http://repub.eur.nl/res/aut/21368/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/32110/ 2012-04-12T00:00:00Z 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. http://repub.eur.nl/res/pub/31071/ 2011-08-27T00:00:00Z http://repub.eur.nl/res/pub/31209/ 2011-08-03T00:00:00Z Relapse rate is decreased during pregnancy in multiple sclerosis (MS). Risk for postpartum relapse is increased in the first 3 months after delivery. We aimed to study clinical course of MS around pregnancy, using clinical as well as self-report scales, including data on quality of life (QoL), and to identify clinical factors predisposing for postpartum relapse . We performed a prospective, longitudinal study among 35 MS patients and 20 controls. In patients we assessed expanded disability status scale (EDSS), the Guy's neurological disability scale (GNDS) and the multiple sclerosis impact scale 29 (MSIS-29). In patients and controls we assessed the MOS 36 item short form health survey questionnaire (SF36), consisting of eight domains. The previously described surge in relapses after delivery was also obvious in this study (p = 0.005). At group level EDSS and MSIS-29 did not show overt fluctuations over time. The GNDS, however, improved during the third trimester, compared to the first trimester (p = 0.003). A concomitant improvement in the SF36 domains vitality (p < 0.001) and general health (p = 0.001) was found in patients. At the final visit, at least 9 months after delivery, no worsening of EDSS, GNDS, MSIS-29 or SF36 was observed compared with the (for MS, beneficial) third trimester. Duration of disease, relapses in the year preceding pregnancy or relapses during pregnancy were not associated with postpartum relapse. QoL is improved during pregnancy. Although relapse rate was increased directly after delivery, in the mid long term after delivery no adverse effects of pregnancy on MS were found. http://repub.eur.nl/res/pub/26487/ 2011-04-01T00:00:00Z Background: During the third trimester of pregnancy multiple sclerosis (MS) disease activity is reduced. It is not fully understood which factors mediate this disease amelioration. Objective: To study alterations of the monocyte transcriptome during pregnancy in MS patients, using a genomewide approach to identify differentially regulated genes. Methods: Women with MS and healthy controls were longitudinally studied, including a visit before pregnancy. Results: RNA-microarray analysis was performed in six patients. We found a significant increase of CD64 (Fc gamma receptor 1a, FcgR1a) during the third trimester compared with baseline, confirmed by RT-PCR in a group of ten patients. Analysis with Ingenuity software was performed using all genes expression of which was altered at least 1.5-fold in at least five out of six patients. Major networks that were altered during MS pregnancy were: cell-to-cell signalling and interaction, immune response, and cell signalling. From the genes selected for Ingenuity analysis, seven additional candidate genes, selected for their biological interest, were tested using RT-PCR in ten patients with MS and nine controls. We found an increased expression of JAK2 and STAT1 directly postpartum in patients with MS and in controls. Conclusion: The increased CD64 expression during pregnancy is indicative of enhanced innate immune functions. http://repub.eur.nl/res/pub/26492/ 2011-04-01T00:00:00Z Background: Acute disseminated encephalomyelitis (ADEM) affects children more frequently than adults. Current studies investigating ADEM in different age groups are difficult to compare. Objective: To investigate whether the clinical presentation, outcome and disease course of ADEM differ between adults and children. Methods: Disease characteristics of 25 adults and 92 children suffering from ADEM between 1988 and 2008 were compared. Results: The most common presenting symptoms of ADEM in both groups were pyramidal signs and encephalopathy. Ataxia occurred more frequently in children (p = 0.002). In general, MRI showed ill-defined and large white matter lesions in both groups, whereas periventricular lesions were more prevalent in adults (p = 0.001). In adults, duration of hospitalization was longer (p = 0.002) and intensive care unit (ICU) admission was more frequently required (p = 0.043). Three adults (12%) and one child (1%) died (p = 0.030). Fewer adults had complete motor recovery after their first clinical event (p < 0.001). In 73 patients follow-up time was ≥ 2 years and most of these patients remained monophasic. Although relapses after ADEM can occur, only one adult (5%) and five children (6%) converted to MS. Conclusions: The clinical presentations in children and adults share similarities, but the disease course and outcome of ADEM is more severe in adults with respect to hospitalization, ICU admission, recovery and mortality. http://repub.eur.nl/res/pub/28400/ 2010-10-01T00:00:00Z About 3-5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field. http://repub.eur.nl/res/pub/28390/ 2010-09-01T00:00:00Z Background: During pregnancy, especially during the third trimester, multiple sclerosis (MS) disease activity is reduced. It is not known which factors mediate this disease amelioration. Objective: To study whether the frequency of two important T-cell subsets, T-helper 17 (Th17) and regulatory T-cells (Treg), is altered in relation to pregnancy-induced MS disease amelioration. Methods: Each individual was tested longitudinally, after sampling of blood at timepoints before pregnancy, during the first and third trimester, and in the early post-partum period. Frequencies of Th17 cells were assessed after short (4 hours) re-stimulation of peripheral blood lymphocytes with PMA and ionomycin, followed by flow cytometry using CD4, CD45RO and IL-17A antibodies. To assess peripheral blood Treg frequencies, we used six-colour flow cytometry with antibodies against CD3, CD4, CD25, CD127, FoxP3 and HLA-DR, to specifically identify Treg. Results: Both MS patients (n = 9) and controls (n = 8) displayed unaltered Th17 frequencies during pregnancy. In contrast, circulating Treg frequency significantly decreased in MS patients (n = 15) during the first and third (p < 0.001) trimesters compared with the period before pregnancy. In the post-partum period, the frequency of circulating Treg again resurged back to near pre-pregnancy levels. In controls (n = 15) comparable frequency kinetics were observed in that post-partum a significant increase in circulating Treg frequency was detected compared with the first (p < 0.001) and third (p = 0.012) trimester. Conclusions: Third trimester amelioration is not related to the fluctuation of circulating Th17 cells. Furthermore, a paradoxical decrease of immunosuppressive circulating Tregs can be observed during this phase, both in MS patients and controls. http://repub.eur.nl/res/pub/19762/ 2010-05-01T00:00:00Z Background: Brain MRI is a useful tool for diagnosing inflammatory demyelinating disorders in children. However, it remains unclear which are the most reliable criteria for distinguishing multiple sclerosis (MS) from monophasic disorders such as acute disseminated encephalomyelitis (ADEM). We therefore compared the 4 current sets of MRI criteria in our Dutch pediatric cohort and determined which are the most useful in clinical practice for distinguishing ADEM from MS. Methods: We included 49 children who had had a demyelinating event and an MRI scan within 2 months of their first clinical attack. Twenty-one patients had ADEM and remained relapse-free after at least 2 years of follow-up. Twenty-eight patients had a definitive diagnosis of MS. We assessed the sensitivity and specificity of the following MRI criteria: Barkhof criteria, KIDMUS criteria, Callen MS-ADEM criteria, and Callen diagnostic MS criteria. Results: The Callen MS-ADEM criteria had the best combination of sensitivity (75%) and specificity (95%). The KIDMUS criteria had higher specificity (100%), but much lower sensitivity (11%). The Barkhof criteria had a sensitivity of 61% and a specificity of 91%. The Callen diagnostic MS criteria were the most sensitive (82%), but were only 52% specific for distinguishing a first attack of MS from ADEM. Conclusions: The results in our cohort demonstrate that the new Callen criteria for multiple sclerosis-acute disseminated encephalomyelitis (MS-ADEM) are the most useful for differentiating a first attack of MS from monophasic ADEM. Although the Callen diagnostic MS criteria are more sensitive, they lack the specificity necessary to differentiate MS from ADEM. http://repub.eur.nl/res/pub/28077/ 2010-01-01T00:00:00Z We sought to identify clinical and radiologic features predicting early relapse after a diagnosis of multiple sclerosis in children. In this nationwide retrospective multicenter study in The Netherlands, we included 28 children with multiple sclerosis with onset before age 16 years. Magnetic resonance images and clinical features at the onset of disease were evaluated. The mean follow-up time was 55 months. Twenty children (71%) had a relapse during follow-up. We found that the presence of at least three of four Barkhof magnetic resonance imaging criteria at the onset of multiple sclerosis signs is predictive of early relapse after a diagnosis of multiple sclerosis in children (P < 0.05). http://repub.eur.nl/res/pub/25308/ 2009-11-27T00:00:00Z Pregnancy has an ameliorating effect on multiple sclerosis (MS), but directly after delivery the risk of a relapse is increased. The pro-inflammatory chemokine interleukin 8 is associated with disease activity. We aimed to investigate whether pregnancy-induced fluctuations of interleukin 8 correlate with periods of enhanced and diminished disease activity. Thirty-six women with MS were prospectively studied before, during and after pregnancy. Serum levels of interleukin 8 were significantly decreased during the third trimester (p = 0.03). High first trimester serum levels of interleukin 8 were associated with a high risk of postpartum relapse (p = 0.007). These results help us to further understand the altered disease course during pregnancy. http://repub.eur.nl/res/pub/25307/ 2009-09-07T00:00:00Z Background: Disease activity in patients with multiple sclerosis (MS) is suppressed during pregnancy, whereas attack frequency increases after delivery. It is yet unclear, which immuno - endocrinological processes mediate these disease fluctuations. Leptin has been identified as a hormone that can influence inflammatory activity. Objective: The aim ofthis study was to investigate whether pregnancy-induced fluctuations of serum leptin levels differed between patients with MS and controls and whether serum leptin levels correlate with periods of enhanced and diminished disease activity. Methods: Women with MS and healthy women were prospectively followed during and after pregnancy. The MS group could be studied already at a timepoint before pregnancy. Serum leptin and soluble leptin receptor (SLR) levels were measured using enzyme-linked immunosorbent assay. Results: Pre-pregnancy serum leptin levels were (mean ± SD) 22.9 ± 12.8 ng/ml in the MS group. These levels increased in the third trimester to 28.5 ± 15.0 ng/ml (P = 0.007). The third trimester serum leptin levels in healthy women were comparable, 29.4 ± 19.0 ng/ml. Serum leptin levels after delivery dropped to 18.5 ± 12.8 ng/ml in women with MS (P < 0.001) and to a lesser extend (22. ± 17.5 ng/ml) in healthy women (P = 0.04). SLR levels showed the same pattern. Remarkably, women with the highest relative decrease in serum leptin levels after delivery had more often a postpartum relapse (P = 0.008). Conclusion: In women with MS, leptin increased during late pregnancy. A postdelivery drop in leptin levels was observed in both the MS and control group. The postdelivery drop was associated with the occurrence of postpartum relapse. http://repub.eur.nl/res/pub/17759/ 2009-01-01T00:00:00Z Background: Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue. Methods: We studied the presence and severity of fatigue in 32 children (18 boys, 14 girls) between 11-17 years old (mean: 14 years, 10 months) with a monophasic inflammatory demyelinating disease (n = 22) or definite MS (n = 10). This was measured with the Checklist Individual Strength. A score of ≥40 on the severity of fatigue subscale indicated the presence of severe fatigue. We also examined the relation between fatigue and depression (assessed by the Child Depression Inventory). Additionally we measured the health-related quality of life (HRQoL), using the TNO-AZL Child Quality of Life child form. We compared the scores of the MS and monophasic patients with the scores of healthy Dutch children. Results: The highest scores on the fatigue scales subjective fatigue and physical activity were found in the children with MS. Only 1 of the monophasic patients suffered from severe fatigue in contrast to 4 of the MS patients. In the MS group fatigue and depression were correlated. MS patients experienced a lower HRQoL on the scales locomotor functioning, cognitive functioning and interaction with peers. Conclusion: The occurrence of fatigue is very rare after a monophasic inflammatory demyelinating event in the past. As expected, fatigue occurs more frequent in paediatric MS patients.