their whole cohort and looked for everything. So when you add it all together, it may make a case for doing screening MRIs, which is not standard care right now."

A 1997 National Neurofibromatosis Foundation consensus statement advocated annual ophthalmological exams to identify optic pathway gliomas in NF1 patients, and recommended neurological exams to diagnose other brain tumors. Considerable controversy surrounds the use of screening MRIs to find asymptomatic tumors. Both the cost and the risk of sedation (required in young children) were considered too great to recommend MRIs routinely.

"The issue is, when you do an MRI scan, you don't just find tumors. You can also find these vascular changes I was talking about," Dr. Tifft told Medscape Pathology. "These are things that predispose kids to stroke and permanent disability. . . . They put people at risk for stroke, but how often do they stroke? Are these incidental findings some of the time? It's hard to find something like that on MRI that appears to be getting worse on imaging — although the child's not symptomatic — and sit on it!" said Dr. Tifft.

MRIs are expensive for adults but not really dangerous, said session comoderator Frank J. Probst, MD, PhD, assistant professor, Department of Molecular and Human Genetics, Baylor College of Medicine, in Houston, Texas, talking with Medscape Pathology. "For a child, even though anesthesia is very, very safe, it's not without risk. I think that there's always concern. There's a trade-off as to whether or not it's worth the risk of anesthesia, even though that risk is low, to get the information that you're going to get from the study."

Dr. Tifft summarized the controversy: "It really is going to boil down to [whether] you're going to get enough bang out of doing [MRIs] in everyone to justify the cost, and justify the potential morbidity for doing this in kids. The answer's not there yet," she said. "We need a bigger multicenter study because some groups do it one way, some groups do it another way. We ought to do just a prospective study to see all comers, what the answer is," said Dr. Tifft. "I don't think any of us know yet."

Dr. Tifft reports an association with Genzyme Therapeutics involving research or other grants, scholarships, or fellowships; with Amicus Therapeutics as an advisor; with Actelion Pharmaceuticals and Shire Pharmaceuticals for research or other grants, scholarships, or fellowships, consulting fees or other remuneration, and travel grants/honoraria. Dr. Probst reports employment at Baylor College of Medicine, and receiving research or other grants, scholarships, or fellowships from the Burroughs Wellcome Fund and the American Academy of Pediatrics.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 204. Presented October 23, 2009.

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