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.

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.

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.

Validation of MRI predictors of multiple sclerosis diagnosis in children with acute CNS demyelination.

BACKGROUND: In a recent Canadian prospective study of children with acute demyelinating syndromes (ADS), we demonstrated that the presence of T2 periventricular and T1-hypointense lesions predicted MS diagnosis. We aimed to validate these predictors in a Dutch cohort of children with ADS. METHODS: Participants with ADS were identified from a prospective cohort or archived dataset. MS was diagnosed based on clinical or MRI evidence of relapsing disease. Baseline MRI scans were evaluated for the presence of the two predictive parameters. Sensitivity, specificity, positive (LR+) and negative likelihood ratios (LR-), and positive (PPV) and negative predictive value (NPV) were calculated to evaluate the performance of the MRI parameters at classifying children as having MS or monophasic demyelination. FINDINGS: Of 115 children identified with ADS between December 1993 and December 2009, MRI scans from 87 children (45 prospective; 47 archived) were evaluated; scans of 28 children were excluded due to incomplete or poor quality imaging. Mean duration of observation was longer in the archived group (7.1 years, SD 3.5) than the prospective cohort (3.3 years, SD 1.4). 30 children were diagnosed with MS. Performance of the parameters was not statistically different between the prospective cohort (sensitivity 93.3% [68.1-99.8]; specificity 86.7% [69.3-96.2]; LR+ 7.0 [2.8-17.6]; LR- 0.08 [0.01-0.5]; PPV 77.8% [52.4-93.6]; NPV 96.3% [81.0-99.9]) and archived group (sensitivity 66.7% [38.4-88.2]; specificity 85.2% [66.3-95.8]; LR+ 4.5 [1.7-11.9]; LR- 0.4 [0.2-0.8]; PPV 71.4% [41.9-91.6]; NPV 82.1% [63.1-93.9]). INTERPRETATION: In an independent Dutch cohort, we confirm that the presence of ≥1 T2 periventricular and ≥1 T1-hypointense lesions reliably identifies children with MS. FUNDING: Dutch MS Research Foundation.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

Pregnancy in multiple sclerosis: clinical and self-report scales.

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.

Disease course and outcome of acute disseminated encephalomyelitis is more severe in adults than in children.

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.

A comparison of MRI criteria for diagnosing pediatric ADEM and MS.

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.

Prognostic factors after a first attack of inflammatory CNS demyelination in children.

OBJECTIVE: To identify clinical, radiologic, or CSF factors that predict conversion to multiple sclerosis (MS) after a first attack of inflammatory demyelination in children. METHODS: In this nationwide retrospective multicenter study in the Netherlands, 117 children below age 16 were included. Fifty-four children presented with a monofocal clinically isolated syndrome (CIS) and 63 children with a polyfocal CIS (PCIS). RESULTS: A second MS-defining attack occurred in 43% of the CIS cases, compared to 21% of the patients with PCIS onset (p < 0.006). Basal ganglia and thalamic lesions and lesions larger than 2 cm on MRI (considered typical of ADEM) were observed during PCIS, irrespective of the presence of encephalopathy. No significant difference in developing MS was found in children with PCIS with or without encephalopathy. Elevated IgG index and presence of oligoclonal CSF bands were more often observed in children who developed MS. Both Barkhof and KIDMUS MRI criteria shared a high specificity and had a high positive predictive value for conversion to MS. In children under the age of 10, the Barkhof criteria had a higher sensitivity than the KIDMUS criteria, but still lower than in older children. CONCLUSIONS: Barkhof and KIDMUS MRI criteria share a high specificity and positive prognostic value for conversion to multiple sclerosis (MS). Sensitivity of these criteria is poor, especially in children below 10 years of age. Basal ganglia lesions can occur in patients who later develop MS. A substantial number of patients presenting with polyfocal onset and no encephalopathy remained monophasic.