Neurodegeneration and humoral response proteins in cerebrospinal fluid associate with pediatric-onset multiple sclerosis and not monophasic demyelinating syndromes in childhood.

BACKGROUND: Pediatric-onset multiple sclerosis (POMS) represents the earliest stage of disease pathogenesis. Investigating the cerebrospinal fluid (CSF) proteome in POMS may provide novel insights into early MS processes. OBJECTIVE: To analyze CSF obtained from children at time of initial central nervous system (CNS) acquired demyelinating syndrome (ADS), to compare CSF proteome of those subsequently ascertained as having POMS versus monophasic acquired demyelinating syndrome (mADS). METHODS: Patients were selected from two prospective pediatric ADS studies. Liquid chromatography-mass spectrometry (LC-MS) was performed in a Dutch discovery cohort (POMS n = 28; mADS n = 39). Parallel reaction monitoring-mass spectrometry (PRM-MS) was performed on selected proteins more abundant in POMS in a combined Dutch and Canadian validation cohort (POMS n = 48; mADS n = 106). RESULTS: Discovery identified 5580 peptides belonging to 576 proteins; 58 proteins were differentially abundant with ⩾2 peptides between POMS and mADS, of which 28 more abundant in POMS. Fourteen had increased abundance in POMS with ⩾8 unique peptides. Five selected proteins were all confirmed within validation. Adjusted for age, 2 out of 5 proteins remained more abundant in POMS, that is, Carboxypeptidase E (CPE) and Semaphorin-7A (SEMA7A). CONCLUSION: This exploratory study identified several CSF proteins associated with POMS and not mADS, potentially reflecting neurodegeneration, compensatory neuroprotection, and humoral response in POMS. The proteins associated with POMS highly correlated with age at CSF sampling.

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, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.

Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses.

Neuromyelitis optica spectrum disorders are a group of rare, but severe autoimmune diseases characterized by inflammation of the optic nerve(s) and/or spinal cord. Although naive B cells are considered key players by escaping central tolerance checkpoints, it remains unclear how their composition and outgrowth differ in patients with neuromyelitis optica spectrum disorders. Under complete treatment-naive circumstances, we found that naive mature/transitional B-cell ratios were reduced in the blood of 10 patients with aquaporin-4 immunoglobulin G-positive disease (neuromyelitis optica spectrum disorders) as compared to 11 both age- and gender-matched healthy controls, eight patients with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders and 10 patients with multiple sclerosis. This was the result of increased proportions of transitional B cells, which were the highest in patients with neuromyelitis optica spectrum disorders with relapses and strongly diminished in a separate group of nine patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders who received corticosteroid treatment. These findings need to be confirmed in longitudinal studies. For purified naive mature B cells of seven patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders with relapses, Toll-like receptor 9 ligand synergized with interferon-γ to enhance plasmablast formation during germinal centre-like cultures. This was not seen for 11 patients without relapses and nine healthy controls. In the neuromyelitis optica spectrum disorders group, in vitro plasmablast formation corresponded to total and anti-aquaporin-4 immunoglobulin G secretion, of which the latter was found only for relapsing cases. These data indicate that naive B-cell homoeostasis is different and selectively targeted by corticosteroids in patients with neuromyelitis optica spectrum disorders. This also supports further exploration of naive B cells for their use in Toll-like receptor 9-dependent in vitro platforms in order to predict the activity of neuromyelitis optica spectrum disorders.

The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults.

OBJECTIVES: The aim of this study was to assess the Dutch nationwide incidence of myelin oligodendrocyte glycoprotein (MOG)-IgG-associated acquired demyelinating syndromes (ADS) and to describe the clinical and serological characteristics of these patients. METHODS: All serum samples for routine diagnostics from February 2014 to December 2017 were sent to the single central reference laboratory for the full-length MOG-IgG cell-based assay (CBA) in the Netherlands. Clinical data from patients known in our National ADS centre were available. RESULTS: A total of 1414 samples of 1277 patients were received; of these, 92 patients (7%) were MOG-IgG-seropositive. The mean incidence was 0.16/100,000 people, with higher seropositivity in children (0.31/100,000) than in adults (0.13/100,000). In MOG-IgG-positive patients at the National ADS centre (61/92, 66%), the most common presenting phenotype is acute disseminated encephalomyelitis (ADEM, 56%) in children and optic neuritis (ON, 44%) in adults. Relapsing disease occurred in 9/34 (26%) children and 11/27 (41%) adults during median follow-up of 27.5 months. Patients were tested MOG-IgG-positive >200 months after the initial attack, suggesting an extended time to first relapse (TTFR). Longitudinal analysis of MOG-IgG (25/61, 41%) showed that 67% of the monophasic patients remain seropositive and 60% in relapsing patients. Majority of seronegative patients had no relapses (89%). CONCLUSION: This nationwide study shows that the overall incidence of MOG-IgG-seropositive disorders is 0.16 per 100,000 people. The distribution over the clinical phenotypes differs between adults and children. Seropositivity can be maintained over years even without clinical activity, while seronegative patients generally had no relapses.

Serum neurofilament light chain in pediatric MS and other acquired demyelinating syndromes.

OBJECTIVE: To explore the correlation between serum and CSF neurofilament light chain (NfL) and the association of NfL levels and future disease activity in pediatric patients with a first attack of acquired demyelinating syndromes (ADS). METHODS: In total, 102 children <18 years with a first attack of CNS demyelination and 23 age-matched controls were included. Clinically definite multiple sclerosis (CDMS) was set as an endpoint for analysis. CSF NfL was tested by the commercially available ELISA (UmanDiagnostics); serum NfL (sNfL) was tested with a Simoa assay. Hazard ratios (HR) were calculated with Cox regression analysis. RESULTS: Of the 102 patients, 47 (46%) were tested for CSF NfL. CSF and serum NfL correlated significantly in the total group (ρ 0.532, p < 0.001) and even more significantly in the subgroup of patients with future CDMS diagnosis (ρ 0.773, p < 0.001). sNfL was higher in patients than in controls (geometric mean 6.1 pg/mL, p < 0.001), and was highest in ADS presenting with encephalopathy (acute disseminated encephalomyelitis, n = 28, 100.4 pg/mL), followed by patients without encephalopathy (ADS-) with future CDMS diagnosis (n = 40, 32.5 pg/mL), and ADS- who remained monophasic (n = 34, 17.6 pg/mL). sNfL levels higher than a median of 26.7 pg/mL at baseline are associated with a shorter time to CDMS diagnosis in ADS- (p = 0.045). HR for CDMS diagnosis was 1.09 for each 10 pg/mL increase of sNfL, after correction for age, oligoclonal bands, and MRI measures (p = 0.012). CONCLUSION: The significant correlation between CSF and serum NfL strengthens its reliability as a peripheral marker of neuroaxonal damage. Higher sNfL levels at baseline were associated with higher probability of future CDMS diagnosis in ADS-.

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.

High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome.

BACKGROUND: A promising biomarker for axonal damage early in the disease course of multiple sclerosis (MS) is neurofilament light chain (NfL). It is unknown whether NfL has the same predictive value for MS diagnosis in children as in adults. OBJECTIVE: To explore the predictive value of NfL levels in cerebrospinal fluid (CSF) for MS diagnosis in paediatric and adult clinically isolated syndrome (CIS) patients. METHODS: A total of 88 adult and 65 paediatric patients with a first attack of demyelination were included and followed (mean follow up-time in adults: 62.8 months (standard deviation (SD) ±38.7 months) and 43.8 months (SD ±27.1 months) in children). Thirty control patients were also included. Lumbar puncture was done within 6 months after onset of symptoms. NfL was determined in CSF using enzyme-linked immunosorbent assay (ELISA). COX regression analyses were used to calculate hazard ratios (HR) for clinically definite multiple sclerosis (CDMS) diagnosis. RESULTS: After adjustments for age, oligoclonal bands (OCB), and asymptomatic T2 lesions on baseline magnetic resonance imaging (MRI), increased NfL levels in both paediatric and adult CIS patients were associated with a shorter time to CDMS diagnosis (children HR = 3.7; p = 0.007, adults HR = 2.1; p = 0.032). For CIS patients with a future CDMS diagnosis, children showed higher NfL levels than adults (geometric mean 4888 vs 2156 pg/mL; p = 0.007). CONCLUSION: CSF NfL levels are associated with CDMS diagnosis in children and adults with CIS. This makes NfL a promising predictive marker for disease course with potential value in clinical practice.

T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes.

BACKGROUND: Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown. OBJECTIVES: To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS. METHODS: Children <18 years with a first demyelinating event were prospectively included and followed. Soluble CD27 was determined in CSF using an enzyme-linked immunosorbent assay (ELISA). Cox regression analyses were used to calculate hazard ratios (HRs) for CDMS. RESULTS: A total of 94 ADS children were included (ADS with encephalopathy (ADS+) n = 33 and ADS without encephalopathy (ADS-) n = 61). Of the 61 ADS- children, 21 (48%) were diagnosed with CDMS during follow-up. At baseline, sCD27 levels were higher in patients with a future CDMS diagnosis ( n = 29) than in monophasic ADS+ ( n = 30), monophasic ADS- ( n = 28) and relapsing non-MS patients ( n = 7; p < 0.001). In ADS- patients, sCD27 was associated with CDMS (HR = 1.8 per 100 U/mL increase in sCD27 levels, p = 0.031), after adjustments for age, oligoclonal bands and the presence of dissemination in space on baseline magnetic resonance imaging (MRI). CONCLUSION: CSF sCD27 levels at first attack of demyelination were associated with CDMS diagnosis in children. This makes sCD27 a potential clinically relevant quantitative marker when performing routine CSF diagnostics.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis followed by optic neuritis (ADEM-ON) is a rare demyelinating syndrome that is different from multiple sclerosis and neuromyelitis optica spectrum disorder. The aim of this study was to describe the disease course, treatment response and outcome of children with ADEM-ON. METHODS: Children of <18 years of age were identified from six countries of the EU Paediatric Demyelinating Disease Consortium. Patients fulfilled the diagnostic criteria for ADEM followed by at least one ON. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were tested in all patients. RESULTS: In this study of 17 patients (nine boys) with ADEM-ON, anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were identified in 16 patients. Age at onset was 6.1 years (interquartile range, 5.1-9.2 years). Twelve patients received oral prednisolone and 10 received maintenance immunosuppression (e.g. azathioprine, intravenous immunoglobulins, Rituximab). During a follow-up of 5.3 years (interquartile range, 1.8-10.2 years), 54 relapses occurred with a median of 3 relapses per patient (range, 1-9 per patient). Patients relapsed on all treatments but no relapses occurred on a prednisolone dose >10 mg/day. Visual and cognitive residual deficits were common in this group. CONCLUSIONS: Acute disseminated encephalomyelitis followed by optic neuritis is an anti-MOG antibody-associated relapsing disorder that can have a heterogeneous disease course. Patients were refractory for maintenance immunosuppression and appeared to be corticosteroid-dependent. Further international collaborations are now required to unify guidelines in this difficult-to-manage group of patients.

Evolution of MRI abnormalities in paediatric acute disseminated encephalomyelitis.

OBJECTIVE: Acute disseminating encephalomyelitis (ADEM) is an inflammatory demyelinating disease affecting the central nervous system and mainly occurs in young children. Children who initially presented with ADEM can be diagnosed with multiple sclerosis (MS) in case new non-encephalopathic clinical symptoms occur with new lesions on MRI at least three months after onset of ADEM. We aim to study the timing of MRI abnormalities related to the evolution of clinical symptoms in our Dutch paediatric ADEM cohort. METHODS: The Dutch database for acquired demyelinating syndromes (ADS) was screened for children under age eighteen fulfilling the international consensus diagnostic criteria for ADEM. Children were eligible when the first MRI was performed within the first three months after onset of clinical symptoms and at least one brain follow-up MRI was available for evaluation. Forty-two children with ADEM were included (median age four years two months). All available MRIs and medical records were assessed and categorised as 'improved', 'deteriorated' and 'unchanged'. RESULTS: We found that during clinical recovery, new lesions and enlargement of existing MRI lesions occurred in the first three months in about 50% of the performed MRIs. In contrast, this was rarely seen more than three months after first onset of ADEM. CONCLUSION: We recommend to perform a brain MRI as a reference scan three months after onset. Follow-up imaging should be compared with this scan in order to prevent an incorrect diagnosis of MS after ADEM.

Disease course after clinically isolated syndrome in children versus adults: a prospective cohort study.

BACKGROUND AND PURPOSE: Clinically isolated syndrome (CIS) is a first demyelinating event of the central nervous system and can be a single event. After CIS, a chronic disease course with ongoing inflammation and relapses might occur, resulting in a diagnosis of multiple sclerosis (MS). As yet, there has been no prospective exploration of whether children and adults with CIS have the same disease course. METHODS: Patients with CIS, whose age ranged from 1 to 50 years, were prospectively followed. We divided the patients into three different age groups, i.e. 1-10, 11-17 and 18-50 years old. Demographic data, disease course, time to MS diagnosis and annualized relapse rates (ARRs) were compared among these groups. RESULTS: We included 383 patients with CIS, of whom 218 (56.9%) were diagnosed with MS. Children of between 11 and 17 years old had the highest rate of MS conversion (83.5% vs. 50.0% in the other age groups together, P < 0.01) and the shortest time to MS diagnosis [median time 2.6 months (interquartile range, 0.6-6.0) vs. 8.2 months (interquartile range, 1.9-28.2) in the other age groups together, P < 0.01). ARRs corrected for follow-up were higher in children of <18 years old than in adults of ≥18 years old with MS (mean ARR, 0.65 vs. 0.43, P < 0.01). CONCLUSION: Children with CIS tend to have a more inflammatory disease course appearing from higher ARRs in all children and the highest rate of MS conversion in 11-17-year-old children. This supports early initiation of disease-modifying therapy in children, perhaps even at the first event in children at high risk for MS in line with clinical practice in adults.

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica.

OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Neurogenic lower urinary tract dysfunction in the early disease phase of paediatric multiple sclerosis.

Neurogenic lower urinary tract dysfunction (LUTD) in multiple sclerosis (MS) is highly prevalent in adults, but has not previously been described in paediatric MS. A total of 24 consecutive children with newly diagnosed MS were prospectively assessed for bladder and bowel problems early after diagnosis. Five of 24 children (21%) showed LUTD during assessment. One of these patients did not report voiding complaints. This high prevalence of LUTD indicates that all recently diagnosed patients with paediatric MS should be evaluated early in their disease and treated for urinary problems in order to prevent potential damage to the upper urinary tract.

Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in the Netherlands.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorders (NMOSDs) are a group of rare inflammatory demyelinating disorders of the central nervous system. The identification of specific antibodies directed to aquaporin 4 (AQP4-IgG) led to the distinction from multiple sclerosis. However, up to 25% of the clinically diagnosed NMO patients are seronegative for AQP4-IgG. A subgroup of these patients might be identified by antibodies directed to myelin oligodendrocyte glycoprotein (MOG-IgG). Our objective was to investigate whether the clinical characteristics of these patients differ. METHODS: Using a cell-based assay, samples of 61 AQP4-IgG seronegative patients and 41 AQP4-IgG seropositive patients with clinically NMOSD were analysed for the presence of MOG-IgG. Clinical characteristics of the AQP4-IgG, MOG-IgG seropositive and double seronegative NMOSD patients were compared. RESULTS: Twenty of the 61 AQP4-IgG seronegative patients tested MOG-IgG seropositive (33%). MOG-IgG seropositive patients were more frequently males in contrast to AQP4-IgG seropositive patients (55% vs. 15%, P < 0.01) and Caucasians (90% vs. 63%, P = 0.03). They more frequently presented with coincident optic neuritis and transverse myelitis (40% vs. 12%, P = 0.02) and had a monophasic disease course (70% vs. 29%, P < 0.01). AQP4-IgG seropositive patients were 2.4 times more likely to suffer from relapses compared with MOG-IgG seropositive patients (relative risk 2.4, 95% confidence interval 1.2-4.7). AQP4-IgG seropositive patients had higher Expanded Disability Status Scale levels at last follow-up (P < 0.01). CONCLUSION: Antibodies directed to MOG identify a subgroup of AQP4-IgG seronegative NMO patients with generally a favourable monophasic disease course.

Incidence of AQP4-IgG seropositive neuromyelitis optica spectrum disorders in the Netherlands: About one in a million.

Neuromyelitis optica (NMO) is a rare autoimmune disease affecting the optic nerves and spinal cord. In the majority of NMO patients anti-aquaporin-4 antibodies (AQP4-IgG) are detected. Here we assessed a nationwide incidence of AQP4-IgG-seropositive NMO spectrum disorders (NMOSD) in the Netherlands based on results of one central laboratory. Data were collected since the introduction of the highly sensitive cell-based assay for six consecutive years. Samples from 2795 individual patients have been received; of them 94 (3.4%) were seropositive. Based on the Dutch population with 16.6 million inhabitants, the mean incidence of AQP4-IgG-seropositive NMOSD was calculated at 0.09 per 100,000 people.

Gray matter-related proteins are associated with childhood-onset multiple sclerosis.

OBJECTIVE: To identify CSF biomarkers for multiple sclerosis (MS) in children with an initial acquired CNS demyelinating syndrome (ADS). METHODS: CSF was collected from a cohort of 39 children with initial ADS, 18 of whom were diagnosed with MS and 21 of whom had a monophasic disease course. Proteomic analysis of trypsinized CSF (20 µL) was performed by nano-liquid chromatography Orbitrap mass spectrometry. Univariate statistical analysis was used to identify differentially abundant proteins between childhood-onset MS and monophasic ADS. RESULTS: A total of 2,260 peptides corresponding to 318 proteins were identified in the total set of samples. Of these 2,260 peptides, 88 were identified as being most distinctive between MS and ADS. Fifty-three peptides, corresponding to 14 proteins, had higher abundance in children with MS compared to children with monophasic ADS. Twelve of these 14 proteins were linked to neuronal functions and structures, such as synapses, axons, and CNS proteases (e.g., neurofascin, carboxypeptidase E, brevican core protein, and contactin-2). The other 2 were functionally related to immune function. The 35 peptides identified with decreased abundance in children with MS corresponded to 7 proteins. Six of them were linked to innate immune function (e.g., haptoglobin, haptoglobin-related protein, C4b-binding protein alpha chain, and monocyte differentiation antigen CD14) and 1 was linked to cellular adhesion (protein diaphanous homolog 1). CONCLUSION: At first onset of ADS, CSF of children diagnosed with MS showed increased abundance of CNS gray matter-related proteins, whereas CSF of children with a monophasic disease course showed increased abundance of innate immunity-related proteins.

Application of the 2012 revised diagnostic definitions for paediatric multiple sclerosis and immune-mediated central nervous system demyelination disorders.

BACKGROUND: Recently, the International Paediatric Multiple Sclerosis Study Group (IPMSSG) definitions for the diagnosis of immune-mediated acquired demyelinating syndromes (ADS) of the central nervous system, including paediatric multiple sclerosis (MS), have been revised. OBJECTIVE: To evaluate the 2012 revised IPMSSG consensus definitions in a cohort of children with ADS prospectively followed from January 2007. METHODS: Children with ADS who had an MRI scan obtained within 90 days after first disease onset were included. The sensitivity and specificity of the 2007 and 2012 IPMSSG consensus definitions were assessed. The time to MS diagnosis applying the 2007 and 2012 definitions was compared using survival analysis and log-rank test. RESULTS: 82 children with ADS were included. 35 children were diagnosed with paediatric MS, of whom 30 experienced a second clinical event. The final diagnosis corresponded applying either the 2007 or 2012 IPMSSG definitions. The revised 2012 definitions had sufficient sensitivity (80%) and high specificity (100%). MS diagnosis was made 3.4 months earlier (χ(2)=8.24, p=0.004) applying the new definitions. In 14 children, MS diagnosis was made at first MRI. CONCLUSIONS: MS diagnosis can be made reliable and early using the 2012 IPMSSG consensus definitions. This is beneficial for adequate counselling of children and their families and for early treatment possibilities.

Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination.

OBJECTIVE: To investigate whether 57 genetic risk loci recently identified in a large-scale genome-wide association study in adult patients with multiple sclerosis (MS) are also associated with a risk for pediatric-onset MS and whether they can predict MS diagnosis in children presenting with acquired demyelinating syndromes (ADS). METHODS: We included 188 children with ADS, of whom 53 were diagnosed with MS, 466 patients with adult-onset MS, and 2,046 adult controls in our cohort study. Weighted genetic risk scores (wGRS) were calculated to evaluate genetic effects. RESULTS: Mean wGRS was significantly higher for patients with pediatric-onset MS (7.32 ± 0.53) as compared with patients with monophasic ADS (7.10 ± 0.47, p = 0.01) and controls (7.11 ± 0.53, p < 0.01). We found no difference in mean wGRS of participants with monophasic ADS (7.10 ± 0.47) and controls (7.11 ± 0.53). The ability of the wGRS for the 57 single nucleotide polymorphisms (SNPs) to discriminate between children with MS and those with monophasic ADS was moderate (area under the curve [AUC] = 0.64), but improved with the addition of sex and HLA-DRB1*15 (AUC = 0.70). The combined effect of 57 SNPs exceeded the effect of HLA-DRB1*15 alone in our risk models for pediatric- and adult-onset MS. CONCLUSION: The previously reported 57 SNPs for adult-onset MS also confer increased susceptibility to pediatric-onset MS, but not to monophasic ADS.

Potential sources affecting the activity concentrations of 238U, 235U, 232Th and some decay products in lettuce and wheat samples.

The activity concentrations of radionuclides within the uranium and thorium series were determined in wheat and lettuce at five sites in France, and in their respective potential sources: crop soils of wheat and crop soils and irrigation waters of lettuce. These data were used to calculate concentration ratios and to enrich the database supported by the technical report series N°472 of the IAEA (2010). For wheat and lettuce, the activity concentrations were in the same range for all radionuclides studied, except for (210)Pb, which had higher activity concentrations in wheat, ranging between 1.3 and 11 Bq kg(−1) (fresh weight) as compared to 0.4 and 0.7 Bq kg(−1) (fresh weight) for lettuce. For wheat, the range of activity concentrations (mBq kg(−1); fresh weight) decreased as (210)Pb > (226)Ra (56­1511) ≈ (228)Ra (86­769) > (228)Th (19­176) ≈ (238)U (11­169) ≈ (234)U (12­150) ≈ (230)Th (9.08­197.18) ≈ (232)Th (8.61­121.45) > (235)U (0.53­7.9). For lettuce, it decreased as (228)Ra (<320­1221) > (210)Pb (409­746) > (226)Ra (30­599) ≈ (228)Th (<29­347) > (238)U (8­120) ≈ (234)U (8­121) ≈ (230)Th (5.21­134.63) ≈ (232)Th (5.25­156.99) > (235)U (0.35­5.63). The species differences may reflect different plant physiologies. Through the study of activity ratios of wheat and lettuce in relation with those of the various radionuclide sources it has been possible to highlight the contribution of the main sources of natural radionuclides. Indeed, irrigation water when the uranium concentration is enhanced (>30 mBq L(−1)) contributed significantly to the activity concentration of uranium in lettuces. Concerning the high activity concentrations of (210)Pb, it could be explained by atmospheric particle deposition. The effect of soil particles resuspension and their adhesion to the plant surface seemed to be important in some cases. The soil-to-plant transfer factors were calculated for lettuce and wheat. The values were lower in wheat than in lettuce except for (210)Pb which had similar values in the two species (0.11­0.13 respectively). For both species, (210)Pb followed by (228)Ra (0.015­0.10) and (226)Ra (0.010­0.051) displayed the highest transfer factor, whereas (238)U had intermediate values (0.0015­0.030) and (232)Th exhibited the lowest (0.0014­0.013).