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

Prognostic factors for relapse and outcome in pediatric acute transverse myelitis

Objective: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. Methods: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5–16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18–75). Results: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). Conclusion: Pediatric ATM patients presenting with clinical

Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging

Objective: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS. Methods: We included 8- to 12-year-old genotyped participants from the Generation R Study in whom T1-weighted volumetric (n = 1,136) and/or diffusion tensor imaging (n = 1,088) had been collected. PRS for MS were calculated based on a large genome-wide association study of MS (n = 41,505) and were regressed on regional volumes, global and tract-specific fractional anisotropy (FA), and global mean diffusivity using linear regression. Results: No associations were observed for the regional volumes. We observed a positive association between the MS PRS and global FA (β = 0.098, standard error [SE] = 0.030, p = 1.08 × 10−3). Tract-specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n = 186) who were scanned in an earlier phase (global FA; β = 0.189, SE = 0.072, p = 9.40 × 10−3). Interpretation: This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain. ANN NEUROL 2020

Pediatric autoimmune encephalitis: Recognition and diagnosis

OBJECTIVE: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute dissemi

Real-world validation of the 2017 McDonald criteria for pediatric MS

Objective To compare the diagnostic accuracy of the McDonald 2017 vs the McDonald 2010 criteria to predict a second attack of MS (clinically definite MS [CDMS]) at the first attack of acquired demyelinating syndromes (ADS). Methods One hundred sixty-four children (aged <18 years) with an incident attack of ADS were included in a prospective multicenter study between June 2006 and December 2016. Brain (and spinal if available) MRI was performed ≤3 months after symptom onset. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were compared at baseline between the 2010 and 2017 criteria. Results Among the 164 patients, 110 patients (67%) presented without encephalopathy (ADS–, female 63%; median age 14.8 years, IQR 11.3–16.1years) and 54 (33%) with encephalopathy (acute disseminated encephalomyelitis [ADEM], female 52%; median age 4.0 years, IQR 2.6–6.1 years). Of the 110 ADS– patients, 52 (47%) were diagnosed with CDMS within a median follow-up of 4.5 years (IQR 2.6–6.7 years). The sensitivity was higher for the 2017 criteria than for the 2010 criteria (83%; 95% CI 67–92, vs 49%; 95% CI 33–65; p < 0.001), but the specificity was lower (73%; 95% CI 59–84 vs 87%; 95% CI 74–94, p = 0.02). At baseline, 48 patients fulfilled the 2017 criteria compared with 27 patients when using the 2010 criteria. The results for children aged <12 years without encephalopathy were similar. In patients with ADEM, 8% fulfilled the 2010 criteria and 10% the 2017 criteria at baseline but no patient fulfilled the criteria for CDMS. Conclusions The McDonald 2017 criteria are more sensitive than the McDonald 2010 criteria for predicting CDMS at baseline. These criteria can also be applied in children aged <12 years without encephalopathy but not in children with ADEM. Classification of evidence This study provides Class II evidence that in children with ADS, the 2017 McDonald criteria are more sensitive but less specific than the 2010 McDonald criteria for predicting CDMS