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.

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.

Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort.

BACKGROUND: Acquired demyelinating syndromes (ADS) in children are a group of distinct first immune-mediated demyelinating events of the central nervous system (CNS). Predictive biomarkers for future diagnosis are lacking. A putative target antigen is myelin oligodendrocyte glycoprotein (MOG). We analyzed the presence of MOG antibodies in a cohort of ADS patients in The Netherlands. METHODS: Using a cell-based assay, we analyzed 117 children with ADS from a nationwide cohort, whom were divided into five groups: optic neuritis (ON; n = 20), transverse myelitis (TM; n = 7), other monofocal ADS (n = 22), polyfocal ADS without encephalopathy (n = 44) and polyfocal ADS with encephalopathy (n = 24). Additionally, we tested children with other neurological diseases (OND; n = 13), healthy children (n = 31) and adult polyfocal ADS plus encephalopathy (ADEM) patients (n = 29). RESULTS: We found that 21 of the 117 children with ADS tested anti-MOG seropositive (18%). The group of patients with ADEM had the highest prevalence of anti-MOG seropositivity (42% versus 18% in the non-encephalopathic polyfocal ADS patients). Although 47 ADS children had a final diagnosis of multiple sclerosis (MS), in only one of them were MOG antibodies detected (2%), with only borderline positivity. Only 1 out of the 29 adult ADEM patients tested anti-MOG seropositive. CONCLUSIONS: MOG antibodies are strongly skewed towards ADS children that present with an ADEM-like disease onset. The presence of such antibodies pleads against a future diagnosis of MS.

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.

Antibodies against aquaporin-4 in neuromyelitis optica: distinction between recurrent and monophasic patients.

The detection of antibodies against aquaporin-4 (AQP4) has improved the diagnosis of neuromyelitis optica (NMO). We evaluated a recently established cell-based anti-AQP4 assay in 273 patients with inflammatory CNS demyelination. The assay had a specificity of 99% and a sensitivity of 56% to detect all NMO patients and of 74% to detect the recurrent NMO patients, similar to the initial studies reported. AQP4 antibodies were absent in monophasic NMO patients, while samples in recurrent cases remained positive during follow-up. We conclude that the pathogenesis of monophasic NMO may be different from that of relapsing NMO.

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.

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.

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.

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.

Barkhof magnetic resonance imaging criteria predict early relapse in pediatric multiple sclerosis.

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).

Fatigue and depression in children with multiple sclerosis and monophasic variants.

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 >or=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.