Childhood onset MS and MS during Pregnancy Rinze Frederik

Chapter 1, the introduction, summarizes current knowledge regarding two special and different situations in multiple sclerosis (MS): Childhood onset MS and MS during pregnancy. Chapter 2 describes the clinical (chapter 2.1-2.3) and biological studies (chapter 2.4-2.6) on pregnancy and MS. In chapter 2.1 we studied the clinical course of multiple sclerosis before, during and after pregnancy. We found that the relapse rate increased in the first three months after delivery, yet normalized within one year after delivery. Health-related quality of life (QoL) was improved during pregnancy, most appreciated in the MOS 36 item short form health survey questionnaire (SF-36) domains vitality and general health. Nine months or more after delivery we found no adverse effects on MS disease activity at group level, measured by the expanded disability status scale (EDSS), multiple sclerosis impact scale 29 (MSIS-29), and the Guy’s neurological disabilitity scale (GNDS). Nine months or more after delivery QoL, measured by the SF-36, was not unfavorably altered when compared with QoL during pregnancy. This indicates that, although the number of relapses is increased in the short term after delivery, there are no adverse effects of pregnancy on disease course in the mid-long term after delivery. Until now the only known predictors of a postpartum relapse are: number of relapses in the year preceding pregnancy, number of relapses during pregnancy and duration of disease. We were not able to reproduce these findings. In chapter 2.2 we describe data on breastfeeding and disease activity that does not support the recent claim that breastfeeding protects against postpartum relapse. In chapter 2.3 we found that high serum levels of the chemokine interleukin-8 (IL-8) during the first trimester were associated with postpartum relapse. The low positive predictive value will likely limit clinical use of IL-8 as a predictor of postpartum relapse. In chapter 2.4 we performed a genome wide approach on alterations of the transcriptome of monocytes of MS patients before and during the third trimester of pregnancy. We found that during pregnancy expression of the Fc receptor CD64 was increased. Our results therefore support the hypothesis that the innate arm of the immune system is more activated during pregnancy. In chapter 2.5 we investigated the numbers of circulating regulatory T cells (Treg) and T helper (Th)17 cells. Unexpectedly, we found that the numbers of circulating Treg were decreased, during the first and third trimester of pregnancy in both MS patients and healthy controls. We found no differences in the frequencies of circulating Th17 cells during pregnancy in MS patients and healthy controls. We concluded that our results did not support our hypothesis that peripheral blood Th17 and Treg cells are directly involved in MS disease course alteration during pregnancy. In chapter 2.6 we studied serum levels of leptin before, during and after pregnancy in MS patients and healthy controls. We observed a significant increase in serum levels of leptin in women with MS during the third trimester, compared to baseline and first trimester samples. Serum levels of leptin during pregnancy were not associated with a postpartum relapse. Therefore, serum levels of leptin during pregnancy cannot be used as a biomarker for postpartum relapse. We found that women with MS with the largest relative decrease in serum leptin levels after delivery more often had a postpartum relapse. Chapter 3 describes the studies on childhood onset in MS. We performed a retrospective nationwide study in all large neuro-pediatric centres in The Netherlands, described in chapter 3.1. We included the full spectrum of acquired demyelinating syndromes (ADS) of the central nervous system. 44% of the children with a monofocal attack developed MS, whereas 21% of the children with a polyfocal attack developed MS. Both the Barkhof MRI-criteria and the KIDMUS MRI-criteria were able to predict a future diagnosis of MS after a first demyelinating event. In the very young, aged under ten, we found that the sensitivity of especially the KIDMUS criteria was very low (18%). Cerebrospinal fluid (CSF) analysis showed that an increased IgG index and presence of oligoclonal banding both were able to predict MS. Strikingly, children with and without encephalopathy both display MRI abnormalities as seen in typical acute disseminated encephalomyelitis (ADEM) cases (large lesions and basal ganglia/thalamic lesions). In chapter 3.2 we found that children with MS, with MRI features consistent with three or four out of the four Barkhof criteria for dissemination in space, were more likely to have a relapse soon after their second, MS defining, attack. We could not reproduce the predictive value of the childhood-onset MS potential index for early severity. In chapter 3.3 we investigated the capacity of all known diagnostic MRI criteria for children to differentiate MS from acute disseminated encephalomyelitis (ADEM). We found that the Callen criteria for discriminating MS from ADEM had the best test properties. In chapter 4, the discussion, the observations from the studies in chapter 2 and 3 are summarized and discussed in relation to current literature. Recommendations for further research are described.

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