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

E.U. paediatric MOG consortium consensus: Part 1 – Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, inc

E.U. paediatric MOG consortium consensus: Part 4 – Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high r

Ketogenic diet treatment in recurrent diffuse intrinsic pontine glioma in children: A safety and feasibility study

Background: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9–11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. Procedure: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. Results: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. Conclusion: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy

Fatigue and physical functioning in children with multiple sclerosis and acute disseminated encephalomyelitis

Background and Objective: Fatigue and physical impairments are a major concern in children with multiple sclerosis (MS) and after acute disseminated encephalomyelitis (post-ADEM). We here aimed to evaluate the interaction between fatigue, exercise capacity, motor performance, neurological status, and quality of life (HRQoL). Methods: In this cross-sectional study, data of 38 children (MS n = 22, post-ADEM n = 16), aged 4–17 years attending our national pediatric MS center, were studied. Fatigue was measured with the Pediatric Quality of Life Multidimensional Fatigue Scale, exercise capacity with the Bruce Protocol, motor performance with the Movement Assessment Battery for Children second edition, HRQoL with the Pediatric Quality of Life Questionnaire, and extent of disability with the Expanded Disability Status Scale (EDSS). Results: Children with MS and post-ADEM experienced more fatigue (p < 0.001), reduced exercise capacity (p < 0.001), and impaired motor performance (p < 0.001), despite low scores on the EDSS. Fatigue, but not the other parameters, was significantly correlated with HRQoL. Fatigue was not correlated with exercise capacity. Conclusion: We confirm the major impact of fatigue on quality of life in children with MS and post-ADEM. Fatigue was not explained by reduced exercise capacity or impaired motor performance. An important finding for clinical practice is that the low EDSS score did not reflect the poor physical functioning

E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high risk of accruing neurological disability (motor and autonomic), which is frequently severe. In contrast, having a single episode of optic neuritis any time during disease course is broadly associated with a lower risk of persistent disability. Furthermore, MOG-ab-associated optic neuritis often results in good functional visual recovery, although retinal axonal loss may be severe. The field of cognitive and behavioural outcome and epilepsy following demyelinating episodes has not been extensively explored, but in recent studies acute disseminated encephalomyelitis (-like) phenotype in the young children was associated with cognitive problems and epilepsy in long-term follow-up. In conclusion, main domains of importance in determining clinical outcome in paediatric MOGAD are visual, motor, autonomic and cognitive function. A standardised evaluation of these outcome domains in all children is of importance to allow adequate rehabilitation and follow-up