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University of California, San Francisco

Regional Pediatric Multiple Sclerosis Center Spring 2011 News Brief

• New studies • Publications

New NIH-sponsored study led by UCSF pediatric MS center to dissect the role of environmental and genetic factors in pediatric MS. Ten centers in the US will enroll patients with early pediatric MS and matched controls to advance our understanding of key environmental exposures during pregnancy and early childhood and genetic factors and their interactions. To know more about this study or to refer participants, please email janace.hart@ucsf.edu or call 415-514 2476.

• Research Updates • Coming Events • Referrals

Are common viral infections risk factors for pediatric MS? Emmanuelle Waubant, M.D., Ph.D. individuals who are HLA-DRB1*1501 positive. In contrast, the infection with herpes simplex virus type 1 in individuals who do not carry the HLA-DRB1*1501 allele is associated with a 4 time higher odds of pediatric MS. These intriguing findings including this gene-environment interaction will be further studied in a large North American case-control study in children. This study sponsored by a grant from the National Institute of Health will also investigate early exposure to a wide range of environmental factors during pregnancy and the first years of life as risks factors for pediatric multiple sclerosis (Waubant et al, Neurology 2011).

The finding that Epstein-Barr virus is associated with increased risk of MS both in adults and children has been consistent in the past 10 years throughout the world. The center at UCSF has led a collaborative study with the other centers of the US Pediatric MS Network sponsored by the National MS Society to evaluate the role of other common viruses typically acquired during childhood. Our group has found that a remote infection with cytomegalovirus is in fact associated with a four time lower odds to develop pediatric MS. In addition, a remote infection with herpes simplex virus type 1 is also associated with a 10 times lower odds of pediatric MS only in

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Pediatric Onset MS and Cognition: Research Updates Laura Julian, Ph.D. Cognitive dysfunction in pediatric onset multiple sclerosis (POMS) is less well understood in comparison to adults with MS, but evidence points to at least a comparable burden of cognitive dysfunction in children compared to adults with MS. Prevalence rates of cognitive dysfunction range from 31% to 53% in current studies. The wide variability in studies is likely due to differences in cohort characteristics and assessment methodology. The literature is sparse with respect to the prognosis of cognitive functioning in POMS is sparse, but suggests that a substantial proportion of patients may experience cognitive decline over time (30-70%). Systematic larger scale longitudinal studies will be critical to determine the course of cognitive functioning in the context of cognitive development.

location and period of development, almost any area of cognitive development may be compromised. In sum, cognitive dysfunction is prevalent and represents a major problem in children and adolescents with MS. A major area of concern is the rate of cognitive decline. These children are at risk for poor academic performance which can affect their academic potential and future vocational activities. Research by the Pediatric MS Centers of Excellence is aimed to better characterize the nature of cognitive dysfunction and identify relevant risk and protective factors for cognitive compromise in POMS. There are many challenges and multiple directions for future research regarding cognitive functioning in pediatric MS. The consequences of cognitive impairment on the daily lives of individuals with MS are substantial and further understanding of these processes and a rapid movement towards effective preventative and treatment strategies is critical.

In adults, cognitive dysfunction occurs on specific domains including speeded processing, working memory, learning and retrieval and executive functions. In children, cognitive compromise may be broader reaching in children compared to adults. For example, studies have observed important language deficits in POMS (expressive language, reading). This observation is not entirely surprising, given the involvement of pathological processes occurs during development of cognitive skills. Depending on the

For more information: Julian L, Trojano M, Amato MP, Krupp LB. Cognitive Dysfunction in Pediatric Onset Multiple Sclerosis. In: Chabas DC and Waubant EL, eds. Demyelinating Disorders of the CNS in Childhood. New York, NY: Cambridge University Press; 2011: 134-143.

The UCSF Regional Pediatric Multiple Sclerosis Center is the only center of its kind on the West Coast. We have been designated by the National Multiple Sclerosis Society as a center of excellence for comprehensive care of children and adolescents with multiple sclerosis (MS) and related diseases, such as acute demyelinating encephalomyelitis (ADEM) and Devic’s disease. To refer a patient please call us at 415-353-3939. UCSF Regional Pediatric Multiple Sclerosis Center 350 Parnassus Ave., Suite 908 San Francisco, CA 94117 Fax: 415-514-2470 www.ucsfhealth.org/pedsms To provide patients with the most comprehensive care possible, our team includes adult and pediatric neurologists, neuropsychologists, a social worker and the neuro-ophthalmology group. In addition, we work with scientists and geneticists who research MS to better understand the condition and improve treatment. We collaborate with other institutions to evaluate and treat patients and work with our adult Multiple Sclerosis Center to ensure a smooth transition of care when our young patients become adults. 2


Pediatric MS incidence is twice as high in African and Asian children compared to whites: The yearly rate of new pediatric MS cases in California was just found to be about 1.6 cases in 100,000 children. African American and Asian children have a risk twice as high as whites. This suggests the possible role of environmental factors as triggers to the disease in young patients (Langer-Gould et al, Neurology 2011).

Update on treatment of severe and refractory MS in the pediatric age group Jonathan Strober, M.D. As more children are being diagnosed with multiple sclerosis, it is important to know that the medications we prescribe are at least as safe and effective as in adults. A recent study on the treatment of 258 patients with refractory pediatric MS, found that 56% of children only needed one therapy while 25% required a change in therapy once and only 8% of patients required three or four therapies over a period of four years.1 Of those children changing medication 37% were changed due to poor tolerance or noncompliance while the rest were changed due to refractory disease. There was no difference in tolerability or compliance amongst all three of the different interferons (Avonex, Betaseron and Rebif) and no difference in the group being treated with glatiramer acetate (Copaxone) compared to the interferon group for tolerability, compliance or breakthrough disease. Interestingly, Hispanic children were more likely to require a change, with 50% of these children requiring a change due to breakthrough disease versus only 24% in the non-Hispanic group. Of those children going on to a second therapy due to refractory disease 58% responded to treatment with the second agent. Of those switching due to poor tolerability or noncompliance almost 1/3 changed therapy again due to the same reason. Overall, the rate of refractory disease in patients treated with first-line therapy seems to be similar for children and adults (approximately 30%).2

sient worsening of previous symptoms immediately after the first infusion. Only 10 adverse events were reported; three patients developed transient headache, two vertigo and one patient each had pharyngitis, itching, nausea, diarrhea and fatigue. Overall, disability scores decreased in 74%. No patient developed gadolinium-enhancing lesions throughout the study. Three patients developed new T2 lesions at six months, but no new T2 lesions were detected at 12 months.

References

Clinicians have also been increasing the use of natalizumab in children. The biggest concern with its use is the possible development of progressive multifocal leukoencephalopathy (PML), estimated to occur in one per 1,000 treated adults. An open-labeled study of this drug to evaluate its safety and efficacy in Italian MS patients under the age of 18 years was published this past year.3 The patients had to have either two or more relapses, or a or a severe relapse with incomplete recovery, in the two years prior while on interferon or glatiramer acetate treatment or at least two relapses in the previous year with new gadolinium-enhancing lesions on MRI without any prior treatment. Nineteen patients were treated. There were no relapses in all patients treated. One patient had tran-

1. Yeh, E.A., E. Waubant, L.B. Krupp, et al., Multiple Sclerosis Therapies in Pediatric Patients With Refractory Multiple Sclerosis. Arch Neurol, 2010. 2. Gauthier, S.A., B.I. Glanz, M. Mandel, et al., Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study. J Neurol Sci, 2009. 284(1-2): p. 116-9. 3. Ghezzi, A., C. Pozzilli, L.M. Grimaldi, et al., Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology, 2010. 75(10): p. 912-7. 4. Clifford, D.B., A. De Luca, D.M. Simpson, et al., Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol, 2010. 9(4): p. 438-46.

Overall, this study showed that natalizumab appears to be safe in pediatric MS. One note of caution, the median treatment duration to onset of symptoms of PML was 25 months in adult cases,4 however the longest treatment duration in the above study was 25 months and this was only for 2 patients. Therefore, these patients will need to be followed for longer periods on treatment before we have a better idea of the true safety of this drug in this age group. Hopefully, the recent ability to test our patients for exposure to JC virus, the reactivation of which is responsible for the development of PML, will also help reduce this risk for those patients where the use of natalizumab would be beneficial. It will also be interesting to see how the incidence of exposure to this virus develops over different age groups.

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NONPROFIT MAIL US Postage PAID San Francisco, CA Permit no. 8285 8103 UCSF Regional Pediatric MS Center 350 Parnassus Avenue, Suite 908 San Francisco, CA 94117

SAVE THE DATE! SATURDAY, MAY 14, 2011

SIXTH ANNUAL PEDIATRIC MS FAMILY DAY Presented by UCSF Regional Pediatric MS Center Team and the National Multiple Sclerosis Society Northern California Chapter Informal gathering of families, children and teenagers living with MS and related diseases Information - Socializing - Lunch info: 415-353-3939, Elsa.Casillas@ucsfmedctr.org


Pediatric MS News for Professionals 2011